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contraction.8 Over the next 4–8 hours, the released mediators and
cytokines induce subsequent cellular inﬂammatory reactions (late
inﬂammatory response), leading to the recurrence of symptoms,
often nasal congestion, which generally persist.8,9 The immuno-
pathological proﬁles of AR and AAS are very similar in terms of
eosinophil, mast cell and Th2 cell inﬁltration. Although structural
changes in airway remodeling are well characterized in AAS, they
may also occur in AR. There are also pathophysiological differences
between AR and AAS. In the AAS disease, mucosal pathological
alterations comprise epithelial hyperplasia, goblet cell metaplasia
and increased mucus generation. In the submucosal layer, smooth
muscle hypertrophy, collagen accumulation and large mucus
glands prevail, leading to airway narrowing and enhanced mucus
generation during an asthma attack,10 with symptoms such as
difﬁculty breathing, wheezing, chest pain, and coughing.11 The
pathogenesis of AD is mainly reﬂected by a complex interplay
between epidermal barrier dysfunction, abnormal skin microbiota
and
dysregulated
type
2
T
cell
immunity.12,13
The
above
pathogenesis induces a series of pathological manifestations such
Received: 2 September 2022 Revised: 20 January 2023 Accepted: 3 February 2023
1National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, P.R. China and 2National
Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 1000210, China
Correspondence: Qi Wang (wangqi710@126.com)
These authors contributed equally: Ji Wang, Yumei Zhou
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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Spared Premotor Areas Undergo Rapid Nonlinear Changes in Functional Organization Following a Focal Ischemic Infarct in Primary Motor Cortex of Squirrel Monkeys


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Neurobiology of Disease
Spared Premotor Areas Undergo Rapid Nonlinear Changes
in Functional Organization Following a Focal Ischemic
Infarct in Primary Motor Cortex of Squirrel Monkeys
Erik J. Plautz,1,2
Scott Barbay,1,2 Shawn B. Frost,1,2 Ann M. Stowe,1 Numa Dancause,1 Elena V. Zoubina,1,2
Ines Eisner-Janowicz,1 David J. Guggenmos,1 and Randolph J. Nudo1,2
1Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160 and 2Landon Center on
Aging, University of Kansas Medical Center, Kansas City, Kansas 66160
Recovery of motor function after stroke is accompanied by reorganization of movement representations in spared cortical
motor regions. It is widely assumed that map reorganization parallels recovery, suggesting a causal relationship. We exam-
ined this assumption by measuring changes in motor representations in eight male and six female squirrel monkeys in the
first few weeks after injury, a time when motor recovery is most rapid. Maps of movement representations were derived
using intracortical microstimulation techniques in primary motor cortex (M1), ventral premotor cortex (PMv), and dorsal
premotor cortex (PMd) in 14 adult squirrel monkeys before and after a focal infarct in the M1 distal forelimb area. Maps
were derived at baseline and at either 2 (n = 7) or 3 weeks (n = 7) postinfarct. In PMv the forelimb maps remained
unchanged at 2 weeks but contracted significantly (242.4%) at 3 weeks. In PMd the forelimb maps expanded significantly
(1110.6%) at 2 weeks but contracted significantly (257.4%) at 3 weeks. Motor deficits were equivalent at both time points.
These results highlight two features of plasticity after M1 lesions. First, significant contraction of distal forelimb motor maps
in both PMv and PMd is evident by 3 weeks. Second, an unpredictable nonlinear pattern of reorganization occurs in the dis-
tal forelimb representation in PMd, first expanding at 2 weeks, and then contracting at 3 weeks postinjury. Together with


