# embeddings_queue

created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1428
encoding: FLOAT32
metadata:
{"title": "Mocrobial metabolites as modulators of the infant gut microbiome and host-microbiome interations in early life", "chroma:document": "Department of Nutrition, Exercise and Sports, University of Copenhagen, Rolighedsvej 30, Frederiksberg \nDK-1958, Denmark\nGUT MICROBES                                              \n2023, VOL. 15, NO. 1, 2192151 \nhttps://doi.org/10.1080/19490976.2023.2192151\n\u00a9 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, \ndistribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted \nManuscript in a repository by the author(s) or with their consent."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1429
encoding: FLOAT32
metadata:
{"title": "Genetic structure of the population with rheumatoid arthritis in north east England: a genetic approach to define different subtypes", "chroma:document": "Annals of the Rheumatic Diseases,\n1986; 45, 881-891\nGenetic structure of the population with rheumatoid\narthritis in north east England: a genetic approach to\ndefine different subtypes\nS S PAPIHA,' J S LANCHBURY,' AND B PAL2\nFrom the 'Department of Human Genetics, Medical School, University of Newcastle upon Tyne; and the\n2Department of Rheumatology, Dryburn Hospital, Durham\nSUMMARY\nClinically and immunologically rheumatoid arthritis (RA) is possibly a heterogeneous\ndisorder. Despite numerous efforts clearer definition of this heterogeneity has been of limited\nsuccess. Measurements of rheumatoid factor (RF) and antinuclear antibodies (ANA) by\nconventional methods define subpopulations of patients with RA and in a few recent studies an\nassociation of human leucocyte antigens (HLA) undoubtedly indicates the immunogenetic\ndifferences in the susceptibility of RA patients with different status of autoantibodies. The\nstudies on a few isolated non-HLA genetic markers in RA are controversial. To understand the\nrole of genetic factors\nin susceptibility 24 single\ngene characters other than HLA were\ninvestigated in 225 patients with RA classified by humoral status (presence or absence of RF and\nANA) into three groups and in 104 healthy control individuals from the north east of England.\nLocus by locus comparison suggested associations of MN, Lewis, and Bf system with RF positive\npatients.\nAlthough\nthe\nassociations\nwith MN and\nLewis\nblood\ngroups\nrequire\nfurther\ninvestigations,\nthe involvement of the Bf locus\nis\nin agreement with the immunological\ncomponent of the disease suggested by HLA associations and it could be due to the phenomenon\nof linkage disequilibrium. Measures of genetic distance applied to the subpopulations of patients\nwith RA, divided according to the presence\nor absence of humoral factors, suggest that\nRF+ANA+, RF-ANA-, and RF+ANA- subgroups are distinct genetic diseases, each affecting a\ndifferent subsection of the population which is genetically distinct. Such genetic heterogeneity"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1430
encoding: FLOAT32
metadata:
{"title": "Genetic structure of the population with rheumatoid arthritis in north east England: a genetic approach to define different subtypes", "chroma:document": "may suggest a different pathogenetic mechanism for each of these subpopulations of rheumatoid\narthritis.\nKey words: blood groups, serum proteins, red cell enzymes, phenotypic variation, genetic\nheterogeneity.\nPresent evidence that genetic factors may play an\nimportant part in the development of rheumatoid\narthritis (RA) comes from twin studies, pedigree\nanalysis, and associations with it of marker variants\nin genetic polymorphic systems. 1-7 The initial inves-\ntigations on monozygotic cotwins showed an inci-\ndence of the disease 33 times that expected, and\nfamily studies showed a relative risk ranging be-\ntween 1 and 15*2 for the first degree relatives. These\nAccepted for publication 21 April 1986.\nCorrespondencc\nto Dr S\nS\nPapiha,\nDcpartment\nof Human\nGenetics, 19 Claremont Placc, Newcastlc upon Tync NE2 4AA\nobservations suggested strong genetic susceptibility\nto the disease.\nIn\nthe\nlast two decades\na few\nretrospective\nanalyses of the literature cast doubt on the validity\nof the existing data on familial aggregation of RA,\nand\nsuggested\na weak\ngenetic\nelement\nin\nthe\naetiology of the disease.8 9 Meanwhile, research on\nits association with human leucocyte antigens once\nagain drew attention to the possibility of genetic\npredisposition coded at or near the HLA-D locus\nsituated on chromosome 6 in man, or a defective\nimmune response gene which may be in linkage\ndisequilibrium with the HLA-D locus.4 1i-12\n881"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1431
encoding: FLOAT32
metadata:
{"title": "Unravelling the proteome of adult rhesus monkey ovaries", "chroma:document": "This journal is \u00a9 The Royal Society of Chemistry 2014\nMol. BioSyst., 2014, 10, 653--662 | 653\nCite this: Mol. BioSyst., 2014,\n10, 653\nUnravelling the proteome of adult rhesus monkey\novaries\u2020\nHui He,\u2021a Hui Teng,\u2021a Tao Zhou,\u2021a Yueshuai Guo,\u2021a Gaigai Wang,a Min Lin,a\nYujie Sun,a Wei Si,b Zuomin Zhou,a Xuejiang Guo*a and Ran Huo*a\nOvarian physiology and pathology are important areas of scientific research. E\ufb00orts have been made to\nidentify the ovary-related transcriptomes in di\ufb00erent species. However, the proteomic studies are limited. The\nrhesus monkey is very similar to humans, and it is widely used in the study of reproductive biology and\nmedicine. In this study, using an optimized proteomics platform, we successfully identified 5723 rhesus\novarian proteins, of which 4325 proteins were consistently identified in all three replicates and with at least 2\nunique peptides. The 4325 proteins were chosen for further analysis. Through gene ontology and pathway\nanalyses,\nwe\nobtained\na\npreliminary\nunderstanding\nof\nthe\nfunction\nof\nthese\nproteins.\nA\nrandom\nimmunohistochemistry analysis was used to determine the expression of proteins in various cell types. By\ncomparing the genes identified in this study with genes that were reported to have relatively high levels of\nexpression in human oocytes, we obtained genes that were predicted to play roles in maintenance of normal\novarian physiology. Searching the identified genes from this study against the MGI database gave us a list of\nproteins those exist in the rhesus monkey ovary and are important for female mouse reproduction as well.\nThe overlap of genes in this study and the genes whose abnormal expression or dysfunction were reported\nto be associated with human polycystic ovary syndrome (PCOS) and premature ovarian failure (POF)\nprompted us to use the rhesus monkey to study these two common causes of female infertility. This study\nmay provide a basis for future studies of human reproductive disorders using the rhesus monkey as a model.\n1. Introduction"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1432
encoding: FLOAT32
metadata:
{"title": "Unravelling the proteome of adult rhesus monkey ovaries", "chroma:document": "Oocytes are stored and grow in the mammalian ovary. Ovulation\ntakes place under the control of the hypothalamus\u2013pituitary\u2013\ngonadal axis and involves the participation of many important\nmolecules. The mammalian ovary plays a key role in oogenesis\nand the secretion of gonadal hormones, such as estrogen,\nprogesterone, and small amounts of androgens, all of which\nare important for the maintenance of normal female sexual\ncharacteristics and normal pregnancies. Follicle, containing\noocyte and granulosa cells, is the basic functional unit of the ovary.\nFolliculogenesis consists of a series of events including the activa-\ntion of the primordial follicle, pre-antral follicle development,\ndominant follicle selection, subordinate follicle apoptosis, antral\nfollicle development and ovulation, mechanisms of which involve\nmany molecules and pathways.1,2 The World Health Organization\nstated that infertility could become the third most prevalent disease\nafter cancer and cardiovascular disease. It was estimated that\napproximately 15% of reproductive age couples who live in\nindustrialized countries are infertile.3 Infertility caused by\nfemale anatomy accounts for more than half of all cases of\ninfertility. There are many reasons for female infertility, within\nwhich ovarian factors including polycystic ovary syndrome\n(PCOS),4 premature ovarian failure (POF),5 ovary cancer etc.\naccount for a large proportion.6 Researchers have identified\nsome genes that are involved in female infertility, as evidenced\nby KO mice and other model systems.7,8 Although there have\nbeen several reports, a considerable amount of information\nabout the ovary remains unknown. To gain more information,\na State Key Laboratory of Reproductive Medicine, Department of Histology and\nEmbryology, Nanjing Medical University, Nanjing 210029, Jiangsu, China.\nE-mail: huoran@njmu.edu.cn, guo_xuejiang@njmu.edu.cn; Fax: +86-25-86862908;\nTel: +86-25-86862038\nb Kunming Primate Research Center and Kunming Institute of Zoology, Chinese"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1433
encoding: FLOAT32
metadata:
{"title": "Unravelling the proteome of adult rhesus monkey ovaries", "chroma:document": "Academy of Sciences, Kunming, Yunnan, China\n\u2020 Electronic supplementary information (ESI) available: Fig. S1 shows the details\nof a selected group of over represented pathways in the ovary. Table S1 shows the\ninformation from the identified proteins and the proteins that overlap with the\nhuman ovarian proteome. Table S2 shows the identified peptide information.\nTable S3 shows the GO and pathway analysis of the identified proteins. Table S4\nshows the primary antibodies used in immunohistochemistry studies. Table S5\nshows the information of the high abundance proteins. Table S6 shows the\noverlapping genes between genes identified in this study and the reported oocyte\noverexpressed genes and the basic functional analysis and classification of these\noverlapping genes. Table S7 shows the female reproductive phenotype annota-\ntions of rhesus ovarian homologous mouse genes. Table S8 shows proteins that\nnot only were identified in this proteome but also were reported to be di\ufb00erently\nexpressed in PCOS ovary and normal ovary. This material is available free of\ncharge via the internet at http://pubs.acs.org. See DOI: 10.1039/c3mb70312f\n\u2021 These authors contributed equally to the work.\nReceived 27th July 2013,\nAccepted 22nd November 2013\nDOI: 10.1039/c3mb70312f\nwww.rsc.org/molecularbiosystems\nMolecular\nBioSystems\nPAPER\nPublished on 25 November 2013. Downloaded by West Lake University on 3/10/2023 5:53:54 AM. \nView Article Online\nView Journal  | View Issue"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1434
encoding: FLOAT32
metadata:
{"title": "Current Evidence and Rationale to Guide Perioperative Management, Including Transfusion Decisions, In Patients With Sickle Cell Disease", "chroma:document": "Copyright \u00a9 2023 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.\nJune 2023 \u2022 Volume 136 \u2022 Number 6 \nwww.anesthesia-analgesia.org 1107\nE   NarratiVe reView article\nPatient Blood Management\nCurrent Evidence and Rationale to Guide Perioperative \nManagement, Including Transfusion Decisions, in \nPatients With Sickle Cell Disease\nRoberta C. G.\u00a0Azbell, MD,* Sophie M.\u00a0Lanzkron, MD, MHS,\u2020 and Payal C.\u00a0Desai, MD\u2021\nSickle cell disease (SCD) is a collection of inherited hemoglobin disorders that results in chronic \nhemolytic anemia, vaso-occlusion, pain, and end organ damage. Surgery in the SCD population \nrequires careful planning, as perioperative stressors can lead to increased sickling and risk of \ninducing or further exacerbating vaso-occlusive episodes (VOEs). Additionally, the underlying \nhypercoagulability and immunocompromised state due to SCD places patients at increased \nrisk of both venous thromboembolism and infection. Judicious fluid administration, temperature \nregulation, thorough preoperative and postoperative analgesic planning, and preoperative trans-\nfusion are all crucial components of decreasing risks of surgery in patients with SCD. (Anesth \nAnalg 2023;136:1107\u201314)\nGLOSSARY\nACS = acute chest syndrome; ASH = American Society of Hematology; CI = confidence interval; \nCT\u00a0= computed tomography; DHTR = delayed hemolytic transfusion reactions; DVT = deep vein \nthrombosis; eGFR = estimated glomerular filtration rate; EQ-5D = EuroQol-5D; HbC = hemoglobin C;  \nHbS = sickle hemoglobin; HELLP = hemolysis, elevated liver enzyme and low platelets; IV = intrave-\nnous; LR = lactated Ringer; NS = normal saline; RCT = randomized control trial; RR = relative risk; \nSCD = sickle cell disease; VOE = vaso-occlusive episode; VTE = venous thromboembolic disease\nS\nickle cell disease (SCD) is a collection of inher-\nited hemoglobin disorders that affects up to \n100,000 people in the United States.1The abnor-\nmality resides in the hemoglobin molecule with the"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1435
encoding: FLOAT32
metadata:
{"title": "Current Evidence and Rationale to Guide Perioperative Management, Including Transfusion Decisions, In Patients With Sickle Cell Disease", "chroma:document": "substitution of valine for glutamic acid in the beta glo-\nbin chain. The resultant abnormal hemoglobin (called \nsickle hemoglobin or HbS) is less soluble than the wild \ntype and forms a polymer upon deoxygenation and \nthat results in shape change from the normal red cell \ndisk to an elongated sickle form. SCD occurs when \nthe HbS mutation is homozygous or is coinherited \nwith another beta globin chain gene mutation such \nas beta thalassemia or hemoglobin C. Patients with \nSCD have a chronic hemolytic anemia and intermit-\ntent episodes of vaso-occlusion of small blood vessels \nleading to acute pain episodes, as well as acute and \nchronic injury to lungs, heart, kidneys, bone, and the \ncentral nervous system.2\nWhen preparing a patient with SCD for surgery, there \nare many factors to consider. Intraoperatively, surgery \nmay lead to hypotension, acidosis, hypoxia, frequent \nexposure to low temperatures, vasoconstriction, venous \nstasis, and increased stress, all of which can promote \nincreased sickling and potentially induce vaso-occlusive \nepisodes (VOEs).3,4 Additionally, patients with SCD have \nhigher risks of perioperative infection due to functional \nasplenia,5 and increased risk of perioperative throm-\nbosis as a result the underlying hypercoagulable state. \nPreoperative planning is required to help minimize the \nrisks of perioperative morbidity and mortality.\nWhile standard tools are used to consider peri-\noperative risks for all patients,6,7 none of these tools \ninclude SCD and likely underestimate the periopera-\ntive risks for this specific patient population. And cur-\nrently, there are no specific tools for perioperative risk \nestimation in SCD.\nGENERAL CONSIDERATION\nFluid Management\nFluid management in the SCD population can \nbe complicated by the presence of underlying \nCopyright \u00a9 2023 The Author(s). Published by Wolters Kluwer Health, \nInc. on behalf of the International Anesthesia Research Society. This is an \nopen-access article distributed under the terms of the Creative Commons"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1436
encoding: FLOAT32
metadata:
{"title": "Current Evidence and Rationale to Guide Perioperative Management, Including Transfusion Decisions, In Patients With Sickle Cell Disease", "chroma:document": "Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), \nwhere it is permissible to download and share the work provided it is prop-\nerly cited. The work cannot be changed in any way or used commercially \nwithout permission from the journal.\nDOI: 10.1213/ANE.0000000000006463\nFrom the *Department of Internal Medicine, The Ohio State University \nWexner Medical Center, Columbus, Ohio; \u2020Department of Internal \nMedicine, Division of Hematology, Johns Hopkins School of Medicine; and \n\u2021Department of Internal Medicine, Division of Hematology, The Ohio State \nWexner Medical Center, Columbus, Ohio.\nAccepted for publication February 8, 2023.\nFunding: None.\nConflicts of Interest: See Disclosures at the end of the article.\nReprints will not be available from the authors.\nAddress correspondence to Roberta C. G. Azbell, MD, Department of Internal \nMedicine, The Ohio State University Wexner Medical Center, 1800 Cannon \nDr, Lincoln Tower, Suite 1110L, Columbus, OH 43210. Address e-mail to \nroberta.azbell@osumc.edu.\nCME"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1437
encoding: FLOAT32
metadata:
{"title": "Social threat, fronto-cingulate-limbic morphometry, and symptom course in depressed adolescents: a longitudinal invesetigation", "chroma:document": "Psychological Medicine\ncambridge.org/psm\nOriginal Article\nCite this article: Ojha A, Teresi GI, Slavich GM,\nGotlib IH, Ho TC (2023). Social threat, fronto-\ncingulate-limbic morphometry, and symptom\ncourse in depressed adolescents: a\nlongitudinal investigation. Psychological\nMedicine 53, 5203\u20135217. https://doi.org/\n10.1017/S0033291722002239\nReceived: 12 November 2021\nRevised: 5 May 2022\nAccepted: 28 June 2022\nFirst published online: 19 September 2022\nKey words:\nAdolescence; amygdala; anterior cingulate\ncortex; depression; nucleus accumbens;\nsocial stress\nAuthor for correspondence:\nTiffany C. Ho, Ph.D.,\nE-mail: tiffany.ho@psych.ucla.edu\n\u00a9 The Author(s), 2022. Published by\nCambridge University Press. This is an Open\nAccess article, distributed under the terms of\nthe Creative Commons Attribution licence\n(http://creativecommons.org/licenses/by/4.0/),\nwhich permits unrestricted re-use, distribution\nand reproduction, provided the original article\nis properly cited.\nSocial threat, fronto-cingulate-limbic\nmorphometry, and symptom course in\ndepressed adolescents: a\nlongitudinal investigation\nAmar Ojha1,2\n, Giana I. Teresi3, George M. Slavich4, Ian H. Gotlib5 and\nTiffany C. Ho6\n1Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; 2Center for Neural Basis of Cognition,\nUniversity of Pittsburgh, Pittsburgh, PA, USA; 3Department of Psychology, University of Pittsburgh, Pittsburgh, PA,\nUSA; 4Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA;\n5Department of Psychology, Stanford University, Stanford, CA, USA and 6Department of Psychiatry and Behavioral\nSciences, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA\nAbstract\nBackground. Psychosocial stressors characterized by social threat, such as interpersonal loss\nand social rejection, are associated with depression in adolescents. Few studies, however, have\nexamined whether social threat affects fronto-cingulate-limbic systems implicated in adoles-\ncent depression."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1438
encoding: FLOAT32
metadata:
{"title": "Social threat, fronto-cingulate-limbic morphometry, and symptom course in depressed adolescents: a longitudinal invesetigation", "chroma:document": "Methods. We assessed lifetime stressor severity across several domains using the Stress and\nAdversity Inventory (STRAIN) in 57 depressed adolescents (16.15 \u00b1 1.32 years, 34 females),\nand examined whether the severity of social threat and non-social threat stressors was asso-\nciated with gray matter volumes (GMVs) in the anterior cingulate cortex (ACC), amygdala,\nhippocampus, and nucleus accumbens (NAcc). We also examined how lifetime social threat\nseverity and GMVs in these regions related to depressive symptoms at baseline and over\n9 months.\nResults. General stressor severity was related to greater depression severity at baseline and\nover 9 months. Moreover, greater severity of social threat (but not non-social threat) stressors\nwas associated with smaller bilateral amygdala and NAcc GMVs, and smaller bilateral surface\nareas of caudal and rostral ACC (all pFDR \u2a7d 0.048). However, neither social threat nor non-\nsocial threat stressor severity was related to hippocampal GMVs (all pFDR \u2a7e 0.318). All\nfronto-cingulate-limbic structures that were associated with the severity of social threat\nwere negatively associated with greater depression severity over 9 months (all pFDR \u2a7d 0.014).\nPost-hoc analyses suggested that gray matter morphometry of bilateral amygdala, NAcc,\nand rostral and caudal ACC mediated the association between social threat and depression\nseverity in adolescents over 9 months (all pFDR < 0.048).\nConclusions. Social threat specifically affects fronto-cingulate-limbic pathways that contribute\nto the maintenance of depression in adolescents.\nIntroduction\nDepression is a leading cause of disability worldwide (World Health Organization, 2017), with\nnearly one in five people experiencing depression during their lifetime (Friedrich, 2017). The\nlifetime prevalence of depression is especially alarming in adolescents, with a cumulative inci-\ndence of 13.6% in males and 36.1% in females by age 18 (Breslau et al., 2017). Moreover, indi-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1439
encoding: FLOAT32
metadata:
{"title": "Social threat, fronto-cingulate-limbic morphometry, and symptom course in depressed adolescents: a longitudinal invesetigation", "chroma:document": "viduals who develop depression during adolescence, as compared to those who develop\ndepression later in life, tend to experience more severe and recurrent episodes of the disorder\n(Naicker, Galambos, Zeng, Senthilselvan, & Colman, 2013; Zisook et al., 2007). Viewed in this\ncontext, adolescence represents an important developmental period marked by heightened\nvulnerability for the onset and adverse consequences of depression. Therefore, it is critical\nto identify psychosocial and neurobiological mechanisms that contribute to depression in\nadolescents.\nSocial stressors and depression: the role of social threat\nAlthough stressful life events often precede and increase risk for depressive episodes across the\nlifespan (Hammen, 2005, 2006), this effect is especially pronounced in adolescents\n(Lewinsohn, Allen, Seeley, & Gotlib, 1999; Monroe & Harkness, 2005). This finding is not sur-\nprising given that adolescence is a period during which environmental demands have outsized"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1440
encoding: FLOAT32
metadata:
{"title": "Mapping mocrostructural gradients of the human striatum in normal aging and Parkinson's disease", "chroma:document": "Drori et al., Sci. Adv. 8, eabm1971 (2022)     15 July 2022\nSCIE N C E A D V A NCES | RESEA R CH  A RT ICL E\n1 of 14\nN E UR OSCIENCE\nMapping microstructural gradients of the human \nstriatum in normal aging and Parkinson\u2019s disease\nElior Drori*, Shai Berman, Aviv A. Mezer\nMapping structural spatial change (i.e., gradients) in the striatum is essential for understanding the function of \nthe basal ganglia in both health and disease. We developed a method to identify and quantify gradients of micro-\nstructure in the single human brain in vivo. We found spatial gradients in the putamen and caudate nucleus of the \nstriatum that were robust across individuals, clinical conditions, and datasets. By exploiting multiparametric \nquantitative MRI, we found distinct, spatially dependent, aging-related alterations in water content and iron con-\ncentration. Furthermore, we found cortico-striatal microstructural covariation, showing relations between striatal \nstructural gradients and cortical hierarchy. In Parkinson\u2019s disease (PD) patients, we found abnormal gradients in \nthe putamen, revealing changes in the posterior putamen that explain patients\u2019 dopaminergic loss and motor \ndysfunction. Our work provides a noninvasive approach for studying the spatially varying, structure-function re-\nlationship in the striatum in vivo, in normal aging and PD.\nINTRODUCTION\nThe striatum, consisting of the caudate nucleus and the putamen, is \na major input structure of the basal ganglia, playing a crucial role in \nmotor and cognitive aspects of goal-directed behavior (1). Changes \nin striatal tissue and interhemispheric asymmetries are associated \nwith motor and cognitive dysfunctions that take place in normal \naging (2) and in neurodegenerative disorders such as Parkinson\u2019s \ndisease (PD), dystonia, and Huntington\u2019s disease (1,\u00a03). The function \nof the striatum is tightly related to its cellular and biochemical prop-\nerties: Histochemical studies highlight the distinct neurochemical"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1441
encoding: FLOAT32
metadata:
{"title": "Mapping mocrostructural gradients of the human striatum in normal aging and Parkinson's disease", "chroma:document": "compartments of the striatal tissue (i.e., striosomes and matrix), \nwhich differ in dopaminergic and cholinergic expression and change \nin distribution and chemical properties along the anatomical axes \nof the striatum (4\u20136). These compartments are thought to constitute \nan organizational feature of striatal connectivity (6\u20138). The connec-\ntivity of the striatum has been linked to the hierarchal organization \nof the cortex, with gradients of sensorimotor, associative, and lim-\nbic domains along the anterior-posterior (i.e., rostral-caudal) and \nventromedial-dorsolateral axes (9,\u00a010). Accordingly, electrophysiol-\nogy and functional magnetic resonance imaging (fMRI) studies have \nprovided evidence for functional and cognitive gradients in the stri-\natum (11\u201314).\nChanges in the striatum\u2019s biological spatial variation (i.e., gradi-\nents; we use these terms interchangeably) are notably apparent in PD, \nmainly along the anterior-posterior axis, which emphasizes acute \ndegeneration in posterior parts of the putamen (15\u201319). This degen-\neration is characterized by the depletion of dopaminergic innerva-\ntion to the striatum, due to the patients\u2019 loss of dopaminergic neurons \nin the substantia nigra pars compacta (1). Positron emission tomog-\nraphy (PET) and single-photon emission computed tomography \n(SPECT) studies in PD patients demonstrate the decrease of dopa-\nmine intake in the striatum (20\u201323). Striatal deterioration, in turn, \naffects motor function, leading to a range of movement impairments \n(1,\u00a024). Hence, gradients in the cellular and neurochemical content \nlevel (i.e., the microenvironment) of the striatum are a key feature \nin understanding the striatum\u2019s dysfunction in PD.\nMicrostructural gradients of the striatum are studied mainly using \ninvasive animal research and human postmortem analyses. In living \nhumans, MRI is the primary noninvasive tool for structural research \nof the brain. Developments in quantitative MRI (qMRI) provide para-\nmetric mappings of biophysical tissue properties, such as the longi-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1442
encoding: FLOAT32
metadata:
{"title": "Mapping mocrostructural gradients of the human striatum in normal aging and Parkinson's disease", "chroma:document": "tudinal relaxation rate R1, which is sensitive to a variety of biological \nsources in the microenvironment of the tissue, including myelin, \nwater content, and iron concentration. Therefore, qMRI has been \nproposed to provide \u201cin vivo histology\u201d of the human brain (25). We \nhypothesized that incorporating a spatial approach in qMRI methods \nto map the heterogeneous microstructural properties of subcortical \nregions, and specifically the striatum, would have important effects \nfor our understanding of aging and PD in\u00a0vivo.\nHere, we present an in\u00a0vivo method to quantify microstructural \ngradients in the caudate and putamen in normal aging and \nPD. Our innovative approach allows the measurement of spatial vari-\nation in microstructure along the main axes of the striatum. Using \nthis approach, we characterize striatal gradients that are related to \nmultiple biological sources, in healthy younger and older adults. Next, \nto detect PD-related microstructural changes, we generalize our re-\nsults to widely available clinical datasets. We investigate how changes \nin striatal gradients are related to PD motor symptomatology, as well \nas to striatal dopamine loss in individual patients. Last, our analysis \nexpands to the relationship between the striatum and the cerebral \ncortex, identifying a gradient of cortico-striatal microstructure net-\nworks, that shows dependency between striatal position and the cor-\ntical circuit hierarchical organization (9,\u00a013).\nRESULTS\nMicrostructural gradients in the striatum\nPrevious studies have identified spatial gradients in the microenvi-\nronment along the axes of the striatum ex\u00a0vivo (4\u20136). To assess spa-\ntial variability in humans in\u00a0vivo, we developed an automatic tool \nto express the main axes of the striatum on the single-subject level \n(Fig.\u00a01A). Our tool uses a region-of-interest (ROI) mask and per-\nforms singular value decomposition (SVD) on the voxel coordi-\nnates to find the main orthogonal axes of a given region. Voxels are"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1443
encoding: FLOAT32
metadata:
{"title": "Mapping mocrostructural gradients of the human striatum in normal aging and Parkinson's disease", "chroma:document": "then divided into seven equally spaced segments along each of the \naxes (see section S1), and the median value of a qMRI parameter \nThe Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of \nJerusalem, Jerusalem, Israel.\n*Corresponding author. Email: elior.drori@mail.huji.ac.il\nCopyright \u00a9 2022 \nThe Authors, some \nrights reserved; \nexclusive licensee \nAmerican Association \nfor the Advancement \nof Science. No claim to \noriginal U.S. Government \nWorks. Distributed \nunder a Creative \nCommons Attribution \nNonCommercial \nLicense 4.0 (CC BY-NC)."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1444
encoding: FLOAT32
metadata:
{"title": "Telemedicine for First-Trimester Medical Abortion in Canada", "chroma:document": "Open camera or QR reader and\nscan code to access this article\nand other resources online.\nTelemedicine for First-Trimester Medical Abortion in Canada:\nResults of a 2019 Survey\nRegina M. Renner, MD, MPH,1,2,* Madeleine Ennis, PhD,1,2,*\nAma Kyeremeh, MPH,2 Wendy V. Norman, MD, MHSc,2\u20134\nSheila Dunn, MD, MSc,2,5 Helen Pymar, MD, MPH,2,6\nand Edith Guilbert, MD, MSc2,7\nDepartments of 1Obstetrics and Gynaecology and 3Family\nPractice, University of British Columbia, Vancouver, Canada.\n2Contraception and Abortion Research Team, Women\u2019s Health\nResearch Institute, British Columbia Women\u2019s Hospital\nand Health Centre, Vancouver, Canada.\n4Faculty of Public Health and Policy, London School of Hygiene\nand Tropical Medicine, London, United Kingdom.\n5Department of Family and Community Medicine, University\nof Toronto, Ontario, Canada.\n6Department of Obstetrics, Gynecology and Reproductive\nSciences, University of Manitoba, Manitoba, Canada.\n7Department of Obstetrics, Gynecology and Reproduction,\nUniversite\u00b4 Laval, Que\u00b4bec City, Canada.\n*Co-first authors.\nAbstract\nIntroduction: Telemedicine has the potential to improve\nabortion access disparities in Canada. We aimed to explore\nthe provision of telemedicine for first-trimester medical abor-\ntion and related barriers in 2019.\nMethods: We conducted a national, cross-sectional, anon-\nymized, web-based survey of clinicians who provided abortion\ncare in 2019 in Canada. We distributed our survey through\nprofessional health organizations to maximize identification\nof possible eligible respondents and used a modified Dillman\ntechnique to foster responses. Questions elicited provider\ndemographics, clinical characteristics, including telemedicine\nfirst-trimester medical abortion and perceived related barri-\ners. Descriptive statistics were analyzed using R software.\nResults: Among 465 respondents, 388 reported providing\nfirst-trimester medical abortion across Canada; 44.0% rep-\norted experience using telemedicine for some components of\ncare: 49.3% of primary care clinicians and 28.7% of spe-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1445
encoding: FLOAT32
metadata:
{"title": "Telemedicine for First-Trimester Medical Abortion in Canada", "chroma:document": "cialists. Telemedicine was used for initial consultation\n(86.0%), prescription (82.2%), or follow-up (92.2%). The\nmedian percentage of telemedicine providers\u2019 patients who\nunderwent a dating ultrasound was 90.0. The majority usu-\nally followed up with patients through quantitative human\nchorionic gonadotropin (hCG) (84.2%). Seventy-eight percent\nperceived barriers to telemedicine; the most common being\ninability to confirm gestational age with ultrasound (43.0%),\nand lack of provincial telemedicine abortion fee code to pay\npractitioners (30.2%), timely access to serum hCG testing\n(24.6%), and nearby emergency services (23.3%).\nDiscussion: In 2019, fewer than half of respondents reported\nproviding some aspects of first-trimester medical abortion\nthrough telemedicine and the majority perceived barriers. Our\nresults can inform knowledge translation activities to reduce\nbarriers and increase telemedicine abortion care in Canada.\nKeywords: telemedicine, abortion induced, surveys, ques-\ntionnaires, Canada, health care, mifepristone\n\u00aa Regina M. Renner et al. 2022; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative\nCommons Attribution Noncommercial License [CC-BY-NC] (http://creativecommons.org/licenses/by-nc/4.0/) which permits any non-\ncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.\n686 TELEMEDICINE and e-HEALTH\nMARY ANN LIEBERT, INC. \u0002 VOL. 29\nNO. 5 \u0002 MAY 2023\nDOI: 10.1089/tmj.2022.0245"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1446
encoding: FLOAT32
metadata:
{"title": "Tissue-based map of the human proteome", "chroma:document": "RESEARCH ARTICLE SUMMARY\n\u25e5\nPROTEOMICS\nTissue-based map of the\nhuman proteome\nMathias Uhl\u00e9n,* Linn Fagerberg, Bj\u00f6rn M. Hallstr\u00f6m, Cecilia Lindskog, Per Oksvold,\nAdil Mardinoglu, \u00c5sa Sivertsson, Caroline Kampf, Evelina Sj\u00f6stedt, Anna Asplund,\nIngMarie Olsson, Karolina Edlund, Emma Lundberg, Sanjay Navani,\nCristina Al-Khalili Szigyarto, Jacob Odeberg, Dijana Djureinovic,\nJenny Ottosson Takanen, Sophia Hober, Tove Alm, Per-Henrik Edqvist, Holger Berling,\nHanna Tegel, Jan Mulder, Johan Rockberg, Peter Nilsson, Jochen M. Schwenk,\nMarica Hamsten, Kalle von Feilitzen, Mattias Forsberg, Lukas Persson,\nFredric Johansson, Martin Zwahlen, Gunnar von Heijne, Jens Nielsen, Fredrik Pont\u00e9n\nINTRODUCTION: Resolving the molecular\ndetails of proteome variation in the different\ntissues and organs of the human body would\ngreatly increase our knowledge of human bi-\nology and disease. Here, we present a map of\nthe human tissue proteome based on quantita-\ntive transcriptomics on a tissue and organ level\ncombined with protein profiling using micro-\narray-based immunohistochemistry to achieve\nspatial localization of proteins down to the\nsingle-cell level. We provide a global analysis\nof the secreted and membrane\nproteins, as well as an analysis\nof the expression profiles for all\nproteins targeted by pharmaceu-\ntical drugs and proteins impli-\ncated in cancer.\nRATIONALE: We have used an\nintegrative omics approach to\nstudy the spatial human pro-\nteome. Samples representing all\nmajor tissues and organs (n =\n44) in the human body have been\nanalyzed based on 24,028 anti-\nbodies corresponding to 16,975\nprotein-encoding genes, comple-\nmented with RNA-sequencing\ndata for 32 of the tissues. The\nantibodies have been used to\nproduce more than 13 million\ntissue-based immunohistochemis-\ntry images, each annotated by\npathologists for all sampled tis-\nsues. To facilitate integration\nwith other biological resources,\nall data are available for down-\nload and cross-referencing.\nRESULTS: We report a genome-\nwide analysis of the tissue"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1447
encoding: FLOAT32
metadata:
{"title": "Tissue-based map of the human proteome", "chroma:document": "specificity of RNA and protein\nexpression covering more than\n90% of the putative protein-\ncoding genes, complemented with analyses\nof various subproteomes, such as predicted\nsecreted proteins (n = 3171) and membrane-\nbound proteins (n = 5570). The analysis shows\nthat almost half of the genes are expressed in\nall analyzed tissues, which suggests that the\ngene products are needed in all cells to main-\ntain \u201chousekeeping\u201d functions such as cell\ngrowth, energy generation, and basic metab-\nolism. Furthermore, there is enrichment in\nmetabolism among these genes, as 60% of all\nmetabolic enzymes are expressed in all ana-\nlyzed tissues. The largest number of tissue-\nenriched genes is found in the testis, followed\nby the brain and the liver.\nAnalysis of the 618 pro-\nteins targeted by clinically\napproved drugs unexpect-\nedly showed that 30% are\nexpressed in all analyzed\ntissues. An analysis of me-\ntabolic activity based on genome-scale meta-\nbolic models (GEMS) revealed liver as the most\nmetabolically active tissue, followed by adipose\ntissue and skeletal muscle.\nCONCLUSIONS: A freely available interactive\nresource is presented as part of the Human\nProtein Atlas portal (www.proteinatlas.org), of-\nfering the possibility to explore the tissue-\nelevated proteomes in tissues and organs and\nto analyze tissue profiles for specific protein\nclasses. Comprehensive lists of proteins ex-\npressed at elevated levels in the different tis-\nsues have been compiled to provide a spatial\ncontext with localization of the proteins in the\nsubcompartments of each tissue and organ\ndown to the single-cell level.\u25aa\nRESEARCH\n394\n23 JANUARY 2015 \u2022 VOL 347 ISSUE 6220\nsciencemag.org SCIENCE\nON OUR WEB SITE\n\u25e5\nRead the full article\nat http://dx.doi.\norg/10.1126/\nscience.1260419\n..................................................\nThe list of author affiliations is available in the full article online.\n*Corresponding author. E-mail: mathias.uhlen@scilifelab.se\nCite this article as M. Uhl\u00e9n et al., Science 347, 1260419\n(2015). DOI: 10.1126/science.1260419"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1448
encoding: FLOAT32
metadata:
{"title": "Tissue-based map of the human proteome", "chroma:document": "The human tissue\u2013enriched proteins. All tissue-enriched proteins are shown for 13 representative tissues or\ngroups of tissues, stratified according to their predicted subcellular localization. Enriched proteins are mainly\nintracellular in testis, mainly membrane bound in brain and kidney, and mainly secreted in pancreas and liver.\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015\nDownloaded from www.sciencemag.org on January 22, 2015"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1449
encoding: FLOAT32
metadata:
{"title": "a sex-associated protein in liver tissue of the rat and its response to endocrine manipulation", "chroma:document": "\u00a9          Nature Publishing Group\n1962"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1450
encoding: FLOAT32
metadata:
{"title": "efficacy of bupropion and cognitive behavioral therapy in the treatment of methamphetamine use disorder", "chroma:document": "REVIEW ARTICLE\nEf\ufb01cacy of bupropion and cognitive behavioral therapy\nin the treatment of methamphetamine use disorder:\na systematic review and meta-analysis\nLuis Fernando Maya Apuy,0000-0000-0000-0000 Marie Antouannet Bernabe\u00b4 Barreto, Luis Alejandro Hurtado Merino\nFacultad de Medicina, Universidad de Piura, Lima, Peru.\nObjectives: We assessed the ef\ufb01cacy of cognitive behavioral therapy and bupropion compared to\ncognitive behavioral therapy alone for methamphetamine use disorder.\nMethods: The selection criteria for this systematic review study with meta-analysis were randomized\nclinical trials on the ef\ufb01cacy of cognitive behavioral therapy and bupropion in the treatment for\nmethamphetamine use disorder (assessed by urine metabolites). The search was conducted in\nPubMed, PubMed Central, LILACS, SciELO, Cochrane Library, SCOPUS, Google Scholar, Ovid\nMedline, Clinicaltrials.gov, and the International Clinical Trials Registry Platform. The primary outcome\nwas relapse. Risk of bias was assessed with the RoB 2 tool. The results of each clinical trial were input\ninto an Excel spreadsheet. We performed a meta-analysis using relative risk and a 95%CI.\nResults: Of the 597 initial articles (498 after removing duplicate records), \ufb01ve were included in the\nmeta-analysis, with an aggregate sample of 539 patients. An overall relative risk of 0.91 (95%CI 0.78-\n1.05) was estimated for relapse.\nConclusion: Our study limitations included publication bias and heterogeneous populations. We\nfound no evidence that cognitive behavioral therapy and bupropion reduced the risk of relapse\ncompared to cognitive behavioral therapy and placebo.\nKeywords: Substance-related\ndisorders;\nantidepressive\nagents,\nsecond-generation;\ncognitive\nbehavioral therapy; methamphetamine\nIntroduction\nMethamphetamine is a highly stimulating derivative of\namphetamine with greater bioavailability in the central\nnervous system (CNS).1 It includes the amino group of\n(S)-amphetamine and bears a methyl substituent. Metham-"}


