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Adult tissue-resident macrophages stem from the embryonal yolk sac and fetal liver.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
CONTEXT Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN Prospective cohort study. SETTING AND PATIENTS In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.
Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer. However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.
Blind individuals often demonstrate enhanced nonvisual perceptual abilities. However, the neural substrate that underlies this improved performance remains to be fully understood. An earlier behavioral study demonstrated that some early-blind people localize sounds more accurately than sighted controls using monaural cues. In order to investigate the neural basis of these behavioral differences in humans, we carried out functional imaging studies using positron emission tomography and a speaker array that permitted pseudo-free-field presentations within the scanner. During binaural sound localization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which was not seen in early-blind individuals. During monaural sound localization (one ear plugged), the subgroup of early-blind subjects who were behaviorally superior at sound localization displayed two activation foci in the occipital cortex. This effect was not seen in blind persons who did not have superior monaural sound localization abilities, nor in sighted individuals. The degree of activation of one of these foci was strongly correlated with sound localization accuracy across the entire group of blind subjects. The results show that those blind persons who perform better than sighted persons recruit occipital areas to carry out auditory localization under monaural conditions. We therefore conclude that computations carried out in the occipital cortex specifically underlie the enhanced capacity to use monaural cues. Our findings shed light not only on intermodal compensatory mechanisms, but also on individual differences in these mechanisms and on inhibitory patterns that differ between sighted individuals and those deprived of vision early in life.
IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence. OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study. INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo. MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically confirmed. RESULTS At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03). CONCLUSIONS AND RELEVANCE Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks. Neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination therapy in smoking cessation. TRIAL REGISTRATION clinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818.
Pluripotent embryonic stem cells (ESCs) maintain self-renewal and the potential for rapid response to differentiation cues. Both ESC features are subject to epigenetic regulation. Here we show that the histone acetyltransferase Mof plays an essential role in the maintenance of ESC self-renewal and pluripotency. ESCs with Mof deletion lose characteristic morphology, alkaline phosphatase (AP) staining, and differentiation potential. They also have aberrant expression of the core transcription factors Nanog, Oct4, and Sox2. Importantly, the phenotypes of Mof null ESCs can be partially suppressed by Nanog overexpression, supporting the idea that Mof functions as an upstream regulator of Nanog in ESCs. Genome-wide ChIP-sequencing and transcriptome analyses further demonstrate that Mof is an integral component of the ESC core transcriptional network and that Mof primes genes for diverse developmental programs. Mof is also required for Wdr5 recruitment and H3K4 methylation at key regulatory loci, highlighting the complexity and interconnectivity of various chromatin regulators in ESCs.
|
Adult tissue-resident macrophages stem from the embryonal yolk sac and fetal liver.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
CONTEXT Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN Prospective cohort study. SETTING AND PATIENTS In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.
Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer. However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.
Blind individuals often demonstrate enhanced nonvisual perceptual abilities. However, the neural substrate that underlies this improved performance remains to be fully understood. An earlier behavioral study demonstrated that some early-blind people localize sounds more accurately than sighted controls using monaural cues. In order to investigate the neural basis of these behavioral differences in humans, we carried out functional imaging studies using positron emission tomography and a speaker array that permitted pseudo-free-field presentations within the scanner. During binaural sound localization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which was not seen in early-blind individuals. During monaural sound localization (one ear plugged), the subgroup of early-blind subjects who were behaviorally superior at sound localization displayed two activation foci in the occipital cortex. This effect was not seen in blind persons who did not have superior monaural sound localization abilities, nor in sighted individuals. The degree of activation of one of these foci was strongly correlated with sound localization accuracy across the entire group of blind subjects. The results show that those blind persons who perform better than sighted persons recruit occipital areas to carry out auditory localization under monaural conditions. We therefore conclude that computations carried out in the occipital cortex specifically underlie the enhanced capacity to use monaural cues. Our findings shed light not only on intermodal compensatory mechanisms, but also on individual differences in these mechanisms and on inhibitory patterns that differ between sighted individuals and those deprived of vision early in life.
IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence. OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study. INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo. MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically confirmed. RESULTS At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03). CONCLUSIONS AND RELEVANCE Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks. Neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination therapy in smoking cessation. TRIAL REGISTRATION clinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818.
Pluripotent embryonic stem cells (ESCs) maintain self-renewal and the potential for rapid response to differentiation cues. Both ESC features are subject to epigenetic regulation. Here we show that the histone acetyltransferase Mof plays an essential role in the maintenance of ESC self-renewal and pluripotency. ESCs with Mof deletion lose characteristic morphology, alkaline phosphatase (AP) staining, and differentiation potential. They also have aberrant expression of the core transcription factors Nanog, Oct4, and Sox2. Importantly, the phenotypes of Mof null ESCs can be partially suppressed by Nanog overexpression, supporting the idea that Mof functions as an upstream regulator of Nanog in ESCs. Genome-wide ChIP-sequencing and transcriptome analyses further demonstrate that Mof is an integral component of the ESC core transcriptional network and that Mof primes genes for diverse developmental programs. Mof is also required for Wdr5 recruitment and H3K4 methylation at key regulatory loci, highlighting the complexity and interconnectivity of various chromatin regulators in ESCs.
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RUNX is not expressed in skin tissue.
BACKGROUND Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).
In bacterial translational initiation, three initiation factors (IFs 1-3) enable the selection of initiator tRNA and the start codon in the P site of the 30S ribosomal subunit. Here, we report 11 single-particle cryo-electron microscopy (cryoEM) reconstructions of the complex of bacterial 30S subunit with initiator tRNA, mRNA, and IFs 1-3, representing different steps along the initiation pathway. IF1 provides key anchoring points for IF2 and IF3, thereby enhancing their activities. IF2 positions a domain in an extended conformation appropriate for capturing the formylmethionyl moiety charged on tRNA. IF3 and tRNA undergo large conformational changes to facilitate the accommodation of the formylmethionyl-tRNA (fMet-tRNA(fMet)) into the P site for start codon recognition.
Blimp1 (Prdm1), the key determinant of primordial germ cells (PGCs), plays a combinatorial role with Prdm14 during PGC specification from postimplantation epiblast cells. They together initiate epigenetic reprogramming in early germ cells toward an underlying pluripotent state, which is equivalent to embryonic stem cells (ESCs). Whereas Prdm14 alone can promote reprogramming and is important for the propagation of the pluripotent state, it is not known whether Blimp1 is similarly involved. By using a genetic approach, we demonstrate that Blimp1 is dispensable for the derivation and maintenance of ESCs and postimplantation epiblast stem cells (epiSCs). Notably, Blimp1 is also dispensable for reprogramming epiSCs to ESCs. Thus, although Blimp1 is obligatory for PGC specification, it is not required for the reversion of epiSCs to ESCs and for their maintenance thereafter. This study suggests that reprogramming, including that of somatic cells to ESCs, may not entail an obligatory route through a Blimp1-positive PGC-like state.
Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity. Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals. CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation. During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta. Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries. Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance.
The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.
|
RUNX is not expressed in skin tissue.
BACKGROUND Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).
In bacterial translational initiation, three initiation factors (IFs 1-3) enable the selection of initiator tRNA and the start codon in the P site of the 30S ribosomal subunit. Here, we report 11 single-particle cryo-electron microscopy (cryoEM) reconstructions of the complex of bacterial 30S subunit with initiator tRNA, mRNA, and IFs 1-3, representing different steps along the initiation pathway. IF1 provides key anchoring points for IF2 and IF3, thereby enhancing their activities. IF2 positions a domain in an extended conformation appropriate for capturing the formylmethionyl moiety charged on tRNA. IF3 and tRNA undergo large conformational changes to facilitate the accommodation of the formylmethionyl-tRNA (fMet-tRNA(fMet)) into the P site for start codon recognition.
Blimp1 (Prdm1), the key determinant of primordial germ cells (PGCs), plays a combinatorial role with Prdm14 during PGC specification from postimplantation epiblast cells. They together initiate epigenetic reprogramming in early germ cells toward an underlying pluripotent state, which is equivalent to embryonic stem cells (ESCs). Whereas Prdm14 alone can promote reprogramming and is important for the propagation of the pluripotent state, it is not known whether Blimp1 is similarly involved. By using a genetic approach, we demonstrate that Blimp1 is dispensable for the derivation and maintenance of ESCs and postimplantation epiblast stem cells (epiSCs). Notably, Blimp1 is also dispensable for reprogramming epiSCs to ESCs. Thus, although Blimp1 is obligatory for PGC specification, it is not required for the reversion of epiSCs to ESCs and for their maintenance thereafter. This study suggests that reprogramming, including that of somatic cells to ESCs, may not entail an obligatory route through a Blimp1-positive PGC-like state.
Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity. Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals. CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation. During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta. Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries. Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance.
The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.
| 0
|
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|
1008
|
aug_601
|
The proliferative capacity of neural progenitors differs across species.
The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2–mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
|
The proliferative capacity of neural progenitors differs across species.
The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2–mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
| 0.5
|
{
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|
1254
|
aug_602
|
Pharmacist attendance at ward rounds reduces adverse events in wards.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network. We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes. In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
The tastes of sugars (sweet) and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells.
|
Pharmacist attendance at ward rounds reduces adverse events in wards.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network. We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes. In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
The tastes of sugars (sweet) and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells.
| 0
|
{
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|
941
|
aug_603
|
Mutations in RIM1 raise levels of IME1 RNA.
Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case–control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10−5), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10−4) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10−9). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.
CONTEXT Long-term travelers, defined here as those traveling for periods of 6 months or longer, face particular challenges regarding malaria prevention. Current guidelines for malaria prevention primarily address prevention of Plasmodium falciparum infections in short-term travelers. OBJECTIVES To examine the risk of malaria in long-term travelers, recent developments in personal protective measures, and the safety and tolerability of malaria chemoprophylaxis during long-term use and to consider prevention strategies including continuous chemoprophylaxis, stand-by emergency self-treatment, seasonal prophylaxis, and strategies to prevent primary infection and relapses from P vivax malaria. EVIDENCE ACQUISITION Comprehensive search of scientific publications including MEDLINE via both OVID and PubMED for relevant studies and articles with a cutoff date of July 2006, using the search terms long-term travel and malaria prevention, long-term malaria chemoprophylaxis, and insect repellent and malaria. Additional references were obtained from searching the bibliographies of the selected articles, from dissertations, and from the proceedings of relevant conferences on travel medicine. There were no language restrictions. EVIDENCE SYNTHESIS Long-term travelers have a higher risk of malaria than short-term travelers. Long-term travelers underuse personal protective measures and adhere poorly to continuous chemoprophylaxis regimens. A number of strategies are used during long-term stays: discontinuation of chemoprophylaxis after the initial period, sequential regimens with different medications for chemoprophylaxis, stand-by emergency self-treatment, and seasonal chemoprophylaxis targeting high-incidence periods or locations. All strategies have advantages and drawbacks. Counterfeit drugs sold in countries endemic for malaria pose serious concern for long-term travelers who purchase their medications overseas. Vivax malaria causes significant illness in travelers, but relapses of vivax malaria are not prevented with the current first-line chemoprophylaxis regimens. Consensus guidelines are needed for prevention of malaria in long-term travelers. CONCLUSIONS Prevention of malaria in long-term travelers is a complex issue and requires expert advice from travel medicine specialists. Recommendations for prevention of malaria in long-term travelers must be individualized.
TAL (transcription activator-like) effectors, secreted by phytopathogenic bacteria, recognize host DNA sequences through a central domain of tandem repeats. Each repeat comprises 33 to 35 conserved amino acids and targets a specific base pair by using two hypervariable residues [known as repeat variable diresidues (RVDs)] at positions 12 and 13. Here, we report the crystal structures of an 11.5-repeat TAL effector in both DNA-free and DNA-bound states. Each TAL repeat comprises two helices connected by a short RVD-containing loop. The 11.5 repeats form a right-handed, superhelical structure that tracks along the sense strand of DNA duplex, with RVDs contacting the major groove. The 12th residue stabilizes the RVD loop, whereas the 13th residue makes a base-specific contact. Understanding DNA recognition by TAL effectors may facilitate rational design of DNA-binding proteins with biotechnological applications.
Bullying is still prevalent in schools and is clearly stressful for victims. 1 2 It may also have undesirable consequences for bullies, with antisocial behaviour persisting into adulthood. Victims are generally reported to be weaker than the bullies. 2 3 This would suggest that very short pupils are more likely to be victims and less likely to be the aggressors. The Wessex growth study allowed us to examine the prevalence of bullying, as experienced or perpetrated by pupils of different heights. Ninety two short normal adolescents who had been below the third centile for height at school entry4 and 117 controls matched for age and sex completed a bullying questionnaire, derived from work by Whitney and Smith.5 There were no refusals or any significant differences in sex or social class between the groups. Mean age (range) was 14.7 (13.4-15.7) years. Mean height SD scores were: short pupils −1.90 (−3.53 to −0.01), controls 0.31 (−1.41 …
Although mast cell functions have classically been related to allergic responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.
Deamidation of N-terminal Gln by Nt(Q)-amidase, an N-terminal amidohydrolase, is a part of the N-end rule pathway of protein degradation. We detected the activity of Nt(Q)-amidase, termed Ntaq1, in mouse tissues, purified Ntaq1 from bovine brains, identified its gene, and began analyzing this enzyme. Ntaq1 is highly conserved among animals, plants, and some fungi, but its sequence is dissimilar to sequences of other amidases. An earlier mutant in the Drosophila Cg8253 gene that we show here to encode Nt(Q)-amidase has defective long-term memory. Other studies identified protein ligands of the uncharacterized human C8orf32 protein that we show here to be the Ntaq1 Nt(Q)-amidase. Remarkably, "high-throughput" studies have recently solved the crystal structure of C8orf32 (Ntaq1). Our site-directed mutagenesis of Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of Nt(Q)-amidase are similar to those of transglutaminases.
|
Mutations in RIM1 raise levels of IME1 RNA.
Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case–control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10−5), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10−4) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10−9). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.
CONTEXT Long-term travelers, defined here as those traveling for periods of 6 months or longer, face particular challenges regarding malaria prevention. Current guidelines for malaria prevention primarily address prevention of Plasmodium falciparum infections in short-term travelers. OBJECTIVES To examine the risk of malaria in long-term travelers, recent developments in personal protective measures, and the safety and tolerability of malaria chemoprophylaxis during long-term use and to consider prevention strategies including continuous chemoprophylaxis, stand-by emergency self-treatment, seasonal prophylaxis, and strategies to prevent primary infection and relapses from P vivax malaria. EVIDENCE ACQUISITION Comprehensive search of scientific publications including MEDLINE via both OVID and PubMED for relevant studies and articles with a cutoff date of July 2006, using the search terms long-term travel and malaria prevention, long-term malaria chemoprophylaxis, and insect repellent and malaria. Additional references were obtained from searching the bibliographies of the selected articles, from dissertations, and from the proceedings of relevant conferences on travel medicine. There were no language restrictions. EVIDENCE SYNTHESIS Long-term travelers have a higher risk of malaria than short-term travelers. Long-term travelers underuse personal protective measures and adhere poorly to continuous chemoprophylaxis regimens. A number of strategies are used during long-term stays: discontinuation of chemoprophylaxis after the initial period, sequential regimens with different medications for chemoprophylaxis, stand-by emergency self-treatment, and seasonal chemoprophylaxis targeting high-incidence periods or locations. All strategies have advantages and drawbacks. Counterfeit drugs sold in countries endemic for malaria pose serious concern for long-term travelers who purchase their medications overseas. Vivax malaria causes significant illness in travelers, but relapses of vivax malaria are not prevented with the current first-line chemoprophylaxis regimens. Consensus guidelines are needed for prevention of malaria in long-term travelers. CONCLUSIONS Prevention of malaria in long-term travelers is a complex issue and requires expert advice from travel medicine specialists. Recommendations for prevention of malaria in long-term travelers must be individualized.
TAL (transcription activator-like) effectors, secreted by phytopathogenic bacteria, recognize host DNA sequences through a central domain of tandem repeats. Each repeat comprises 33 to 35 conserved amino acids and targets a specific base pair by using two hypervariable residues [known as repeat variable diresidues (RVDs)] at positions 12 and 13. Here, we report the crystal structures of an 11.5-repeat TAL effector in both DNA-free and DNA-bound states. Each TAL repeat comprises two helices connected by a short RVD-containing loop. The 11.5 repeats form a right-handed, superhelical structure that tracks along the sense strand of DNA duplex, with RVDs contacting the major groove. The 12th residue stabilizes the RVD loop, whereas the 13th residue makes a base-specific contact. Understanding DNA recognition by TAL effectors may facilitate rational design of DNA-binding proteins with biotechnological applications.
Bullying is still prevalent in schools and is clearly stressful for victims. 1 2 It may also have undesirable consequences for bullies, with antisocial behaviour persisting into adulthood. Victims are generally reported to be weaker than the bullies. 2 3 This would suggest that very short pupils are more likely to be victims and less likely to be the aggressors. The Wessex growth study allowed us to examine the prevalence of bullying, as experienced or perpetrated by pupils of different heights. Ninety two short normal adolescents who had been below the third centile for height at school entry4 and 117 controls matched for age and sex completed a bullying questionnaire, derived from work by Whitney and Smith.5 There were no refusals or any significant differences in sex or social class between the groups. Mean age (range) was 14.7 (13.4-15.7) years. Mean height SD scores were: short pupils −1.90 (−3.53 to −0.01), controls 0.31 (−1.41 …
Although mast cell functions have classically been related to allergic responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.
Deamidation of N-terminal Gln by Nt(Q)-amidase, an N-terminal amidohydrolase, is a part of the N-end rule pathway of protein degradation. We detected the activity of Nt(Q)-amidase, termed Ntaq1, in mouse tissues, purified Ntaq1 from bovine brains, identified its gene, and began analyzing this enzyme. Ntaq1 is highly conserved among animals, plants, and some fungi, but its sequence is dissimilar to sequences of other amidases. An earlier mutant in the Drosophila Cg8253 gene that we show here to encode Nt(Q)-amidase has defective long-term memory. Other studies identified protein ligands of the uncharacterized human C8orf32 protein that we show here to be the Ntaq1 Nt(Q)-amidase. Remarkably, "high-throughput" studies have recently solved the crystal structure of C8orf32 (Ntaq1). Our site-directed mutagenesis of Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of Nt(Q)-amidase are similar to those of transglutaminases.
| 0
|
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|
816
|
aug_604
|
The innate immune response struggles to remove small numbers of parasites.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
OBJECTIVES We investigated the role of cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cachexia development in newly diagnosed nonsmall cell lung cancer (NSCLC) patients. METHODS : We evaluated 44 (M/F:41/3) NSCLC patients and 12 (M/F:10/2) age matched healthy smokers. NSCLC cases with a weight loss of > or =10% consisted the cachectic group (n:23, M/F:21/2) and the ones with <10% weight loss consisted the noncachectic group (n:21, M/F:19/2). RESULTS Body mass index (BMI) of cachectics was significantly lower than that of noncachectics (21.0 +/- 2.9 versus 24.5 +/- 3.6, P = 0.02) and controls (21.0 +/- 2.9 versus 25.5 +/- 2.6, P = 0.01). Serum TNF-alpha level did not differ between cachectic and noncachectics (37.3 +/- 39.1 and 51.6 +/- 84.2 pg/mL, respectively). However, it was significantly higher in NSCLC patients compared with controls (44.1 +/- 64.3 and 15.1 +/- 14.3 pg/mL, P = 0.03). Serum IL-6 level was not different between 3 groups (6.4 +/- 4.1, 8.9 +/- 16.3, and 4.1 +/- 3.5 pg/mL, respectively) but it correlated significantly with TNF-alpha (r = 0.4, P = 0.006) and BMI (r = -0.3, P = 0.03). Erythrocyte sedimentation rate (ESR) correlated significantly with TNF-alpha (r = 0.4, P = 0.003) and BMI (r = -0.3, P = 0.03). Among 44 cases, survival of 12 and 17 patients was recorded in cachectics and noncachectics, with no statistical difference (12.2 +/- 3.7 and 11.2 +/- 1.0 months, respectively). CONCLUSIONS TNF-alpha and IL-6 levels did not differ significantly between cachectics and noncachectics. However, significant correlations between IL-6, BMI, and TNF-alpha suggested that these cytokines acted as cofactors in weight loss. Survival was neither influenced by BMI, nor the cytokine levels in the present study. The significant correlation of ESR with TNF-alpha suggested that ESR could provide valuable clue for considerable weight loss in the follow-up of NSCLC patients.
Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose. Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms.
CRISPR-Cas (clustered, regularly interspaced short palindromic repeats coupled with CRISPR-associated proteins) is a bacterial immunity system that protects against invading phages or plasmids. In the process of CRISPR adaptation, short pieces of DNA ('spacers') are acquired from foreign elements and integrated into the CRISPR array. So far, it has remained a mystery how spacers are preferentially acquired from the foreign DNA while the self chromosome is avoided. Here we show that spacer acquisition is replication-dependent, and that DNA breaks formed at stalled replication forks promote spacer acquisition. Chromosomal hotspots of spacer acquisition were confined by Chi sites, which are sequence octamers highly enriched on the bacterial chromosome, suggesting that these sites limit spacer acquisition from self DNA. We further show that the avoidance of self is mediated by the RecBCD double-stranded DNA break repair complex. Our results suggest that, in Escherichia coli, acquisition of new spacers largely depends on RecBCD-mediated processing of double-stranded DNA breaks occurring primarily at replication forks, and that the preference for foreign DNA is achieved through the higher density of Chi sites on the self chromosome, in combination with the higher number of forks on the foreign DNA. This model explains the strong preference to acquire spacers both from high copy plasmids and from phages.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
|
The innate immune response struggles to remove small numbers of parasites.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
OBJECTIVES We investigated the role of cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cachexia development in newly diagnosed nonsmall cell lung cancer (NSCLC) patients. METHODS : We evaluated 44 (M/F:41/3) NSCLC patients and 12 (M/F:10/2) age matched healthy smokers. NSCLC cases with a weight loss of > or =10% consisted the cachectic group (n:23, M/F:21/2) and the ones with <10% weight loss consisted the noncachectic group (n:21, M/F:19/2). RESULTS Body mass index (BMI) of cachectics was significantly lower than that of noncachectics (21.0 +/- 2.9 versus 24.5 +/- 3.6, P = 0.02) and controls (21.0 +/- 2.9 versus 25.5 +/- 2.6, P = 0.01). Serum TNF-alpha level did not differ between cachectic and noncachectics (37.3 +/- 39.1 and 51.6 +/- 84.2 pg/mL, respectively). However, it was significantly higher in NSCLC patients compared with controls (44.1 +/- 64.3 and 15.1 +/- 14.3 pg/mL, P = 0.03). Serum IL-6 level was not different between 3 groups (6.4 +/- 4.1, 8.9 +/- 16.3, and 4.1 +/- 3.5 pg/mL, respectively) but it correlated significantly with TNF-alpha (r = 0.4, P = 0.006) and BMI (r = -0.3, P = 0.03). Erythrocyte sedimentation rate (ESR) correlated significantly with TNF-alpha (r = 0.4, P = 0.003) and BMI (r = -0.3, P = 0.03). Among 44 cases, survival of 12 and 17 patients was recorded in cachectics and noncachectics, with no statistical difference (12.2 +/- 3.7 and 11.2 +/- 1.0 months, respectively). CONCLUSIONS TNF-alpha and IL-6 levels did not differ significantly between cachectics and noncachectics. However, significant correlations between IL-6, BMI, and TNF-alpha suggested that these cytokines acted as cofactors in weight loss. Survival was neither influenced by BMI, nor the cytokine levels in the present study. The significant correlation of ESR with TNF-alpha suggested that ESR could provide valuable clue for considerable weight loss in the follow-up of NSCLC patients.
Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose. Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms.
CRISPR-Cas (clustered, regularly interspaced short palindromic repeats coupled with CRISPR-associated proteins) is a bacterial immunity system that protects against invading phages or plasmids. In the process of CRISPR adaptation, short pieces of DNA ('spacers') are acquired from foreign elements and integrated into the CRISPR array. So far, it has remained a mystery how spacers are preferentially acquired from the foreign DNA while the self chromosome is avoided. Here we show that spacer acquisition is replication-dependent, and that DNA breaks formed at stalled replication forks promote spacer acquisition. Chromosomal hotspots of spacer acquisition were confined by Chi sites, which are sequence octamers highly enriched on the bacterial chromosome, suggesting that these sites limit spacer acquisition from self DNA. We further show that the avoidance of self is mediated by the RecBCD double-stranded DNA break repair complex. Our results suggest that, in Escherichia coli, acquisition of new spacers largely depends on RecBCD-mediated processing of double-stranded DNA breaks occurring primarily at replication forks, and that the preference for foreign DNA is achieved through the higher density of Chi sites on the self chromosome, in combination with the higher number of forks on the foreign DNA. This model explains the strong preference to acquire spacers both from high copy plasmids and from phages.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
| 0.285714
|
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|
1223
|
aug_605
|
Less than 10% of patients exposed to radiation have activated markers of mesenchymal stem cells.
Previous studies investigating the role of smooth muscle cells (SMCs) and macrophages in the pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliable methods for clearly identifying each of these cell types. Here, using Myh11-CreERT2 ROSA floxed STOP eYFP Apoe−/− mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation–sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis.
|
Less than 10% of patients exposed to radiation have activated markers of mesenchymal stem cells.
Previous studies investigating the role of smooth muscle cells (SMCs) and macrophages in the pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliable methods for clearly identifying each of these cell types. Here, using Myh11-CreERT2 ROSA floxed STOP eYFP Apoe−/− mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation–sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis.
| 1
|
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|
689
|
aug_606
|
DUSP4 downregulation deactivates the Ras-ERK pathway
BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is a long-standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouse epiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast. We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2.
Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.
CONTEXT Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. OBJECTIVE To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). MAIN OUTCOME MEASURE Serum intact PTH as determined by calcium intake and vitamin D. RESULTS A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). CONCLUSIONS As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates.
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.
|
DUSP4 downregulation deactivates the Ras-ERK pathway
BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is a long-standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouse epiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast. We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2.
Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.
CONTEXT Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. OBJECTIVE To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). MAIN OUTCOME MEASURE Serum intact PTH as determined by calcium intake and vitamin D. RESULTS A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). CONCLUSIONS As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates.
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.
| 0.4
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308
|
aug_607
|
Roughly 55% of women with chronic pelvic pain have no underlying pathology.
CONTEXT Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain. OBJECTIVE To assess the effectiveness of LUNA in patients with chronic pelvic pain. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005. Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years. INTERVENTION Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation. MAIN OUTCOME MEASURES The primary outcome was pain, which was assessed by a visual analogue scale. Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS). RESULTS After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). No differences were observed between the LUNA group and the no LUNA group for quality of life. CONCLUSION Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation. TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN41196151.
|
Roughly 55% of women with chronic pelvic pain have no underlying pathology.
CONTEXT Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain. OBJECTIVE To assess the effectiveness of LUNA in patients with chronic pelvic pain. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005. Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years. INTERVENTION Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation. MAIN OUTCOME MEASURES The primary outcome was pain, which was assessed by a visual analogue scale. Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS). RESULTS After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). No differences were observed between the LUNA group and the no LUNA group for quality of life. CONCLUSION Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation. TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN41196151.
| 1
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1058
|
aug_608
|
Immune complex triggered cell death leads to extracellular release of nuclear DNA.
We compared conscious and nonconscious processing of briefly flashed words using a visual masking procedure while recording intracranial electroencephalogram (iEEG) in ten patients. Nonconscious processing of masked words was observed in multiple cortical areas, mostly within an early time window (<300 ms), accompanied by induced gamma-band activity, but without coherent long-distance neural activity, suggesting a quickly dissipating feedforward wave. In contrast, conscious processing of unmasked words was characterized by the convergence of four distinct neurophysiological markers: sustained voltage changes, particularly in prefrontal cortex, large increases in spectral power in the gamma band, increases in long-distance phase synchrony in the beta range, and increases in long-range Granger causality. We argue that all of those measures provide distinct windows into the same distributed state of conscious processing. These results have a direct impact on current theoretical discussions concerning the neural correlates of conscious access.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
OBJECTIVE To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition. DESIGN Population based, cross sectional study. SETTING Epidemiology of Vascular Ageing study, Nantes, France. PARTICIPANTS 780 participants (mean age 69, 58.5% women) with detailed headache assessment. MAIN OUTCOME MEASURES Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination. RESULTS 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions. CONCLUSIONS In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.
Asymmetric cell division and apoptosis (programmed cell death) are two fundamental processes that are important for the development and function of multicellular organisms. We have found that the processes of asymmetric cell division and apoptosis can be functionally linked. Specifically, we show that asymmetric cell division in the nematode Caenorhabditis elegans is mediated by a pathway involving three genes, dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail, that directly control the enzymatic machinery responsible for apoptosis. Interestingly, the MIDA1-like protein GlsA of the alga Volvox carteri, as well as the Snail-related proteins Snail, Escargot, and Worniu of Drosophila melanogaster, have previously been implicated in asymmetric cell division. Therefore, C. elegans dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail may be components of a pathway involved in asymmetric cell division that is conserved throughout the plant and animal kingdoms. Furthermore, based on our results, we propose that this pathway directly controls the apoptotic fate in C. elegans, and possibly other animals as well.
CONTEXT Dexamethasone is widely used to prevent postoperative nausea and vomiting (PONV) in pediatric tonsillectomy. OBJECTIVE To assess whether dexamethasone dose-dependently reduces the risk of PONV at 24 hours after tonsillectomy. DESIGN, SETTING, AND PATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing elective tonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007. INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg) or placebo intravenously after induction of anesthesia. Acetaminophen-codeine and ibuprofen were given as postoperative analgesia. Follow-up continued until the 10th postoperative day. MAIN OUTCOME MEASURES The primary end point was prevention of PONV at 24 hours; secondary end points were decrease in the need for ibuprofen at 24 hours and evaluation of adverse effects. RESULTS At 24 hours, 24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) had experienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI, 13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P<.001 for linear trend). Children who received dexamethasone received significantly less ibuprofen. There were 26 postoperative bleeding episodes in 22 children. Two of 53 (4%; 95% CI, 0.5%-13%) children who received placebo had bleeding compared with 6 of 53 (11%; 95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003). Dexamethasone, 0.5 mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5). Eight children had to undergo emergency reoperation because of bleeding, all of whom had received dexamethasone. The trial was stopped early for safety reasons. CONCLUSION In this study of children undergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but was associated with an increased risk of postoperative bleeding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00403806.
BACKGROUND Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study's finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV. METHODS AND FINDINGS We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study's major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled. CONCLUSIONS Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors' Summary.
|
Immune complex triggered cell death leads to extracellular release of nuclear DNA.
We compared conscious and nonconscious processing of briefly flashed words using a visual masking procedure while recording intracranial electroencephalogram (iEEG) in ten patients. Nonconscious processing of masked words was observed in multiple cortical areas, mostly within an early time window (<300 ms), accompanied by induced gamma-band activity, but without coherent long-distance neural activity, suggesting a quickly dissipating feedforward wave. In contrast, conscious processing of unmasked words was characterized by the convergence of four distinct neurophysiological markers: sustained voltage changes, particularly in prefrontal cortex, large increases in spectral power in the gamma band, increases in long-distance phase synchrony in the beta range, and increases in long-range Granger causality. We argue that all of those measures provide distinct windows into the same distributed state of conscious processing. These results have a direct impact on current theoretical discussions concerning the neural correlates of conscious access.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
OBJECTIVE To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition. DESIGN Population based, cross sectional study. SETTING Epidemiology of Vascular Ageing study, Nantes, France. PARTICIPANTS 780 participants (mean age 69, 58.5% women) with detailed headache assessment. MAIN OUTCOME MEASURES Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination. RESULTS 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions. CONCLUSIONS In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.
Asymmetric cell division and apoptosis (programmed cell death) are two fundamental processes that are important for the development and function of multicellular organisms. We have found that the processes of asymmetric cell division and apoptosis can be functionally linked. Specifically, we show that asymmetric cell division in the nematode Caenorhabditis elegans is mediated by a pathway involving three genes, dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail, that directly control the enzymatic machinery responsible for apoptosis. Interestingly, the MIDA1-like protein GlsA of the alga Volvox carteri, as well as the Snail-related proteins Snail, Escargot, and Worniu of Drosophila melanogaster, have previously been implicated in asymmetric cell division. Therefore, C. elegans dnj-11 MIDA1, ces-2 HLF, and ces-1 Snail may be components of a pathway involved in asymmetric cell division that is conserved throughout the plant and animal kingdoms. Furthermore, based on our results, we propose that this pathway directly controls the apoptotic fate in C. elegans, and possibly other animals as well.
CONTEXT Dexamethasone is widely used to prevent postoperative nausea and vomiting (PONV) in pediatric tonsillectomy. OBJECTIVE To assess whether dexamethasone dose-dependently reduces the risk of PONV at 24 hours after tonsillectomy. DESIGN, SETTING, AND PATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing elective tonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007. INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg) or placebo intravenously after induction of anesthesia. Acetaminophen-codeine and ibuprofen were given as postoperative analgesia. Follow-up continued until the 10th postoperative day. MAIN OUTCOME MEASURES The primary end point was prevention of PONV at 24 hours; secondary end points were decrease in the need for ibuprofen at 24 hours and evaluation of adverse effects. RESULTS At 24 hours, 24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) had experienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI, 13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P<.001 for linear trend). Children who received dexamethasone received significantly less ibuprofen. There were 26 postoperative bleeding episodes in 22 children. Two of 53 (4%; 95% CI, 0.5%-13%) children who received placebo had bleeding compared with 6 of 53 (11%; 95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003). Dexamethasone, 0.5 mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5). Eight children had to undergo emergency reoperation because of bleeding, all of whom had received dexamethasone. The trial was stopped early for safety reasons. CONCLUSION In this study of children undergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but was associated with an increased risk of postoperative bleeding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00403806.
BACKGROUND Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study's finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV. METHODS AND FINDINGS We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study's major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled. CONCLUSIONS Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors' Summary.
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555
|
aug_609
|
In S. cerevisiae, the absence of RNA surveillance pathways reduces sensitivity to high iron conditions.
Tight regulation of the expression of mRNAs encoding iron uptake proteins is essential to control iron homeostasis and avoid intracellular iron toxicity. We show that many mRNAs encoding iron uptake or iron mobilization proteins are expressed in iron-replete conditions in the absence of the S. cerevisiae RNase III ortholog Rnt1p or of the nuclear exosome component Rrp6p. Extended forms of these mRNAs accumulate in the absence of Rnt1p or of the 5'-->3' exonucleases Xrn1p and Rat1p, showing that multiple degradative pathways contribute to the surveillance of aberrant forms of these transcripts. RNase III-deficient cells are hypersensitive to high iron concentrations, suggesting that Rnt1p-mediated RNA surveillance is required to prevent iron toxicity. These results show that RNA surveillance through multiple ribonucleolytic pathways plays a role in iron homeostasis in yeast to avoid the potentially toxic effects of the expression of the iron starvation response in iron-replete conditions.
|
In S. cerevisiae, the absence of RNA surveillance pathways reduces sensitivity to high iron conditions.