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previous results demonstrating reliable map expansions in PMv several weeks to months after M1 injury, the subacute time
period may represent a critical window for the timing of therapeutic interventions.
Key words: cortical plasticity; ICMS; motor maps; premotor cortex; recovery of function; stroke
Significance Statement
The relationship between motor recovery and motor map reorganization after cortical injury has rarely been examined in
acute/subacute periods. In nonhuman primates, premotor maps were examined at 2 and 3 weeks after injury to primary
motor cortex. Although maps are known to expand late after injury, the present study demonstrates early map expansion at
2 weeks (dorsal premotor cortex) followed by contraction at 3 weeks (dorsal and ventral premotor cortex). This nonlinear
map reorganization during a time of gradual behavioral recovery suggests that the relationship between map plasticity and
motor recovery is much more complex than previously thought. It also suggests that rehabilitative motor training may have
its most potent effects during this early dynamic phase of map reorganization.
Introduction
Stroke remains one of the major causes of death and disability
worldwide (Gorelick, 2019). Although advances have been made
in acute stroke therapy, interventions generally are limited to a
few hours following stroke (Hollist et al., 2021). Delays in treat-
ment often result in chronic motor impairments requiring inten-
sive physical rehabilitation and restorative therapies to improve
function. Animal models remain useful for addressing underly-
ing mechanisms of recovery and offer therapeutic targets to de-
velop or refine current rehabilitative therapies (Bundy and
Nudo, 2019). Principally, a large effort has been made to under-
stand the capacity of the brain to reorganize after an ischemic
Received July 23, 2022; revised Jan. 10, 2023; accepted Jan. 13, 2023.
Author contributions: E.J.P. and R.J.N. designed research; E.J.P., S.B., S.B.F., A.M.S., N.D., E.V.Z., I.E.-J., and


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D.J.G. performed research; E.J.P. and S.B. analyzed data; and E.P., S.B., and R.J.N. wrote the paper.
This work was supported by National Institues of Health Grants U54 NS048126, NIH R01 NS30853, and P30
HD002528 and Northstar Neuroscience. We thank Bob Cross, Caleb Dunham, Erica Hoover, Diane Larson, and
Phuong Nguyen for technical assistance and Scott Bury, Pei-chun Fang, David McNeal, Michael Taylor, and Ed
Urban for assistance with collection of mapping data.
The authors declare no competing financial interests.
Correspondence should be sent to Randolph J. Nudo at rnudo@kumc.edu or Erik Plautz at
erik.plautz@utsouthwestern.edu.
https://doi.org/10.1523/JNEUROSCI.1452-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, March 15, 2023 • 43(11):2021–2032 • 2021


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Vol.:(0123456789)
1 3
Inflammopharmacology (2023) 31:1167–1182 
https://doi.org/10.1007/s10787-023-01193-1
REVIEW
Inﬂammopharmacology
Thalidomide interaction with inflammation in idiopathic pulmonary 
fibrosis
Nikitha Naomi Dsouza1 · Varun Alampady1 · Krishnaprasad Baby1 · Swastika Maity1 · Bharath Harohalli Byregowda1 · 
Yogendra Nayak1 
Received: 10 November 2022 / Accepted: 4 March 2023 / Published online: 25 March 2023 
© The Author(s) 2023
Abstract
The “Thalidomide tragedy” is a landmark in the history of the pharmaceutical industry. Despite limited clinical trials, there 
is a continuous effort to investigate thalidomide as a drug for cancer and inflammatory diseases such as rheumatoid arthritis, 
lepromatous leprosy, and COVID-19. This review focuses on the possibilities of targeting inflammation by repurposing tha-
lidomide for the treatment of idiopathic pulmonary fibrosis (IPF). Articles were searched from the Scopus database, sorted, 
and selected articles were reviewed. The content includes the proven mechanisms of action of thalidomide relevant to IPF. 
Inflammation, oxidative stress, and epigenetic mechanisms are major pathogenic factors in IPF. Transforming growth factor-β 
(TGF-β) is the major biomarker of IPF. Thalidomide is an effective anti-inflammatory drug in inhibiting TGF-β, interleu-
kins (IL-6 and IL-1β), and tumour necrosis factor-α (TNF-α). Thalidomide binds cereblon, a process that is involved in the 
proposed mechanism in specific cancers such as breast cancer, colon cancer, multiple myeloma, and lung cancer. Cereblon 
is involved in activating AMP-activated protein kinase (AMPK)-TGF-β/Smad signalling, thereby attenuating fibrosis. The 
past few years have witnessed an improvement in the identification of biomarkers and diagnostic technologies in respiratory 
diseases, partly because of the COVID-19 pandemic. Hence, investment in clinical trials with a systematic plan can help 
repurpose thalidomide for pulmonary fibrosis.
Graphical Abstract