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topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1451
encoding: FLOAT32
metadata:
{"title": "efficacy of bupropion and cognitive behavioral therapy in the treatment of methamphetamine use disorder", "chroma:document": "phetamine is stronger than amphetamine because a\ngreater amount reaches the brain at the same dose.2 Its\nmechanism of action consists in increasing monoamine\nlevels in the CNS, mainly dopamine, due to monoamine\noxidase enzyme inhibition and an additive effect on the\ntyrosine hydroxylase enzyme. After use, a feeling of\neuphoria, energy, and alertness is experienced.3\nA 2020 survey by the U.S. National Institute on Drug\nAbuse found a methamphetamine use disorder preva-\nlence of 0.6%.4 According the United Nations Of\ufb01ce on\nDrugs and Crime,5 the prevalence of amphetamine use\ndisorder was 2.31, 6.10, 5.65, and 2.31% in Australia\n(2020), Haiti (2018), the United States (2020), and Austria\n(2020), respectively.\nChronic methamphetamine use is associated with\nmedical\nproblems,\nsuch\nas\nneuronal\ndamage\nand\ncognitive disorder, cardiovascular involvement (especially\nstrokes), dental disease, and infection (HIV, hepatitis B\nvirus, and hepatitis C virus). Methamphetamine use is\nalso linked to increased crime.6\nThe pathology of use disorder is associated with posi-\ntive reinforcement and stimulation of the reward system,\nin which dopamine plays an important role during initial\ndrug use. As use becomes more habitual, stimulation of\nthe dorsal striatal regions occurs.7 The dopaminergic\nsystem exhibits modulatory effects on many brain regions\nrelated to cognitive functioning, including front striatal and\nlimbic structures. This is associated with complaints of\ncognitive dysfunction, including memory problems and\nself-reported de\ufb01cits in everyday functioning.8 Moreover,\nmethamphetamine consumption can create a psycholo-\ngical obsession due to drug-induced elation.9\nThe \ufb01rst-line treatment for methamphetamine use\ndisorder is psychotherapy; there is no effective drug for\ntreatment.1 However, psychotherapy is not always avail-\nable, which leads to a search for other treatment options.\nIn addition, the ef\ufb01cacy of psychotherapy decreases after\ndischarge.10\nCorrespondence: Marie Antouannet Bernabe\u00b4 Barreto, San Felipe"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1452
encoding: FLOAT32
metadata:
{"title": "efficacy of bupropion and cognitive behavioral therapy in the treatment of methamphetamine use disorder", "chroma:document": "Avenue 1079/1804, Jesus Maria, Lima, 15072, Peru.\nE-mail: marie.bernabe@alum.udep.edu.pe\nSubmitted Nov 28 2022, accepted Feb 13 2023.\nHow to cite this article: Apuy LFM, Barreto MAB, Merino LAH.\nEf\ufb01cacy of bupropion and cognitive behavioral therapy in the\ntreatment of methamphetamine use disorder: a systematic review\nand meta-analysis. Braz J Psychiatry. 2023;45:280-285. http://doi.\norg/10.47626/1516-4446-2022-2979\nBraz J Psychiatry. 2023 May-Jun;45(3):280-285\ndoi:10.47626/1516-4446-2022-2979\nBrazilian Psychiatric Association\n00000000-0002-7316-1185"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1453
encoding: FLOAT32
metadata:
{"title": "Nasopharyngeal lymphatic plexus is a hub for cerebospinal fluid drainage", "chroma:document": "Nature | www.nature.com | 1\nArticle\nNasopharyngeal lymphatic plexus is a hub \nfor cerebrospinal fluid drainage\nJin-Hui Yoon1,7, Hokyung Jin1,2,7, Hae Jin Kim3,7, Seon Pyo Hong1, Myung Jin Yang1,2, \nJi Hoon Ahn1, Young-Chan Kim1,2, Jincheol Seo4, Yongjeon Lee4, Donald M. McDonald5,6, \nMichael J. Davis3,8\u2009\u2709 & Gou Young Koh1,2,8\u2009\u2709\nCerebrospinal fluid (CSF) in the subarachnoid space around the brain has long  \nbeen known to drain through the lymphatics to cervical lymph nodes1\u201317, but the \nconnections and regulation have been challenging to identify. Here, using fluorescent \nCSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal \nlymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This \nplexus had unusual valves and short lymphangions but no smooth-muscle coverage, \nwhereas downstream deep cervical lymphatics had typical semilunar valves, long \nlymphangions and smooth muscle coverage that transported CSF to the deep cervical \nlymph nodes. \u03b1-Adrenergic and nitric oxide signalling in the smooth muscle cells \nregulated CSF drainage through the transport properties of deep cervical lymphatics. \nDuring ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical \nlymphatics were not similarly altered, and CSF outflow could still be increased by \nadrenergic or nitric oxide signalling. Single-cell analysis of gene expression in \nlymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed \nincreased type I interferon signalling and other inflammatory cytokines. The \nimportance of evidence for the nasopharyngeal lymphatic plexus functioning as a \nCSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant \npharmacological activation of deep cervical lymphatic transport towards lymph \nnodes can still increase CSF outflow, offering an approach for augmenting CSF \nclearance in age-related neurological conditions in which greater efflux would be \nbeneficial."}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1454
encoding: FLOAT32
metadata:
{"title": "Nasopharyngeal lymphatic plexus is a hub for cerebospinal fluid drainage", "chroma:document": "CSF is essential for mechanical protection, nourishment and clearing \nof neurotransmitters, metabolites and protein aggregates such as \namyloid-\u03b2 and tau from the central nervous system17,19. CSF is continu-\nously secreted by the choroid plexus into the cerebral ventricles and \nsubarachnoid space, circulates within and around the brain and spinal \ncord, and turns over 3 to 5 times per day19. The regulation of CSF produc-\ntion, circulation and drainage is receiving increasing attention due to \nevidence that reduced CSF secretion and/or clearance during ageing \ncould contribute to the development of Alzheimer\u2019s disease and other \nneurodegenerative conditions20\u201323.\nAmong the known routes for CSF drainage from the subarach-\nnoid space are lymphatics in the cribriform plate, where olfactory \nnerves pass through the ethmoid bone, and in the perineurium of \ncranial nerves8,17,24. Lymphatics in the dura mater also function as a \nCSF drainage route9\u201317,25. However, despite solid documentation of the \ncontribution of lymphatics to CSF clearance, the connections between \nthe subarachnoid space and extracranial lymphatics involved in CSF  \nclearance have been challenging to elucidate.\nA landmark study1 provided evidence for CSF outflow to the naso-\npharynx by finding Richardson\u2019s blue dye in the lymphatics of the nasal \nand palatal mucosa after injection of the tracer into the subarachnoid \nspace1. Other studies4\u20137 revealed that dye or Microfil silicone rubber \ninjected into the subarachnoid space subsequently appears in the nasal \nlymphatics and in the perineurium of cranial nerves. A previous study12 \nreported that CSF can drain through lymphatics of the pharynx. A mag-\nnetic resonance imaging (MRI) study26 provided further evidence of \nCSF outflow through the cribriform plate to the nasopharynx. A recent \nstudy27 provided additional observations on the connections between \nthe subarachnoid space and lymphatic vessels around olfactory nerves \nthat cross the cribriform plate en route to the nasal mucosa. Another"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1455
encoding: FLOAT32
metadata:
{"title": "Nasopharyngeal lymphatic plexus is a hub for cerebospinal fluid drainage", "chroma:document": "study16 observed connections between intracranial lymphatics and \nextracranial lymphatics using light-sheet fluorescence microscopy \nafter injection of ovalbumin\u2013Alexa Fluor 555 (OVA\u2013Alexa Fluor 555)\u00a0con-\njugate into CSF or by MRI after systemic injection of gadolinium-based \ncontrast agent. However, tracing OVA\u2013Alexa Fluor 555 in fixed tissues \nwas confounded by phagocytosis of the tracer by macrophages. Our \nhttps://doi.org/10.1038/s41586-023-06899-4\nReceived: 28 March 2023\nAccepted: 24 November 2023\nPublished online: xx xx xxxx\nOpen access\n Check for updates\n1Center for Vascular Research, Institute for Basic Science, Daejeon, Republic of Korea. 2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and \nTechnology (KAIST), Daejeon, Republic of Korea. 3Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA. 4National Primates Research Center, Korea \nResearch Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea. 5Department of Anatomy, Cardiovascular Research Institute, University of California, San Francisco, San \nFrancisco, CA, USA. 6Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. 7These authors contributed equally: Jin-Hui Yoon, \nHokyung Jin, Hae Jin Kim. 8These authors jointly supervised this work: Michael J. Davis, Gou Young Koh. \u2709e-mail: davismj@health.missouri.edu; gykoh@kaist.ac.kr"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1456
encoding: FLOAT32
metadata:
{"title": "Unbiased transciprtion factor CRISPR screen identifies ANF800 as master repressor of enteroendocrine differentiation", "chroma:document": "DIFFERENTIATION\nUnbiased transcription factor CRISPR screen\nidentifies ZNF800 as master repressor of\nenteroendocrine differentiation\nLin Lin1,2,3*, Jeff DeMartino2,3, Daisong Wang1,2, Gijs J. F. van Son2,3, Reinier van der Linden1,2,\nHarry Begthel1,2, Jeroen Korving1,2, Amanda Andersson-Rolf1,2, Stieneke van den Brink1,2,\nCarmen Lopez-Iglesias4, Willine J. van de Wetering4, Aleksandra Balwierz3, Thanasis Margaritis3,\nMarc van de Wetering2,3, Peter J. Peters4, Jarno Drost2,3, Johan H. van Es1,2, Hans Clevers1,2,3*\u2020\nEnteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach,\nsmall intestine (SI), and colon. EECs regulate aspects of metabolic activity, including insulin levels,\nsatiety, gastrointestinal secretion, and motility. The generation of different EEC lineages is not\ncompletely understood. In this work, we report a CRISPR knockout screen of the entire repertoire\nof transcription factors (TFs) in adult human SI organoids to identify dominant TFs controlling\nEEC differentiation. We discovered ZNF800 as a master repressor for endocrine lineage commitment,\nwhich particularly restricts enterochromaffin cell differentiation by directly controlling an endocrine\nTF network centered on PAX4. Thus, organoid models allow unbiased functional CRISPR screens\nfor genes that program cell fate.\nE\nnteroendocrine cells (EECs) are special-\nized epithelial cells of the intestinal tract\nthat, like all other epithelial cell lineages,\nderive from regionally specified Lgr5+ in-\ntestinal stem cells (ISCs) (1\u20135). Balanced\ndifferentiation of EEC lineages from ISCs is\ngoverned by a network of transcription fac-\ntors (TFs) (6\u201312). RNA sequencing and organ-\noid technology have illuminated the temporal\nhierarchy of gene expression profiles during\nEEC development (13, 14). By using a time-\nresolved reporter allele of Neurog3 (master\nregulator of endocrine development) (15, 16),\na real-time and lineage-specific map of mouse\nEEC differentiation in vivo was constructed at"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1457
encoding: FLOAT32
metadata:
{"title": "Unbiased transciprtion factor CRISPR screen identifies ANF800 as master repressor of enteroendocrine differentiation", "chroma:document": "single cell\u2013level resolution (12). Overexpres-\nsion of NEUROG3 can generate endocrine\ncells for functional characterization in human\npancreatic duct cells (17). Leveraging human\ngut organoids, this strategy enabled profiling\nof EEC subtypes along the proximal-distal\ngastrointestinal axis (18). TFs known to specify\nEEC subtypes in mice were further examined in\nhuman organoids, revealing a predominantly\nconserved regulatory mechanism downstream\nof NEUROG3 activation. However, discrepancies\nbetween mouse and human data were also ob-\nserved. The regulatory mechanisms upstream\nof NEUROG3 and the endogenous repressive\nfactors that control NEUROG3 expression at\nthe adult stage remain largely unknown. In this\nwork, we established an organoid-based plat-\nform in combination with high-throughput ge-\nnetic screening for the unbiased discovery of TFs\nthat govern human EEC lineage commitment.\nResults\nTFome-wide CRISPR knockout screen in\nhuman SI organoids\nOptimized human SI organoids exhibit the\nspontaneous generation of all major cell line-\nages, including EEC subtypes, without TF over-\nexpression (19). For the current study, we\naimed to establish a CRISPR screening platform\nspanning the entire repertoire of transcription\nfactors (TFome) in human intestinal organoids\nto allow for unbiased and systematic discov-\nery of TFs that govern cell lineage commitment\nfrom adult LGR5+ intestinal stem cells. We\nused a CRISPR knockout library comprising\n7210 single-guide RNAs (sgRNAs) targeting\n1800 human TFs, alongside 100 negative con-\ntrols (20\u201322). In the human ileum organoid\nline used, EECs were marked by CHGA-IRES-\niRFP670, goblet cells by MUC2-mNeonGreen,\nand Paneth cells by DEFA5-IRES-DsRed (fig.\nS1A). We performed lentiviral-mediated library\nintegration in expanding SI organoids (Fig. 1A).\nLibrary coverage was assessed by sequencing\nthe integrated sgRNAs, comparing the organ-\noids after transduction with the plasmid pool.\nFate separation of CHGA+ EECs and MUC2+\ncells occurs early in secretory progenitors,"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1458
encoding: FLOAT32
metadata:
{"title": "Unbiased transciprtion factor CRISPR screen identifies ANF800 as master repressor of enteroendocrine differentiation", "chroma:document": "whereas DEFA5+ Paneth cells emerge later from\nMUC2+ progenitors (19), illustrating sequential\nfate decisions of ISCs (23, 24). We aimed to\ntrack the early CHGA+/MUC2+ binary fate\ndecision. After two-step organoid differentia-\ntion (19), we analyzed bulk populations as well\nas sorted EECs (CHGA+), goblet cells (MUC2+)\nand the CHGA\u2013/MUC2\u2013/DEFA5\u2013 population\n(fig. S1B). 0 to ~0.7% sgRNAs yielded zero\nreads in bulk populations, indicating robust\ncoverage (fig. S2A). Normalized read-count\ndistribution and Pearson correlations demon-\nstrated high concordance between biological\nreplicates (fig. S2, B and C). sgRNAs that target\nessential ISC genes [KLF5 (25) and TCF7L2/\nTCF4 (26\u201329)] were depleted, along with\n\u201cgeneric\u201d cell fitness genes (POLR2L, MYC,\nand RAD51) at both expansion and differen-\ntiation culturing stages (b score < \u20131; FDR <\n0.05 versus plasmid library) (fig. S2D and table\nS1). Furthermore, sgRNAs targeting IRF2, an\ninterferon pathway TF, were highly enriched\nupon differentiation, consistent with existing\nliterature (30, 31).\nsgRNAs were then assessed in CHGA+ EECs\nand MUC2+ goblet cells versus the triple\nreporter\u2013negative cell population (Fig. 1B\nand table S2). As expected, NEUROG3, SOX4,\nand INSM1 sgRNAs were depleted in EECs\n(8, 15, 16, 32). Additionally, NFIC, TEF, and\nZHX2 appeared essential for EEC commitment.\nFor each of these, clonal knockout organoids\nrevealed a mild yet significant reduction of\nCHGA+ EECs (Fig. 1, B and C, and fig. S3, A to\nC). Conversely, GFI1 sgRNAs were enriched in\nEECs (Fig. 1, B and C). Mouse Gfi1 is crucial\nfor goblet cell differentiation by suppression\nof Neurog3-driven EEC cell fate (23, 33).\nIndeed, GFI1 knockout in human organoids\nabrogated goblet cell formation while increas-\ning EEC numbers (fig. S3, A and C, and fig. S14,\nC and D).\nZNF800 represses EEC differentiation\nThe strongest repressor of EEC differentiation\nin the screen, ZNF800, is a C2H2 zinc-finger TF\nof unknown function (Fig. 1, B and C) (34).\nHuman ZNF800 is broadly expressed, includ-"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1459
encoding: FLOAT32
metadata:
{"title": "Unbiased transciprtion factor CRISPR screen identifies ANF800 as master repressor of enteroendocrine differentiation", "chroma:document": "ing in the SI and colon epithelium (fig. S4, A\nand B). ZNF800\u2212/\u2212 organoids contained in-\ncreased EECs and strongly reduced goblet and\nPaneth cell numbers (Fig. 1, D and E, and fig.\nS4, C and G). Transmission electron micros-\ncopy confirmed the absence of goblet and\nPaneth cells with the characteristic apical\nsecretory vesicles and the increase of EECs\nwith the basolateral secretory granules (Fig. 1F).\nSimilarly, ZNF800 knockout in colon organoid\nlines from two different donors also resulted\nin a significant increase in EECs (fig. S4, D to G).\nWe next performed single-cell RNA sequenc-\ning (scRNA-seq) to study the phenotype of\nZNF800\u2212/\u2212 organoids. For equal representa-\ntion, CHGA+ cells were sorted from wild type\n(WT) and ZNF800\u2212/\u2212 organoids and pooled\nwith CHGA\u2013 cells from the same lines in a 1:4\nratio (Fig. 2A and fig. S5A). Major intestinal\ncell types were identified by graph-based clus-\ntering analysis (Fig. 2B and fig. S5B). We\nobserved the expected reduction of goblet cells\nRESEARCH\n1Hubrecht Institute, Royal Netherlands Academy of Arts and\nSciences (KNAW) and UMC Utrecht, Utrecht, Netherlands.\n2Oncode Institute, Utrecht, Netherlands. 3Princess Maxima\nCenter for Pediatric Oncology, Utrecht, Netherlands. 4The\nMaastricht Multimodal Molecular Imaging Institute,\nMaastricht University, Maastricht, Netherlands.\n*Corresponding author. Email: l.lin@hubrecht.eu (L.L.);\nh.clevers@hubrecht.eu (H.C.)\n\u2020Current address: Pharma Research and Early Development of\nF. Hoffmann\u2013La Roche Ltd., Basel, Switzerland.\nLin et al., Science 382, 451\u2013458 (2023)\n27 October 2023\n1 of 8\nDownloaded from https://www.science.org at Tsinghua University on October 26, 2023"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1460
encoding: FLOAT32
metadata:
{"title": "TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons", "chroma:document": "Nature | www.nature.com | 1\nArticle\nTNRC18 engages H3K9me3 to mediate \nsilencing of endogenous retrotransposons\nShuai Zhao1,2,3,4,12, Jiuwei Lu5,12, Bo Pan1,2, Huitao Fan4,11, Stephanie D. Byrum6, Chenxi Xu1,2,3,4, \nArum Kim1,2,4, Yiran Guo1,2,7, Krishna L. Kanchi4, Weida Gong4, Tongyu Sun8, Aaron J. Storey6, \nNathaniel T. Burkholder9, Samuel G. Mackintosh6, Peyton C. Kuhlers10, Ricky D. Edmondson6, \nBrian D. Strahl4,9, Yarui Diao2,8, Alan J. Tackett6, Jesse R. Raab4,10, Ling Cai2,3,10, Jikui Song5,13\u2009\u2709 & \nGang Greg Wang1,2,3,4,9,13\u2009\u2709\nTrimethylation of histone H3 lysine\u20099 (H3K9me3) is crucial for the regulation of gene \nrepression and heterochromatin formation, cell-fate determination and organismal \ndevelopment1. H3K9me3 also provides an essential mechanism for silencing \ntransposable elements1\u20134. However, previous studies have shown that canonical \nH3K9me3 readers (for example, HP1 (refs. 5\u20139) and MPP8 (refs. 10\u201312)) have limited \nroles in silencing endogenous retroviruses (ERVs), one of the main transposable \nelement classes in the mammalian genome13. Here we report that trinucleotide- \nrepeat-containing\u200918 (TNRC18), a poorly understood chromatin regulator, recognizes \nH3K9me3 to mediate the silencing of ERV class\u2009I (ERV1) elements such as LTR12 (ref. 14). \nBiochemical, biophysical and structural studies identified the carboxy-terminal \nbromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3- \nspecific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for \nthe direct recruitment of co-repressors such as HDAC\u2013Sin3\u2013NCoR complexes, thus \nenforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis \nthat disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal \ndeath in mice and, in multiple mammalian cell models, led to derepressed expression \nof ERVs, which affected the landscape of cis-regulatory elements and, therefore, \ngene-expression programmes. Collectively, we describe a new H3K9me3-sensing and"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1461
encoding: FLOAT32
metadata:
{"title": "TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons", "chroma:document": "regulatory pathway that operates to epigenetically silence evolutionarily young ERVs \nand exert substantial effects on host genome integrity, transcriptomic regulation, \nimmunity and development.\nAlmost half of the human genome is made up of transposable elements \n(TEs), many of which are retrotransposons such as long terminal repeats \n(LTRs) and non-LTRs15\u201317. Non-LTRs include long interspersed elements \n(LINEs) and short interspersed elements (SINEs), whereas LTRs consist \nof ERVs. To maintain host genome integrity, TEs are tightly regulated \nby various silencing mechanisms enforced by histone modification, \nDNA methylation, histone chaperone and/or noncoding RNAs15,18. \nNotably, H3K9me3, a histone mark characteristic of constitutive het-\nerochromatin, is enriched at TEs1,15. H3K9me3 is deposited by its writer \nenzymes such as SETDB1 (also known as ESET)1,19\u201321 and recognized by \nthe H3K9me3-reading chromodomain harboured within heterochro-\nmatin protein\u20091 (HP1) family proteins5\u20139. SETDB1 loss causes global TE \nactivation13; however, such a large TE-activation phenotype cannot be \nrecapitulated by HP1 loss13, which indicates the existence of unknown \nH3K9me3-associated mechanisms for mediating TE repression. Chro-\nmodomain within M-phase phosphoprotein\u20098 (MPP8), a component \nof the human silencing hub (HUSH) complex2, was identified as an \nH3K9me3-specific reader10\u201312. However, depletion of the HUSH complex \nmainly caused LINE1 derepression, which demonstrates that MPP8\u2013\nHUSH has a major role in silencing non-LTR (LINE1) TEs2\u20134. It remains \nelusive what H3K9me3 reader mediates silencing of LTRs (ERVs), a \nTE class that occupies approximately 8% of the human genome and \npotentially carries gene regulatory functions15,16,18.\nCasID identifies TNRC18 as an ERV binder\nWe sought to identify mammalian ERV regulators using CasID22 \n(Extended Data Fig.\u00a01a), in which a fusion protein of endonuclease- \nhttps://doi.org/10.1038/s41586-023-06688-z\nReceived: 25 July 2022\nAccepted: 27 September 2023"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1462
encoding: FLOAT32
metadata:
{"title": "TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons", "chroma:document": "Published online: xx xx xxxx\n Check for updates\n1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. 2Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA. \n3Department of Pathology, Duke University School of Medicine, Durham, NC, USA. 4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, \nChapel Hill, NC, USA. 5Department of Biochemistry, University of California, Riverside, CA, USA. 6Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, \nLittle Rock, AR, USA. 7Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 8Department of Cell Biology, Duke University School of \nMedicine, Durham, NC, USA. 9Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. 10Department of Genetics, \nUniversity of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. 11Present address: The First Affiliated Hospital of Harbin Medical University, Harbin, P. R. China. 12These \nauthors contributed equally: Shuai Zhao, Jiuwei Lu. 13These authors jointly supervised this work: Jikui Song and Gang Greg Wang. \u2709e-mail: jikui.song@ucr.edu; greg.wang@duke.edu"}


created_at: 2024-01-19 12:53:35
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: 1463
encoding: FLOAT32
metadata:
{"title": "ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis", "chroma:document": "Article\nABCG2 is an itaconate exporter that limits\nantibacterial innate immunity by alleviating TFEB-\ndependent lysosomal biogenesis\nGraphical abstract\nHighlights\nd A custom-designed CRISPR screen identi\ufb01es ABCG2 as an\nitaconate exporter\nd ABCG2 directly exports itaconate depending on its ATPase\nactivity\nd ABCG2-mediated itaconate export alleviates TFEB-\ndependent lysosomal biogenesis\nd ABCG2-mediated itaconate export limits antibacterial innate\nimmunity\nAuthors\nChao Chen, Zhenxing Zhang,\nCaiyun Liu, Pengkai Sun, Ping Liu,\nXinjian Li\nCorrespondence\nlixinjian@ibp.ac.cn\nIn brief\nIt has been reported that itaconate is a\nlysosomal inducer that promotes\nantibacterial innate immunity. Here, Chen\net al. reveal that ATP-binding cassette\ntransporter G2 (ABCG2) is an itaconate\nexporter. ABCG2-mediated itaconate\nexport limits antibacterial innate\nimmunity by alleviating itaconate-\ninduced TFEB activation and lysosomal\nbiogenesis.\nChen et al., 2024, Cell Metabolism 36, 1\u201313\nMarch 5, 2024 \u00aa 2023 Elsevier Inc.\nhttps://doi.org/10.1016/j.cmet.2023.12.015\nll"}


created_at: 2024-01-22 08:59:52
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: ch1
encoding: FLOAT32
metadata:
{"title": "ABCG2 \u662f\u4e00\u79cd\u4f0a\u5b83\u5eb7\u9178\u8f93\u51fa\u5668\uff0c\u5b83\u901a\u8fc7\u51cf\u8f7b TFEB \u4f9d\u8d56\u6027\u6eb6\u9176\u4f53\u751f\u7269\u751f\u6210\u6765\u9650\u5236\u6297\u83cc\u5148\u5929\u6027\u514d\u75ab\u6eb6\u9176\u4f53\u751f\u7269\u751f\u6210"}


created_at: 2024-01-22 08:59:52
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: ch2
encoding: FLOAT32
metadata:
{"title": "TNRC18 \u4e0e H3K9me3 \u7ed3\u5408\uff0c\u4ecb\u5bfc\u5185\u6e90\u6027\u9006\u8f6c\u5f55\u8f6c\u5ea7\u5b50\u7684\u6c89\u9ed8"}


created_at: 2024-01-22 08:59:52
topic: persistent://default/default/e46a62c8-f631-4b0d-b6c6-0d8d30ab5865
id: ch3
encoding: FLOAT32
metadata:
{"title": "\u65e0\u504f\u89c1\u7684\u8f6c\u5f55\u56e0\u5b50CRISPR\u7b5b\u9009\u786e\u5b9a ZNF800 \u662f\u80a0\u5185\u5206\u6ccc\u5206\u5316\u7684\u4e3b\u6291\u5236\u56e0\u5b50\u80a0\u5185\u5206\u6ccc\u5206\u5316"}


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Alzheimer’s Association Report
2013 Alzheimer’s disease facts and ﬁgures
Alzheimer’s Association*
Abstract
This report provides information to increase understanding of the public health impact of Alz-
heimer’s disease (AD), including incidence and prevalence, mortality rates, health expenditures
and costs of care, and effect on caregivers and society in general. It also explores the roles and unique
challenges of long-distance caregivers, as well as interventions that target those challenges. An
estimated 5.2 million Americans have AD. Approximately 200,000 people younger than 65 years
with AD comprise the younger onset AD population; 5 million comprise the older onset AD popu-
lation. Throughout the coming decades, the baby boom generation is projected to add about 10
million to the total number of people in the United States with AD. Today, someone in America
develops AD every 68 seconds. By 2050, one new case of AD is expected to develop every 33 sec-
onds, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8
million. AD is the sixth leading cause of death in the United States and the ﬁfth leading cause of death
in Americans age 65 years or older. Between 2000 and 2010, the proportion of deaths resulting from
heart disease, stroke, and prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the pro-
portion resulting from AD increased 68%. The number of deaths from AD as determined by ofﬁcial
death certiﬁcates (83,494 in 2010) likely underrepresents the number of AD-related deaths in the
United States. A projected 450,000 older Americans with AD will die in 2013, and a large proportion
will die as a result of complications of AD. In 2012, more than 15 million family members and other
unpaid caregivers provided an estimated 17.5 billion hours of care to people with AD and other
dementias, a contribution valued at more than $216 billion. Medicare payments for services to ben-


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eﬁciaries age 65 years and older with AD and other dementias are three times as great as payments for
beneﬁciaries without these conditions, and Medicaid payments are 19 times as great. Total payments
in 2013 for health care, long-term care, and hospice services for people age 65 years and older with
dementia are expected to be $203 billion (not including the contributions of unpaid caregivers). An
estimated 2.3 million caregivers of people with AD and other dementias live at least 1 hour away from
the care recipient. These “long-distance caregivers” face unique challenges, including difﬁculty in
assessing the care recipient’s true health condition and needs, high rates of family disagreement
regarding caregiving decisions, and high out-of-pocket expenses for costs related to caregiving.
Out-of-pocket costs for long-distance caregivers are almost twice as high as for local caregivers.
 2013 The Alzheimer’s Association.
Keywords:
Alzheimer’s disease; Dementia; Diagnostic criteria; Prevalence; Incidence; Mortality; Caregivers; Family care-
giver; Spouse caregiver; Health care costs; Health care expenditures; Long-term care costs; Medicare spending;
Medicaid spending; Long-distance caregiver; Activities of daily living; Instrumental activities of daily living
1. About this report
2013 Alzheimer’s Disease Facts and Figures is a statisti-
cal resource for US data related to Alzheimer’s disease
(AD), the most common type of dementia, as well as other
dementias. Background and context for interpretation of
the data are contained in the Overview. This information
includes deﬁnitions of the various types of dementia and
a summary of current knowledge about AD. Additional
sections address prevalence, mortality, caregiving, and
use and costs of care and services. This special report fo-
cuses on long-distance caregivers of people with AD and
other dementias.
Speciﬁc information in this year’s Alzheimer’s Disease
Facts and Figures includes the following:


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*Corresponding authors: William Thies, Ph.D., and Laura Bleiler. Tel.:
312-335-5893; Fax: 866-521-8007. E-mail address: lbleiler@alz.org
1552-5260 2013 The Alzheimer’s Association.
http://dx.doi.org/10.1016/j.jalz.2013.02.003
Alzheimer’s & Dementia 9 (2013) 208–245
. 
Open access under CC BY-NC-ND license. 
Open access under CC BY-NC-ND license.


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Androgens increase excitatory neurogenic potential in human 
brain organoids
Iva Kelava1,3,*, Ilaria Chiaradia1, Laura Pellegrini1, Alex T. Kalinka2, Madeline A. 
Lancaster1,*
1Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue. CB2 0QH 
Cambridge, United Kingdom
2Milner Therapeutics Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, 
Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW
Abstract
The biological basis of male-female brain differences has been difficult to elucidate in humans. 
The most striking morphological difference is size, with males having on average a larger 
brain than females 1,2 , yet a mechanistic understanding of how this difference arises remains 
to be elucidated. Here, we use brain organoids 3 to demonstrate that while sex chromosomal 
complement has no observable effect on neurogenesis, sex steroids, namely androgens, lead to 
increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic 
analysis and functional studies demonstrate downstream effects on HDAC activity and mTOR 
pathway. Finally, we show that androgens specifically increase neurogenic output of excitatory 
neuronal progenitors, while inhibitory neuronal progenitors are not increased. These findings 
uncover a hitherto unknown role for androgens in regulating excitatory neuron number and 
represent a first step towards understanding the origin of human sex-related brain differences.
Introduction
Sex-based brain differences are controversial, yet negating their existence has detrimental 
consequences for all sexes and genders, and for developing accurate diagnostic tools 
and effective drugs. One of the most striking differences is divergent susceptibility to 
certain neurological conditions 4,5 , for example, autism spectrum disorder (ASD) 6 and 
schizophrenia 7 , pointing to differences in brain structure and/or function. Indeed, decades 
of research in model organisms has revealed numerous sex-specific morphological and


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behavioural differences 8–10 . However, the presence of sex-specific characteristics in 
* Corresponding authors: Correspondence to Iva Kelava or Madeline A. Lancaster. mlancast@mrc-lmb.cam.ac.uk, 
ik9@sanger.ac.uk .
3Current address: Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1RQ
Author contributions 
I.K. conceived the study, performed experiments, analysed data and wrote the paper. I.C. performed experiments and analysed the 
data. L.P. performed experiments. A.T.K. performed bioinformatics analysis. M.A.L. supervised the study, analysed data and co-wrote 
the paper.
Conflict of interest 
M.A.L. is an inventor on several patents related to cerebral organoids, is co-founder and scientific advisory board member of a:head 
bio, and scientific advisory board member of the Roche Institute for Translational Bioengineering.
Europe PMC Funders Group
Author Manuscript
Nature. Author manuscript; available in PMC 2022 August 01.
Published in final edited form as:
Nature. 2022 February 01; 602(7895): 112–116. doi:10.1038/s41586-021-04330-4.
 Europe PMC Funders Author Manuscripts
 Europe PMC Funders Author Manuscripts


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Association Between Levels of Hormones and Risk of Esophageal Adenocarcinoma and Barrett\220s Esophagus


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Association Between Levels of Hormones and Risk of 
Esophageal Adenocarcinoma and Barrett’s Esophagus
Shao-Hua Xie*,a, Rui Fang‡,a, Mingtao Huang‡, Juncheng Dai‡,§, Aaron P. Thrift∥,¶, Lesley A. 
Anderson#, Wong-Ho Chow**, Leslie Bernstein‡‡, Marilie D. Gammon§§, Harvey A. Risch∥∥, 
Nicholas J. Shaheen¶¶, Brian J. Reid##, Anna H. Wu***, Prasad G. Iyer‡‡‡, Geoffrey Liu§§§, 
Douglas A. Corley∥∥∥, David C. Whiteman¶¶¶, Carlos Caldas###, Paul D. Pharoah****,‡‡‡‡, 
Laura J. Hardie§§§§, Rebecca C. Fitzgerald∥∥∥∥, Hongbing Shen‡,§, Thomas L. Vaughan##, 
Jesper Lagergren*,¶¶¶¶
*Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska 
Institutet, Karolinska University Hospital, Stockholm, Sweden
‡Department of Epidemiology and Biostatistics, International Joint Research Center on 
Environment and Human Health, Center for Global Health, School of Public Health
§Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation 
Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
∥Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
¶Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of 
Medicine, Houston, Texas
#Centre for Public Health, Queen’s University Belfast, Belfast, United Kingdom
**Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas
‡‡Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive 
Cancer Center, Duarte, California
§§Department of Epidemiology, Gillings School of Global Public Health
¶¶Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina, 
Chapel Hill, North Carolina
∥∥Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, 
Connecticut
##Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, 
Washington


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Reprint requests: Address requests for reprints to: Shao-Hua Xie, MD, PhD, Upper Gastrointestinal Surgery, Department of 
Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, NS 67, SE 171 76 Stockholm, Sweden. 
shaohua.xie@ki.se.
aAuthors share co-first authorship.
Conflicts of interest
The authors disclose no conflicts.
Supplementary Material
Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and 
Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/jxgh.2019.11.030.
HHS Public Access
Author manuscript
Clin Gastroenterol Hepatol. Author manuscript; available in PMC 2020 November 01.
Published in final edited form as:
Clin Gastroenterol Hepatol. 2020 November ; 18(12): 2701–2709.e3. doi:10.1016/j.cgh.2019.11.030.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Depressed caudate and ventral striatum dopamine transporter availability in de novo Depressed Parkinson's disease


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Contents lists available at ScienceDirect
Neurobiology of Disease
journal homepage: www.elsevier.com/locate/ynbdi
“Depressed” caudate and ventral striatum dopamine transporter availability
in de novo Depressed Parkinson's disease
Sang-Won Yooa, Yoon-Sang Oha, Eo-Jin Hwanga,b, Dong-Woo Ryua, Kwang-Soo Leea,
Chul Hyoung Lyooc, Joong-Seok Kima,⁎
a Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
b Department of Radiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
c Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
A R T I C L E I N F O
Keywords:
Parkinson's disease
Depression
Dopamine transporter uptake
Montgomery–Asberg depression rating scale
Caudate
Ventral striatum
A B S T R A C T
Depression can occur before the onset of motor symptoms in Parkinson's disease (PD) patients. The pathophy-
siology of depression in PD involves various brain regions and relevant functional circuits. This study in-
vestigated whether there exist distinctive patterns of presynaptic monoamine transporter densities in the basal
ganglia depending on the degree of depression in patients with PD. A total of 123 early and drug-naïve PD
patients were enrolled. Their aﬀective status was evaluated by the Montgomery–Asberg Depression Rating Scale
(MADRS), and subjects were subgrouped into one of the following three groups according to their MADRS
scores: no depression, mild depression, and moderate-to-severe depression. All patients underwent positron
emission tomography (PET)
using
18F-N-(3-ﬂuoropropyl)-2beta-carbon
ethoxy-3beta-(4-iodophenyl)
nor-
tropane. The PET images were normalized, and diﬀerences in the regional standardized uptake value ratios
(SUVRs) for each side of the caudate, putamen, globus pallidus, thalamus, and ventral striatum were analyzed
and compared between the three groups. A trend analysis was performed across the groups to discern any


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associations between SUVR values of the basal ganglia and depression severity. The SUVR values of the caudate,
anterior caudate nuclei, and ventral striatum declined as MADRS increased. The SUVR values of the striatum
showed an inverse dose-dependent trend of antero- and ventroposterior gradient across the groups. This result
indirectly revealed the involvement of the associative and limbic circuitry of the brain that are modulated by
monoamines in early PD with depression. This might suggest an in vivo causal relationship between the ventral
striatum, caudate and depression.
1. Introduction
Mood disturbances, such as depression, are known to occur even
before the onset of motor symptoms in patients with Parkinson's disease
(PD) (Pont-Sunyer et al., 2015). The prevalence of depression in PD is
estimated to be 30–35%; the mild depressive mood often persists during
disease progression and is a risk factor for moderate to severe depres-
sion (Aarsland et al., 2011).
Depression involves diﬀerent sets of regional brain circuitry, such as
the limbic and associative loops, and information processing through
these circuits is mediated by distinctive monoamines, such as dopa-
mine, serotonin, and noradrenaline, relevant to the particular brain
areas (Aarsland et al., 2011; Stahl, 2013; Tremblay et al., 2015). When
these connections are disrupted, depression occurs. It has been known
that PD pathology encroaches upon these circuits, evoking mood dis-
orders (Aarsland et al., 2011; Frisina et al., 2009).
18F-N-(3-ﬂuoropropyl)-2beta-carbon
ethoxy-3beta-(4-iodophenyl)
nortropane (18F-FP-CIT) and positron emission tomography (PET) can
assess the functional integrity of the presynaptic nigrostriatal system. It
has now become an important, albeit not essential, tool in diagnosing
idiopathic PD (Kägi et al., 2010; Postuma et al., 2015). Not only does it
reﬂect PD severity, it also implicates the interactions of diﬀerent
monoaminergic systems, such as the dopaminergic, noradrenergic, and


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serotonergic systems (Hesse et al., 2009; Remy et al., 2005).
In PD, the posterior and dorsal striatum (sensorimotor territory) is
more aﬀected than the anterior and ventral parts of the striatum (as-
sociative and limbic territories) (Tremblay et al., 2015). Depending on
the distinctive brain circuits, a diﬀerent threshold of dopaminergic
https://doi.org/10.1016/j.nbd.2019.104563
Received 19 June 2019; Received in revised form 26 July 2019; Accepted 31 July 2019
⁎ Corresponding author at: Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222, Banpo-daero, Seocho-
gu, Seoul 06591, Republic of Korea.
E-mail address: neuronet@catholic.ac.kr (J.-S. Kim).
Neurobiology of Disease 132 (2019) 104563
Available online 01 August 2019
0969-9961/ ©
 2019 Elsevier Inc. All rights reserved.
T


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Experimental and Statistical Considerations to Avoid False Conclusions in Proteomics Studies Using Differential In-gel Electrophoresis*


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Experimental and Statistical Considerations to
Avoid False Conclusions in Proteomics Studies
Using Differential In-gel Electrophoresis*□
S
Natasha A. Karp‡§, Paul S. McCormick¶, Matthew R. Russell‡**,
and Kathryn S. Lilley‡ ‡‡
In quantitative proteomics, the false discovery rate (FDR)
can be defined as the number of false positives within
statistically significant changes in expression. False posi-
tives accumulate during the simultaneous testing of expres-
sion changes across hundreds or thousands of protein or
peptide species when univariate tests such as the Student’s
t test are used. Currently most researchers rely solely on
the estimation of p values and a significance threshold, but
this approach may result in false positives because it does
not account for the multiple testing effect. For each spe-
cies, a measure of significance in terms of the FDR can be
calculated, producing individual q values. The q value main-
tains power by allowing the investigator to achieve an ac-
ceptable level of true or false positives within the calls of
significance. The q value approach relies on the use of the
correct statistical test for the experimental design. In this
situation, a uniform p value frequency distribution when
there are no differences in expression between two sam-
ples should be obtained. Here we report a bias in p value
distribution in the case of a three-dye DIGE experiment
where no changes in expression are occurring. The bias
was shown to arise from correlation in the data from the use
of a common internal standard. With a two-dye schema,
where each sample has its own internal standard, such bias
was removed, enabling the application of the q value to two
different proteomics studies. In the case of the first study,
we demonstrate that 80% of calls of significance by the
more traditional method are false positives. In the second,
we show that calculating the q value gives the user control
over the FDR. These studies demonstrate the power and


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ease of use of the q value in correcting for multiple testing.
This work also highlights the need for robust experimental
design that includes the appropriate application of statisti-
cal
procedures.
Molecular
&
Cellular
Proteomics
6:
1354–1364, 2007.
Quantitative proteomics, the study of global changes in
protein expression, is a rapidly growing field where two-di-
mensional (2D)1 gel electrophoresis (1, 2), differential labeling
of protein and peptides with stable isotopes (3), and label-free
mass spectrometric peak intensity measurements (4) are piv-
otal approaches to measuring changes in the expression level
of proteins. The output of large scale genomic sequencing
and gene expression studies have driven the need to globally
assess protein behavior, which is central to our understanding
of cellular function and disease processes. In quantitative
studies, the quantitation of the protein or peptide signal allows
the comparison of protein levels from one state with another.
Regardless of the technique used, the data generated can be
analyzed with a variety of statistical approaches. In a simple
comparison of two samples, changes in protein expression
are considered to be significant when above a specified
threshold (5). More rigorous studies incorporating replicates
use univariate (1, 6) or multivariate statistical methods (1, 7) to
analyze the data. Univariate methods, such as the Student’s t
test, analyze the data from each individual protein species to
determine whether the differences between the samples are
significant. In multivariate methods, such as principle compo-
nent analysis, all the data are simultaneously analyzed to look
for patterns in expression. Each of these statistical methods
involves a number of mathematical assumptions; however,
these assumptions are often ignored, potentially leading to
erroneous results (8). Regardless of the analytical method
used to collect the proteomics data, subtle issues with sta-
tistical analysis must be overcome to ensure that valid con-
clusions are made.


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To date, the majority of published quantitative proteomics
studies have used the established 2D gel electrophoresis
approach for quantitation and applied a univariate test to
identify protein species with significant changes in expression
(8), although an increased number of studies are now using
non-gel-based approaches. These tests calculate the proba-
bility (p) of observing a test statistic more extreme than the
one calculated from the data given that the samples are from
the same population (i.e. that any apparent change in expres-
sion occurs by chance alone). Typically an expression change
From the ‡Department of Biochemistry, University of Cambridge,
Building O, Downing Site, Cambridge CB2 1QW, United Kingdom and
¶Department of Chemistry, University Chemical Laboratory, Lensfield
Road, Cambridge CB2 1EW, United Kingdom
Received, July 26, 2006, and in revised form, May 14, 2007
Published, MCP Papers in Press, May 17, 2007, DOI 10.1074/
mcp.M600274-MCP200
1 The abbreviations used are: 2D, two-dimensional; FDR, false
discovery rate; SA, standardized abundance; ECA, E. carotovora;
PCER, per comparison error rate; FWER, familywise error rate; Q,
quantile.
Research
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
1354
Molecular & Cellular Proteomics 6.8
This paper is available on line at http://www.mcponline.org
This is an Open Access article under the CC BY license.