Tight regulation of the expression of mRNAs encoding iron uptake proteins is essential to control iron homeostasis and avoid intracellular iron toxicity. We show that many mRNAs encoding iron uptake or iron mobilization proteins are expressed in iron-replete conditions in the absence of the S. cerevisiae RNase III ortholog Rnt1p or of the nuclear exosome component Rrp6p. Extended forms of these mRNAs accumulate in the absence of Rnt1p or of the 5'-->3' exonucleases Xrn1p and Rat1p, showing that multiple degradative pathways contribute to the surveillance of aberrant forms of these transcripts. RNase III-deficient cells are hypersensitive to high iron concentrations, suggesting that Rnt1p-mediated RNA surveillance is required to prevent iron toxicity. These results show that RNA surveillance through multiple ribonucleolytic pathways plays a role in iron homeostasis in yeast to avoid the potentially toxic effects of the expression of the iron starvation response in iron-replete conditions.
| 1
|
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|
566
|
aug_610
|
Tumor development occurs in conjunction with upregulation of pro-inflammatory cytokines.
Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.
|
Tumor development occurs in conjunction with upregulation of pro-inflammatory cytokines.
Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.
| 1
|
{
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|
1331
|
aug_611
|
Side effects associated with antidepressants increases risk of stroke.
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections.
OBJECTIVE To investigate the association between gastric cancer and prior infection with Helicobacter pylori. DESIGN Case-control comparison of prevalence of IgG antibodies to H pylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases. Presence of H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbent assay (ELISA). SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies (the British United Provident Association study and the Caerphilly collaborative heart disease study), who had provided blood samples during 1975-1982. RESULTS 20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody. The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01). The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039). CONCLUSIONS H pylori infection may be an important cause of gastric cancer; between 35% and 55% of all cases may be associated with such an infection.
BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council.
The tricyclic antidepressant, amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine. However, its efficacy in episodic tension-type headache has not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study. Amitriptyline significantly reduced (P < 0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache.
OBJECTIVES To investigate the association between antidepressant treatment and risk of several potential adverse outcomes in older people with depression and to examine risks by class of antidepressant, duration of use, and dose. DESIGN Cohort study of people aged 65 and over diagnosed as having depression. SETTING 570 general practices in the United Kingdom supplying data to the QResearch primary care database. PARTICIPANTS 60,746 patients diagnosed as having a new episode of depression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 and followed up until 31 December 2008. MAIN OUTCOME MEASURES Hazard ratios associated with antidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction, stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potential confounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use and for commonly prescribed individual drugs. RESULTS 54,038 (89.0%) patients received at least one prescription for an antidepressant during follow-up. A total of 1,398,359 antidepressant prescriptions were issued: 764,659 (54.7%) for selective serotonin reuptake inhibitors, 442,192 (31.6%) for tricyclic antidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189,305 (13.5%) for the group of other antidepressants. The associations with the adverse outcomes differed significantly between the antidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated with the highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) and hyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. The group of other antidepressants was associated with the highest adjusted hazard ratios for all cause mortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transient ischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to 3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes. Significantly different associations also existed between the individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, and venlafaxine (both in the group of other antidepressants) were associated with the highest rates for some of these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while not taking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotonin reuptake inhibitors, and 11.43% for other antidepressants. CONCLUSIONS Selective serotonin reuptake inhibitors and drugs in the group of other antidepressants were associated with an increased risk of several adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone, mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is an observational study, it is susceptible to confounding by indication, channelling bias, and residual confounding, so differences in characteristics between patients prescribed different antidepressant drugs that could account for some of the associations between the drugs and the adverse outcomes may remain. Further research is needed to confirm these findings, but the risks and benefits of different antidepressants should be carefully evaluated when these drugs are prescribed to older people.
|
Side effects associated with antidepressants increases risk of stroke.
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections.
OBJECTIVE To investigate the association between gastric cancer and prior infection with Helicobacter pylori. DESIGN Case-control comparison of prevalence of IgG antibodies to H pylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases. Presence of H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbent assay (ELISA). SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies (the British United Provident Association study and the Caerphilly collaborative heart disease study), who had provided blood samples during 1975-1982. RESULTS 20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody. The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01). The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039). CONCLUSIONS H pylori infection may be an important cause of gastric cancer; between 35% and 55% of all cases may be associated with such an infection.
BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council.
The tricyclic antidepressant, amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine. However, its efficacy in episodic tension-type headache has not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study. Amitriptyline significantly reduced (P < 0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache.
OBJECTIVES To investigate the association between antidepressant treatment and risk of several potential adverse outcomes in older people with depression and to examine risks by class of antidepressant, duration of use, and dose. DESIGN Cohort study of people aged 65 and over diagnosed as having depression. SETTING 570 general practices in the United Kingdom supplying data to the QResearch primary care database. PARTICIPANTS 60,746 patients diagnosed as having a new episode of depression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 and followed up until 31 December 2008. MAIN OUTCOME MEASURES Hazard ratios associated with antidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction, stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potential confounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use and for commonly prescribed individual drugs. RESULTS 54,038 (89.0%) patients received at least one prescription for an antidepressant during follow-up. A total of 1,398,359 antidepressant prescriptions were issued: 764,659 (54.7%) for selective serotonin reuptake inhibitors, 442,192 (31.6%) for tricyclic antidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189,305 (13.5%) for the group of other antidepressants. The associations with the adverse outcomes differed significantly between the antidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated with the highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) and hyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. The group of other antidepressants was associated with the highest adjusted hazard ratios for all cause mortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transient ischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to 3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes. Significantly different associations also existed between the individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, and venlafaxine (both in the group of other antidepressants) were associated with the highest rates for some of these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while not taking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotonin reuptake inhibitors, and 11.43% for other antidepressants. CONCLUSIONS Selective serotonin reuptake inhibitors and drugs in the group of other antidepressants were associated with an increased risk of several adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone, mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is an observational study, it is susceptible to confounding by indication, channelling bias, and residual confounding, so differences in characteristics between patients prescribed different antidepressant drugs that could account for some of the associations between the drugs and the adverse outcomes may remain. Further research is needed to confirm these findings, but the risks and benefits of different antidepressants should be carefully evaluated when these drugs are prescribed to older people.
| 0.285714
|
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|
1084
|
aug_612
|
Integrated care is successful at tackling multiple comorbidities.
OBJECTIVE To evaluate the effectiveness of integrated care for chronic physical diseases and depression in reducing disability and improving quality of life. DESIGN A randomised controlled trial of multi-condition collaborative care for depression and poorly controlled diabetes and/or risk factors for coronary heart disease compared with usual care among middle aged and elderly people SETTING Fourteen primary care clinics in Seattle, Washington. PARTICIPANTS Patients with diabetes or coronary heart disease, or both, and blood pressure above 140/90 mm Hg, low density lipoprotein concentration >3.37 mmol/L, or glycated haemoglobin 8.5% or higher, and PHQ-9 depression scores of ≥ 10. INTERVENTION A 12 month intervention to improve depression, glycaemic control, blood pressure, and lipid control by integrating a "treat to target" programme for diabetes and risk factors for coronary heart disease with collaborative care for depression. The intervention combined self management support, monitoring of disease control, and pharmacotherapy to control depression, hyperglycaemia, hypertension, and hyperlipidaemia. MAIN OUTCOME MEASURES Social role disability (Sheehan disability scale), global quality of life rating, and World Health Organization disability assessment schedule (WHODAS-2) scales to measure disabilities in activities of daily living (mobility, self care, household maintenance). RESULTS Of 214 patients enrolled (106 intervention and 108 usual care), disability and quality of life measures were obtained for 97 intervention patients at six months (92%) and 92 at 12 months (87%), and for 96 usual care patients at six months (89%) and 92 at 12 months (85%). Improvements from baseline on the Sheehan disability scale (-0.9, 95% confidence interval -1.5 to -0.2; P = 0.006) and global quality of life rating (0.7, 0.2 to 1.2; P = 0.005) were significantly greater at six and 12 months in patients in the intervention group. There was a trend toward greater improvement in disabilities in activities of daily living (-1.5, -3.3 to 0.4; P = 0.10). CONCLUSIONS Integrated care that covers chronic physical disease and comorbid depression can reduce social role disability and enhance global quality of life. Trial registration Clinical Trials NCT00468676.
|
Integrated care is successful at tackling multiple comorbidities.
OBJECTIVE To evaluate the effectiveness of integrated care for chronic physical diseases and depression in reducing disability and improving quality of life. DESIGN A randomised controlled trial of multi-condition collaborative care for depression and poorly controlled diabetes and/or risk factors for coronary heart disease compared with usual care among middle aged and elderly people SETTING Fourteen primary care clinics in Seattle, Washington. PARTICIPANTS Patients with diabetes or coronary heart disease, or both, and blood pressure above 140/90 mm Hg, low density lipoprotein concentration >3.37 mmol/L, or glycated haemoglobin 8.5% or higher, and PHQ-9 depression scores of ≥ 10. INTERVENTION A 12 month intervention to improve depression, glycaemic control, blood pressure, and lipid control by integrating a "treat to target" programme for diabetes and risk factors for coronary heart disease with collaborative care for depression. The intervention combined self management support, monitoring of disease control, and pharmacotherapy to control depression, hyperglycaemia, hypertension, and hyperlipidaemia. MAIN OUTCOME MEASURES Social role disability (Sheehan disability scale), global quality of life rating, and World Health Organization disability assessment schedule (WHODAS-2) scales to measure disabilities in activities of daily living (mobility, self care, household maintenance). RESULTS Of 214 patients enrolled (106 intervention and 108 usual care), disability and quality of life measures were obtained for 97 intervention patients at six months (92%) and 92 at 12 months (87%), and for 96 usual care patients at six months (89%) and 92 at 12 months (85%). Improvements from baseline on the Sheehan disability scale (-0.9, 95% confidence interval -1.5 to -0.2; P = 0.006) and global quality of life rating (0.7, 0.2 to 1.2; P = 0.005) were significantly greater at six and 12 months in patients in the intervention group. There was a trend toward greater improvement in disabilities in activities of daily living (-1.5, -3.3 to 0.4; P = 0.10). CONCLUSIONS Integrated care that covers chronic physical disease and comorbid depression can reduce social role disability and enhance global quality of life. Trial registration Clinical Trials NCT00468676.
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|
648
|
aug_613
|
Cytosolic proteins bind to iron-responsive elements on mRNAs coding for TFRC1.
Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.
|
Cytosolic proteins bind to iron-responsive elements on mRNAs coding for TFRC1.
Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.
| 1
|
{
"query_id": "301",
"original_query_id": "301",
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"3553087"
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"3553087"
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"3553087"
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"type": "pathfinderrag_test"
}
|
301
|
aug_614
|
PCSK9 inhibitors decrease plasma Lp(a) levels.
BACKGROUND Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date. METHODS Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured. RESULTS Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations. CONCLUSIONS Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a). CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971.
|
PCSK9 inhibitors decrease plasma Lp(a) levels.
BACKGROUND Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date. METHODS Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured. RESULTS Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations. CONCLUSIONS Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a). CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971.
| 1
|
{
"query_id": "901",
"original_query_id": "901",
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"6540064"
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"6540064"
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}
|
901
|
aug_615
|
There was an estimated 30 million cases of pneumonia in young children worldwide in 2010.
BACKGROUND The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. METHODS We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. FINDINGS We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. INTERPRETATION Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. FUNDING WHO.
|
There was an estimated 30 million cases of pneumonia in young children worldwide in 2010.
BACKGROUND The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. METHODS We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. FINDINGS We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. INTERPRETATION Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. FUNDING WHO.
| 1
|
{
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}
|
1297
|
aug_616
|
Individuals with Alzheimers who participate in six months of physical activity improve cognitive function for up to 18 months.
In single-stranded ribonucleic acid (RNA) viruses, virus capsid assembly and genome packaging are intertwined processes. Using cryo-electron microscopy and single particle analysis we determined the asymmetric virion structure of bacteriophage MS2, which includes 178 copies of the coat protein, a single copy of the A-protein and the RNA genome. This reveals that in situ, the viral RNA genome can adopt a defined conformation. The RNA forms a branched network of stem-loops that almost all allocate near the capsid inner surface, while predominantly binding to coat protein dimers that are located in one-half of the capsid. This suggests that genomic RNA is highly involved in genome packaging and virion assembly.
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
Background Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.
Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
|
Individuals with Alzheimers who participate in six months of physical activity improve cognitive function for up to 18 months.
In single-stranded ribonucleic acid (RNA) viruses, virus capsid assembly and genome packaging are intertwined processes. Using cryo-electron microscopy and single particle analysis we determined the asymmetric virion structure of bacteriophage MS2, which includes 178 copies of the coat protein, a single copy of the A-protein and the RNA genome. This reveals that in situ, the viral RNA genome can adopt a defined conformation. The RNA forms a branched network of stem-loops that almost all allocate near the capsid inner surface, while predominantly binding to coat protein dimers that are located in one-half of the capsid. This suggests that genomic RNA is highly involved in genome packaging and virion assembly.
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
Background Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.
Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
| 0
|
{
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|
621
|
aug_617
|
DRD1 proteins enable Pol V transcription in vivo.
Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Breast cancer may originate in utero. We reviewed the available evidence on the association between birthweight and the risk of breast cancer. To date, 26 research papers addressing this issue have been published. The majority of studies identified a positive link between birthweight and premenopausal, but not postmenopausal, breast cancer. The relative risk estimate for breast cancer comparing women with high birthweight to women with low birthweight combining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidence interval 1.13-1.34). The mechanisms underlying this association likely include elevated levels of growth factors that may increase the number of susceptible stem cells in the mammary gland or initiate tumors through DNA mutations. Loss of imprinting (LOI) of growth hormone genes relevant for intrauterine growth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormones evidenced by high birthweight. LOI of IGF2 has also been found in mammary tumor tissue. The role of environmental factors that stimulate such epigenetic regulation of gene expression remains to be elucidated.
Over the past two decades there have been significant achievements in the control of a handful of important human tropical infections [1]. These achievements include the substantive reductions in the prevalence and incidence of the so-called neglected diseases such as lymphatic filariasis, onchocerciasis, guinea worm, leprosy, and trachoma (Box 1) [2]. Each of these neglected diseases is a poverty-promoting and often stigmatizing condition occurring primarily in rural areas of low-income countries (Box 2) [3]. They are ancient afflictions, described in the Bible and other ancient texts, which have burdened humanity for millennia [3]. But now, as a result of aggressive regional vertical interventions, there is a possibility that some neglected tropical infections could be eventually controlled to the point of elimination in some areas of endemicity [2–8]. In the case of guinea worm infection, disease eradication might also soon be possible [9]. Box 2. Common Features of the Neglected Tropical Diseases Ancient afflictions that have burdened humanity for centuries Poverty-promoting conditions Associated with stigma Rural areas of low-income countries and fragile states No commercial markets for products that target these diseases Interventions, when applied, have a history of success
The antibacterial peptide microcin J25 (MccJ25) inhibits transcription by bacterial RNA polymerase (RNAP). Biochemical results indicate that inhibition of transcription occurs at the level of NTP uptake or NTP binding by RNAP. Genetic results indicate that inhibition of transcription requires an extensive determinant, comprising more than 50 amino acid residues, within the RNAP secondary channel (also known as the "NTP-uptake channel" or "pore"). Biophysical results indicate that inhibition of transcription involves binding of MccJ25 within the RNAP secondary channel. Molecular modeling indicates that binding of MccJ25 within the RNAP secondary channel obstructs the RNAP secondary channel. We conclude that MccJ25 inhibits transcription by binding within and obstructing the RNAP secondary channel--acting essentially as a "cork in a bottle. " Obstruction of the RNAP secondary channel represents an attractive target for drug discovery.
Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes through Foxk-Sin3-mediated transcriptional control.
|
DRD1 proteins enable Pol V transcription in vivo.
Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Breast cancer may originate in utero. We reviewed the available evidence on the association between birthweight and the risk of breast cancer. To date, 26 research papers addressing this issue have been published. The majority of studies identified a positive link between birthweight and premenopausal, but not postmenopausal, breast cancer. The relative risk estimate for breast cancer comparing women with high birthweight to women with low birthweight combining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidence interval 1.13-1.34). The mechanisms underlying this association likely include elevated levels of growth factors that may increase the number of susceptible stem cells in the mammary gland or initiate tumors through DNA mutations. Loss of imprinting (LOI) of growth hormone genes relevant for intrauterine growth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormones evidenced by high birthweight. LOI of IGF2 has also been found in mammary tumor tissue. The role of environmental factors that stimulate such epigenetic regulation of gene expression remains to be elucidated.
Over the past two decades there have been significant achievements in the control of a handful of important human tropical infections [1]. These achievements include the substantive reductions in the prevalence and incidence of the so-called neglected diseases such as lymphatic filariasis, onchocerciasis, guinea worm, leprosy, and trachoma (Box 1) [2]. Each of these neglected diseases is a poverty-promoting and often stigmatizing condition occurring primarily in rural areas of low-income countries (Box 2) [3]. They are ancient afflictions, described in the Bible and other ancient texts, which have burdened humanity for millennia [3]. But now, as a result of aggressive regional vertical interventions, there is a possibility that some neglected tropical infections could be eventually controlled to the point of elimination in some areas of endemicity [2–8]. In the case of guinea worm infection, disease eradication might also soon be possible [9]. Box 2. Common Features of the Neglected Tropical Diseases Ancient afflictions that have burdened humanity for centuries Poverty-promoting conditions Associated with stigma Rural areas of low-income countries and fragile states No commercial markets for products that target these diseases Interventions, when applied, have a history of success
The antibacterial peptide microcin J25 (MccJ25) inhibits transcription by bacterial RNA polymerase (RNAP). Biochemical results indicate that inhibition of transcription occurs at the level of NTP uptake or NTP binding by RNAP. Genetic results indicate that inhibition of transcription requires an extensive determinant, comprising more than 50 amino acid residues, within the RNAP secondary channel (also known as the "NTP-uptake channel" or "pore"). Biophysical results indicate that inhibition of transcription involves binding of MccJ25 within the RNAP secondary channel. Molecular modeling indicates that binding of MccJ25 within the RNAP secondary channel obstructs the RNAP secondary channel. We conclude that MccJ25 inhibits transcription by binding within and obstructing the RNAP secondary channel--acting essentially as a "cork in a bottle. " Obstruction of the RNAP secondary channel represents an attractive target for drug discovery.
Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes through Foxk-Sin3-mediated transcriptional control.
| 0
|
{
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}
|
305
|
aug_618
|
HAND2 methylation is a key step in early endometrial carcinogenesis.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.
|
HAND2 methylation is a key step in early endometrial carcinogenesis.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.
| 0.5
|
{
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|
488
|
aug_619
|
Rhythmic expression of Cry1 translates directly into a circadian regulation of cAMP signaling in hepatic glucose metabolism.
During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.
|
Rhythmic expression of Cry1 translates directly into a circadian regulation of cAMP signaling in hepatic glucose metabolism.
During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.
| 1
|
{
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|
1045
|
aug_620
|
Tuberculosis incidence occurs at higher rates in more sparsely populated areas in the UK.
Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue. Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members of this family have been crystallized in conformations with inaccessible active sites. We have trapped human TG2 in complex with an inhibitor that mimics inflammatory gluten peptide substrates and have solved, at 2-A resolution, its x-ray crystal structure. The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earlier transglutaminase structures. The active site is exposed, revealing that catalysis takes place in a tunnel, bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize the tetrahedral reaction intermediates. Site-directed mutagenesis was used to investigate the acyl-acceptor side of the tunnel, yielding mutants with a marked increase in preference for hydrolysis over transamidation. By providing the ability to visualize this activated conformer, our results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients.
Pluripotent stem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and the developmentally more advanced epiblast stem cells (EpiSCs; ref. ). In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive epigenetic marks. In contrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards the embryonic cell types. The transition from naive to primed pluripotency therefore represents a pivotal event in cellular differentiation. But the signals that control this fundamental differentiation step remain unclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors for ESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins in combination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of any undefined factors, and support the derivation of new ESC lines, including ones from non-permissive mouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primed pluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor.
The tastes of sugars (sweet) and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells.
This paper seeks to establish the strength of association between contemporary tuberculosis (TB) in England and Wales and several potential aetiological factors. It presents an ecological analysis of standardised annual TB mortality rates for the 403 local authority districts between 1982 and 1992, disaggregated by age and sex. Social, demographic and ethnicity measures from the 1981 and 1991 censuses and standardised annual AIDS-related mortality rates for young men are used to calculate Poisson regression models. A strong association was found between all TB mortality groups and overcrowding at the household level. For women, no other measures improved the explanatory power of the models. In multiple regressions, both poverty and AIDS-related mortality explained additional variation in the model for younger men. The link between ethnicity and tuberculosis notifications was not reflected in this analysis of mortality. For all groups no evidence of a positive relationship with ethnicity was found, once overcrowding had been accounted for. The significance of household as opposed to district level crowding suggests that prolonged contact is required for disease transmission. Regression analysis indicates that it is the overcrowding and poverty among ethnic populations that is significant for their tuberculosis mortality. The fact that the relationship between AIDS and TB is confined to the group most typical of AIDS patients provides evidence that AIDS has little influence on the level of tuberculosis mortality in the wider population. Explanations for the observed relationship include preferential certification, migration for treatment and shortcomings in health care provision.
|
Tuberculosis incidence occurs at higher rates in more sparsely populated areas in the UK.
Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue. Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members of this family have been crystallized in conformations with inaccessible active sites. We have trapped human TG2 in complex with an inhibitor that mimics inflammatory gluten peptide substrates and have solved, at 2-A resolution, its x-ray crystal structure. The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earlier transglutaminase structures. The active site is exposed, revealing that catalysis takes place in a tunnel, bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize the tetrahedral reaction intermediates. Site-directed mutagenesis was used to investigate the acyl-acceptor side of the tunnel, yielding mutants with a marked increase in preference for hydrolysis over transamidation. By providing the ability to visualize this activated conformer, our results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients.
Pluripotent stem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and the developmentally more advanced epiblast stem cells (EpiSCs; ref. ). In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive epigenetic marks. In contrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards the embryonic cell types. The transition from naive to primed pluripotency therefore represents a pivotal event in cellular differentiation. But the signals that control this fundamental differentiation step remain unclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors for ESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins in combination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of any undefined factors, and support the derivation of new ESC lines, including ones from non-permissive mouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primed pluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor.
The tastes of sugars (sweet) and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells.
This paper seeks to establish the strength of association between contemporary tuberculosis (TB) in England and Wales and several potential aetiological factors. It presents an ecological analysis of standardised annual TB mortality rates for the 403 local authority districts between 1982 and 1992, disaggregated by age and sex. Social, demographic and ethnicity measures from the 1981 and 1991 censuses and standardised annual AIDS-related mortality rates for young men are used to calculate Poisson regression models. A strong association was found between all TB mortality groups and overcrowding at the household level. For women, no other measures improved the explanatory power of the models. In multiple regressions, both poverty and AIDS-related mortality explained additional variation in the model for younger men. The link between ethnicity and tuberculosis notifications was not reflected in this analysis of mortality. For all groups no evidence of a positive relationship with ethnicity was found, once overcrowding had been accounted for. The significance of household as opposed to district level crowding suggests that prolonged contact is required for disease transmission. Regression analysis indicates that it is the overcrowding and poverty among ethnic populations that is significant for their tuberculosis mortality. The fact that the relationship between AIDS and TB is confined to the group most typical of AIDS patients provides evidence that AIDS has little influence on the level of tuberculosis mortality in the wider population. Explanations for the observed relationship include preferential certification, migration for treatment and shortcomings in health care provision.
| 0.333333
|
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|
1327
|
aug_621
|
Increased diastolic blood pressure (DBP) is associated with abdominal aortic aneurysm.
Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework-potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed.
OBJECTIVE To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches. DESIGN Meta-analysis. DATA SOURCES Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks. DATA EXTRACTION Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index. RESULTS 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and -0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02 and -0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=-0.11, 95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). CONCLUSIONS Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
CONTEXT Chronic low back pain (LBP) with degenerative lumbar osteoarthritis (OA) is widespread in the adult population. Although glucosamine is increasingly used by patients with chronic LBP, little is known about its effect in this setting. OBJECTIVE To investigate the effect of glucosamine in patients with chronic LBP and degenerative lumbar OA. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, placebo-controlled trial conducted at Oslo University Hospital Outpatient Clinic, Oslo, Norway, with 250 patients older than 25 years of age with chronic LBP (>6 months) and degenerative lumbar OA. INTERVENTIONS Daily intake of 1500 mg of oral glucosamine (n = 125) or placebo (n = 125) for 6 months, with assessment of effect after the 6-month intervention period and at 1 year (6 months postintervention). MAIN OUTCOME MEASURES The primary outcome was pain-related disability measured with the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes were numerical scores from pain-rating scales of patients at rest and during activity, and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument. Data collection occurred during the intervention period at baseline, 6 weeks, 3 and 6 months, and again 6 months following the intervention at 1 year. Group differences were analyzed using linear mixed models analysis. RESULTS At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4-10.0) for glucosamine and 9.7 (95% CI, 8.9-10.5) for the placebo group (P = .37). At 6 months, the mean RMDQ score was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2-5.8). At 1 year, the mean RMDQ scores were 4.8 (95% CI, 3.9-5.6) for glucosamine and 5.5 (95% CI, 4.7-6.4) for the placebo group. No statistically significant difference in change between groups was found when assessed after the 6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P = .97), and quality-of-life EQ-5D (P = .20). Mild adverse events were reported in 40 patients in the glucosamine group and 46 in the placebo group (P = .48). CONCLUSIONS Among patients with chronic LBP and degenerative lumbar OA, 6-month treatment with oral glucosamine compared with placebo did not result in reduced pain-related disability after the 6-month intervention and after 1-year follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00404079.
CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606.
|
Increased diastolic blood pressure (DBP) is associated with abdominal aortic aneurysm.
Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework-potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed.
OBJECTIVE To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches. DESIGN Meta-analysis. DATA SOURCES Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks. DATA EXTRACTION Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index. RESULTS 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and -0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02 and -0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=-0.11, 95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). CONCLUSIONS Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
CONTEXT Chronic low back pain (LBP) with degenerative lumbar osteoarthritis (OA) is widespread in the adult population. Although glucosamine is increasingly used by patients with chronic LBP, little is known about its effect in this setting. OBJECTIVE To investigate the effect of glucosamine in patients with chronic LBP and degenerative lumbar OA. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, placebo-controlled trial conducted at Oslo University Hospital Outpatient Clinic, Oslo, Norway, with 250 patients older than 25 years of age with chronic LBP (>6 months) and degenerative lumbar OA. INTERVENTIONS Daily intake of 1500 mg of oral glucosamine (n = 125) or placebo (n = 125) for 6 months, with assessment of effect after the 6-month intervention period and at 1 year (6 months postintervention). MAIN OUTCOME MEASURES The primary outcome was pain-related disability measured with the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes were numerical scores from pain-rating scales of patients at rest and during activity, and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument. Data collection occurred during the intervention period at baseline, 6 weeks, 3 and 6 months, and again 6 months following the intervention at 1 year. Group differences were analyzed using linear mixed models analysis. RESULTS At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4-10.0) for glucosamine and 9.7 (95% CI, 8.9-10.5) for the placebo group (P = .37). At 6 months, the mean RMDQ score was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2-5.8). At 1 year, the mean RMDQ scores were 4.8 (95% CI, 3.9-5.6) for glucosamine and 5.5 (95% CI, 4.7-6.4) for the placebo group. No statistically significant difference in change between groups was found when assessed after the 6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P = .97), and quality-of-life EQ-5D (P = .20). Mild adverse events were reported in 40 patients in the glucosamine group and 46 in the placebo group (P = .48). CONCLUSIONS Among patients with chronic LBP and degenerative lumbar OA, 6-month treatment with oral glucosamine compared with placebo did not result in reduced pain-related disability after the 6-month intervention and after 1-year follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00404079.
CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606.
| 0
|
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|
607
|
aug_622
|
Distant CREs are important for transcriptional regulation.
The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.
|
Distant CREs are important for transcriptional regulation.
The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.
| 1
|
{
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|
351
|
aug_623
|
Polymeal nutrition increases cardiovascular mortality.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
Studying how protein transmembrane domains transmit signals across membranes is beset by unique challenges. Here, we discuss the circumstances that have led to success and reflect on what has been learned from these examples. Such efforts suggest that some of the most interesting properties of transmembrane helix interactions may be the least amenable to study by current techniques.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
OBJECTIVE Although the Polypill concept (proposed in 2003) is promising in terms of benefits for cardiovascular risk management, the potential costs and adverse effects are its main pitfalls. The objective of this study was to identify a tastier and safer alternative to the Polypill: the Polymeal. METHODS Data on the ingredients of the Polymeal were taken from the literature. The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds. Data from the Framingham heart study and the Framingham offspring study were used to build life tables to model the benefits of the Polymeal in the general population from age 50, assuming multiplicative correlations. RESULTS Combining the ingredients of the Polymeal would reduce cardiovascular disease events by 76%. For men, taking the Polymeal daily represented an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years. The corresponding differences for women were 4.8, 8.1, and 3.3 years. CONCLUSION The Polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population.
|
Polymeal nutrition increases cardiovascular mortality.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
Studying how protein transmembrane domains transmit signals across membranes is beset by unique challenges. Here, we discuss the circumstances that have led to success and reflect on what has been learned from these examples. Such efforts suggest that some of the most interesting properties of transmembrane helix interactions may be the least amenable to study by current techniques.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
OBJECTIVE Although the Polypill concept (proposed in 2003) is promising in terms of benefits for cardiovascular risk management, the potential costs and adverse effects are its main pitfalls. The objective of this study was to identify a tastier and safer alternative to the Polypill: the Polymeal. METHODS Data on the ingredients of the Polymeal were taken from the literature. The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds. Data from the Framingham heart study and the Framingham offspring study were used to build life tables to model the benefits of the Polymeal in the general population from age 50, assuming multiplicative correlations. RESULTS Combining the ingredients of the Polymeal would reduce cardiovascular disease events by 76%. For men, taking the Polymeal daily represented an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years. The corresponding differences for women were 4.8, 8.1, and 3.3 years. CONCLUSION The Polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population.
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F4/80+ macrophages regulate mature osteoblast maintenance.
OBJECTIVE To determine the effectiveness and cost effectiveness of using information from circulating biomarkers to inform the prioritisation process of patients with stable angina awaiting coronary artery bypass graft surgery. DESIGN Decision analytical model comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgency scores, and a risk score) and three strategies based on a risk score using biomarkers: a routinely assessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), or both. The order in which to perform coronary artery bypass grafting in a cohort of patients was determined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years (QALYs) were compared. DATA SOURCES Swedish Coronary Angiography and Angioplasty Registry (9935 patients with stable angina awaiting coronary artery bypass grafting and then followed up for cardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects (relative risks) of biomarkers. RESULTS The observed risk of cardiovascular events while on the waiting list for coronary artery bypass grafting was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients). Using a cost effectiveness threshold of pound20,000- pound30,000 (euro22,000-euro33,000; $32,000-$48,000) per additional QALY, a prioritisation strategy using a risk score with estimated glomerular filtration rate was the most cost effective strategy (cost per additional QALY was < pound410 compared with the Ontario urgency score). The impact on population health of implementing this strategy was 800 QALYs per 100,000 patients at an additional cost of pound 245,000 to the National Health Service. The prioritisation strategy using a risk score with C reactive protein was associated with lower QALYs and higher costs compared with a risk score using estimated glomerular filtration rate. CONCLUSION Evaluating the cost effectiveness of prognostic biomarkers is important even when effects at an individual level are small. Formal prioritisation of patients awaiting coronary artery bypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along with simple, routinely collected clinical information was cost effective. Prioritisation strategies based on the prognostic information conferred by C reactive protein, which is not currently measured in this context, or a combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be cost effective. The widespread practice of using only implicit or informal means of clinically ordering the waiting list may be harmful and should be replaced with formal prioritisation approaches.
Blind individuals often demonstrate enhanced nonvisual perceptual abilities. However, the neural substrate that underlies this improved performance remains to be fully understood. An earlier behavioral study demonstrated that some early-blind people localize sounds more accurately than sighted controls using monaural cues. In order to investigate the neural basis of these behavioral differences in humans, we carried out functional imaging studies using positron emission tomography and a speaker array that permitted pseudo-free-field presentations within the scanner. During binaural sound localization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which was not seen in early-blind individuals. During monaural sound localization (one ear plugged), the subgroup of early-blind subjects who were behaviorally superior at sound localization displayed two activation foci in the occipital cortex. This effect was not seen in blind persons who did not have superior monaural sound localization abilities, nor in sighted individuals. The degree of activation of one of these foci was strongly correlated with sound localization accuracy across the entire group of blind subjects. The results show that those blind persons who perform better than sighted persons recruit occipital areas to carry out auditory localization under monaural conditions. We therefore conclude that computations carried out in the occipital cortex specifically underlie the enhanced capacity to use monaural cues. Our findings shed light not only on intermodal compensatory mechanisms, but also on individual differences in these mechanisms and on inhibitory patterns that differ between sighted individuals and those deprived of vision early in life.
Objective To explore the in vitro maintenance and characterization of human embryonic stem cells(hESCs).Methods hESCs were cultured on feeder layer with ES culture medium,which consists of 20% Knockout Serum Replacement,Knockout DMEM and 10 ng/mL bFGF.Undifferentiated status of hESCs was identified by cell morphology,and the expressions of cell surface marker SSEA-1,SSEA-3 and TRA-1-60.G banding technique was employed for cell karyotype analysis. Pluropotency of cells were analyzed via in vitro embyoid body(EB) formation and in vivo terotoma formation. Results Most of cells showed undifferentiated properties in cell morphology and normal karyotype throughout extended culture periods. They maintained undifferentiated status with positive immunoreactivity to SSEA-3,SSEA-4 and TRA-1-60.in vitro EB formation and in vivo teratoma formation demonstrated the pluripotency of human ES cells. Conclusion The fundamental requirement to hESCs for research and clinical application were their undifferentiated status and pluropotency in culture. Our result demonstrated their potential for these purposes.
Exosomes are emerging mediators of intercellular communication; whether the release of exosomes has an effect on the exosome donor cells in addition to the recipient cells has not been investigated to any extent. Here, we examine different exosomal miRNA expression profiles in primary mouse colon tumour, liver metastasis of colon cancer and naive colon tissues. In more advanced disease, higher levels of tumour suppressor miRNAs are encapsulated in the exosomes. miR-193a interacts with major vault protein (MVP). Knockout of MVP leads to miR-193a accumulation in the exosomal donor cells instead of exosomes, inhibiting tumour progression. Furthermore, miR-193a causes cell cycle G1 arrest and cell proliferation repression through targeting of Caprin1, which upregulates Ccnd2 and c-Myc. Human colon cancer patients with more advanced disease show higher levels of circulating exosomal miR-193a. In summary, our data demonstrate that MVP-mediated selective sorting of tumour suppressor miRNA into exosomes promotes tumour progression.
BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council.
BACKGROUND The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING Bill & Melinda Gates Foundation.
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F4/80+ macrophages regulate mature osteoblast maintenance.