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Keywords Thalidomide · Idiopathic pulmonary fibrosis · Drug repurposing · Cereblon · Anti-inflammatory
Introduction
Idiopathic pulmonary fibrosis (IPF) is a progressive intersti-
tial lung disease characterized by chronic fibrotic scarring 
of lung tissues, leading to a deterioration of lung function 
 * Yogendra Nayak 
 
yogendra.nayak@manipal.edu
1 
Department of Pharmacology, Manipal College 
of Pharmaceutical Sciences, Manipal Academy of Higher 
Education, Manipal, Karnataka 576104, India


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Linking Individual Differences in Personalized Functional Network Topography to Psychopathology in Youth


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Linking Individual Differences in Personalized Functional 
Network Topography to Psychopathology in Youth
Zaixu Cui,
Adam R. Pines,
Bart Larsen,
Valerie J. Sydnor,
Hongming Li,
Azeez Adebimpe,
Aaron F. Alexander-Bloch,
Dani S. Bassett,
Max Bertolero,
Monica E. Calkins,
Christos Davatzikos,
Damien A. Fair,
Ruben C. Gur,
Raquel E. Gur,
Tyler M. Moore,
Sheila Shanmugan,
Russell T. Shinohara,
Jacob W. Vogel,
Cedric H. Xia,
Yong Fan,
Theodore D. Satterthwaite
Penn Lifespan Informatics and Neuroimaging Center (ZC, ARP, BL, VJS, AA, MB, SS, JWV, 
CHX, TDS); Departments of Psychiatry (ZC, ARP, BL, VJS, AA, AFA-B, DSB, MB, MEC, 
RCG, REG, TMM, SS, JWV, CHX, TDS) and Radiology (HL, CD, RCG, REG, YF); Center for 
Biomedical Image Computation and Analytics (HL, CD, RCG, REG, RTS, YF, TDS); Departments 
of Bioengineering (DSB, CD), Neurology (DSB, RCG, REG), Electrical and Systems Engineering 
(DSB, CD), Physics and Astronomy (DSB); and the Penn Statistics in Imaging and Visualization 
Center (RTS, TDS), Department of Biostatistics, Epidemiology and Informatics, University of 
Pennsylvania; Department of Child and Adolescent Psychiatry and Behavioral Science (AFA-B), 
The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Santa Fe Institute (DSB), 
Santa Fe, New Mexico; Masonic Institute for the Developing Brain (DAF), Institute of Child 
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Address correspondence to Zaixu Cui, Ph.D., at cuizaixu@cibr.ac.cn, or Theodore D. Satterthwaite, M.D., M.A., at 
sattertt@pennmedicine.upenn.edu. 
Supplementary material cited in this article is available online at https://doi.org/10.1016/j.biopsych.2022.05.014.
HHS Public Access
Author manuscript
Biol Psychiatry. Author manuscript; available in PMC 2023 March 27.
Published in final edited form as:
Biol Psychiatry. 2022 December 15; 92(12): 973–983. doi:10.1016/j.biopsych.2022.05.014.
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Proteomic characteristics and diagnostic potential of exhaled breath particles in patients with COVID-19


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Hirdman et al. Clinical Proteomics           (2023) 20:13  
https://doi.org/10.1186/s12014-023-09403-2
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.
Clinical Proteomics
Proteomic characteristics and diagnostic 
potential of exhaled breath particles in patients 
with COVID-19
Gabriel Hirdman1,2,3, Embla Bodén1,2,3, Sven Kjellström4, Carl‑Johan Fraenkel5,6, Franziska Olm1,2,3, 
Oskar Hallgren1,2,3 and Sandra Lindstedt1,2,3,7* 
Abstract 
Background SARS‑CoV‑2 has been shown to predominantly infect the airways and the respiratory tract and too 
often have an unpredictable and different pathologic pattern compared to other respiratory diseases. Current clinical 
diagnostical tools in pulmonary medicine expose patients to harmful radiation, are too unspecific or even invasive. 
Proteomic analysis of exhaled breath particles (EBPs) in contrast, are non‑invasive, sample directly from the pathologi‑