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0 0  M O N T H  2 0 1 6  |  V O L  0 0 0  |  N A T U R E  |  1
ARTICLE
doi:10.1038/nature18637
A comprehensive transcriptional map of 
primate brain development
Trygve E. Bakken1*, Jeremy A. Miller1*, Song-Lin Ding1*, Susan M. Sunkin1, Kimberly A. Smith1, Lydia Ng1, Aaron Szafer1, 
Rachel A. Dalley1, Joshua J. Royall1, Tracy Lemon1, Sheila Shapouri1, Kaylynn Aiona1, James Arnold1, Jeffrey L. Bennett2, 
Darren Bertagnolli1, Kristopher Bickley1, Andrew Boe1, Krissy Brouner1, Stephanie Butler1, Emi Byrnes1, Shiella Caldejon1, 
Anita Carey1, Shelby Cate1, Mike Chapin1, Jefferey Chen1, Nick Dee1, Tsega Desta1, Tim A. Dolbeare1, Nadia Dotson1, 
Amanda Ebbert1, Erich Fulfs1, Garrett Gee1, Terri L. Gilbert1, Jeff Goldy1, Lindsey Gourley1, Ben Gregor1, Guangyu Gu1, Jon Hall1, 
Zeb Haradon1, David R. Haynor3, Nika Hejazinia1, Anna Hoerder-Suabedissen4, Robert Howard1, Jay Jochim1, Marty Kinnunen1, 
Ali Kriedberg1, Chihchau L. Kuan1, Christopher Lau1, Chang-Kyu Lee1, Felix Lee1, Lon Luong1, Naveed Mastan1, Ryan May1, 
Jose Melchor1, Nerick Mosqueda1, Erika Mott1, Kiet Ngo1, Julie Nyhus1, Aaron Oldre1, Eric Olson1, Jody Parente1, 
Patrick D. Parker1, Sheana Parry1, Julie Pendergraft1, Lydia Potekhina1, Melissa Reding1, Zackery L. Riley1, Tyson Roberts1, 
Brandon Rogers1, Kate Roll1, David Rosen1, David Sandman1, Melaine Sarreal1, Nadiya Shapovalova1, Shu Shi1, Nathan Sjoquist1, 
Andy J. Sodt1, Robbie Townsend1, Lissette Velasquez1, Udi Wagley1, Wayne B. Wakeman1, Cassandra White1, Crissa Bennett1, 
Jennifer Wu1, Rob Young1, Brian L. Youngstrom1, Paul Wohnoutka1, Richard A. Gibbs5, Jeffrey Rogers5, John G. Hohmann1, 
Michael J. Hawrylycz1, Robert F. Hevner6, Zoltán Molnár4, John W. Phillips1, Chinh Dang1, Allan R. Jones1, David G. Amaral2, 
Amy Bernard1 & Ed S. Lein1
The primate brain develops through a series of stereotyped processes 
that are conserved across mammals1, including the specification, 
migration, and maturation of diverse cell types and the formation and


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refinement of functional neuronal circuits. There are also primate- 
specific features of brain development that increase anatomical2, 
cognitive3, and behavioural complexity4, and may explain why many 
human neurological and neuropsychiatric diseases are inadequately 
modelled in rodents5. These features include a larger cortical progen-
itor pool in the outer subventricular zone not present in rodents2 and 
protracted myelination6, synapse production7, and pruning8. Rhesus 
monkeys and humans share a greatly expanded neocortex and special-
ization of areas (most notably primary visual cortex2), compared to 
mouse brains, reflecting the more recent common ancestor of humans 
and rhesus monkeys (25 million years ago) than humans and mice 
(70 million years ago)9. Likewise, the rhesus monkey and human 
brain10 share more similar patterns of gene expression than do mouse 
and human brains11. The rhesus monkey thus provides a valuable proxy 
for human brain development, particularly during prenatal and early 
postnatal development stages that are difficult to sample in humans, 
and also provides a comparator to study human-specific features such 
as prolonged maturation or neoteny6,12,13.
Molecular programs responsible for brain development remain 
incompletely understood in any species, due to the spatiotemporal 
complexity of these processes and the resource intensity of methods 
needed to probe them. Transcriptome-based approaches have accel-
erated understanding of variation in gene expression programs related 
to brain structure and function in adult and developing humans14–17 
and rhesus monkeys10,18, albeit with limited anatomical resolution and 
developmental coverage. Recent studies in adult mice19,20 and humans21 
have profiled individual cortical cells and demonstrated robust tran-
scriptional differences between neuronal and non-neuronal cell types 
and large-scale changes over the course of development. Although 
these approaches offer cellular resolution in targeted domains, a global


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picture of gene expression changes over development across the com-
plete cellular milieu has been lacking.
This project had the aim of creating a transcriptional atlas of non- 
human primate brain, combining fine anatomical precision with 
dense temporal coverage across prenatal and postnatal development 
The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely 
related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) 
brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical 
division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes 
more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like 
molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental 
timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including 
cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, 
autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment 
within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, 
although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny 
compared to monkey.
1Allen Institute for Brain Science, Seattle, Washington 98109, USA. 2Department of Psychiatry and Behavioral Science, California National Primate Research Center, The M.I.N.D. Institute, 
University of California, Davis, Sacramento, California 95817, USA. 3Department of Radiology, University of Washington, Seattle, Washington 98195, USA. 4Department of Physiology, Anatomy


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and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. 5Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, 
Houston, Texas 77030, USA. 6Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington 98101, USA.
*These authors contributed equally to this work.
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


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A current view on Tau protein phosphorylation in
Alzheimer’s disease
Susanne Wegmann1, Jacek Biernat2 and
Eckhard Mandelkow2
Abstract
The functions of the neuronal microtubule-associated protein
Tau in the central nervous system are regulated by manifold
posttranslational modifications at more than 50 sites. Tau in
healthy neurons carries multiple phosphate groups, mostly in
its microtubule assembly domain. Elevated phosphorylation
and aggregation of Tau are widely considered pathological
hallmarks in Alzheimer’s disease (AD) and other tauopathies,
triggering the quest for Tau posttranslational modifications in
the disease context. However, the phosphorylation patterns of
physiological and pathological Tau are surprisingly similar and
heterogenous, making it difficult to identify specific modifica-
tions as therapeutic targets and biomarkers for AD. We present
a concise summary of - and view on - important previous and
recent advances in Tau phosphorylation analysis in the context
of AD.
Addresses
1 German Center for Neurodegenerative Diseases (DZNE), Berlin,
Germany
2 German Center for Neurodegenerative Diseases (DZNE) & CAESAR
Research Center, Bonn, Germany
Corresponding author: Wegmann, Susanne (susanne.wegmann@
dzne.de)
Current Opinion in Neurobiology 2021, 69:131–138
This review comes from a themed issue on Molecular Neuroscience
Edited by Frank Bradke and Yukiko Goda
For a complete overview see the Issue and the Editorial
https://doi.org/10.1016/j.conb.2021.03.003
0959-4388/© 2021 The Authors. Published by Elsevier Ltd. This is an
open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
Abbreviations
Ser, serine; Thr, threonine; Tyr, tyrosine; Lys, lysine; Arg, arginine; Leu,
Leucine; G, Gly; TBS, tris-buffered saline; GG, glycine–glycine; LRGG,
Leu–Arg–Gly–Gly; AD, Alzheimer’s disease; CSF, cerebrospinal fluid;
MAP, microtubule-associated protein; MAPT, Tau gene; MT, microtu-
bule; MS, mass spectrometry; NFTs, neurofibrillary tangles; PTM, post-


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translational modification; Pi, phosphate group; PRR, proline-rich region
(of Tau protein); RD, repeat domain (of Tau protein); Rg, radius of
gyration.
Introduction
The microtubule-associated protein Tau contributes to
the stability of axonal microtubules (MTs) in the brain
and, in this role, is involved in the regulation of axon
outgrowth and axonal transport. The binding of Tau to
MTs is regulated by post-translational modiﬁcations
(PTMs), mostly phosphorylation [14], which also con-
trols various other less characterized functions of Tau
[51]. Tau was initially discovered by Kirschner and col-
leagues, in a search for MT-associated proteins (MAPs)
that enhance MTself-assembly [61]. From a biomedical
perspective, the interest in Tau rose sharply when Tau
was identiﬁed as a principal component of neuroﬁbril-
lary tangles (NFTs), a pathological hallmark found in the
brains of Alzheimer’s disease (AD) [27]. By implication,
the progressive pathological accumulation of phosphor-
ylated and aggregated Tau has since been used for the
staging of AD and other tauopathies [10,33]. However,
the causal relationship between phosphorylation and
aggregation is still a matter of debate. Interestingly, fetal
Tau and Tau from AD brain appear to have a similar high
Tau phosphorylation levels, despite the absence of ag-
gregation of fetal Tau during neuronal development
[12,38,63].
Tau
is
a
highly
soluble
intrinsically
disordered
protein that occurs in six main isoforms in the human
central nervous system [25]. The isoforms differ in their
content of three alternatively spliced exons, producing
Tau isoforms with 0, 1, or 2 inserts in the N-terminal
projection domain (N1 and N2 isoforms), and 3 or 4
pseudo-repeats (3R and 4R isoforms) in the Tau repeat
domain (RD), which covers most of the MT-assembly
domain1
and
is
responsible
for
Tau
aggregation
(Figure 1). Along the amino acid (aa) sequence of Tau,
w85 putative phosphorylation sites (p-sites) have been
predicted (Ser, Thr, Tyr), of which >50 are found to be


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modiﬁed in Tau ([21,42]; Tau phosphorylation site
table: https://www.kcl.ac.uk/people/diane-hanger). The
distribution of p-sites in the Tau sequence is asym-
metric, such that most of the nonmodiﬁed sites are
located in the acidic N-terminal half (up to residue
1 The RD (Figure 1) is often described in the literature as ‘microtubule-binding
domain’ (MTBD). This term is misleading, as the RD alone has only a weak afﬁnity for
microtubules. Efﬁcient binding and assembly of microtubules is achieved by the RD
plus the ﬂanking domains, herein denoted as ‘MT assembly domain’ (Figure 1).
Available online at www.sciencedirect.com
ScienceDirect
Current Opinion in
Neurobiology
www.sciencedirect.com
Current Opinion in Neurobiology 2021, 69:131–138


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Article
A deep proteome and transcriptome abundance
atlas of 29 healthy human tissues
Dongxue Wang1,†
, Basak Eraslan2,3,†, Thomas Wieland4, Björn Hallström5, Thomas Hopf4,
Daniel Paul Zolg1, Jana Zecha1, Anna Asplund6, Li-hua Li1, Chen Meng1, Martin Frejno1
,
Tobias Schmidt1, Karsten Schnatbaum7, Mathias Wilhelm1, Frederik Ponten6
, Mathias Uhlen5,
Julien Gagneur2,*
, Hannes Hahne4,**
& Bernhard Kuster1,8,***
Abstract
Genome-,
transcriptome-
and
proteome-wide
measurements
provide
insights
into
how
biological
systems
are
regulated.
However, fundamental aspects relating to which human proteins
exist, where they are expressed and in which quantities are not
fully understood. Therefore, we generated a quantitative proteome
and transcriptome abundance atlas of 29 paired healthy human
tissues from the Human Protein Atlas project representing human
genes by 18,072 transcripts and 13,640 proteins including 37 with-
out
prior
protein-level
evidence.
The
analysis
revealed
that
hundreds of proteins, particularly in testis, could not be detected
even for highly expressed mRNAs, that few proteins show tissue-
specific expression, that strong differences between mRNA and
protein quantities within and across tissues exist and that protein
expression is often more stable across tissues than that of tran-
scripts. Only 238 of 9,848 amino acid variants found by exome
sequencing could be confidently detected at the protein level
showing that proteogenomics remains challenging, needs better
computational methods and requires rigorous validation. Many
uses of this resource can be envisaged including the study of gene/
protein expression regulation and biomarker specificity evaluation.
Keywords human proteome; human transcriptome; proteogenomics;
quantitative mass spectrometry; RNA-Seq
Subject Categories Genome-Scale & Integrative Biology; Methods &
Resources
DOI 10.15252/msb.20188503 | Received 20 June 2018 | Revised 1 January
2019 | Accepted 8 January 2019
Mol Syst Biol. (2019) 15: e8503
See also: B Eraslan et al (February 2019)


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Introduction
Delineating the factors that govern protein expression and activity
in cells is among the most fundamental research topics in biology.
Although the number of potential protein-coding genes in the
human genome is stabilizing at about 20,000, high-quality evidence
for their physical existence has not yet been found for all and
intense efforts are ongoing to identify these currently ~13% “miss-
ing proteins” (Omenn et al, 2017). While it is also generally
accepted that the quantities of proteins vary greatly within and
across different cell types, tissues and body fluids (Kim et al, 2014;
Wilhelm et al, 2014), this has not been analysed systematically for
many human tissues. Furthermore, it is not very clear yet how the
many anabolic and catabolic processes are coordinated to give rise
to the often vast differences in the levels of proteins. Messenger
RNA levels are important determinants for protein abundance
(Vogel et al, 2010; Schwanha¨usser et al, 2011), and extensive
mRNA expression maps of human cell types and tissues have been
generated as proxies for estimating protein abundance (GTEx
Consortium, 2013; Uhle´n et al, 2015; Thul et al, 2017). However,
other studies have also highlighted the much higher dynamic range
of protein than transcript abundance as well as a rather poor
correlation of mRNA and protein levels suggesting that further and
possibly
diverse
regulatory
elements
play
important
roles
(Schwanha¨usser et al, 2011; Liu et al, 2016; Franks et al, 2017).
Decades of careful research revealed numerous mRNA elements
affecting translation or mRNA stability such as codon usage, start
1
Chair of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany
2
Computational Biology, Department of Informatics, Technical University of Munich, Garching bei München, Germany
3
Department of Biochemistry, Quantitative Biosciences Munich, Gene Center, Ludwig Maximilian Universität, München, Germany
4 OmicScouts GmbH, Freising, Germany
5


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5
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
6
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
7
JPT Peptide Technologies GmbH, Berlin, Germany
8
Center for Integrated Protein Science Munich (CIPSM), Munich, Germany
*Corresponding author. Tel: +49 89 289 19411; E-mail: gagneur@in.tum.de
**Corresponding author. Tel: +49 8161 976289 0; Fax: +49 8161 976289 1; E-mail: hannes.hahne@omicscouts.com
***Corresponding author. Tel: +49 8161 71 5696; Fax: +49 8161 71 5931; E-mail: kuster@tum.de
†These authors contributed equally to this work
ª 2019 The Authors. Published under the terms of the CC BY 4.0 license
Molecular Systems Biology
15: e8503 | 2019
1 of 16


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RESEARCH ARTICLE
A Draft Map of Rhesus Monkey Tissue
Proteome for Biomedical Research
Jin-Gyun Lee1, Kimberly Q. McKinney1, Yong-Yook Lee1, Hae-Na Chung1, Antonis
J. Pavlopoulos1, Kook Y. Jung1, Woong-Ki Kim2, Marcelo J. Kuroda3, David K. Han4,
Sunil Hwang1*
1 Proteomics Laboratory for Clinical and Translational Research, Carolinas HealthCare System, Charlotte,
North Carolina, United States of America, 2 Department of Microbiology and Molecular Cell Biology, Eastern
Virginia Medical School, Norfolk, Virginia, United States of America, 3 Tulane National Primate Research
Center, Tulane University, Covington, Louisiana, United States of America, 4 Department of Cell Biology and
Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, United States
of America
* sunil.hwang@carolinas.org
Abstract
Though the rhesus monkey is one of the most valuable non-human primate animal models
for various human diseases because of its manageable size and genetic and proteomic
similarities with humans, proteomic research using rhesus monkeys still remains challeng-
ing due to the lack of a complete protein sequence database and effective strategy. To in-
vestigate the most effective and high-throughput proteomic strategy, comparative data
analysis was performed employing various protein databases and search engines. The Uni-
Prot databases of monkey, human, bovine, rat and mouse were used for the comparative
analysis and also a universal database with all protein sequences from all available species
was tested. At the same time, de novo sequencing was compared to the SEQUEST search
algorithm to identify an optimal work flow for monkey proteomics. Employing the most effec-
tive strategy, proteomic profiling of monkey organs identified 3,481 proteins at 0.5% FDR
from 9 male and 10 female tissues in an automated, high-throughput manner. Data are
available via ProteomeXchange with identifier PXD001972. Based on the success of this al-


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ternative interpretation of MS data, the list of proteins identified from 12 organs of male and
female subjects will benefit future rhesus monkey proteome research.
Introduction
Since the human genome project was completed in 2003, proteomics has become a powerful
tool for understanding the large and global characteristics of proteins within a broad range of
biomedical research platforms [1–3]. To achieve automated peptide sequencing using tandem
mass spectrometry (MS/MS), development of database search algorithms such as SEQUEST,
Mascot and X!Tandem, have been geared toward the few species with well-annotated protein
databases[4–7]. However, automated and high-throughput peptide sequencing with mass spec-
trometry analysis has been hindered for research in species with incomplete or uncertain
PLOS ONE | DOI:10.1371/journal.pone.0126243
May 14, 2015
1 / 18
OPEN ACCESS
Citation: Lee J-G, McKinney KQ, Lee Y-Y, Chung H-
N, Pavlopoulos AJ, Jung KY, et al. (2015) A Draft
Map of Rhesus Monkey Tissue Proteome for
Biomedical Research. PLoS ONE 10(5): e0126243.
doi:10.1371/journal.pone.0126243
Academic Editor: Xuejiang Guo, Nanjing Medical
University, CHINA
Received: October 7, 2014
Accepted: March 28, 2015
Published: May 14, 2015
Copyright: © 2015 Lee et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: These raw data are
available from http://proteomecentral.
proteomexchange.org/cgi/GetDataset?ID=
PXD001972.
Funding: This research was supported by a
Carolinas HealthCare System Cannon Research
Grant (CRG 08-026). The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.


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ARTICLE
doi:10.1038/nature13302
A draft map of the human proteome
Min-Sik Kim1,2, Sneha M. Pinto3, Derese Getnet1,4, Raja Sekhar Nirujogi3, Srikanth S. Manda3, Raghothama Chaerkady1,2,
Anil K. Madugundu3, Dhanashree S. Kelkar3, Ruth Isserlin5, Shobhit Jain5, Joji K. Thomas3, Babylakshmi Muthusamy3,
Pamela Leal-Rojas1,6, Praveen Kumar3, Nandini A. Sahasrabuddhe3, Lavanya Balakrishnan3, Jayshree Advani3, Bijesh George3,
Santosh Renuse3, Lakshmi Dhevi N. Selvan3, Arun H. Patil3, Vishalakshi Nanjappa3, Aneesha Radhakrishnan3, Samarjeet Prasad1,
Tejaswini Subbannayya3, Rajesh Raju3, Manish Kumar3, Sreelakshmi K. Sreenivasamurthy3, Arivusudar Marimuthu3,
Gajanan J. Sathe3, Sandip Chavan3, Keshava K. Datta3, Yashwanth Subbannayya3, Apeksha Sahu3, Soujanya D. Yelamanchi3,
Savita Jayaram3, Pavithra Rajagopalan3, Jyoti Sharma3, Krishna R. Murthy3, Nazia Syed3, Renu Goel3, Aafaque A. Khan3,
Sartaj Ahmad3, Gourav Dey3, Keshav Mudgal7, Aditi Chatterjee3, Tai-Chung Huang1, Jun Zhong1, Xinyan Wu1,2, Patrick G. Shaw1,
Donald Freed1, Muhammad S. Zahari2, Kanchan K. Mukherjee8, Subramanian Shankar9, Anita Mahadevan10,11, Henry Lam12,
Christopher J. Mitchell1, Susarla Krishna Shankar10,11, Parthasarathy Satishchandra13, John T. Schroeder14, Ravi Sirdeshmukh3,
Anirban Maitra15,16, Steven D. Leach1,17, Charles G. Drake16,18, Marc K. Halushka15, T. S. Keshava Prasad3, Ralph H. Hruban15,16,
Candace L. Kerr19{, Gary D. Bader5, Christine A. Iacobuzio-Donahue15,16,17, Harsha Gowda3 & Akhilesh Pandey1,2,3,4,15,16,20
Theavailabilityofhumangenomesequencehastransformedbiomedicalresearchoverthepastdecade.However,anequiv-
alent map for the human proteome with direct measurements of proteins and peptides does not exist yet. Here we present
a draft map of the human proteome using high-resolution Fourier-transform mass spectrometry. In-depth proteomic
profiling of 30 histologically normal human samples, including 17 adult tissues, 7 fetal tissues and 6 purified primary hae-


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matopoietic cells, resulted in identification of proteins encoded by 17,294 genes accounting forapproximately 84% of the
total annotated protein-coding genes in humans. A unique and comprehensive strategy for proteogenomic analysis
enabled us to discover a number of novel protein-coding regions, which includes translated pseudogenes, non-coding
RNAs and upstream open reading frames. This large human proteome catalogue (available as an interactive web-based
resource at http://www.humanproteomemap.org) will complement available human genome and transcriptome data to
accelerate biomedical research in health and disease.
Analysis of the complete human genome sequence has thus far led to
theidentificationofapproximately20,687protein-codinggenes1,although
the annotation still continues to be refined. Mass spectrometryhas rev-
olutionized proteomics studies in a manner analogous to the impact of
next-generationsequencingongenomicsandtranscriptomics2–4.Several
groups, including ours, have used mass spectrometry to catalogue com-
plete proteomes of unicellular organisms5–7 and to explore proteomes
ofhigherorganisms,includingmouse8andhuman9,10.Todevelopadraft
mapofthehumanproteomebysystematicallyidentifyingandannotat-
ing protein-coding genes in the human genome, we carried out prote-
omic profiling of 30 histologically normal human tissues and primary
cells using high-resolution mass spectrometry. We generated tandem
massspectracorrespondingtoproteinsencodedby17,294genes,account-
ing for approximately 84% of the annotated protein-coding genes in
thehumangenome—toourknowledgethelargestcoverageofthehuman
proteomereportedsofar.Thisincludesmassspectrometricevidencefor
proteins encoded by2,535genes that havenot been previously observed
asevidencedbytheirabsenceinlarge community-based proteomic data
sets—PeptideAtlas11, GPMDB12 and neXtProt13 (which includes anno-
tations from the Human Protein Atlas14).
A general limitation of current proteomics methods is their depen-


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dence on predefined protein sequence databases for identifying pro-
teins. To overcome this, we also used a comprehensive proteogenomic
analysis strategy to identify novel peptides/proteins that are currently
not part of annotated protein databases. This approach revealed novel
protein-coding genes in the human genome that are missing from cur-
rent genome annotations in addition to evidence of translation of several
annotatedpseudogenesaswellasnon-codingRNAs.Asdiscussedbelow,
we provide evidence for revisinghundreds ofentries in protein databases
based on our data. This includes novel translationstart sites, gene/exon
extensions and novel coding exons for annotated genes in the human
genome.
Generating a high-quality mass spectrometry data set
To generate a baseline proteomic profile in humans, we studied 30 his-
tologicallynormalhumancellandtissuetypes,including17adulttissues,
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 2Department of Biological Chemistry, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205, USA. 3Institute of Bioinformatics, International Tech Park, Bangalore 560066, India. 4Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana
70130, USA. 5The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. 6Department of Pathology, Universidad de La Frontera,Center of Genetic and Immunological Studies-Scientific
and Technological Bioresource Nucleus, Temuco 4811230, Chile. 7School of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. 8Department of Neurosurgery,
Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India. 9Department of Internal Medicine Armed Forces Medical College, Pune 411040, India. 10Department of
Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India. 11Human Brain Tissue Repository, Neurobiology Research Centre, National Institute of Mental Health and


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Neurosciences, Bangalore 560029, India. 12Department of Chemical and Biomolecular Engineering and Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear
Water Bay, Hong Kong. 13Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India. 14Department of Medicine, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21224, USA. 15The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231,
USA. 16Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. 17Department of Surgery, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21231, USA. 18Departments of Immunology and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
19Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine Baltimore, Maryland 21205, USA. 20Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana
70130, USA. {Present address: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
2 9
M A Y 2 0 1 4
| V O L 5 0 9 |
N A T U R E
| 5 7 5
©2014 Macmillan Publishers Limited. All rights reserved


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A proteomic atlas of the legume, M. truncatula, and its nitrogen 
fixing endosymbiont, S. meliloti
Catherine E. Minogue1,2, Harald Marx1,2, Dhileepkumar Jayaraman3, Alicia L. Richards2, 
Nicholas W. Kwiecien2, Alireza F. Sihapirani4, Shanmugam Rajasekar3, Junko Maeda5, 
Kevin Garcia5, Angel R. Del Valle-Echevarria5, Jeremy Volkening6, Michael S. Westphall2, 
Sushmita Roy7,8, Michael R. Sussman6, Jean-Michel Ané3,5, Joshua J. Coon2,9,*
1Co-first author
2Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
3Department of Agronomy, University of Wisconsin-Madison, Madison, WI 53706, USA
4Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
5Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA
6Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
7Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, 
WI 53706, USA
8Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53706, USA
9Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, 
USA
Abstract
Leguminous plants ‘fix’ atmospheric nitrogen through complex symbiotic relationships with 
rhizobial soil bacteria. These plants play a key role in agricultural sustainability because, unlike 
other major crops (e.g., corn, wheat and rice), they require no expensive and environmentally 
deleterious fertilizer. Much like the fundamental and unique insights obtained from the study of 
plant pathogens, research on symbiotic bacteria and their host plants is providing new mechanistic 
information on plant growth and development. In this resource we describe a large-scale, 
quantitative proteomic study, which includes key post-translational modifications, to establish the 
first global proteomic blueprint of a legume and its rhizobial endosymbiont. By quantifying over 
*Corresponding author. jcoon@chem.wisc.edu.
Author contributions


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H.M., C.E.M, D.J., J.M.A. and J.J.C. conceived and designed the study. D.J., S.R., J.M., provided the plant material. C.E.M, A.L.R. 
and M.S.W. performed the proteomics experiments. H.M. and C.E.M. analyzed the data. H.M., C.E.M., D.J., K.G. and A.R.D.E. 
interpreted the data. N.W.K. and H.M. and built the website. A.F.S., J.V. and S.R. generated the regulatory network. The paper was 
written by C.E.M., H.M., D.J., M.R.S., K.G., A.R.D.E, J.M.A. and J.J.C. and was edited by all authors.
Accession codes
The raw mass spectrometry data was submitted via ProteomeXchange (Vizca{\’{\i}}no, J. A. et al., 2014) to the PRIDE repository 
(PXD002692) (Vizca{\’{\i}}no, et al., 2013).
Supplementary information
Supplemental information includes seven figures and four tables and can be found with this article online.
HHS Public Access
Author manuscript
Nat Biotechnol. Author manuscript; available in PMC 2021 October 31.
Published in final edited form as:
Nat Biotechnol. 2016 November ; 34(11): 1198–1205. doi:10.1038/nbt.3681.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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A Quantitative Proteome Map of the Human Body
Lihua Jiang1,3, Meng Wang1,3, Shin Lin2, Ruiqi Jian1, Xiao Li1, Joanne Chan1, Guanlan 
Dong1, Huaying Fang1, Aaron E. Robinson1, GTEx Consortium, Michael P. Snyder1,4,*
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
2Division of Cardiology, University of Washington, Seattle, WA 98195, USA
3These authors contributed equally
4Lead Contact
SUMMARY
Determining protein levels in each tissue and how they compare with RNA levels is important for 
understanding human biology and disease as well as regulatory processes that control protein 
levels. We quantified the relative protein levels from over 12,000 genes across 32 normal human 
tissues. Tissue-specific or tissue-enriched proteins were identified and compared to transcriptome 
data. Many ubiquitous transcripts are found to encode tissue-specific proteins. Discordance of 
RNA and protein enrichment revealed potential sites of synthesis and action of secreted proteins. 
The tissue-specific distribution of proteins also provides an in-depth view of complex biological 
events that require the interplay of multiple tissues. Most importantly, our study demonstrated that 
protein tissue-enrichment information can explain phenotypes of genetic diseases, which cannot be 
obtained by transcript information alone. Overall, our results demonstrate how understanding 
protein levels can provide insights into regulation, secretome, metabolism, and human diseases.
Graphical Abstract
*Correspondence: mpsnyder@stanford.edu.
AUTHOR CONTRIBUTIONS
L.J. led this project in generating proteomics data, data analysis, and manuscript preparation. M.W. developed statistical methods for 
proteomics data analysis and integration. S.L. performed the initial data analysis and SNP database construction. R.J. and J.C. did 
proteomics sample preparation and mass spectrometry data acquisition and contributed to making figures. X.L. did the analysis on the


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association of tissue-enriched proteins to diseases. H.F. contributed to the discussion of data analysis. G.D. contributed to SNP and 
isoform early data analysis. A.R. did SNP peptide spectra library search. M.P.S. contributed to project supervision and manuscript 
review and revision. All the authors contributed to manuscript revision.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.cell.2020.08.036.
DECLARATION OF INTERESTS
M.P.S. is a cofounder and is on the scientific advisory board of Personalis, Filtircine, SensOmics, Qbio, January, Mirvie, Oralome, and 
Proteus. He is also on the scientific advisory board (SAB) of Genapsys and Jupiter. The other authors declare no competing interests.
HHS Public Access
Author manuscript
Cell. Author manuscript; available in PMC 2021 October 01.
Published in final edited form as:
Cell. 2020 October 01; 183(1): 269–283.e19. doi:10.1016/j.cell.2020.08.036.
Author Manuscript
Author Manuscript
Author Manuscript
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IMAGES: THE KAROLINSKA INSTITUTE WITH THE ALLEN INSTITUTE FOR BRAIN SCIENCE
SPECIAL SECTION
O
ur brain is composed of 86 billion neurons and a similar number 
of non-neuronal cells. The National Institute of Health’s Brain Re-
search through Advancing Innovative Neurotechnologies (BRAIN) 
Initiative - Cell Census Network (BICCN), which was ﬁ rst launched 
in 2017, is a consortium of centers distributed in the United States 
and Europe that work together toward the goal of characterizing 
cell types and their functions in the brains of humans, nonhuman 
primates (NHPs), and rodents.
In Science, Science Advances, and Science Translational Medi-
cine, we present the results of this monumental eff ort. By leveraging the 
most-advanced technologies, which, until now, were mostly applied to ani-
mal models, the studies examine the cellular composition of the adult and 
developing human brain at the transcriptional, epigenetic, and functional 
levels. The studies are organized around ﬁ ve main themes: (i) adult hu-
man single-cell atlasing, including studies using single-cell transcriptomic 
and epigenomic analyses to characterize the human brain; (ii) adult NHP 
single-cell atlasing, which focuses on similar single-cell analyses in marmo-
set and macaque brain; (iii) comparative single-cell analyses that compare 
cellular composition in human versus NHP brain; (iv) human and NHP 
brain development single-cell analyses that focus on the characterization 
of developmental dynamics in developing human and NHP brain; and (iv) 
human neuronal cell-type functional and anatomical analysis and model-
ing, which includes the physiological and anatomical characterization of 
cellular properties in living human tissues, and the modeling of cell types 
and specialized cellular properties in humans versus rodent models.
The data collected by the BICCN will now allow researchers to tackle fun-
damental scientiﬁ c questions about the human brain and its genetic orga-


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nization. The era of cellular human brain research is knocking at our door! 
10.1126/science.adl0913
The background depicts three-
dimensional renderings of 
reconstructed neurons obtained from 
living brain slices. The diversity in 
color and shape represents the wide 
variety of neuronal subtypes that 
make up the human brain.
By Mattia Maroso
PERSPECTIVE
A family portrait of human brain cells  
p. 168
RESEARCH ARTICLES
Interindividual variation in human 
cortical cell type abundance and 
expression  p. 170
Molecular programs of regional 
specifi cation and neural stem cell fate 
progression in macaque telencephalon  
p. 171
Comprehensive cell atlas of the 
fi rst-trimester developing human brain  
p. 172
Single-cell analysis of prenatal and 
postnatal human cortical development  
p. 173
Single-cell DNA methylation and 3D 
genome architecture in the human 
brain  p. 174
Transcriptomic diversity of cell types 
across the adult human brain  
p. 175
Transcriptomic cytoarchitecture 
reveals principles of human neocortex 
organization  p. 176
Signature morphoelectric properties of 
diverse GABAergic interneurons in the 
human neocortex  p. 177
Morphoelectric and transcriptomic 
divergence of the layer 1 interneuron 
repertoire in human versus mouse 
neocortex  p. 178
Comparative transcriptomics reveals 
human-specifi c cortical features  
p. 179
A comparative atlas of single-cell 
chromatin accessibility in the human 
brain  p. 180
Spatiotemporal molecular dynamics 
of the developing human thalamus  
p. 181
RELATED ITEMS
SCIENCE ADVANCES BRAIN CELL 
CENSUS SECTION 
10.1126/SCIADV.ADL0650
SCIENCE TRANSLATIONAL MEDICINE 
RESEARCH ARTICLE BY AMENT ET AL. 
10.1126/SCITRANSLMED.ADE1283
SCIENCE.ORG/COLLECTIONS/
BRAIN-CELL-CENSUS
A QUEST INTO THE  
HUMAN BRAIN
166    13 OCTOBER 2023 • VOL 382 ISSUE 6667
science.org  SCIENCE
Downloaded from https://www.science.org on October 13, 2023


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Differential Changes in Functional Connectivity of Striatum-Prefrontal and Striatum-Motor Circuits in Premanifest Huntingtons Disease


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Research Article
Neurodegener Dis
Differential Changes in Functional Connectivity 
of Striatum-Prefrontal and Striatum-Motor 
Circuits in Premanifest Huntington’s Disease
Martin Kronenbuerger a, b    Jun Hua c, d    Jee Y.A. Bang a, e    Kia E. Ultz a    Xinyuan Miao c, d    
Xiaoyu Zhang c, d    James J. Pekar c, d    Peter C.M. van Zijl c, d    Wenzhen Duan e, f    
Russell L. Margolis e–g    Christopher A. Ross e–g    
a
 Division of Movement Disorders, Department of Neurology, Johns Hopkins University School of Medicine, 
Baltimore, MD, USA; b
 Department of Neurology, University Medicine Greifswald, Greifswald, Germany; c
 Department 
of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; d
 F.M. Kirby Research Center for 
Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA; e
 Department of Psychiatry and Behavioral 
Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; f
 Department of Neuroscience and 
Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; g
 Department of Neurology,  
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Received: June 13, 2019
Accepted: June 19, 2019
Published online: August 14, 2019
Martin Kronenbuerger
Department of Neurology, University of Greifswald
Ferdinand-Sauerbruch-Strasse
DE–17475 Greifswald (Germany)
E-Mail martin.kronenbuerger @ med.uni-greifswald.de
© 2019 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/ndd
DOI: 10.1159/000501616
Keywords
Functional connectivity · Prefrontal cortex · Chorea · 
Premanifest period · Magnetic resonance imaging, 7 T
Abstract
Background: Huntington’s disease (HD) is a progressive neu-
rodegenerative disorder. The striatum is one of the first brain 
regions that show detectable atrophy in HD. Previous studies 
using functional magnetic resonance imaging (fMRI) at 3 tes-
la (3 T) revealed reduced functional connectivity between stri-
atum and motor cortex in the prodromal period of HD. Neu-


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roanatomical and neurophysiological studies have suggested 
segregated corticostriatal pathways with distinct loops in-
volving different cortical regions, which may be investigated 
using fMRI at an ultra-high field (7 T) with enhanced sensitiv-
ity compared to lower fields. Objectives: We performed fMRI 
at 7 T to assess functional connectivity between the striatum 
and several chosen cortical areas including the motor and 
prefrontal cortex, in order to better understand brain changes 
in the striatum-cortical pathways. Method: 13 manifest sub-
jects (age 51 ± 13 years, cytosine-adenine-guanine [CAG]  
repeat 45 ± 5, Unified Huntington’s Disease Rating Scale  
[UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset 
premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, 
UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset 
premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2,  
UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 
15 years) were studied. The functional connectivity between 
the striatum and several cortical areas was measured by rest-
ing state fMRI at 7 T and analyzed in all participants. Results: 
Compared to controls, functional connectivity between stria-
tum and premotor area, supplementary motor area, inferior 
frontal as well as middle frontal regions was altered in HD (all 
p values < 0.001). Specifically, decreased striatum-motor con-
nectivity but increased striatum-prefrontal connectivity were 
found in premanifest HD subjects. Altered functional connec-
M.K. and J.H. contributed equally to this paper.
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Annals of the Rheumatic Diseases, 1980, 39, 147-151
Immunocytological studies of lymph nodes in
rheumatoid arthritis and malignant lymphoma
R. F. WILLKENS, GILBERT F. ROTH, GUNNAR HUSBY, AND
R. C. WILLIAMS, JR.
From the Department ofMedicine, Division ofArthritis, Harborview Medical Center, University of Washington
School of Medicine, Seattle, Washington, USA, and the Department of Medicine, Bernalillo County Medical
Center, University ofNew Mexico School ofMedicine, Albuquerque, New Mexico 87131, Mexico
SLTmmARY
Lymph nodes obtained from 9 patients with active rheumatoid arthritis were stained
by immunological techniques permitting identification of B and T cell areas within the nodes. The
lymph nodes were also compared with those obtained from patients with lymphoma. The rheumatoid
lymph nodes showed prominent B cell staining in the follicular centres by the EAC and fluores-
ceinated immunoglobulin techniques. Interfollicular areas were intensely stained with anti-theta
globulin. In contrast, lymphoma nodes stained less intensely with fluoresceinated immunoglobulins
but stained like benign nodes with EAC. The difference in staining may reflect the degree of dis-
organisation of the neoplastic follicle and/or the different sensitivity of these 2 methods in the
detection of B cells. The differences in staining are helpful in distinguishing the benign changes
associated with chronic inflammation from neoplastic B cell proliferative changes seen in lymph
nodes.
Some patients with rheumatoid arthritis (RA) have
lymphadenopathy, and several histological studies
have been published on the lymph nodes from such
patients.' 5 The histological similarity of nodes
from rheumatoid arthritis and nodular lymphoma
has
occasionally led
to incorrect
diagnosis and
inappropriate therapy.2 4 The present study com-
pared lymph nodes, and in some instances splenic
tissues, from patients with RA and from patients
with malignant lymphoma, as well as normal lymph
nodes. Particular attention was directed at identi-


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fication of relative patterns of lymph node archi-
tecture as well as the types of lymphoid cells present
as identified by immunological techniques developed
for use with frozen tissue sections.6 7
Materials and methods
PATIENTS STUDIED
Axillary lymph nodes were obtained from 9 patients
with
active rheumatoid
arthritis.
Patients
were
classified as definite or classical RA on the basis of
Accepted for publication 23 August 1978
Correspondence to Robert F. Willkens, MD, Harborview
Medical Center, 325 Ninth Avenue, Seattle, Washington
98104, USA.
Table 1
Characterisation ofpatients with rheumatoid
arthritis
Patient
Duration of ESR
RF
ANA
Therapy
disease
(mm/h)
(years)
1
20
17
1:64
pi
Gold2
2
5
76
1:5120
N
Steroids
3
21
17
1:320
P
Gold
4
21
6
1:2080
P
Gold,
steroids
5
13
46
1:1280
N
Cytoxan
6
3
62
N
N
-
7
5
11
N
P
Gold
8
7
18
1:512
P
Gold
9
7
16
1:5120
P
Gold,
steroids
iP-positive, N-negative.
2A11 patients were on salicylates or another nonsteroidal anti-inflam-
matory drug in addition to drug(s) listed.
ARA criteria.8 An outline of age, sex, and clinical
status of all studied patients is given in Table 1.
For comparison lymph nodes or spleen were
obtained from 3 patients with lymphoma, and nor-
mal lymph nodes were obtained from 3 subjects
during surgical procedures for nonmalignant con-
ditions. Mediastinal thymoma was obtained from 1
patient for study.
-47


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REVIEW
Open Access
Adult hippocampal neurogenesis and its role in
Alzheimer’s disease
Yangling Mu* and Fred H Gage
Abstract
The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages
of Alzheimer’s disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus
represents an early critical event in the course of AD. Although causal links have not been established, a variety of
key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively
or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural
plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease
manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment,
whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair
mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD,
and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.
Keywords: Alzheimer’s disease, adult neurogenesis, hippocampus, neural stem cell
Introduction
Alzheimer’s disease (AD), first described by the German
neuropathologist Alois Alzheimer as Dementia Praecox
in 1907, is an age-related neurodegenerative disease
characterized by progressive loss of memory and dete-
rioration of cognitive functions. Individuals with the dis-
order usually experience difficulties in learning,
performance speed, recall accuracy and/or problem sol-
ving [1]. The gradual intraneuronal accumulation of
neurofibrillary tangles formed as a result of abnormal
hyperphosphorylation of cytoskeletal tau protein, extra-
cellular deposition of amyloid-b (Ab) protein as senile
plaques, and massive neuronal death represent impor-
tant neuropathological hallmarks of AD [2]. These


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pathologies are evident in specific, vulnerable brain
areas and the hippocampus is one of the earliest to be
affected [3]. The hippocampus is a mammalian brain
structure that lies under the medial temporal lobe, with
one on each side of the brain. Although there is a lack
of consensus relating to terms describing the hippocam-
pus and its adjacent cortex, the term hippocampus or
hippocampal formation generally applies to the dentate
gyrus (DG), the hippocampus proper - composed of
CA1, CA2 and CA3 fields - and the subiculum. The
organization of the hippocampal circuitry has been tra-
ditionally characterized as a unidirectional, trisynaptic
excitatory pathway (reviewed in [4]). Briefly, the entorh-
inal cortex (EC) provides the main source of input to
the hippocampus through connections to the DG. Infor-
mation flow then proceeds from DG to CA3 to CA1. In
turn, CA1 projects to the subiculum and sends the hip-
pocampal output back to the deep layers of EC. Beha-
vioral studies have long suggested that the hippocampus
plays a critical role in learning and memory [5], which
depend on functional and structural changes occurring
in the hippocampus, such as long-term potentiation
(LTP) and synaptic remodeling [6,7]. The discovery of a
de novo production of neurons in the adult DG has
introduced the possibility of a new form of plasticity
that could sustain memory processes. A growing body
of evidence supports the view that promotion of adult
hippocampal neurogenesis improves pattern separation
and spatial memory [8,9]. In contrast, a decline in neu-
rogenesis may underlie cognitive impairments associated
with aging and disorders such as AD [10,11]. Interest-
ingly, increasing evidence shows that central molecular
players in AD influence the generation of new
* Correspondence: ymu@salk.edu
Laboratory of Genetics, the Salk Institute for Biological Studies, La Jolla, CA
92037, USA
Mu and Gage Molecular Neurodegeneration 2011, 6:85
http://www.molecularneurodegeneration.com/content/6/1/85


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© 2011 Mu and Gage; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.