OBJECTIVE To determine the effectiveness and cost effectiveness of using information from circulating biomarkers to inform the prioritisation process of patients with stable angina awaiting coronary artery bypass graft surgery. DESIGN Decision analytical model comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgency scores, and a risk score) and three strategies based on a risk score using biomarkers: a routinely assessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), or both. The order in which to perform coronary artery bypass grafting in a cohort of patients was determined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years (QALYs) were compared. DATA SOURCES Swedish Coronary Angiography and Angioplasty Registry (9935 patients with stable angina awaiting coronary artery bypass grafting and then followed up for cardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects (relative risks) of biomarkers. RESULTS The observed risk of cardiovascular events while on the waiting list for coronary artery bypass grafting was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients). Using a cost effectiveness threshold of pound20,000- pound30,000 (euro22,000-euro33,000; $32,000-$48,000) per additional QALY, a prioritisation strategy using a risk score with estimated glomerular filtration rate was the most cost effective strategy (cost per additional QALY was < pound410 compared with the Ontario urgency score). The impact on population health of implementing this strategy was 800 QALYs per 100,000 patients at an additional cost of pound 245,000 to the National Health Service. The prioritisation strategy using a risk score with C reactive protein was associated with lower QALYs and higher costs compared with a risk score using estimated glomerular filtration rate. CONCLUSION Evaluating the cost effectiveness of prognostic biomarkers is important even when effects at an individual level are small. Formal prioritisation of patients awaiting coronary artery bypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along with simple, routinely collected clinical information was cost effective. Prioritisation strategies based on the prognostic information conferred by C reactive protein, which is not currently measured in this context, or a combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be cost effective. The widespread practice of using only implicit or informal means of clinically ordering the waiting list may be harmful and should be replaced with formal prioritisation approaches.
Blind individuals often demonstrate enhanced nonvisual perceptual abilities. However, the neural substrate that underlies this improved performance remains to be fully understood. An earlier behavioral study demonstrated that some early-blind people localize sounds more accurately than sighted controls using monaural cues. In order to investigate the neural basis of these behavioral differences in humans, we carried out functional imaging studies using positron emission tomography and a speaker array that permitted pseudo-free-field presentations within the scanner. During binaural sound localization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which was not seen in early-blind individuals. During monaural sound localization (one ear plugged), the subgroup of early-blind subjects who were behaviorally superior at sound localization displayed two activation foci in the occipital cortex. This effect was not seen in blind persons who did not have superior monaural sound localization abilities, nor in sighted individuals. The degree of activation of one of these foci was strongly correlated with sound localization accuracy across the entire group of blind subjects. The results show that those blind persons who perform better than sighted persons recruit occipital areas to carry out auditory localization under monaural conditions. We therefore conclude that computations carried out in the occipital cortex specifically underlie the enhanced capacity to use monaural cues. Our findings shed light not only on intermodal compensatory mechanisms, but also on individual differences in these mechanisms and on inhibitory patterns that differ between sighted individuals and those deprived of vision early in life.
Objective To explore the in vitro maintenance and characterization of human embryonic stem cells(hESCs).Methods hESCs were cultured on feeder layer with ES culture medium,which consists of 20% Knockout Serum Replacement,Knockout DMEM and 10 ng/mL bFGF.Undifferentiated status of hESCs was identified by cell morphology,and the expressions of cell surface marker SSEA-1,SSEA-3 and TRA-1-60.G banding technique was employed for cell karyotype analysis. Pluropotency of cells were analyzed via in vitro embyoid body(EB) formation and in vivo terotoma formation. Results Most of cells showed undifferentiated properties in cell morphology and normal karyotype throughout extended culture periods. They maintained undifferentiated status with positive immunoreactivity to SSEA-3,SSEA-4 and TRA-1-60.in vitro EB formation and in vivo teratoma formation demonstrated the pluripotency of human ES cells. Conclusion The fundamental requirement to hESCs for research and clinical application were their undifferentiated status and pluropotency in culture. Our result demonstrated their potential for these purposes.
Exosomes are emerging mediators of intercellular communication; whether the release of exosomes has an effect on the exosome donor cells in addition to the recipient cells has not been investigated to any extent. Here, we examine different exosomal miRNA expression profiles in primary mouse colon tumour, liver metastasis of colon cancer and naive colon tissues. In more advanced disease, higher levels of tumour suppressor miRNAs are encapsulated in the exosomes. miR-193a interacts with major vault protein (MVP). Knockout of MVP leads to miR-193a accumulation in the exosomal donor cells instead of exosomes, inhibiting tumour progression. Furthermore, miR-193a causes cell cycle G1 arrest and cell proliferation repression through targeting of Caprin1, which upregulates Ccnd2 and c-Myc. Human colon cancer patients with more advanced disease show higher levels of circulating exosomal miR-193a. In summary, our data demonstrate that MVP-mediated selective sorting of tumour suppressor miRNA into exosomes promotes tumour progression.
BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council.
BACKGROUND The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING Bill & Melinda Gates Foundation.
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H4 G94P proteins inhibit chromatin assembly, which decreases free histones.
T cell receptor (TCR-CD3) triggering involves both receptor clustering and conformational changes at the cytoplasmic tails of the CD3 subunits. The mechanism by which TCRalphabeta ligand binding confers conformational changes to CD3 is unknown. By using well-defined ligands, we showed that induction of the conformational change requires both multivalent engagement and the mobility restriction of the TCR-CD3 imposed by the plasma membrane. The conformational change is elicited by cooperative rearrangements of two TCR-CD3 complexes and does not require accompanying changes in the structure of the TCRalphabeta ectodomains. This conformational change at CD3 reverts upon ligand dissociation and is required for T cell activation. Thus, our permissive geometry model provides a molecular mechanism that rationalizes how the information of ligand binding to TCRalphabeta is transmitted to the CD3 subunits and to the intracellular signaling machinery.
Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
The most conspicuous event in the cell cycle is the alignment of chromosomes in metaphase. Chromosome alignment fosters faithful segregation through the formation of bi-oriented attachments of kinetochores to spindle microtubules. Notably, numerous kinetochore-microtubule (k-MT) attachment errors are present in early mitosis (prometaphase), and the persistence of those errors is the leading cause of chromosome mis-segregation in aneuploid human tumour cells that continually mis-segregate whole chromosomes and display chromosomal instability. How robust error correction is achieved in prometaphase to ensure error-free mitosis remains unknown. Here we show that k-MT attachments in prometaphase cells are considerably less stable than in metaphase cells. The switch to more stable k-MT attachments in metaphase requires the proteasome-dependent destruction of cyclin A in prometaphase. Persistent cyclin A expression prevents k-MT stabilization even in cells with aligned chromosomes. By contrast, k-MTs are prematurely stabilized in cyclin-A-deficient cells. Consequently, cells lacking cyclin A display higher rates of chromosome mis-segregation. Thus, the stability of k-MT attachments increases decisively in a coordinated fashion among all chromosomes as cells transit from prometaphase to metaphase. Cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation.
Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.
Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem or progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage conversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering.
OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials, SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.
|
H4 G94P proteins inhibit chromatin assembly, which decreases free histones.
T cell receptor (TCR-CD3) triggering involves both receptor clustering and conformational changes at the cytoplasmic tails of the CD3 subunits. The mechanism by which TCRalphabeta ligand binding confers conformational changes to CD3 is unknown. By using well-defined ligands, we showed that induction of the conformational change requires both multivalent engagement and the mobility restriction of the TCR-CD3 imposed by the plasma membrane. The conformational change is elicited by cooperative rearrangements of two TCR-CD3 complexes and does not require accompanying changes in the structure of the TCRalphabeta ectodomains. This conformational change at CD3 reverts upon ligand dissociation and is required for T cell activation. Thus, our permissive geometry model provides a molecular mechanism that rationalizes how the information of ligand binding to TCRalphabeta is transmitted to the CD3 subunits and to the intracellular signaling machinery.
Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
The most conspicuous event in the cell cycle is the alignment of chromosomes in metaphase. Chromosome alignment fosters faithful segregation through the formation of bi-oriented attachments of kinetochores to spindle microtubules. Notably, numerous kinetochore-microtubule (k-MT) attachment errors are present in early mitosis (prometaphase), and the persistence of those errors is the leading cause of chromosome mis-segregation in aneuploid human tumour cells that continually mis-segregate whole chromosomes and display chromosomal instability. How robust error correction is achieved in prometaphase to ensure error-free mitosis remains unknown. Here we show that k-MT attachments in prometaphase cells are considerably less stable than in metaphase cells. The switch to more stable k-MT attachments in metaphase requires the proteasome-dependent destruction of cyclin A in prometaphase. Persistent cyclin A expression prevents k-MT stabilization even in cells with aligned chromosomes. By contrast, k-MTs are prematurely stabilized in cyclin-A-deficient cells. Consequently, cells lacking cyclin A display higher rates of chromosome mis-segregation. Thus, the stability of k-MT attachments increases decisively in a coordinated fashion among all chromosomes as cells transit from prometaphase to metaphase. Cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation.
Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.
Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem or progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage conversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering.
OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials, SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.
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KRT17 modulates the expression of the transcriptional regulator AIRE in diseased epithelia.
Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy–induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.
Blind individuals often demonstrate enhanced nonvisual perceptual abilities. However, the neural substrate that underlies this improved performance remains to be fully understood. An earlier behavioral study demonstrated that some early-blind people localize sounds more accurately than sighted controls using monaural cues. In order to investigate the neural basis of these behavioral differences in humans, we carried out functional imaging studies using positron emission tomography and a speaker array that permitted pseudo-free-field presentations within the scanner. During binaural sound localization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which was not seen in early-blind individuals. During monaural sound localization (one ear plugged), the subgroup of early-blind subjects who were behaviorally superior at sound localization displayed two activation foci in the occipital cortex. This effect was not seen in blind persons who did not have superior monaural sound localization abilities, nor in sighted individuals. The degree of activation of one of these foci was strongly correlated with sound localization accuracy across the entire group of blind subjects. The results show that those blind persons who perform better than sighted persons recruit occipital areas to carry out auditory localization under monaural conditions. We therefore conclude that computations carried out in the occipital cortex specifically underlie the enhanced capacity to use monaural cues. Our findings shed light not only on intermodal compensatory mechanisms, but also on individual differences in these mechanisms and on inhibitory patterns that differ between sighted individuals and those deprived of vision early in life.
Nuclear transcription is not restricted to genes but occurs throughout the intergenic and noncoding space of eukaryotic genomes. The functional significance of this widespread noncoding transcription is mostly unknown. We show that Arabidopsis RNA polymerase IVb/Pol V, a multisubunit nuclear enzyme required for siRNA-mediated gene silencing of transposons and other repeats, transcribes intergenic and noncoding sequences, thereby facilitating heterochromatin formation and silencing of overlapping and adjacent genes. Pol IVb/Pol V transcription requires the chromatin-remodeling protein DRD1 but is independent of siRNA biogenesis. However, Pol IVb/Pol V transcription and siRNA production are both required to silence transposons, suggesting that Pol IVb/Pol V generates RNAs or chromatin structures that serve as scaffolds for siRNA-mediated heterochromatin-forming complexes. Pol IVb/Pol V function provides a solution to a paradox of epigenetic control: the need for transcription in order to transcriptionally silence the same region.
To identify previously unknown platelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays. Bioinformatical analysis of MK-up-regulated genes identified 151 transcripts encoding transmembrane domain-containing proteins. Although many of these were known platelet genes, a number of previously unidentified or poorly characterized transcripts were also detected. Many of these transcripts, including G6b, G6f, LRRC32, LAT2, and the G protein-coupled receptor SUCNR1, encode proteins with structural features or functions that suggest they may be involved in the modulation of platelet function. Immunoblotting on platelets confirmed the presence of the encoded proteins, and flow cytometric analysis confirmed the expression of G6b, G6f, and LRRC32 on the surface of platelets. Through comparative analysis of expression in platelets and other blood cells we demonstrated that G6b, G6f, and LRRC32 are restricted to the platelet lineage, whereas LAT2 and SUCNR1 were also detected in other blood cells. The identification of the succinate receptor SUCNR1 in platelets is of particular interest, because physiologically relevant concentrations of succinate were shown to potentiate the effect of low doses of a variety of platelet agonists.
CONTEXT High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease. Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown. OBJECTIVE To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS Double-blind randomized controlled trial (2001-2006) in 36 US Department of Veterans Affairs medical centers. Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease (estimated creatinine clearance < or =30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels (> or = 15 micromol/L). INTERVENTION Participants received a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or a placebo. MAIN OUTCOME MEASURES The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality, time to initiation of dialysis, and time to thrombosis of arteriovenous access in hemodialysis patients. RESULTS Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group. It was lowered 6.3 micromol/L (25.8%; P < .001) in the vitamin group and 0.4 micromol/L (1.7%; P = .14) in the placebo group at 3 months, but there was no significant effect on mortality (448 vitamin group deaths vs 436 placebo group deaths) (hazard ratio [HR], 1.04; 95% CI, 0.91-1.18). No significant effects were demonstrated for secondary outcomes or adverse events: there were 129 MIs in the vitamin group vs 150 for placebo (HR, 0.86; 95% CI, 0.67-1.08), 37 strokes in the vitamin group vs 41 for placebo (HR, 0.90; 95% CI, 0.58-1.40), and 60 amputations in the vitamin group vs 53 for placebo (HR, 1.14; 95% CI, 0.79-1.64). In addition, the composite of MI, stroke, and amputations plus mortality (P = .85), time to dialysis (P = .38), and time to thrombosis in hemodialysis patients (P = .97) did not differ between the vitamin and placebo groups. CONCLUSION Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00032435.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
|
KRT17 modulates the expression of the transcriptional regulator AIRE in diseased epithelia.
Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy–induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.
Blind individuals often demonstrate enhanced nonvisual perceptual abilities. However, the neural substrate that underlies this improved performance remains to be fully understood. An earlier behavioral study demonstrated that some early-blind people localize sounds more accurately than sighted controls using monaural cues. In order to investigate the neural basis of these behavioral differences in humans, we carried out functional imaging studies using positron emission tomography and a speaker array that permitted pseudo-free-field presentations within the scanner. During binaural sound localization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which was not seen in early-blind individuals. During monaural sound localization (one ear plugged), the subgroup of early-blind subjects who were behaviorally superior at sound localization displayed two activation foci in the occipital cortex. This effect was not seen in blind persons who did not have superior monaural sound localization abilities, nor in sighted individuals. The degree of activation of one of these foci was strongly correlated with sound localization accuracy across the entire group of blind subjects. The results show that those blind persons who perform better than sighted persons recruit occipital areas to carry out auditory localization under monaural conditions. We therefore conclude that computations carried out in the occipital cortex specifically underlie the enhanced capacity to use monaural cues. Our findings shed light not only on intermodal compensatory mechanisms, but also on individual differences in these mechanisms and on inhibitory patterns that differ between sighted individuals and those deprived of vision early in life.
Nuclear transcription is not restricted to genes but occurs throughout the intergenic and noncoding space of eukaryotic genomes. The functional significance of this widespread noncoding transcription is mostly unknown. We show that Arabidopsis RNA polymerase IVb/Pol V, a multisubunit nuclear enzyme required for siRNA-mediated gene silencing of transposons and other repeats, transcribes intergenic and noncoding sequences, thereby facilitating heterochromatin formation and silencing of overlapping and adjacent genes. Pol IVb/Pol V transcription requires the chromatin-remodeling protein DRD1 but is independent of siRNA biogenesis. However, Pol IVb/Pol V transcription and siRNA production are both required to silence transposons, suggesting that Pol IVb/Pol V generates RNAs or chromatin structures that serve as scaffolds for siRNA-mediated heterochromatin-forming complexes. Pol IVb/Pol V function provides a solution to a paradox of epigenetic control: the need for transcription in order to transcriptionally silence the same region.
To identify previously unknown platelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays. Bioinformatical analysis of MK-up-regulated genes identified 151 transcripts encoding transmembrane domain-containing proteins. Although many of these were known platelet genes, a number of previously unidentified or poorly characterized transcripts were also detected. Many of these transcripts, including G6b, G6f, LRRC32, LAT2, and the G protein-coupled receptor SUCNR1, encode proteins with structural features or functions that suggest they may be involved in the modulation of platelet function. Immunoblotting on platelets confirmed the presence of the encoded proteins, and flow cytometric analysis confirmed the expression of G6b, G6f, and LRRC32 on the surface of platelets. Through comparative analysis of expression in platelets and other blood cells we demonstrated that G6b, G6f, and LRRC32 are restricted to the platelet lineage, whereas LAT2 and SUCNR1 were also detected in other blood cells. The identification of the succinate receptor SUCNR1 in platelets is of particular interest, because physiologically relevant concentrations of succinate were shown to potentiate the effect of low doses of a variety of platelet agonists.
CONTEXT High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease. Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown. OBJECTIVE To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS Double-blind randomized controlled trial (2001-2006) in 36 US Department of Veterans Affairs medical centers. Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease (estimated creatinine clearance < or =30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels (> or = 15 micromol/L). INTERVENTION Participants received a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or a placebo. MAIN OUTCOME MEASURES The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality, time to initiation of dialysis, and time to thrombosis of arteriovenous access in hemodialysis patients. RESULTS Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group. It was lowered 6.3 micromol/L (25.8%; P < .001) in the vitamin group and 0.4 micromol/L (1.7%; P = .14) in the placebo group at 3 months, but there was no significant effect on mortality (448 vitamin group deaths vs 436 placebo group deaths) (hazard ratio [HR], 1.04; 95% CI, 0.91-1.18). No significant effects were demonstrated for secondary outcomes or adverse events: there were 129 MIs in the vitamin group vs 150 for placebo (HR, 0.86; 95% CI, 0.67-1.08), 37 strokes in the vitamin group vs 41 for placebo (HR, 0.90; 95% CI, 0.58-1.40), and 60 amputations in the vitamin group vs 53 for placebo (HR, 1.14; 95% CI, 0.79-1.64). In addition, the composite of MI, stroke, and amputations plus mortality (P = .85), time to dialysis (P = .38), and time to thrombosis in hemodialysis patients (P = .97) did not differ between the vitamin and placebo groups. CONCLUSION Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00032435.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
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1-1% of colorectal cancer patients are diagnosed with regional or distant metastases.
Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.
Cardiovascular disease is a leading cause of death worldwide. The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts. We discuss state-of-the-art methods for generating de novo cardiomyocytes from hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
OBJECTIVES To determine the extent to which type of hospital admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer. DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006. SETTING Hospital episode statistics (HES) dataset. PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer. MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment. RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies. For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34). There were some improvements in disparities between age groups but not for patients living in deprived areas over time. Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer. These findings did not improve with time. For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47). Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26). Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection. For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59). Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care.
|
1-1% of colorectal cancer patients are diagnosed with regional or distant metastases.
Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.
Cardiovascular disease is a leading cause of death worldwide. The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts. We discuss state-of-the-art methods for generating de novo cardiomyocytes from hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
OBJECTIVES To determine the extent to which type of hospital admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer. DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006. SETTING Hospital episode statistics (HES) dataset. PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer. MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment. RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies. For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34). There were some improvements in disparities between age groups but not for patients living in deprived areas over time. Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer. These findings did not improve with time. For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47). Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26). Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection. For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59). Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care.
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aug_628
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Misunderstandings between doctors and patients can lead to non-adherence.
Self-renewal and differentiation of stem cells depend on asymmetric division and polarized motility processes that in other cell types are modulated by nonmuscle myosin-II (MII) forces and matrix mechanics. Here, mass spectrometry-calibrated intracellular flow cytometry of human hematopoiesis reveals MIIB to be a major isoform that is strongly polarized in hematopoietic stem cells and progenitors (HSC/Ps) and thereby downregulated in differentiated cells via asymmetric division. MIIA is constitutive and activated by dephosphorylation during cytokine-triggered differentiation of cells grown on stiff, endosteum-like matrix, but not soft, marrow-like matrix. In vivo, MIIB is required for generation of blood, while MIIA is required for sustained HSC/P engraftment. Reversible inhibition of both isoforms in culture with blebbistatin enriches for long-term hematopoietic multilineage reconstituting cells by 5-fold or more as assessed in vivo. Megakaryocytes also become more polyploid, producing 4-fold more platelets. MII is thus a multifunctional node in polarized division and niche sensing.
Recognition of modified histones by ‘reader’ proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific ‘Ser 31’ residue in a composite pocket formed by the tandem bromo–PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.
To characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as at a single-cell level. A subpopulation of Sox2+ cells gives rise to cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response to mitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs as well as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role in maintaining the constant size of the NSC pool and producing newly born neurons during adult neurogenesis.
Whereas domestication of livestock, pets, and crops is well documented, it is still unclear to what extent microbes associated with the production of food have also undergone human selection and where the plethora of industrial strains originates from. Here, we present the genomes and phenomes of 157 industrial Saccharomyces cerevisiae yeasts. Our analyses reveal that today's industrial yeasts can be divided into five sublineages that are genetically and phenotypically separated from wild strains and originate from only a few ancestors through complex patterns of domestication and local divergence. Large-scale phenotyping and genome analysis further show strong industry-specific selection for stress tolerance, sugar utilization, and flavor production, while the sexual cycle and other phenotypes related to survival in nature show decay, particularly in beer yeasts. Together, these results shed light on the origins, evolutionary history, and phenotypic diversity of industrial yeasts and provide a resource for further selection of superior strains. PAPERCLIP.
Biogenesis of ribosomes is an essential cellular process conserved across all eukaryotes and is known to require >170 genes for the assembly, modification, and trafficking of ribosome components through multiple cellular compartments. Despite intensive study, this pathway likely involves many additional genes. Here, we employ network-guided genetics-an approach for associating candidate genes with biological processes that capitalizes on recent advances in functional genomic and proteomic studies-to computationally identify additional ribosomal biogenesis genes. We experimentally evaluated >100 candidate yeast genes in a battery of assays, confirming involvement of at least 15 new genes, including previously uncharacterized genes (YDL063C, YIL091C, YOR287C, YOR006C/TSR3, YOL022C/TSR4). We associate the new genes with specific aspects of ribosomal subunit maturation, ribosomal particle association, and ribosomal subunit nuclear export, and we identify genes specifically required for the processing of 5S, 7S, 20S, 27S, and 35S rRNAs. These results reveal new connections between ribosome biogenesis and mRNA splicing and add >10% new genes-most with human orthologs-to the biogenesis pathway, significantly extending our understanding of a universally conserved eukaryotic process.
BACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas. We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk. METHODS AND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013). We applied space-time scan statistics and mathematical models to confirm the findings. We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks. In the study area, this population density was typical of villages and some peri-urban areas. Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range. Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks. CONCLUSIONS Rural areas may contribute at least as much to the dissemination of dengue fever as cities. Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts. Please see later in the article for the Editors' Summary.
|
Misunderstandings between doctors and patients can lead to non-adherence.
Self-renewal and differentiation of stem cells depend on asymmetric division and polarized motility processes that in other cell types are modulated by nonmuscle myosin-II (MII) forces and matrix mechanics. Here, mass spectrometry-calibrated intracellular flow cytometry of human hematopoiesis reveals MIIB to be a major isoform that is strongly polarized in hematopoietic stem cells and progenitors (HSC/Ps) and thereby downregulated in differentiated cells via asymmetric division. MIIA is constitutive and activated by dephosphorylation during cytokine-triggered differentiation of cells grown on stiff, endosteum-like matrix, but not soft, marrow-like matrix. In vivo, MIIB is required for generation of blood, while MIIA is required for sustained HSC/P engraftment. Reversible inhibition of both isoforms in culture with blebbistatin enriches for long-term hematopoietic multilineage reconstituting cells by 5-fold or more as assessed in vivo. Megakaryocytes also become more polyploid, producing 4-fold more platelets. MII is thus a multifunctional node in polarized division and niche sensing.
Recognition of modified histones by ‘reader’ proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific ‘Ser 31’ residue in a composite pocket formed by the tandem bromo–PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.
To characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as at a single-cell level. A subpopulation of Sox2+ cells gives rise to cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response to mitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs as well as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role in maintaining the constant size of the NSC pool and producing newly born neurons during adult neurogenesis.
Whereas domestication of livestock, pets, and crops is well documented, it is still unclear to what extent microbes associated with the production of food have also undergone human selection and where the plethora of industrial strains originates from. Here, we present the genomes and phenomes of 157 industrial Saccharomyces cerevisiae yeasts. Our analyses reveal that today's industrial yeasts can be divided into five sublineages that are genetically and phenotypically separated from wild strains and originate from only a few ancestors through complex patterns of domestication and local divergence. Large-scale phenotyping and genome analysis further show strong industry-specific selection for stress tolerance, sugar utilization, and flavor production, while the sexual cycle and other phenotypes related to survival in nature show decay, particularly in beer yeasts. Together, these results shed light on the origins, evolutionary history, and phenotypic diversity of industrial yeasts and provide a resource for further selection of superior strains. PAPERCLIP.
Biogenesis of ribosomes is an essential cellular process conserved across all eukaryotes and is known to require >170 genes for the assembly, modification, and trafficking of ribosome components through multiple cellular compartments. Despite intensive study, this pathway likely involves many additional genes. Here, we employ network-guided genetics-an approach for associating candidate genes with biological processes that capitalizes on recent advances in functional genomic and proteomic studies-to computationally identify additional ribosomal biogenesis genes. We experimentally evaluated >100 candidate yeast genes in a battery of assays, confirming involvement of at least 15 new genes, including previously uncharacterized genes (YDL063C, YIL091C, YOR287C, YOR006C/TSR3, YOL022C/TSR4). We associate the new genes with specific aspects of ribosomal subunit maturation, ribosomal particle association, and ribosomal subunit nuclear export, and we identify genes specifically required for the processing of 5S, 7S, 20S, 27S, and 35S rRNAs. These results reveal new connections between ribosome biogenesis and mRNA splicing and add >10% new genes-most with human orthologs-to the biogenesis pathway, significantly extending our understanding of a universally conserved eukaryotic process.
BACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas. We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk. METHODS AND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013). We applied space-time scan statistics and mathematical models to confirm the findings. We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks. In the study area, this population density was typical of villages and some peri-urban areas. Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range. Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks. CONCLUSIONS Rural areas may contribute at least as much to the dissemination of dengue fever as cities. Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts. Please see later in the article for the Editors' Summary.
| 0
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|
792
|
aug_629
|
In rhesus macaques, daily subcutaneous injections of tenofovir protects against rectally transmitted simian-human immunodeficiency virus.
The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS) administration. Atm(-/-) mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice. Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment. Atm(-/-) mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment. Markers of reactive oxygen and nitrogen species-mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice. Atm(-/-) mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
Background Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined.
To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition.
In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.
|
In rhesus macaques, daily subcutaneous injections of tenofovir protects against rectally transmitted simian-human immunodeficiency virus.
The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS) administration. Atm(-/-) mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice. Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment. Atm(-/-) mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment. Markers of reactive oxygen and nitrogen species-mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice. Atm(-/-) mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
Background Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined.
To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition.
In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.
| 0
|
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|
584
|
aug_630
|
Reduced phosphorylation of PP2A suppresses HDAC4 dephosphorylation.
Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely in vitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers. These cells have, therefore, potential for in vitro differentiation studies, gene function, and so on. The aim of this study was to produce a human embryonic stem cell line. An inner cell mass of a human blastocyst was separated and cultured on mouse embryonic fibroblasts in embryonic stem cell medium with related additives. The established line was evaluated by morphology; passaging; freezing and thawing; alkaline phosphatase; Oct-4 expression; anti-surface markers including Tra-1-60 and Tra-1-81; and karyotype and spontaneous differentiation. Differentiated cardiomyocytes and neurons were evaluated by transmission electron microscopy and immunocytochemistry. Here, we report the derivation of a new embryonic stem cell line (Royan H1) from a human blastocyst that remains undifferentiated in morphology during continuous passaging for more than 30 passages, maintains a normal XX karyotype, is viable after freezing and thawing, and expresses alkaline phosphatase, Oct-4, Tra-1-60, and Tra-1-81. These cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers in the presence or absence of recombinant human leukemia inhibitory factor. Royan H1 cells can differentiate in vitro in the absence of feeder cells and can produce embryoid bodies that can further differentiate into beating cardiomyocytes as well as neurons. These results define Royan H1 cells as a new human embryonic stem cell line.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
|
Reduced phosphorylation of PP2A suppresses HDAC4 dephosphorylation.
Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely in vitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers. These cells have, therefore, potential for in vitro differentiation studies, gene function, and so on. The aim of this study was to produce a human embryonic stem cell line. An inner cell mass of a human blastocyst was separated and cultured on mouse embryonic fibroblasts in embryonic stem cell medium with related additives. The established line was evaluated by morphology; passaging; freezing and thawing; alkaline phosphatase; Oct-4 expression; anti-surface markers including Tra-1-60 and Tra-1-81; and karyotype and spontaneous differentiation. Differentiated cardiomyocytes and neurons were evaluated by transmission electron microscopy and immunocytochemistry. Here, we report the derivation of a new embryonic stem cell line (Royan H1) from a human blastocyst that remains undifferentiated in morphology during continuous passaging for more than 30 passages, maintains a normal XX karyotype, is viable after freezing and thawing, and expresses alkaline phosphatase, Oct-4, Tra-1-60, and Tra-1-81. These cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers in the presence or absence of recombinant human leukemia inhibitory factor. Royan H1 cells can differentiate in vitro in the absence of feeder cells and can produce embryoid bodies that can further differentiate into beating cardiomyocytes as well as neurons. These results define Royan H1 cells as a new human embryonic stem cell line.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
| 0.4
|
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|
1027
|
aug_631
|
Tumor development occurs in conjunction with upregulation of pro-inflammatory cytokines.
Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.
|
Tumor development occurs in conjunction with upregulation of pro-inflammatory cytokines.
Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.
| 1
|
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|
1331
|
aug_632
|
In rhesus macaques, daily subcutaneous injections of emtricitabine are ineffective at protecting against rectally transmitted simian-human immunodeficiency virus.
BACKGROUND In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. METHODS AND FINDINGS We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. CONCLUSIONS This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.
|
In rhesus macaques, daily subcutaneous injections of emtricitabine are ineffective at protecting against rectally transmitted simian-human immunodeficiency virus.
BACKGROUND In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. METHODS AND FINDINGS We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. CONCLUSIONS This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.
| 1
|
{
"query_id": "582",
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"context_doc_ids": [
"14260013"
],
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"14260013"
],
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"type": "pathfinderrag_test"
}
|
582
|
aug_633
|
HAND2 methylation is a key step in early endometrial carcinogenesis.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.
|
HAND2 methylation is a key step in early endometrial carcinogenesis.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.
| 0.5
|
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|
488
|
aug_634
|
Antimicrobial agents are more effective due to the pressure of antimicrobial usage.
Overusing antibiotics is not the only cause and reducing use is not the only solution W arning signs of antimicrobial resistance, chinks in the antimicrobial armour, began to appear in the middle of the last century, and by the 1990s various reports had signalled the dangers of excessive or inappropriate use of antibiotics in clinical medicine and of the use of antibiotics in animal feed as growth promoters.1–3 Overuse of antimicrobials emerged as the main culprit, and reducing their use was seen as the answer. But it may not be that simple. The idea that reducing antibiotic use would redress the problem formed part of a positive response on the part of the United Kingdom government to the House of Lords report,1 including a public information campaign, surveillance of resistance along the food chain, targets with respect to hospital acquired infections, and setting up of an overarching advisory body on all aspects of antibiotic use. However, the concept of overuse has proved too simplistic, for, although the evidence of overprescribing as the …
|
Antimicrobial agents are more effective due to the pressure of antimicrobial usage.
Overusing antibiotics is not the only cause and reducing use is not the only solution W arning signs of antimicrobial resistance, chinks in the antimicrobial armour, began to appear in the middle of the last century, and by the 1990s various reports had signalled the dangers of excessive or inappropriate use of antibiotics in clinical medicine and of the use of antibiotics in animal feed as growth promoters.1–3 Overuse of antimicrobials emerged as the main culprit, and reducing their use was seen as the answer. But it may not be that simple. The idea that reducing antibiotic use would redress the problem formed part of a positive response on the part of the United Kingdom government to the House of Lords report,1 including a public information campaign, surveillance of resistance along the food chain, targets with respect to hospital acquired infections, and setting up of an overarching advisory body on all aspects of antibiotic use. However, the concept of overuse has proved too simplistic, for, although the evidence of overprescribing as the …
| 1
|
{
"query_id": "122",
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"31460499"
],
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"31460499"
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}
|
122
|
aug_635
|
Roughly 55% of women with chronic pelvic pain have no underlying pathology.
CONTEXT Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain. OBJECTIVE To assess the effectiveness of LUNA in patients with chronic pelvic pain. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005. Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years. INTERVENTION Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation. MAIN OUTCOME MEASURES The primary outcome was pain, which was assessed by a visual analogue scale. Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS). RESULTS After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). No differences were observed between the LUNA group and the no LUNA group for quality of life. CONCLUSION Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation. TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN41196151.
|
Roughly 55% of women with chronic pelvic pain have no underlying pathology.
CONTEXT Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain. OBJECTIVE To assess the effectiveness of LUNA in patients with chronic pelvic pain. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005. Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years. INTERVENTION Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation. MAIN OUTCOME MEASURES The primary outcome was pain, which was assessed by a visual analogue scale. Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS). RESULTS After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). No differences were observed between the LUNA group and the no LUNA group for quality of life. CONCLUSION Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation. TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN41196151.
| 1
|
{
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"13027590"
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|
1058
|
aug_636
|
Foxp3 represses the expression of transcriptional regulators implicated in memory T cell development.
Blood monocytes are well-characterized precursors for macrophages and dendritic cells. Subsets of human monocytes with differential representation in various disease states are well known. In contrast, mouse monocyte subsets have been characterized minimally. In this study we identify three subpopulations of mouse monocytes that can be distinguished by differential expression of Ly-6C, CD43, CD11c, MBR, and CD62L. The subsets share the characteristics of extensive phagocytosis, similar expression of M-CSF receptor (CD115), and development into macrophages upon M-CSF stimulation. By eliminating blood monocytes with dichloromethylene-bisphosphonate-loaded liposomes and monitoring their repopulation, we showed a developmental relationship between the subsets. Monocytes were maximally depleted 18 h after liposome application and subsequently reappeared in the circulation. These cells were exclusively of the Ly-6C(high) subset, resembling bone marrow monocytes. Serial flow cytometric analyses of newly released Ly-6C(high) monocytes showed that Ly-6C expression on these cells was down-regulated while in circulation. Under inflammatory conditions elicited either by acute infection with Listeria monocytogenes or chronic infection with Leishmania major, there was a significant increase in immature Ly-6C(high) monocytes, resembling the inflammatory left shift of granulocytes. In addition, acute peritoneal inflammation recruited preferentially Ly-6C(med-high) monocytes. Taken together, these data identify distinct subpopulations of mouse blood monocytes that differ in maturation stage and capacity to become recruited to inflammatory sites.
Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA). Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive. Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA. Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos. Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming. Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA. These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation.
Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
|
Foxp3 represses the expression of transcriptional regulators implicated in memory T cell development.
Blood monocytes are well-characterized precursors for macrophages and dendritic cells. Subsets of human monocytes with differential representation in various disease states are well known. In contrast, mouse monocyte subsets have been characterized minimally. In this study we identify three subpopulations of mouse monocytes that can be distinguished by differential expression of Ly-6C, CD43, CD11c, MBR, and CD62L. The subsets share the characteristics of extensive phagocytosis, similar expression of M-CSF receptor (CD115), and development into macrophages upon M-CSF stimulation. By eliminating blood monocytes with dichloromethylene-bisphosphonate-loaded liposomes and monitoring their repopulation, we showed a developmental relationship between the subsets. Monocytes were maximally depleted 18 h after liposome application and subsequently reappeared in the circulation. These cells were exclusively of the Ly-6C(high) subset, resembling bone marrow monocytes. Serial flow cytometric analyses of newly released Ly-6C(high) monocytes showed that Ly-6C expression on these cells was down-regulated while in circulation. Under inflammatory conditions elicited either by acute infection with Listeria monocytogenes or chronic infection with Leishmania major, there was a significant increase in immature Ly-6C(high) monocytes, resembling the inflammatory left shift of granulocytes. In addition, acute peritoneal inflammation recruited preferentially Ly-6C(med-high) monocytes. Taken together, these data identify distinct subpopulations of mouse blood monocytes that differ in maturation stage and capacity to become recruited to inflammatory sites.
Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA). Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive. Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA. Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos. Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming. Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA. These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation.
Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
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435
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aug_637
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Early patent ductus ateriosus (PDA) screening decreases in-hospital mortality.
Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8−/−) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvβ3 integrin– and αvβ5 integrin–dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.
The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.
IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. EXPOSURES Early screening echocardiography before day 3 of life. MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity.
Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain. Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway. Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. (2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors.
In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
OBJECTIVE To evaluate the effects of dietary and lifestyle interventions in pregnancy on maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes. DESIGN Systematic review and meta-analysis. DATA SOURCES Major databases from inception to January 2012 without language restrictions. STUDY SELECTION Randomised controlled trials that evaluated any dietary or lifestyle interventions with potential to influence maternal weight during pregnancy and outcomes of pregnancy. DATA SYNTHESIS Results summarised as relative risks for dichotomous data and mean differences for continuous data. RESULTS We identified 44 relevant randomised controlled trials (7278 women) evaluating three categories of interventions: diet, physical activity, and a mixed approach. Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to 1.89 kg) in gestational weight gain with any intervention compared with control. With all interventions combined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) and the incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age (1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated with reduced birth weight (mean difference -60 g, -120 to -10 g). Interventions were associated with a reduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), with no significant effect on other critically important outcomes. Dietary intervention resulted in the largest reduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancy outcomes compared with other interventions. The overall evidence rating was low to very low for important outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and preterm delivery. CONCLUSIONS Dietary and lifestyle interventions in pregnancy can reduce maternal gestational weight gain and improve outcomes for both mother and baby. Among the interventions, those based on diet are the most effective and are associated with reductions in maternal gestational weight gain and improved obstetric outcomes.
|
Early patent ductus ateriosus (PDA) screening decreases in-hospital mortality.
Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8−/−) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvβ3 integrin– and αvβ5 integrin–dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.
The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.
IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. EXPOSURES Early screening echocardiography before day 3 of life. MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity.
Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain. Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway. Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. (2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors.
In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
OBJECTIVE To evaluate the effects of dietary and lifestyle interventions in pregnancy on maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes. DESIGN Systematic review and meta-analysis. DATA SOURCES Major databases from inception to January 2012 without language restrictions. STUDY SELECTION Randomised controlled trials that evaluated any dietary or lifestyle interventions with potential to influence maternal weight during pregnancy and outcomes of pregnancy. DATA SYNTHESIS Results summarised as relative risks for dichotomous data and mean differences for continuous data. RESULTS We identified 44 relevant randomised controlled trials (7278 women) evaluating three categories of interventions: diet, physical activity, and a mixed approach. Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to 1.89 kg) in gestational weight gain with any intervention compared with control. With all interventions combined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) and the incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age (1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated with reduced birth weight (mean difference -60 g, -120 to -10 g). Interventions were associated with a reduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), with no significant effect on other critically important outcomes. Dietary intervention resulted in the largest reduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancy outcomes compared with other interventions. The overall evidence rating was low to very low for important outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and preterm delivery. CONCLUSIONS Dietary and lifestyle interventions in pregnancy can reduce maternal gestational weight gain and improve outcomes for both mother and baby. Among the interventions, those based on diet are the most effective and are associated with reductions in maternal gestational weight gain and improved obstetric outcomes.
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aug_638
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Foxp3 represses the expression of transcriptional regulators implicated in memory T cell development.
Blood monocytes are well-characterized precursors for macrophages and dendritic cells. Subsets of human monocytes with differential representation in various disease states are well known. In contrast, mouse monocyte subsets have been characterized minimally. In this study we identify three subpopulations of mouse monocytes that can be distinguished by differential expression of Ly-6C, CD43, CD11c, MBR, and CD62L. The subsets share the characteristics of extensive phagocytosis, similar expression of M-CSF receptor (CD115), and development into macrophages upon M-CSF stimulation. By eliminating blood monocytes with dichloromethylene-bisphosphonate-loaded liposomes and monitoring their repopulation, we showed a developmental relationship between the subsets. Monocytes were maximally depleted 18 h after liposome application and subsequently reappeared in the circulation. These cells were exclusively of the Ly-6C(high) subset, resembling bone marrow monocytes. Serial flow cytometric analyses of newly released Ly-6C(high) monocytes showed that Ly-6C expression on these cells was down-regulated while in circulation. Under inflammatory conditions elicited either by acute infection with Listeria monocytogenes or chronic infection with Leishmania major, there was a significant increase in immature Ly-6C(high) monocytes, resembling the inflammatory left shift of granulocytes. In addition, acute peritoneal inflammation recruited preferentially Ly-6C(med-high) monocytes. Taken together, these data identify distinct subpopulations of mouse blood monocytes that differ in maturation stage and capacity to become recruited to inflammatory sites.
Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA). Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive. Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA. Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos. Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming. Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA. These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation.
Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
|
Foxp3 represses the expression of transcriptional regulators implicated in memory T cell development.
Blood monocytes are well-characterized precursors for macrophages and dendritic cells. Subsets of human monocytes with differential representation in various disease states are well known. In contrast, mouse monocyte subsets have been characterized minimally. In this study we identify three subpopulations of mouse monocytes that can be distinguished by differential expression of Ly-6C, CD43, CD11c, MBR, and CD62L. The subsets share the characteristics of extensive phagocytosis, similar expression of M-CSF receptor (CD115), and development into macrophages upon M-CSF stimulation. By eliminating blood monocytes with dichloromethylene-bisphosphonate-loaded liposomes and monitoring their repopulation, we showed a developmental relationship between the subsets. Monocytes were maximally depleted 18 h after liposome application and subsequently reappeared in the circulation. These cells were exclusively of the Ly-6C(high) subset, resembling bone marrow monocytes. Serial flow cytometric analyses of newly released Ly-6C(high) monocytes showed that Ly-6C expression on these cells was down-regulated while in circulation. Under inflammatory conditions elicited either by acute infection with Listeria monocytogenes or chronic infection with Leishmania major, there was a significant increase in immature Ly-6C(high) monocytes, resembling the inflammatory left shift of granulocytes. In addition, acute peritoneal inflammation recruited preferentially Ly-6C(med-high) monocytes. Taken together, these data identify distinct subpopulations of mouse blood monocytes that differ in maturation stage and capacity to become recruited to inflammatory sites.
Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA). Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive. Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA. Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos. Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming. Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA. These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation.
Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
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435
|
aug_639
|
Reduced phosphorylation of PP2A suppresses HDAC4 dephosphorylation.
Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely in vitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers. These cells have, therefore, potential for in vitro differentiation studies, gene function, and so on. The aim of this study was to produce a human embryonic stem cell line. An inner cell mass of a human blastocyst was separated and cultured on mouse embryonic fibroblasts in embryonic stem cell medium with related additives. The established line was evaluated by morphology; passaging; freezing and thawing; alkaline phosphatase; Oct-4 expression; anti-surface markers including Tra-1-60 and Tra-1-81; and karyotype and spontaneous differentiation. Differentiated cardiomyocytes and neurons were evaluated by transmission electron microscopy and immunocytochemistry. Here, we report the derivation of a new embryonic stem cell line (Royan H1) from a human blastocyst that remains undifferentiated in morphology during continuous passaging for more than 30 passages, maintains a normal XX karyotype, is viable after freezing and thawing, and expresses alkaline phosphatase, Oct-4, Tra-1-60, and Tra-1-81. These cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers in the presence or absence of recombinant human leukemia inhibitory factor. Royan H1 cells can differentiate in vitro in the absence of feeder cells and can produce embryoid bodies that can further differentiate into beating cardiomyocytes as well as neurons. These results define Royan H1 cells as a new human embryonic stem cell line.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
|
Reduced phosphorylation of PP2A suppresses HDAC4 dephosphorylation.
Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely in vitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers. These cells have, therefore, potential for in vitro differentiation studies, gene function, and so on. The aim of this study was to produce a human embryonic stem cell line. An inner cell mass of a human blastocyst was separated and cultured on mouse embryonic fibroblasts in embryonic stem cell medium with related additives. The established line was evaluated by morphology; passaging; freezing and thawing; alkaline phosphatase; Oct-4 expression; anti-surface markers including Tra-1-60 and Tra-1-81; and karyotype and spontaneous differentiation. Differentiated cardiomyocytes and neurons were evaluated by transmission electron microscopy and immunocytochemistry. Here, we report the derivation of a new embryonic stem cell line (Royan H1) from a human blastocyst that remains undifferentiated in morphology during continuous passaging for more than 30 passages, maintains a normal XX karyotype, is viable after freezing and thawing, and expresses alkaline phosphatase, Oct-4, Tra-1-60, and Tra-1-81. These cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers in the presence or absence of recombinant human leukemia inhibitory factor. Royan H1 cells can differentiate in vitro in the absence of feeder cells and can produce embryoid bodies that can further differentiate into beating cardiomyocytes as well as neurons. These results define Royan H1 cells as a new human embryonic stem cell line.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
| 0.4
|
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|
1027
|
aug_640
|
The NF-κB essential modulator gene prevents intestinal inflammation by inhibiting receptor-interacting protein (RIP) kinase 1 kinase activity-mediated epithelial cell death.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
|
The NF-κB essential modulator gene prevents intestinal inflammation by inhibiting receptor-interacting protein (RIP) kinase 1 kinase activity-mediated epithelial cell death.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
| 1
|
{
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|
1171
|
aug_641
|
DUSP4 downregulation deactivates the Ras-ERK pathway
BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is a long-standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouse epiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast. We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2.
Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.
CONTEXT Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. OBJECTIVE To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). MAIN OUTCOME MEASURE Serum intact PTH as determined by calcium intake and vitamin D. RESULTS A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). CONCLUSIONS As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates.
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.
|
DUSP4 downregulation deactivates the Ras-ERK pathway
BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is a long-standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouse epiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast. We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2.
Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.
CONTEXT Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. OBJECTIVE To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). MAIN OUTCOME MEASURE Serum intact PTH as determined by calcium intake and vitamin D. RESULTS A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). CONCLUSIONS As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates.
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.
| 0.4
|
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|
308
|
aug_642
|
The US health care system can save up to $5 billion if 7% of patients waiting for kidney transplants participate in the optimized national kidney paired donation program.
CONTEXT Blood type and crossmatch incompatibility will exclude at least one third of patients in need from receiving a live donor kidney transplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity to match for compatible transplants. Despite its increasing popularity, very few transplants have resulted from KPD. OBJECTIVE To determine the potential impact of improved matching schemes on the number and quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION We developed a model that simulates pools of incompatible donor/recipient pairs. We designed a mathematically verifiable optimized matching algorithm and compared it with the scheme currently used in some centers and regions. Simulated patients from the general community with characteristics drawn from distributions describing end-stage renal disease patients eligible for renal transplantation and their willing and eligible live donors. MAIN OUTCOME MEASURES Number of kidneys matched, HLA mismatch of matched kidneys, and number of grafts surviving 5 years after transplantation. RESULTS A national optimized matching algorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs 4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and a reduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with an extension of the currently used first-accept scheme to a national level. Furthermore, highly sensitized patients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched; P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized national KPD program, the health care system could save as much as $750 million. CONCLUSIONS The combination of a national KPD program and a mathematically optimized matching algorithm yields more matches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing their matching priorities and the security of knowing that the greatest number of high-quality matches will be found and distributed equitably.
IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase.
|
The US health care system can save up to $5 billion if 7% of patients waiting for kidney transplants participate in the optimized national kidney paired donation program.
CONTEXT Blood type and crossmatch incompatibility will exclude at least one third of patients in need from receiving a live donor kidney transplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity to match for compatible transplants. Despite its increasing popularity, very few transplants have resulted from KPD. OBJECTIVE To determine the potential impact of improved matching schemes on the number and quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION We developed a model that simulates pools of incompatible donor/recipient pairs. We designed a mathematically verifiable optimized matching algorithm and compared it with the scheme currently used in some centers and regions. Simulated patients from the general community with characteristics drawn from distributions describing end-stage renal disease patients eligible for renal transplantation and their willing and eligible live donors. MAIN OUTCOME MEASURES Number of kidneys matched, HLA mismatch of matched kidneys, and number of grafts surviving 5 years after transplantation. RESULTS A national optimized matching algorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs 4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and a reduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with an extension of the currently used first-accept scheme to a national level. Furthermore, highly sensitized patients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched; P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized national KPD program, the health care system could save as much as $750 million. CONCLUSIONS The combination of a national KPD program and a mathematically optimized matching algorithm yields more matches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing their matching priorities and the security of knowing that the greatest number of high-quality matches will be found and distributed equitably.
IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase.
| 0.4
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|
1184
|
aug_643
|
The US health care system can save up to $5 billion if 7% of patients waiting for kidney transplants participate in the optimized national kidney paired donation program.
CONTEXT Blood type and crossmatch incompatibility will exclude at least one third of patients in need from receiving a live donor kidney transplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity to match for compatible transplants. Despite its increasing popularity, very few transplants have resulted from KPD. OBJECTIVE To determine the potential impact of improved matching schemes on the number and quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION We developed a model that simulates pools of incompatible donor/recipient pairs. We designed a mathematically verifiable optimized matching algorithm and compared it with the scheme currently used in some centers and regions. Simulated patients from the general community with characteristics drawn from distributions describing end-stage renal disease patients eligible for renal transplantation and their willing and eligible live donors. MAIN OUTCOME MEASURES Number of kidneys matched, HLA mismatch of matched kidneys, and number of grafts surviving 5 years after transplantation. RESULTS A national optimized matching algorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs 4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and a reduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with an extension of the currently used first-accept scheme to a national level. Furthermore, highly sensitized patients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched; P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized national KPD program, the health care system could save as much as $750 million. CONCLUSIONS The combination of a national KPD program and a mathematically optimized matching algorithm yields more matches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing their matching priorities and the security of knowing that the greatest number of high-quality matches will be found and distributed equitably.
IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase.
|
The US health care system can save up to $5 billion if 7% of patients waiting for kidney transplants participate in the optimized national kidney paired donation program.
CONTEXT Blood type and crossmatch incompatibility will exclude at least one third of patients in need from receiving a live donor kidney transplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity to match for compatible transplants. Despite its increasing popularity, very few transplants have resulted from KPD. OBJECTIVE To determine the potential impact of improved matching schemes on the number and quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION We developed a model that simulates pools of incompatible donor/recipient pairs. We designed a mathematically verifiable optimized matching algorithm and compared it with the scheme currently used in some centers and regions. Simulated patients from the general community with characteristics drawn from distributions describing end-stage renal disease patients eligible for renal transplantation and their willing and eligible live donors. MAIN OUTCOME MEASURES Number of kidneys matched, HLA mismatch of matched kidneys, and number of grafts surviving 5 years after transplantation. RESULTS A national optimized matching algorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs 4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and a reduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with an extension of the currently used first-accept scheme to a national level. Furthermore, highly sensitized patients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched; P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized national KPD program, the health care system could save as much as $750 million. CONCLUSIONS The combination of a national KPD program and a mathematically optimized matching algorithm yields more matches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing their matching priorities and the security of knowing that the greatest number of high-quality matches will be found and distributed equitably.
IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase.
| 0.4
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|
1184
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aug_644
|
Myelin sheaths are lipid-rich cellular structures.
We report a newly developed technique for high-resolution in vivo imaging of myelinated axons in the brain, spinal cord and peripheral nerve that requires no fluorescent labeling. This method, based on spectral confocal reflectance microscopy (SCoRe), uses a conventional laser-scanning confocal system to generate images by merging the simultaneously reflected signals from multiple lasers of different wavelengths. Striking color patterns unique to individual myelinated fibers are generated that facilitate their tracing in dense axonal areas. These patterns highlight nodes of Ranvier and Schmidt-Lanterman incisures and can be used to detect various myelin pathologies. Using SCoRe we carried out chronic brain imaging up to 400 μm deep, capturing de novo myelination of mouse cortical axons in vivo. We also established the feasibility of imaging myelinated axons in the human cerebral cortex. SCoRe adds a powerful component to the evolving toolbox for imaging myelination in living animals and potentially in humans.
CONTEXT Pharmacist review of medication orders in the intensive care unit (ICU) has been shown to prevent errors, and pharmacist consultation has reduced drug costs. However, whether pharmacist participation in the ICU at the time of drug prescribing reduces adverse events has not been studied. OBJECTIVE To measure the effect of pharmacist participation on medical rounds in the ICU on the rate of preventable adverse drug events (ADEs) caused by ordering errors. DESIGN Before-after comparison between phase 1 (baseline) and phase 2 (after intervention implemented) and phase 2 comparison with a control unit that did not receive the intervention. SETTING A medical ICU (study unit) and a coronary care unit (control unit) in a large urban teaching hospital. PATIENTS Seventy-five patients randomly selected from each of 3 groups: all admissions to the study unit from February 1, 1993, through July 31, 1993 (baseline) and all admissions to the study unit (postintervention) and control unit from October 1, 1994, through July 7, 1995. In addition, 50 patients were selected at random from the control unit during the baseline period. INTERVENTION A senior pharmacist made rounds with the ICU team and remained in the ICU for consultation in the morning, and was available on call throughout the day. MAIN OUTCOME MEASURES Preventable ADEs due to ordering (prescribing) errors and the number, type, and acceptance of interventions made by the pharmacist. Preventable ADEs were identified by review of medical records of the randomly selected patients during both preintervention and postintervention phases. Pharmacists recorded all recommendations, which were then analyzed by type and acceptance. RESULTS The rate of preventable ordering ADEs decreased by 66% from 10.4 per 1000 patient-days (95% confidence interval [CI], 7-14) before the intervention to 3.5 (95% CI, 1-5; P<.001) after the intervention. In the control unit, the rate was essentially unchanged during the same time periods: 10.9 (95% CI, 6-16) and 12.4 (95% CI, 8-17) per 1000 patient-days. The pharmacist made 366 recommendations related to drug ordering, of which 362 (99%) were accepted by physicians. CONCLUSIONS The presence of a pharmacist on rounds as a full member of the patient care team in a medical ICU was associated with a substantially lower rate of ADEs caused by prescribing errors. Nearly all the changes were readily accepted by physicians.
OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials, SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.
The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
BACKGROUND Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).
Embryos have the ability to self-regulate and regenerate normal structures after being sectioned in half. How is such a morphogenetic field established? We discovered that quadruple knockdown of ADMP and BMP2/4/7 in Xenopus embryos eliminates self-regulation, causing ubiquitous neural induction throughout the ectoderm. ADMP transcription in the Spemann organizer is activated at low BMP levels. When ventral BMP2/4/7 signals are depleted, Admp expression increases, allowing for self-regulation. ADMP has BMP-like activity and signals via the ALK-2 receptor. It is unable to signal dorsally because of inhibition by Chordin. The ventral BMP antagonists Sizzled and Bambi further refine the pattern. By transplanting dorsal or ventral wild-type grafts into ADMP/BMP2/4/7-depleted hosts, we demonstrate that both poles serve as signaling centers that can induce histotypic differentiation over considerable distances. We conclude that dorsal and ventral BMP signals and their extracellular antagonists expressed under opposing transcriptional regulation provide a molecular mechanism for embryonic self-regulation.
|
Myelin sheaths are lipid-rich cellular structures.
We report a newly developed technique for high-resolution in vivo imaging of myelinated axons in the brain, spinal cord and peripheral nerve that requires no fluorescent labeling. This method, based on spectral confocal reflectance microscopy (SCoRe), uses a conventional laser-scanning confocal system to generate images by merging the simultaneously reflected signals from multiple lasers of different wavelengths. Striking color patterns unique to individual myelinated fibers are generated that facilitate their tracing in dense axonal areas. These patterns highlight nodes of Ranvier and Schmidt-Lanterman incisures and can be used to detect various myelin pathologies. Using SCoRe we carried out chronic brain imaging up to 400 μm deep, capturing de novo myelination of mouse cortical axons in vivo. We also established the feasibility of imaging myelinated axons in the human cerebral cortex. SCoRe adds a powerful component to the evolving toolbox for imaging myelination in living animals and potentially in humans.
CONTEXT Pharmacist review of medication orders in the intensive care unit (ICU) has been shown to prevent errors, and pharmacist consultation has reduced drug costs. However, whether pharmacist participation in the ICU at the time of drug prescribing reduces adverse events has not been studied. OBJECTIVE To measure the effect of pharmacist participation on medical rounds in the ICU on the rate of preventable adverse drug events (ADEs) caused by ordering errors. DESIGN Before-after comparison between phase 1 (baseline) and phase 2 (after intervention implemented) and phase 2 comparison with a control unit that did not receive the intervention. SETTING A medical ICU (study unit) and a coronary care unit (control unit) in a large urban teaching hospital. PATIENTS Seventy-five patients randomly selected from each of 3 groups: all admissions to the study unit from February 1, 1993, through July 31, 1993 (baseline) and all admissions to the study unit (postintervention) and control unit from October 1, 1994, through July 7, 1995. In addition, 50 patients were selected at random from the control unit during the baseline period. INTERVENTION A senior pharmacist made rounds with the ICU team and remained in the ICU for consultation in the morning, and was available on call throughout the day. MAIN OUTCOME MEASURES Preventable ADEs due to ordering (prescribing) errors and the number, type, and acceptance of interventions made by the pharmacist. Preventable ADEs were identified by review of medical records of the randomly selected patients during both preintervention and postintervention phases. Pharmacists recorded all recommendations, which were then analyzed by type and acceptance. RESULTS The rate of preventable ordering ADEs decreased by 66% from 10.4 per 1000 patient-days (95% confidence interval [CI], 7-14) before the intervention to 3.5 (95% CI, 1-5; P<.001) after the intervention. In the control unit, the rate was essentially unchanged during the same time periods: 10.9 (95% CI, 6-16) and 12.4 (95% CI, 8-17) per 1000 patient-days. The pharmacist made 366 recommendations related to drug ordering, of which 362 (99%) were accepted by physicians. CONCLUSIONS The presence of a pharmacist on rounds as a full member of the patient care team in a medical ICU was associated with a substantially lower rate of ADEs caused by prescribing errors. Nearly all the changes were readily accepted by physicians.
OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials, SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.
The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
BACKGROUND Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown. METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated. RESULTS At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy. CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).
Embryos have the ability to self-regulate and regenerate normal structures after being sectioned in half. How is such a morphogenetic field established? We discovered that quadruple knockdown of ADMP and BMP2/4/7 in Xenopus embryos eliminates self-regulation, causing ubiquitous neural induction throughout the ectoderm. ADMP transcription in the Spemann organizer is activated at low BMP levels. When ventral BMP2/4/7 signals are depleted, Admp expression increases, allowing for self-regulation. ADMP has BMP-like activity and signals via the ALK-2 receptor. It is unable to signal dorsally because of inhibition by Chordin. The ventral BMP antagonists Sizzled and Bambi further refine the pattern. By transplanting dorsal or ventral wild-type grafts into ADMP/BMP2/4/7-depleted hosts, we demonstrate that both poles serve as signaling centers that can induce histotypic differentiation over considerable distances. We conclude that dorsal and ventral BMP signals and their extracellular antagonists expressed under opposing transcriptional regulation provide a molecular mechanism for embryonic self-regulation.
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In pediatric tissue, most T cells are naive T cell emigrants from the thymus.
Dynamically polarized membrane proteins define different cell boundaries and have an important role in intercellular communication—a vital feature of multicellular development. Efflux carriers for the signalling molecule auxin from the PIN family are landmarks of cell polarity in plants and have a crucial involvement in auxin distribution-dependent development including embryo patterning, organogenesis and tropisms. Polar PIN localization determines the direction of intercellular auxin flow, yet the mechanisms generating PIN polarity remain unclear. Here we identify an endocytosis-dependent mechanism of PIN polarity generation and analyse its developmental implications. Real-time PIN tracking showed that after synthesis, PINs are initially delivered to the plasma membrane in a non-polar manner and their polarity is established by subsequent endocytic recycling. Interference with PIN endocytosis either by auxin or by manipulation of the Arabidopsis Rab5 GTPase pathway prevents PIN polarization. Failure of PIN polarization transiently alters asymmetric auxin distribution during embryogenesis and increases the local auxin response in apical embryo regions. This results in ectopic expression of auxin pathway-associated root-forming master regulators in embryonic leaves and promotes homeotic transformation of leaves to roots. Our results indicate a two-step mechanism for the generation of PIN polar localization and the essential role of endocytosis in this process. It also highlights the link between endocytosis-dependent polarity of individual cells and auxin distribution-dependent cell fate establishment for multicellular patterning.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Burns are one of the most devastating conditions encountered in medicine. The injury represents an assault on all aspects of the patient, from the physical to the psychological. It affects all ages, from babies to elderly people, and is a problem in both the developed and developing world. All of us have experienced the severe pain that even a small burn can bring. However the pain and distress caused by a large burn are not limited to the immediate event. The visible physical and the invisible psychological scars are long lasting and often lead to chronic disability. Burn injuries represent a diverse and varied challenge to medical and paramedical staff. Correct management requires a skilled multidisciplinary approach that addresses all the problems facing a burn patient. This series provides an overview of the most important aspects of burn injuries for hospital and non-hospital healthcare workers.workers. Figure 1 Top: Child with 70% full thickness burns, which required resuscitation, intensive care support, and extensive debridement and skin grafting. Left: The same child one year later at a burns camp, having made a good recovery. A reasonable outcome is possible ...
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.
|
In pediatric tissue, most T cells are naive T cell emigrants from the thymus.
Dynamically polarized membrane proteins define different cell boundaries and have an important role in intercellular communication—a vital feature of multicellular development. Efflux carriers for the signalling molecule auxin from the PIN family are landmarks of cell polarity in plants and have a crucial involvement in auxin distribution-dependent development including embryo patterning, organogenesis and tropisms. Polar PIN localization determines the direction of intercellular auxin flow, yet the mechanisms generating PIN polarity remain unclear. Here we identify an endocytosis-dependent mechanism of PIN polarity generation and analyse its developmental implications. Real-time PIN tracking showed that after synthesis, PINs are initially delivered to the plasma membrane in a non-polar manner and their polarity is established by subsequent endocytic recycling. Interference with PIN endocytosis either by auxin or by manipulation of the Arabidopsis Rab5 GTPase pathway prevents PIN polarization. Failure of PIN polarization transiently alters asymmetric auxin distribution during embryogenesis and increases the local auxin response in apical embryo regions. This results in ectopic expression of auxin pathway-associated root-forming master regulators in embryonic leaves and promotes homeotic transformation of leaves to roots. Our results indicate a two-step mechanism for the generation of PIN polar localization and the essential role of endocytosis in this process. It also highlights the link between endocytosis-dependent polarity of individual cells and auxin distribution-dependent cell fate establishment for multicellular patterning.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Burns are one of the most devastating conditions encountered in medicine. The injury represents an assault on all aspects of the patient, from the physical to the psychological. It affects all ages, from babies to elderly people, and is a problem in both the developed and developing world. All of us have experienced the severe pain that even a small burn can bring. However the pain and distress caused by a large burn are not limited to the immediate event. The visible physical and the invisible psychological scars are long lasting and often lead to chronic disability. Burn injuries represent a diverse and varied challenge to medical and paramedical staff. Correct management requires a skilled multidisciplinary approach that addresses all the problems facing a burn patient. This series provides an overview of the most important aspects of burn injuries for hospital and non-hospital healthcare workers.workers. Figure 1 Top: Child with 70% full thickness burns, which required resuscitation, intensive care support, and extensive debridement and skin grafting. Left: The same child one year later at a burns camp, having made a good recovery. A reasonable outcome is possible ...
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.
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580
|
aug_646
|
Exhaustion of B cells contributes to poor Ab response in HIV-infected individuals.
The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses. The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to make recommendations that Enterprise stakeholders can use to plan new activities. Most effective viral vaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus, and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potent antiviral neutralizing antibodies. However, unlike acute viral pathogens, HIV-1 chronically replicates in the host and evades the antibody response. This immune evasion, along with the large genetic variation among HIV-1 strains worldwide, has posed major obstacles to vaccine development. Current HIV vaccine candidates do not elicit neutralizing antibodies against most circulating virus strains, and thus the induction of a protective antibody response remains a major priority for HIV-1 vaccine development. For an antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays that measure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolates representing the major genetic subtypes (clades) of HIV-1 [2]. Although it is not known what magnitude and breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccine immunogens elicit antibodies that neutralize only a minority of circulating isolates. Thus, much progress needs to be made in this area. Also, though virus neutralization is considered a critical benchmark for a vaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccine immunogens. The main targets for neutralizing antibodies to HIV-1 are the surface gp120 and trans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding and the subsequent membrane fusion events that allow the virus to gain entry into cells [3]. Antibodies neutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such as CD4+ T cells [4,5]. In order to chronically replicate in the host, the virus exploits several mechanisms to shield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linked glycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8]. These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitness constraints. Information on the precise location and molecular structure of these vulnerable regions could be valuable for the rational design of improved vaccine immunogens. Participants in the workshop identified four areas that, if given proper attention, could provide key information that would bring the field closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2) role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulation of B cell responses.
|
Exhaustion of B cells contributes to poor Ab response in HIV-infected individuals.
The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses. The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to make recommendations that Enterprise stakeholders can use to plan new activities. Most effective viral vaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus, and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potent antiviral neutralizing antibodies. However, unlike acute viral pathogens, HIV-1 chronically replicates in the host and evades the antibody response. This immune evasion, along with the large genetic variation among HIV-1 strains worldwide, has posed major obstacles to vaccine development. Current HIV vaccine candidates do not elicit neutralizing antibodies against most circulating virus strains, and thus the induction of a protective antibody response remains a major priority for HIV-1 vaccine development. For an antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays that measure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolates representing the major genetic subtypes (clades) of HIV-1 [2]. Although it is not known what magnitude and breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccine immunogens elicit antibodies that neutralize only a minority of circulating isolates. Thus, much progress needs to be made in this area. Also, though virus neutralization is considered a critical benchmark for a vaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccine immunogens. The main targets for neutralizing antibodies to HIV-1 are the surface gp120 and trans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding and the subsequent membrane fusion events that allow the virus to gain entry into cells [3]. Antibodies neutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such as CD4+ T cells [4,5]. In order to chronically replicate in the host, the virus exploits several mechanisms to shield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linked glycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8]. These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitness constraints. Information on the precise location and molecular structure of these vulnerable regions could be valuable for the rational design of improved vaccine immunogens. Participants in the workshop identified four areas that, if given proper attention, could provide key information that would bring the field closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2) role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulation of B cell responses.
| 1
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|
398
|
aug_647
|
Mice that lack Interferon-γ or its receptor are highly susceptible to experimental autoimmune myocarditis.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair.
|
Mice that lack Interferon-γ or its receptor are highly susceptible to experimental autoimmune myocarditis.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair.
| 0.4
|
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|
780
|
aug_648
|
Algerian physicians constitue the largest component of sub-Saharan Africa-trained physicians in the United States.
CONTEXT Bioterrorist attacks involving letters and mail-handling systems in Washington, DC, resulted in Bacillus anthracis (anthrax) spore contamination in the Hart Senate Office Building and other facilities in the US Capitol's vicinity. OBJECTIVE To provide information about the nature and extent of indoor secondary aerosolization of B anthracis spores. DESIGN Stationary and personal air samples, surface dust, and swab samples were collected under semiquiescent (minimal activities) and then simulated active office conditions to estimate secondary aerosolization of B anthracis spores. Nominal size characteristics, airborne concentrations, and surface contamination of B anthracis particles (colony-forming units) were evaluated. RESULTS Viable B anthracis spores reaerosolized under semiquiescent conditions, with a marked increase in reaerosolization during simulated active office conditions. Increases were observed for B anthracis collected on open sheep blood agar plates (P<.001) and personal air monitors (P =.01) during active office conditions. More than 80% of the B anthracis particles collected on stationary monitors were within an alveolar respirable size range of 0.95 to 3.5 micro m. CONCLUSIONS Bacillus anthracis spores used in a recent terrorist incident reaerosolized under common office activities. These findings have important implications for appropriate respiratory protection, remediation, and reoccupancy of contaminated office environments.
RNA processing is carried out in close proximity to the site of transcription, suggesting a regulatory link between transcription and pre-mRNA splicing. Using an in vitro transcription/splicing assay, we demonstrate that an association of RNA polymerase II (Pol II) transcription and pre-mRNA splicing is required for efficient gene expression. Pol II-synthesized RNAs containing functional splice sites are protected from nuclear degradation, presumably because the local concentration of the splicing machinery is sufficiently high to ensure its association over interactions with nucleases. Furthermore, the process of transcription influences alternative splicing of newly synthesized pre-mRNAs. Because other RNA polymerases do not provide similar protection from nucleases, and their RNA products display altered splicing patterns, the link between transcription and RNA processing is RNA Pol II-specific. We propose that the connection between transcription by Pol II and pre-mRNA splicing guarantees an extended half-life and proper processing of nascent pre-mRNAs.
BACKGROUND The large-scale emigration of physicians from sub-Saharan Africa (SSA) to high-income nations is a serious development concern. Our objective was to determine current emigration trends of SSA physicians found in the physician workforce of the United States. METHODS AND FINDINGS We analyzed physician data from the World Health Organization (WHO) Global Health Workforce Statistics along with graduation and residency data from the 2011 American Medical Association Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currently practice in the US. We estimated emigration proportions, year of US entry, years of practice before emigration, and length of time in the US. According to the 2011 AMA-PM, 10,819 physicians were born or trained in 28 SSA countries. Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) were US-trained, and 12% (n = 1,323) were trained outside both SSA and the US. We estimated active physicians (age ≤ 70 years) to represent 96% (n = 10,377) of the total. Migration trends among SSA-trained physicians increased from 2002 to 2011 for all but one principal source country; the exception was South Africa whose physician migration to the US decreased by 8% (-156). The increase in last-decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and >200% (+244) in Sudan. Liberia was the most affected by migration to the US with 77% (n = 175) of its estimated physicians in the 2011 AMA-PM. On average, SSA-trained physicians have been in the US for 18 years. They practiced for 6.5 years before US entry, and nearly half emigrated during the implementation years (1984-1999) of the structural adjustment programs. CONCLUSION Physician emigration from SSA to the US is increasing for most SSA source countries. Unless far-reaching policies are implemented by the US and SSA countries, the current emigration trends will persist, and the US will remain a leading destination for SSA physicians emigrating from the continent of greatest need. Please see later in the article for the Editors' Summary.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown. METHODS AND RESULTS In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01). CONCLUSIONS These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.
CONTEXT Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. OBJECTIVE To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). INTERVENTIONS Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. MAIN OUTCOME MEASURES The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. RESULTS There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). CONCLUSIONS These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00052026.
|
Algerian physicians constitue the largest component of sub-Saharan Africa-trained physicians in the United States.