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Marcaje colinérgico en la corteza cerebral y el hipocampo en algunas especies animales y su relación con la enfermedad de Alzheimer


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Cómo
 citar
 este
 artículo:
 Orta-Salazar
 E,  et
 al.
 Marcaje
 colinérgico
 en
 la
 corteza
 cerebral
 y  el
 hipocampo
 en
 algunas
especies
 animales
 y  su
 relación
 con
 la
 enfermedad
 de
 Alzheimer.
 Neurología.
 2014.
 doi:10.1016/j.nrl.2012.10.007
ARTICLE IN PRESS
+Model
NRL-432;
 
No.
 of
 Pages
 7
Neurología.
 2014;xxx(xx):xxx—xxx
NEUROLOGÍA
www.elsevier.es/neurologia
REVISIÓN
Marcaje
 colinérgico
 en  la  corteza
 cerebral
 y  el  hipocampo
 en
algunas
 especies
 animales
 y su  relación  con  la enfermedad
de
 Alzheimer
E.
 Orta-Salazar a, C.A.
 Cuellar-Lemus a, S. Díaz-Cintra b y
 A.I.
 Feria-Velasco a,∗
a Centro
 Universitario
 de
 Ciencias
 Biológicas
 y
 Agropecuarias
 (CUCBA),
 Universidad
 de
 Guadalajara,
 Zapopan,
 México
b Instituto
 de
 Neurobiología
 (INB),
 Campus
 UNAM-Juriquilla,
 Juriquilla,
 Querétaro,
 México
Recibido
 el
 24
 de
 septiembre
 de
 2012;
 aceptado
 el
 4
 de
 octubre
 de
 2012
PALABRAS
 CLAVE
Inervación
colinérgica;
Colina
acetiltransferasa;
Acetilcolinesterasa;
Corteza
 cerebral;
Hipocampo;
Enfermedad
 de
Alzheimer
Resumen
Introducción:
 El
 sistema
 colinérgico
 incluye
 neuronas
 localizadas
 en
 el
 cerebro
 basal
 anterior
y
 sus
 axones
 largos
 proyectan
 a
 la
 corteza
 cerebral
 e
 hipocampo.
 Este
 sistema
 modula
 la
 función
cognitiva.
 En
 la
 enfermedad
 de
 Alzheimer
 (EA)
 y  en
 el
 proceso
 de
 envejecimiento
 la
 disfunción
colinérgica
 hay
 una
 asociación
 entre
 el
 deterioro
 cognitivo
 y
 el
 da˜no
 progresivo
 de
 las
 ﬁbras
colinérgicas,
 lo
 que
 conduce
 al
 postulado
 de
 la
 hipótesis
 colinérgica.
Desarrollo:
 En
 la
 EA
 se
 producen
 alteraciones
 en
 la
 expresión
 y
 en
 la
 actividad
 de
 la
 colina
acetiltransferasa
 (ChAT)
 y
 la
 acetilcolinesterasa
 (AChE),
 enzimas
 especíﬁcas
 relacionadas
 con
 la
función
 del
 SC.
 Ambas
 proteínas
 juegan
 un
 papel
 importante
 en
 la
 transmisión
 colinérgica
 mos-
trando
 variaciones
 en
 la
 corteza
 cerebral
 y  en
 el
 hipocampo,
 tanto
 por
 el
 envejecimiento,
 como
por
 la
 EA.


key: chroma:document
string_value:
la
 EA.
 En
 ambas
 estructuras,
 los
 desórdenes
 demenciales
 están
 asociados
 a
 la
 destrucción
severa
 y
 desorganización
 de
 las
 proyecciones
 colinérgicas
 que
 se
 encuentran
 afectadas.
 Para
el
 estudio
 de
 este
 sistema
 se
 han
 usado
 marcadores
 especíﬁcos
 como
 los
 anticuerpos
 contra
ChAT
 y
 AChE
 que
 han
 sido
 empleados
 en
 las
 técnicas
 de
 inmuhistoquímica
 de
 luz
 y
 micro-
scopia
 electrónica
 en
 algunas
 especies
 animales.
Conclusiones:
 En
 este
 trabajo
 se
 hace
 una
 revisión
 de
 los
 principales
 estudios
 inmunomorfo-
lógicos
 de
 la
 corteza
 cerebral
 e
 hipocampo
 de
 varias
 especies
 animales
 con
 énfasis
 en
 el
 SC
 y
su
 relación
 con
 la
 EA.
©
 2012
 Sociedad
 Espa˜nola
 de
 Neurología.
 Publicado
 por
 Elsevier
 España,
 S.L.
 Todos
 los
 derechos
reservados.
KEYWORDS
Cholinergic
innervation;
Cholinergic
 markers
 in
 the
 cortex
 and
 hippocampus
 of  some
 animal
 species
 and
 their
correlation
 to
 Alzheimer’s
 disease
Abstract
Introduction:
 The
 cholinergic
 system
 includes
 neurons
 located
 in
 the
 basal
 forebrain
 and
their
 long
 axons
 that
 reach
 the
 cerebral
 cortex
 and
 the
 hippocampus.
 This
 system
 modulates
∗ Autor
 para
 correspondencia.
Correo
 electrónico:
 alfredoferia1340@hotmail.com
 (A.I.
 Feria-Velasco).
0213-4853/$
 –  see
 front
 matter
 ©
 2012
 Sociedad
 Espa˜nola
 de
 Neurología.
 Publicado
 por
 Elsevier
 España,
 S.L.
 Todos
 los
 derechos
 reservados.
doi:10.1016/j.nrl.2012.10.007


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Comprehensive identification of peptides in tandem mass spectra using an efficient open search engine


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nature biotechnology   advance online publication 
1
b r i e f  c o m m u n i c at i o n s
1Key Laboratory of Intelligent Information Processing of Chinese Academy of Sciences (CAS), Institute of Computing Technology, CAS, Beijing, China. 2University 
of Chinese Academy of Sciences, Beijing, China. 3National Institute of Biological Sciences, Beijing, Beijing, China. 4State Key Laboratory of Proteomics, Beijing 
Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. 5State Key Laboratory of Biocontrol and 
Guangdong Provincial Key Laboratory of Plant Resources, College of Ecology and Evolution, Sun Yat-Sen University, Guangzhou, China. 6These authors contributed 
equally to this work. Correspondence should be addressed to S.-M.H. (smhe@ict.ac.cn) or H.C. (chihao@ict.ac.cn).
Received 3 December 2017; accepted 3 August 2018; published online 8 October 2018; doi:10.1038/nbt.4236
Matching tandem mass (MS/MS) spectra to peptide sequences  
contained in databases has long been the dominant approach for 
shotgun proteomics. However, >50% of spectra go unmatched1. One 
reason for this is that the current restricted search engines cannot 
identify peptides with unexpected modifications2–5. Another is that 
semi- and nonspecific digestion, in-source fragmentation, and cof-
ragmentation of coeluting peptides6,7, collectively referred to as the 
‘dark matter’ of shotgun proteomics8,9, hinder peptide identification. 
Open search engines enlarge the search space with more types of 
modifications to retrieve more peptide candidates, but these are very 
time consuming, and it is still difficult to reliably identify >50% of 
the spectra1,9.
We developed a computationally efficient search engine, Open-
pFind, that improves peptide and protein identification by matching 
MS/MS spectra to a substantially expanded search space. Open-
pFind consists of two search steps: one open and one restricted 
(Supplementary Fig. 1). First, a sequence-tag-based strategy is used


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to match spectra to a much larger set of possible peptide sequences 
in the open search (Fig. 1a). Based on these open search results, a 
restricted search is then performed in which several key parameters, 
including modification types and protein sequence entries, are auto-
matically set by semi-supervised machine learning.
comprehensive identification 
of peptides in tandem mass 
spectra using an efficient open 
search engine
Hao Chi1,2,6 , Chao Liu1,2,6, Hao Yang1,2,6, Wen-Feng Zeng1,2, 
Long Wu1,2, Wen-Jing Zhou1,2, Rui-Min Wang1,2,  
Xiu-Nan Niu1,2, Yue-He Ding3, Yao Zhang4,5, 
Zhao-Wei Wang1,2, Zhen-Lin Chen1,2, Rui-Xiang Sun1,2, 
Tao Liu1, Guang-Ming Tan1, Meng-Qiu Dong3 ,  
Ping Xu4, Pei-Heng Zhang1 & Si-Min He1,2
We present a sequence-tag-based search engine, Open-pFind, 
to identify peptides in an ultra-large search space that includes 
coeluting peptides, unexpected modifications and digestions. 
Our method detects peptides with higher precision and speed 
than seven other search engines. Open-pFind identified  
70–85% of the tandem mass spectra in four large-scale 
datasets and 14,064 proteins, each supported by at least two 
protein-unique peptides, in a human proteome dataset. 
We compared the performance of Open-pFind with that of seven 
other search engines using a 15N/13C metabolically labeled dataset 
(Dong-Ecoli-QE; Supplementary Tables 1 and 2 and Supplementary 
Fig. 2). Open-pFind identified 50.5% more peptide-spectrum matches 
(PSMs), 11.3% more distinct peptides and 6.9% more distinct peptide 
sequences than the second-best search engine (Fig. 1b) at a peptide-
level false discovery rate (FDR) of 1%. Here, a distinct peptide is 
defined by its amino acid sequence and all of its modifications, and a 
distinct peptide sequence is defined by just its amino acid sequence. 
Of the PSMs identified by Open-pFind, 54.9% were obtained from 
the restricted search space (Fig. 1c), whereas 45.1% were obtained 
from the extended search space produced by semi-tryptic/nonspecific


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digestions, unexpected modifications (including mutations), coelut-
ing peptides and the combination of these factors.
The Dong-Ecoli-QE dataset was mainly used to evaluate search 
engine precision (Supplementary Fig. 3), which was measured by the 
fraction of correct results among all of the results reported. Given the 
design of this dataset, if a PSM identification is estimated to be correct 
for an unlabeled peptide, the corresponding precursor ions with 15N 
or 13C labeling should generally be observed in full mass scans and 
valid quantitation ratios should be obtained. For an unlabeled peptide, 
if the corresponding labeled precursor ion is not observed, which 
results in an invalid or not-a-number quantitation ratio (reported 
as the NaN ratio by pQuant10), then the corresponding PSM is more 
likely to be incorrect. Generally, a smaller percentage of NaN ratio 
results indicates higher precision, and precision can be estimated 
independently of the target-decoy approach via the percentage of 
Nan ratio results (Supplementary Note 1).
We started with PSMs assigned to either unmodified peptides or 
peptides with four common modifications (cysteine carbamidometh-
ylation, methionine oxidation, N-terminal glutamine-to-pyroglutamic 
acid conversion and protein N-terminal acetylation; Supplementary 
Table 3 and Supplementary Fig. 4). The percentage of NaN ratio 
results was <1% for PSMs consistently identified by both Open-pFind 
and every other search engine in the paired comparison (Fig. 1d). 
This confirms that the PSMs identified consistently by different search 
engines are more credible. For PSMs uniquely identified by Open-
pFind, the percentage with a NaN ratio remained at ~1%, whereas this 
percentage rose to >10% for the majority of PSMs uniquely identified 
by other search engines. Similar results were obtained when the same 
analysis was performed on another metabolically labeled dataset (Xu-
Yeast-QEHF; Supplementary Fig. 5). We then examined all of the


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PSMs, without excluding any modifications. The percentage of PSMs 
with NaN ratio results increased substantially for open search engines 
(Supplementary Fig. 6). Even in this context, the Open-pFind results 
had the second smallest percentage of NaN ratio PSMs, second only 
to pFind, indicating that the PSMs from the extended search space of


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Cytology, architecture, development, and connections of the primate striatum: Hints for human pathology


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Neurobiology of Disease 176 (2023) 105945
Available online 5 December 2022
0969-9961/© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Cytology, architecture, development, and connections of the primate 
striatum: Hints for human pathology 
Natalia L´opez-Gonz´alez del Rey a,b, Miguel ´Angel García-Cabezas a,c,* 
a PhD Program in Neuroscience UAM-Cajal; Madrid, Spain 
b HM CINAC (Centro Integral de Neurociencias Abarca Campal). Hospital Universitario HM Puerta del Sur. HM Hospitales. Madrid, Spain 
c Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Aut´onoma de Madrid; Madrid, Spain   
A R T I C L E  I N F O   
Keywords: 
Striatum 
Basal ganglia 
Nucleus accumbens 
Caudate 
Putamen 
Cerebral cortex 
Cortical type 
Myelin 
Plasticity 
Neurodegeneration 
A B S T R A C T   
Degeneration of neurons and circuits across the striatum shows stereotyped time-course and spatial topography 
patterns that are distinct for Huntington’s disease, Parkinson’s disease, or the Tauopathies. These patterns of 
neurodegeneration in humans have not yet been systematically related to developmental, connectional, cellular, 
and chemical factors studied in human and non-human primates, that may underlie potential differences in 
selective vulnerability across striatal sectors. Relating primate anatomy to human pathology could provide new 
venues for identifying molecular, cellular, and connectional factors linked to the degeneration of striatal neurons 
and circuits. This review describes and summarizes several developmental, cellular, structural, and connectional 
features of the primate striatum in relation to patterns of neurodegeneration in the striatum of humans and of 
non-human primate models. We review (1) the types of neurons in the primate striatum, (2) the cyto-, myelo-, 
and chemoarchitecture of the primate striatum, (3) the developmental origin of the striatum in light of modern


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patterning studies, (4) the organization of corticostriatal projections in relation to cortical types, and (5) the 
topography and time-course of neuron loss, glial reaction, and protein aggregation induced by neurodegenerative 
diseases in humans and in non-human primate models across striatal sectors and their corresponding cortical 
areas. We summarize current knowledge about key aspects of primate striatal anatomy and human pathology and 
indicate knowledge gaps that should be addressed in future studies. We aim to identify factors for selective 
vulnerability to neurodegeneration of striatal neurons and circuits and obtain hints that could help elucidate 
striatal pathology in humans.   
1. Introduction 
Striatal neurons and their circuits are involved in several neurode-
generative diseases, chiefly Parkinson’s and Huntington’s diseases (Rub 
et al., 2016; Singh et al., 2016), but also Alzheimer’s disease, fronto-
temporal dementia, and tangle-predominant dementia (Suenaga et al., 
1990; Halabi et al., 2013; Kawakami et al., 2014). Degeneration of 
neurons and circuits across the striatum is not random; on the contrary, 
it shows stereotyped time-course and spatial topography patterns that 
are distinct for each neurodegenerative disease. In spite of such distinct 
patterns of degeneration, the cytological, connectional, developmental, 
and chemical factors that may underlie potential differences of selective 
vulnerability have not been systematically described across striatal 
sectors in relation to spatial topography and time-course of 
neurodegenerative pathology. This approach would provide new venues 
for identifying molecular, cellular, and connectional factors linked to the 
selective degeneration of striatal neurons and circuits. 
In this review we describe and summarize several developmental, 
cellular, structural, and connectional features of the primate striatum in 
relation to patterns of neurodegeneration across striatal sectors in


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humans with neurodegenerative diseases and in non-human primate 
models of neurodegeneration. We review (1) the types of neurons that 
populate the primate striatum and their participation in basal ganglia 
circuits, (2) the cyto-, myelo-, and chemoarchitecture of the primate 
striatum, (3) the embryonic development of the striatum in light of 
modern studies of subpallial patterning, neurogenesis, and morpho-
genesis, (4) the organization of corticostriatal projections in relation to 
cortical types revealed by synaptic tract-tracing studies in non-human 
* Corresponding author at: Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Aut´onoma de Madrid, Calle Arzobispo 
Morcillo 4, 28029 Madrid, Spain. 
E-mail address: garcia.cabezas@uam.es (M.´A. García-Cabezas).  
Contents lists available at ScienceDirect 
Neurobiology of Disease 
journal homepage: www.elsevier.com/locate/ynbdi 
https://doi.org/10.1016/j.nbd.2022.105945 
Received 4 May 2022; Received in revised form 19 November 2022; Accepted 3 December 2022


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Statistical Tools 
42
Practical Proteomics 1/2007
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 
www.practical.proteomics-journal.com
Design and Analysis Issues 
in Quantitative Proteomics 
Studies
Natasha A. Karp and 
Kathryn S. Lilley
Introduction
Proteomics is the study of ‘the entire protein complement 
expressed by a genome in a cell or tissue type’, and is a ma-
jor tool in the post-genomics era [1]. Quantitative proteomics 
is the comparison of distinct proteomes (e.g. control versus 
treatment or control versus disease) to identify protein spe-
cies with changes in expression or post-translational state.  
There are now numerous different methods to interrogate 
the proteome in a quantitative manner. Simplistically, these 
fall into two major categories; methods based around 2D gel 
electrophoresis (2-DE) with post staining [2, 3] or pre-label-
ling [4, 5], or methodologies where quantiﬁ cation occurs us-
ing mass spectrometric measurement, for example stable 
isotope labelling, both in vitro [6–8] or in vivo [9], and label-
free approaches [10, 11].  Whichever method is employed, 
after deﬁ ning the biological question to be answered by the 
study under consideration, an experimental design is then 
formulated. This design will include the methodologies to 
DOI 10.1002/pmic.200700683
  Department of Biochemistry, 
 Cambridge University, Cambridge, UK
 Dr. Kathryn Lilley
 University of Cambridge,
 Department of Biochemistry,
 Cambridge System Biology Centre,
 Tennis Court Road,
 Cambridge CB2 1QR, UK
 Fax: +44-1223-760255
 k.s.lilley@bioc.cam.ac.uk
Abbreviations:
FDR, false discovery rate
FWER, family wise error rate
PCER, per comparison error rate
Quantitative proteomics is the comparison of 
distinct proteomes which enables the iden-
tiﬁ cation of protein species which exhibit 
changes in expression or post-translational 
state in response to a given stimulus. Many 
different quantitative techniques are being 
utilized and generate large datasets. Inde-
pendent of the technique used, these large


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datasets need robust data analysis to ensure 
valid conclusions are drawn from such stud-
ies.  Approaches to address the problems that 
arise with large datasets are discussed to give 
insight into the types of statistical analyses of 
data appropriate for the various experimental 
strategies that can be employed by quantita-
tive proteomic studies.  This review also high-
lights the importance of employing a robust 
experimental design and highlights various is-
sues surrounding the design of experiments. 
The concepts and examples discussed within 
will show how robust design and analysis 
will lead to conﬁ dent results that will ensure 
quantitative proteomics delivers.


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Amyloid in osteoarthritic hip joints: deposits in relation to chonodromatosis, pyrophosphate, and inflammatory cell infiltrate in the synovial membrane and fibrous capsule


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string_value:
Annals ofthe Rheumatic Diseases, 1983, 42, 659-664
Amyloid in osteoarthritic hip joints: deposits in
relation to chondromatosis, pyrophosphate, and
inflammatory cell infiltrate in the synovial membrane
and fibrous capsule
CHR. LADEFOGED
From the Institute ofPathology, Odense University Hospital, Odense, Denmark
SUMMARY
The relationship between osteoarthritic change and amyloid degeneration was studied
in 116 joint capsules from osteoarthritic hip joints. Twenty-seven (23%) contained amyloid
deposits. Twenty-eight joint capsules showed chondroid metaplasia in the fibrous part. Signifi-
cantly more amyloid degeneration was found among these. Six joint capsules contained pyro-
phosphate crystals. Five of these were positive for amyloid. Chronic inflammation of the joint
capsule was found in 80 % of the cases and was negatively correlated with amyloid degeneration,
which is in good agreement with the biphasic theory for the pathogenesis of amyloid. Further
investigation is necessary to decide how chondroid metaplasia takes part in the production of
amyloid.
In 1972 Christensen and S0rensen' published 17
cases of amyloid degeneration in hip joint capsules.
The cases were from an unselected series consisting
of 43 patients operated on for severe osteoarthritis
coxae (46 capsules). This seems to be the first histo-
logical
investigation
of the
correlation
between
amyloidosis and osteoarthritis.
This paper describes amyloid deposits in the fi-
brous part of the capsule from osteoarthritic hip
joints
in
relation
to secondary
chondromatosis,
pyrophosphate
deposits,
and
inflammatory
cell
infiltration.
Material and methods
The
material
for
light
microscopy
comprised
approximately 5 x 3 x 2 cm pieces of tissue from the
synovial membrane and the fibrous capsule. They
were removed at each of 1 16 consecutive operations
for osteoarthritis coxae. Four patients had their hips
resected bilaterally.
The average age of the patients was 61 years (range
32-74), and 47 of them were women. None had


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clinical signs of primary amyloidosis, myelomatosis,
or
tuberculosis.
One
patient
had
concurrent
Accepted for publication 9 November 1982.
Correspondence
to Dr C. Ladefoged,
Institute
of Pathology,
Sonderborg Hospital, 6400 Sonderborg, Denmark.
rheumatoid arthritis. The operations were carried
out according to the method of Chamley at the
department
of Orthopaedic
Surgery
0,
of
the
Odense University Hospital.
The control material consisted of tissue from 25
autopsy hip joint capsules without osteoarthritic
changes such as hyaline degeneration, vascular pro-
liferation with perivascular fibrosis, inflammatory
cell infiltration, chondroid metaplasia, or calcifica-
tion. No macroscopic signs of osteoarthritis were
seen on the femoral heads. The average age of the
patients was 67 years, and 13 capsules were from
women.
No
cases
of
generalised
amyloidosis,
rheumatoid arthritis, tuberculosis, or myelomatosis
were found in the control material.
The tissue was immediately fixed in 10% formalin
and kept in it for approximately 24 hours. Thereafter
representative pieces were removed from both the
synovial membrane and the fibrous capsule and
embedded in paraffin after dehydration in ethanol
and xylene. Sections 6 gm thick were then stained
with haematoxylin and eosin, alcian blue 8GX,
alkaline Congo red, and,
in selected cases, van
Gieson's connective tissue stain. Amyloid was con-
sidered to be specifically demonstrated when the
yellowish-red colour of the alkaline Congo red stain-
ing showed green dichroism on polansation micros-
copy.3
Electron microscopy was performed only on the
659


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Nature | Vol 604 | 28 April 2022 | 723
Article
Cell transcriptomic atlas of the non-human 
primate Macaca fascicularis
Lei Han1,2,3,36, Xiaoyu Wei1,4,36, Chuanyu Liu1,2,3,36, Giacomo Volpe5,36, Zhenkun Zhuang1,6,36, 
Xuanxuan Zou1,4,36, Zhifeng Wang1,2,36, Taotao Pan1,2, Yue Yuan1,4, Xiao Zhang7, Peng Fan7, 
Pengcheng Guo7, Yiwei Lai8, Ying Lei1,2,3, Xingyuan Liu7, Feng Yu8, Shuncheng Shangguan9, 
Guangyao Lai9, Qiuting Deng1,4, Ya Liu1,2, Liang Wu1,2,4, Quan Shi1,10, Hao Yu1, Yunting Huang1,11, 
Mengnan Cheng1,4, Jiangshan Xu1,4, Yang Liu1,4, Mingyue Wang1, Chunqing Wang1,4, 
Yuanhang Zhang1,4, Duo Xie1,4, Yunzhi Yang12, Yeya Yu12, Huiwen Zheng12, Yanrong Wei12, 
Fubaoqian Huang1,6, Junjie Lei1,4, Waidong Huang1,4, Zhiyong Zhu1,4, Haorong Lu1,11, Bo Wang1,11, 
Xiaofeng Wei1,11, Fengzhen Chen1,11, Tao Yang1,11, Wensi Du1,11, Jing Chen1,11, Shibo Xu13, 
Juan An8,14, Carl Ward8, Zongren Wang15, Zhong Pei16, Chi-Wai Wong17, Xiaolei Liu7, 
Huafeng Zhang18, Mingyuan Liu7, Baoming Qin19, Axel Schambach20,21, Joan Isern22, 
Liqiang Feng23, Yan Liu13, Xiangyu Guo24,25, Zhen Liu26, Qiang Sun26, Patrick H. Maxwell27, 
Nick Barker28, Pura Muñoz-Cánoves29, Ying Gu1, Jan Mulder30,31, Mathias Uhlen30,31, Tao Tan32, 
Shiping Liu1,2,3, Huanming Yang1,33, Jian Wang1,33, Yong Hou1,2,3,12 ✉, Xun Xu1,2,12,34 ✉, 
Miguel A. Esteban7,8,35 ✉ & Longqi Liu1,2,3,12 ✉
Studying tissue composition and function in non-human primates (NHPs) is crucial to 
understand the nature of our own species. Here we present a large-scale cell 
transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult 
NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a 
species phylogenetically close to humans. To demonstrate the utility of the atlas, we 
have reconstructed the cell–cell interaction networks that drive Wnt signalling across 
the body, mapped the distribution of receptors and co-receptors for viruses causing 
human infectious diseases, and intersected our data with human genetic disease


key: chroma:document
string_value:
orthologues to establish potential clinical associations. Our M. fascicularis cell atlas 
constitutes an essential reference for future studies in humans and NHPs.
A major obstacle to building a comprehensive human cell atlas1 is 
obtaining a full range of ‘high-quality’ samples of sufficient size. Given 
their evolutionary proximity, non-human primates (NHPs) represent 
the nearest-to-human alternative. Generating an NHP cell atlas (NHPCA) 
would produce a catalogue of features that could be used to study 
human physiology, disease and ageing. It would also provide insights 
into the evolutionary mechanisms underlying different body function 
between NHPs and humans.
NHPs comprise a large and diverse group of species with major 
ecological, dietary, locomotor and behavioural differences2. Because 
of their characteristics, including a more frequent reproductive 
cycle and wide availability, macaques, in particular Macaca fas-
cicularis (also known as cynomolgus, crab-eating or long-tailed 
monkey), are now used for research purposes worldwide3. Here we 
used adult M. fascicularis tissues to generate the largest NHP cell 
transcriptomic dataset thus far. To facilitate exploration of this 
https://doi.org/10.1038/s41586-022-04587-3
Received: 11 March 2021
Accepted: 23 February 2022
Published online: 13 April 2022
 Check for updates
1BGI-Shenzhen, Shenzhen, China. 2BGI-Beijing, Beijing, China. 3Shenzhen Bay Laboratory, Shenzhen, China. 4College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 
China. 5Hematology and Cell Therapy Unit, IRCCS–Istituto Tumori ‘Giovanni Paolo II’, Bari, Italy. 6School of Biology and Biological Engineering, South China University of Technology, 
Guangzhou, China. 7State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin


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University, Changchun, China. 8Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 9Joint School of Life 
Sciences, Guangzhou Institutes of Biomedicine and Health and Guangzhou Medical University, Guangzhou, China. 10Department of Biology, University of Copenhagen, Copenhagen, Denmark. 
11China National GeneBank, BGI-Shenzhen, Shenzhen, China. 12BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China. 13Institute 
for Stem Cells and Neural Regeneration, School of Pharmacy, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China. 14University of Science and 
Technology of China, Hefei, China. 15Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 16Department of Neurology, First Affiliated Hospital, Sun Yat-sen 
University, Guangzhou, China. 17Huazhen Biosciences, Guangzhou, China. 18Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China. 19Laboratory of Metabolism 
and Cell Fate, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 20Institute of Experimental Hematology, Hannover Medical School, 
Hannover, Germany. 21Division of Hematology/Oncology, Harvard Medical School, MA, Boston, USA. 22Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain. 23State Key 
Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. 24Jinan University, Guangzhou, China. 25Hubei Topgene 
Biotechnology Co., Ltd, Wuhan, China. 26Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain 
Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. 27Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge,


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Cambridge, UK. 28A*STAR Institute of Molecular and Cell Biology, Singapore, Singapore. 29Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), ICREA and 
CIBERNED, Barcelona, Spain. 30Department of Protein Science, Science for Life Laboratory, KTH–Royal Institute of Technology, Stockholm, Sweden. 31Department of Neuroscience, Karolinska 
Institute, Stockholm, Sweden. 32State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 
China. 33James D. Watson Institute of Genome Sciences, Hangzhou, China. 34Guangdong Provincial Key Laboratory of Genome Read and Write, Shenzhen, China. 35Institute of Stem Cells and 
Regeneration, Chinese Academy of Sciences, Beijing, China. 36These authors contributed equally: Lei Han, Xiaoyu Wei, Chuanyu Liu, Giacomo Volpe, Zhenkun Zhuang, Xuanxuan Zou,  
Zhifeng Wang. ✉e-mail: houyong@genomics.cn; xuxun@genomics.cn; miguel@gibh.ac.cn; liulongqi@genomics.cn


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Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor


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ARTICLE
OPEN
Prenatal stress modulates HPA axis homeostasis of offspring
through dentate TERT independently of glucocorticoids
receptor
Meng-Ying Liu1,2,8, Lu-Lu Wei1,8, Xian-Hui Zhu1,3,8, Hua-Chen Ding
4,8, Xiang-Hu Liu1, Huan Li5,6, Yuan-Yuan Li3, Zhou Han1,2,
Lian-Di Li1, Zi-Wei Du1, Ya-Ping Zhou1, Jing Zhang1, Fan Meng1, Yu-Lin Tang3, Xiao Liu6✉, Chun Wang4✉ and Qi-Gang Zhou
1,3,4,7✉
© The Author(s) 2022
In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are
released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in
the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the
homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in
adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without
hippocampal GR deﬁciency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the
developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability
of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of
glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the ﬁrst exon of mouse Tert gene accounted for TERT
deﬁciency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism
underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for
maintaining HPA axis homeostasis.
Molecular Psychiatry (2023) 28:1383–1395; https://doi.org/10.1038/s41380-022-01898-9
INTRODUCTION
Maternal exposure to stresses during pregnancy reprograms the


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hypothalamic–pituitary–adrenal (HPA) axis of the offspring [1, 2].
The HPA axis is a critical adaptive system of the body for facing
with urgently physical and psychological challenges [3]. Although
acute or short-term activation of the HPA axis is beneﬁcial for
reacting to stimuli, chronic or long-term activation causes harmful
effects [4]. It has been well-documented over the last 40 years that
hyperactivity of the HPA axis is highly associated with the
pathology of adolescents’ depression [4]. Maternal stress-induced
excessive glucocorticoids cross the placenta, impairing fetal HPA
development and changing the HPA axis activity balance in the
offspring [5–9]. However, the molecular mechanism underlying
the gestational stress-induced fetal HPA axis dysfunction remains
largely unknown.
The hippocampus is a major component exerting inhibitory
modulation of the activity of the paraventricular nucleus (PVN) in
the hypothalamus, playing an important role in maintaining the
homeostasis of the HPA axis [10–12]. The endogenous receptor for
glucocorticoids, glucocorticoid receptor (GR), is a widely expressed
nuclear hormone receptor in the brain, with the highest density in
the hippocampus [13, 14]. Activation of hippocampal GR exerts
negative feedback modulation of the HPA axis activity by inhibiting
the expression of corticotropinreleasing factor or hormone (CRF or
CRH) in the PVN region, consequently causing decreased secretion
of glucocorticoids from the adrenal cortex [11]. Decreased number
and/or impaired function of the GR have been reported in patients
with depression in clinic [15, 16]. Preclinical studies suggest that the
dysfunction of GR in the PFC and hippocampus are involved in the
chronic stress-induced attenuation of the negative feedback
[17, 18]. The decreased expression and impaired function of GR
are also implicated in the prenatal stress-caused elevated HPA
axis reactivity in the offspring [7, 19, 20]. Accumulating evidences
support the hypothesis that the impairment of the central stress


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hormone negative regulation system is causally involved in the
development of depression [21]. However, a challenging question is
whether there is a mechanism beyond GR for maintaining the
homeostasis of the HPA axis in depression?
Telomerase are composed of the highly conserved catalytic
telomerase reverse transcriptase (TERT), the telomerase RNA
Received: 24 May 2020 Accepted: 18 November 2022
Published online: 8 December 2022
1State Key Laboratory of Reproductive Medicine, Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China. 2Department of
Pharmacy, The Afﬁliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. 3Department of Clinical Pharmacy, Sir Run Run Hospital, Nanjing Medical
University, Nanjing, China. 4Department of Psychiatry, Afﬁliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China. 5School of Applied Science, Temasek
Polytechnic, Singapore, Singapore. 6College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. 7The Key Center of Gene Technology Drugs of Jiangsu Province,
Nanjing Medical University, Nanjing, China. 8These authors contributed equally: Meng-Ying Liu, Lu-Lu Wei, Xian-Hui Zhu, Hua-Chen Ding. ✉email: liuxiao04_0@163.com;
fm51109@163.com; qigangzhou@njmu.edu.cn
www.nature.com/mp
Molecular Psychiatry
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ARTICLE IN PRESS 
JID: ARCMED 
[mNS; March 26, 2021;21:0 ] 
Archives of Medical Research xxx (xxxx) xxx 
Circulating Levels of Sex Steroid Hormones and Gastric Cancer 
Yelda A. Leal, a , ∗ Minkyo Song, b Jovanny Zabaleta, c Gilberto Medina-Escobedo, d Patrick Caron, e 
Aurelio Lopez-Colombo, f Chantal Guillemette, e and M. Constanza Camargo b 
a Centro Institucional de Capacitación y Registro de Cáncer, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional "Ignacio García 
Téllez,” Instituto Mexicano de Seguro Social (IMSS), Mérida, Yucatán, México 
b Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA 
c Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA 
d Departamento de Patología, UMAE, Centro Médico Nacional "Ignacio García Téllez," IMSS, Mérida, Yucatán, México 
e Pharmacogenomics Laboratory, Centre Hospitalier de l’Universite Laval de Quebec, Research Center and Faculty of Pharmacy, Laval University, 
Quebec City, Quebec, Canada 
f UMAE, Centro Médico Nacional “Manuel Ávila Camacho,” IMSS, Puebla, Puebla, México 
Received for publication August 26, 2020; accepted March 4, 2021 (ARCMED_2021_2647). 
Abstract 
Background and Aims. Men develop gastric cancer more frequently than women, yet 
little is known about the mechanisms underlying this sex difference. Sex steroid hor- 
mones may inﬂuence gastric cancer risk. We therefore assessed whether major circulat- 
ing adrenal precursors, androgens and estrogens were associated with gastric cancer in 
a high-risk Mexican population. 
Methods. Blood samples were collected at time of diagnosis from 50 noncardia gastric 
cancer patients and 50 histologically conﬁrmed non-atrophic gastritis controls. Serum 
levels of estradiol, testosterone and dehydroepiandrosterone (DHEA) measured with a 
validated mass spectrometry method were categorized in tertiles as low (T1), middle


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(T2), and high (T3). Unconditional logistic regression models were used to calculate 
odds ratios (ORs) and 95% conﬁdence intervals (CI), adjusting for age, sex, and edu- 
cation. 
Results. Levels of DHEA were inversely associated with gastric cancer ( p -trend per 
tertile increase: < 0.0001), with adjusted ORs (95% CI) of T2 and T3 (vs. T1) of 0.25 
(0.09–0.70) and 0.10 (0.03–0.34), respectively. Levels of estradiol and testosterone were 
not signiﬁcantly associated with gastric cancer. 
Conclusions. Our study provides evidence that higher concentration of circulating DHEA 
may be associated with lower risk of noncardia gastric cancer. Longitudinal studies are 
needed to evaluate the temporality of this association and investigate mechanisms of 
disease pathogenesis. © 2021 Instituto Mexicano del Seguro Social (IMSS). Published 
by Elsevier Inc. All rights reserved. 
Key Words: Androgens, Dehydroepiandrosterone, DHEA, Gastric cancer, Estrogens, Estradiol, 
Testosterone. 
Address reprint requests to: Yelda A. Leal, Centro Institucional de 
Capacitación y Registro de Cáncer, Unidad Médica de Alta Especiali- 
dad, Centro Médico Nacional “Ignacio García Téllez”, Instituto Mexicano 
de Seguro Social, Mérida, Yucatán, México. Tel: + 52 999-285-69-71; 
E-mail: yelda_leal03@yahoo.com.mx or yelda.leal@imss.gob.mx 
Introduction 
Gastric cancer is the third most common cause of death 
from cancer globally ( 1 ). Noncardia gastric cancer arises 
through a multistep process of chronic inﬂammation initi- 
ated by Helicobacter pylori infection: non-atrophic gastri- 
tis, multifocal atrophic gastritis, intestinal metaplasia, dys- 
plasia, and invasive adenocarcinoma ( 2 ). Notably, for most 
0188-4409/$ - see front matter. Copyright © 2021 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved. 
https://doi.org/10.1016/j.arcmed.2021.03.001


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Please cite this article as: Leal et al. , Circulating Levels of Sex Steroid Hormones and Gastric Cancer, Archives of Medical Research, https://doi.org/ 
10.1016/j.arcmed.2021.03.001


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Environmental enteric dysfunction: gut and microbiota 
adaptation in pregnancy and infancy
Carrie A. Cowardin1, Sana Syed1,2, Najeeha Iqbal2, Zehra Jamil2, Kamran Sadiq2, Junaid 
Iqbal2, Syed Asad Ali2, Sean R. Moore1
1Division of Paediatric Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, 
Child Health Research Center, University of Virginia, Charlottesville, VA, USA.
2Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan.
Abstract
Environmental enteric dysfunction (EED) is a subclinical syndrome of intestinal inflammation, 
malabsorption and barrier disruption that is highly prevalent in low- and middle-income countries 
in which poverty, food insecurity and frequent exposure to enteric pathogens impair growth, 
immunity and neurodevelopment in children. In this Review, we discuss advances in our 
understanding of EED, intestinal adaptation and the gut microbiome over the ‘first 1,000 days’ 
of life, spanning pregnancy and early childhood. Data on maternal EED are emerging, and they 
mirror earlier findings of increased risks for preterm birth and fetal growth restriction in mothers 
with either active inflammatory bowel disease or coeliac disease. The intense metabolic demands 
of pregnancy and lactation drive gut adaptation, including dramatic changes in the composition, 
function and mother-to-child transmission of the gut microbiota. We urgently need to elucidate 
the mechanisms by which EED undermines these critical processes so that we can improve global 
strategies to prevent and reverse intergenerational cycles of undernutrition.
Introduction
In low- and middle-income countries (LMICs), maternal stunting is a risk factor for 
low birthweight and subsequent childhood stunting, thereby perpetuating a vicious 
intergenerational cycle of undernutrition. This cycle has adverse consequences for children’s 
survival, growth and neurodevelopment1. Maternal gut function during pregnancy is critical


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to healthy fetal and child development2, asdemonstrated by studies of other enteropathies 
such as coeliac disease and inflammatory bowel disease. Environmental enteric dysfunction 
Reprints and permissions information is available at www.nature.com/reprints.
Correspondence should be addressed to Sean R. Moore. sean.moore@virginia.edu.
Author contributions
S.R.M. and C.A.C. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and 
reviewed/edited the manuscript before submission. S.S., N.I., Z.J. and J.I. researched data for the article, wrote the article, and 
reviewed/edited the manuscript before submission. K.S. wrote the article and reviewed/edited the manuscript before submission. 
S.A.A. researched data for the article, made a substantial contribution to discussion of content, and reviewed/edited the manuscript 
before submission.
Competing interests
S.R.M. was a paid consultant for Takeda on paediatric short bowel syndrome in 2020. S.R.M. receives royalties from UpToDate for a 
chapter entitled “Persistent diarrhoea in children in resource-limited countries”. The other authors declare no competing interests.
HHS Public Access
Author manuscript
Nat Rev Gastroenterol Hepatol. Author manuscript; available in PMC 2023 October 01.
Published in final edited form as:
Nat Rev Gastroenterol Hepatol. 2023 April ; 20(4): 223–237. doi:10.1038/s41575-022-00714-7.
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Conservation, acquisition, and functional impact of sex-biased 
gene expression in mammals
Sahin Naqvi1,2, Alexander K. Godfrey1,2, Jennifer F. Hughes1, Mary L. Goodheart1,3, 
Richard N. Mitchell4, David C. Page1,2,3,*
1Whitehead Institute, Cambridge MA 02142
2Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139
3Howard Hughes Medical Institute, Whitehead Institute, Cambridge MA 02142
4Brigham and Women’s Hospital, Harvard Medical School, Boston MA 02115
Abstract
Sex differences abound in human health and disease, as in other mammals employed as models. 
Unknown is the extent to which sex differences are conserved at the molecular level across species 
and tissues. We surveyed sex differences in gene expression in human, macaque, mouse, rat, and 
dog, across 12 tissues. In each tissue, we identified hundreds of genes with conserved sex-biased 
expression – findings that, combined with genomic analyses of human height, explain ~12% of the 
difference in height between females and males. We surmise that conserved sex biases in 
expression of genes otherwise operating equivalently in females and males contribute to sex 
differences in traits. However, most sex-biased expression arose during the mammalian radiation, 
suggesting careful attention to interspecies divergence when modeling human sex differences.
One sentence summary:
RNA sequencing of twelve tissues in five species reveals conservation, acquisition, and the 
functional impact of sex-biased gene expression.
Males and females exhibit differences across a wide range of biological processes. Studies in 
humans have documented sex differences in anthropometric traits (1), energy metabolism 
(2), brain morphology (3), and immune (4) and cardiac (5) function. Sex differences are also 
evident in the incidence, prevalence, and mortality across diseases, including autoimmune 
disorders (6), cardiovascular diseases (7), and autism (8). Beyond humans, sex differences


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are common in other mammals, many of which are models of sex-biased human traits and 
diseases (9). For example, males are larger than females in most mammalian species (10), 
*Correspondence to: dcpage@wi.mit.edu.
Author contributions: S.N., A.K.G, J.F.H., and D.C.P. designed the study. J.F.H. procured cyno tissue samples. M.L.G. procured 
mouse and rat tissue samples, with assistance from S.N. S.N. processed tissue samples and performed computational analyses, with 
assistance from A.K.G. R.N.M. performed histological evaluations on human tissue sections. D.C.P. supervised work. S.N. and D.C.P. 
wrote the paper.
Data and code availability: Raw RNA sequencing data (.fastq files) have been deposited in the Gene Expression Omnibus (accession 
number GSE125483). Processed data (expression count/TPM matrices and sample metadata) and code required to reproduce the 
analyses are available at http://pagelab.wi.mit.edu/page/papers/Naqvi_et_al_2019 and at Zenodo (doi: 10.5281/zenodo.2658829).
HHS Public Access
Author manuscript
Science. Author manuscript; available in PMC 2019 December 06.
Published in final edited form as:
Science. 2019 July 19; 365(6450): . doi:10.1126/science.aaw7317.
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Nature | www.nature.com | 1
Article
Construction of a human cell landscape at 
single-cell level
Xiaoping Han1,2,19 ✉, Ziming Zhou1,19, Lijiang Fei1,19, Huiyu Sun1,19, Renying Wang1,19, Yao Chen3,19, 
Haide Chen1,4,19, Jingjing Wang1,4,19, Huanna Tang5, Wenhao Ge6, Yincong Zhou7, Fang Ye1, 
Mengmeng Jiang1, Junqing Wu1, Yanyu Xiao1, Xiaoning Jia8, Tingyue Zhang1, Xiaojie Ma9,  
Qi Zhang10, Xueli Bai10, Shujing Lai1, Chengxuan Yu1, Lijun Zhu6, Rui Lin11, Yuchi Gao12,  
Min Wang13, Yiqing Wu3, Jianming Zhang14, Renya Zhan15, Saiyong Zhu9, Hailan Hu8, 
Changchun Wang16, Ming Chen7, He Huang2,17,18, Tingbo Liang10, Jianghua Chen5,  
Weilin Wang6, Dan Zhang3 & Guoji Guo1,2,4,17,18 ✉
Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex 
systems1. However, a comprehensive single-cell atlas has not been achieved for 
humans. Here we use single-cell mRNA sequencing to determine the cell-type 
composition of all major human organs and construct a scheme for the human cell 
landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have 
not been well characterized. We established a ‘single-cell HCL analysis’ pipeline that 
helps to define human cell identity. Finally, we performed a single-cell comparative 
analysis of landscapes from human and mouse to identify conserved genetic 
networks. We found that stem and progenitor cells exhibit strong transcriptomic 
stochasticity, whereas differentiated cells are more distinct. Our results provide a 
useful resource for the study of human biology.
Individual cells are fundamental units of life. Breakthroughs in 
single-cell mRNA sequencing have greatly enhanced our ability 
to identify the transcriptomes of individual types of cell2–5. Using 
high-throughput barcoding strategies, it is now possible to profile thou-
sands of single cells at the same time6,7. These methods have allowed 
the mapping of cell atlases for whole organisms8–15. For example, cell 
atlases for the mammalian system have been generated by analysing


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both fetal and adult mouse tissues16–19. Despite extensive efforts in 
dissecting the cellular compositions of various human tissues20–32, to 
our knowledge a comprehensive cell landscape for humans has not 
been achieved.
Constructing an HCL using microwell-seq
Microwell-seq is a cost-effective single-cell mRNA sequencing technol-
ogy that offers advantages over existing technologies in doublet rate 
and cell-type compatibility16. Sequencing titration experiments and 
cross-platform comparison suggest that this method can robustly 
detect rare populations even at low sequencing depth (Supplementary 
Table 1, Extended Data Fig. 1a). Using microwell-seq, we embarked 
upon the creation of a basic landscape of major human cell types using 
samples from a Chinese Han population. Donated tissues were per-
fused or washed and prepared as single-cell suspensions using specific 
protocols (Supplementary Table 1). Our analyses included samples of 
both fetal and adult tissue and covered 60 human tissue types (two to 
four replicates per tissue type in general; Extended Data Fig. 1b). We 
also analysed seven types of cell culture, including induced pluripotent 
stem (iPS) cells, embryoid body cells, haematopoietic cells derived from 
co-cultures of human H9 and mouse OP9 cells33, and pancreatic beta 
cells derived from H9 cells using a seven-stage protocol34(Extended 
Data Fig. 1b). Single cells were processed using microwell-seq16 and 
sequenced at around 3,000 reads per cell; data were then processed 
using published pipelines35 (Fig. 1a). Altogether, 702,968 single cells 
passed our quality control tests (Supplementary Table 1).
In a global view, the complete human tissue data set is grouped into 
102 major clusters (Fig. 1b; Supplementary Table 2). Multiple tissues, 
including artery, trachea, pleura, omentum, oesophagus and fallopian 
tube, contributed to the defined adult stromal/mesenchymal cells, 
such as cluster 4 (C4), C18, C27, and C70. Other clusters with substantial


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multi-tissue contributions correspond to fetal stromal cells (C7, C10, 
C17, C19, C21, C64, and C72), endothelial cells (C8, C20, C29, and C66), 
macrophages (C2, C51, C69, and C78), and fetal epithelial cells (C1) 
https://doi.org/10.1038/s41586-020-2157-4
Received: 23 October 2018
Accepted: 12 March 2020
Published online: 25 March 2020
 Check for updates
1Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China. 2Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang 
University School of Medicine, Hangzhou, China. 3Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China. 4Zhejiang 
Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Hangzhou, China. 5Kidney Disease Center, 
The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 6Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University 
School of Medicine, Hangzhou, China. 7College of Life Sciences, Zhejiang University, Hangzhou, China. 8Center for Neuroscience, Zhejiang University School of Medicine, Hangzhou, China. 
9Life Sciences Institute, Zhejiang University, Hangzhou, China. 10Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 
Hangzhou, China. 11Hangzhou Repugene Technology, Hangzhou, China. 12Annoroad Gene Technology, Beijing, China. 13Veritas Genetics Asia, Hangzhou, China. 14Department of Neurosurgery, 
The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 15Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 
Hangzhou, China. 16Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer


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Hospital, Hangzhou, China. 17Institute of Hematology, Zhejiang University, Hangzhou, China. 18Stem Cell Institute, Zhejiang University, Hangzhou, China. 19These authors contributed equally: 
Xiaoping Han, Ziming Zhou, Lijiang Fei, Huiyu Sun, Renying Wang, Yao Chen, Haide Chen, Jingjing Wang. ✉e-mail: xhan@zju.edu.cn; ggj@zju.edu.cn


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The potential role of opioid vaccines and monoclonal antibodies 
in the opioid overdose crisis
Suky Martineza, Hannah Harrisa, Thomas Chaob, Rachel Lubaa, Marco Pravetonic, Sandra 
D Comera, Jermaine D Jonesa
aDivision on Substance Use Disorders, Columbia University Irving Medical Center & New York 
State Psychiatric Institute, New York, NY, USA
bBehavioural Reward Affect + Impulsivity Neuroscience Lab, Faculty of Medicine, the University of 
British Columbia, Vancouver, Bc, Canada
cDepartment of Psychiatry and Behavioral Sciences, University of Washington School of 
Medicine, Seattle, WA, USA
Keywords
Opioids; overdose; opioid vaccines; monoclonal antibodies; immunotherapies
1. The need for continued development of medications to treat opioid 
overdose
Since the late 1990s, the U.S. has experienced an exponential increase in opioid-related 
overdose deaths and made substantial economic expenditures to address the harms 
associated with opioid use disorder (OUD) [1,2]. As the epidemic has evolved, we have 
observed a substantial increase in the detection of potent, illicitly manufactured fentanyls 
in opioid drug supplies as well as in cocaine and methamphetamine drug supplies, and 
within counterfeit pills sold as oxycodone, benzodiazepines, and other prescription drugs. 
This has led to increases in the rates of opioid-related overdose among those with OUD and 
among those who are not traditionally at risk such as psychostimulant users and recreational 
CONTACT Suky Martinez, suky.martinez@nyspi.columbia.edu, Division on Substance Use Disorders, Columbia University Irving 
Medical Center, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA. 
Declaration of interests
Within the past three years, JD Jones received compensation (in the form of partial salary support) and has served as a paid 
consultant to Alkermes and the World Health Organization. Within the past three years, SD Comer has received research funding from