CONTEXT Bioterrorist attacks involving letters and mail-handling systems in Washington, DC, resulted in Bacillus anthracis (anthrax) spore contamination in the Hart Senate Office Building and other facilities in the US Capitol's vicinity. OBJECTIVE To provide information about the nature and extent of indoor secondary aerosolization of B anthracis spores. DESIGN Stationary and personal air samples, surface dust, and swab samples were collected under semiquiescent (minimal activities) and then simulated active office conditions to estimate secondary aerosolization of B anthracis spores. Nominal size characteristics, airborne concentrations, and surface contamination of B anthracis particles (colony-forming units) were evaluated. RESULTS Viable B anthracis spores reaerosolized under semiquiescent conditions, with a marked increase in reaerosolization during simulated active office conditions. Increases were observed for B anthracis collected on open sheep blood agar plates (P<.001) and personal air monitors (P =.01) during active office conditions. More than 80% of the B anthracis particles collected on stationary monitors were within an alveolar respirable size range of 0.95 to 3.5 micro m. CONCLUSIONS Bacillus anthracis spores used in a recent terrorist incident reaerosolized under common office activities. These findings have important implications for appropriate respiratory protection, remediation, and reoccupancy of contaminated office environments.
RNA processing is carried out in close proximity to the site of transcription, suggesting a regulatory link between transcription and pre-mRNA splicing. Using an in vitro transcription/splicing assay, we demonstrate that an association of RNA polymerase II (Pol II) transcription and pre-mRNA splicing is required for efficient gene expression. Pol II-synthesized RNAs containing functional splice sites are protected from nuclear degradation, presumably because the local concentration of the splicing machinery is sufficiently high to ensure its association over interactions with nucleases. Furthermore, the process of transcription influences alternative splicing of newly synthesized pre-mRNAs. Because other RNA polymerases do not provide similar protection from nucleases, and their RNA products display altered splicing patterns, the link between transcription and RNA processing is RNA Pol II-specific. We propose that the connection between transcription by Pol II and pre-mRNA splicing guarantees an extended half-life and proper processing of nascent pre-mRNAs.
BACKGROUND The large-scale emigration of physicians from sub-Saharan Africa (SSA) to high-income nations is a serious development concern. Our objective was to determine current emigration trends of SSA physicians found in the physician workforce of the United States. METHODS AND FINDINGS We analyzed physician data from the World Health Organization (WHO) Global Health Workforce Statistics along with graduation and residency data from the 2011 American Medical Association Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currently practice in the US. We estimated emigration proportions, year of US entry, years of practice before emigration, and length of time in the US. According to the 2011 AMA-PM, 10,819 physicians were born or trained in 28 SSA countries. Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) were US-trained, and 12% (n = 1,323) were trained outside both SSA and the US. We estimated active physicians (age ≤ 70 years) to represent 96% (n = 10,377) of the total. Migration trends among SSA-trained physicians increased from 2002 to 2011 for all but one principal source country; the exception was South Africa whose physician migration to the US decreased by 8% (-156). The increase in last-decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and >200% (+244) in Sudan. Liberia was the most affected by migration to the US with 77% (n = 175) of its estimated physicians in the 2011 AMA-PM. On average, SSA-trained physicians have been in the US for 18 years. They practiced for 6.5 years before US entry, and nearly half emigrated during the implementation years (1984-1999) of the structural adjustment programs. CONCLUSION Physician emigration from SSA to the US is increasing for most SSA source countries. Unless far-reaching policies are implemented by the US and SSA countries, the current emigration trends will persist, and the US will remain a leading destination for SSA physicians emigrating from the continent of greatest need. Please see later in the article for the Editors' Summary.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown. METHODS AND RESULTS In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01). CONCLUSIONS These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.
CONTEXT Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. OBJECTIVE To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). INTERVENTIONS Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. MAIN OUTCOME MEASURES The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. RESULTS There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). CONCLUSIONS These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00052026.
| 0.285714
|
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|
96
|
aug_649
|
Aggravated inflammation is dependent on NLRP3 inflammasome activation.
Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a ‘danger signal’ released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1β activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1β receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.
|
Aggravated inflammation is dependent on NLRP3 inflammasome activation.
Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a ‘danger signal’ released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1β activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1β receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.
| 1
|
{
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|
93
|
aug_650
|
ScPif1p has reduced binding ability to G-rich ssDNA compared to non-G-rich ssDNA.
Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo–isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.
CONTEXT Chronic tension-type headaches are characterized by near-daily headaches and often are difficult to manage in primary practice. Behavioral and pharmacological therapies each appear modestly effective, but data are lacking on their separate and combined effects. OBJECTIVE To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for chronic tension-type headaches. DESIGN AND SETTING Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2 outpatient sites in Ohio. PARTICIPANTS Two hundred three adults (mean age, 37 years; 76% women) with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo). INTERVENTIONS Participants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to 100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stress management (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plus placebo (n = 49), or stress management therapy plus antidepressant medication (n = 53). MAIN OUTCOME MEASURES Monthly headache index scores calculated as the mean of pain ratings (0-10 scale) recorded by participants in a daily diary 4 times per day; number of days per month with at least moderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores, compared by intervention group. RESULTS Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, but antidepressant medication yielded more rapid improvements in headache activity. Combined therapy was more likely to produce clinically significant (>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication (38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P =.001). On other measures the combined therapy and its 2 component therapies produced similar outcomes. CONCLUSIONS Our results indicate that antidepressant medication and stress management therapy are each modestly effective in treating chronic tension-type headaches. Combined therapy may improve outcome relative to monotherapy.
Breast cancer may originate in utero. We reviewed the available evidence on the association between birthweight and the risk of breast cancer. To date, 26 research papers addressing this issue have been published. The majority of studies identified a positive link between birthweight and premenopausal, but not postmenopausal, breast cancer. The relative risk estimate for breast cancer comparing women with high birthweight to women with low birthweight combining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidence interval 1.13-1.34). The mechanisms underlying this association likely include elevated levels of growth factors that may increase the number of susceptible stem cells in the mammary gland or initiate tumors through DNA mutations. Loss of imprinting (LOI) of growth hormone genes relevant for intrauterine growth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormones evidenced by high birthweight. LOI of IGF2 has also been found in mammary tumor tissue. The role of environmental factors that stimulate such epigenetic regulation of gene expression remains to be elucidated.
Oct4 is a well-known transcription factor that plays fundamental roles in stem cell self-renewal, pluripotency, and somatic cell reprogramming. However, limited information is available on Oct4-associated protein complexes and their intrinsic protein-protein interactions that dictate Oct4's critical regulatory activities. Here we employed an improved affinity purification approach combined with mass spectrometry to purify Oct4 protein complexes in mouse embryonic stem cells (mESCs), and discovered many novel Oct4 partners important for self-renewal and pluripotency of mESCs. Notably, we found that Oct4 is associated with multiple chromatin-modifying complexes with documented as well as newly proved functional significance in stem cell maintenance and somatic cell reprogramming. Our study establishes a solid biochemical basis for genetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploring alternative factor-based reprogramming strategies.
CONTEXT The epidemic of heart failure has yet to be fully investigated, and data on incidence, survival, and sex-specific temporal trends in community-based populations are limited. OBJECTIVE To test the hypothesis that the incidence of heart failure has declined and survival after heart failure diagnosis has improved over time but that secular trends have diverged by sex. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study using the resources of the Rochester Epidemiology Project conducted in Olmsted County, Minnesota. Patients were 4537 Olmsted County residents (57% women; mean [SD] age, 74 [14] years) with a diagnosis of heart failure between 1979 and 2000. Framingham criteria and clinical criteria were used to validate the diagnosis MAIN OUTCOME MEASURES Incidence of heart failure and survival after heart failure diagnosis. RESULTS The incidence of heart failure was higher among men (378/100 000 persons; 95% confidence interval [CI], 361-395 for men; 289/100 000 persons; 95% CI, 277-300 for women) and did not change over time among men or women. After a mean follow-up of 4.2 years (range, 0-23.8 years), 3347 deaths occurred, including 1930 among women and 1417 among men. Survival after heart failure diagnosis was worse among men than women (relative risk, 1.33; 95% CI, 1.24-1.43) but overall improved over time (5-year age-adjusted survival, 43% in 1979-1984 vs 52% in 1996-2000, P<.001). However, men and younger persons experienced larger survival gains, contrasting with less or no improvement for women and elderly persons. CONCLUSION In this community-based cohort, the incidence of heart failure has not declined during 2 decades, but survival after onset of heart failure has increased overall, with less improvement among women and elderly persons.
Combinatorial transcription factor (TF) interactions control cellular phenotypes and, therefore, underpin stem cell formation, maintenance, and differentiation. Here, we report the genome-wide binding patterns and combinatorial interactions for ten key regulators of blood stem/progenitor cells (SCL/TAL1, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1, and GFI1B), thus providing the most comprehensive TF data set for any adult stem/progenitor cell type to date. Genome-wide computational analysis of complex binding patterns, followed by functional validation, revealed the following: first, a previously unrecognized combinatorial interaction between a heptad of TFs (SCL, LYL1, LMO2, GATA2, RUNX1, ERG, and FLI-1). Second, we implicate direct protein-protein interactions between four key regulators (RUNX1, GATA2, SCL, and ERG) in stabilizing complex binding to DNA. Third, Runx1(+/-)::Gata2(+/-) compound heterozygous mice are not viable with severe hematopoietic defects at midgestation. Taken together, this study demonstrates the power of genome-wide analysis in generating novel functional insights into the transcriptional control of stem and progenitor cells.
|
ScPif1p has reduced binding ability to G-rich ssDNA compared to non-G-rich ssDNA.
Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo–isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.
CONTEXT Chronic tension-type headaches are characterized by near-daily headaches and often are difficult to manage in primary practice. Behavioral and pharmacological therapies each appear modestly effective, but data are lacking on their separate and combined effects. OBJECTIVE To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for chronic tension-type headaches. DESIGN AND SETTING Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2 outpatient sites in Ohio. PARTICIPANTS Two hundred three adults (mean age, 37 years; 76% women) with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo). INTERVENTIONS Participants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to 100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stress management (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plus placebo (n = 49), or stress management therapy plus antidepressant medication (n = 53). MAIN OUTCOME MEASURES Monthly headache index scores calculated as the mean of pain ratings (0-10 scale) recorded by participants in a daily diary 4 times per day; number of days per month with at least moderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores, compared by intervention group. RESULTS Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, but antidepressant medication yielded more rapid improvements in headache activity. Combined therapy was more likely to produce clinically significant (>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication (38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P =.001). On other measures the combined therapy and its 2 component therapies produced similar outcomes. CONCLUSIONS Our results indicate that antidepressant medication and stress management therapy are each modestly effective in treating chronic tension-type headaches. Combined therapy may improve outcome relative to monotherapy.
Breast cancer may originate in utero. We reviewed the available evidence on the association between birthweight and the risk of breast cancer. To date, 26 research papers addressing this issue have been published. The majority of studies identified a positive link between birthweight and premenopausal, but not postmenopausal, breast cancer. The relative risk estimate for breast cancer comparing women with high birthweight to women with low birthweight combining all studies including both pre- and postmenopausal breast cancer was 1.23 (95% confidence interval 1.13-1.34). The mechanisms underlying this association likely include elevated levels of growth factors that may increase the number of susceptible stem cells in the mammary gland or initiate tumors through DNA mutations. Loss of imprinting (LOI) of growth hormone genes relevant for intrauterine growth, such as insulin-like growth factor 2 (IGF2), leads to abnormally high levels of these hormones evidenced by high birthweight. LOI of IGF2 has also been found in mammary tumor tissue. The role of environmental factors that stimulate such epigenetic regulation of gene expression remains to be elucidated.
Oct4 is a well-known transcription factor that plays fundamental roles in stem cell self-renewal, pluripotency, and somatic cell reprogramming. However, limited information is available on Oct4-associated protein complexes and their intrinsic protein-protein interactions that dictate Oct4's critical regulatory activities. Here we employed an improved affinity purification approach combined with mass spectrometry to purify Oct4 protein complexes in mouse embryonic stem cells (mESCs), and discovered many novel Oct4 partners important for self-renewal and pluripotency of mESCs. Notably, we found that Oct4 is associated with multiple chromatin-modifying complexes with documented as well as newly proved functional significance in stem cell maintenance and somatic cell reprogramming. Our study establishes a solid biochemical basis for genetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploring alternative factor-based reprogramming strategies.
CONTEXT The epidemic of heart failure has yet to be fully investigated, and data on incidence, survival, and sex-specific temporal trends in community-based populations are limited. OBJECTIVE To test the hypothesis that the incidence of heart failure has declined and survival after heart failure diagnosis has improved over time but that secular trends have diverged by sex. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study using the resources of the Rochester Epidemiology Project conducted in Olmsted County, Minnesota. Patients were 4537 Olmsted County residents (57% women; mean [SD] age, 74 [14] years) with a diagnosis of heart failure between 1979 and 2000. Framingham criteria and clinical criteria were used to validate the diagnosis MAIN OUTCOME MEASURES Incidence of heart failure and survival after heart failure diagnosis. RESULTS The incidence of heart failure was higher among men (378/100 000 persons; 95% confidence interval [CI], 361-395 for men; 289/100 000 persons; 95% CI, 277-300 for women) and did not change over time among men or women. After a mean follow-up of 4.2 years (range, 0-23.8 years), 3347 deaths occurred, including 1930 among women and 1417 among men. Survival after heart failure diagnosis was worse among men than women (relative risk, 1.33; 95% CI, 1.24-1.43) but overall improved over time (5-year age-adjusted survival, 43% in 1979-1984 vs 52% in 1996-2000, P<.001). However, men and younger persons experienced larger survival gains, contrasting with less or no improvement for women and elderly persons. CONCLUSION In this community-based cohort, the incidence of heart failure has not declined during 2 decades, but survival after onset of heart failure has increased overall, with less improvement among women and elderly persons.
Combinatorial transcription factor (TF) interactions control cellular phenotypes and, therefore, underpin stem cell formation, maintenance, and differentiation. Here, we report the genome-wide binding patterns and combinatorial interactions for ten key regulators of blood stem/progenitor cells (SCL/TAL1, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1, and GFI1B), thus providing the most comprehensive TF data set for any adult stem/progenitor cell type to date. Genome-wide computational analysis of complex binding patterns, followed by functional validation, revealed the following: first, a previously unrecognized combinatorial interaction between a heptad of TFs (SCL, LYL1, LMO2, GATA2, RUNX1, ERG, and FLI-1). Second, we implicate direct protein-protein interactions between four key regulators (RUNX1, GATA2, SCL, and ERG) in stabilizing complex binding to DNA. Third, Runx1(+/-)::Gata2(+/-) compound heterozygous mice are not viable with severe hematopoietic defects at midgestation. Taken together, this study demonstrates the power of genome-wide analysis in generating novel functional insights into the transcriptional control of stem and progenitor cells.
| 0
|
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|
1068
|
aug_651
|
Polymeal nutrition increases cardiovascular mortality.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
Studying how protein transmembrane domains transmit signals across membranes is beset by unique challenges. Here, we discuss the circumstances that have led to success and reflect on what has been learned from these examples. Such efforts suggest that some of the most interesting properties of transmembrane helix interactions may be the least amenable to study by current techniques.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
OBJECTIVE Although the Polypill concept (proposed in 2003) is promising in terms of benefits for cardiovascular risk management, the potential costs and adverse effects are its main pitfalls. The objective of this study was to identify a tastier and safer alternative to the Polypill: the Polymeal. METHODS Data on the ingredients of the Polymeal were taken from the literature. The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds. Data from the Framingham heart study and the Framingham offspring study were used to build life tables to model the benefits of the Polymeal in the general population from age 50, assuming multiplicative correlations. RESULTS Combining the ingredients of the Polymeal would reduce cardiovascular disease events by 76%. For men, taking the Polymeal daily represented an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years. The corresponding differences for women were 4.8, 8.1, and 3.3 years. CONCLUSION The Polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population.
|
Polymeal nutrition increases cardiovascular mortality.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
Studying how protein transmembrane domains transmit signals across membranes is beset by unique challenges. Here, we discuss the circumstances that have led to success and reflect on what has been learned from these examples. Such efforts suggest that some of the most interesting properties of transmembrane helix interactions may be the least amenable to study by current techniques.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
OBJECTIVE Although the Polypill concept (proposed in 2003) is promising in terms of benefits for cardiovascular risk management, the potential costs and adverse effects are its main pitfalls. The objective of this study was to identify a tastier and safer alternative to the Polypill: the Polymeal. METHODS Data on the ingredients of the Polymeal were taken from the literature. The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds. Data from the Framingham heart study and the Framingham offspring study were used to build life tables to model the benefits of the Polymeal in the general population from age 50, assuming multiplicative correlations. RESULTS Combining the ingredients of the Polymeal would reduce cardiovascular disease events by 76%. For men, taking the Polymeal daily represented an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years. The corresponding differences for women were 4.8, 8.1, and 3.3 years. CONCLUSION The Polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population.
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959
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aug_652
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Mice that lack Interferon-γ or its receptor are highly susceptible to experimental autoimmune myocarditis.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair.
|
Mice that lack Interferon-γ or its receptor are highly susceptible to experimental autoimmune myocarditis.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair.
| 0.4
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780
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aug_653
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PRC1-bound plasmids sediment at a slower rate in unbound plasmids than in sucrose gradients.
Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
The transcriptional status of a gene can be maintained through multiple rounds of cell division during development. This epigenetic effect is believed to reflect heritable changes in chromatin folding and histone modifications or variants at target genes, but little is known about how these chromatin features are inherited through cell division. A particular challenge for maintaining transcription states is DNA replication, which disrupts or dilutes chromatin-associated proteins and histone modifications. PRC1-class Polycomb group protein complexes are essential for development and are thought to heritably silence transcription by altering chromatin folding and histone modifications. It is not known whether these complexes and their effects are maintained during DNA replication or subsequently re-established. We find that when PRC1-class Polycomb complex-bound chromatin or DNA is replicated in vitro, Polycomb complexes remain bound to replicated templates. Retention of Polycomb proteins through DNA replication may contribute to maintenance of transcriptional silencing through cell division.
Humoral immunity depends on both rapid and long-term antibody production against invading pathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated. Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses.
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
|
PRC1-bound plasmids sediment at a slower rate in unbound plasmids than in sucrose gradients.
Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
The transcriptional status of a gene can be maintained through multiple rounds of cell division during development. This epigenetic effect is believed to reflect heritable changes in chromatin folding and histone modifications or variants at target genes, but little is known about how these chromatin features are inherited through cell division. A particular challenge for maintaining transcription states is DNA replication, which disrupts or dilutes chromatin-associated proteins and histone modifications. PRC1-class Polycomb group protein complexes are essential for development and are thought to heritably silence transcription by altering chromatin folding and histone modifications. It is not known whether these complexes and their effects are maintained during DNA replication or subsequently re-established. We find that when PRC1-class Polycomb complex-bound chromatin or DNA is replicated in vitro, Polycomb complexes remain bound to replicated templates. Retention of Polycomb proteins through DNA replication may contribute to maintenance of transcriptional silencing through cell division.
Humoral immunity depends on both rapid and long-term antibody production against invading pathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated. Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses.
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
| 0.333333
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916
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aug_654
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Knockout proximal tubule-specific deletion of the BMP receptor Alk3 causes epithelial damage.
BACKGROUND Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). OBJECTIVE The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. METHODS Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONS Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
OBJECTIVE To determine whether individual fruits are differentially associated with risk of type 2 diabetes. DESIGN Prospective longitudinal cohort study. SETTING Health professionals in the United States. PARTICIPANTS 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women from the Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies. MAIN OUTCOME MEASURE Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires. RESULTS During 3,464,641 person years of follow-up, 12,198 participants developed type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.97 [corrected] to 0.99). With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts). CONCLUSION Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk of type 2 diabetes. Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, is significantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice is associated with a higher risk.
Clomifene is widely used for inducing ovulation.1 It is structurally related to diethylstilbestrol, which has been linked to vaginal and cervical clear cell adenocarcinoma in women exposed in utero. The adverse effect is less severe in sons, although links to testicular cancer and urogenital anomalies, such as epididymal cysts, have been reported.2 3 A recent study also found an increased risk of hypospadias in the sons of women exposed to diethylstilbestrol in utero.4 Clomifene has a half life of about five days, but its metabolites have been found in blood samples on day 22 of the menstrual cycle and in faeces up to six weeks after administration.5 The occurrence of hypospadias may be increasing. Little is known about the risk of hypospadias in boys born to women who have used clomifene to induce ovulation. ### Methods and results Our case-control study was done in the Danish counties of North Jutland, Aarhus, Viborg, and …
Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets.
Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development. Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress. This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress.
|
Knockout proximal tubule-specific deletion of the BMP receptor Alk3 causes epithelial damage.
BACKGROUND Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). OBJECTIVE The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. METHODS Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONS Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
OBJECTIVE To determine whether individual fruits are differentially associated with risk of type 2 diabetes. DESIGN Prospective longitudinal cohort study. SETTING Health professionals in the United States. PARTICIPANTS 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women from the Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies. MAIN OUTCOME MEASURE Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires. RESULTS During 3,464,641 person years of follow-up, 12,198 participants developed type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.97 [corrected] to 0.99). With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts). CONCLUSION Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk of type 2 diabetes. Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, is significantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice is associated with a higher risk.
Clomifene is widely used for inducing ovulation.1 It is structurally related to diethylstilbestrol, which has been linked to vaginal and cervical clear cell adenocarcinoma in women exposed in utero. The adverse effect is less severe in sons, although links to testicular cancer and urogenital anomalies, such as epididymal cysts, have been reported.2 3 A recent study also found an increased risk of hypospadias in the sons of women exposed to diethylstilbestrol in utero.4 Clomifene has a half life of about five days, but its metabolites have been found in blood samples on day 22 of the menstrual cycle and in faeces up to six weeks after administration.5 The occurrence of hypospadias may be increasing. Little is known about the risk of hypospadias in boys born to women who have used clomifene to induce ovulation. ### Methods and results Our case-control study was done in the Danish counties of North Jutland, Aarhus, Viborg, and …
Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets.
Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development. Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress. This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress.
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670
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aug_655
|
HAND2 methylation is a key step in early endometrial carcinogenesis.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.
|
HAND2 methylation is a key step in early endometrial carcinogenesis.
Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction.
BACKGROUND Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
BACKGROUND Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.
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488
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aug_656
|
BiP is a general endoplasmic reticulum stress marker.
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
|
BiP is a general endoplasmic reticulum stress marker.
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
| 0.5
|
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|
176
|
aug_657
|
Whole brain radiotherapy increases the occurrence of new brain metastases.
OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials, SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.
CONTEXT In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTS Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONS Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). MAIN OUTCOME MEASURES The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. RESULTS The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. CONCLUSIONS Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: C000000412.
BACKGROUND Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults. METHODS In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured. FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficial responses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles. In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles. INTERPRETATION Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects. FUNDING British Heart Foundation.
BACKGROUND Results of the few cohort studies from countries with low incomes or middle incomes suggest a lower incidence of dementia than in high-income countries. We assessed incidence of dementia according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, the effect of dementia at baseline on mortality, and the independent effects of age, sex, socioeconomic position, and indicators of cognitive reserve. METHODS We did a population-based cohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident 10/66 and DSM-IV dementia 3-5 years after cohort inception. We used questionnaires to obtain information about age in years, sex, educational level, literacy, occupational attainment, and number of household assets. We obtained information about mortality from all sites. For participants who had died, we interviewed a friend or relative to ascertain the likelihood that they had dementia before death. FINDINGS 12,887 participants were interviewed at baseline. 11,718 were free of dementia, of whom 8137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Incidence for 10/66 dementia varied between 18·2 and 30·4 per 1000 person-years, and were 1·4-2·7 times higher than were those for DSM-IV dementia (9·9-15·7 per 1000 person-years). Mortality hazards were 1·56-5·69 times higher in individuals with dementia at baseline than in those who were dementia-free. Informant reports suggested a high incidence of dementia before death; overall incidence might be 4-19% higher if these data were included. 10/66 dementia incidence was independently associated with increased age (HR 1·67; 95% CI 1·56-1·79), female sex (0·72; 0·61-0·84), and low education (0·89; 0·81-0·97), but not with occupational attainment (1·04; 0·95-1·13). INTERPRETATION Our results provide supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer substantial protection against the onset of dementia. FUNDING Wellcome Trust Health Consequences of Population Change Programme, WHO, US Alzheimer's Association, FONACIT/ CDCH/ UCV.
|
Whole brain radiotherapy increases the occurrence of new brain metastases.
OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials, SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.
CONTEXT In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTS Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONS Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). MAIN OUTCOME MEASURES The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. RESULTS The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. CONCLUSIONS Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: C000000412.
BACKGROUND Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults. METHODS In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured. FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficial responses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles. In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles. INTERPRETATION Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects. FUNDING British Heart Foundation.
BACKGROUND Results of the few cohort studies from countries with low incomes or middle incomes suggest a lower incidence of dementia than in high-income countries. We assessed incidence of dementia according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, the effect of dementia at baseline on mortality, and the independent effects of age, sex, socioeconomic position, and indicators of cognitive reserve. METHODS We did a population-based cohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident 10/66 and DSM-IV dementia 3-5 years after cohort inception. We used questionnaires to obtain information about age in years, sex, educational level, literacy, occupational attainment, and number of household assets. We obtained information about mortality from all sites. For participants who had died, we interviewed a friend or relative to ascertain the likelihood that they had dementia before death. FINDINGS 12,887 participants were interviewed at baseline. 11,718 were free of dementia, of whom 8137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Incidence for 10/66 dementia varied between 18·2 and 30·4 per 1000 person-years, and were 1·4-2·7 times higher than were those for DSM-IV dementia (9·9-15·7 per 1000 person-years). Mortality hazards were 1·56-5·69 times higher in individuals with dementia at baseline than in those who were dementia-free. Informant reports suggested a high incidence of dementia before death; overall incidence might be 4-19% higher if these data were included. 10/66 dementia incidence was independently associated with increased age (HR 1·67; 95% CI 1·56-1·79), female sex (0·72; 0·61-0·84), and low education (0·89; 0·81-0·97), but not with occupational attainment (1·04; 0·95-1·13). INTERPRETATION Our results provide supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer substantial protection against the onset of dementia. FUNDING Wellcome Trust Health Consequences of Population Change Programme, WHO, US Alzheimer's Association, FONACIT/ CDCH/ UCV.
| 0.4
|
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|
1376
|
aug_658
|
Induction of urokinase receptor signaling in podocytes causes foot process effacement and proteinuria.
Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Mice lacking uPAR (Plaur−/−) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.
|
Induction of urokinase receptor signaling in podocytes causes foot process effacement and proteinuria.
Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Mice lacking uPAR (Plaur−/−) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.
| 1
|
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|
626
|
aug_659
|
British male students are bullied more than British female students.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
How the number of immune cells recruited to sites of infection is determined and adjusted to differences in the cellular stoichiometry between host and pathogen is unknown. Here, we have uncovered a role for reactive oxygen species (ROS) as sensors of microbe size. By sensing the differential localization of ROS generated in response to microbes of different size, neutrophils tuned their interleukin (IL)-1β expression via the selective oxidation of NF-κB, in order to implement distinct inflammatory programs. Small microbes triggered ROS intracellularly, suppressing IL-1β expression to limit neutrophil recruitment as each phagocyte eliminated numerous pathogens. In contrast, large microbes triggered ROS extracellularly, amplifying IL-1β expression to recruit numerous neutrophils forming cooperative clusters. Defects in ROS-mediated microbe size sensing resulted in large neutrophil infiltrates and clusters in response to small microbes that contribute to inflammatory disease. These findings highlight the impact of ROS localization on signal transduction.
IMPORTANCE The need for surgery for the majority of patients with displaced proximal humeral fractures is unclear, but its use is increasing. OBJECTIVE To evaluate the clinical effectiveness of surgical vs nonsurgical treatment for adults with displaced fractures of the proximal humerus involving the surgical neck. DESIGN, SETTING, AND PARTICIPANTS A pragmatic, multicenter, parallel-group, randomized clinical trial, the Proximal Fracture of the Humerus Evaluation by Randomization (PROFHER) trial, recruited 250 patients aged 16 years or older (mean age, 66 years [range, 24-92 years]; 192 [77%] were female; and 249 [99.6%] were white) who presented at the orthopedic departments of 32 acute UK National Health Service hospitals between September 2008 and April 2011 within 3 weeks after sustaining a displaced fracture of the proximal humerus involving the surgical neck. Patients were followed up for 2 years (up to April 2013) and 215 had complete follow-up data. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in the primary analysis. INTERVENTIONS Fracture fixation or humeral head replacement were performed by surgeons experienced in these techniques. Nonsurgical treatment was sling immobilization. Standardized outpatient and community-based rehabilitation was provided to both groups. MAIN OUTCOMES AND MEASURES Primary outcome was the Oxford Shoulder Score (range, 0-48; higher scores indicate better outcomes) assessed during a 2-year period, with assessment and data collection at 6, 12, and 24 months. Sample size was based on a minimal clinically important difference of 5 points for the Oxford Shoulder Score. Secondary outcomes were the Short-Form 12 (SF-12), complications, subsequent therapy, and mortality. RESULTS There was no significant mean treatment group difference in the Oxford Shoulder Score averaged over 2 years (39.07 points for the surgical group vs 38.32 points for the nonsurgical group; difference of 0.75 points [95% CI, -1.33 to 2.84 points]; P = .48) or at individual time points. There were also no significant between-group differences over 2 years in the mean SF-12 physical component score (surgical group: 1.77 points higher [95% CI, -0.84 to 4.39 points]; P = .18); the mean SF-12 mental component score (surgical group: 1.28 points lower [95% CI, -3.80 to 1.23 points]; P = .32); complications related to surgery or shoulder fracture (30 patients in surgical group vs 23 patients in nonsurgical group; P = .28), requiring secondary surgery to the shoulder (11 patients in both groups), and increased or new shoulder-related therapy (7 patients vs 4 patients, respectively; P = .58); and mortality (9 patients vs 5 patients; P = .27). Ten medical complications (2 cardiovascular events, 2 respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during the postoperative hospital stay. CONCLUSIONS AND RELEVANCE Among patients with displaced proximal humeral fractures involving the surgical neck, there was no significant difference between surgical treatment compared with nonsurgical treatment in patient-reported clinical outcomes over 2 years following fracture occurrence. These results do not support the trend of increased surgery for patients with displaced fractures of the proximal humerus. TRIAL REGISTRATION isrctn.com Identifier: ISRCTN50850043.
CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent. OBJECTIVE To test the effects of exercise training on health status among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007. INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models. MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle. RESULTS Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected. CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.
Tight regulation of the expression of mRNAs encoding iron uptake proteins is essential to control iron homeostasis and avoid intracellular iron toxicity. We show that many mRNAs encoding iron uptake or iron mobilization proteins are expressed in iron-replete conditions in the absence of the S. cerevisiae RNase III ortholog Rnt1p or of the nuclear exosome component Rrp6p. Extended forms of these mRNAs accumulate in the absence of Rnt1p or of the 5'-->3' exonucleases Xrn1p and Rat1p, showing that multiple degradative pathways contribute to the surveillance of aberrant forms of these transcripts. RNase III-deficient cells are hypersensitive to high iron concentrations, suggesting that Rnt1p-mediated RNA surveillance is required to prevent iron toxicity. These results show that RNA surveillance through multiple ribonucleolytic pathways plays a role in iron homeostasis in yeast to avoid the potentially toxic effects of the expression of the iron starvation response in iron-replete conditions.
|
British male students are bullied more than British female students.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
How the number of immune cells recruited to sites of infection is determined and adjusted to differences in the cellular stoichiometry between host and pathogen is unknown. Here, we have uncovered a role for reactive oxygen species (ROS) as sensors of microbe size. By sensing the differential localization of ROS generated in response to microbes of different size, neutrophils tuned their interleukin (IL)-1β expression via the selective oxidation of NF-κB, in order to implement distinct inflammatory programs. Small microbes triggered ROS intracellularly, suppressing IL-1β expression to limit neutrophil recruitment as each phagocyte eliminated numerous pathogens. In contrast, large microbes triggered ROS extracellularly, amplifying IL-1β expression to recruit numerous neutrophils forming cooperative clusters. Defects in ROS-mediated microbe size sensing resulted in large neutrophil infiltrates and clusters in response to small microbes that contribute to inflammatory disease. These findings highlight the impact of ROS localization on signal transduction.
IMPORTANCE The need for surgery for the majority of patients with displaced proximal humeral fractures is unclear, but its use is increasing. OBJECTIVE To evaluate the clinical effectiveness of surgical vs nonsurgical treatment for adults with displaced fractures of the proximal humerus involving the surgical neck. DESIGN, SETTING, AND PARTICIPANTS A pragmatic, multicenter, parallel-group, randomized clinical trial, the Proximal Fracture of the Humerus Evaluation by Randomization (PROFHER) trial, recruited 250 patients aged 16 years or older (mean age, 66 years [range, 24-92 years]; 192 [77%] were female; and 249 [99.6%] were white) who presented at the orthopedic departments of 32 acute UK National Health Service hospitals between September 2008 and April 2011 within 3 weeks after sustaining a displaced fracture of the proximal humerus involving the surgical neck. Patients were followed up for 2 years (up to April 2013) and 215 had complete follow-up data. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in the primary analysis. INTERVENTIONS Fracture fixation or humeral head replacement were performed by surgeons experienced in these techniques. Nonsurgical treatment was sling immobilization. Standardized outpatient and community-based rehabilitation was provided to both groups. MAIN OUTCOMES AND MEASURES Primary outcome was the Oxford Shoulder Score (range, 0-48; higher scores indicate better outcomes) assessed during a 2-year period, with assessment and data collection at 6, 12, and 24 months. Sample size was based on a minimal clinically important difference of 5 points for the Oxford Shoulder Score. Secondary outcomes were the Short-Form 12 (SF-12), complications, subsequent therapy, and mortality. RESULTS There was no significant mean treatment group difference in the Oxford Shoulder Score averaged over 2 years (39.07 points for the surgical group vs 38.32 points for the nonsurgical group; difference of 0.75 points [95% CI, -1.33 to 2.84 points]; P = .48) or at individual time points. There were also no significant between-group differences over 2 years in the mean SF-12 physical component score (surgical group: 1.77 points higher [95% CI, -0.84 to 4.39 points]; P = .18); the mean SF-12 mental component score (surgical group: 1.28 points lower [95% CI, -3.80 to 1.23 points]; P = .32); complications related to surgery or shoulder fracture (30 patients in surgical group vs 23 patients in nonsurgical group; P = .28), requiring secondary surgery to the shoulder (11 patients in both groups), and increased or new shoulder-related therapy (7 patients vs 4 patients, respectively; P = .58); and mortality (9 patients vs 5 patients; P = .27). Ten medical complications (2 cardiovascular events, 2 respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during the postoperative hospital stay. CONCLUSIONS AND RELEVANCE Among patients with displaced proximal humeral fractures involving the surgical neck, there was no significant difference between surgical treatment compared with nonsurgical treatment in patient-reported clinical outcomes over 2 years following fracture occurrence. These results do not support the trend of increased surgery for patients with displaced fractures of the proximal humerus. TRIAL REGISTRATION isrctn.com Identifier: ISRCTN50850043.
CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent. OBJECTIVE To test the effects of exercise training on health status among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007. INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models. MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle. RESULTS Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected. CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.
Tight regulation of the expression of mRNAs encoding iron uptake proteins is essential to control iron homeostasis and avoid intracellular iron toxicity. We show that many mRNAs encoding iron uptake or iron mobilization proteins are expressed in iron-replete conditions in the absence of the S. cerevisiae RNase III ortholog Rnt1p or of the nuclear exosome component Rrp6p. Extended forms of these mRNAs accumulate in the absence of Rnt1p or of the 5'-->3' exonucleases Xrn1p and Rat1p, showing that multiple degradative pathways contribute to the surveillance of aberrant forms of these transcripts. RNase III-deficient cells are hypersensitive to high iron concentrations, suggesting that Rnt1p-mediated RNA surveillance is required to prevent iron toxicity. These results show that RNA surveillance through multiple ribonucleolytic pathways plays a role in iron homeostasis in yeast to avoid the potentially toxic effects of the expression of the iron starvation response in iron-replete conditions.
| 0
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187
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aug_660
|
Reduced phosphorylation of PP2A suppresses HDAC4 dephosphorylation.
Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely in vitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers. These cells have, therefore, potential for in vitro differentiation studies, gene function, and so on. The aim of this study was to produce a human embryonic stem cell line. An inner cell mass of a human blastocyst was separated and cultured on mouse embryonic fibroblasts in embryonic stem cell medium with related additives. The established line was evaluated by morphology; passaging; freezing and thawing; alkaline phosphatase; Oct-4 expression; anti-surface markers including Tra-1-60 and Tra-1-81; and karyotype and spontaneous differentiation. Differentiated cardiomyocytes and neurons were evaluated by transmission electron microscopy and immunocytochemistry. Here, we report the derivation of a new embryonic stem cell line (Royan H1) from a human blastocyst that remains undifferentiated in morphology during continuous passaging for more than 30 passages, maintains a normal XX karyotype, is viable after freezing and thawing, and expresses alkaline phosphatase, Oct-4, Tra-1-60, and Tra-1-81. These cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers in the presence or absence of recombinant human leukemia inhibitory factor. Royan H1 cells can differentiate in vitro in the absence of feeder cells and can produce embryoid bodies that can further differentiate into beating cardiomyocytes as well as neurons. These results define Royan H1 cells as a new human embryonic stem cell line.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
|
Reduced phosphorylation of PP2A suppresses HDAC4 dephosphorylation.
Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely in vitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers. These cells have, therefore, potential for in vitro differentiation studies, gene function, and so on. The aim of this study was to produce a human embryonic stem cell line. An inner cell mass of a human blastocyst was separated and cultured on mouse embryonic fibroblasts in embryonic stem cell medium with related additives. The established line was evaluated by morphology; passaging; freezing and thawing; alkaline phosphatase; Oct-4 expression; anti-surface markers including Tra-1-60 and Tra-1-81; and karyotype and spontaneous differentiation. Differentiated cardiomyocytes and neurons were evaluated by transmission electron microscopy and immunocytochemistry. Here, we report the derivation of a new embryonic stem cell line (Royan H1) from a human blastocyst that remains undifferentiated in morphology during continuous passaging for more than 30 passages, maintains a normal XX karyotype, is viable after freezing and thawing, and expresses alkaline phosphatase, Oct-4, Tra-1-60, and Tra-1-81. These cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers in the presence or absence of recombinant human leukemia inhibitory factor. Royan H1 cells can differentiate in vitro in the absence of feeder cells and can produce embryoid bodies that can further differentiate into beating cardiomyocytes as well as neurons. These results define Royan H1 cells as a new human embryonic stem cell line.
Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD.
Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
| 0.4
|
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|
1027
|
aug_661
|
NR5A2 does not play a role in development of endometrial tissues.
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
OBJECTIVE To investigate the association between gastric cancer and prior infection with Helicobacter pylori. DESIGN Case-control comparison of prevalence of IgG antibodies to H pylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases. Presence of H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbent assay (ELISA). SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies (the British United Provident Association study and the Caerphilly collaborative heart disease study), who had provided blood samples during 1975-1982. RESULTS 20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody. The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01). The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039). CONCLUSIONS H pylori infection may be an important cause of gastric cancer; between 35% and 55% of all cases may be associated with such an infection.
As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization.
Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IκB kinase–dependent nuclear factor-κB activation pathway. H. pylori–mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori–associated gastric carcinogenesis.
CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth. Changes in physical activity or diet may therefore influence risk of forearm fracture. OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years. DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001. MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods. RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001. Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001). The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls. CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present. Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase.
Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.
|
NR5A2 does not play a role in development of endometrial tissues.
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
OBJECTIVE To investigate the association between gastric cancer and prior infection with Helicobacter pylori. DESIGN Case-control comparison of prevalence of IgG antibodies to H pylori in blood samples collected prospectively, before diagnosis of gastric cancer in the cases. Presence of H pylori antibody (greater than 10 micrograms IgG/ml) determined by enzyme linked immunosorbent assay (ELISA). SUBJECTS 29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies (the British United Provident Association study and the Caerphilly collaborative heart disease study), who had provided blood samples during 1975-1982. RESULTS 20 of the 29 cases (69%) and 54 of the 116 controls (47%) were positive for H pylori specific antibody. The median specific IgG concentration was significantly higher in the cases than controls (90 micrograms/ml v 3.6 micrograms/ml, p less than 0.01). The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 (95% confidence interval 1.04 to 7.97, 2p = 0.039). CONCLUSIONS H pylori infection may be an important cause of gastric cancer; between 35% and 55% of all cases may be associated with such an infection.
As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization.
Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IκB kinase–dependent nuclear factor-κB activation pathway. H. pylori–mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori–associated gastric carcinogenesis.
CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth. Changes in physical activity or diet may therefore influence risk of forearm fracture. OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years. DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001. MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods. RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001. Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001). The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls. CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present. Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase.
Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.
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NR5A2 is important in reverse cholesterol transport in humans.
The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.
The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.
Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles. We demonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae. GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons. Purified motile vesicles showed GAPDH enzymatic activity and produced ATP. Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport. Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons. This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons.
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.
Gram-negative bacteria have an outer membrane (OM) that functions as a barrier to protect the cell from toxic compounds such as antibiotics and detergents. The OM is a highly asymmetric bilayer composed of phospholipids, glycolipids, and proteins. Assembly of this essential organelle occurs outside the cytoplasm in an environment that lacks obvious energy sources such as ATP, and the mechanisms involved are poorly understood. We describe the identification of a multiprotein complex required for the assembly of proteins in the OM of Escherichia coli. We also demonstrate genetic interactions between genes encoding components of this protein assembly complex and imp, which encodes a protein involved in the assembly of lipopolysaccharides (LPS) in the OM. These genetic interactions suggest a role for YfgL, one of the lipoprotein components of the protein assembly complex, in a homeostatic control mechanism that coordinates the overall OM assembly process.
Importance Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Exposures Presence of SCT. Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons). Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.
|
NR5A2 is important in reverse cholesterol transport in humans.
The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.
The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.
Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles. We demonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae. GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons. Purified motile vesicles showed GAPDH enzymatic activity and produced ATP. Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport. Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons. This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons.
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.
Gram-negative bacteria have an outer membrane (OM) that functions as a barrier to protect the cell from toxic compounds such as antibiotics and detergents. The OM is a highly asymmetric bilayer composed of phospholipids, glycolipids, and proteins. Assembly of this essential organelle occurs outside the cytoplasm in an environment that lacks obvious energy sources such as ATP, and the mechanisms involved are poorly understood. We describe the identification of a multiprotein complex required for the assembly of proteins in the OM of Escherichia coli. We also demonstrate genetic interactions between genes encoding components of this protein assembly complex and imp, which encodes a protein involved in the assembly of lipopolysaccharides (LPS) in the OM. These genetic interactions suggest a role for YfgL, one of the lipoprotein components of the protein assembly complex, in a homeostatic control mechanism that coordinates the overall OM assembly process.
Importance Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Exposures Presence of SCT. Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons). Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.
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Stroke patients with prior use of direct oral anticoagulants have a higher risk of in-hospital mortality than stroke patients with prior use of warfarin.
As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization.
Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain. Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway. Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. (2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors.
OBJECTIVE Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.
Importance Although non–vitamin K antagonist oral anticoagulants (NOACs) are increasingly used to prevent thromboembolic disease, there are limited data on NOAC-related intracerebral hemorrhage (ICH). Objective To assess the association between preceding oral anticoagulant use (warfarin, NOACs, and no oral anticoagulants [OACs]) and in-hospital mortality among patients with ICH. Design, Setting, and Participants Retrospective cohort study of 141 311 patients with ICH admitted from October 2013 to December 2016 to 1662 Get With The Guidelines–Stroke hospitals. Exposures Anticoagulation therapy before ICH, defined as any use of OACs within 7 days prior to hospital arrival. Main Outcomes and Measures In-hospital mortality. Results Among 141 311 patients with ICH (mean [SD] age, 68.3 [15.3] years; 48.1% women), 15 036 (10.6%) were taking warfarin and 4918 (3.5%) were taking NOACs preceding ICH, and 39 585 (28.0%) and 5783 (4.1%) were taking concomitant single and dual antiplatelet agents, respectively. Patients with prior use of warfarin or NOACs were older and had higher prevalence of atrial fibrillation and prior stroke. Acute ICH stroke severity (measured by the National Institutes of Health Stroke Scale) was not significantly different across the 3 groups (median, 9 [interquartile range, 2-21] for warfarin, 8 [2-20] for NOACs, and 8 [2-19] for no OACs). The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, −5.7% [97.5% CI, −7.3% to −4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, −15.0% [95.5% CI, −26.3% to −3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, −5.0% [97.5% CI, −6.8% to −3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant. Conclusions and Relevance Among patients with ICH, prior use of NOACs or warfarin was associated with higher in-hospital mortality compared with no OACs. Prior use of NOACs, compared with prior use of warfarin, was associated with lower risk of in-hospital mortality.
|
Stroke patients with prior use of direct oral anticoagulants have a higher risk of in-hospital mortality than stroke patients with prior use of warfarin.
As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization.
Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain. Investigating how this step might be regulated by a deubiquitinase (DUB) activity will provide new insight for understanding Notch receptor activation and downstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway. Our results support two new and provocative conclusions: (1) The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. (2) The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors.
OBJECTIVE Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.
Importance Although non–vitamin K antagonist oral anticoagulants (NOACs) are increasingly used to prevent thromboembolic disease, there are limited data on NOAC-related intracerebral hemorrhage (ICH). Objective To assess the association between preceding oral anticoagulant use (warfarin, NOACs, and no oral anticoagulants [OACs]) and in-hospital mortality among patients with ICH. Design, Setting, and Participants Retrospective cohort study of 141 311 patients with ICH admitted from October 2013 to December 2016 to 1662 Get With The Guidelines–Stroke hospitals. Exposures Anticoagulation therapy before ICH, defined as any use of OACs within 7 days prior to hospital arrival. Main Outcomes and Measures In-hospital mortality. Results Among 141 311 patients with ICH (mean [SD] age, 68.3 [15.3] years; 48.1% women), 15 036 (10.6%) were taking warfarin and 4918 (3.5%) were taking NOACs preceding ICH, and 39 585 (28.0%) and 5783 (4.1%) were taking concomitant single and dual antiplatelet agents, respectively. Patients with prior use of warfarin or NOACs were older and had higher prevalence of atrial fibrillation and prior stroke. Acute ICH stroke severity (measured by the National Institutes of Health Stroke Scale) was not significantly different across the 3 groups (median, 9 [interquartile range, 2-21] for warfarin, 8 [2-20] for NOACs, and 8 [2-19] for no OACs). The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, −5.7% [97.5% CI, −7.3% to −4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, −15.0% [95.5% CI, −26.3% to −3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, −5.0% [97.5% CI, −6.8% to −3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant. Conclusions and Relevance Among patients with ICH, prior use of NOACs or warfarin was associated with higher in-hospital mortality compared with no OACs. Prior use of NOACs, compared with prior use of warfarin, was associated with lower risk of in-hospital mortality.
| 0.4
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1103
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aug_664
|
Approximately 250,000 people are infected with human T-cell lymphotropic virus type 1 in the United Kingdom.
Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance. Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure. Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle. Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin. Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity. Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance.
Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p. Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.
The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here, we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, we identify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved in extracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3 triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitination and degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through the recruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA from ubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafA becomes polyubiquitinated and degraded to allow the response to terminate.
Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
CONTEXT Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. OBJECTIVE To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. DESIGN, SETTING, AND PATIENTS One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. INTERVENTION Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. MAIN OUTCOME MEASURES The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. RESULTS Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) CONCLUSION Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00658073.
|
Approximately 250,000 people are infected with human T-cell lymphotropic virus type 1 in the United Kingdom.
Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance. Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure. Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle. Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin. Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity. Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance.
Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p. Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.
The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here, we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, we identify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved in extracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3 triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitination and degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through the recruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA from ubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafA becomes polyubiquitinated and degraded to allow the response to terminate.
Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
CONTEXT Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. OBJECTIVE To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. DESIGN, SETTING, AND PATIENTS One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. INTERVENTION Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. MAIN OUTCOME MEASURES The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. RESULTS Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) CONCLUSION Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00658073.
| 0.333333
|
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126
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aug_665
|
Knockout proximal tubule-specific deletion of the BMP receptor Alk3 causes epithelial damage.
BACKGROUND Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). OBJECTIVE The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. METHODS Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONS Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
OBJECTIVE To determine whether individual fruits are differentially associated with risk of type 2 diabetes. DESIGN Prospective longitudinal cohort study. SETTING Health professionals in the United States. PARTICIPANTS 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women from the Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies. MAIN OUTCOME MEASURE Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires. RESULTS During 3,464,641 person years of follow-up, 12,198 participants developed type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.97 [corrected] to 0.99). With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts). CONCLUSION Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk of type 2 diabetes. Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, is significantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice is associated with a higher risk.
Clomifene is widely used for inducing ovulation.1 It is structurally related to diethylstilbestrol, which has been linked to vaginal and cervical clear cell adenocarcinoma in women exposed in utero. The adverse effect is less severe in sons, although links to testicular cancer and urogenital anomalies, such as epididymal cysts, have been reported.2 3 A recent study also found an increased risk of hypospadias in the sons of women exposed to diethylstilbestrol in utero.4 Clomifene has a half life of about five days, but its metabolites have been found in blood samples on day 22 of the menstrual cycle and in faeces up to six weeks after administration.5 The occurrence of hypospadias may be increasing. Little is known about the risk of hypospadias in boys born to women who have used clomifene to induce ovulation. ### Methods and results Our case-control study was done in the Danish counties of North Jutland, Aarhus, Viborg, and …
Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets.
Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development. Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress. This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress.
|
Knockout proximal tubule-specific deletion of the BMP receptor Alk3 causes epithelial damage.
BACKGROUND Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). OBJECTIVE The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. METHODS Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONS Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
OBJECTIVE To determine whether individual fruits are differentially associated with risk of type 2 diabetes. DESIGN Prospective longitudinal cohort study. SETTING Health professionals in the United States. PARTICIPANTS 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women from the Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies. MAIN OUTCOME MEASURE Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires. RESULTS During 3,464,641 person years of follow-up, 12,198 participants developed type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.97 [corrected] to 0.99). With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts). CONCLUSION Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk of type 2 diabetes. Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, is significantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice is associated with a higher risk.
Clomifene is widely used for inducing ovulation.1 It is structurally related to diethylstilbestrol, which has been linked to vaginal and cervical clear cell adenocarcinoma in women exposed in utero. The adverse effect is less severe in sons, although links to testicular cancer and urogenital anomalies, such as epididymal cysts, have been reported.2 3 A recent study also found an increased risk of hypospadias in the sons of women exposed to diethylstilbestrol in utero.4 Clomifene has a half life of about five days, but its metabolites have been found in blood samples on day 22 of the menstrual cycle and in faeces up to six weeks after administration.5 The occurrence of hypospadias may be increasing. Little is known about the risk of hypospadias in boys born to women who have used clomifene to induce ovulation. ### Methods and results Our case-control study was done in the Danish counties of North Jutland, Aarhus, Viborg, and …
Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets.
Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development. Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress. This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress.
| 0
|
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|
670
|
aug_666
|
Bcp1 is a chaperone for Rpl23.
Biogenesis of ribosomes is an essential cellular process conserved across all eukaryotes and is known to require >170 genes for the assembly, modification, and trafficking of ribosome components through multiple cellular compartments. Despite intensive study, this pathway likely involves many additional genes. Here, we employ network-guided genetics-an approach for associating candidate genes with biological processes that capitalizes on recent advances in functional genomic and proteomic studies-to computationally identify additional ribosomal biogenesis genes. We experimentally evaluated >100 candidate yeast genes in a battery of assays, confirming involvement of at least 15 new genes, including previously uncharacterized genes (YDL063C, YIL091C, YOR287C, YOR006C/TSR3, YOL022C/TSR4). We associate the new genes with specific aspects of ribosomal subunit maturation, ribosomal particle association, and ribosomal subunit nuclear export, and we identify genes specifically required for the processing of 5S, 7S, 20S, 27S, and 35S rRNAs. These results reveal new connections between ribosome biogenesis and mRNA splicing and add >10% new genes-most with human orthologs-to the biogenesis pathway, significantly extending our understanding of a universally conserved eukaryotic process.
|
Bcp1 is a chaperone for Rpl23.
Biogenesis of ribosomes is an essential cellular process conserved across all eukaryotes and is known to require >170 genes for the assembly, modification, and trafficking of ribosome components through multiple cellular compartments. Despite intensive study, this pathway likely involves many additional genes. Here, we employ network-guided genetics-an approach for associating candidate genes with biological processes that capitalizes on recent advances in functional genomic and proteomic studies-to computationally identify additional ribosomal biogenesis genes. We experimentally evaluated >100 candidate yeast genes in a battery of assays, confirming involvement of at least 15 new genes, including previously uncharacterized genes (YDL063C, YIL091C, YOR287C, YOR006C/TSR3, YOL022C/TSR4). We associate the new genes with specific aspects of ribosomal subunit maturation, ribosomal particle association, and ribosomal subunit nuclear export, and we identify genes specifically required for the processing of 5S, 7S, 20S, 27S, and 35S rRNAs. These results reveal new connections between ribosome biogenesis and mRNA splicing and add >10% new genes-most with human orthologs-to the biogenesis pathway, significantly extending our understanding of a universally conserved eukaryotic process.
| 1
|
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|
173
|
aug_667
|
Major antigen-induced signals from the T cell receptor and secondary signals from costimulatory receptors are required for T cell activation.
Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.
Earth-abundant first-row (3d) transition metal–based catalysts have been developed for the oxygen-evolution reaction (OER); however, they operate at overpotentials substantially above thermodynamic requirements. Density functional theory suggested that non-3d high-valency metals such as tungsten can modulate 3d metal oxides, providing near-optimal adsorption energies for OER intermediates. We developed a room-temperature synthesis to produce gelled oxyhydroxides materials with an atomically homogeneous metal distribution. These gelled FeCoW oxyhydroxides exhibit the lowest overpotential (191 millivolts) reported at 10 milliamperes per square centimeter in alkaline electrolyte. The catalyst shows no evidence of degradation after more than 500 hours of operation. X-ray absorption and computational studies reveal a synergistic interplay between tungsten, iron, and cobalt in producing a favorable local coordination environment and electronic structure that enhance the energetics for OER.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
OBJECTIVE To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables. DESIGN Systematic review and meta-analysis. DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials. STUDY SELECTION Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference). DATA EXTRACTION Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality. RESULTS 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section. CONCLUSION Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.
|
Major antigen-induced signals from the T cell receptor and secondary signals from costimulatory receptors are required for T cell activation.
Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.
Earth-abundant first-row (3d) transition metal–based catalysts have been developed for the oxygen-evolution reaction (OER); however, they operate at overpotentials substantially above thermodynamic requirements. Density functional theory suggested that non-3d high-valency metals such as tungsten can modulate 3d metal oxides, providing near-optimal adsorption energies for OER intermediates. We developed a room-temperature synthesis to produce gelled oxyhydroxides materials with an atomically homogeneous metal distribution. These gelled FeCoW oxyhydroxides exhibit the lowest overpotential (191 millivolts) reported at 10 milliamperes per square centimeter in alkaline electrolyte. The catalyst shows no evidence of degradation after more than 500 hours of operation. X-ray absorption and computational studies reveal a synergistic interplay between tungsten, iron, and cobalt in producing a favorable local coordination environment and electronic structure that enhance the energetics for OER.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
OBJECTIVE To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables. DESIGN Systematic review and meta-analysis. DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials. STUDY SELECTION Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference). DATA EXTRACTION Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality. RESULTS 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section. CONCLUSION Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.
| 0
|
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|
749
|
aug_668
|
Sudden death can occur in patients with orthostatic hypertension without cardiac conduction abnormalities.
BACKGROUND Patients with familial amyloid polyneuropathy, a rare hereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does not induce heart failure but is associated with sudden death, conduction disturbances, and an increased risk of complications during anesthesia. Although cardiac sympathetic denervation has been clearly demonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated. METHODS AND RESULTS Twenty-one patients were studied (age, 39+/-11 years; normal coronary arteries; left ventricular ejection fraction 68+/-9%). To evaluate the density and affinity constants of myocardial muscarinic receptors, PET with (11)C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, was used. Cardiac beta-receptor functional efficiency was studied by the heart rate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and 15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher in patients than in control subjects (B'(max), 35.5+/-8.9 versus 26.1+/-6.7 pmol/mL, P=0.003), without change in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower in patients compared with control subjects despite a similar basal HR (DeltaHR after atropine, 11+/-21% versus 62+/-17%; P<0.001), consistent with parasympathetic denervation. Incremental infusion of isoproterenol induced a similar increase in HR in patients and control subjects. CONCLUSIONS Cardiac autonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardial muscarinic receptors but without change in cardiac beta-receptor responsiveness to catecholamines.
|
Sudden death can occur in patients with orthostatic hypertension without cardiac conduction abnormalities.
BACKGROUND Patients with familial amyloid polyneuropathy, a rare hereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does not induce heart failure but is associated with sudden death, conduction disturbances, and an increased risk of complications during anesthesia. Although cardiac sympathetic denervation has been clearly demonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated. METHODS AND RESULTS Twenty-one patients were studied (age, 39+/-11 years; normal coronary arteries; left ventricular ejection fraction 68+/-9%). To evaluate the density and affinity constants of myocardial muscarinic receptors, PET with (11)C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, was used. Cardiac beta-receptor functional efficiency was studied by the heart rate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and 15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher in patients than in control subjects (B'(max), 35.5+/-8.9 versus 26.1+/-6.7 pmol/mL, P=0.003), without change in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower in patients compared with control subjects despite a similar basal HR (DeltaHR after atropine, 11+/-21% versus 62+/-17%; P<0.001), consistent with parasympathetic denervation. Incremental infusion of isoproterenol induced a similar increase in HR in patients and control subjects. CONCLUSIONS Cardiac autonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardial muscarinic receptors but without change in cardiac beta-receptor responsiveness to catecholamines.
| 1
|
{
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|
1112
|
aug_669
|
The innate immune response struggles to remove small numbers of parasites.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
OBJECTIVES We investigated the role of cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cachexia development in newly diagnosed nonsmall cell lung cancer (NSCLC) patients. METHODS : We evaluated 44 (M/F:41/3) NSCLC patients and 12 (M/F:10/2) age matched healthy smokers. NSCLC cases with a weight loss of > or =10% consisted the cachectic group (n:23, M/F:21/2) and the ones with <10% weight loss consisted the noncachectic group (n:21, M/F:19/2). RESULTS Body mass index (BMI) of cachectics was significantly lower than that of noncachectics (21.0 +/- 2.9 versus 24.5 +/- 3.6, P = 0.02) and controls (21.0 +/- 2.9 versus 25.5 +/- 2.6, P = 0.01). Serum TNF-alpha level did not differ between cachectic and noncachectics (37.3 +/- 39.1 and 51.6 +/- 84.2 pg/mL, respectively). However, it was significantly higher in NSCLC patients compared with controls (44.1 +/- 64.3 and 15.1 +/- 14.3 pg/mL, P = 0.03). Serum IL-6 level was not different between 3 groups (6.4 +/- 4.1, 8.9 +/- 16.3, and 4.1 +/- 3.5 pg/mL, respectively) but it correlated significantly with TNF-alpha (r = 0.4, P = 0.006) and BMI (r = -0.3, P = 0.03). Erythrocyte sedimentation rate (ESR) correlated significantly with TNF-alpha (r = 0.4, P = 0.003) and BMI (r = -0.3, P = 0.03). Among 44 cases, survival of 12 and 17 patients was recorded in cachectics and noncachectics, with no statistical difference (12.2 +/- 3.7 and 11.2 +/- 1.0 months, respectively). CONCLUSIONS TNF-alpha and IL-6 levels did not differ significantly between cachectics and noncachectics. However, significant correlations between IL-6, BMI, and TNF-alpha suggested that these cytokines acted as cofactors in weight loss. Survival was neither influenced by BMI, nor the cytokine levels in the present study. The significant correlation of ESR with TNF-alpha suggested that ESR could provide valuable clue for considerable weight loss in the follow-up of NSCLC patients.
Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose. Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms.
CRISPR-Cas (clustered, regularly interspaced short palindromic repeats coupled with CRISPR-associated proteins) is a bacterial immunity system that protects against invading phages or plasmids. In the process of CRISPR adaptation, short pieces of DNA ('spacers') are acquired from foreign elements and integrated into the CRISPR array. So far, it has remained a mystery how spacers are preferentially acquired from the foreign DNA while the self chromosome is avoided. Here we show that spacer acquisition is replication-dependent, and that DNA breaks formed at stalled replication forks promote spacer acquisition. Chromosomal hotspots of spacer acquisition were confined by Chi sites, which are sequence octamers highly enriched on the bacterial chromosome, suggesting that these sites limit spacer acquisition from self DNA. We further show that the avoidance of self is mediated by the RecBCD double-stranded DNA break repair complex. Our results suggest that, in Escherichia coli, acquisition of new spacers largely depends on RecBCD-mediated processing of double-stranded DNA breaks occurring primarily at replication forks, and that the preference for foreign DNA is achieved through the higher density of Chi sites on the self chromosome, in combination with the higher number of forks on the foreign DNA. This model explains the strong preference to acquire spacers both from high copy plasmids and from phages.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
|
The innate immune response struggles to remove small numbers of parasites.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
OBJECTIVES We investigated the role of cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cachexia development in newly diagnosed nonsmall cell lung cancer (NSCLC) patients. METHODS : We evaluated 44 (M/F:41/3) NSCLC patients and 12 (M/F:10/2) age matched healthy smokers. NSCLC cases with a weight loss of > or =10% consisted the cachectic group (n:23, M/F:21/2) and the ones with <10% weight loss consisted the noncachectic group (n:21, M/F:19/2). RESULTS Body mass index (BMI) of cachectics was significantly lower than that of noncachectics (21.0 +/- 2.9 versus 24.5 +/- 3.6, P = 0.02) and controls (21.0 +/- 2.9 versus 25.5 +/- 2.6, P = 0.01). Serum TNF-alpha level did not differ between cachectic and noncachectics (37.3 +/- 39.1 and 51.6 +/- 84.2 pg/mL, respectively). However, it was significantly higher in NSCLC patients compared with controls (44.1 +/- 64.3 and 15.1 +/- 14.3 pg/mL, P = 0.03). Serum IL-6 level was not different between 3 groups (6.4 +/- 4.1, 8.9 +/- 16.3, and 4.1 +/- 3.5 pg/mL, respectively) but it correlated significantly with TNF-alpha (r = 0.4, P = 0.006) and BMI (r = -0.3, P = 0.03). Erythrocyte sedimentation rate (ESR) correlated significantly with TNF-alpha (r = 0.4, P = 0.003) and BMI (r = -0.3, P = 0.03). Among 44 cases, survival of 12 and 17 patients was recorded in cachectics and noncachectics, with no statistical difference (12.2 +/- 3.7 and 11.2 +/- 1.0 months, respectively). CONCLUSIONS TNF-alpha and IL-6 levels did not differ significantly between cachectics and noncachectics. However, significant correlations between IL-6, BMI, and TNF-alpha suggested that these cytokines acted as cofactors in weight loss. Survival was neither influenced by BMI, nor the cytokine levels in the present study. The significant correlation of ESR with TNF-alpha suggested that ESR could provide valuable clue for considerable weight loss in the follow-up of NSCLC patients.
Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose. Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms.
CRISPR-Cas (clustered, regularly interspaced short palindromic repeats coupled with CRISPR-associated proteins) is a bacterial immunity system that protects against invading phages or plasmids. In the process of CRISPR adaptation, short pieces of DNA ('spacers') are acquired from foreign elements and integrated into the CRISPR array. So far, it has remained a mystery how spacers are preferentially acquired from the foreign DNA while the self chromosome is avoided. Here we show that spacer acquisition is replication-dependent, and that DNA breaks formed at stalled replication forks promote spacer acquisition. Chromosomal hotspots of spacer acquisition were confined by Chi sites, which are sequence octamers highly enriched on the bacterial chromosome, suggesting that these sites limit spacer acquisition from self DNA. We further show that the avoidance of self is mediated by the RecBCD double-stranded DNA break repair complex. Our results suggest that, in Escherichia coli, acquisition of new spacers largely depends on RecBCD-mediated processing of double-stranded DNA breaks occurring primarily at replication forks, and that the preference for foreign DNA is achieved through the higher density of Chi sites on the self chromosome, in combination with the higher number of forks on the foreign DNA. This model explains the strong preference to acquire spacers both from high copy plasmids and from phages.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
| 0.285714
|
{
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|
1223
|
aug_670
|
BiP is a general endoplasmic reticulum stress marker.
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
|
BiP is a general endoplasmic reticulum stress marker.
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
| 0.5
|
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|
176
|
aug_671
|
Ultrasound guidance significantly reduces the number of needle insertion attempts necessary for a given procedure.
OBJECTIVE To determine whether ultrasound imaging can reduce the risk of failed lumbar punctures or epidural catheterisations, when compared with standard palpation methods, and whether ultrasound imaging can reduce traumatic procedures, insertion attempts, and needle redirections. DESIGN Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2012, without restriction by language or publication status. REVIEW METHODS Randomised trials that compared ultrasound imaging with standard methods (no imaging) in the performance of a lumbar puncture or epidural catheterisation were identified. RESULTS 14 studies with a total of 1334 patients were included (674 patients assigned to the ultrasound group, 660 to the control group). Five studies evaluated lumbar punctures and nine evaluated epidural catheterisations. Six of 624 procedures conducted in the ultrasound group failed; 44 of 610 procedures in the control group failed. Ultrasound imaging reduced the risk of failed procedures (risk ratio 0.21 (95% confidence interval 0.10 to 0.43), P<0.001). Risk reduction was similar when subgroup analysis was performed for lumbar punctures (risk ratio 0.19 (0.07 to 0.56), P=0.002) or epidural catheterisations (0.23 (0.09 to 0.60), P=0.003). Ultrasound imaging also significantly reduced the risk of traumatic procedures (risk ratio 0.27 (0.11 to 0.67), P=0.005), the number of insertion attempts (mean difference -0.44 (-0.64 to -0.24), P<0.001), and the number of needle redirections (mean difference -1.00 (-1.24 to -0.75), P<0.001). CONCLUSIONS Ultrasound imaging can reduce the risk of failed or traumatic lumbar punctures and epidural catheterisations, as well as the number of needle insertions and redirections. Ultrasound may be a useful adjunct for these procedures.
|
Ultrasound guidance significantly reduces the number of needle insertion attempts necessary for a given procedure.
OBJECTIVE To determine whether ultrasound imaging can reduce the risk of failed lumbar punctures or epidural catheterisations, when compared with standard palpation methods, and whether ultrasound imaging can reduce traumatic procedures, insertion attempts, and needle redirections. DESIGN Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2012, without restriction by language or publication status. REVIEW METHODS Randomised trials that compared ultrasound imaging with standard methods (no imaging) in the performance of a lumbar puncture or epidural catheterisation were identified. RESULTS 14 studies with a total of 1334 patients were included (674 patients assigned to the ultrasound group, 660 to the control group). Five studies evaluated lumbar punctures and nine evaluated epidural catheterisations. Six of 624 procedures conducted in the ultrasound group failed; 44 of 610 procedures in the control group failed. Ultrasound imaging reduced the risk of failed procedures (risk ratio 0.21 (95% confidence interval 0.10 to 0.43), P<0.001). Risk reduction was similar when subgroup analysis was performed for lumbar punctures (risk ratio 0.19 (0.07 to 0.56), P=0.002) or epidural catheterisations (0.23 (0.09 to 0.60), P=0.003). Ultrasound imaging also significantly reduced the risk of traumatic procedures (risk ratio 0.27 (0.11 to 0.67), P=0.005), the number of insertion attempts (mean difference -0.44 (-0.64 to -0.24), P<0.001), and the number of needle redirections (mean difference -1.00 (-1.24 to -0.75), P<0.001). CONCLUSIONS Ultrasound imaging can reduce the risk of failed or traumatic lumbar punctures and epidural catheterisations, as well as the number of needle insertions and redirections. Ultrasound may be a useful adjunct for these procedures.
| 1
|
{
"query_id": "1340",
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"15482274"
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"type": "pathfinderrag_test"
}
|
1340
|
aug_672
|
Drosophila supracellular actomyosin structures are found at boundaries in wing imaginal discs.
Subdividing proliferating tissues into compartments is an evolutionarily conserved strategy of animal development [1-6]. Signals across boundaries between compartments can result in local expression of secreted proteins organizing growth and patterning of tissues [1-6]. Sharp and straight interfaces between compartments are crucial for stabilizing the position of such organizers and therefore for precise implementation of body plans. Maintaining boundaries in proliferating tissues requires mechanisms to counteract cell rearrangements caused by cell division; however, the nature of such mechanisms remains unclear. Here we quantitatively analyzed cell morphology and the response to the laser ablation of cell bonds in the vicinity of the anteroposterior compartment boundary in developing Drosophila wings. We found that mechanical tension is approximately 2.5-fold increased on cell bonds along this compartment boundary as compared to the remaining tissue. Cell bond tension is decreased in the presence of Y-27632 [7], an inhibitor of Rho-kinase whose main effector is Myosin II [8]. Simulations using a vertex model [9] demonstrate that a 2.5-fold increase in local cell bond tension suffices to guide the rearrangement of cells after cell division to maintain compartment boundaries. Our results provide a physical mechanism in which the local increase in Myosin II-dependent cell bond tension directs cell sorting at compartment boundaries.
As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization.
|
Drosophila supracellular actomyosin structures are found at boundaries in wing imaginal discs.
Subdividing proliferating tissues into compartments is an evolutionarily conserved strategy of animal development [1-6]. Signals across boundaries between compartments can result in local expression of secreted proteins organizing growth and patterning of tissues [1-6]. Sharp and straight interfaces between compartments are crucial for stabilizing the position of such organizers and therefore for precise implementation of body plans. Maintaining boundaries in proliferating tissues requires mechanisms to counteract cell rearrangements caused by cell division; however, the nature of such mechanisms remains unclear. Here we quantitatively analyzed cell morphology and the response to the laser ablation of cell bonds in the vicinity of the anteroposterior compartment boundary in developing Drosophila wings. We found that mechanical tension is approximately 2.5-fold increased on cell bonds along this compartment boundary as compared to the remaining tissue. Cell bond tension is decreased in the presence of Y-27632 [7], an inhibitor of Rho-kinase whose main effector is Myosin II [8]. Simulations using a vertex model [9] demonstrate that a 2.5-fold increase in local cell bond tension suffices to guide the rearrangement of cells after cell division to maintain compartment boundaries. Our results provide a physical mechanism in which the local increase in Myosin II-dependent cell bond tension directs cell sorting at compartment boundaries.
As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization.
| 1
|
{
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"type": "pathfinderrag_test"
}
|
355
|
aug_673
|
FoxO3a activation in neuronal death is inhibited by reactive oxygen species (ROS).
The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
|
FoxO3a activation in neuronal death is inhibited by reactive oxygen species (ROS).