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Alkermes, BioXcel Therapeutics, Corbus, Go Medical, Intra-cellular Therapies, Janssen, and Lyndra. SD Comer has also consulted 
for: Alkermes, Clinilabs, Opiant, and Otsuka, and she has received honoraria from the World Health Organization. SD. Comer is 
also the recipient of NIH funding to study opioid vaccines and monoclonal antibodies. M Pravetoni has filed patents disclosing the 
composition and methods of use of vaccines and monoclonal antibodies for substance use disorders. Dr. Pravetoni is also the recipient 
of NIH funding to study opioid vaccines and monoclonal antibodies.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or 
financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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Author manuscript
Expert Opin Investig Drugs. Author manuscript; available in PMC 2023 June 06.
Published in final edited form as:
Expert Opin Investig Drugs. 2023 March ; 32(3): 181–185. doi:10.1080/13543784.2023.2187286.
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news & views
PROTEOMICS
Deciphering the human phosphoproteome
Machine learning provides a functional score for ~120,000 human phosphorylation sites.
Giulia Franciosa, Ana Martinez-Val and Jesper V. Olsen
S
ite-specific protein phosphorylation 
is one of the most important post-
translational modifications that 
cells use to modulate their signaling 
pathways. To study signaling networks 
at a systems-wide scale, the method of 
choice is mass spectrometry (MS)-based 
phosphoproteomics1. Tens of thousands 
of phosphorylation sites can be routinely 
identified in a single experiment, but 
functional interpretation of these sites 
remains challenging2. In this issue, Ochoa 
et al.3 apply a machine learning approach to 
public datasets and construct a functional 
landscape of the human phosphoproteome. 
Their results will help phosphoproteomics 
researchers to prioritize phosphorylation 
sites from large-scale datasets according to 
biological relevance.
A few minutes after a cell receives a 
signaling cue, such as stimulation by a 
growth factor, thousands of phosphosites 
on its signaling proteins are phosphorylated 
or dephosphorylated, altering the 
proteins’ activity, subcellular localization, 
protein–protein interactions or stability1. 
Phosphorylation is added by protein kinases 
and removed by phosphatases.  
This interplay is tightly controlled in healthy 
cells, and its breakdown is associated with 
diseases such as cancer and metabolic 
disorders, making kinases prominent drug 
targets for the pharmaceutical industry4.
In MS-based phosphoproteomics, 
proteins are first digested into peptides. As 
phosphorylation is a low-stoichiometric 
modification, phosphopeptides in the 
sample are first enriched, and then analyzed 
by liquid chromatography and tandem mass 
spectrometry (LC-MS/MS). Improvements 
over the past decade in sample preparation, 
mass spectrometers and the associated 
computational proteomics tools have led to 
an exponential increase in the amount of 
phosphoproteomics data. PhosphoSitePlus,


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the largest database of post-translational 
modifications5, contains >200,000  
annotated phosphosites. But, for more 
than 95% of these, the biological function 
or upstream kinase are unknown2. The 
proteomics field still lacks tools to identify 
functional phosphosites in an unbiased, 
large-scale manner.
Current methods for bioinformatics 
analysis of phosphoproteomics datasets 
typically focus on the most highly regulated 
phosphosites using gene ontology, protein 
network and pathway analysis tools. Yet 
most of these tools treat phosphosite 
regulation as changes in protein expression, 
and they collapse information from multiple 
phosphosites in a protein. By contrast, 
activated kinases are usually identified 
through bulk analysis of phosphosites using 
kinase–substrate enrichment methods. 
These tools often rely on known kinase–
substrate relationships and/or enrichment 
of predicted kinase recognition motifs6. 
This information is often integrated with a 
functional kinase network6 and/or with the 
phosphosites identified in the kinase itself7.
These strategies have been used 
successfully to extract important biological 
information from phosphoproteomics 
datasets, but they often neglect the unique 
information encoded in individual 
phosphosites, which can provide deeper 
insight into biological phenotypes8. 
However, systematic analysis of individual 
phosphosites is currently not feasible. 
Instead, phosphosites on relevant proteins 
in a signaling pathway of interest are often 
selected manually for functional validation 
and follow up.
P-site functional score
1
0.5
0
FOXO3-S253
MYC-S62
MAPK1-T185
KMT2A-S1850
NCOR2-SS2245
SRRM2-S2142
MaxQuant
FDR 1%
PRIDE database
~ 7,000 experiments
119,809
human phosphosites
CCD86-S255
CFL1-Y89
ATG4B-Y8
m/z
V A L S P K
b1 b2
b3
b4
b5
y5
y4
y3
y2
y1
A1
A3 A2
A4
B1 B2 B3 B4
C1 C2 C3
D1
D3 D2
D4
E2 E3 E1
E4
F1 F2 F3 F4
C4
Phosphoproteomics analysis
Unraveling phosphorylation
functionality
P
P
P
P
MS evidence
Structure
Conservation
Regulation


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Fig. 1 | Reanalysis of phosphoproteomics datasets in the PRIDE database provides functional scores for individual phosphosites. To rank phosphosites by 
their functional importance, Ochoa et al.3 used a machine-learning approach that integrates information about the phosphosites’ regulation, structure and 
conservation, as well as MS-based evidence. The resulting functional score ranks the sites according to their biological significance, which can be used to 
prioritize candidates for subsequent detailed investigation.
NatuRE BIotEchNology | www.nature.com/naturebiotechnology


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Decoding Sex-Biased Gene Expression
Patterns in Heart Disease
S
ex, a biological determinant of a person’s
anatomy and physiology, has vital impli-
cations on disease incidence and preva-
lence,
and
ultimately
clinical
outcome.1
Recognized across reproductive and nonrepro-
ductive organs, distinct phenotypes differen-
tiate women from men not only during the
reproductive years but also throughout all of
life. Sexually dimorphic expression of sex-
linked genes, however, does not account for
all sex differences.2 Rather, the complexity of
sex differences in health and disease goes
beyond
a sex chromosomeedirected
and
hormone-centric axis. Indeed, most autosomal
genes with sex-biased expression lack androgen
or estrogen response elements.3 In this context,
sex-biased gene expression could engender
(patho)phenotypic sex differences whereby
autosomal genes, operating identically in males
and females to inﬂuence a trait, are expressed
more or less abundantly in one vs the other sex.
An integrative foundation on which to ascertain
sex differences is emerging through large-scale
data sets, typically sourced from healthy tis-
sues and organs containing multiple cell types.
Although a systems-level genetic architecture is
thereby increasingly delineated, less is known
regarding the recondite sex-segregated differ-
entiators of disease vulnerability.
This issue of Mayo Clinic Proceedings
features a cell-speciﬁc deciphering of gene
expression patterns underpinning sex-biased
dysregulation in cardiomyopathy.4 Using
patient-derived cardiomyocytes, Gaignebet
et al4 report linkage of an inﬂammation-
related gene signature with poor organ
function in males but not in females. In this
way, this innovative work ushers in an era of
sex-related pathophysiology decoded at a
cell-autonomous, molecular level.
Sex in Cardiology
Half of the adult population in the United
Statesd51.2% of men and 44.7% of womend
lives with a cardiovascular condition, under-
scoring the effect on public health.5 Notably,


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males and females demonstrate distinct sus-
ceptibilities for cardiovascular disorders. For
example, premenopausal women, compared
with age-matched men, are at reduced risk
for coronary heart disease, whereas post-
menopausal status is linked with aggravated
cardiovascularmorbidityandmortality.6Aslife
expectancy in men and women is continuously
increasingly, with that of women to exceed 90
years of age in this decade, there is an increased
emphasis on safeguarding the vulnerable heart.
Decoding diverse disease trajectories and car-
dioprotective patterns naturally occurring in a
sex-biased or age-dependent manner would
inform a path toward more personalized care.
Sex-Biased Gene Proﬁling
A contributor to poor prognosis in heart dis-
ease is maladaptive myocardial remodeling,
known to adopt sex-distinctive features.
Males are particularly susceptible and prone
to cardiomegaly in the setting of hemody-
namic stress. A case in point is advanced left
ventricular
hypertrophy
developing
in
response to pressure overload imposed by
aortic stenosis,7 a clinical condition studied
by Gaignebet et al.4 Of note, degenerative
aortic stenosis in the elderly is the major eti-
ology of nonrheumatic valvular heart disease
that accounts for 25,000 deaths annually in
this country. Despite a similar extent of
outﬂow obstruction in patients undergoing
aortic valve replacement, the left ventricle in
males demonstrated structural and functional
maladaptation, characterized by an exagger-
ated increase in chamber size, wall thickness,
and mass index and an aggravated decline in
contractility. In a sex-biased genomic proﬁle,
2 discrete inﬂammatory genes, CCN2 and
NFKB1, were recognized by high expression
in cardiomyocytes obtained from male pa-
tients and remarkably correlated negatively
See also page 688
EDITORIAL
636
Mayo Clin Proc. n April 2020;95(4):636-638 n https://doi.org/10.1016/j.mayocp.2020.02.013
www.mayoclinicproceedings.org n ª 2020 Mayo Foundation for Medical Education and Research


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Organ Weights in Relation to Age and Sex in Cynomolgus 
Monkeys (Macaca fascicularis)
Rachel Amato1, Jean F. Gardin2, Janet A. Tooze2, J. Mark Cline2
1University of Georgia, Athens, Georgia, USA
2Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
Abstract
Laboratory animal research is an important contributor to both human and animal medicine. 
Currently, there is extensive use of cynomolgus monkeys (Macaca fascicularis) in pathology and 
toxicology research. The purpose of this study was to define reference values for absolute and 
percentage organ weights in M fascicularis of different ages and sex. Organ weights were obtained 
from necropsies of 1022 cynomolgus monkeys at the Wake Forest School of Medicine from 1997 
to 2018. Distributions of absolute and percentage weights for each organ were described; sex and 
age groups were compared using analysis of variance. Age effects on percentage of body weights 
for each organ were analyzed within each sex. Diet effects were also analyzed. This evaluation 
showed that male body weights and absolute organ weights were greater for all age groups; 
however, female organ to body weight percentages were greater for most organs. Percentage of 
organ weight to body weight declined for the adrenals, brain, lung, thyroid and thymus during 
maturation, whereas percentage weight of pancreas, prostate, testes, and uterus increased. Animals 
consuming a high-fat, Western-type diet had a lower body weight than animals consuming a 
carbohydrate-rich chow diet. This information will be useful for further toxicology and pathology 
studies concerning cynomolgus monkeys.
Keywords
organ weights; nonhuman primate; cynomolgus; pathology; sex differences; development
Introduction
Due to the genetic and physiologic similarity among primates, nonhuman primates are 
often used in a laboratory research setting as models.1 Currently, there is extensive use 
of cynomolgus monkeys (Macaca fascicularis) in research.2,3 So far, these monkeys have


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Corresponding Author: J. Mark Cline, Department of Pathology, Section on Comparative Medicine, Wake Forest School of 
Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. jmcline@wakehealth.edu.
Author Contributions
Authors contributed to conception or design (RA, JG, JC); data acquisition, analysis, or interpretation (RA, JG, JT, JC); drafting 
the manuscript (RA, JG, JC); and critically revising the manuscript (RA, JG, JT, JC). All authors gave final approval and agreed to 
be accountable for all aspects of work in ensuring that questions relating to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
HHS Public Access
Author manuscript
Toxicol Pathol. Author manuscript; available in PMC 2022 July 24.
Published in final edited form as:
Toxicol Pathol. 2022 July ; 50(5): 574–590. doi:10.1177/01926233221088283.
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Behavioral context affects social signal representations within single primate prefrontal cortex neurons


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Behavioral context affects social signal representations within 
single primate prefrontal cortex neurons
Vladimir Jovanovic1,2, Adam Ryan Fishbein1, Lisa de la Mothe3, Kuo-Fen Lee4, Cory 
Thomas Miller1,2,*
1Cortical Systems and Behavior Laboratory, University of California, San Diego, La Jolla, CA 
92093, USA
2Neurosciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA
3Department of Psychology, Tennessee State University, Nashville, TN 37209, USA
4Laboratory for Peptide Biology, Salk Institute, La Jolla, CA 92093, USA
Summary.
We tested whether social signal processing in more traditional, head-restrained contexts is 
representative of the putative natural analog – social communication – by comparing responses 
to vocalizations within individual neurons in marmoset prefrontal cortex (PFC) across a series 
of behavioral contexts ranging from traditional to naturalistic. Although vocalization responsive 
neurons were evident in all contexts, cross-context consistency was notably limited. A response to 
these social signals when subjects were head-restrained was not predictive of a comparable neural 
response to the identical vocalizations during natural communication. This pattern was evident 
both within individual neurons and at a population level, as PFC activity could be reliably decoded 
for the behavioral context in which vocalizations were heard. These results suggests that neural 
representations of social signals in primate PFC are not static, but highly flexible and likely reflect 
how nuances of the dynamic behavioral contexts affect the perception of these signals and what 
they communicate.
eTOC.
*Lead Contact: corymiller@ucsd.edu.
Author Contributions
VJ designed the experiment, conducted the experiment, analyzed the data and wrote the paper
ARF analyzed the neurophysiology data and wrote the paper
LDM analyzed the anatomy data
KFL analyzed the anatomy data
CTM designed the experiment, supervised the experiment and wrote the paper
Inclusion and Diversity


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One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community.
Declaration of Interests
The authors declare no competing interests
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our 
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review 
of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered 
which could affect the content, and all legal disclaimers that apply to the journal pertain.
HHS Public Access
Author manuscript
Neuron. Author manuscript; available in PMC 2023 April 20.
Published in final edited form as:
Neuron. 2022 April 20; 110(8): 1318–1326.e4. doi:10.1016/j.neuron.2022.01.020.
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Eur J Clin Invest. 2023;53:e13885. 
 
  | 1 of 13
https://doi.org/10.1111/eci.13885
wileyonlinelibrary.com/journal/eci
Received: 1 July 2022 | Accepted: 4 October 2022
DOI: 10.1111/eci.13885  
N A R R AT I V E  R E V I E W
Sex- specific and hormone- related differences in vascular 
remodelling in atherosclerosis
Anaïs Yerly1,2,3 |   Emiel P. C. van der Vorst4,5,6
 |   Iris Baumgartner1,2 |   
Sarah Maike Bernhard1,2 |   Marc Schindewolf1,2 |   Yvonne Döring1,2,4,5
1Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
2Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
3Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
4Institute for Cardiovascular Prevention (IPEK), Ludwig- Maximilians- University Munich (LMU), Munich, Germany
5DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
6Institute for Molecular Cardiovascular Research (IMCAR) and Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 
Aachen, Germany
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided 
the original work is properly cited.
© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation 
Journal Foundation.
Correspondence
Yvonne Döring, Division of Angiology, 
Swiss Cardiovascular Center, 
Inselspital, Bern University Hospital, 
University of Bern, Bern, Switzerland.
Email: yvonne.doering@insel.ch
Funding information
Aard- en Levenswetenschappen, 
Nederlandse Organisatie voor 
Wetenschappelijk Onderzoek, 
Grant/Award Number: 91619053; 
Schweizerischer Nationalfonds zur 
Förderung der Wissenschaftlichen 
Forschung, Grant/Award Number: 
310030_197655, 4078P0_198297 and 
CRSII5_193694
Abstract


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Abstract
Atherosclerosis, a lipid- driven inflammatory disease, is the main underlying 
cause of cardiovascular diseases (CVDs) both in men and women. Sex- related 
dimorphisms regarding CVDs and atherosclerosis were observed since more than 
a decade ago. Inflammatory mediators such as cytokines, but also endothelial 
dysfunction, vascular smooth muscle cell migration and proliferation lead to vas-
cular remodelling but are differentially affected by sex. Each year a greater num-
ber of men die of CVDs compared with women and are also affected by CVDs 
at an earlier age (40– 70 years old) while women develop atherosclerosis- related 
complications mainly after menopause (60+ years). The exact biological reasons 
behind this discrepancy are still not well- understood. From the numerous animal 
studies on atherosclerosis, only a few include both sexes and even less investigate 
and highlight the sex- specific differences that may arise. Endogenous sex hor-
mones such as testosterone and oestrogen modulate the atherosclerotic plaque 
composition and the frequency of such plaques. In men, testosterone seems to 
act like a double- edged sword as its decrease with ageing correlates with an in-
creased risk of atherosclerotic CVDs, while testosterone is also reported to pro-
mote inflammatory immune cell recruitment into the atherosclerotic plaque. In 
premenopausal women, oestrogen exerts anti- atherosclerotic effects, which de-
cline together with its level after menopause resulting in increased CVD risk in 
ageing women. However, the interplay of sex hormones, sex- specific immune re-
sponses and other sex- related factors is still incompletely understood. This review


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Dopaminergic modulation of striatal function and Parkinson’s 
disease
Shenyu Zhai1, Weixing Shen1, Steven M Graves2, and D James Surmeier1
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 
60611, USA
2Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, 
USA
Abstract
The striatum is richly innervated by mesencephalic dopaminergic neurons that modulate a diverse 
array of cellular and synaptic functions that control goal-directed actions and habits. The loss of 
this innervation has long been thought to be the principal cause of the cardinal motor symptoms of 
Parkinson’s disease (PD). Moreover, chronic, pharmacological overstimulation of striatal 
dopamine (DA) receptors is generally viewed as the trigger for levodopa-induced dyskinesia (LID) 
in late-stage PD patients. Here, we discuss recent advances in our understanding of the 
relationship between the striatum and DA, particularly as it relates to PD and LID. First, it has 
become clear that chronic perturbations of DA levels in PD and LID bring about cell type-specific, 
homeostatic changes in spiny projection neurons (SPNs) that tend to normalize striatal activity. 
Second, perturbations in DA signaling also bring about non-homeostatic aberrations in synaptic 
plasticity that contribute to disease symptoms. Third, it has become evident that striatal 
interneurons are major determinants of network activity and behavior in PD and LID. Finally, 
recent work examining the activity of SPNs in freely moving animals has revealed that the 
pathophysiology induced by altered DA signaling is not limited to imbalance in the average 
spiking in direct and indirect pathways, but involves more nuanced disruptions of neuronal 
ensemble activity.
Keywords
Parkinson’s disease; levodopa-induced dyskinesia; striatum; dopamine; synaptic plasticity; 
interneurons
Introduction
The cardinal motor symptoms of Parkinson’s disease (PD) are caused by progressive


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degeneration of dopaminergic neurons in the substantia nigra (SN) (Surmeier et al. 2014). In 
the early stages of the disease, these symptoms of PD are effectively alleviated by dopamine 
Corresponding author: D James Surmeier (j-surmeier@northwestern.edu). 
Conflict of interest
The authors declare that they have no conflict of interest.
HHS Public Access
Author manuscript
J Neural Transm (Vienna). Author manuscript; available in PMC 2020 April 01.
Published in final edited form as:
J Neural Transm (Vienna). 2019 April ; 126(4): 411–422. doi:10.1007/s00702-019-01997-y.
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Episodic Recognition Memory and the Hippocampus in 
Parkinson’s disease: A Review
Tanusree Das, PhDa, Jaclyn Joyce Hwanga,c, and Kathleen L Poston, MD, MSa,b
aDepartment of Neurology and Neurological Sciences, Stanford University School of Medicine, 
Stanford, CA, USA. tanusree@stanford.edu
bDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
cDepartment of Neuroscience, University of Pittsburgh. jjh107@pitt.edu
Abstract
Parkinson’s disease is a progressive neurodegenerative disorder of aging. The hallmark 
pathophysiology includes the development of neuronal Lewy bodies in the substantia nigra of the 
midbrain with subsequent loss of dopaminergic neurons. These neuronal losses lead to the 
characteristic motor symptoms of bradykinesia, rigidity, and rest tremor. In addition to these 
cardinal motor symptoms patients with PD experience a wide range of non-motor symptoms, the 
most important being cognitive impairments that in many circumstances lead to dementia. People 
with PD experience a wide range of cognitive impairments; in this review we will focus on 
memory impairment in PD and specifically episodic memory, which are memories of day-to-day 
events of life. Importantly, these memory impairments severely impact the lives of patients and 
caregivers alike.
Traditionally episodic memory is considered to be markedly dependent on the hippocampus; 
therefore, it is important to understand the exact nature of PD episodic memory deficits in relation 
to hippocampal function and dysfunction. In this review, we discuss an aspect of episodic memory 
called recognition memory and its subcomponents called recollection and familiarity. Recognition 
memory is believed to be impaired in PD; thus, we discuss what aspects of the hippocampus are 
expected to be deficient in function as they relate to these recognition memory impairments. In 
addition to the hippocampus as a whole, we will discuss the role of hippocampal subfields in 
recognition memory impairments.
Keywords


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Keywords
Episodic memory; Recognition memory; Hippocampus; Parkinson’s disease; Hippocampal 
subfields
Corresponding author Kathleen L. Poston, MD, MS, Department of Neurology and Neurological Sciences, Stanford University 
School of Medicine, 780 Welch Road, CJ Huang Building, Palo Alto, CA, USA 94304, klposton@stanford.edu. 
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our 
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of 
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be 
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
HHS Public Access
Author manuscript
Cortex. Author manuscript; available in PMC 2020 April 01.
Published in final edited form as:
Cortex. 2019 April ; 113: 191–209. doi:10.1016/j.cortex.2018.11.021.
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Themed Section: Biological Sex and Cardiovascular Pharmacology
REVIEW
Effects of biological sex on
the pathophysiology of
the heart
Loubina Fazal1,2, Feriel Azibani1, Nicolas Vodovar1,
Alain Cohen Solal1,2,3, Claude Delcayre1 and Jane-Lise Samuel1,2,3
1UMR-S 942, Inserm, Paris, France, 2University Paris-Diderot, Paris, France, and 3AP-HP Hôpital
Lariboisière, Paris, France
Correspondence
Jane-Lise Samuel, UMR-S 942
Inserm, 41 bd de la Chapelle,
75475 Paris Cedex 10,
France. E-mail:
jane-lise.samuel@inserm.fr
----------------------------------------------------------------
Keywords
heart; gender; hypertrophy;
cardiac failure
----------------------------------------------------------------
Received
18 March 2013
Revised
15 May 2013
Accepted
2 June 2013
Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of
biological sex on cardiovascular pathophysiology have long been known, the sex-speciﬁc mechanisms mediating these
processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac
structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the
response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that
should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches.
LINKED ARTICLES
This article is part of a themed section on Biological Sex and Cardiovascular Pharmacology. To view the other articles in this
section visit http://dx.doi.org/10.1111/bph.2014.171.issue-3
Abbreviations
AR, androgen receptor; CVD, cardiovascular disease; DOCA, deoxycorticosterone acetate; E-C, excitation-contraction;
ET-1, endothelin-1; ER, oestrogen receptor; HRT, hormone replacement therapy; LV, left ventricular; MI, myocardial
infarction; NP, natriuretic peptide; PCH, pathological cardiac hypertrophy; PR, progesterone receptor; RAAS,


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renin-angiotensin-aldosterone system; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; TAC, thoracic aorta
constriction; VSMC, vascular smooth muscle cell
Introduction
Cardiovascular diseases (CVDs) are the leading cause of death
in men and women in industrialized countries. Over the last
decade, while little change was noticed on the sex ratio of
cohorts in the majority of CVD studies (Mosca et al., 2011),
several clinical trials provided evidence that sex is an impor-
tant determinant of cardiovascular events in patients with
vascular diseases or high-risk diabetes mellitus. Indeed,
female diabetic patients had a higher risk for acute myocar-
dial infarction compared to male diabetics (Kappert et al.,
2012). Women also exhibited a marked increase in the inci-
dence of left ventricular (LV) hypertrophy after the meno-
pause, when the prevalence of arterial hypertension increases
(Lopez-Ruiz et al., 2008). Furthermore, women generally
display better cardiac function and survival in the face of
CVD than men, although this advantage is lost when com-
paring
postmenopausal
women
with
age-matched
men
(Fujimoto et al., 2013).
The effects of biological sex on cardiovascular physiol-
ogy or pathology have long been known, but the biological
mechanisms responsible for sex-related differences started to
be unravelled over the last decades. Indeed, sex steroid hor-
mones (oestrogens in female, testosterone in male) contrib-
ute signiﬁcantly to the sex-based differences in the outcome
of cardiac diseases, although the contribution of environ-
mental oestrogen-like molecules, such as phytoestrogens,
must not be neglected. Thus, hormonal therapy such as
the hormone replacement therapy (HRT) after menopause
using synthetic oestrogens and progesterone, while broadly
debated, may help to understand the effects of oestrogen in
cardiac pathophysiology. In addition, some elucidation of
the interrelation between the sex steroid hormones and
peptides and/or hormones directly involved in the cardiac


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physiopathology such as the components of the renin
angiotensin-aldosterone system, and the natriuretic peptides
(NPs) will be provided. At least, as adequate exercise and
nutrition programmes were shown to improve the preven-
tion and the treatment of CVD and metabolic disorders
(Hagey and Warren, 2008), these lifestyle patterns are begin-
ning to be taken into account in the treatment of post-
menopausal women. The collection of such data will be of
interest to analyse the relation between exercise, sex and
CVD.
BJP
British Journal of
Pharmacology
DOI:10.1111/bph.12279
www.brjpharmacol.org
British Journal of Pharmacology (2014) 171 555–566
555
© 2013 The British Pharmacological Society


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Elevated Serotonin and 
Reduced Dopamine in 
Subregionall; Divided 
Hunti&ton’s Disease 
Striatum 
Stephen J. Kish, PhD,+ Kathleen Shannak, BSc,” 
and Oleh Hornykiewicz, MD*t 
We measured the rostrocaudal distribution of serotonin, 
dopamine, and their metabolites in Huntington’s disease 
striatum (caudate and putamen). Mean levels of sero- 
tonin or 5-hydroxyindoleacetic acid were elevated in 
most striatal subdivisions, whereas concentrations of 
dopamine or its metabolite homovanillic acid were 
slightly to markedly reduced. Dopamine and serotonin 
were at control levels in the nucleus accumbens and 
substantia nigra. Whereas the above-normal serotonin 
can most likely be accounted for by striatal atrophy, the 
reduced dopamine suggests either a marked down- 
regulation of nigrostriatal dopamine neurons or an 
actual reduction in the arborization of the striatal 
dopamine neurons. As experimental animal data sug- 
gest, the relative excess of striatal serotonin or one of its 
metabolites may facilitate the neurodegenerative pro- 
cess in Huntington’s disease striatum. 
Kish SJ, Shannak K, Hornykiewicz 0: Elevated 
serotonin and reduced dopamine in subregionally 
divided Huntington’s disease striaturn. 
Ann Neurol 22:386-389, 1987 
Biochemical analyses of postmortem brain of Hunting- 
ton’s disease (HD) patients have consistently shown a 
marked decrease of neurochemical markers of the in- 
trinsic striatal neurons containing gamma-aminobutyric 
acid (GABA) [19, 241, acetylcholine [6, 15, 241, sub- 
stance P [S, 10, 131, and increased somatostatin 12, 
181. This is in accord with the well-established neuro- 
pathology of HD, which has identified a massive, but 
selective, loss of the intrinsic neuronal cell populations 
in the caudate nucleus and putamen. In contrast, litera- 
ture on the neurochemistry in HD brain of the affer- 
ent neuronal systems innervating striatal nuclei, espe- 
cially the dopamine and serotonin systems, remains 
contradictory and sparse. Thus, the striatal level of


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From the ‘Human Brain Laboratory, Clarke Institute of Psychiatry, 
Toronto, the Departments of Psychiatry and Pharmacology, Univer- 
sity of Toronto, Toronto, Ontario, Canada, and the tInstitute of 
Biochemical Pharmacology, University of Vienna, Vienna, Austria. 
Received Dec 9, 1986, and in revised form Mar 4, 1987. Accepted 
Mar 7, 1987. 
Address correspondence to Dr Kish, Human Brain Laboratory, 
Clarke Institute of Psychiatry, Toronto, Ontario, Canada, M5T lR8. 
chemical markers of dopamine neurons has been vari- 
ously reported as normal, reduced, or elevated [ S ,  6, 
15, 16, 20, 241, and the level of serotonin has been 
found to be somewhat elevated in the caudate nucleus 
and putamen (5-hydroxyindoleacetic acid I5-HIAA) 
not examined) {51. Knowledge of the precise behavior 
of striatal dopamine and serotonin in the brain of HD 
patients is relevant, particularly because dopamine an- 
tagonists are the only clinical measure for controlling, 
even in part, the involuntary abnormal movements, 
and reduction of striatal serotonin recently has been 
found to partially protect the striatum from the neuro- 
toxic effect of kainic acid in a rat model of HD 141. 
In view of the marked regional variation within HD 
striatum and of the severity of neurodegenerative 
change 125) as well as the neurochemical and func- 
tional heterogeneity of mammalian striatal nuclei (see 
Ill), we performed a detailed subregional distribution 
study of both dopamine and serotonin, and their 
metabolites homovanillic acid (HVA) and 5-HIAA, in 
four regions of the HD basal ganglia: the caudate nu- 
cleus, the putamen, the nucleus accumbens, and the 
substantia nigra. 
Patients and Methods 
Brains were obtained at autopsy from 7 patients (5 males, 2 
females) who died with the clinical diagnosis of HD (mean 
age k standard error of the mean [SEMI: 58 ? 4 years) and 
11 patients (8 males, 3 females) who died without any evi- 
dence of neurological or psychiatric disorder (control sub-


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jects) (mean age: 59 ? 4 years). Drug information could be 
obtained on 5 of the 7 patients with HD. Of these 5 patients, 
all had received long-term administration of neuroleptic 
drugs for varying periods of time. 
At autopsy, one half-brain was immersed in formalin fixa- 
tive for neuropathological analysis, whereas the other half- 
brain was immediately frozen at - 80°C for biochemical ex- 
amination. The mean death-to-freezing intervals for the 
patients with HD (15 ? 3 hours, mean ’. SEM) and the 
control subjects (12 ? 2 hours) did not differ significantly 
( p  
Serotonin, 5-HIAA, dopamine, and HVA were measured 
using minor modifications of the high-pressure liquid chro- 
matography-electrochemical method of Felice et a1 [I I]. 
0.05, Student’s two-tailed t test). 
Results 
Neuropathological Findings 
Gross and microscopic examination revealed features 
typical of HD, consisting of severe to moderate cell 
loss and gliosis in the caudate head with less severe cell 
loss in the putamen. Cell loss and gliosis were variable 
in the globus pallidus and minimal in the nucleus ac- 
cumbens. The substantia nigra of the HD cases ap- 
peared normal histologically. 
Neurocbemical Findings 
When compared with the corresponding control 
means, serotonin levels (Table 1) were generally ele- 
386


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Contents lists available at ScienceDirect
Journal of Proteomics
journal homepage: www.elsevier.com/locate/jprot
Review
Gender proteomics I. Which proteins in non-sexual organs
Elisabetta Gianazzaa,⁎, Ingrid Millerb, Uliano Guerrinia, Luca Palazzoloa, Chiara Parravicinia,
Ivano Eberinia
a Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, I-20133 Milano, Italy
b Institut für Medizinische Biochemie, Veterinärmedizinische Universität Wien, Veterinärplatz 1, A-1210 Wien, Austria
A R T I C L E I N F O
Keywords:
Sex
Male
Female
Diﬀerential proteins
Physiology
Pathology
A B S T R A C T
Diﬀerences related to gender have long been neglected but recent investigations show that they are widespread
and may be recognized with all types of omics approaches, both in tissues and in biological ﬂuids. Our review
compiles evidence collected with proteomics techniques in our species, mainly focusing on baseline parameters
in non-sexual organs in healthy men and women. Data from human specimens had to be replaced with in-
formation from other mammals every time invasive procedures of sample procurement were involved.
Signiﬁcance: As our knowledge, and the methods to build it, get reﬁned, gender diﬀerences need to receive more
and more attention, as they inﬂuence the outcome of all aspects in lifestyle, including diet, exercise and en-
vironmental factors. In turn this background modulates a diﬀerential susceptibility to some disease, or a diﬀerent
pathogenetic mechanism, depending on gender, and a diﬀerent response to pharmacological therapy. Preparing
this review we meant to raise awareness about the gender issue. We anticipate that more and more often, in the
future, separate evaluations will be carried out on male and female subjects as an alternative – and an upgrade –
to the current approach of reference and test groups being ‘matched for age and sex’.
1. Introduction
A thorough and systematic assessment of the expression level for the


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product(s) of each of the protein-coding genes identiﬁed in the human
genome is being carried out through the construction of a Human
Protein Atlas (http://www.proteinatlas.org) as part of the HUPO en-
deavor (https://www.hupo.org). At the level of organ proteomes, the
Atlas database contrasts testis and prostate to endometrium, ovary and
placenta. No data on the contrary are reported about the occurrence of
diﬀerential regulation of any protein at sites other than gonads and
genitals; sex (and age) of tissue donors together with diagnosis are only
included in speciﬁc histological and Ref-seq data. No sex-speciﬁc in-
formation is available either from the ProteomicsDB repository, which
collects thousands of LC-MS/MS experiments involving human tissues,
cell lines and body ﬂuids to provide a draft of the human proteome [1].
Our review aims at ﬁlling this gap by compiling evidence on gender-
speciﬁc diﬀerences at the proteomic level throughout organs and tis-
sues. Such diﬀerences have been reported for dioichous plants and for
many animals in all phyla. We will focus our report on humans and, to a
minor extent, on laboratory animals, as their specimens are analyzed
under a number of experimental settings as models of physiological and
pathological conditions in our species. As we have long ago seen in our
investigations [2–4] and as we summarize in Fig. 1, the diﬀerences
between plasma/serum and urine proteomes between males and fe-
males in one of these species, Rattus norvegicus, are so obvious that the
origin of the specimens can be easily guessed from the spot pattern in a
2-DE slab. Subtler yet signiﬁcant diﬀerences are observed in human
body ﬂuids and in some human and animal tissues, as we are going to
detail in the following.
Our reference list only contains a little > 100 items. Indeed, on
most topics, the reports pointing out gender diﬀerences, and proving
some features being dependent of sex, amount to a very small fraction
of the total of proteomics investigations. In some more cases, mostly


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dealing with the search for biomarkers of disease, the possible occur-
rence of gender diﬀerences was investigated and eventually ruled out:
several features were thus proven independent of sex; to keep our ac-
count focused, we do not review these reports but we like to stress that
relevance and reliability are equal between evidence in favor or in
disfavor of a given conclusion. In most cases, however, the investigated
features were made operationally independent of sex through com-
parison/s between/among sex-matched experimental groups; this was
most often the case with diﬃcult to obtain clinical specimens from
human patients. This amounts to disregard the inﬂuence of sex, if any,
and was routine till recently. Indeed, also the endeavor of gender
medicine, as aiming at understanding the diﬀerences of patho-phy-
siology, clinical signs, prevention and treatment of diseases equally
http://dx.doi.org/10.1016/j.jprot.2017.10.002
Received 19 July 2017; Received in revised form 26 September 2017; Accepted 4 October 2017
⁎ Corresponding author.
E-mail address: elisabetta.gianazza@unimi.it (E. Gianazza).
Journal of Proteom
ics xxx (xxxx) xxx–xxx
1874-3919/ ©
 2017 Published by Elsevier B.V.
Please cite this article as: Gianazza, E., Journal of Proteom
ics (2017), http://dx.doi.org/10.1016/j.jprot.2017.10.002


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Nature | Vol 594 | 10 June 2021 | 227
Article
Evolutionary and biomedical insights from a 
marmoset diploid genome assembly
Chentao Yang1,2,19, Yang Zhou1,19, Stephanie Marcus3,19, Giulio Formenti3,4, Lucie A. Bergeron2, 
Zhenzhen Song5, Xupeng Bi1, Juraj Bergman6, Marjolaine Marie C. Rousselle6, 
Chengran Zhou1, Long Zhou1, Yuan Deng1,2, Miaoquan Fang1, Duo Xie1, Yuanzhen Zhu1, 
Shangjin Tan1, Jacquelyn Mountcastle4, Bettina Haase4, Jennifer Balacco4, Jonathan Wood7, 
William Chow7, Arang Rhie8, Martin Pippel9,10, Margaret M. Fabiszak11, Sergey Koren8, 
Olivier Fedrigo4, Winrich A. Freiwald11,12, Kerstin Howe7, Huanming Yang1,5,13,14, 
Adam M. Phillippy8, Mikkel Heide Schierup6, Erich D. Jarvis3,4,15 & Guojie Zhang2,16,17,18 ✉
The accurate and complete assembly of both haplotype sequences of a diploid 
organism is essential to understanding the role of variation in genome functions, 
phenotypes and diseases1. Here, using a trio-binning approach, we present a 
high-quality, diploid reference genome, with both haplotypes assembled 
independently at the chromosome level, for the common marmoset (Callithrix 
jacchus), an primate model system that is widely used in biomedical research2,3. The 
full spectrum of heterozygosity between the two haplotypes involves 1.36% of the 
genome—much higher than the 0.13% indicated by the standard estimation based on 
single-nucleotide heterozygosity alone. The de novo mutation rate is 0.43 × 10−8 per 
site per generation, and the paternal inherited genome acquired twice as many 
mutations as the maternal. Our diploid assembly enabled us to discover a recent 
expansion of the sex-differentiation region and unique evolutionary changes in the 
marmoset Y chromosome. In addition, we identified many genes with signatures of 
positive selection that might have contributed to the evolution of Callithrix biological 
features. Brain-related genes were highly conserved between marmosets and 
humans, although several genes experienced lineage-specific copy number variations


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or diversifying selection, with implications for the use of marmosets as a model 
system.
A diploid organism carries two haploid genomes with a range of vari-
ants, which make substantial contributions to phenotypic variation4. 
Phased haplotype assemblies can help to reveal the cis- and trans-acting 
variants on the two homologous genomes. However, most contempo-
rary de novo genome-sequencing efforts produce a single mosaic refer-
ence genome derived from parts of both maternal and paternal alleles, 
with variations between homologous chromosomes normally being 
disregarded. As a consequence, these methods usually fail to assemble 
genomic regions with high heterogeneity, resulting in fragmented 
sequences. A few methods have been developed to produce partial 
haplotype-phased genome assemblies and showed power in using 
long sequencing reads to produce long haplotigs (haplotype-specific 
contigs)5,6. However, producing an assembly that is completely phased 
at the chromosome level for both haplotypes of a diploid genome 
remains a challenge. Here, as part of the Vertebrate Genomes Project, 
we used a trio-binning approach7,8 to produce a chromosome-level, 
fully haplotype-resolved diploid genome assembly for the common 
marmoset, C. jacchus. This New World primate has been established 
as an animal model for a broad range of biomedical research such as 
neuroscience, stem cell biology and regenerative medicine2,3. With 
our high-quality diploid assembly, we discovered new properties of 
heterozygosity on both autosomes and sex chromosomes of this pri-
mate species.
Diploid genome assembly
We generated 63×-coverage PacBio continuous long reads, 55× 10X 
Genomics Chromium linked-reads, 154× Bionano optical molecules, 
https://doi.org/10.1038/s41586-021-03535-x
Received: 20 September 2020
Accepted: 12 April 2021
Published online: 28 April 2021
Open access
 Check for updates


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1BGI-Shenzhen, Shenzhen, China. 2Villum Centre for Biodiversity Genomics, Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen, Denmark. 
3Laboratory of Neurogenetics of Language, The Rockefeller University, New York, NY, USA. 4Vertebrate Genome Laboratory, The Rockefeller University, New York, NY, USA. 5University of the 
Chinese Academy of Sciences, Beijing, China. 6Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. 7Wellcome Sanger Institute, Hinxton, UK. 8Genome Informatics Section, 
Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 9Max Planck Institute of Molecular Cell Biology 
and Genetics, Dresden, Germany. 10Center for Systems Biology, Dresden, Germany. 11Laboratory of Neural Systems, The Rockefeller University, New York, NY, USA. 12Center for Brains, Minds and 
Machines (CBMM), The Rockefeller University, New York, NY, USA. 13James D. Watson Institute of Genome Sciences, Hangzhou, China. 14Guangdong Provincial Academician Workstation of BGI 
Synthetic Genomics, BGI-Shenzhen, Shenzhen, China. 15Howard Hughes Medical Institute, Chevy Chase, MD, USA. 16State Key Laboratory of Genetic Resources and Evolution, Kunming 
Institute of Zoology, Chinese Academy of Sciences, Kunming, China. 17China National GeneBank, BGI-Shenzhen, Shenzhen, China. 18Center for Excellence in Animal Evolution and Genetics, 
Chinese Academy of Sciences, Kunming, China. 19These authors contributed equally: Chentao Yang, Yang Zhou, Stephanie Marcus. ✉e-mail: guojie.zhang@bio.ku.dk


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Expression of Trk isoforms in brain regions and in the striatum of patients with Alzheimer's disease


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Expression of Trk Isoforms in Brain Regions and in the Striatum
of Patients with Alzheimer’s Disease
Pierre Dubus, Baptiste Faucheux,* Florence Boissie`re,* Alexis Groppi, Claude Vital,† Anne Vital,†
Yves Agid,* Etienne C. Hirsch,* and Jean Philippe Merlio
Laboratoire d’Histologie-Embryologie, EA 2406 Universite´ de Bordeaux 2, BP 8, 33076 Bordeaux Cedex, France; *INSERM U289, Hoˆpital
de la Salpeˆtrie`re, 75651 Paris Cedex 13, France; and †Service d’Anatomie Pathologique, Hoˆpital Pellegrin, 33076 Bordeaux Cedex, France
Received November 30, 1998; accepted March 23, 2000
The TrkAII tyrosine kinase receptor differs from the
TrkAI isoform by an insertion of six amino acids in the
extracellular domain. We used RT-PCR to determine
their respective distribution in rat and human brain.
Only trkAII transcripts were detected in 12 rat brain
regions, while both trkAI and trkAII transcripts were
detected in the cerebellum and pituitary gland. In hu-
man, both trkAI and trkAII transcripts were detected
in the frontal, temporal, and occipital cortex and thal-
amus, while only trkAI transcripts were detected in
the hippocampus and cerebellum. In the caudate and
putamen,
trkAII
transcripts
were
exclusively
de-
tected. Thereafter, we studied the expression of TrkA
isoforms in the striatum of ﬁve patients with Alzhei-
mer’s disease (AD), four patients with non-AD demen-
tia, seven patients with Parkinson’s disease, and six
paired nondemented elderly control individuals. In
controls and non-AD patients, a constant expression of
trkAII transcripts was detected within all striatum
parts. In AD patients, a heterogeneous decrease in
trkAII expression was observed in the caudate, puta-
men, and ventral striatum, resulting either in a drop of
trkAII transcript levels or in a weak coampliﬁcation of
trkAII and trkAI transcripts. The alteration of TrkAII
gene expression paralleled those of choline acetyl-
transferase. Together with previous data, this sug-
gests that the alteration of trk gene expression could


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contribute to a decrease in NGF binding sites and its
protective
effects
on
cholinergic
neurons
of
AD
patients.
© 2000 Academic Press
Key Words: Trk; nerve growth factor; neurotrophin;
striatum; human brain; PCR; Alzheimer’s disease; Par-
kinson’s disease.
INTRODUCTION
Nerve growth factor (NGF) is critical for the devel-
opment and maintenance of restricted neuronal popu-
lations in the brain, which include cholinergic neurons
of the basal forebrain and the striatum (reviewed in
(46, 56)). These cells express high-afﬁnity binding sites
for NGF (45, 55) that require the presence of a tyrosine
kinase receptor Trk or TrkA (26, 28). Binding of NGF
to TrkA triggers activation of its kinase and autophos-
phorylation, resulting in a cascade of intracellular
events mediating NGF neurotrophic support (reviewed
in (3)). The accessory presence of the low-afﬁnity p75
neurotrophin receptor (p75NTR) in cells expressing
both receptors may modulate TrkA and NGF interac-
tions (for review see (9)).
All NGF-dependent neurons have been shown to ex-
press trkA transcripts both in the developing and in the
adult CNS (23, 24, 39). While other neurotrophins such
as NT-3 or NT-4/5 may activate TrkA with a lower
efﬁciency than NGF (5, 15), NGF does not bind to other
members of the Trk family such as TrkB or TrkC (25).
Several truncated receptors lacking the kinase do-
main have been identiﬁed for TrkB and TrkC but not
for TrkA (reviewed in (3)). The trkA protooncogene
encodes two tyrosine protein kinase isoforms differing
in a six-amino-acid residue present in the extracellular
region of the TrkAII isoform (4, 37, 38). Their expres-
sion is the result of alternative splicing of a miniexon in
the pre-mRNA, and both receptors include the NGF-
binding site in their ectodomain (4). Functional studies
have suggested that the two isoforms have similar
biological properties in both ﬁbroblast cell lines and
COS cells expressing ectopic TrkA (4, 28, 38). However,
in PC12-transfected cell lines, both isoforms are com-


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parably activated by NGF, but the TrkAII isoform
showed higher activation by NT-3 than the TrkAI iso-
form (12). In addition, the expression of each variant
primarily appeared to be tissue-speciﬁc with a predom-
inant expression of trkAII transcripts over trkAI tran-
scripts in neuronal cells and a unique expression of
trkAI in cells of nonneuronal origin (4).
The short nucleotide sequence speciﬁc to trkAII tran-
scripts does not allow the anatomical distribution of
each isoform to be investigated by in situ hybridization
(ISH). Therefore, we decided to examine the expression
of TrkA isoforms in rat and human brain regions by
means of RT-PCR. Differences between rat and human
Experimental Neurology 165, 285–294 (2000)
doi:10.1006/exnr.2000.7447, available online at http://www.idealibrary.com on
285
0014-4886/00 $35.00
Copyright © 2000 by Academic Press
All rights of reproduction in any form reserved.