The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
| 1
|
{
"query_id": "430",
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"28937856"
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"type": "pathfinderrag_test"
}
|
430
|
aug_674
|
Individuals with Alzheimers who participate in six months of physical activity improve cognitive function for up to 18 months.
In single-stranded ribonucleic acid (RNA) viruses, virus capsid assembly and genome packaging are intertwined processes. Using cryo-electron microscopy and single particle analysis we determined the asymmetric virion structure of bacteriophage MS2, which includes 178 copies of the coat protein, a single copy of the A-protein and the RNA genome. This reveals that in situ, the viral RNA genome can adopt a defined conformation. The RNA forms a branched network of stem-loops that almost all allocate near the capsid inner surface, while predominantly binding to coat protein dimers that are located in one-half of the capsid. This suggests that genomic RNA is highly involved in genome packaging and virion assembly.
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
Background Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.
Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
|
Individuals with Alzheimers who participate in six months of physical activity improve cognitive function for up to 18 months.
In single-stranded ribonucleic acid (RNA) viruses, virus capsid assembly and genome packaging are intertwined processes. Using cryo-electron microscopy and single particle analysis we determined the asymmetric virion structure of bacteriophage MS2, which includes 178 copies of the coat protein, a single copy of the A-protein and the RNA genome. This reveals that in situ, the viral RNA genome can adopt a defined conformation. The RNA forms a branched network of stem-loops that almost all allocate near the capsid inner surface, while predominantly binding to coat protein dimers that are located in one-half of the capsid. This suggests that genomic RNA is highly involved in genome packaging and virion assembly.
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.
Background Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.
Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.
Correction for: Kurreeman FAS, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, et al. (2007) A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis. PLoS Med 4(9): e278. doi:10.1371/journal.pmed.0040278 In Table 1, the allele ratio in column eight (Allele Ratiosb: Cases, Controls) refers to allele A: allele B and not allele1:allele2 as described in footnote b, with Allele A being the Susceptibility Allele as denoted in column seven. The footnote should read: bNumber of alleles were compared in cases versus controls: allele A: allele B cases, allele A: allele B controls. Allele A refers to the susceptibility alleles as given in column seven.
Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements. It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription. We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers. Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A. Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs. These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP. They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions. Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption.
| 0
|
{
"query_id": "621",
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"1410197",
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|
621
|
aug_675
|
The DESMOND program caused substantial weight loss in most participants.
OBJECTIVE To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years. DESIGN Three year follow-up of a multicentre cluster randomised controlled trial in primary care, with randomisation at practice level. SETTING 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS 731 of the 824 participants included in the original trial were eligible for follow-up. Biomedical data were collected on 604 (82.6%) and questionnaire data on 513 (70.1%) participants. INTERVENTION A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES The primary outcome was glycated haemoglobin (HbA(1c)) levels. The secondary outcomes were blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, emotional impact of diabetes, and drug use at three years. RESULTS HbA(1c) levels at three years had decreased in both groups. After adjusting for baseline and cluster the difference was not significant (difference -0.02, 95% confidence interval -0.22 to 0.17). The groups did not differ for the other biomedical and lifestyle outcomes and drug use. The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years (P<0.01). Depression scores and quality of life did not differ at three years. CONCLUSION A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs. TRIAL REGISTRATION Current Controlled Trials ISRCTN17844016.
|
The DESMOND program caused substantial weight loss in most participants.
OBJECTIVE To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years. DESIGN Three year follow-up of a multicentre cluster randomised controlled trial in primary care, with randomisation at practice level. SETTING 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS 731 of the 824 participants included in the original trial were eligible for follow-up. Biomedical data were collected on 604 (82.6%) and questionnaire data on 513 (70.1%) participants. INTERVENTION A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES The primary outcome was glycated haemoglobin (HbA(1c)) levels. The secondary outcomes were blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, emotional impact of diabetes, and drug use at three years. RESULTS HbA(1c) levels at three years had decreased in both groups. After adjusting for baseline and cluster the difference was not significant (difference -0.02, 95% confidence interval -0.22 to 0.17). The groups did not differ for the other biomedical and lifestyle outcomes and drug use. The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years (P<0.01). Depression scores and quality of life did not differ at three years. CONCLUSION A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs. TRIAL REGISTRATION Current Controlled Trials ISRCTN17844016.
| 1
|
{
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}
|
1156
|
aug_676
|
TNFAIP3 is a glioblastoma tumor enhancer.
Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.
|
TNFAIP3 is a glioblastoma tumor enhancer.
Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.
| 1
|
{
"query_id": "1134",
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|
1134
|
aug_677
|
Increased mobility of retrotransposons is assosciated with mutation and higher tumorigenesis rates.
Studying how protein transmembrane domains transmit signals across membranes is beset by unique challenges. Here, we discuss the circumstances that have led to success and reflect on what has been learned from these examples. Such efforts suggest that some of the most interesting properties of transmembrane helix interactions may be the least amenable to study by current techniques.
To characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as at a single-cell level. A subpopulation of Sox2+ cells gives rise to cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response to mitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs as well as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role in maintaining the constant size of the NSC pool and producing newly born neurons during adult neurogenesis.
DNA methylation plays an important role in biological processes in human health and disease. Recent technological advances allow unbiased whole-genome DNA methylation (methylome) analysis to be carried out on human cells. Using whole-genome bisulfite sequencing at 24.7-fold coverage (12.3-fold per strand), we report a comprehensive (92.62%) methylome and analysis of the unique sequences in human peripheral blood mononuclear cells (PBMC) from the same Asian individual whose genome was deciphered in the YH project. PBMC constitute an important source for clinical blood tests world-wide. We found that 68.4% of CpG sites and <0.2% of non-CpG sites were methylated, demonstrating that non-CpG cytosine methylation is minor in human PBMC. Analysis of the PBMC methylome revealed a rich epigenomic landscape for 20 distinct genomic features, including regulatory, protein-coding, non-coding, RNA-coding, and repeat sequences. Integration of our methylome data with the YH genome sequence enabled a first comprehensive assessment of allele-specific methylation (ASM) between the two haploid methylomes of any individual and allowed the identification of 599 haploid differentially methylated regions (hDMRs) covering 287 genes. Of these, 76 genes had hDMRs within 2 kb of their transcriptional start sites of which >80% displayed allele-specific expression (ASE). These data demonstrate that ASM is a recurrent phenomenon and is highly correlated with ASE in human PBMCs. Together with recently reported similar studies, our study provides a comprehensive resource for future epigenomic research and confirms new sequencing technology as a paradigm for large-scale epigenomics studies.
|
Increased mobility of retrotransposons is assosciated with mutation and higher tumorigenesis rates.
Studying how protein transmembrane domains transmit signals across membranes is beset by unique challenges. Here, we discuss the circumstances that have led to success and reflect on what has been learned from these examples. Such efforts suggest that some of the most interesting properties of transmembrane helix interactions may be the least amenable to study by current techniques.
To characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as at a single-cell level. A subpopulation of Sox2+ cells gives rise to cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response to mitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs as well as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role in maintaining the constant size of the NSC pool and producing newly born neurons during adult neurogenesis.
DNA methylation plays an important role in biological processes in human health and disease. Recent technological advances allow unbiased whole-genome DNA methylation (methylome) analysis to be carried out on human cells. Using whole-genome bisulfite sequencing at 24.7-fold coverage (12.3-fold per strand), we report a comprehensive (92.62%) methylome and analysis of the unique sequences in human peripheral blood mononuclear cells (PBMC) from the same Asian individual whose genome was deciphered in the YH project. PBMC constitute an important source for clinical blood tests world-wide. We found that 68.4% of CpG sites and <0.2% of non-CpG sites were methylated, demonstrating that non-CpG cytosine methylation is minor in human PBMC. Analysis of the PBMC methylome revealed a rich epigenomic landscape for 20 distinct genomic features, including regulatory, protein-coding, non-coding, RNA-coding, and repeat sequences. Integration of our methylome data with the YH genome sequence enabled a first comprehensive assessment of allele-specific methylation (ASM) between the two haploid methylomes of any individual and allowed the identification of 599 haploid differentially methylated regions (hDMRs) covering 287 genes. Of these, 76 genes had hDMRs within 2 kb of their transcriptional start sites of which >80% displayed allele-specific expression (ASE). These data demonstrate that ASM is a recurrent phenomenon and is highly correlated with ASE in human PBMCs. Together with recently reported similar studies, our study provides a comprehensive resource for future epigenomic research and confirms new sequencing technology as a paradigm for large-scale epigenomics studies.
| 0.5
|
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617
|
aug_678
|
Algerian physicians constitue the largest component of sub-Saharan Africa-trained physicians in the United States.
CONTEXT Bioterrorist attacks involving letters and mail-handling systems in Washington, DC, resulted in Bacillus anthracis (anthrax) spore contamination in the Hart Senate Office Building and other facilities in the US Capitol's vicinity. OBJECTIVE To provide information about the nature and extent of indoor secondary aerosolization of B anthracis spores. DESIGN Stationary and personal air samples, surface dust, and swab samples were collected under semiquiescent (minimal activities) and then simulated active office conditions to estimate secondary aerosolization of B anthracis spores. Nominal size characteristics, airborne concentrations, and surface contamination of B anthracis particles (colony-forming units) were evaluated. RESULTS Viable B anthracis spores reaerosolized under semiquiescent conditions, with a marked increase in reaerosolization during simulated active office conditions. Increases were observed for B anthracis collected on open sheep blood agar plates (P<.001) and personal air monitors (P =.01) during active office conditions. More than 80% of the B anthracis particles collected on stationary monitors were within an alveolar respirable size range of 0.95 to 3.5 micro m. CONCLUSIONS Bacillus anthracis spores used in a recent terrorist incident reaerosolized under common office activities. These findings have important implications for appropriate respiratory protection, remediation, and reoccupancy of contaminated office environments.
RNA processing is carried out in close proximity to the site of transcription, suggesting a regulatory link between transcription and pre-mRNA splicing. Using an in vitro transcription/splicing assay, we demonstrate that an association of RNA polymerase II (Pol II) transcription and pre-mRNA splicing is required for efficient gene expression. Pol II-synthesized RNAs containing functional splice sites are protected from nuclear degradation, presumably because the local concentration of the splicing machinery is sufficiently high to ensure its association over interactions with nucleases. Furthermore, the process of transcription influences alternative splicing of newly synthesized pre-mRNAs. Because other RNA polymerases do not provide similar protection from nucleases, and their RNA products display altered splicing patterns, the link between transcription and RNA processing is RNA Pol II-specific. We propose that the connection between transcription by Pol II and pre-mRNA splicing guarantees an extended half-life and proper processing of nascent pre-mRNAs.
BACKGROUND The large-scale emigration of physicians from sub-Saharan Africa (SSA) to high-income nations is a serious development concern. Our objective was to determine current emigration trends of SSA physicians found in the physician workforce of the United States. METHODS AND FINDINGS We analyzed physician data from the World Health Organization (WHO) Global Health Workforce Statistics along with graduation and residency data from the 2011 American Medical Association Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currently practice in the US. We estimated emigration proportions, year of US entry, years of practice before emigration, and length of time in the US. According to the 2011 AMA-PM, 10,819 physicians were born or trained in 28 SSA countries. Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) were US-trained, and 12% (n = 1,323) were trained outside both SSA and the US. We estimated active physicians (age ≤ 70 years) to represent 96% (n = 10,377) of the total. Migration trends among SSA-trained physicians increased from 2002 to 2011 for all but one principal source country; the exception was South Africa whose physician migration to the US decreased by 8% (-156). The increase in last-decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and >200% (+244) in Sudan. Liberia was the most affected by migration to the US with 77% (n = 175) of its estimated physicians in the 2011 AMA-PM. On average, SSA-trained physicians have been in the US for 18 years. They practiced for 6.5 years before US entry, and nearly half emigrated during the implementation years (1984-1999) of the structural adjustment programs. CONCLUSION Physician emigration from SSA to the US is increasing for most SSA source countries. Unless far-reaching policies are implemented by the US and SSA countries, the current emigration trends will persist, and the US will remain a leading destination for SSA physicians emigrating from the continent of greatest need. Please see later in the article for the Editors' Summary.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown. METHODS AND RESULTS In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01). CONCLUSIONS These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.
CONTEXT Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. OBJECTIVE To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). INTERVENTIONS Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. MAIN OUTCOME MEASURES The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. RESULTS There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). CONCLUSIONS These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00052026.
|
Algerian physicians constitue the largest component of sub-Saharan Africa-trained physicians in the United States.
CONTEXT Bioterrorist attacks involving letters and mail-handling systems in Washington, DC, resulted in Bacillus anthracis (anthrax) spore contamination in the Hart Senate Office Building and other facilities in the US Capitol's vicinity. OBJECTIVE To provide information about the nature and extent of indoor secondary aerosolization of B anthracis spores. DESIGN Stationary and personal air samples, surface dust, and swab samples were collected under semiquiescent (minimal activities) and then simulated active office conditions to estimate secondary aerosolization of B anthracis spores. Nominal size characteristics, airborne concentrations, and surface contamination of B anthracis particles (colony-forming units) were evaluated. RESULTS Viable B anthracis spores reaerosolized under semiquiescent conditions, with a marked increase in reaerosolization during simulated active office conditions. Increases were observed for B anthracis collected on open sheep blood agar plates (P<.001) and personal air monitors (P =.01) during active office conditions. More than 80% of the B anthracis particles collected on stationary monitors were within an alveolar respirable size range of 0.95 to 3.5 micro m. CONCLUSIONS Bacillus anthracis spores used in a recent terrorist incident reaerosolized under common office activities. These findings have important implications for appropriate respiratory protection, remediation, and reoccupancy of contaminated office environments.
RNA processing is carried out in close proximity to the site of transcription, suggesting a regulatory link between transcription and pre-mRNA splicing. Using an in vitro transcription/splicing assay, we demonstrate that an association of RNA polymerase II (Pol II) transcription and pre-mRNA splicing is required for efficient gene expression. Pol II-synthesized RNAs containing functional splice sites are protected from nuclear degradation, presumably because the local concentration of the splicing machinery is sufficiently high to ensure its association over interactions with nucleases. Furthermore, the process of transcription influences alternative splicing of newly synthesized pre-mRNAs. Because other RNA polymerases do not provide similar protection from nucleases, and their RNA products display altered splicing patterns, the link between transcription and RNA processing is RNA Pol II-specific. We propose that the connection between transcription by Pol II and pre-mRNA splicing guarantees an extended half-life and proper processing of nascent pre-mRNAs.
BACKGROUND The large-scale emigration of physicians from sub-Saharan Africa (SSA) to high-income nations is a serious development concern. Our objective was to determine current emigration trends of SSA physicians found in the physician workforce of the United States. METHODS AND FINDINGS We analyzed physician data from the World Health Organization (WHO) Global Health Workforce Statistics along with graduation and residency data from the 2011 American Medical Association Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currently practice in the US. We estimated emigration proportions, year of US entry, years of practice before emigration, and length of time in the US. According to the 2011 AMA-PM, 10,819 physicians were born or trained in 28 SSA countries. Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) were US-trained, and 12% (n = 1,323) were trained outside both SSA and the US. We estimated active physicians (age ≤ 70 years) to represent 96% (n = 10,377) of the total. Migration trends among SSA-trained physicians increased from 2002 to 2011 for all but one principal source country; the exception was South Africa whose physician migration to the US decreased by 8% (-156). The increase in last-decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and >200% (+244) in Sudan. Liberia was the most affected by migration to the US with 77% (n = 175) of its estimated physicians in the 2011 AMA-PM. On average, SSA-trained physicians have been in the US for 18 years. They practiced for 6.5 years before US entry, and nearly half emigrated during the implementation years (1984-1999) of the structural adjustment programs. CONCLUSION Physician emigration from SSA to the US is increasing for most SSA source countries. Unless far-reaching policies are implemented by the US and SSA countries, the current emigration trends will persist, and the US will remain a leading destination for SSA physicians emigrating from the continent of greatest need. Please see later in the article for the Editors' Summary.
&NA; Immune cells communicate by exchanging cytokines to achieve a context‐appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self‐assembled niches scaled with the density of cytokine‐consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80–120 &mgr;m, which resulted in a high degree of cell‐to‐cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non‐genetic cell‐to‐cell variability that is often overlooked in single‐cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors. Graphical Abstract Figure. No caption available. HighlightsCytokine penetration in tissues is governed by a diffusion‐consumption mechanismSpherical cytokine niches are generated around cytokine‐producing cellsThe characteristic niche size depends on the density of cytokine consumersCytokine niches are a source of variability in otherwise identical cells &NA; Cytokine‐mediated communication allows immune cells to achieve a context‐appropriate response, but the distance over which this communication happens is unclear. Oyler‐Yaniv et al. (2017) show that a simple diffusion‐consumption mechanism quantitatively describes the spatial spread of cytokines in vivo and results in localized niches of high cytokine concentrations that contribute to cell‐to‐cell variability.
BACKGROUND Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown. METHODS AND RESULTS In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01). CONCLUSIONS These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.
CONTEXT Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. OBJECTIVE To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). INTERVENTIONS Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. MAIN OUTCOME MEASURES The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. RESULTS There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). CONCLUSIONS These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00052026.
| 0.285714
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|
96
|
aug_679
|
Female carriers of the Apolipoprotein E4 (APOE4) allele have decreased risk for dementia.
OBJECTIVE To assess the performance and impact of primary human papillomavirus (HPV) DNA screening with cytology triage compared with conventional cytology on cervical cancer and severe pre-cancerous lesions. DESIGN Randomised trial. SETTING Population based screening programme for cervical cancer in southern Finland in 2003-5. PARTICIPANTS 58 076 women, aged 30-60, invited to the routine population based screening programme for cervical cancer. INTERVENTIONS Primary HPV DNA test (hybrid capture II) with cytology triage if the result was positive or conventional cytological screening (reference). MAIN OUTCOME MEASURES Rate of cervical cancer, cervical intraepithelial neoplasia (CIN) grade III, and adenocarcinoma in situ (as a composite outcome referred to as CIN III+) during 2003-7 through record linkage between files from the screening registry and the national cancer registry. RESULTS In the HPV and conventional arms there were 95 600 and 95 700 woman years of follow-up and 76 and 53 cases of CIN III+, respectively (of which six and eight were cervical cancers). The relative rate of CIN III+ in the HPV arm versus the conventional arm was 1.44 (95% confidence interval 1.01 to 2.05) among all women invited for screening and 1.77 (1.16 to 2.74) among those who attended. Among women with a normal or negative test result, the relative rate of subsequent CIN III+ was 0.28 (0.04 to 1.17). The rate of cervical cancer between arms was 0.75 (0.25 to 2.16) among women invited for screening and 1.98 (0.52 to 9.38) among those who attended. CONCLUSIONS When incorporated into a well established organised screening programme, primary HPV screening with cytology triage was more sensitive than conventional cytology in detecting CIN III+ lesions. The number of cases of cervical cancer was small, but considering the high probability of progression of CIN III the findings are of importance regarding cancer prevention. TRIAL REGISTRATION Current Controlled Trials ISRCTN23885553.
BACKGROUND Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART. METHODS AND FINDINGS Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results. CONCLUSIONS Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.
CONTEXT Exogenous estrogen use may lower risk of dementia in postmenopausal women. A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied. OBJECTIVE To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause. DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands. PARTICIPANTS A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia. MAIN OUTCOME MEASURES Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause. RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD. After adjusting for age, dementia was not clearly associated with length of reproductive period. However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84). The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08). For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively. Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed. CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause.
|
Female carriers of the Apolipoprotein E4 (APOE4) allele have decreased risk for dementia.
OBJECTIVE To assess the performance and impact of primary human papillomavirus (HPV) DNA screening with cytology triage compared with conventional cytology on cervical cancer and severe pre-cancerous lesions. DESIGN Randomised trial. SETTING Population based screening programme for cervical cancer in southern Finland in 2003-5. PARTICIPANTS 58 076 women, aged 30-60, invited to the routine population based screening programme for cervical cancer. INTERVENTIONS Primary HPV DNA test (hybrid capture II) with cytology triage if the result was positive or conventional cytological screening (reference). MAIN OUTCOME MEASURES Rate of cervical cancer, cervical intraepithelial neoplasia (CIN) grade III, and adenocarcinoma in situ (as a composite outcome referred to as CIN III+) during 2003-7 through record linkage between files from the screening registry and the national cancer registry. RESULTS In the HPV and conventional arms there were 95 600 and 95 700 woman years of follow-up and 76 and 53 cases of CIN III+, respectively (of which six and eight were cervical cancers). The relative rate of CIN III+ in the HPV arm versus the conventional arm was 1.44 (95% confidence interval 1.01 to 2.05) among all women invited for screening and 1.77 (1.16 to 2.74) among those who attended. Among women with a normal or negative test result, the relative rate of subsequent CIN III+ was 0.28 (0.04 to 1.17). The rate of cervical cancer between arms was 0.75 (0.25 to 2.16) among women invited for screening and 1.98 (0.52 to 9.38) among those who attended. CONCLUSIONS When incorporated into a well established organised screening programme, primary HPV screening with cytology triage was more sensitive than conventional cytology in detecting CIN III+ lesions. The number of cases of cervical cancer was small, but considering the high probability of progression of CIN III the findings are of importance regarding cancer prevention. TRIAL REGISTRATION Current Controlled Trials ISRCTN23885553.
BACKGROUND Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART. METHODS AND FINDINGS Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results. CONCLUSIONS Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.
CONTEXT Exogenous estrogen use may lower risk of dementia in postmenopausal women. A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied. OBJECTIVE To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause. DESIGN AND SETTING The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands. PARTICIPANTS A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche, age at menopause, and type of menopause. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for development of dementia. MAIN OUTCOME MEASURES Incidence of dementia, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria, and AD, based on National Institute of Neurological Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, compared by quartiles of reproductive period among women with natural menopause. RESULTS During 21 046 person-years of follow-up (median follow-up, 6.3 years), 199 women developed dementia, including 159 who developed AD. After adjusting for age, dementia was not clearly associated with length of reproductive period. However, after adjusting for multiple covariates, women with natural menopause and more reproductive years had an increased risk of dementia (adjusted rate ratio [RR] for women with >39 reproductive years [highest quartile] compared with <34 reproductive years [lowest quartile], 1.78; 95% confidence interval [CI], 1.12-2.84). The adjusted RR per year of increase was 1.04 (95% CI, 1.01-1.08). For risk of AD, the adjusted RRs were 1.51 (95% CI, 0.91-2.50) and 1.03 (95% CI, 1.00-1.07), respectively. Risk of dementia associated with a longer reproductive period was most pronounced in APOE epsilon4 carriers (adjusted RR for >39 reproductive years compared with <34 reproductive years, 4.20 [95% CI, 1.97-8.92] for dementia and 3.42 [95% CI, 1.51-7.75] for AD), whereas in noncarriers, no clear association with dementia or AD was observed. CONCLUSION Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause.
| 0.5
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413
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aug_680
|
1-1% of colorectal cancer patients are diagnosed with regional or distant metastases.
Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.
Cardiovascular disease is a leading cause of death worldwide. The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts. We discuss state-of-the-art methods for generating de novo cardiomyocytes from hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
OBJECTIVES To determine the extent to which type of hospital admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer. DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006. SETTING Hospital episode statistics (HES) dataset. PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer. MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment. RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies. For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34). There were some improvements in disparities between age groups but not for patients living in deprived areas over time. Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer. These findings did not improve with time. For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47). Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26). Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection. For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59). Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care.
|
1-1% of colorectal cancer patients are diagnosed with regional or distant metastases.
Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.
Cardiovascular disease is a leading cause of death worldwide. The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts. We discuss state-of-the-art methods for generating de novo cardiomyocytes from hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges.
Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function. SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined. Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype. PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes. Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation. Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings.
OBJECTIVES To determine the extent to which type of hospital admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer. DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006. SETTING Hospital episode statistics (HES) dataset. PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer. MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment. RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies. For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34). There were some improvements in disparities between age groups but not for patients living in deprived areas over time. Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer. These findings did not improve with time. For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47). Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26). Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection. For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59). Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care.
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aug_681
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In rhesus macaques, daily subcutaneous injections of tenofovir protects against rectally transmitted simian-human immunodeficiency virus.
The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS) administration. Atm(-/-) mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice. Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment. Atm(-/-) mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment. Markers of reactive oxygen and nitrogen species-mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice. Atm(-/-) mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
Background Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined.
To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition.
In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.
|
In rhesus macaques, daily subcutaneous injections of tenofovir protects against rectally transmitted simian-human immunodeficiency virus.
The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS) administration. Atm(-/-) mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice. Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment. Atm(-/-) mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment. Markers of reactive oxygen and nitrogen species-mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice. Atm(-/-) mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
Background Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined.
To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition.
In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues.
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584
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aug_682
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A T helper 2 cell (Th2) environment impedes disease development in patients with systemic lupus erythematosus (SLE).
In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.
|
A T helper 2 cell (Th2) environment impedes disease development in patients with systemic lupus erythematosus (SLE).
In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.
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28
|
aug_683
|
The proliferative capacity of neural progenitors differs across species.
The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2–mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
|
The proliferative capacity of neural progenitors differs across species.
The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2–mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.
Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output.
Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
| 0.5
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1254
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aug_684
|
A deficiency of vitamin B6 decreases blood levels of homocysteine.
OBJECTIVE To establish the mental health needs of homeless children and families before and after rehousing. DESIGN Cross sectional, longitudinal study. SETTING City of Birmingham. SUBJECTS 58 rehoused families with 103 children aged 2-16 years and 21 comparison families of low socioeconomic status in stable housing, with 54 children. MAIN OUTCOME MEASURES Children's mental health problems and level of communication; mothers' mental health problems and social support one year after rehousing. RESULTS Mental health problems remained significantly higher in rehoused mothers and their children than in the comparison group (mothers 26% v 5%, P = 0.04; children 39% v 11%, P = 0.0003). Homeless mothers continued to have significantly less social support at follow up. Mothers with a history of abuse and poor social integration were more likely to have children with persistent mental health problems. CONCLUSIONS Homeless families have a high level of complex needs that cannot be met by conventional health services and arrangements. Local strategies for rapid rehousing into permanent accommodation, effective social support and health care for parents and children, and protection from violence and intimidation should be developed and implemented.
Importance Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making. Objectives To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017. Exposures Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time. Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications. Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02). Conclusions and Relevance Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
Objective To explore the in vitro maintenance and characterization of human embryonic stem cells(hESCs).Methods hESCs were cultured on feeder layer with ES culture medium,which consists of 20% Knockout Serum Replacement,Knockout DMEM and 10 ng/mL bFGF.Undifferentiated status of hESCs was identified by cell morphology,and the expressions of cell surface marker SSEA-1,SSEA-3 and TRA-1-60.G banding technique was employed for cell karyotype analysis. Pluropotency of cells were analyzed via in vitro embyoid body(EB) formation and in vivo terotoma formation. Results Most of cells showed undifferentiated properties in cell morphology and normal karyotype throughout extended culture periods. They maintained undifferentiated status with positive immunoreactivity to SSEA-3,SSEA-4 and TRA-1-60.in vitro EB formation and in vivo teratoma formation demonstrated the pluripotency of human ES cells. Conclusion The fundamental requirement to hESCs for research and clinical application were their undifferentiated status and pluropotency in culture. Our result demonstrated their potential for these purposes.
The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses. The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to make recommendations that Enterprise stakeholders can use to plan new activities. Most effective viral vaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus, and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potent antiviral neutralizing antibodies. However, unlike acute viral pathogens, HIV-1 chronically replicates in the host and evades the antibody response. This immune evasion, along with the large genetic variation among HIV-1 strains worldwide, has posed major obstacles to vaccine development. Current HIV vaccine candidates do not elicit neutralizing antibodies against most circulating virus strains, and thus the induction of a protective antibody response remains a major priority for HIV-1 vaccine development. For an antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays that measure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolates representing the major genetic subtypes (clades) of HIV-1 [2]. Although it is not known what magnitude and breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccine immunogens elicit antibodies that neutralize only a minority of circulating isolates. Thus, much progress needs to be made in this area. Also, though virus neutralization is considered a critical benchmark for a vaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccine immunogens. The main targets for neutralizing antibodies to HIV-1 are the surface gp120 and trans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding and the subsequent membrane fusion events that allow the virus to gain entry into cells [3]. Antibodies neutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such as CD4+ T cells [4,5]. In order to chronically replicate in the host, the virus exploits several mechanisms to shield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linked glycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8]. These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitness constraints. Information on the precise location and molecular structure of these vulnerable regions could be valuable for the rational design of improved vaccine immunogens. Participants in the workshop identified four areas that, if given proper attention, could provide key information that would bring the field closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2) role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulation of B cell responses.
Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA). Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive. Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA. Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos. Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming. Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA. These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation.
|
A deficiency of vitamin B6 decreases blood levels of homocysteine.
OBJECTIVE To establish the mental health needs of homeless children and families before and after rehousing. DESIGN Cross sectional, longitudinal study. SETTING City of Birmingham. SUBJECTS 58 rehoused families with 103 children aged 2-16 years and 21 comparison families of low socioeconomic status in stable housing, with 54 children. MAIN OUTCOME MEASURES Children's mental health problems and level of communication; mothers' mental health problems and social support one year after rehousing. RESULTS Mental health problems remained significantly higher in rehoused mothers and their children than in the comparison group (mothers 26% v 5%, P = 0.04; children 39% v 11%, P = 0.0003). Homeless mothers continued to have significantly less social support at follow up. Mothers with a history of abuse and poor social integration were more likely to have children with persistent mental health problems. CONCLUSIONS Homeless families have a high level of complex needs that cannot be met by conventional health services and arrangements. Local strategies for rapid rehousing into permanent accommodation, effective social support and health care for parents and children, and protection from violence and intimidation should be developed and implemented.
Importance Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making. Objectives To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017. Exposures Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time. Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications. Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02). Conclusions and Relevance Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
Objective To explore the in vitro maintenance and characterization of human embryonic stem cells(hESCs).Methods hESCs were cultured on feeder layer with ES culture medium,which consists of 20% Knockout Serum Replacement,Knockout DMEM and 10 ng/mL bFGF.Undifferentiated status of hESCs was identified by cell morphology,and the expressions of cell surface marker SSEA-1,SSEA-3 and TRA-1-60.G banding technique was employed for cell karyotype analysis. Pluropotency of cells were analyzed via in vitro embyoid body(EB) formation and in vivo terotoma formation. Results Most of cells showed undifferentiated properties in cell morphology and normal karyotype throughout extended culture periods. They maintained undifferentiated status with positive immunoreactivity to SSEA-3,SSEA-4 and TRA-1-60.in vitro EB formation and in vivo teratoma formation demonstrated the pluripotency of human ES cells. Conclusion The fundamental requirement to hESCs for research and clinical application were their undifferentiated status and pluropotency in culture. Our result demonstrated their potential for these purposes.
The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses. The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 [1], and to make recommendations that Enterprise stakeholders can use to plan new activities. Most effective viral vaccines work, at least in part, by generating antibodies that inactivate or neutralize the invading virus, and the existing data strongly suggest that an optimally effective HIV-1 vaccine should elicit potent antiviral neutralizing antibodies. However, unlike acute viral pathogens, HIV-1 chronically replicates in the host and evades the antibody response. This immune evasion, along with the large genetic variation among HIV-1 strains worldwide, has posed major obstacles to vaccine development. Current HIV vaccine candidates do not elicit neutralizing antibodies against most circulating virus strains, and thus the induction of a protective antibody response remains a major priority for HIV-1 vaccine development. For an antibody-based HIV-1 vaccine, progress in vaccine design is generally gauged by in vitro assays that measure the ability of vaccine-induced antibodies to neutralize a broad spectrum of viral isolates representing the major genetic subtypes (clades) of HIV-1 [2]. Although it is not known what magnitude and breadth of neutralization will predict protection in vaccine recipients, it is clear that current vaccine immunogens elicit antibodies that neutralize only a minority of circulating isolates. Thus, much progress needs to be made in this area. Also, though virus neutralization is considered a critical benchmark for a vaccine, this may not be the only benchmark for predicting success with antibody-based HIV-1 vaccine immunogens. The main targets for neutralizing antibodies to HIV-1 are the surface gp120 and trans-membrane gp41 envelope glycoproteins (Env) that mediate receptor and coreceptor binding and the subsequent membrane fusion events that allow the virus to gain entry into cells [3]. Antibodies neutralize the virus by binding these viral spikes and blocking virus entry into susceptible cells, such as CD4+ T cells [4,5]. In order to chronically replicate in the host, the virus exploits several mechanisms to shield itself against antibody recognition, including a dense outer coating of sugar molecules (N-linked glycans) and the strategic positioning of cysteine–cysteine loop structures on the gp120 molecule [6–8]. These shielding mechanisms, although highly effective, have vulnerabilities imposed by fitness constraints. Information on the precise location and molecular structure of these vulnerable regions could be valuable for the rational design of improved vaccine immunogens. Participants in the workshop identified four areas that, if given proper attention, could provide key information that would bring the field closer to an effective antibody-based HIV-1 vaccine: (1) structure-assisted immunogen design, (2) role of Fc receptors and complement, (3) assay standardization and validation, and (4) immunoregulation of B cell responses.
Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA). Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive. Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA. Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos. Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming. Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA. These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation.
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aug_685
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Increased diastolic blood pressure (DBP) is associated with abdominal aortic aneurysm.
Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework-potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed.
OBJECTIVE To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches. DESIGN Meta-analysis. DATA SOURCES Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks. DATA EXTRACTION Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index. RESULTS 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and -0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02 and -0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=-0.11, 95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). CONCLUSIONS Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
CONTEXT Chronic low back pain (LBP) with degenerative lumbar osteoarthritis (OA) is widespread in the adult population. Although glucosamine is increasingly used by patients with chronic LBP, little is known about its effect in this setting. OBJECTIVE To investigate the effect of glucosamine in patients with chronic LBP and degenerative lumbar OA. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, placebo-controlled trial conducted at Oslo University Hospital Outpatient Clinic, Oslo, Norway, with 250 patients older than 25 years of age with chronic LBP (>6 months) and degenerative lumbar OA. INTERVENTIONS Daily intake of 1500 mg of oral glucosamine (n = 125) or placebo (n = 125) for 6 months, with assessment of effect after the 6-month intervention period and at 1 year (6 months postintervention). MAIN OUTCOME MEASURES The primary outcome was pain-related disability measured with the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes were numerical scores from pain-rating scales of patients at rest and during activity, and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument. Data collection occurred during the intervention period at baseline, 6 weeks, 3 and 6 months, and again 6 months following the intervention at 1 year. Group differences were analyzed using linear mixed models analysis. RESULTS At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4-10.0) for glucosamine and 9.7 (95% CI, 8.9-10.5) for the placebo group (P = .37). At 6 months, the mean RMDQ score was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2-5.8). At 1 year, the mean RMDQ scores were 4.8 (95% CI, 3.9-5.6) for glucosamine and 5.5 (95% CI, 4.7-6.4) for the placebo group. No statistically significant difference in change between groups was found when assessed after the 6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P = .97), and quality-of-life EQ-5D (P = .20). Mild adverse events were reported in 40 patients in the glucosamine group and 46 in the placebo group (P = .48). CONCLUSIONS Among patients with chronic LBP and degenerative lumbar OA, 6-month treatment with oral glucosamine compared with placebo did not result in reduced pain-related disability after the 6-month intervention and after 1-year follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00404079.
CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606.
|
Increased diastolic blood pressure (DBP) is associated with abdominal aortic aneurysm.
Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
The marginal costs and benefits of converting malaria programmes from a control to an elimination goal are central to strategic decisions, but empirical evidence is scarce. We present a conceptual framework to assess the economics of elimination and analyse a central component of that framework-potential short-term to medium-term financial savings. After a review that showed a dearth of existing evidence, the net present value of elimination in five sites was calculated and compared with effective control. The probability that elimination would be cost-saving over 50 years ranged from 0% to 42%, with only one site achieving cost-savings in the base case. These findings show that financial savings should not be a primary rationale for elimination, but that elimination might still be a worthy investment if total benefits are sufficient to outweigh marginal costs. Robust research into these elimination benefits is urgently needed.
OBJECTIVE To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches. DESIGN Meta-analysis. DATA SOURCES Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks. DATA EXTRACTION Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index. RESULTS 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and -0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02 and -0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=-0.11, 95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). CONCLUSIONS Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time.
CONTEXT Although cerebral palsy (CP) among extremely premature infants has been reported as a major morbidity outcome, there are difficulties comparing published CP rates from many sites over various birth years. OBJECTIVE To assess the changes in population-based, gestational age-specific prevalence rates of CP among extremely premature infants over 30 years. DESIGN Prospective population-based longitudinal outcome study. SETTING AND PARTICIPANTS In Northern Alberta, 2318 infants 20 to 27 weeks' gestational age with birth weights of 500 to 1249 g were liveborn from 1974 through 2003. By 2 years of age, 1437 (62%) had died, 23 (1%) were lost to follow-up, and 858 (37%) had received multidisciplinary neurodevelopmental assessment. MAIN OUTCOME MEASURE Population-based prevalence rates of CP were determined. Logistic regression with linear spline was used to assess changes in CP prevalence over time. RESULTS At age 2 years, 122 (14.2%) of 858 survivors had CP. This diagnosis was confirmed for each child by age 3 years or older. Among those whose gestational age was 20 to 25 weeks, population-based survival increased from 4% to 31% (P<.001), while CP prevalence per 1000 live births increased monotonically from 0 to 110 until the years 1992-1994 (P<.001) and decreased thereafter to 22 in the years 2001-2003 (P<.001). Among those whose gestational age was 26 to 27 weeks, population-based survival increased from 23% to between 75% and 80% (P<.001), while CP prevalence per 1000 live births increased monotonically from 15 to 155 until the years 1992-1994 (P<.001) and then decreased to 16 in the years 2001-2003 (P<.001). For all survivors born in the years 2001-2003, CP prevalence was 19 per 1000 live births. CONCLUSION Population-based CP prevalence rates for children whose gestational age was 20 to 27 weeks and whose birth weight ranged from 500 to 1249 g show steady reductions in the last decade with stable or reducing mortality, reversing trends prior to 1992-1994.
CONTEXT Chronic low back pain (LBP) with degenerative lumbar osteoarthritis (OA) is widespread in the adult population. Although glucosamine is increasingly used by patients with chronic LBP, little is known about its effect in this setting. OBJECTIVE To investigate the effect of glucosamine in patients with chronic LBP and degenerative lumbar OA. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, placebo-controlled trial conducted at Oslo University Hospital Outpatient Clinic, Oslo, Norway, with 250 patients older than 25 years of age with chronic LBP (>6 months) and degenerative lumbar OA. INTERVENTIONS Daily intake of 1500 mg of oral glucosamine (n = 125) or placebo (n = 125) for 6 months, with assessment of effect after the 6-month intervention period and at 1 year (6 months postintervention). MAIN OUTCOME MEASURES The primary outcome was pain-related disability measured with the Roland Morris Disability Questionnaire (RMDQ). Secondary outcomes were numerical scores from pain-rating scales of patients at rest and during activity, and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument. Data collection occurred during the intervention period at baseline, 6 weeks, 3 and 6 months, and again 6 months following the intervention at 1 year. Group differences were analyzed using linear mixed models analysis. RESULTS At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4-10.0) for glucosamine and 9.7 (95% CI, 8.9-10.5) for the placebo group (P = .37). At 6 months, the mean RMDQ score was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2-5.8). At 1 year, the mean RMDQ scores were 4.8 (95% CI, 3.9-5.6) for glucosamine and 5.5 (95% CI, 4.7-6.4) for the placebo group. No statistically significant difference in change between groups was found when assessed after the 6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P = .97), and quality-of-life EQ-5D (P = .20). Mild adverse events were reported in 40 patients in the glucosamine group and 46 in the placebo group (P = .48). CONCLUSIONS Among patients with chronic LBP and degenerative lumbar OA, 6-month treatment with oral glucosamine compared with placebo did not result in reduced pain-related disability after the 6-month intervention and after 1-year follow-up. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00404079.
CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606.
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607
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aug_686
|
Major antigen-induced signals from the T cell receptor and secondary signals from costimulatory receptors are required for T cell activation.
Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.
Earth-abundant first-row (3d) transition metal–based catalysts have been developed for the oxygen-evolution reaction (OER); however, they operate at overpotentials substantially above thermodynamic requirements. Density functional theory suggested that non-3d high-valency metals such as tungsten can modulate 3d metal oxides, providing near-optimal adsorption energies for OER intermediates. We developed a room-temperature synthesis to produce gelled oxyhydroxides materials with an atomically homogeneous metal distribution. These gelled FeCoW oxyhydroxides exhibit the lowest overpotential (191 millivolts) reported at 10 milliamperes per square centimeter in alkaline electrolyte. The catalyst shows no evidence of degradation after more than 500 hours of operation. X-ray absorption and computational studies reveal a synergistic interplay between tungsten, iron, and cobalt in producing a favorable local coordination environment and electronic structure that enhance the energetics for OER.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
OBJECTIVE To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables. DESIGN Systematic review and meta-analysis. DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials. STUDY SELECTION Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference). DATA EXTRACTION Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality. RESULTS 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section. CONCLUSION Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.
|
Major antigen-induced signals from the T cell receptor and secondary signals from costimulatory receptors are required for T cell activation.
Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.
Earth-abundant first-row (3d) transition metal–based catalysts have been developed for the oxygen-evolution reaction (OER); however, they operate at overpotentials substantially above thermodynamic requirements. Density functional theory suggested that non-3d high-valency metals such as tungsten can modulate 3d metal oxides, providing near-optimal adsorption energies for OER intermediates. We developed a room-temperature synthesis to produce gelled oxyhydroxides materials with an atomically homogeneous metal distribution. These gelled FeCoW oxyhydroxides exhibit the lowest overpotential (191 millivolts) reported at 10 milliamperes per square centimeter in alkaline electrolyte. The catalyst shows no evidence of degradation after more than 500 hours of operation. X-ray absorption and computational studies reveal a synergistic interplay between tungsten, iron, and cobalt in producing a favorable local coordination environment and electronic structure that enhance the energetics for OER.
The metabolic stress-sensing enzyme AMP-activated protein kinase (AMPK) is responsible for regulating metabolism in response to energy supply and demand. Drugs that activate AMPK may be useful in the treatment of metabolic diseases including type 2 diabetes. We have determined the crystal structure of AMPK in complex with its activator 5-(5-hydroxyl-isoxazol-3-yl)-furan-2-phosphonic acid (C2), revealing two C2-binding sites in the γ-subunit distinct from nucleotide sites. C2 acts synergistically with the drug A769662 to activate AMPK α1-containing complexes independent of upstream kinases. Our results show that dual drug therapies could be effective AMPK-targeting strategies to treat metabolic diseases.
OBJECTIVE To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables. DESIGN Systematic review and meta-analysis. DATA SOURCES Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials. STUDY SELECTION Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference). DATA EXTRACTION Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality. RESULTS 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section. CONCLUSION Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
AgRP neuron activity drives feeding and weight gain whereas that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting.
| 0
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|
749
|
aug_687
|
Pharmacist attendance at ward rounds reduces adverse events in wards.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network. We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes. In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
The tastes of sugars (sweet) and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells.
|
Pharmacist attendance at ward rounds reduces adverse events in wards.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA-damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 (radiation sensitive 53) kinase-dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo and seem to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the Tyr 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the ubiquitin conjugating enzymes (E2) Ubc4 and Ubc5, as well as the ubiquitin ligase (E3) Tom1 (temperature dependent organization in mitotic nucleus 1), as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network. We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes. In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
The tastes of sugars (sweet) and glutamate (umami) are thought to be detected by T1r receptors expressed in taste cells. Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells.
| 0
|
{
"query_id": "941",
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|
941
|
aug_688
|
Inhibiting glucose-6-phospate dehydrogenase improves lipogenesis by deactivating LKB1-AMPK signaling.
BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.
It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.
The overall size and structure of a synaptic terminal is an important determinant of its function. In a large-scale mutagenesis screen, designed to identify Drosophila mutants with abnormally structured neuromuscular junctions (NMJs), we discovered mutations in Drosophila mical, a conserved gene encoding a multi-domain protein with a N-terminal monooxygenase domain. In mical mutants, synaptic boutons do not sprout normally over the muscle surface and tend to form clusters along synaptic branches and at nerve entry sites. Consistent with high expression of MICAL in somatic muscles, immunohistochemical stainings reveal that the subcellular localization and architecture of contractile muscle filaments are dramatically disturbed in mical mutants. Instead of being integrated into a regular sarcomeric pattern, actin and myosin filaments are disorganized and accumulate beneath the plasmamembrane. Whereas contractile elements are strongly deranged, the proposed organizer of sarcomeric structure, D-Titin, is much less affected. Transgenic expression of interfering RNA molecules demonstrates that MICAL is required in muscles for the higher order arrangement of myofilaments. Ultrastructural analysis confirms that myosin-rich thick filaments enter submembranous regions and interfere with synaptic development, indicating that the disorganized myofilaments may cause the synaptic growth phenotype. As a model, we suggest that the filamentous network around synaptic boutons restrains the spreading of synaptic branches.
Background Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet. This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance. Methods and Findings We selected for study nine adults with celiac disease who had a history of oats exposure. Four of the patients had clinical symptoms on an oats-containing diet, and three of these four patients had intestinal inflammation typical of celiac disease at the time of oats exposure. We established oats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from two other patients who appeared to tolerate oats. The avenin-reactive T-cell lines recognized avenin peptides in the context of HLA-DQ2. These peptides have sequences rich in proline and glutamine residues closely resembling wheat gluten epitopes. Deamidation (glutamine→glutamic acid conversion) by tissue transglutaminase was involved in the avenin epitope formation. Conclusions We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. Oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet. Clinical follow-up of celiac disease patients eating oats is advisable.
IMPORTANCE The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01295827.
|
Inhibiting glucose-6-phospate dehydrogenase improves lipogenesis by deactivating LKB1-AMPK signaling.
BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease. METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis. CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.
It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life.
The overall size and structure of a synaptic terminal is an important determinant of its function. In a large-scale mutagenesis screen, designed to identify Drosophila mutants with abnormally structured neuromuscular junctions (NMJs), we discovered mutations in Drosophila mical, a conserved gene encoding a multi-domain protein with a N-terminal monooxygenase domain. In mical mutants, synaptic boutons do not sprout normally over the muscle surface and tend to form clusters along synaptic branches and at nerve entry sites. Consistent with high expression of MICAL in somatic muscles, immunohistochemical stainings reveal that the subcellular localization and architecture of contractile muscle filaments are dramatically disturbed in mical mutants. Instead of being integrated into a regular sarcomeric pattern, actin and myosin filaments are disorganized and accumulate beneath the plasmamembrane. Whereas contractile elements are strongly deranged, the proposed organizer of sarcomeric structure, D-Titin, is much less affected. Transgenic expression of interfering RNA molecules demonstrates that MICAL is required in muscles for the higher order arrangement of myofilaments. Ultrastructural analysis confirms that myosin-rich thick filaments enter submembranous regions and interfere with synaptic development, indicating that the disorganized myofilaments may cause the synaptic growth phenotype. As a model, we suggest that the filamentous network around synaptic boutons restrains the spreading of synaptic branches.
Background Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations. It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet. Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet. This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance. Methods and Findings We selected for study nine adults with celiac disease who had a history of oats exposure. Four of the patients had clinical symptoms on an oats-containing diet, and three of these four patients had intestinal inflammation typical of celiac disease at the time of oats exposure. We established oats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from two other patients who appeared to tolerate oats. The avenin-reactive T-cell lines recognized avenin peptides in the context of HLA-DQ2. These peptides have sequences rich in proline and glutamine residues closely resembling wheat gluten epitopes. Deamidation (glutamine→glutamic acid conversion) by tissue transglutaminase was involved in the avenin epitope formation. Conclusions We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation. Oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet. Clinical follow-up of celiac disease patients eating oats is advisable.
IMPORTANCE The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01295827.
| 0.285714
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635
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aug_689
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Induction of urokinase receptor signaling in podocytes causes foot process effacement and proteinuria.
Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Mice lacking uPAR (Plaur−/−) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.
|
Induction of urokinase receptor signaling in podocytes causes foot process effacement and proteinuria.
Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Mice lacking uPAR (Plaur−/−) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.
| 1
|
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626
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aug_690
|
miRNAs enforce homeostasis by suppressing low-level ''leaky'' transcription.
Nanotechnologies are emerging platforms that could be useful in measuring, understanding, and manipulating stem cells. Examples include magnetic nanoparticles and quantum dots for stem cell labeling and in vivo tracking; nanoparticles, carbon nanotubes, and polyplexes for the intracellular delivery of genes/oligonucleotides and protein/peptides; and engineered nanometer-scale scaffolds for stem cell differentiation and transplantation. This review examines the use of nanotechnologies for stem cell tracking, differentiation, and transplantation. We further discuss their utility and the potential concerns regarding their cytotoxicity.
BACKGROUND The diagnosis of hypertension has traditionally been based on blood-pressure measurements in the clinic, but home and ambulatory measurements better correlate with cardiovascular outcome, and ambulatory monitoring is more accurate than both clinic and home monitoring in diagnosing hypertension. We aimed to compare the cost-effectiveness of different diagnostic strategies for hypertension. METHODS We did a Markov model-based probabilistic cost-effectiveness analysis. We used a hypothetical primary-care population aged 40 years or older with a screening blood-pressure measurement greater than 140/90 mm Hg and risk-factor prevalence equivalent to the general population. We compared three diagnostic strategies-further blood pressure measurement in the clinic, at home, and with an ambulatory monitor-in terms of lifetime costs, quality-adjusted life years, and cost-effectiveness. FINDINGS Ambulatory monitoring was the most cost-effective strategy for the diagnosis of hypertension for men and women of all ages. It was cost-saving for all groups (from -£56 [95% CI -105 to -10] in men aged 75 years to -£323 [-389 to -222] in women aged 40 years) and resulted in more quality-adjusted life years for men and women older than 50 years (from 0·006 [0·000 to 0·015] for women aged 60 years to 0·022 [0·012 to 0·035] for men aged 70 years). This finding was robust when assessed with a wide range of deterministic sensitivity analyses around the base case, but was sensitive if home monitoring was judged to have equal test performance to ambulatory monitoring or if treatment was judged effective irrespective of whether an individual was hypertensive. INTERPRETATION Ambulatory monitoring as a diagnostic strategy for hypertension after an initial raised reading in the clinic would reduce misdiagnosis and save costs. Additional costs from ambulatory monitoring are counterbalanced by cost savings from better targeted treatment. Ambulatory monitoring is recommended for most patients before the start of antihypertensive drugs. FUNDING National Institute for Health Research and the National Institute for Health and Clinical Excellence.
Autoantibodies to DNA and histones (chromatin) are the defining antigen specificity in systemic lupus erythematosus (SLE) and related musculoskeletal disorders but the mechanisms responsible for their induction remain mysterious. That situation rapidly changed once neutrophil extracellular chromatin traps (NETs) were discovered and observed to play a conserved role in innate immune responses to a broad variety of microbial pathogens. At the center of an infectious process, neutrophils exert various antimicrobial defenses, including the release of nuclear chromatin into the extracellular space. The externalized NETs, a complex meshwork of nuclear chromatin and antimicrobial proteins, serve to immobilize and degrade microbial pathogens. Here, we critically evaluate the evidence supporting NETs versus apoptotic bodies as a source for nuclear antigens in autoimmunity. We also discuss the possibility that NET chromatin forms an essential component of immune deposits in the pathogenesis of glomerulonephritis in SLE and other autoimmune immune complex diseases.
Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development. Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress. This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress.
BACKGROUND The main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people. The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies. METHODS Collaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)). The analyses were adjusted for age, sex, smoking status, and study. To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other. FINDINGS In both sexes, mortality was lowest at about 22.5-25 kg/m(2). Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI 1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepatic mortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% for neoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20 [1.07-1.34] and 1.20 [1.16-1.25], respectively). Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer. These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI. INTERPRETATION Although other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22.5-25 kg/m(2). The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal. At 30-35 kg/m(2), median survival is reduced by 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects of smoking). The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases, and is not fully explained.
Recognition of modified histones by ‘reader’ proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific ‘Ser 31’ residue in a composite pocket formed by the tandem bromo–PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.
|
miRNAs enforce homeostasis by suppressing low-level ''leaky'' transcription.
Nanotechnologies are emerging platforms that could be useful in measuring, understanding, and manipulating stem cells. Examples include magnetic nanoparticles and quantum dots for stem cell labeling and in vivo tracking; nanoparticles, carbon nanotubes, and polyplexes for the intracellular delivery of genes/oligonucleotides and protein/peptides; and engineered nanometer-scale scaffolds for stem cell differentiation and transplantation. This review examines the use of nanotechnologies for stem cell tracking, differentiation, and transplantation. We further discuss their utility and the potential concerns regarding their cytotoxicity.
BACKGROUND The diagnosis of hypertension has traditionally been based on blood-pressure measurements in the clinic, but home and ambulatory measurements better correlate with cardiovascular outcome, and ambulatory monitoring is more accurate than both clinic and home monitoring in diagnosing hypertension. We aimed to compare the cost-effectiveness of different diagnostic strategies for hypertension. METHODS We did a Markov model-based probabilistic cost-effectiveness analysis. We used a hypothetical primary-care population aged 40 years or older with a screening blood-pressure measurement greater than 140/90 mm Hg and risk-factor prevalence equivalent to the general population. We compared three diagnostic strategies-further blood pressure measurement in the clinic, at home, and with an ambulatory monitor-in terms of lifetime costs, quality-adjusted life years, and cost-effectiveness. FINDINGS Ambulatory monitoring was the most cost-effective strategy for the diagnosis of hypertension for men and women of all ages. It was cost-saving for all groups (from -£56 [95% CI -105 to -10] in men aged 75 years to -£323 [-389 to -222] in women aged 40 years) and resulted in more quality-adjusted life years for men and women older than 50 years (from 0·006 [0·000 to 0·015] for women aged 60 years to 0·022 [0·012 to 0·035] for men aged 70 years). This finding was robust when assessed with a wide range of deterministic sensitivity analyses around the base case, but was sensitive if home monitoring was judged to have equal test performance to ambulatory monitoring or if treatment was judged effective irrespective of whether an individual was hypertensive. INTERPRETATION Ambulatory monitoring as a diagnostic strategy for hypertension after an initial raised reading in the clinic would reduce misdiagnosis and save costs. Additional costs from ambulatory monitoring are counterbalanced by cost savings from better targeted treatment. Ambulatory monitoring is recommended for most patients before the start of antihypertensive drugs. FUNDING National Institute for Health Research and the National Institute for Health and Clinical Excellence.
Autoantibodies to DNA and histones (chromatin) are the defining antigen specificity in systemic lupus erythematosus (SLE) and related musculoskeletal disorders but the mechanisms responsible for their induction remain mysterious. That situation rapidly changed once neutrophil extracellular chromatin traps (NETs) were discovered and observed to play a conserved role in innate immune responses to a broad variety of microbial pathogens. At the center of an infectious process, neutrophils exert various antimicrobial defenses, including the release of nuclear chromatin into the extracellular space. The externalized NETs, a complex meshwork of nuclear chromatin and antimicrobial proteins, serve to immobilize and degrade microbial pathogens. Here, we critically evaluate the evidence supporting NETs versus apoptotic bodies as a source for nuclear antigens in autoimmunity. We also discuss the possibility that NET chromatin forms an essential component of immune deposits in the pathogenesis of glomerulonephritis in SLE and other autoimmune immune complex diseases.
Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development. Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress. This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress.
BACKGROUND The main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people. The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies. METHODS Collaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)). The analyses were adjusted for age, sex, smoking status, and study. To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other. FINDINGS In both sexes, mortality was lowest at about 22.5-25 kg/m(2). Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI 1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepatic mortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% for neoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20 [1.07-1.34] and 1.20 [1.16-1.25], respectively). Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer. These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI. INTERPRETATION Although other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22.5-25 kg/m(2). The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal. At 30-35 kg/m(2), median survival is reduced by 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects of smoking). The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases, and is not fully explained.
Recognition of modified histones by ‘reader’ proteins plays a critical role in the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions after RNA polymerase II elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin to a relatively repressive state, thus suppressing cryptic transcription. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies. Here we show that the candidate tumour suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II elongation. Structural studies show that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific ‘Ser 31’ residue in a composite pocket formed by the tandem bromo–PWWP domains of ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumour cell growth; low expression levels of ZMYND11 in breast cancer patients correlate with worse prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone-variant-mediated transcription elongation control to tumour suppression.
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1393
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aug_691
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Increased conversion of PGE 2 to PPARy ligand 15-ket-PGE 2 causes accumulation of PGE.
Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.
Pluripotent mouse embryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions. In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells has proven elusive. Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS) cells. NS cells were derived first from mouse ES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic. After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produce neurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia. Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can be generated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying differentiation. These homogenous cultures will enable delineation of molecular mechanisms that define a tissue-specific stem cell and allow direct comparison with pluripotent ES cells.
|
Increased conversion of PGE 2 to PPARy ligand 15-ket-PGE 2 causes accumulation of PGE.
Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.
Pluripotent mouse embryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions. In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells has proven elusive. Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS) cells. NS cells were derived first from mouse ES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic. After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produce neurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia. Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can be generated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying differentiation. These homogenous cultures will enable delineation of molecular mechanisms that define a tissue-specific stem cell and allow direct comparison with pluripotent ES cells.
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606
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aug_692
|
Pre-mRNAs associated with spliceosomal components are less stable than unassociated splicing substrates.
Multicellular animals rapidly clear dying cells from their bodies. Many of the pathways that mediate this cell removal are conserved through evolution. Here, we identify srgp-1 as a negative regulator of cell clearance in both Caenorhabditis elegans and mammalian cells. Loss of srgp-1 function results in improved engulfment of apoptotic cells, whereas srgp-1 overexpression inhibits apoptotic cell corpse removal. We show that SRGP-1 functions in engulfing cells and functions as a GTPase activating protein (GAP) for CED-10 (Rac1). Interestingly, loss of srgp-1 function promotes not only the clearance of already dead cells, but also the removal of cells that have been brought to the verge of death through sublethal apoptotic, necrotic or cytotoxic insults. In contrast, impaired engulfment allows damaged cells to escape clearance, which results in increased long-term survival. We propose that C. elegans uses the engulfment machinery as part of a primitive, but evolutionarily conserved, survey mechanism that identifies and removes unfit cells within a tissue.
Human cytomegalovirus (HCMV) is one of the largest known DNA viruses. It is ubiquitous, and following resolution of primary productive infection, it persists in the human host by establishing a lifelong latent infection in myeloid lineage cells such as monocytes and their progenitors. Most adults with HCMV infection are healthy but it can cause neurologic deficits in infants, and remains an important cause of morbidity and mortality in the immunosuppressed patient. Microarray-based studies of HCMV have provided useful information about genes that are transcriptionally active during both productive and latent phases of infection. This chapter describes how to study genes in HCMV using microarrays and two cell types (productively infected human foreskin fibroblasts, and latently infected primary human myeloid progenitor cells).
Importance Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making. Objectives To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017. Exposures Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time. Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications. Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02). Conclusions and Relevance Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.
BACKGROUND Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. METHODS In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. FINDINGS The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. INTERPRETATION Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. FUNDING British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.
|
Pre-mRNAs associated with spliceosomal components are less stable than unassociated splicing substrates.
Multicellular animals rapidly clear dying cells from their bodies. Many of the pathways that mediate this cell removal are conserved through evolution. Here, we identify srgp-1 as a negative regulator of cell clearance in both Caenorhabditis elegans and mammalian cells. Loss of srgp-1 function results in improved engulfment of apoptotic cells, whereas srgp-1 overexpression inhibits apoptotic cell corpse removal. We show that SRGP-1 functions in engulfing cells and functions as a GTPase activating protein (GAP) for CED-10 (Rac1). Interestingly, loss of srgp-1 function promotes not only the clearance of already dead cells, but also the removal of cells that have been brought to the verge of death through sublethal apoptotic, necrotic or cytotoxic insults. In contrast, impaired engulfment allows damaged cells to escape clearance, which results in increased long-term survival. We propose that C. elegans uses the engulfment machinery as part of a primitive, but evolutionarily conserved, survey mechanism that identifies and removes unfit cells within a tissue.
Human cytomegalovirus (HCMV) is one of the largest known DNA viruses. It is ubiquitous, and following resolution of primary productive infection, it persists in the human host by establishing a lifelong latent infection in myeloid lineage cells such as monocytes and their progenitors. Most adults with HCMV infection are healthy but it can cause neurologic deficits in infants, and remains an important cause of morbidity and mortality in the immunosuppressed patient. Microarray-based studies of HCMV have provided useful information about genes that are transcriptionally active during both productive and latent phases of infection. This chapter describes how to study genes in HCMV using microarrays and two cell types (productively infected human foreskin fibroblasts, and latently infected primary human myeloid progenitor cells).
Importance Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making. Objectives To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017. Exposures Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time. Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications. Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02). Conclusions and Relevance Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.
BACKGROUND Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. METHODS In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. FINDINGS The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. INTERPRETATION Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. FUNDING British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
In systemic lupus erythematosus (SLE), self-reactive antibodies can target the kidney (lupus nephritis), leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE causes their homing to lymph nodes, promoting T helper type 2 (T(H)2) cell differentiation and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in mice lacking the Src family protein tyrosine kinase Lyn (Lyn(-/-) mice). Individuals with SLE also have elevated serum IgE, self-reactive IgEs and activated basophils that express CD62 ligand (CD62L) and the major histocompatibility complex (MHC) class II molecule human leukocyte antigen-DR (HLA-DR), parameters that are associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of subjects with SLE. Thus, in Lyn(-/-) mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in individuals with SLE IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.
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"sampling_strategy_version": "context_builder_v2.3_msmarco_balanced_f1",
"augmented": true,
"original_id": "",
"type": "pathfinderrag_test"
}
|
963
|
aug_693
|
Hypothalamic glutamate neurotransmission is unrelated to energy balance.
The importance of neuropeptides in the hypothalamus has been experimentally established. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia.
In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedial hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center.
The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.
|
Hypothalamic glutamate neurotransmission is unrelated to energy balance.
The importance of neuropeptides in the hypothalamus has been experimentally established. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia.
In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding and neuropeptide-Y (NPY) neurons stimulate feeding. We tested whether neurons in the ventromedial hypothalamic nucleus (VMH), a known satiety center, activate anorexigenic neuronal pathways in the ARC by projecting either excitatory synaptic inputs to POMC neurons and/or inhibitory inputs to NPY neurons. Using laser scanning photostimulation in brain slices from transgenic mice, we found that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs. POMC neurons received strong excitatory input from the medial VMH (mVMH), whereas NPY neurons did not and, instead, received weak inhibitory input only from within the ARC. The strength of the excitatory input from the mVMH to POMC neurons was diminished by fasting. These data identify a new molecularly defined circuit that is dynamically regulated by nutritional state in a manner consistent with the known role of the VMH as a satiety center.
The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.
| 1
|
{
"query_id": "541",
"original_query_id": "541",
"context_doc_ids": [
"45154987",
"25007443",
"11886686"
],
"gold_doc_ids_in_context": [
"25007443",
"11886686",
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"context_size": 3,
"generation_version": "1.0.0",
"generation_timestamp": "2025-07-24T12:04:39.274392",
"dataset": "scifact",
"generation_date": "2025-07-22T13:26:34",
"generator_version": "1.0.0",
"positive_samples_considered": [
"11886686",
"45154987",
"25007443"
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"45154987"
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"augmented": true,
"original_id": "",
"type": "pathfinderrag_test"
}
|
541
|
aug_694
|
Sequence conservation in gene regulatory regions between species is a high-accuracy predictor of conserved functionality.
Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity.
The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.
Objective To explore the in vitro maintenance and characterization of human embryonic stem cells(hESCs).Methods hESCs were cultured on feeder layer with ES culture medium,which consists of 20% Knockout Serum Replacement,Knockout DMEM and 10 ng/mL bFGF.Undifferentiated status of hESCs was identified by cell morphology,and the expressions of cell surface marker SSEA-1,SSEA-3 and TRA-1-60.G banding technique was employed for cell karyotype analysis. Pluropotency of cells were analyzed via in vitro embyoid body(EB) formation and in vivo terotoma formation. Results Most of cells showed undifferentiated properties in cell morphology and normal karyotype throughout extended culture periods. They maintained undifferentiated status with positive immunoreactivity to SSEA-3,SSEA-4 and TRA-1-60.in vitro EB formation and in vivo teratoma formation demonstrated the pluripotency of human ES cells. Conclusion The fundamental requirement to hESCs for research and clinical application were their undifferentiated status and pluropotency in culture. Our result demonstrated their potential for these purposes.
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
|
Sequence conservation in gene regulatory regions between species is a high-accuracy predictor of conserved functionality.
Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity.
The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.
Objective To explore the in vitro maintenance and characterization of human embryonic stem cells(hESCs).Methods hESCs were cultured on feeder layer with ES culture medium,which consists of 20% Knockout Serum Replacement,Knockout DMEM and 10 ng/mL bFGF.Undifferentiated status of hESCs was identified by cell morphology,and the expressions of cell surface marker SSEA-1,SSEA-3 and TRA-1-60.G banding technique was employed for cell karyotype analysis. Pluropotency of cells were analyzed via in vitro embyoid body(EB) formation and in vivo terotoma formation. Results Most of cells showed undifferentiated properties in cell morphology and normal karyotype throughout extended culture periods. They maintained undifferentiated status with positive immunoreactivity to SSEA-3,SSEA-4 and TRA-1-60.in vitro EB formation and in vivo teratoma formation demonstrated the pluripotency of human ES cells. Conclusion The fundamental requirement to hESCs for research and clinical application were their undifferentiated status and pluropotency in culture. Our result demonstrated their potential for these purposes.
Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.
| 0.4
|
{
"query_id": "1074",
"original_query_id": "1074",
"context_doc_ids": [
"17150648",
"14658685",
"2462673",
"87610599"
],
"gold_doc_ids_in_context": [
"14658685"
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"context_f1": 0.4,
"context_size": 4,
"generation_version": "1.0.0",
"generation_timestamp": "2025-07-24T12:04:39.274420",
"dataset": "scifact",
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"generator_version": "1.0.0",
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"14658685"
],
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"87610599",
"17150648",
"2462673"
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"actual_context_size": 4,
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"augmented": true,
"original_id": "",
"type": "pathfinderrag_test"
}
|
1074
|
aug_695
|
Varenicline monotherapy is more effective after 26 weeks of treatment compared to combination nicotine replacement therapies with varenicline or bupropion.
IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence. OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study. INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo. MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically confirmed. RESULTS At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03). CONCLUSIONS AND RELEVANCE Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks. Neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination therapy in smoking cessation. TRIAL REGISTRATION clinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818.
|
Varenicline monotherapy is more effective after 26 weeks of treatment compared to combination nicotine replacement therapies with varenicline or bupropion.
IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence. OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study. INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo. MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically confirmed. RESULTS At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03). CONCLUSIONS AND RELEVANCE Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks. Neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination therapy in smoking cessation. TRIAL REGISTRATION clinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818.
| 1
|
{
"query_id": "1360",
"original_query_id": "1360",
"context_doc_ids": [
"11614737"
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"context_f1": 1,
"context_size": 1,
"generation_version": "1.0.0",
"generation_timestamp": "2025-07-24T12:04:39.274463",
"dataset": "scifact",
"generation_date": "2025-07-22T13:26:34",
"generator_version": "1.0.0",
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|
1360
|
aug_696
|
Rhythmic expression of Cry1 translates directly into a circadian regulation of cAMP signaling in hepatic glucose metabolism.
During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.
|
Rhythmic expression of Cry1 translates directly into a circadian regulation of cAMP signaling in hepatic glucose metabolism.
During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.
| 1
|
{
"query_id": "1045",
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"22500262"
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"22500262"
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"generation_version": "1.0.0",
"generation_timestamp": "2025-07-24T12:04:39.274492",
"dataset": "scifact",
"generation_date": "2025-07-22T13:26:34",
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"type": "pathfinderrag_test"
}
|
1045
|
aug_697
|
BiP is a general endoplasmic reticulum stress marker.
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
|
BiP is a general endoplasmic reticulum stress marker.
IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.
To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
| 0.5
|
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|
176
|
aug_698
|
Expression of oncolytic virus antigens as peptides makes relapse more likely.
To identify previously unknown platelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays. Bioinformatical analysis of MK-up-regulated genes identified 151 transcripts encoding transmembrane domain-containing proteins. Although many of these were known platelet genes, a number of previously unidentified or poorly characterized transcripts were also detected. Many of these transcripts, including G6b, G6f, LRRC32, LAT2, and the G protein-coupled receptor SUCNR1, encode proteins with structural features or functions that suggest they may be involved in the modulation of platelet function. Immunoblotting on platelets confirmed the presence of the encoded proteins, and flow cytometric analysis confirmed the expression of G6b, G6f, and LRRC32 on the surface of platelets. Through comparative analysis of expression in platelets and other blood cells we demonstrated that G6b, G6f, and LRRC32 are restricted to the platelet lineage, whereas LAT2 and SUCNR1 were also detected in other blood cells. The identification of the succinate receptor SUCNR1 in platelets is of particular interest, because physiologically relevant concentrations of succinate were shown to potentiate the effect of low doses of a variety of platelet agonists.
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.
CONTEXT Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN Prospective cohort study. SETTING AND PATIENTS In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.
Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
|
Expression of oncolytic virus antigens as peptides makes relapse more likely.
To identify previously unknown platelet receptors we compared the transcriptomes of in vitro differentiated megakaryocytes (MKs) and erythroblasts (EBs). RNA was obtained from purified, biologically paired MK and EB cultures and compared using cDNA microarrays. Bioinformatical analysis of MK-up-regulated genes identified 151 transcripts encoding transmembrane domain-containing proteins. Although many of these were known platelet genes, a number of previously unidentified or poorly characterized transcripts were also detected. Many of these transcripts, including G6b, G6f, LRRC32, LAT2, and the G protein-coupled receptor SUCNR1, encode proteins with structural features or functions that suggest they may be involved in the modulation of platelet function. Immunoblotting on platelets confirmed the presence of the encoded proteins, and flow cytometric analysis confirmed the expression of G6b, G6f, and LRRC32 on the surface of platelets. Through comparative analysis of expression in platelets and other blood cells we demonstrated that G6b, G6f, and LRRC32 are restricted to the platelet lineage, whereas LAT2 and SUCNR1 were also detected in other blood cells. The identification of the succinate receptor SUCNR1 in platelets is of particular interest, because physiologically relevant concentrations of succinate were shown to potentiate the effect of low doses of a variety of platelet agonists.
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts.
CONTEXT Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN Prospective cohort study. SETTING AND PATIENTS In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.
Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
| 0.333333
|
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|
403
|
aug_699
|
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