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Review
Gender differences in autoimmune disease
S.T. Ngo a,b,1, F.J. Steyn a,1, P.A. McCombe b,c,⇑
a School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia
b University of Queensland Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia
c Department of Neurology, Royal Brisbane & Women’s Hospital, Herston, Queensland, Australia
a r t i c l e
i n f o
Article history:
Available online 2 May 2014
Keywords:
Autoimmunity
Gender
Sex differences
Immune system
a b s t r a c t
Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in
damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect speciﬁc organs
or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby
females are generally more frequently affected than males. In this review, we consider gender differences
in systemic and organ-speciﬁc autoimmune diseases, and we summarize human data that outlines the
prevalence of common autoimmune diseases speciﬁc to adult males and females in countries commonly
surveyed. We discuss possible mechanisms for sex speciﬁc differences including gender differences in
immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones,
genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a
signiﬁcant inﬂuence on the development of autoimmune disease. Thus, considerations of gender should
be at the forefront of all studies that attempt to deﬁne mechanisms that underpin autoimmune disease.
 2014 Published by Elsevier Inc.
1. Introduction
Autoimmune disease, ﬁrst recognized by Ian Mackay and
Macfarlane Burnet, is characterized by the failure of an organism
to tolerate its own cells and tissues, resulting in an aberrant
immune response by lymphocytes and/or antibodies (Mackay
and Burnet, 1963). This leads to pathological changes and dysfunc-


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tion of the tissue that is the target of the self-directed immune
response. Autoimmune diseases can be systemic or can affect
speciﬁc organs or body systems including the endocrine, gastro-
intestinal and liver, rheumatological, and neurological systems. In
this review, we discuss systemic and organ-speciﬁc autoimmune
diseases. In general there is a greater prevalence of autoimmune
disease in females than males, although there are exceptions. To
demonstrate sex differences in autoimmune disease, we summa-
rize human data to provide an overview of the prevalence in males
and females of common autoimmune diseases in countries
commonly surveyed. We then discuss possible mechanisms for
sex speciﬁc differences.
1.1. Autoimmunity and autoimmune disease – key considerations for
sexual dimorphism
Autoimmune diseases comprise a range of diseases in which the
immune response to self-antigens results in damage or dysfunction
of tissues (Mackay and Burnet, 1963). Criteria have been developed
that allow a disease to be classiﬁed as autoimmune (Rose and
Bona, 1993). These criteria include the identiﬁcation of a target
antigen, the presence of antibodies and/or T cells in the target
organ, and the transfer of disease to animals by cells or antibodies
(Rose and Bona, 1993; Witebsky et al., 1957). The immune system
is comprised of multiple cell types of a single lineage. Collectively,
these cells contribute to acquired and innate immunity. Interac-
tions between acquired and innate immune function may aggra-
vate autoimmune responses. A strong inﬂammatory component,
with inﬁltration of tissue with macrophages and lymphocytes, is
associated with many organ-speciﬁc autoimmune diseases, such
as in rheumatoid arthritis (RA) and multiple sclerosis (MS). Non-
inﬂammatory conditions like myasthenia gravis (MG) are anti-
body-mediated, although there may be some minor lymphocyte
inﬁltration. Systemic lupus erythematosus (SLE) is another impor-
tant antibody-mediated disease.
The origin of autoimmune disease is a disruption of immune


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tolerance of self-antigens. This is thought to occur in genetically
susceptible individuals after exposure to environmental triggers
(Mackay, 2001). Autoimmune diseases are strongly associated with
http://dx.doi.org/10.1016/j.yfrne.2014.04.004
0091-3022/ 2014 Published by Elsevier Inc.
⇑ Corresponding author at: University of Queensland Centre for Clinical Research,
University of Queensland, Herston, Queensland, Australia. Fax: +61 7 38327447.
E-mail address: pamela.mccombe@uq.edu.au (P.A. McCombe).
1 Authors contributed equally.
Frontiers in Neuroendocrinology 35 (2014) 347–369
Contents lists available at ScienceDirect
Frontiers in Neuroendocrinology
journal homepage: www.elsevier.com/locate/yfrne
Open access under CC BY-NC-ND license.
Open access under CC BY-NC-ND license.


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Hippocampal neurogenesis: learning to remember
Orly Lazarov* and Carolyn Hollands
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA
Abstract
Alzheimer’s disease, the most prevalent form of dementia in the elderly, is characterized by 
progressive memory loss and cognitive dysfunction. It has become increasingly clear that while 
neuronal cell loss in the entorhinal cortex and hippocampus occurs in Alzheimer’s disease, it is 
preceded by a long period of deficits in the connectivity of the hippocampal formation that 
contributes to the vulnerability of these circuits. Hippocampal neurogenesis plays a role in the 
maintenance and function of the dentate gyrus and hippocampal circuitry. This review will 
examine the evidence suggesting that hippocampal neurogenesis plays a role in cognitive function 
that is affected in Alzheimer’s disease, will discuss the cognitive assessments used for the 
detection of Alzheimer’s disease in humans and rodent models of familial Alzheimer’s disease, 
and their value for unraveling the mechanism underlying the development of cognitive 
impairments and dementia.
Graphical Abstract
Associate Professor, University of Illinois at Chicago, Department of Anatomy and Cell Biology, 808 South Wood Street, CME 578, 
Chicago, IL 60612, USA. Phone: 312-355-0548, fax: 312 413 0354. 
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing 
this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it 
is published in its final citable form. Please note that during the production process errors may be discovered which could affect the 
content, and all legal disclaimers that apply to the journal pertain.
Conflict of interest
The authors declare no conflict of interest on the content of this review.
HHS Public Access
Author manuscript
Prog Neurobiol. Author manuscript; available in PMC 2017 March 01.


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Published in final edited form as:
Prog Neurobiol. 2016 ; 138-140: 1–18. doi:10.1016/j.pneurobio.2015.12.006.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Genome-Wide DNA Methylation Profile Indicates Potential Epigenetic Regulation of Aging in the Rhesus Macaque Thymus


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string_value:
Citation: Qiu, H.; Li, H.; Fan, R.;
Song, Y.; Pan, X.; Zhang, C.; Li, J.
Genome-Wide DNA Methylation
Proﬁle Indicates Potential Epigenetic
Regulation of Aging in the Rhesus
Macaque Thymus. Int. J. Mol. Sci.
2022, 23, 14984. https://doi.org/
10.3390/ijms232314984
Academic Editor: Zhe Liang
Received: 21 October 2022
Accepted: 24 November 2022
Published: 29 November 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional afﬁl-
iations.
Copyright:
© 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed
under
the
terms
and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
 
International Journal of 
Molecular Sciences
Article
Genome-Wide DNA Methylation Proﬁle Indicates Potential
Epigenetic Regulation of Aging in the Rhesus Macaque Thymus
Hong Qiu
, Haobo Li, Ruiwen Fan, Yang Song, Xuan Pan, Chunhui Zhang and Jing Li *
Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences,
Sichuan University, Chengdu 610064, China
* Correspondence: lijingsk@scu.edu.cn
Abstract: We analyzed whole-genome bisulﬁte sequencing (WGBS) and RNA sequencing data of two
young (1 year old) and two adult (9 years old) rhesus macaques (Macaca mulatta) to characterize the
genomic DNA methylation proﬁle of the thymus and explore the molecular mechanism of age-related
changes in the thymus. Combining the two-omics data, we identiﬁed correlations between DNA
methylation and gene expression and found that DNA methylation played an essential role in the
functional changes of the aging thymus, especially in immunity and coagulation. The hypomethyla-
tion levels of C3 and C5AR2 and the hypermethylation level of C7 may lead to the high expressions
of these genes in adult rhesus macaque thymuses, thus activating the classical complement path-
way and the alternative pathway and enhancing their innate immune function. Adult thymuses


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had an enhanced coagulation pathway, which may have resulted from the hypomethylation and
upregulated expressions of seven coagulation-promoting factor genes (F13A1, CLEC4D, CLEC4E,
FCN3, PDGFRA, FGF2 and FGF7) and the hypomethylation and low expression of CPB2 to inhibit
the degradation of blood clots. Furthermore, the functional decline in differentiation, activation and
maturation of T cells in adult thymuses was also closely related to the changes in methylation levels
and gene expression levels of T cell development genes (CD3G, GAD2, ADAMDEC1 and LCK) and
the thymogenic hormone gene TMPO. A comparison of the age-related methylated genes among
four mammal species revealed that most of the epigenetic clocks were species-speciﬁc. Furthermore,
based on the genomic landscape of allele-speciﬁc DNA methylation, we identiﬁed several age-related
clustered sequence-dependent allele-speciﬁc DNA methylated (cS-ASM) genes. Overall, these DNA
methylation patterns may also help to assist with understanding the mechanisms of the aging thymus
with the epigenome.
Keywords: DNA methylation; mRNA expression; thymus; aging; ASM
1. Introduction
As one of the key immunological organs, the thymus is an essential organ for the
generation of the adaptive immune system and involves the differentiation and maturation
of T lymphocytes (T cells) [1]. The thymus is also an organ of the endocrine system and by
using the thymic hormone and thymosin, it regulates immune function [2]. The organ and
thymic hormone have synergistic or antagonistic actions within several endocrine glands [2].
In most mammals, a peculiar feature of the thymus is that it shrinks or disappears as an
individual gets older. The thymus starts deteriorating after birth, and thymic cells are
eventually replaced by adipocytes [3,4]. Along with the age-related decrease in size and
activity of the thymus comes an associated functional decline [5,6]. However, the molecular
regulation mechanism of thymus development and aging remains unresolved.


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As an important epigenetic modification, DNA methylation plays vital roles in cell
differentiation, tissue-specific gene expression, genomic imprinting and X chromosome
inactivation in both animals and plants. DNA methylation mainly regulates gene silencing
Int. J. Mol. Sci. 2022, 23, 14984. https://doi.org/10.3390/ijms232314984
https://www.mdpi.com/journal/ijms


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RESEARCH ARTICLE
Human Lung Tissue Transcriptome: Influence
of Sex and Age
Matteo Dugo1‡, Chiara E. Cotroneo2¤‡, Emilie Lavoie-Charland3, Matteo Incarbone4,
Luigi Santambrogio5, Lorenzo Rosso5, Maarten van den Berge6, David Nickle7, Peter
D. Pare´8,9, Yohan Bosse´3,10, Tommaso A. Dragani2*, Francesca Colombo2
1 Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei
Tumori, Milan, Italy, 2 Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto
Nazionale dei Tumori, Milan, Italy, 3 Institut Universitaire de cardiologie et de pneumologie de Que´bec,
Que´bec, Canada, 4 Department of Surgery, San Giuseppe Hospital–MultiMedica, Milan, Italy, 5 Fondazione
IRCCS Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, 6 University of Groningen, University
Medical Center Groningen, Department of Pulmonology, Groningen Research Institute for Asthma and COPD
(GRIAC), Groningen, The Netherlands, 7 Merck & Co. Inc., Rahway, NJ, United States of America,
8 University of British Columbia Center for Heart Lung Innovation and Institute for Heart and Lung Health,
St. Paul’s Hospital, Vancouver, BC, Canada, 9 Respiratory Division, Department of Medicine, The University
of British Columbia, Vancouver, BC, Canada, 10 Department of Molecular Medicine, Laval University,
Que´bec, Canada
¤ Current address: UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield,
Dublin, Ireland.
‡ These authors are co-first authors on this work.
* tommaso.dragani@istitutotumori.mi.it
Abstract
Background
Sex and age strongly influence the pathophysiology of human lungs, but scarce information
is available about their effects on pulmonary gene expression.
Methods
We followed a discovery-validation strategy to identify sex- and age-related transcriptional
differences in lung.
Results
We identified transcriptional profiles significantly associated with sex (215 genes; FDR <


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0.05) and age at surgery (217 genes) in non-involved lung tissue resected from 284 lung
adenocarcinoma patients. When these profiles were tested in three independent series of
non-tumor lung tissue from an additional 1,111 patients, we validated the association with
sex and age for 25 and 22 genes, respectively. Among the 17 sex-biased genes mapping on
chromosome X, 16 have been reported to escape X-chromosome inactivation in other tis-
sues or cells, suggesting that this mechanism influences lung transcription too. Our 22 age-
related genes partially overlap with genes modulated by age in other tissues, suggesting
that the aging process has similar consequences on gene expression in different organs.
Finally, seven genes whose expression was modulated by sex in non-tumor lung tissue,
but no age-related gene, were also validated using publicly available data from 990 lung
PLOS ONE | DOI:10.1371/journal.pone.0167460
November 30, 2016
1 / 16
a11111
OPEN ACCESS
Citation: Dugo M, Cotroneo CE, Lavoie-Charland E,
Incarbone M, Santambrogio L, Rosso L, et al.
(2016) Human Lung Tissue Transcriptome:
Influence of Sex and Age. PLoS ONE 11(11):
e0167460. doi:10.1371/journal.pone.0167460
Editor: Baochuan Lin, Defense Threat Reduction
Agency, UNITED STATES
Received: September 23, 2015
Accepted: November 15, 2016
Published: November 30, 2016
Copyright: © 2016 Dugo et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: Gene expression data
were deposited in the Gene Expression Omnibus
database (GEO, http://www.ncbi.nlm.nih.gov/geo/)
with accession number GSE71181.
Funding: This work was supported by grants from
the Italian Association for Cancer Research (AIRC,
grant no. 14714). One of the authors (D.N.) has an
affiliation to a commercial funder of this research
(Merck & Co. Inc.); the funder provided support in


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the form of salary for the author (D.N.), but did not
have any additional role in the study design, data
collection and analysis, decision to publish, or
preparation of the manuscript. The specific roles of


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The aTSR Domain of Plasmodium Circumsporozoite Protein Bound Heparan Sulfates and Elicited High Titers of Sporozoite Binding Antibody After Displayed by Nanoparticles


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O R I G I N A L  R E S E A R C H
The αTSR Domain of Plasmodium Circumsporozoite 
Protein Bound Heparan Sulfates and Elicited High 
Titers of Sporozoite Binding Antibody After 
Displayed by Nanoparticles
Ming Xia1, Frank Vago2, Ling Han
3, Pengwei Huang1, Linh Nguyen3, Geert-Jan Boons4–6, John S Klassen3, 
Wen Jiang2, Ming Tan
1,7
1Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2Department of Biological Sciences, Purdue 
University, West Lafayette, IN, USA; 3Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada; 4Complex Carbohydrate 
Research Center, University of Georgia, Athens, GA, USA; 5Department of Chemistry, University of Georgia, Athens, GA, USA; 6Department of 
Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht 
University, Utrecht, the Netherlands; 7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Correspondence: Ming Tan, Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 
45229-3039, USA, Tel +1 513-636-0510, Fax +1 513-636-7655, Email ming.tan@cchmc.org 
Introduction: Malaria is a devastating infectious illness caused by protozoan Plasmodium parasites. The circumsporozoite protein 
(CSP) on Plasmodium sporozoites binds heparan sulfate proteoglycan (HSPG) receptors for liver invasion, a critical step for 
prophylactic and therapeutic interventions.
Methods: In this study, we characterized the αTSR domain that covers region III and the thrombospondin type-I repeat (TSR) of the 
CSP using various biochemical, glycobiological, bioengineering, and immunological approaches.
Results: We found for the first time that the αTSR bound heparan sulfate (HS) glycans through support by a fused protein, indicating that 
the αTSR is a key functional domain and thus a vaccine target. When the αTSR was fused to the S domain of norovirus VP1, the fusion


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protein self-assembled into uniform S60-αTSR nanoparticles. Three-dimensional structure reconstruction revealed that each nanoparticle 
consists of an S60 nanoparticle core and 60 surface displayed αTSR antigens. The nanoparticle displayed αTSRs retained the binding 
function to HS glycans, indicating that they maintained authentic conformations. Both tagged and tag-free S60-αTSR nanoparticles were 
produced via the Escherichia coli system at high yield by scalable approaches. They are highly immunogenic in mice, eliciting high titers 
of αTSR-specific antibody that bound specifically to the CSPs of Plasmodium falciparum sporozoites at high titer.
Discussion and Conclusion: Our data demonstrated that the αTSR is an important functional domain of the CSP. The S60-αTSR 
nanoparticle displaying multiple αTSR antigens is a promising vaccine candidate potentially against attachment and infection of 
Plasmodium parasites.
Keywords: malaria, Plasmodium, αTSR domain, receptor binding domain, S60 nanoparticle, malaria vaccine, norovirus
Introduction
Malaria is a deadly, transmissible human disease caused by unicellular protozoan parasites that are members of the 
Plasmodium genus in the family Plasmodiidae. The World Health Organization (WHO) estimated that about 40% of the 
global population is at risk of Plasmodium infection and that Plasmodium infection resulted in approximately 241 million 
malaria cases in 2020, claiming around 627,000 lives worldwide.1 Thus, malaria remains a major threat to global public 
health. Various countermeasures have been attempted to prevent malaria, including control of mosquito vectors carrying 
Plasmodium parasites, generations of antimalarial drugs, and development of vaccines.2 However, due to the resistance 
against insecticide by mosquitos and the diminished effects of antimalarial medicines owing to the resistance developed 
International Journal of Nanomedicine 2023:18 3087–3107                                               
3087


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3087
© 2023 Xia et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php 
and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work 
you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For 
permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
International Journal of Nanomedicine                                                 
Dovepress
open access to scientific and medical research
Open Access Full Text Article
Received: 29 January 2023
Accepted: 31 May 2023
Published: 8 June 2023


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Maximising sensitivity for detecting changes in protein expression: Experimental design using minimal CyDyes


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REGULAR ARTICLE
Maximising sensitivity for detecting changes in protein
expression: Experimental design using minimal CyDyes
Natasha A. Karp and Kathryn S. Lilley
Department of Biochemistry, Cambridge University, Cambridge, UK
DIGE is a powerful tool for measuring changes in protein expression between samples. Here we
assess the assumptions of normality and heterogeneity of variance that underlie the univariate
statistical tests routinely used to detect proteins with expression changes. Furthermore, the
technical variance experienced in a multigel experiment is assessed here and found to be repro-
ducible within- and across-sample types. Utilising the technical variance measured, a power
study is completed for several ‘typical’ fold changes in expression commonly used as thresholds
by researchers. Based on this study using DeCyder, guidance is given on the number of gel
replicates that are needed for the experiment to have sufficient sensitivity to detect expression
changes. A two-dye system based on utilising just Cy3 and Cy5 was found to be more reproduci-
ble than the three-dye system. A power and cost-benefit analysis performed here suggests that
the traditional three-dye system would use fewer resources in studies where multiple samples
are compared. Technical variance was shown to encompass both experimental and analytical
noise and thus is dependent on the analytical software utilised. Data is provided as a resource to
the community to assess alternative software and upgrades.
Received: February 15, 2005
Revised: March 17, 2005
Accepted: March 17, 2005
Keywords:
DIGE / Expression proteomics / Power / 2-DE / Variation
Proteomics 2005, 5, 3105–3115
3105
1
Introduction
2-DE is a common method utilised to simultaneously sepa-
rate and quantitate thousands of proteins to assess expres-
sion changes in protein levels from one state to another.
Proteins are separated according to their pI and molecular
weight. The resulting spot patterns can be visualised by pre-


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labelling the sample prior to the separation, e.g. radioactivity
[1], fluorescence [2–5] or post-separation with total protein
stains such as colloidal CBB [6], SYPRO Ruby or deep purple
[7, 8]. The gels are converted to digital images using scan-
ning devices and these images are processed to detect the
spots, quantitate the spot volumes and match the spots pat-
terns across different gels. Statistical methods are then
employed to detect protein spots with statistical significant
changes in expression.
Early comparative proteomics relied on using images
from different gels. Gel-to-gel variation, however, led to
problematic detection and quantification of differences in
protein expression. A significant advancement in reproduci-
bility was made by Ünlü et al. [9] who multiplexed fluores-
cently resolvable dyes (CyDyes) within a gel, which enabled
the comparison of multiple samples within the same gel. Gel
running effects are thus comparable within the same gel
allowing a more accurate comparison of spot volume. This
approach has been commercialised by GE Healthcare (Swe-
den) (formerly Amersham Bioscience). A multigel approach
has been demonstrated to significantly improve accuracy of
quantitation by using one dye to label a standard sample that
is present in every gel [10]. This standard sample is used to
match the spot patterns across a gel series and to calculate a
standardised abundance (SA) value for a spot, which can
then be compared across many gels.
Correspondence: Dr. Kathryn Lilley, Department of Biochemistry,
University of Cambridge, Building O, Downing Site, Cambridge,
CB2 1QW, UK
E-mail: k.s.lilley@bioc.cam.ac.uk
Fax: 144-1223-333-345
Abbreviations: ASB14, amidosulfobetaine-14; ECA, Erwinia caro-
tovora; log10SA, log10(standardised abundance); SA, standard-
ised abundance
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.proteomics-journal.de
DOI 10.1002/pmic.200500083


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Frontiers in Microbiology
01
frontiersin.org
Multi-omics analysis reveals the 
host–microbe interactions in 
aged rhesus macaques
Jue Xu 1†, Yue Lan 2†, Xinqi Wang 2, Ke Shang 2, Xu Liu 3, 
Jiao Wang 2, Jing Li 2, Bisong Yue 3, Meiying Shao 1* and 
Zhenxin Fan 2,3*
1 West China School of Public Health and West China Fourth Hospital, Chengdu, Sichuan, China, 
2 Key Laboratory of Bioresources and Ecoenvironment (Ministry of Education), College of Life 
Sciences, Sichuan University, Chengdu, China, 3 Sichuan Key Laboratory of Conservation Biology on 
Endangered Wildlife, College of Life Sciences, Sichuan University, Chengdu, China
Aging is a complex multifactorial process that greatly affects animal health. 
Multi-omics analysis is widely applied in evolutionary biology and biomedical 
research. However, whether multi-omics can provide sufficient information to 
reveal comprehensive changes in aged non-human primates remains unclear. 
Here, we explored changes in host–microbe interactions with aging in Chinese 
rhesus macaques (Macaca mulatta lasiota, CRs) using multi-omics analysis. 
Results showed marked changes in the oral and gut microbiomes between 
young and aged CRs, including significantly reduced probiotic abundance 
and increased pathogenic bacterial abundance in aged CRs. Notably, the 
abundance of Lactobacillus, which can metabolize tryptophan to produce aryl 
hydrocarbon receptor (AhR) ligands, was decreased in aged CRs. Consistently, 
metabolomics detected a decrease in the plasma levels of AhR ligands. In 
addition, free fatty acid, acyl carnitine, heparin, 2-(4-hydroxyphenyl) propionic 
acid, and docosahexaenoic acid ethyl ester levels were increased in aged CRs, 
which may contribute to abnormal fatty acid metabolism and cardiovascular 
disease. Transcriptome analysis identified changes in the expression of genes 
associated with tryptophan metabolism and inflammation. In conclusion, 
many potential links among different omics were found, suggesting that aged


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CRs face multiple metabolic problems, immunological disorders, and oral 
and gut diseases. We determined that tryptophan metabolism is critical for 
the physiological health of aged CRs. Our findings demonstrate the value of 
multi-omics analyses in revealing host–microbe interactions in non-human 
primates and suggest that similar approaches could be applied in evolutionary 
and ecological research of other species.
KEYWORDS
non-human primates, multi-omics, oral and gut microbiome, blood transcriptome 
and metabolome, aging
TYPE Original Research
PUBLISHED 27 September 2022
DOI 10.3389/fmicb.2022.993879
OPEN ACCESS
EDITED BY
Zhigang Zhang,  
Yunnan University,  
China
REVIEWED BY
Binghua Sun,  
Anhui University,  
China
Zhang Wang,  
South China Normal University, China
*CORRESPONDENCE
Meiying Shao  
shaomeiying2013@163.com  
Zhenxin Fan  
zxfan@scu.edu.cn
†These authors have contributed equally to 
this work
SPECIALTY SECTION
This article was submitted to  
Evolutionary and Genomic Microbiology,  
a section of the journal  
Frontiers in Microbiology
RECEIVED 14 July 2022
ACCEPTED 08 September 2022
PUBLISHED 27 September 2022
CITATION
Xu J, Lan Y, Wang X, Shang K, Liu X, Wang J, 
Li J, Yue B, Shao M and Fan Z (2022) Multi-
omics analysis reveals the host–microbe 
interactions in aged rhesus macaques.
Front. Microbiol. 13:993879.
doi: 10.3389/fmicb.2022.993879
COPYRIGHT
© 2022 Xu, Lan, Wang, Shang, Liu, Wang, 
Li, Yue, Shao and Fan. This is an open-
access article distributed under the terms 
of the Creative Commons Attribution 
License (CC BY). The use, distribution or 
reproduction in other forums is permitted, 
provided the original author(s) and the 
copyright owner(s) are credited and that 
the original publication in this journal is 
cited, in accordance with accepted 
academic practice. No use, distribution or 
reproduction is permitted which does not 
comply with these terms.


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Inﬂuence of Sex on the Progression of
Chronic Kidney Disease
Joel Neugarten, MD, and Ladan Golestaneh, MD
CME Activity
Target Audience: The target audience for Mayo Clinic Proceedings is primar-
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their current knowledge of clinical medicine and who wish to stay abreast
of advances in medical research.
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understand best practices in diagnosis and management of conditions
encountered in the clinical setting.
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In support of improving patient care, Mayo
Clinic College of Medicine and Science is
jointly accredited by the Accreditation Council
for Continuing Medical Education (ACCME),
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dentialing
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(ANCC)
to
provide
continuing education for the healthcare team.
Credit Statements:
AMA: Mayo Clinic College of Medicine and Science designates this journal-
based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).
Physicians should claim only the credit commensurate with the extent of
their participation in the activity.
MOC Credit Statement: Successful completion of this CME activity, which in-
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earn up to 1 MOC point in the American Board of Internal Medicine’s
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It is the CME activity provider’s responsibility to submit participant completion
information to ACCME for the purpose of granting ABIM MOC credit.
Learning Objectives: On completion of this article, you should be able to


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(1) critically analyze the data that suggest that sex inﬂuences the progression
of chronic kidney disease, (2) describe the effects of sex hormones on the
renin-angiotensin system, and (3) describe the effects of sex hormones on
renal physiology.
Disclosures: As a provider accredited by ACCME, Mayo Clinic College of
Medicine and Science (Mayo School of Continuous Professional Develop-
ment) must ensure balance, independence, objectivity, and scientiﬁc rigor
in its educational activities. Course Director(s), Planning Committee mem-
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presentation.
In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L.
Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the
content of this program but have no relevant ﬁnancial relationship(s)
with industry. Drs Neugarten and Golestaneh report no competing
interests.
Method of Participation: In order to claim credit, participants must com-
plete the following:
1. Read the activity.
2. Complete the online CME Test and Evaluation. Participants must achieve
a score of 80% on the CME Test. One retake is allowed.
Visit www.mayoclinicproceedings.org, select CME, and then select CME arti-
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Estimated Time: The estimated time to complete each article is approxi-


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mately 1 hour.
Hardware/Software: PC or MAC with Internet access.
Date of Release: 7/1/2019
Expiration Date: 6/30/2021 (Credit can no longer be offered after it has
passed the expiration date.)
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Questions? Contact dletcsupport@mayo.edu.
Abstract
The role that sex plays in the development and progression of chronic kidney disease remains a
subject of controversy. The lack of clarity in this important area reﬂects complex interactions between
biological factors and cultural and socioeconomic inﬂuences that impact the relationship between sex
and renal disease. Certainly, additional observational studies are indicated; however, innovative ap-
proaches are required to isolate biological processes from cultural inﬂuences. Despite these limitations,
available data suggest that the progression of renal disease is slower in women than in men and that
this sexual dimorphism is primarily due to direct actions of sex hormones on cellular metabolism. The
extent to which differences in lifestyle factors between the sexes inﬂuence sexual dimorphism in the
progression of chronic kidney disease remains to be elucidated.
ª 2019 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(7):1339-1356
S
ex inﬂuences the incidence and prev-
alence of many renal diseases as well
as the rate of progression of these dis-
orders. In animal models of aging and cystic
kidney disease and after renal ablation, male
animals have a worse renal prognosis than fe-
males.1 Manipulation of the hormonal envi-
ronment by gonadectomy or administration
From the Albert Einstein
College of Medicine, Renal
Division, Monteﬁore
Medical Center, Bronx,
NY
THEMATIC REVIEW ON WOMEN’S HEALTH
Mayo Clin Proc. n July 2019;94(7):1339-1356
n https://doi.org/10.1016/j.mayocp.2018.12.024
www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research
1339


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Annals of the Rheumatic Diseases, 1980, 39, 445-448
Circulating immune complexes in patients with
ankylosing spondylitis
G.
S. PANAYI, J. SLANEY, AND B. D. WILLIAMS*
From the Departments ofMedicine and Rheumatology, Guy's Hospital Medical School, London SE] 9RT
SUMMARY
EDTA plasma samples from 13 patients with ankylosing spondylitis (AS) were frac-
tionated on Sephadex G-200 and the quantities of C3 and IgG within the first protein peak deter-
mined by a sensitive haemagglutination-inhibition assay. Seven patients with AS had C3 detectable
in the first peak and this was associated with an increased concentration of IgG in the corresponding
fraction. These 7 patients had more active disease but did not have more peripheral arthritis. Our
results indicate that circulating immune complexes capable of initiating complement activation
are present in the circulation of patients with ankylosing spondylitis.
Despite the striking association between ankylosing
spondylitis (AS) and HLA B27 the role of immuno-
logical factors in the pathogenesis of the disease is
not clear. Recently it has been proposed that AS
may be related
in some way to infection with
Klebsiella pneuomoniae,
a bacterium which may
possess antigens cross-reacting with HLA B27.1
One way by which immune reactions may be
involved in tissue damage in AS may be via the
deposition of immune complexes. In a previous
paper we presented evidence that immune com-
plexes are present in the circulation of patients with
this disease. The complexes were detected by the
technique
of
inhibition
of
antibody-dependent
cell-mediated cytotoxicity (ADCC).2 However, these
complexes may not be of pathological importance,
since they may not activate the complement system.
Complement activation is an important mechanism
for the induction of inflammation. There is some
evidence that activation does occur in AS, since raised
serum levels of C3 and C4 inactivation products
have been noted.3 We therefore decided to investi-
gate this possibility by measuring the amount of


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macromolecular C3 in EDTA-plasma of AS patients
as evidence of complexed or activated complement.
Materials and methods
PATIENTS
Thirteen patients with AS were studied. The duration
of disease, presence of morning stiffness, inflam-
Accepted for publication 14 September 1979
Correspondence to Dr G. S. Panayi,
*Present address, Department of Medicine, Royal Post-
graduate Medical School, Ducane Road, London W13.
mation in peripheral joints, and the erythrocyte
sedimentation rate were noted. All patients were
HLA B27 positive. None had active uveitis at the
time of study.
LABORATORY METHODS
Collection and storage ofplasma. Blood was collected
into EDTA (final concentration 0.01M), rapidly
separated,
aliquoted,
and
the
plasma
samples
stored at -700C until used.
Macromolecular C3 assay (MMC3). Details of
this method have already been published.4 Briefly,
the method consists of fractionating EDTA-plasma
on Sephadex G-200. The presence of MMC3
is
indicated by a change in distribution in C3 with its
appearance within the first peak of G-200 eluted
fractions.
Plasma C3 and C4 levels. These were determined
by
radial
immunodiffusion
using
monospecific
anti-sera and results expressed as a percentage of a
pool of normal plasma.
Detection ofIgG. The concentration of IgG in the
various Sephadex G-200 fractions was determined
by a microhaemagglutination assay. Washed, group
O rhesus
positive human red blood
cells were
sensitised with human anti-D serum and after 2
washings in Veronal-buffered saline were resuspended
at 0
- 5% concentration. Sephadex G-200 eluted
plasma fractions were serially diluted with buffer
in plastic microtitre microagglutination trays, and
an equal volume of an appropriate dilution of an
anti-IgG antiserum (containing 2 minimum agglu-
tinating doses) was added. After incubation at room
temperature for 60 minutes the sensitised cells were
445


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Received: 18 July 2018 |
Accepted: 6 December 2018
DOI: 10.1002/jcp.28052
O R I G I N A L R E S E A R C H A R T I C L E
Region‐resolved proteomics profiling of monkey heart
Hao‐Liang Hu1*
| Yu Kang2* | Yong Zeng1* | Ming Zhang3 | Qiong Liao1 |
Ming‐Qiang Rong1
| Qin Zhang2 | Ren Lai3
1The National & Local Joint Engineering
Laboratory of Animal Peptide Drug
Development, College of Life Sciences, Hunan
Normal University, Changsha, China
2Division of Cardiology, West China Hospital,
Sichuan University, Chengdu, Sichuan, China
3Key Laboratory of Animal Models and Human
Disease Mechanisms of Chinese Academy of
Sciences &Yunnan Province, Kunming
Institute of Zoology, Chinese Academy of
Sciences (CAS), Kunming, Yunnan, China
Correspondence
Ming‐Qiang Rong, The National & Local Joint
Engineering Laboratory of Animal Peptide
Drug Development, College of Life Sciences,
Hunan Normal University, 410081 Changsha,
China.
Email: rongmq@hunnu.edu.cn
Qin Zhang, Cardiology Division, West China
Hospital, Sichuan University, Chengdu,
610041 Sichuan, China.
Email: qzhang2000cn@163.com
Ren Lai, Key Laboratory of Animal Models and
Human Disease Mechanisms of Chinese
Academy of Sciences &Yunnan Province,
Kunming Institute of Zoology, Chinese
Academy of Sciences (CAS), 650223 Kunming,
Yunnan, China.
Email: rlai@mail.kiz.ac.cn
Funding information
National Natural Science Foundation of China,
Grant/Award Numbers: 81573320, 81470508
Abstract
Nonhuman primates (NHPs) play an indispensable role in biomedical research
because of their similarities in genetics, physiological, and neurological function to
humans. Proteomics profiling of monkey heart could reveal significant cardiac
biomarkers and help us to gain a better understanding of the pathogenesis of heart
disease. However, the proteomic study of monkey heart is relatively lacking. Here, we
performed the proteomics profiling of the normal monkey heart by measuring three
major anatomical regions (vessels, valves, and chambers) based on iTRAQ‐coupled


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LC‐MS/MS analysis. Over 3,200 proteins were identified and quantified from three
heart tissue samples. Furthermore, multiple bioinformatics analyses such as gene
ontology analysis, protein–protein interaction analysis, and gene‐diseases association
were used to investigate biological network of those proteins from each area. More
than 60 genes in three heart regions are implicated with heart diseases such as
hypertrophic cardiomyopathy, heart failure, and myocardial infarction. These genes
associated with heart disease are mainly enriched in citrate cycle, amino acid
degradation, and glycolysis pathway. At the anatomical level, the revelation of
molecular characteristics of the healthy monkey heart would be an important starting
point to investigate heart disease. As a unique resource, this study can serve as a
reference map for future in‐depth research on cardiac disease‐related NHP model
and novel biomarkers of cardiac injury.
K E Y W O R D S
bioinformatics analysis, gene‐disease associations, monkey heart, proteomics
1
|
INTRODUCTION
The heart, which composed of vessels, valves, and chambers, pumps
adequate blood to organs and tissues, then provides oxygen and
nutrients to the whole body, as well as assists in the removal of
metabolic wastes. Periodic dilatation and contraction of the heart is
caused by a complicated interaction between biological electrocar-
diac signals and mechanical forces (Kwon et al., 2016). The heart
vessels consist largely of endothelium, vascular smooth muscle and
adventitia. The four valves open or close precisely on differential
blood pressure, which is mainly made up of endothelial cells (ECs)
and interstitial cells (ICs; Liu, Joag, & Gotlieb, 2007; Taylor, Batten,
Brand, Thomas, & Yacoub, 2003). The atria and ventricles are divided
by valves to prevent blood reflux, and the principal cell type of the
heart chambers is cardiomyocytes (CMs). Besides, cardiac fibroblasts
(CFs) produce the extracellular matrix (ECM) scaffold of the heart


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and are estimated to constitute more than half of total heart cells
(Bergmann et al., 2015).
Cardiovascular
disease
is
one
of
the
leading
causes
of
mortality. The inflammatory reaction in the vessel walls is working
to promote atherosclerosis (Bryan et al., 2014; Gimbrone &
Garcia‐Cardena, 2016; McAlpine & Swirski, 2016). Valve disorder,
J Cell Physiol. 2019;234:13720–13734.
wileyonlinelibrary.com/journal/jcp
13720
|
© 2019 Wiley Periodicals, Inc.
*These authors contributed equally to this work.
 10974652, 2019, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jcp.28052 by Westlake University, Wiley Online Library on [09/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License


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Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants


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ARTICLE
Long-read assembly of the Chinese rhesus
macaque genome and identiﬁcation of ape-speciﬁc
structural variants
Yaoxi He1,2,3,4,8, Xin Luo1,2,3,4,8, Bin Zhou1,2,3,4,8, Ting Hu1,2,3,4,8, Xiaoyu Meng
1,2,3,4,8, Peter A. Audano5,
Zev N. Kronenberg5, Evan E. Eichler
5,6, Jie Jin
7, Yongbo Guo1,2,3,4, Yanan Yang1,2, Xuebin Qi
1,2,3 &
Bing Su1,2,3
We present a high-quality de novo genome assembly (rheMacS) of the Chinese rhesus
macaque (Macaca mulatta) using long-read sequencing and multiplatform scaffolding
approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8),
rheMacS increases sequence contiguity 75-fold, closing 21,940 of the remaining assembly
gaps (60.8 Mbp). We improve gene annotation by generating more than two million full-
length transcripts from ten different tissues by long-read RNA sequencing. We sequence
resolve 53,916 structural variants (96% novel) and identify 17,000 ape-speciﬁc structural
variants (ASSVs) based on comparison to ape genomes. Many ASSVs map within ChIP-seq
predicted enhancer regions where apes and macaque show diverged enhancer activity and
gene expression. We further characterize a subset that may contribute to ape- or great-ape-
speciﬁc phenotypic traits, including taillessness, brain volume expansion, improved manual
dexterity, and large body size. The rheMacS genome assembly serves as an ideal reference
for future biomedical and evolutionary studies.
https://doi.org/10.1038/s41467-019-12174-w
OPEN
1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China. 2 Primate
Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China. 3 Center for Excellence in Animal Evolution and
Genetics, Chinese Academy of Sciences, Kunming 650223, China. 4 Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing


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100101, China. 5 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. 6 Howard Hughes Medical
Institute, University of Washington, Seattle, WA 98195, USA. 7 Nextomics Biosciences, Wuhan 430000, China. 8These authors contributed equally: Yaoxi
He, Xin Luo, Bin Zhou, Ting Hu, and Xiaoyu Meng. Correspondence and requests for materials should be addressed to B.S. (email: sub@mail.kiz.ac.cn)
NATURE COMMUNICATIONS |   (2019) 10:4233 | https://doi.org/10.1038/s41467-019-12174-w | www.nature.com/naturecommunications
1
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www.sciencemag.org/content/348/6235/660/suppl/DC1 
 
 
 
 
Supplementary Materials for 
 
The human transcriptome across tissues and individuals 
 
Marta Melé, Pedro G. Ferreira, Ferran Reverter, David S. DeLuca, Jean Monlong, 
Michael Sammeth, Taylor R. Young, Jakob M Goldmann, Dmitri D. Pervouchine, 
Timothy J. Sullivan, Rory Johnson, Ayellet V. Segrè, Sarah Djebali, Anastasia Niarchou, 
The GTEx Consortium, Fred A. Wright, Tuuli Lappalaienen, Miquel Calvo, Gad Getz, 
Emmanouil Dermitzakis, Kristin G. Ardlie,* Roderic Guigó* 
 
*Corresponding author. E-mail: kardlie@broadinstitute.org (K.G.A.); roderic.guigo@crg.cat (R.G.) 
 
Published 8 May 2015, Science 348, 660 (2015) 
DOI: 10.1126/science.aaa0355 
 
This PDF file includes: 
 
Materials and Methods 
Figs. S1 to S25 
Tables S1 to S20 
Captions for data tables S4 to S7 and S9 to S18


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The mechanisms underlying the 
different distribution of adipose 
tissue in men and women are unclear. 
New research in mice sheds some 
light on this issue.
Men are more likely to 
accumulate visceral white adipose 
tissue (VWAT), which has negative 
consequences for metabolic health, 
whereas women are more likely to 
accumulate subcutaneous white 
adipose tissue (SWAT), which is 
thought to be protective. To 
investigate the mechanisms 
underlying this difference, a team  
of researchers led by Matthew 
Rodeheffer developed an in vivo 
adipogenesis assay to study how fat 
mass expands in mice. “Focusing on 
in vivo assays is critical for the study 
of adipose given the responsiveness of  
adipose tissue to nutritional and 
hormonal cues and it’s integration 
into whole-body physiology,” 
explains Rodeheffer.
The investigators found that 
obesity as a result of a high-fat diet 
induces adipocyte hyperplasia in just 
the VWAT of male mice. By contrast, 
the same conditions resulted in 
adipocyte hyperplasia in both VWAT 
and SWAT in female mice. “These 
depot-dependent differences in 
adipogenesis are influenced by the 
tissue microenvironment in the 
different depots, not by cell-intrinsic 
differences in adipocyte precursors,” 
says Rodeheffer.
Ovariectomized female mice had a 
male-like response to a high-fat diet, 
which suggests that sex hormones 
might be involved in the differences in 
adipogenesis between the sexes. To 
test this idea, the researchers 
administered oestrogen to male mice. 
When these mice were fed a high-fat 
diet, adipocyte hyperplasia was 
increased in the SWAT, which indicates 
that oestrogen influences the 
response of SWAT to a high-fat diet. 
“Now that we have characterized 
adipocyte hyperplasia in obesity at the 
cellular level, we are focusing on how 
dietary changes drive obesogenic 
adipogenesis and what components of 
the adipose tissue microenvironment 
influence adipocyte hyperplasia in 
obesity,” concludes Rodeheffer.
Claire Greenhill
 ADIPOSE TISSUE


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Sex differences in adipogenesis
ORIGINAL ARTICLE Jeffery, E. et al. The adipose 
tissue microenvironment regulates depot-specific 
adipogenesis in obesity. Cell Metab. http://dx.doi.
org/10.1016/j.cmet.2016.05.012 (2016)
FURTHER READING Karpe, F. & Pinnick, K. E. 
Biology of upper-body and lower-body adipose 
tissue—link to whole-body phenotypes. Nat. Rev. 
Endocrinol. 11, 90–100 (2015)
RESEARCH HIGHLIGHTS
NATURE REVIEWS | ENDOCRINOLOGY 
 www.nature.com/nrendo
Nature Reviews Endocrinology | Published online 1 Jul 2016; doi:10.1038/nrendo.2016.109
©
 
2016
 
M
acm
illan
 
Publishers
 
Lim
ited.
 
All
 
rights
 
reserved.


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ResouRce
https://doi.org/10.1038/s41592-022-01526-y
1Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany. 2College of Life Science, Northwest University, Xi’an, China. 
3Bavarian Biomolecular Mass Spectrometry Center, Technical University of Munich, Freising, Germany. 4Division of Translational Cancer Research, German 
Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. 5Chair of Translational Cancer Research and Institute for 
Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. 6Department of Internal 
Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 7Center for Translational Cancer Research (TranslaTUM), School 
of Medicine, Technical University of Munich, Munich, Germany. 8Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of 
Munich, Munich, Germany. 9Institute of Radiation Medicine, Department of Radiation Sciences, Helmholtz Zentrum München, Neuherberg, Germany. 
10German Cancer Consortium (DKTK), Munich, Germany. 11German Cancer Research Center (DKFZ), Heidelberg, Germany. 12Population epigenetics 
and epigenomics, Technical University of Munich, Freising, Germany. 13Institute of Advanced Study (IAS), Technical University of Munich, Freising, 
Germany. 14Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental 
Health, Neuherberg, Germany. 15Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, 
Germany. 16Medical Clinic and Policlinic II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 17Chair of Experimental Genetics, 
TUM School of Life Sciences, Technical University of Munich, Freising, Germany. 18German Center for Diabetes Research (DZD), Neuherberg, Germany.


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19Computational Mass Spectrometry, Technical University of Munich, Freising, Germany. 20University Medical Center Göttingen, Department of  
General, Visceral and Pediatric Surgery, Göttingen, Germany. 21These authors contributed equally: Piero Giansanti, Patroklos Samaras, Yangyang Bian. 
✉e-mail: kuster@tum.de
T
he mouse is arguably among the most important mamma-
lian model systems for basic, translational and biomedical 
research1. The initial sequencing of the mouse genome in 
2002 as well as systematic transcriptome analyses of mouse tissues 
in 2004 marked important milestones as these provided impor-
tant informational tools to better understand the human genome 
and human (patho-)physiology2,3. As most biological processes are 
controlled by proteins and their posttranslational modifications 
(PTMs), adding a proteomic dimension is a logical consequence. An 
initial analysis of 28 mouse tissues provided evidence for roughly 
7,300 proteins and an earlier phosphoproteomic investigation iden-
tified roughly 36,000 phosphorylation sites (p-sites) in nine tis-
sues4,5. Here, we substantially extend these efforts by analyzing the 
proteomes and phosphoproteomes of 41 adult tissues of C57BL/6N 
mice covering 15 major anatomical systems and 66 KrasG12D pancre-
atic ductal adenocarcinoma (PDAC) cell lines using a quantitative 
mass spectrometry (MS)-based approach (Fig. 1a).
Results
A high-quality map of the mouse proteome. Following state-of- 
the-art protocols for protein identification and error propaga-
tion control (Methods), we identified 17,883 proteins (17,771 
and 12,971 from tissues and cell lines, respectively) representing 
16,995 of the 22,437 protein-coding genes annotated in UniProtKB  
(Fig. 1b and Supplementary Table 1). The phosphoproteomes  
(Fig. 1c,d and Supplementary Table 2) covered 40,562 and 22,113 
Mass spectrometry-based draft of the mouse 
proteome
Piero Giansanti   1,21, Patroklos Samaras   1,21, Yangyang Bian   1,2,21, Chen Meng3, Andrea Coluccio4,5,6,7,


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Martin Frejno   1, Hannah Jakubowsky4,5,6,7, Sophie Dobiasch8,9,10,11, Rashmi R. Hazarika12,13, 
Julia Rechenberger   1, Julia Calzada-Wack14, Johannes Krumm1, Sebastian Mueller6,7,15, 
Chien-Yun Lee   1, Nicole Wimberger   4,5,6,7, Ludwig Lautenbacher   1, Zonera Hassan16, 
Yun-Chien Chang1, Chiara Falcomatà4,5,6,7, Florian P. Bayer1, Stefanie Bärthel   4,5,6,7, Tobias Schmidt   1,  
Roland Rad4,6,7,15, Stephanie E. Combs8,9,10,11, Matthew The1, Frank Johannes12,13, Dieter Saur   4,5,6,7,  
Martin Hrabe de Angelis   14,17,18, Mathias Wilhelm   1,19, Günter Schneider   16,20 and 
Bernhard Kuster   1,3,10,11,13 ✉
The laboratory mouse ranks among the most important experimental systems for biomedical research and molecular refer-
ence maps of such models are essential informational tools. Here, we present a quantitative draft of the mouse proteome and 
phosphoproteome constructed from 41 healthy tissues and several lines of analyses exemplify which insights can be gleaned 
from the data. For instance, tissue- and cell-type resolved profiles provide protein evidence for the expression of 17,000 genes, 
thousands of isoforms and 50,000 phosphorylation sites in vivo. Proteogenomic comparison of mouse, human and Arabidopsis 
reveal common and distinct mechanisms of gene expression regulation and, despite many similarities, numerous differentially 
abundant orthologs that likely serve species-specific functions. We leverage the mouse proteome by integrating phenotypic 
drug (n > 400) and radiation response data with the proteomes of 66 pancreatic ductal adenocarcinoma (PDAC) cell lines 
to reveal molecular markers for sensitivity and resistance. This unique atlas complements other molecular resources for the 
mouse and can be explored online via ProteomicsDB and PACiFIC.
NATuRE METHoDS | www.nature.com/naturemethods


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Nature | www.nature.com | 1
Article
Mass-spectrometry-based draft of the 
Arabidopsis proteome
Julia Mergner1, Martin Frejno1, Markus List2, Michael Papacek3, Xia Chen4, Ajeet Chaudhary4, 
Patroklos Samaras1, Sandra Richter5, Hiromasa Shikata6,7, Maxim Messerer8, Daniel Lang8, 
Stefan Altmann9, Philipp Cyprys10, Daniel P. Zolg1, Toby Mathieson11, Marcus Bantscheff11, 
Rashmi R. Hazarika12,13, Tobias Schmidt1, Corinna Dawid14, Andreas Dunkel14,  
Thomas Hofmann14, Stefanie Sprunck10, Pascal Falter-Braun9,15, Frank Johannes12,13,  
Klaus F. X. Mayer8,16, Gerd Jürgens5, Mathias Wilhelm1, Jan Baumbach2, Erwin Grill3,  
Kay Schneitz4, Claus Schwechheimer6 & Bernhard Kuster1,13,17 ✉
Plants are essential for life and are extremely diverse organisms with unique 
molecular capabilities1. Here we present a quantitative atlas of the transcriptomes, 
proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis 
thaliana. Our analysis provides initial answers to how many genes exist as proteins 
(more than 18,000), where they are expressed, in which approximate quantities  
(a dynamic range of more than six orders of magnitude) and to what extent they are 
phosphorylated (over 43,000 sites). We present examples of how the data may be 
used, such as to discover proteins that are translated from short open-reading frames, 
to uncover sequence motifs that are involved in the regulation of protein production, 
and to identify tissue-specific protein complexes or phosphorylation-mediated 
signalling events. Interactive access to this resource for the plant community is 
provided by the ProteomicsDB and ATHENA databases, which include powerful 
bioinformatics tools to explore and characterize Arabidopsis proteins, their 
modifications and interactions.
The plant model organism A. thaliana has revolutionized our under-
standing of plant biology and influenced many other areas of the life 
sciences1. Knowledge derived from Arabidopsis has also provided mech-


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anistic understanding of important agronomic traits in crop species2. 
The Arabidopsis genome was sequenced 20 years ago, and hundreds of 
natural variants have since been analysed at the genome and epigenome 
level3,4. By contrast, the Arabidopsis proteome as the main executer of 
most biological processes is far less comprehensively characterized. To 
address this gap, we used state-of-the-art mass spectrometry and RNA 
sequencing (RNA-seq) analyses to provide the first, to our knowledge, 
integrated proteomic, phosphoproteomic and transcriptomic atlas of 
Arabidopsis. We use select examples to show how this rich molecular 
resource can be used to explore the function of single proteins or entire 
pathways across several omics levels.
Multi-omics atlas of Arabidopsis
We generated an expression atlas covering, on average, 17,603 ± 1,317 
(mean ± s.d.) transcripts, 14,430 ± 911 proteins and 14,689 ± 2,509 
phosphorylation sites (P-sites) per tissue, using a reproducible bio-
chemical and analytical approach (Fig. 1a, b, Extended Data Fig. 1a–c, 
Supplementary Data 1, 2). In total, the protein abundance data cover 
18,210 out of the 27,655 protein-coding genes (66%) annotated in Ara-
port115. This is a substantial increase compared with the percentage of 
genes with evidence at the protein level reported in UniProt (27%)6, and 
more than double the number of proteins identified in an earlier tissue 
proteome analysis7 (Fig. 1c, Extended Data Fig. 1d–f). In addition, we 
report tissue-resolved quantitative evidence for a total of 43,903 P-sites, 
making this study one of the most comprehensive single Arabidopsis 
phosphoproteomes published so far (Fig. 1c). We found that 47% of the 
expressed proteome was phosphorylated in at least one instance, con-
firming earlier analyses of individual phosphoproteomes or informa-
tion assembled in the PhosPhAT database8,9 (Extended Data Fig. 1g, h).  
The actual figures in plantae are likely to be considerably higher as


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there is limited overlap between these data sources. This can be readily 
explained by technical factors (such as insufficient sequence cover-
age) and, more importantly, differences in plant genotypes or stimuli 
that influence phosphorylation. The above figures are similar to those 
https://doi.org/10.1038/s41586-020-2094-2
Received: 4 June 2019
Accepted: 17 January 2020
Published online: xx xx xxxx
 Check for updates
1Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM), Freising, Germany. 2Chair of Experimental Bioinformatics, Technical University of Munich (TUM), Freising, Germany. 
3Chair of Botany, Technical University of Munich (TUM), Freising, Germany. 4Plant Developmental Biology, Technical University of Munich (TUM), Freising, Germany. 5Center for Plant Molecular 
Biology, University of Tübingen, Tübingen, Germany. 6Chair of Plant Systems Biology, Technical University of Munich (TUM), Freising, Germany. 7Devision of Plant Environmental Responses, 
National Institute for Basic Biology, Okazaki, Japan. 8Plant Genome and Systems Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Munich-Neuherberg, 
Germany. 9Institute of Network Biology (INET), Helmholtz Center Munich, German Research Center for Environmental Health, Munich-Neuherberg, Germany. 10Cell Biology and Plant 
Biochemistry, University of Regensburg, Regensburg, Germany. 11Cellzome GmbH, Heidelberg, Germany. 12Population Epigenetics and Epigenomics, Technical University of Munich (TUM), 
Freising, Germany. 13Institute of Advanced Study (IAS), Technical University of Munich (TUM), Freising, Germany. 14Chair of Food Chemistry and Molecular Sensory Science, Technical University 
of Munich (TUM), Freising, Germany. 15Chair of Microbe-Host Interactions, Ludwigs-Maximilians-University (LMU), Munich, Germany. 16Plant Genome Biology, Technical University of Munich


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(TUM), Freising, Germany. 17Bavarian Biomolecular Mass Spectrometry Center (BayBioMS), Technical University of Munich (TUM), Freising, Germany. ✉e-mail: kuster@tum.de


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ARTICLE
doi:10.1038/nature13319
Mass-spectrometry-based draft of the
human proteome
Mathias Wilhelm1,2*, Judith Schlegl2*, Hannes Hahne1*, Amin Moghaddas Gholami1*, Marcus Lieberenz2, Mikhail M. Savitski3,
Emanuel Ziegler2, Lars Butzmann2, Siegfried Gessulat2, Harald Marx1, Toby Mathieson3, Simone Lemeer1, Karsten Schnatbaum4,
Ulf Reimer4, Holger Wenschuh4, Martin Mollenhauer5, Julia Slotta-Huspenina5, Joos-Hendrik Boese2, Marcus Bantscheff3,
Anja Gerstmair2, Franz Faerber2 & Bernhard Kuster1,6
Proteomesarecharacterized bylarge protein-abundancedifferences, cell-type- and time-dependentexpression patterns
and post-translational modifications, all of which carry biological information that is not accessible by genomics or tran-
scriptomics. Here we present a mass-spectrometry-based draft of the human proteome and a public, high-performance,
in-memory database for real-time analysis of terabytes of big data, called ProteomicsDB. The information assembled from
humantissues,celllinesandbodyfluidsenabledestimationofthesizeoftheprotein-coding genome, andidentifiedorgan-
specific proteins and a large number of translated lincRNAs (long intergenic non-coding RNAs). Analysis of messenger
RNA and protein-expression profiles ofhuman tissues revealedconserved controlofproteinabundance, and integrationof
drug-sensitivity data enabled the identification of proteins predicting resistance or sensitivity. The proteome profiles also
hold considerable promise for analysing the composition and stoichiometry of protein complexes. ProteomicsDB thus
enables navigation of proteomes, provides biological insight and fosters the development of proteomic technology.
Thelarge-scaleinterrogationofbiologicalsystemsbymass-spectrometry-
based proteomics provides insights into protein abundance, cell-type
and time-dependent expression patterns, post-translational modifica-
tions (PTMs) and protein–protein interactions, all of which carry bio-
logicalinformationthatisbest investigated attheproteinlevel.Perhaps


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surprisingly,itisstillnotclearwhichofthe19,629humangenesannotated
in Swiss-Prot1 (20,493 in UniProt) are translated into proteins. Therefore,
major efforts are underway to identify these genes, including the Human
ProteomeProject(HPP),whichaimstobroadlycharacterizethehuman
proteome, the Human Protein Atlas project (HPA), which seeks to gen-
erate antibodiesfor allhuman proteins, and theProteomeXchange con-
sortium,whichfacilitates thegatheringandsharingofproteomic data2–4.
Despite the fact that a plethora of individual human proteomic studies
exist, only a few systematic efforts to assemble and characterize human
proteomeshave beenreported so far5,6. In part this is because most pro-
teomic data do not reside in public repositories, proteomic data annota-
tion is often sketchy, and the data generation and processing platforms
are of varying capability, performance and maturity. Importantly, there
is alsoa notable challenge in making ‘big data’ (that is, large amounts of
data that are difficult or impossible to process using traditional techno-
logyandalgorithms)morewidelyaccessibletothescientificcommunity,
because the development of scalable analysis tools is only in its infancy.
Assembly of the proteome in ProteomicsDB
Here we present a draft of the human proteome assembled using data
from 16,857 liquid chromatography tandem-mass-spectrometry (LC-
MS/MS) experiments involving human tissues, cell lines, body fluids,
aswellasdatafromPTMstudiesandaffinitypurifications.Wealsopres-
enttheanalysisoftheassembleddata,inProteomicsDB,anin-memory
database designed for the real-time analysis of big data (https://www.
proteomicsdb.org).Forthisstudy (Fig. 1a), wecombined dataavailable
fromrepositoriesandotherwisecontributedbycolleagues(60%oftotal)
with published as well as new data from the authors’ laboratories (40%
of total; Supplementary Table 1 and Supplementary Information). To
maximize proteome coverage, we reprocessed all experiments using
MaxQuant7 and Mascot8, and the resulting 1.1-billion peptide spec-


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trummatches(PSMs)wereimportedintoProteomicsDB.Thedatabase
(Fig. 1b) comprisesa publicrepository, a webinterface featuring several
data views and analysis tools, and an application programming inter-
face (API). At the heart of ProteomicsDB is an ‘in-memory’ computa-
tionalresourcecommanding2terabytes(TB)ofrandomaccessmemory
(RAM)and160centralprocessorunits(CPUs),whichenablesthestorage
of alldata in the main memory,all of the time. This makes computational
tasks very efficient, illustrated by the capability to display and annotate
any of the approximately 71-million currently identified peptide-mass
spectra in real time (Extended Data Fig. 1). Controlling the quality of
peptide and protein identifications is important but exactly how this is
best accomplished is still debated in the community9,10. For the current
assemblyoftheproteome,wereliedonhighresolutionmass-spectrometry
datatokeepfalseidentificationslow.Weappliedatwo-stepfilteringprocess,
firstbycontrollingthefalsediscoveryrate(FDR)at1%forPSMsgenerated
by each LC-MS/MS experiment using a global target-decoy approach11.
Peptide identifications then had to pass a length-dependent Mascot or
Andromedascorethresholdof5%localFDRonthetotalaggregateddata
and we categorically rejected all peptides shorter than seven amino acids
(Extended Data Figs 1 and 2, and Supplementary Information). Com-
parison to 27 published studies shows thatthisschemeisinlinewith the
often-used 1% protein FDR criterion (Supplementary Table 1) and avoids
the unsolved issue of artificially high protein FDRs when analysing large
data sets12 (Extended Data Fig. 2 and Supplementary Information).
Proteomic annotation of the genome
At the time of writing, ProteomicsDB held protein evidence for 18,097
of the 19,629 human genes annotated in Swiss-Prot (92%) as well as
*These authors contributed equally to this work.


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1Chair of Proteomics and Bioanalytics, Technische Universita¨t Mu¨nchen, Emil-Erlenmeyer Forum 5, 85354 Freising, Germany. 2SAP AG, Dietmar-Hopp-Allee 16, 69190 Walldorf, Germany. 3Cellzome
GmbH, Meyerhofstraße 1, 69117 Heidelberg, Germany. 4JPT Peptide Technologies GmbH, Volmerstraße 5, 12489 Berlin, Germany. 5Institute of Pathology, Technische Universita¨t Mu¨nchen, Trogerstraße
18, 81675 Mu¨nchen, Germany. 6Center for Integrated Protein Science Munich, Germany.
5 8 2 |
N A T U R E
| V O L 5 0 9
| 2 9
M A Y 2 0 1 4
©2014 Macmillan Publishers Limited. All rights reserved


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Resource
Multilayered omics reveal sex- and depot-dependent
adipose progenitor cell heterogeneity
Graphical abstract
Highlights
d Integrated multilayer omics reveal molecular heterogeneity of
adipose progenitors
d Proteomic analysis highlights metabolic heterogeneity of
adipose progenitors
d PPARg phosphorylation underlies sex differences in iWAT
APC differentiation
d Glutathione metabolism and AhR signaling regulate
progenitor cell fate and function
Authors
Bo Shan, Clive S. Barker, Mengle Shao,
Qianbin Zhang, Rana K. Gupta,
Yibo Wu
Correspondence
rana.gupta@utsouthwestern.edu
(R.K.G.),
wulabproteomics@gmail.com (Y.W.)
In brief
Adipose tissue harbors functionally
distinct progenitor cell subpopulations.
Shan et al. utilize multilayered omics to
dissect adipose progenitor cell
heterogeneity in three dimensions:
progenitor subpopulation, sex, and
anatomical localization. Functional
analysis unveils mechanisms underlying
sex differences in preadipocyte activation
and pathways controlling the adipogenic
and pro-inﬂammatory properties of
distinct progenitor subpopulations.
Shan et al., 2022, Cell Metabolism 34, 783–799
May 3, 2022 ª 2022 The Authors. Published by Elsevier Inc.
https://doi.org/10.1016/j.cmet.2022.03.012
ll


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science.sciencemag.org/content/365/6450/eaaw7317/suppl/DC1 
 
 
 
 
 
 
 
Supplementary Materials for 
 
Conservation, acquisition, and functional impact of sex-biased gene 
expression in mammals 
 
Sahin Naqvi, Alexander K. Godfrey, Jennifer F. Hughes, Mary L. Goodheart,  
Richard N. Mitchell, David C. Page* 
 
*Corresponding author. Email: dcpage@wi.mit.edu 
 
Published 19 July 2019, Science 365, eaaw7317 (2019)  
DOI: 10.1126/science.aaw7317 
 
This PDF file includes: 
 
Materials and Methods 
Figs. S1 to S26 
Tables S3 and S8 
Captions for Tables S1, S2, S4 to S7, and S9


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Molecular and cellular mechanisms of dopamine-mediated behavioral
plasticity in the striatum
Milica Cerovic a, Raffaele d’Isa b, Raffaella Tonini c, Riccardo Brambilla b,⇑
a School of Biosciences, Cardiff University, CF10 3AX Cardiff, UK
b Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientiﬁc Institute and University, 20132 Milano, Italy
c Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, 16163 Genova, Italy
a r t i c l e
i n f o
Article history:
Available online xxxx
Keywords:
Striatum
Nucleus accumbens
Basal ganglia
Long-term potentiation
Long-term depression
Instrumental learning
L-DOPA induced dyskinesia
Drug addiction
Ras–ERK signaling
Endocannabinoids
a b s t r a c t
The striatum is the input structure of the basal ganglia system. By integrating glutamatergic signals from
cortical and subcortical regions and dopaminergic signals from mesolimbic nuclei the striatum functions
as an important neural substrate for procedural and motor learning as well as for reward-guided behav-
iors. In addition, striatal activity is signiﬁcantly altered in pathological conditions in which either a loss of
dopamine innervation (Parkinson’s disease) or aberrant dopamine-mediated signaling (drug addiction
and L-DOPA induced dyskinesia) occurs. Here we discuss cellular mechanisms of striatal synaptic plastic-
ity and aspects of cell signaling underlying striatum-dependent behavior, with a major focus on the neu-
romodulatory action of the endocannabinoid system and on the role of the Ras–ERK cascade.
 2013 Elsevier Inc. All rights reserved.
1. Introduction
Amongst brain regions involved in cognitive processing, the
dorsal striatum and its ventral extension, the nucleus accumbens,
have been implicated in a variety of processes in experimental ani-
mal models, including motor control, instrumental learning and
habit formation, reward and drug addiction. Importantly, current
views maintain that within the same striatal sub-regions speciﬁc


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signaling cascades may simultaneously control distinct (but possi-
bly overlapping) gene expression programs resulting from differ-
ent forms of learning, including stimulus–response (S–R) and
drug of abuse related behaviors. At the same time, it has become
clear that a derangement of these molecular mechanisms may oc-
cur at the striatal level in neurological conditions in which either
dopamine (DA) is lost, like in Parkinson’s Disease (PD), or made
available through pharmacotherapy with the dopamine precursor
L-DOPA or related dopaminergic agonists whose chronic use al-
most invariably result in aberrant adaptations. Considering the
central role of the striatum in the control of movement and some
aspects of cognition it is not surprising that aberrant modulation
of striatal function is a critical aspect in a number of pathologies
besides PD, including L-Dopa induced dyskinesia (LID), Hunting-
ton’s disease (HD), drug abuse, obsessive compulsive disorder, Tou-
rette’s syndrome and schizophrenia.
Importantly, synaptic plasticity mechanisms in different re-
gions of the striatum, including long-term potentiation (LTP) and
depression (LTD), as well as depotentiation, are interesting cellular
models of striatal function and dysfunction and may provide a link
between cellular and system events.
In this review, we will ﬁrst describe how normal and patholog-
ical synaptic plasticity occurs in the striatum and then we will fo-
cus
on
speciﬁc molecular
mechanisms
controlling striatum-
dependent behavior.
2. Striatal organization and function
The striatum is a heterogeneous structure that can be subdi-
vided at different levels. The major division is in the dorsal and
ventral portions. Dorsal striatum (DS) in primates is composed of
the caudate–putamen complex, while in rodents this region is
functionally divided into medial and lateral dorsal striatum. The
ventral part is referred to as nucleus accumbens (NAc) that may
be further divided into core and shell. All these sub-regions have


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similar histological appearance and no sharp anatomical borders
are present. Thus, their distinct functions may arise from speciﬁc
connections to different brain structures. From the neurochemical
point of view, the NAc receives its major glutamatergic excitatory
1074-7427/$ - see front matter  2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.nlm.2013.06.013
⇑ Corresponding author.
E-mail address: brambilla.riccardo@hsr.it (R. Brambilla).
Neurobiology of Learning and Memory xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Neurobiology of Learning and Memory
journal homepage: www.elsevier.com/locate/ynlme
Please cite this article in press as: Cerovic, M., et al. Molecular and cellular mechanisms of dopamine-mediated behavioral plasticity in the striatum. Neu-
robiology of Learning and Memory (2013), http://dx.doi.org/10.1016/j.nlm.2013.06.013


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Multi-omics analysis reveals changes in tryptophan and cholesterol metabolism before and after sexual maturation in captive macaques


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Liu et al. BMC Genomics          (2023) 24:308  
https://doi.org/10.1186/s12864-023-09404-3
RESEARCH
Open Access
© The Author(s) 2023. Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which 
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the 
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or 
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line 
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory 
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this 
licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco 
mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
BMC Genomics
Multi-omics analysis reveals changes 
in tryptophan and cholesterol metabolism 
before and after sexual maturation in captive 
macaques
Xu Liu1, Xuyuan Liu2, Xinqi Wang2, Ke Shang1, Jiawei Li1, Yue Lan1, Jiao Wang2, Jing Li1, Bisong Yue1,2, 
Miao He3* and Zhenxin Fan1* 
Abstract 
Rhesus macaques (Macaca mulatta, RMs) are widely used in sexual maturation studies due to their high genetic and 
physiological similarity to humans. However, judging sexual maturity in captive RMs based on blood physiological 
indicators, female menstruation, and male ejaculation behavior can be inaccurate. Here, we explored changes 
in RMs before and after sexual maturation based on multi-omics analysis and identified markers for determining


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sexual maturity. We found that differentially expressed microbiota, metabolites, and genes before and after sexual 
maturation showed many potential correlations. Specifically, genes involved in spermatogenesis (TSSK2, HSP90AA1, 
SOX5, SPAG16, and SPATC1) were up-regulated in male macaques, and significant changes in gene (CD36), metabolites 
(cholesterol, 7-ketolithocholic acid, and 12-ketolithocholic acid), and microbiota (Lactobacillus) related to cholesterol 
metabolism were also found, suggesting the sexually mature males have stronger sperm fertility and cholesterol 
metabolism compared to sexually immature males. In female macaques, most differences before and after sexual 
maturity were related to tryptophan metabolism, including changes in IDO1, IDO2, IFNGR2, IL1Β, IL10, L-tryptophan, 
kynurenic acid (KA), indole-3-acetic acid (IAA), indoleacetaldehyde, and Bifidobacteria, indicating that sexually mature 
females exhibit stronger neuromodulation and intestinal immunity than sexually immature females. Cholesterol 
metabolism-related changes (CD36, 7-ketolithocholic acid, 12-ketolithocholic acid) were also observed in female and 
male macaques. Exploring differences before and after sexual maturation through multi-omics, we identified potential 
biomarkers of sexual maturity in RMs, including Lactobacillus (for males) and Bifidobacterium (for females) valuable for 
RM breeding and sexual maturation research.
Keywords Rhesus macaques, Sexual maturity, Multi-omics, Gut microbiome, Blood transcriptome and metabolome
*Correspondence:
Miao He
hemiao@ibt.pumc.edu.cn
Zhenxin Fan
zxfan@scu.edu.cn
Full list of author information is available at the end of the article


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REVIEW
published: 08 October 2015
doi: 10.3389/fnsys.2015.00138
Frontiers in Systems Neuroscience | www.frontiersin.org
1
October 2015 | Volume 9 | Article 138
Edited by:
Lili-Naz Hazrati,
University of Toronto, Canada
Reviewed by:
Fahad Sultan,
University Tübingen, Germany
Krystal Lynn Parker,
University of Iowa, USA
Iman Kamali Sarvestani,
University of Toronto, Canada
*Correspondence:
Oury Monchi,
Health Science Center, Hotchkiss
Brain Institute, University of Calgary,
Room 2915, 3330 Hospital DR NW,
Calgary T2N 1N4, AB, Canada
oury.monchi@ucalgary.ca
†These authors have contributed
equally to this manuscript.
Received: 05 May 2015
Accepted: 22 September 2015
Published: 08 October 2015
Citation:
Hanganu A, Provost J-S and
Monchi O (2015) Neuroimaging
studies of striatum in cognition part II:
Parkinson’s disease.
Front. Syst. Neurosci. 9:138.
doi: 10.3389/fnsys.2015.00138
Neuroimaging studies of striatum in
cognition part II: Parkinson’s disease
Alexandru Hanganu 1, 2, 3 †, Jean-Sebastien Provost 3, 4 and Oury Monchi 1, 2, 3* †
1 Department of Clinical Neurosciences and Department of Radiology, Cumming School of Medicine, University of Calgary,
Calgary, AB, Canada, 2 Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada, 3 Centre de Recherche de
l’Institut Universitaire de Gériatrie de Montréal, Université de Montréal, Montréal, QC, Canada, 4 Department of Psychology,
Faculty of Arts and Sciences, University of Montreal, Montreal, QC, Canada
In recent years a gradual shift in the deﬁnition of Parkinson’s disease (PD) has
been established, from a classical akinetic-rigid movement disorder to a multi-system
neurodegenerative disease. While the pathophysiology of PD is complex and goes much
beyond the nigro-striatal degeneration, the striatum has been shown to be responsible
for many cognitive functions. Patients with PD develop impairments in multiple cognitive
domains and the PD model is probably the most extensively studied regarding striatum


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dysfunction and its inﬂuence on cognition. Up to 40% of PD patients present cognitive
impairment even in the early stages of disease development. Thus, understanding the
key patterns of striatum and connecting regions’ inﬂuence on cognition will help develop
more speciﬁc approaches to alleviate cognitive impairment and slow down its decline.
This review focuses on the contribution of neuroimaging studies in understanding how
striatum impairment affects cognition in PD.
Keywords: striatum, cognition, Parkinson’s disease, neuroimaging, dopamine
Introduction
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that aﬀects up to 2% of
individuals aged 65 years and older (Rijk et al., 1997) and has an incidence of 14 per 100,000
individuals (Hirtz et al., 2007). In people over 70 years the incidence is much higher—160 per
100,000 individuals (Hirtz et al., 2007), and aﬀects nearly 10% of people older than 80 years (von
Campenhausen et al., 2005). Furthermore, the prevalence of PD is expected to double by 2030
(Dorsey et al., 2007). While PD is associated with a complex pathophysiology that can potentially
aﬀect most of the brain, the motor cardinal symptoms of PD are largely due to degeneration of
dopamine (DA) neurons in the substantia nigra pars compacta (Albin et al., 1989). This pattern of
neurodegeneration starts from dorsal striatum and extends to more ventral parts of the striatum as
the disease progresses (Kish et al., 1988).
Since the second part of the 1980’s it is becoming increasingly clear that cognitive deﬁcits can
be present even at the early stages of PD (Taylor et al., 1986; Taylor and Saint-Cyr, 1995; Dubois
and Pillon, 1996). Initial investigations in mild to moderately aﬀected PD patients emphasized
deﬁcits in executive functions (e.g., planning and set-shifting), which resemble those found in
patients with frontal lobe damage (Taylor et al., 1986; Owen et al., 1990, 1992). These are consistent


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with the fronto-striatal dysfunction occurring in PD reported by our group and many others.
However, non-frontal cognitive deﬁcits including visuospatial and language function diﬃculties
are also recognized in early-PD patients and at various stages of disease progression. In the context
of this review we concentrate on the cognitive deﬁcits that are most likely to originate from the


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Sexual Dimorphism in Cardiovascular Biomarkers: Clinical and 
Research Implications
Emily S. Lau, MD, MPH1, Aleksandra Binek, PhD2, Sarah J. Parker, PhD, MS2, Svati H. Shah, 
MD, MS, MHS3, Markella V. Zanni, MD4, Jennifer E Van Eyk, PhD2, Jennifer E. Ho, MD5
1Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
2Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
3Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA
4Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital, Boston, 
Massachusetts, USA
5Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, 
Massachusetts, USA
Abstract
Sex-based differences in cardiovascular disease (CVD) presentation, diagnosis, and response 
to therapies are well established, but mechanistic understanding and translation to clinical 
applications are limited. Blood-based biomarkers have become an important tool for interrogating 
biologic pathways. Understanding sexual dimorphism in the relationship between biomarkers and 
CVD will enhance our insights into CVD pathogenesis in women, with potential to translate 
to improved individualized care for men and women with or at risk for CVD. In this review, 
we examine how biologic sex associates with differential levels of blood-based biomarkers and 
influences the effect of biomarkers on disease outcomes. We further summarize key differences 
in blood-based cardiovascular biomarkers along central biologic pathways, including myocardial 
stretch/injury, inflammation, adipose tissue metabolism, and fibrosis pathways in men vs women. 
Finally, we present recommendations for leveraging our current knowledge of sex differences in 
blood-based biomarkers for future research and clinical innovation.
Keywords
Biomarkers; Cardiovascular Disease; Women; Sex; Gender
INTRODUCTION
Sex-related differences in cardiovascular disease (CVD) risk, pathophysiology, disease


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presentation, response to therapy, and prognosis have been well characterized, but 
mechanistic understanding and implications for clinical practice are incompletely 
Correspondence to: Jennifer E. Ho, MD, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, E/CLS 945, Boston, MA 
02215-5491, Phone: 617-735-4102, Fax: 617-735-4207, jho@bidmc.harvard.edu. 
HHS Public Access
Author manuscript
Circ Res. Author manuscript; available in PMC 2023 February 18.
Published in final edited form as:
Circ Res. 2022 February 18; 130(4): 578–592. doi:10.1161/CIRCRESAHA.121.319916.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Neuroendocrine Asymmetry
Ida Gerendai and Be´la Hala´sz
Neuroendocrine Research Laboratory, Department of Human Morphology and Developmental
Biology, Semmelweis University of Medicine, Budapest, Hungary
The information available at present clearly indicates that asymmetry exists from the
level of elementary particles to the human cerebral cortex, the latest stage of evolution.
Cerebral lateralization is one of the well-known asymmetries. This paper summarizes
the data published in the past decades on the asymmetry of the neuroendocrine system.
The information on the sided-differences between the gonads, adrenals, and thyroid lobes
and that on the lateralization of hypothalamic, limbic, and other brain structures
participating in the control of the endocrine glands as well as relevant clinical observa-
tions are reviewed here. The innervation of the peripheral endocrine glands is also brieﬂy
summarized because the afferent and efferent ﬁbers of these glands may represent one
part of the pathway involved in neuroendocrine asymmetry. The data reviewed clearly
indicate that some kind of asymmetry (morphological, biochemical, physiological, patho-
logical) is evident at different levels of the neuroendocrine system (at limbic, hypotha-
lamic, peripheral endocrine glands and their innervation) and there are species, sex, and
age differences. Most of the information accumulated deals with the CNS–gonadal
system. A majority of the observations suggest that in both male and female rats there is
a predominance of the right half of brain structures controlling gonadal function. The
asymmetry, however, is not restricted to CNS structures: it also exists at the level of the
gonads, including their innervation. It appears that the characteristic pattern of the
CNS–gonadal system becomes ﬁxed only after sexual maturation. Very few reports are
available suggesting some kind of asymmetry of the CNS–adrenal cortex and the
CNS–thyroid system. There are convincing ﬁndings consistent with the view that in


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addition to the hypothalamo-adenohypophyseal system acting via the general circulation
on the peripheral endocrine glands, there is also a pure neural link between the CNS and
the gonads, the CNS and the adrenal gland, and also between the CNS and the thyroid.
This link contains afferent and efferent pathways and is able to modulate the functional
activity or the responsiveness of the gland. It may also serve as a neural reﬂex arc. It is
assumed that the neuroendocrine asymmetry expresses itself through (i) hypophysiotro-
phic neurohormones and hormones of the peripheral endocrine glands, (ii) neural
pathways, or (iii) a combination of (i) and (ii). The authors hope that this publication, in
addition to providing an overview, will also stimulate research, both basic and clinical, in
this exciting area of neuroendocrinology. KEY WORDS: asymmetry; hypothalamus; limbic
system; neuroendocrine; endocrine glands; innervation.
r 1997 Academic Press
HISTORICAL INTRODUCTION
The ﬁrst evidence for cerebral asymmetry was provided by Paul Broca in
1861 (16). He reported that disturbance of language function called aphasia
Address correspondence and reprint requests to Be´la Hala´sz, Department of Human Morphol-
ogy, Tu¨zolto´ u.58., H-1094 Budapest, Hungary, Telephone: (36-1) 215-5847, Fax: (36-1) 215-3064.
FRONTIERS IN NEUROENDOCRINOLOGY 18, 354–381 (1997)
ARTICLE NO. FN970154
354
0091-3022/97 $25.00
Copyright r 1997 by Academic Press
All rights of reproduction in any form reserved.


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Neurofilament and neural cell adhesion molecule immunocytochemistry of Huntington's disease striatum


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Newoflament and Neural Cell 
Adhesion Mo1ecul.e Immunocytochemistry 
of Huntington’s Disease Striatum 
Kuninobu Nihei, MD, PhD, and Neil W. Kowall, MD 
~ 
We examined normal and Huntington’s disease (HI)) human striatum with specific monoclonal antibodies to nonphos- 
phorylated (SMI 32) and phosphorylated (SMI 31) neurofilament and neural cell adhesion molecule (NCAM). SMI 32 
identifies medium-sized neuronal perikarya and dendrites in normal striatum. Axons are not immunoreactive. In 
high-grade HD striatum (grades 3 and 4) SMI 32 neurons are morphologically abnormal and significantly depleted. 
Dendritic arbors are intensely immunoreactive, tortuous, and fragmented, especially in the subependymal zone. Prolif- 
erative SMI 32-positive sprout-like structures and axon-like processes are seen. SMI 31 normally stains a fine meshwork 
of axon-like processes that become intensely immunoreactive, condensed, convoluted, and fragmented in HD. NCAM 
staining is minimal in normal striatum, but, in HD striatum, many dot- and thread-like structures are found, especially 
in the subependymal region. The abnormalities revealed by SMI 31, SMI 32, and NCAM suggest that neurofilament 
phosphorylation is altered and growth related proteins are reexpressed in HD. Dephosphorylation and destabilization 
of the cytoskeleton may contribute to neuronal inlury and death in HD. 
Nihei K, Kowall NW. Neurofilament and neural cell adhesion molecule ~mmunocytochemistry of 
Huntington’s disease striatum Ann Neurol 1992,3 1 59-63 
Huntington’s disease (HD) is a hereditary disorder 
characterized pathologically by depletion of specific 
neuronal subsets in the striatum, cortex, and hypothala- 
mus [l-51. Local circuit neurons without spines resist 
degeneration in the striatum and cortex, whereas spiny 
projection neurons show early evidence of degenera- 
tion. Graveland and colleagues 161 used a rapid Golgi 
impregnation procedure to demonstrate a range of 
morphological changes affecting the dendritic tree of


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spiny striatal neurons in HD. Dendritic pruning, spine 
loss, and bizarre proliferative changes occur, suggesting 
that abortive regeneration may occur in tandem with 
degeneration in HD. Recently, Ferrante and associates 
[ 7) used section-Golgi and calbindin immunocyto- 
chemical methods to identify spiny neurons and to 
show that proliferative dendritic changes may be an 
early feature of HD striatum preceding dendritic prun- 
ing and neuronal loss. 
The neuronal cytoskeleton has a critical role in the 
development and maintenance of neuronal morphol- 
ogy. Alterations of neuronal morphology in HD associ- 
ated with selective patterns of neuronal degeneration 
may therefore be associated with specific alterations 
in the neuronal cytoskeleton. Specific cytoskeletal 
changes may be associated with both degenerative and 
proliferative changes in HD, as has been shown in Alz- 
heimer’s disease (AD) CS, 91. 
In AD, proliferative dendritic changes occur in con- 
junction with neuronal loss and reorganization of the 
neuronal cytoskeleton 181. As in HD, a subset of pyra- 
midal projection neurons enriched in neurofilament 
immunoreactivity degenerates [lo}. Selective loss of 
projection neurons in AD is associated with sprouting 
of remaining axonal terminals that occupy vacated syn- 
aptic sites. This progression is well illustrated by the 
reorganization of synaptic terminals in the molecular 
layer of the dentate gyms in AD. Selective depletion 
of layer I1 entorhinal stellate neurons that project to 
the dentate gyrus is associated with proliferation of 
local peptidergic and acetylcholinesterase-positive axon 
terminals, along with increased immunoreactivity for 
the axonal growth-cone marker, neural cell adhesion 
molecule (NCAM) [ll-141. 
In this study, we chose specific markers for post- 
translational isoforms of 
neurofilament 
and the 
growth-cone marker NCAM to examine patterns of 
cytoskeletal protein alteration and axonal proliferation 
in HD striatum. The antibody designated SMI 32 rec-


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ognizes a phosphatase-resistant epitope in the heavy 
and medium neurofilament polypeptides that are pri- 
From the Experimental Neuropdrhology Laboratory and Neurology 
Service, Massachusetts General Hospital, Boston, MA. 
Received Mar 18, 1991, and in revised form Jun 5. Accepted for 
publication Jun 7, 1991. 
Address correspondence to Dr Kowall, Neurology Service, Massa- 
chusetts General Hospital, Boston, MA 02 114. 
Copyright 0 1792 by the American Neurological Association 
59


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Developmental mechanisms underlying the evolution of human 
cortical circuits
Pierre Vanderhaeghen1,2,†, Franck Polleux3,4,†
1VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium
2Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
3Department of Neuroscience, Columbia University Medical Center, New York, NY, USA
4Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
Abstract
The brain of modern humans has evolved remarkable computational abilities that enable 
higher cognitive functions. These capacities are tightly linked to an increase in the size and 
connectivity of the cerebral cortex, which is thought to have resulted from evolutionary changes 
in the mechanisms of cortical development. Convergent progress in evolutionary genomics, 
developmental biology and neuroscience has recently enabled the identification of genomic 
changes that act as human-specific modifiers of cortical development. These modifiers influence 
most aspects of corticogenesis, from the timing and complexity of cortical neurogenesis to 
synaptogenesis and the assembly of cortical circuits. Mutations of human-specific genetic 
modifiers of corticogenesis have started to be linked to neurodevelopmental disorders, providing 
evidence for their physiological relevance and suggesting potential relationships between the 
evolution of the human brain and its sensitivity to specific diseases.
Introduction
Approximately 6-8 million years ago, the common ancestor of great apes (chimpanzees 
and bonobos) and species of the homo lineage lived in Africa. Following the divergence 
of hominins, one branch, through multiple radiation (in which new species emerge) and 
extinction events, gave rise to Homo sapiens approximately 300,000 years ago 1. As a 
result of this evolution, the brain of modern humans displays remarkable cognitive abilities 
that enable functions such as elaborate working memory, self-awareness, advanced forms


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of communication, complex tool making and cultural development 2,3. The mechanisms 
underlying the evolutionary emergence of human cognitive abilities constitute a long-
standing topic of interest in neuroscience that has recently been transformed by the 
coalescence of major advances in comparative genomics [G], developmental neurobiology 
† pierre.vanderhaeghen@kuleuven.be; fp2304@columbia.edu.
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
HHS Public Access
Author manuscript
Nat Rev Neurosci. Author manuscript; available in PMC 2023 May 01.
Published in final edited form as:
Nat Rev Neurosci. 2023 April ; 24(4): 213–232. doi:10.1038/s41583-023-00675-z.
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New experimental and clinical links between the hippocampus and the dopaminergic system in Parkinson's disease


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www.thelancet.com/neurology   Vol 12   August 2013 
811
Review
New experimental and clinical links between the hippocampus 
and the dopaminergic system in Parkinson’s disease
Paolo Calabresi, Anna Castrioto, Massimiliano Di Filippo, Barbara Picconi
Parkinson’s disease is a common progressive neurodegenerative disease, of which the main neuropathological 
hallmark is dopaminergic neuronal loss. Increased attention has been directed towards non-motor symptoms in 
Parkinson’s disease, such as cognitive impairment and behavioural disorders. Clinical and experimental ﬁ ndings 
support the view that the hippocampus, a temporal lobe structure involved in physiological learning and memory, is 
also implicated in the cognitive dysfunction seen in some patients with Parkinson’s disease. Moreover, emerging data 
suggest interactions between the dopaminergic systems and the hippocampus in synaptic plasticity, adaptive memory, 
and motivated behaviour. This structure is also implicated in the pathophysiology of other non-motor symptoms, 
such as impulse control disorders, anosmia, and fatigue. Evidence from clinical observations and experimental 
studies suggest a complex hippocampal cross-talk among the dopaminergic and other transmitter systems. 
Furthermore, neurotrophic factors might interact with the hippocampal dopaminergic system having possible 
implications on the non-motor symptoms seen in patients with Parkinson’s disease.
Introduction
Parkinson’s disease is a common progressive neuro-
degenerative disease, of which the main neuropathological 
hallmarks are dopaminergic neuronal loss in the pars 
compacta of the substantia nigra and accumulation of 
intraneuronal inclusions called Lewy bodies and Lewy 
neurites.1 Clinically, Parkinson’s disease is a motor disorder 
dominated by bradykinesia, rigidity, resting tremor, and 
postural instability that has a good response to 
dopaminergic replacement therapy. However, the classic 
view of Parkinson’s disease as a pure motor and


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dopaminergic disorder is changing. In the advanced stages 
of Parkinson’s disease, most disability comes from motor 
symptoms such as axial signs that do not respond to 
dopaminergic therapy, which suggests the involvement of 
systems other than the dopaminergic. Additionally, a wide 
range of non-motor symptoms is present in patients with 
Parkinson’s disease,2,3 which occur not only in the advanced 
stages, but also in the early phases. Many symptoms, such 
as hyposmia, rapid eye movement sleep behaviour 
disorder, constipation, depression, anxiety, and apathy, 
might precede the onset of motor disease.2,3 The 
mechanisms underlying these symptoms are complex, 
and neuropathological and clinical ﬁ ndings have shown 
that both the dopaminergic and non-dopaminergic 
systems, including the brainstem acetylcholine, noradren-
aline, and serotonin systems, are involved.2–5 For example, 
Lewy body deposition occurs during the early stages in the 
dorsal motor nucleus of the vagus nerve and in the locus 
coeruleus, and at advanced stages neuronal loss is seen in 
the cholinergic and serotoninergic brainstem systems.5
Several studies6,7 have shown that apathy in Parkinson’s 
disease responds to dopaminergic treatment, which 
suggests that apathy is related to dopaminergic 
dysfunction. Conversely, a serotoninergic change in the 
basal ganglia and limbic structures  has been related to 
fatigue, another non-motor symptom of Parkinson’s 
disease.8 Similarly, depression seems to be related not 
only to dopaminergic dysfunction,9 but also to 
hippocampal serotoninergic dysfunction.10 Moreover, 
emerging data for non-motor symptoms in Parkinson’s 
disease, such as cognitive impairment and behavioural 
disorders, support the role of the hippocampus in 
cognitive function and behaviour.11–13
The hippocampus is a temporal lobe structure 
implicated in learning and memory processes.14 In the 
traditional view of Parkinson’s disease, the hippocampus 
was not considered to have a role, except for its possible


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implications in dementia. However, emerging data from 
animal models15,16 and human studies17–19 have altered this 
view and suggest a key role of the interaction between 
dopamine transmission and hippocampal synaptic 
plasticity in memory and behaviour.20–22 Any imbalance in 
this interaction might be implicated in the genesis of not 
only dementia, but also other neuropsychiatric aspects of 
Parkinson’s disease.
Several reviews have discussed the potential association 
of the pathophysiological mechanisms of early mani-
festations,23 non-motor symptoms,2 neuropsychiatric 
issues,12,13,24  and dopamine and reward,11 with the interplay 
between the hippocampus and the ventral striatum in 
Parkinson’s disease.16,21
In this Review, we summarise the major ﬁ ndings from 
clinical observations and experimental studies using 
models of Parkinson’s disease that support a crucial 
interaction between dopaminergic systems and the 
hippocampus, and their involvement in Parkinson’s 
disease.
Anatomical and functional links between the 
hippocampus, basal ganglia, and dopaminergic 
systems
The hippocampus is a medial temporal lobe structure 
implicated in declarative memory (eg, referring to events 
in a speciﬁ c place and time).14,25 Recently, in parallel to the 
increasing insight into neuropsychiatric symptoms in 
Parkinson’s disease, it has been hypothesised that 
dopamine and its interactions with the hippocampus 
Lancet Neurol 2013; 12: 811–21
Clinica Neurologica, Università 
degli Studi di Perugia, Ospedale 
S Maria della Misericordia, 
Perugia, Italy 
(Prof P Calabresi MD, 
A Castrioto MD, 
M Di Filippo PhD); Istituto di 
Ricovero e Cura a Carattere 
Scientiﬁ co (IRCCS) Fondazione 
Santa Lucia, Rome, Italy 
(Prof P Calabresi, B Picconi PhD); 
and Movement Disorder Unit, 
Department of Psychiatry and 
Neurology, CHU de Grenoble, 
Joseph Fourier University, 
Grenoble, France (A Castrioto)
Correspondence to:
Prof Paolo Calabresi, Clinica 
Neurologica, Università degli 
Studi di Perugia, Ospedale


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Nature Reviews Drug Discovery | Volume 22 | June 2023 | 449–475
449
nature reviews drug discovery
https://doi.org/10.1038/s41573-023-00672-y
Review article
 Check for updates
Therapeutic strategies for COVID-19: 
progress and lessons learned
Guangdi Li 
  1 
, Rolf Hilgenfeld 
  2 
, Richard Whitley 
  3 
 & Erik De Clercq 
  4 
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has stimulated 
tremendous efforts to develop therapeutic strategies that target 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or 
human proteins to control viral infection, encompassing hundreds 
of potential drugs and thousands of patients in clinical trials. So far, 
a few small-molecule antiviral drugs (nirmatrelvir–ritonavir, remdesivir 
and molnupiravir) and 11 monoclonal antibodies have been marketed 
for the treatment of COVID-19, mostly requiring administration within 
10 days of symptom onset. In addition, hospitalized patients with 
severe or critical COVID-19 may benefit from treatment with previously 
approved immunomodulatory drugs, including glucocorticoids 
such as dexamethasone, cytokine antagonists such as tocilizumab 
and Janus kinase inhibitors such as baricitinib. Here, we summarize 
progress with COVID-19 drug discovery, based on accumulated findings 
since the pandemic began and a comprehensive list of clinical and 
preclinical inhibitors with anti-coronavirus activities. We also discuss 
the lessons learned from COVID-19 and other infectious diseases with 
regard to drug repurposing strategies, pan-coronavirus drug targets, 
in vitro assays and animal models, and platform trial design for the 
development of therapeutics to tackle COVID-19, long COVID and 
pathogenic coronaviruses in future outbreaks.
Sections
Introduction
Viral targets for antiviral 
agents
Host targets for antiviral 
agents
Targeting immune and 
inflammatory responses  
and coagulation
Outlook and challenges
Conclusions


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1Xiangya School of Public Health, Central South University; Hunan Children’s Hospital, Changsha, China. 
2Institute of Molecular Medicine & German Center for Infection Research (DZIF), University of Lübeck, Lübeck, 
Germany. 3Department of Paediatrics, Microbiology, Medicine and Neurosurgery, University of Alabama 
at Birmingham, Birmingham, AL, USA. 4Department of Microbiology, Immunology and Transplantation, 
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. 
 e-mail: liguangdi.research@gmail.com; 
rolf.hilgenfeld@uni-luebeck.de; rwhitley@uabmc.edu; erik.declercq@kuleuven.be


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European Journal of Pharmacology 895 (2021) 173862
Available online 12 January 2021
0014-2999/© 2021 Elsevier B.V. All rights reserved.
Parkinson’s disease in women: Mechanisms underlying sex differences 
Bhupesh Vaidya, Kritika Dhamija, Priyanka Guru, Shyam Sunder Sharma * 
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab, India   
A R T I C L E  I N F O   
Keywords: 
Parkinson’s disease 
Estrogen replacement therapy 
Neuroendocrine 
Therapeutic strategies 
Molecular 
Genetic 
A B S T R A C T   
Parkinson’s disease is a neurodegenerative disease which is associated with different motor, cognitive and mood- 
related problems. Though it has been established that Parkinson’s disease is less prevalent in women in com-
parison to men, the differences tend to diminish with the advancing age. Different genetic, hormonal, neuro-
endocrinal and molecular players contribute towards the differences in the Parkinson’s disease pathogenesis. 
Furthermore, data available with respect to the therapeutic management of Parkinson’s disease in females is 
limited; women often tend to suffer more from the side effects of the currently available drugs. The present 
review highlights the sex-specific differences which play a role in the manifestation of these symptoms and side 
effects of the currently available therapeutic strategies. We have also discussed the current and upcoming 
therapeutic strategies which are in the clinical trials such as adenosine 2A (A2A) receptor antagonists, estrogen 
replacement therapy, α-synuclein targeting vaccines and antibodies, Botulinum toxin A, Fas-associated factor-1 
(FAF-1) inhibitors, thiazolidinediones, 5-HT1A receptor agonists, dopamine D1/D5 receptor agonists, Glucagon- 
like peptide 1 (GLP-1) analogues and certain plant based principles for the treatment of Parkinson’s disease in 
women.   
1. Introduction 
Human brain exhibits differential gene expression across sex as a


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result of genetic and environmental factors (Bisaglia and Bubacco, 2020; 
Cannon and Greenamyre, 2011). These factors may predispose a 
particular sex to a variety of diseases and disorders including neurode-
generative diseases like Parkinson’s disease and Alzheimer’s disease 
(Hanamsagar and Bilbo, 2016; Thapak et al., 2020a; Thapak et al., 
2020b; Wang et al., 2020). A whole genome-based gene expression and 
splicing study in the human post mortem brain samples also illustrated 
that 2.6% of the genes expressed in the brain show sex-based differential 
gene expression. Additionally, 95% of the genes were observed to show 
sex-biased splicing (Trabzuni et al., 2013). This warrants a need to look 
for novel strategies which take into account the sex differences to 
improve currently available therapeutic regimens for the treatment of 
neurodegenerative conditions such as Parkinson’s disease. 
General epidemiological trends in Parkinson’s disease showed an 
increase in the number of cases, from 2.5 million in 1990 to nearly 7 to 
10 million in 2020. Though age-standardized incidence rates have 
shown no change in the ratio of male to female affected during this time, 
it has been widely reported that males tend to have a higher prevalence 
than females in Parkinson’s disease (Wooten et al., 2004). However, 
incidence rates among men is comparitevely lower in asian men in 
comparison to women. Additionally, overall ratio of males to females 
affected with Parkinson’s disease also tends to increase with age (Liu 
et al., 2016; Van Den Eeden et al., 2003). Hence, there is a need to look 
at the gender differences more seriously to understand the variation in 
these prevalence rates (Feigin et al., 2019; Statistics). 
Despite the late-onset and less prevalence, women tend to show a 
higher mortality ratio of 3.76 in comparison to 2.28 in men suffering 
from Parkinson’s disease (Morgan et al., 2014). One of the reasons for 
this could be the higher life expectancy of women in comparison to men


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(Elbaz et al., 2002). In addition, women tend to have faster disease 
progression in comparison to men. A recent multi-centric trial also 
suggested that women are also less likely to have informal caregiver 
support from family and friends making them more vulnerable to have 
inferior quality of life in comparison to men (Cerri et al., 2019; 
Dahodwala et al., 2018). Further, it necessitates them to have paid 
caregivers which are less likely in case of male patients with Parkinson’s 
disease (Cerri et al., 2019). 
There is a range of pathophysiological factors reported in the liter-
ature which contribute to the sex differences in Parkinson’s disease but 
these have mostly been overlooked both at the preclinical and clinical 
stages. A report which analyzed the United States Food and Drug 
Administration drug withdrawals between 1997 and 2000 showed that 8 
* Corresponding author. 
E-mail address: sssharma@niper.ac.in (S.S. Sharma).  
Contents lists available at ScienceDirect 
European Journal of Pharmacology 
journal homepage: www.elsevier.com/locate/ejphar 
https://doi.org/10.1016/j.ejphar.2021.173862 
Received 1 October 2020; Received in revised form 10 December 2020; Accepted 7 January 2021


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Supplementary figures for 
Sex differences in inter-individual gene expression variability across human tissues 
 
Authors: 
Samuel Khodursky1, Caroline S. Jiang2, Eric B. Zheng1, Roger Vaughan2, Daniel R. Schrider3, Li Zhao1,* 
Affiliations: 
1Laboratory of Evolutionary Genetics and Genomics, The Rockefeller University, New York, NY 10065, 
USA 
2Department of Biostatistics, The Rockefeller University, New York, NY 10065, USA 
3Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA 
Correspondence to: lzhao@rockefeller.edu


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Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo


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RESEARCH ARTICLE General Interest
Transcriptional sex and regional differences in paired human atrial and
ventricular cardiac biopsies collected in vivo
X Jane Synnergren,1 Kristina Vukusic,2 Pierre Dönnes,3 Marianne Jonsson,2 Anders Lindahl,2
Göran Dellgren,4 Anders Jeppsson,4 and Julia Asp2,5
1Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden; 2Department of Laboratory
Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 3SciCross AB,
Skövde, Sweden; 4Department of Cardiothoracic Surgery, Sahlgrenska University Hospital Gothenburg, Sweden and
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg,
Gothenburg, Sweden; and 5Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
Submitted 24 April 2019; accepted in ﬁnal form 23 December 2019
Synnergren J, Vukusic K, Dönnes P, Jonsson M, Lindahl A,
Dellgren G, Jeppsson A, Asp J. Transcriptional sex and regional
differences in paired human atrial and ventricular cardiac biopsies col-
lected in vivo. Physiol Genomics 52: 110–120, 2020. First published
December 23, 2019; doi:10.1152/physiolgenomics.00036.2019.—Tran-
scriptional studies of the human heart provide insight into physiolog-
ical and pathophysiological mechanisms, essential for understanding
the fundamental mechanisms of normal cardiac function and how they
are altered by disease. To improve the understanding of why men and
women may respond differently to the same therapeutic treatment it is
crucial to learn more about sex-speciﬁc transcriptional differences. In
this study the transcriptome of right atrium and left ventricle was
compared across sex and regional location. Paired biopsies from ﬁve
male and ﬁve female patients undergoing aortic valve replacement or
coronary artery bypass grafting were included. Gene expression anal-
ysis identiﬁed 620 differentially expressed transcripts in atrial and


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ventricular tissue in men and 471 differentially expressed transcripts
in women. In total 339 of these transcripts overlapped across sex but
notably, 281 were unique in the male tissue and 162 in the female
tissue, displaying marked sex differences in the transcriptional ma-
chinery. The transcriptional activity was signiﬁcantly higher in atrias
than in ventricles as 70% of the differentially expressed genes were
upregulated in the atrial tissue. Furthermore, pathway- and functional
annotation analyses performed on the differentially expressed genes
showed enrichment for a more heterogeneous composition of biolog-
ical processes in atrial compared with the ventricular tissue, and a
dominance of differentially expressed genes associated with infection
disease was observed. The results reported here provide increased
insights about transcriptional differences between the cardiac atrium
and ventricle but also reveal transcriptional differences in the human
heart that can be attributed to sex.
cardiac tissue; differentially expressed genes; gender; gene expres-
sion; left ventricle; microarray; right atrium; sex; transcription
INTRODUCTION
Sex differences affect the manifestation of cardiovascular
disease and therapeutic responses. Men are more likely to
suffer from occlusive coronary artery disease (CAD) (30) and
stroke (6). Women exhibit higher incidence of nonobstructive
CAD and microvascular dysfunction (30). Notably, within the
patient population suffering from diabetes Type 2 the female
sex has cardioprotective effects (1). Sex disparities are partic-
ularly prominent when it comes to cellular electrophysiology,
resting heart rates, and arrhythmia susceptibility (3, 24, 38).
Female myocytes are reported to have longer action potential
and greater susceptibility after depolarizations than male myo-
cytes (3, 38). Moreover, female sex is a risk factor for the
development of torsade de pointes arrhythmias, not only in
congenital long QT syndromes, but also in acquired long QT


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syndromes that can arise as an adverse effect of drug treat-
ments (3, 24, 42). Thus, it is of particular importance to learn
more about sex-speciﬁc transcriptional differences to under-
stand why men and women may respond differently to the
same therapeutic treatment and hence to improve the develop-
ment of more efﬁcient and safe treatments for cardiovascular
diseases (34).
Although animal studies provide important information
about cardiovascular disease, animal-based models are not
equivalent to human. This is reﬂected by the fact that several
approved drugs have been withdrawn from the market due to
toxic effects in humans, although no such side effects were
observed in any animal studies (25). However, cardiac tissue of
human origin for studies of molecular mechanisms is hard to
come by, and the lack of access to cardiac tissue greatly
hampers cardiac research of human relevance. Open cardiac
surgery procedures provide an opportunity to collect human
cardiac biopsies. From technical aspects it is easier to collect
biopsies from the auricula of the right atrium than from the
other three chambers of the heart. The right atrium is easily
accessed after sternotomy and is regularly manipulated when
cardiopulmonary bypass is established. For studies of heart
function, however, the material from the less accessible left
ventricle may be more relevant since this chamber executes the
contractile work for the systemic circulation. Although studies
on gene expression proﬁles from different parts of the human
heart have been performed (3–5, 13, 22, 23), it is still not
elucidated to what extent the transcriptome of the left ventricle
can be represented by the auricula of the right atrium.
To reveal pathological, functional, and regulatory mecha-
nisms in tissues and organs, large-scale transcriptional studies
are extensively used. The gene expression pattern in a speciﬁc
Address for reprint requests and other correspondence: J. Synnergren, Univ.
of Skövde Systems Biology Research Center, Box 408, SE-541 28 Skövde,


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Sweden (e-mail: jane.synnergren@his.se).
Physiol Genomics 52: 110–120, 2020.
First published December 23, 2019; doi:10.1152/physiolgenomics.00036.2019.
1094-8341/20 Copyright © 2020 the American Physiological Society
110
Downloaded from journals.physiology.org/journal/physiolgenomics (061.050.124.187) on September 26, 2022.


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Annals of the Rheumatic Diseases, 1980, 39, 31-36
Gold binding to blood cells and serum proteins
during chrysotherapy
R.
J. VAN DE STADT AND B. ABBO-TILSTRA
From the Amsterdam Centre for Rheumatic Diseases, Amsterdam, Holland
SUMMARY
The binding of gold to peripheral erythrocytes and serum protein fractions was studied
during chrysotherapy of
1 to 2 years' duration in 43 patients with rheumatoid arthritis. In 45%
of the patients more than 10% of the gold was found to be strongly bound to blood cells. 5-15%
of the metal is bound to non-albumin protein fractions at serum gold concentrations larger than
2 mg/ml. In contrast to the cellular binding of gold the relative binding of gold to non-albumin
proteins was inversely proportional to the serum concentrations. Binding to neither blood cells nor
to non-albumin protein fractions was found to be correlated with clinical parameters.
Gold salts have been used in the treatment of rheu-
matoid
arthritis (RA) for more than 40
years.
Although chrysotherapy has proved to be fairly
beneficial in the management of rheumatoid arth-
ritis, controversy still exists on the optimal dosage
schedule (Krusius
et
al.,
1970;
Freyberg,
1972;
Lorber, et al., 1973, 1975; Cats, 1976; Rothermich
et al., 1976; Sharp et al., 1977). Most reports indicate
a
lack
of correlation
between
pharmacological
and clinical parameters, including the occurrence
of adverse reactions (Krusius et al., 1970; Freyberg,
1972; Gerber et al., 1972; Mascarenhas et al., 1972;
Rubinstein and Dietz,
1973; Jessop and Johns,
1973; Lorber, et al., 1973, 1975; Gottlieb et al.,
1974; Sharp et al., 1977).
In vitro experiments suggest that most of the gold
in the circulation is bound to albumin (Lawrence,
1961; McQueen, and Dykes, 1969; Mascarenhas
et at., 1972; Campion et al., 1974; Danpure, 1976;
Ward et al., 1977), whereas a minor fraction seems
to
be bound
to
immunoglobulins,
complement
(Lorber et al., 1972; Schultz et al., 1973; Ward et
al.,
1977), or to low molecular weight materials


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(Campion et al., 1974; Ward et al., 1977). Almost
all of these studies have been performed in vitro.
In only one study (Ward et al., 1977) was the gold
distribution measured in the blood of patients with
rheumatoid
arthritis
receiving chrysotherapy.
In
the study presented here the binding of gold to
erythrocytes and the distribution of gold among the
Accepted for publication 6 March 1979
Correspondence to Dr R. J. van de Stadt, Reuma Revali-
datie Centrum, Dr Jan van Breemenstraat Adm. Helfrich-
straat, 1056 AB Amsterdam, W. Holland.
serum proteins was studied in relationship to clinical
parameters.
Material and methods
PATIENTS
Forty-two patients comprising 18 men (age range
22-75 years) and 24 women (age range 22-76 years)
with
definite
or
classical
rheumatoid
arthritis
lasting for more than 6 months and fulfilling the
criteria of the American Rheumatism Association
(Ropes et al., 1959) were admitted. None of the
patients
had
previously
received
chrysotherapy,
corticosteroids, immunosuppressive
drugs,
or D-
penicillamine. Only medication with nonsteroidal
anti-inflammatory drugs was allowed simultaneously
with the gold therapy. During the trial all patients
received
aurothioglucose
(20%
oily
suspension,
Noury Pharma, Oss) by intramuscular injections
according to the following standard schedule: The
first week 5 mg twice a week, the second week 10 mg
twice a week, the third week 20 mg once, after which
the dose was increased to 30, 40, and 50 mg a week
subsequently in most of the cases. All patients were
followed up for 1 to 2 years in this study.
CLINICAL TESTING PROCEDURES
Before admission
to
the
trial and subsequently
at 3-month intervals a complete physical examination
was made of all patients. On each occasion the fol-
lowing parameters were assessed; number of ARA
criteria, subjective judgment of clinician and patient,
pain, morning stiffness, weariness,
grip strength,
walking time over 10 metres, circumference of large
31


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Journal of Neurology, Neurosurgery, and Psychiatry 1983 ;46:145-151
Perceptual motor dysfunction in Parkinson's disease:
a deficit in sequential and predictive voluntary
movement
YAAKOV STERN,*t RICHARD MAYEUX,t JEFFREY ROSEN,* JOYCE ILSONt
From the Departments of Psychology, City University of New York* and Neurology, Columbia University
College ofPhysicians and Surgeons, t New York, USA
SUMMARY
We studied the ability of Parkinsonian patients and controls to generate voluntary
movements on a tracing task. Subjects were videotaped while tracing designs of increasing
complexity, presented on a vertical, transparent screen. Some designs were presented in a
degraded form and subjects filled in their missing sections. Subjects also received a constructional
task and a test of general intellectual ability. The quality of errors on the tracing task differed in the
Parkinsonian and control groups. Parkinsonian patients made two distinct types of errors. One
probably related to the motor disorders of the disease, but another seemed to be related to a higher
level of control over sequential and predictive movements. The latter correlated with performance
on the constructional and general intellectual tasks. These results suggest that Parkinson's disease
may affect basal ganglia structures that are necessary for voluntary movements which require
sequencing or planning. Clinically this may be observed in perceptual motor tasks since they
require both voluntary movement and sequential organisation of behaviour.
Impairments in perceptual motor or visuospatial
tasks are among the most frequently encountered
abnormalities
in
neuropsychological
studies
of
Parkinson's disease.5 Many of these tasks require
voluntary movements, so these deficits could reflect
nothing more than the disordered movement of
Parkinson's disease. Alternatively, this disturbance
in perceptual motor tasks suggests that there may
also be a loss of higher order motor control that is
distinct from the characteristic motor disorders of
Parkinson's disease.


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Certain deficits on tracking
tasks in Parkinson's disease can be characterised as
an inability to generate and sequence predictive
movements, that is movements that must be accom-
plished without external feedback to guide them. For
example, Flowers6 demonstrated that while Park-
insonian patients could successfully track a target
moving on an oscilloscope screen in a regular pattern
at a sufficiently slow speed, tracking performance
degenerated when the target was momentarily re-
moved from the screen. This perceptual motor deficit
Address
for reprint
requests:
Dr Mayeux, The Neurological
Institute, 710 West 168th Street, New York, New York 10032, USA.
Received 8 April 1982 and in revised form 27 September 1982
Accepted 4 October 1982
may be a result of impaired generation of control of
sequential and predictive voluntary movements.
To examine this hypothesis, we tested patients
with a simplified version of Flowers' tracking task,6
and with a constructional task. In addition, general
intellectual function and the severity of symptoms
were assessed. We expected that certain errors in
tracing would relate to the severity of patients'
Parkinsonism,
that
is
tremor,
rigidity
or
bradykinesia. However, we anticipated that other
errors
in
tracing,
particularly
those demanding
predictive movement, might be related to perfor-
mance on the constructional and general intelligence
tests and not to the severity of the Parkinsonism. This
work was presented in part at the 33rd annual
meeting of the American Academy of Neurology.'
Methods
Subjects
Eighteen patients with Parkinson's disease and 14 healthy,
elderly adult controls volunteered and gave informed
consent. We excluded people with a history or overt signs of
dementia as defined by the DSM 111.8 Fourteen of the 18
patients were on levodopa therapy (table 1). All subjects
were examined by the same neurologist. For the patients,
we used a standardised evaluation form rating 21 signs and
145


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Dopaminergic retinal cell loss and visual dysfunction in 
Parkinson’s disease
Isabel Ortuño-Lizarán, PhD1, Xavier Sánchez-Sáez, MSc1, Pedro Lax, PhD1, Geidy E. 
Serrano, PhD2, Thomas G. Beach, MD, PhD2, Charles H. Adler, MD, PhD3, Nicolás Cuenca, 
PhD1,4
1Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
2Banner Sun Health Research Institute, Sun City, AZ, USA
3Mayo Clinic Arizona, Scottsdale, AZ, USA
4Institute Ramón Margalef, University of Alicante, Alicante, Spain
Abstract
Objective: Considering the demonstrated implication of the retina in PD pathology and the 
importance of dopaminergic cells in this tissue, we aimed to analyze the state of the dopaminergic 
amacrine cells and some of their main post-synaptic neurons in the retina of PD.
Methods: Using immunohistochemistry and confocal microscopy, we evaluated morphology, 
number, and synaptic connections of dopaminergic cells and their post-synaptic cells, AII 
amacrine and melanopsin-containing retinal ganglion cells, in control and PD eyes from human 
donors.
Results: In PD, dopaminergic amacrine cell number was reduced between a 58% and a 26% in 
different retinal regions, involving a decline in the number of synaptic contacts with AII amacrine 
cells (by 60%) and melanopsin cells (by 35%). Despite losing their main synaptic input, AII cells 
were not reduced in number, but they showed cellular alterations compromising their adequate 
function: i) a loss of mitochondria inside their lobular appendages, that may indicate an energetic 
failure and ii) a loss of connexin 36, suggesting alterations in the AII coupling and in visual signal 
transmission from the rod pathway.
Interpretation: The dopaminergic system impairment and the affection of the rod pathway 
through the AII cells may explain and be partially responsible for the reduced contrast sensitivity 
or electroretinographic response described in PD. Also, dopamine reduction and the loss of


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synaptic contacts with melanopsin cells may contribute to the melanopsin retinal ganglion cell 
loss previously described and to the disturbances in circadian rhythm and sleep reported in PD 
patients. These data support the idea that the retina reproduces brain neurodegeneration and is 
highly involved in PD pathology.
Corresponding author: Nicolás Cuenca, cuenca@ua.es.
Author Contributions: IOL, PL, GS, TB, CA and NC contributed to the study conception and design. Data collection was performed 
by IOL, XSS, GS and analysis and interpretation by IOL, XSS, PL, GS, TB, CA, and NC. IOL wrote the first draft of the manuscript 
and all authors made comments on previous versions. All authors read and approved the final version.
Potential Conflicts of Interest: The authors declare that they have no conflict of interest.
HHS Public Access
Author manuscript
Ann Neurol. Author manuscript; available in PMC 2023 March 10.
Published in final edited form as:
Ann Neurol. 2020 November ; 88(5): 893–906. doi:10.1002/ana.25897.
Author Manuscript
Author Manuscript
Author Manuscript
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Stabilized HIV-1 envelope immunization induces neutralizing antibodies to the CD4bs and protects macaques against mucosal infect\
ion


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Stabilized HIV-1 envelope immunization induces neutralizing 
antibodies to the CD4bs and protects macaques against 
mucosal infection
Kevin O. Saunders1,2,3,4,*, Robert J. Edwards1,5,†, Kedamawit Tilahun1,5,†, Kartik Manne1,5,†, 
Xiaozhi Lu1,5, Derek W. Cain1,5, Kevin Wiehe1,5, Wilton B. Williams1,2,4, Katayoun 
Mansouri1,5, Giovanna E. Hernandez1,5, Laura Sutherland1,5, Richard Scearce1,5, Robert 
Parks1,5, Maggie Barr1,5, Todd DeMarco1,5, Chloe M. Eater1,5, Amanda Eaton1,2, 
Georgeanna Morton6, Benjamin Mildenberg6, Yunfei Wang1,5, R. Wes Rountree1,5, Mark A. 
Tomai7, Christopher B. Fox8, M. Anthony Moody1,9, S. Munir Alam1,5, Sampa Santra6, Mark 
G. Lewis10, Thomas N. Denny1,5, George M. Shaw11, David C. Montefiori1,2, Priyamvada 
Acharya1,2,*, Barton F. Haynes1,4,5,*
1Duke Human Vaccine Institute, Duke University Medical Center; Durham, NC 27710.
2Department of Surgery, Duke University Medical Center; Durham, NC 27710.
3Department of Microbiology and Molecular Genetics, Duke University Medical Center; Durham, 
NC 27710.
4Department of Immunology, Duke University Medical Center; Durham, NC, 27710, USA.
5Department of Medicine, Duke University Medical Center; Durham, NC, 27710, USA.
6Beth Israel Deaconess Medical Center; Boston, MA, 02215, USA.
73M Corporate Research Materials Lab, 3M Company; St. Paul, MN, 55144, USA.
8Infectious Disease Research Institute; Seattle, WA, 98102, USA.
*Corresponding author: Priyamvada.acharya@duke.edu, Kevin.saunders@duke.edu, Barton.haynes@dm.duke.edu.
†Contributed equally
Author contributions:
KOS, GMS, BFH conceptualized and designed the study. XL, KT, DWC, MAM, and KOS isolated, sequenced, produced, and 
characterized binding activity of mAbs. K Manne, RJE, K Mansouri, and PA performed electron microscopy experiments. DCM and 
AE performed HIV-1 neutralization assays. WBW and KW performed next-generation sequencing and antibody sequence analysis. 
RP, MB, and BFH performed serum binding and blocking assays and analyzed data. GEH and CME expressed virus antigens and


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performed antibody binding assays. SMA performed binding assays with recombinant trimers. MGL, LS, RS, SS, GM and BM 
performed macaque procedures. TD and TND performed viral load PCR experiments. MAT and CBF produced adjuvants for the 
macaque immunization study. GMS generated challenge stocks. MGL, BFH, KOS, and GMS analyzed challenge data. YW and RWR 
performed statistical analyses. KOS, RJE, PA, and BFH wrote the original draft of the manuscript, which was edited by all authors.
Supplementary Materials
Materials and Methods 
Fig. S1 to S19
Table S1 to S4
MDAR Reproducibility Checklist 
Data File S1 
Competing interests: IDRI has filed patents on emulsion and Alum formulations of 3M-052 and GLA on which CBF is an inventor. 
CBF is also on the scientific advisory board of Maxvax. MAT is an employee of 3M Company. 3M company had no role in the 
execution of the study, data collection, or data interpretation. BFH and KOS have filed patents regarding the use of CH505 TF 
chTrimer as an immunogen (PCT / US2017 / 020249). All other authors declare no competing interests.
HHS Public Access
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Sci Transl Med. Author manuscript; available in PMC 2023 March 23.
Published in final edited form as:
Sci Transl Med. 2022 September 07; 14(661): eabo5598. doi:10.1126/scitranslmed.abo5598.
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Rapid plasticity of higher-order thalamocortical inputs during 
sensory learning
Nicholas J. Audette1,2, Sarah M. Bernhard1, Ajit Ray1, Luke T. Stewart1, Alison L. 
Barth1,2,3,*
1Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
2Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
3Lead Contact
Abstract
Neocortical circuits are sensitive to experience, showing both anatomical and electrophysiological 
changes in response to altered sensory input. We examined input- and cell-type specific changes 
in thalamo- and intracortical pathways during learning using an automated, home-cage sensory 
association training (SAT) paradigm coupling multi-whisker stimulation to a water reward. 
We found that POm, but not VPM, drives increased cortical activity after 24 hours of SAT, 
when behavioral evidence of learning first emerges. Synaptic strengthening within the POm 
thalamocortical pathway was first observed at thalamic inputs to L5 and was not generated by 
sensory stimulation alone. Synaptic changes in L2 were delayed relative to L5, requiring 48 hours 
of SAT to drive synaptic plasticity at thalamic and intracortical inputs onto L2 Pyr neurons. These 
data identify the POm thalamocortical circuit as a site of rapid synaptic plasticity during learning 
and suggest a temporal sequence to learning-evoked synaptic changes in the sensory cortex.
Introduction
Experience-dependent plasticity is a cardinal feature of the neocortex. Abundant evidence 
indicates that motor or perceptual learning drives changes in neocortical circuits, with 
changes observed in fMRI signals (Shibata et al., 2016; Summerfield et al., 2006), altered 
topographic organization (retino-, tono- or somatotopy; (Harris et al., 2001; Kilgard, 1998; 
Schwartz et al., 2002)), enhanced feature-selective responses and increased spike output to 
previously undetectable stimuli (Glazewski and Barth, 2015; Karni and Sagi, 1991), and


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increased synaptic strength (Cheetham et al., 2008; Clem, 2010; Rioult-Pedotti et al., 2000).
How is learning associated with plasticity in specific neocortical circuits? In rodent 
somatosensory cortex, experience-dependent changes are concentrated in infra- and 
*Correspondence: albarth@andrew.cmu.edu.
Author Contributions
Conceptualization, N.J.A. and A.L.B.; Methodology, N.J.A., S.M. B., A.L.B.; Software, S.M.B.; Formal Analysis, N.J.A.; 
Investigation, N.J.A., L.T.S., A.R.; Writing – Original Draft, N.J.A., A.L.B.; Writing – Reviewing & Editing, N.J.A., S.B., L.T.S., 
A.R., A.L.B.; Visualization, N.J.A.; Supervision, A.L.B.; Funding Acquisition, N.J.A., A.R., A.L.B.
Declaration of Interests
The authors declare no competing interests.
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Author manuscript
Neuron. Author manuscript; available in PMC 2023 March 24.
Published in final edited form as:
Neuron. 2019 July 17; 103(2): 277–291.e4. doi:10.1016/j.neuron.2019.04.037.
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Immunogenomics of killer cell Ig-like receptor \(KIR\) and HLA class I: Co-evolution and consequences for human health


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Immunogenomics of killer cell Ig-like receptor (KIR) and HLA 
class I: Co-evolution and consequences for human health
Nicholas R. Pollock, BSc,
Genelle F. Harrison, PhD,
Paul J. Norman, PhD
Division of Biomedical Informatics and Personalized Medicine and Department of Immunology 
and Microbiology. Anschutz Medical Campus, University of Colorado, Aurora, CO, USA.
Abstract
Interactions of killer cell immunoglobin-like receptors (KIR) with human leukocyte antigens 
(HLA) class I regulate effector functions of key cytotoxic cells of innate and adaptive immunity. 
The extreme diversity of this interaction is genetically determined, having evolved in the 
ever-changing environment of pathogen exposure. Diversity of KIR and HLA genes is further 
facilitated by their independent segregation on separate chromosomes. That fetal implantation 
relies on many of the same types of immune cells as infection control, places certain constraints 
on the evolution of KIR interactions with HLA. Consequently, specific inherited combinations 
of receptors and ligands may predispose to specific immune mediated diseases, including 
autoimmunity. Combinatorial diversity of KIR and HLA class I can also differentiate success 
rates of immunotherapy directed to these diseases. Progress towards both etiopathology and 
predicting response to therapy is being achieved through detailed characterization of the extent 
and consequences of the combinatorial diversity of KIR and HLA. Achieving these goals is 
more tractable with the development of integrated analyses of molecular evolution, function and 
pathology that will establish guidelines for understanding and managing risks. Here we present 
what is known about the co-evolution of KIR with HLA class I and the impact of their complexity 
on immune function and homeostasis.
Keywords
killer cell Ig-like receptors (KIR); human leucocyte antigen (HLA); natural killer (NK) cells; 
innate immunity; reproduction; autoimmunity


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The ability of the immune system to distinguish healthy from unhealthy cells is critical for 
the effective control of pathogens and aberrant cell growth. The system must also diversify 
to survive in the face of emerging and evolving challenges. Killer cell immunoglobin-like 
receptor (KIR) interactions with their cognate ligands, human leukocyte antigen (HLA) class 
Corresponding Author: Paul J. Norman, Division of Biomedical Informatics and Personalized Medicine, Building 500, Anschutz 
Medical Campus, Aurora, CO 80045, USA. paul.norman@cuanschutz.edu Tel: 303-724-4481. 
Competing Interests
The authors declare no financial or other conflict of interest that could impact this work.
HHS Public Access
Author manuscript
J Allergy Clin Immunol Pract. Author manuscript; available in PMC 2023 March 25.
Published in final edited form as:
J Allergy Clin Immunol Pract. 2022 July ; 10(7): 1763–1775. doi:10.1016/j.jaip.2022.04.036.
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Decussating Axons Segregate within the Anterior Core of the 
Primate Optic Chiasm
Jonathan C. Horton,
Mikayla D. Dilbeck,
John R. Economides
Program in Neuroscience, Department of Ophthalmology, University of California, San Francisco, 
San Francisco, CA 94143 USA
Abstract
Background—The axons of ganglion cells in the nasal retina decussate at the optic chiasm. It 
is unclear why tumours cause more injury to crossing nasal fibres, thereby giving rise to temporal 
visual field loss in each eye. To address this issue, the course of fibres through the optic chiasm 
was examined following injection of a different fluorescent tracer into each eye of a monkey.
Methods—Under general anaesthesia, cholera toxin subunit B -- Alexa Fluor 488 was injected 
into the right eye and cholera toxin subunit B -- Alexa Fluor 594 was injected into the left eye of 
a single normal adult male rhesus monkey. After a week’s survival for anterograde transport, serial 
coronal sections through the primary optic pathway were examined.
Results—Crossing fibres were confined mainly to a core zone within the anterior and mid 
portions of the optic chiasm. This zone of decussation was delineated by segregated, interwoven 
sheets of green (right eye) and red (left eye) fibres. It expanded steadily to fill more of the optic 
chiasm as fibres coursed posteriorly towards the optic tracts. Eventually, crossed fibres became 
completely intermingled with uncrossed fibres, so that ocular separation was lost.
Conclusions—Crossing fibres are concentrated primarily within a distinct, central compartment 
located within the anterior two thirds of the optic chiasm. Sellar tumours focus their compressive 
force on this portion of the structure, explaining why they so often produce visual field loss in the 
temporal fields.
Corresponding author: Jonathan C. Horton MD, PhD, University of California, San Francisco, Jonathan.Horton@ucsf.edu, 10 Koret 
Way, San Francisco, CA 94143-0730, Phone: 650-288-8736.


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Contributorship Statement: All 3 authors participated in the experiment, analysis of the data, and authorship of the manuscript.
1The contents of this article were in part presented at a Festschrift in celebration of the career of Dr. Gordon Plant on this 
retirement. The event took place in March 2021 and was hosted by the Royal Society of Medicine and the United Kingdom 
Neuro-Ophthalmology Society. A video recording of the entire event is available at http://uknos.com.
Competing interests None Declared.
Patient consent for publication Not required.
Ethics Approval UCSF Institutional Animal Care and Use Committee Approval Number AN194334-01C. UCSF Human Research 
Protection Program Institutional Review Board: Exemption.
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Author manuscript
Br J Ophthalmol. Author manuscript; available in PMC 2023 April 01.
Published in final edited form as:
Br J Ophthalmol. 2023 April ; 107(4): 447–452. doi:10.1136/bjo-2022-322235.
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REVIEW ARTICLE
OPEN
Pathogenesis of allergic diseases and implications for
therapeutic interventions
Ji Wang1, Yumei Zhou1, Honglei Zhang1, Linhan Hu1, Juntong Liu1, Lei Wang2, Tianyi Wang1, Haiyun Zhang1, Linpeng Cong1 and
Qi Wang1✉
Allergic diseases such as allergic rhinitis (AR), allergic asthma (AAS), atopic dermatitis (AD), food allergy (FA), and eczema are
systemic diseases caused by an impaired immune system. Accompanied by high recurrence rates, the steadily rising incidence rates
of these diseases are attracting increasing attention. The pathogenesis of allergic diseases is complex and involves many factors,
including maternal-fetal environment, living environment, genetics, epigenetics, and the body’s immune status. The pathogenesis
of allergic diseases exhibits a marked heterogeneity, with phenotype and endotype deﬁning visible features and associated
molecular mechanisms, respectively. With the rapid development of immunology, molecular biology, and biotechnology, many
new biological drugs have been designed for the treatment of allergic diseases, including anti-immunoglobulin E (IgE), anti-
interleukin (IL)-5, and anti-thymic stromal lymphopoietin (TSLP)/IL-4, to control symptoms. For doctors and scientists, it is becoming
more and more important to understand the inﬂuencing factors, pathogenesis, and treatment progress of allergic diseases. This
review aimed to assess the epidemiology, pathogenesis, and therapeutic interventions of allergic diseases, including AR, AAS, AD,
and FA. We hope to help doctors and scientists understand allergic diseases systematically.
Signal Transduction and Targeted Therapy  (2023) 8:138 
; https://doi.org/10.1038/s41392-023-01344-4
INTRODUCTION
Allergic diseases are systemic disorders caused by an impaired
immune system. Different allergic diseases, including AR, AAS, AD,
FA and eczema, are caused by complex interactions between
genetic and environmental factors. Allergic diseases are listed by
the World Health Organization (WHO) as one of the top three


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disorders to be prevented and controlled in the 21st century. An
allergic disease, whilst a systemic disease, can also manifest as
different local maladies, all of which may lead to anaphylactic
shock in severe cases. The incidence of allergic diseases is high,
bringing much suffering to patients. It is estimated that nearly
500 million and 300 million individuals worldwide have AR and
AAS, respectively,1 with an increasing number of cases. For AAS,
mortality rates in women and men are 90 and 170 per million
individuals, respectively. About 96% of asthma deaths occur in
low-and-middle-income countries.2 It is currently estimated that
FA affects 1–10% of the total population.3 The global prevalence
rate of AD is 8%,4,5 with a lifetime prevalence reaching 20%.6 In
2019, there were 171.17 million patients worldwide with AD.7
Due to the different sites of allergic diseases, the clinical and
pathological manifestations also differ. In AR, after stimulation by
allergens, including airborne dust mites associated with fecal
particles, cockroach remains, pet dander, molds and pollens,
inﬂammatory cells such as mast cells, CD4+ T cells, B cells,
macrophages and eosinophils inﬁltrate the lining of the nasal
cavity, with inﬁltration into the nasal mucosa. T helper 2 (Th2) cells
promote the release of immunoglobulin and cytokines, including
interleukin (IL)-3, IL-4, IL-5, and IL-13; meanwhile, IgE is also
produced by plasma cells. There is, however, still some uncertainty
around the source of IgE production. Follicular helper T (Tfh) cells
are a subpopulation of CD4+ T-effector cells, and in recent years it
has been discovered that the key cells regulating IgE production
are not Th2 cells, but Tfh cells. Allergens cross-link IgE that interact
with mast cells, which further induces the release of multiple
mediators
(including
histamine
and
leukotrienes),
promotes
arteriole dilation and vascular permeability, and causes pruritus,
runny nose, mucus secretion, and pulmonary smooth muscle