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cal source and presents as a novel explorative and diagnostical tool.
Methods Patients with PCR‑verified COVID‑19 infection (COV‑POS, n = 20), and patients with respiratory symptoms 
but with > 2 negative polymerase chain reaction (PCR) tests (COV‑NEG, n = 16) and healthy controls (HCO, n = 12) 
were prospectively recruited. EBPs were collected using a “particles in exhaled air” (PExA 2.0) device. Particle per 
exhaled volume (PEV) and size distribution profiles were compared. Proteins were analyzed using liquid chromatog‑
raphy‑mass spectrometry. A random forest machine learning classification model was then trained and validated on 
EBP data achieving an accuracy of 0.92.
Results Significant increases in PEV and changes in size distribution profiles of EBPs was seen in COV‑POS and 
COV‑NEG compared to healthy controls. We achieved a deep proteome profiling of EBP across the three groups 
with proteins involved in immune activation, acute phase response, cell adhesion, blood coagulation, and known 
components of the respiratory tract lining fluid, among others. We demonstrated promising results for the use of an 
integrated EBP biomarker panel together with particle concentration for diagnosis of COVID‑19 as well as a robust 
method for protein identification in EBPs.
Conclusion Our results demonstrate the promising potential for the use of EBP fingerprints in biomarker discovery 
and for diagnosing pulmonary diseases, rapidly and non‑invasively with minimal patient discomfort.
Keywords Exhaled breath particles, Proteomics, COVID‑19, LC–MS/MS, Breath analysis
*Correspondence:
Sandra Lindstedt
sandra.lindstedt_ingemansson@med.lu.se
Full list of author information is available at the end of the article


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A tripartite view of the posterior cingulate cortex
Brett L. Foster1, Seth R. Koslov1, Lyndsey Aponik-Gremillion2,3, Megan E. Monko4, 
Benjamin Y. Hayden4,5, Sarah R. Heilbronner4
1Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 
Philadelphia, PA, USA.
2Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
3Department of Health Sciences, Dumke College for Health Professionals, Weber State 
University, Ogden, UT, USA.
4Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
5Center for Magnetic Resonance Research and Center for Neural Engineering, University of 
Minnesota, Minneapolis, MN, USA.
Abstract
The posterior cingulate cortex (PCC) is one of the least understood regions of the cerebral 
cortex. By contrast, the anterior cingulate cortex has been the subject of intensive investigation in 
humans and model animal systems, leading to detailed behavioural and computational theoretical 
accounts of its function. The time is right for similar progress to be made in the PCC given 
its unique anatomical and physiological properties and demonstrably important contributions to 
higher cognitive functions and brain diseases. Here, we describe recent progress in understanding 
the PCC, with a focus on convergent findings across species and techniques that lay a foundation 
for establishing a formal theoretical account of its functions. Based on this converging evidence, 
we propose that the broader PCC region contains three major subregions – the dorsal PCC, ventral 
PCC and retrosplenial cortex – that respectively support the integration of executive, mnemonic 
and spatial processing systems. This tripartite subregional view reconciles inconsistencies in prior 
unitary theories of PCC function and offers promising new avenues for progress.
Introduction
The posterior cingulate cortex (PCC) is one of the most poorly understood regions of the 
cerebrum1-3. In general, the PCC has not received the consistent empirical and theoretical


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Reprints and permissions information is available at www.nature.com/reprints.
Correspondence should be addressed to Brett L. Foster. brett.foster@pennmedicine.upenn.edu.
Author contributions
All authors contributed to researching data for the article and writing the article. B.L.F., S.R.K., S.R.H. and B.Y.H. contributed 
significantly to discussion of article content and reviewed and/or edited the article.
Competing interests
The authors declare no competing interests.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/
s41583-022-00661-x.
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Nat Rev Neurosci. Author manuscript; available in PMC 2023 March 27.
Published in final edited form as:
Nat Rev Neurosci. 2023 March ; 24(3): 173–189. doi:10.1038/s41583-022-00661-x.
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Insufficient Oligodendrocyte Turnover in Optic Nerve Contributes to Age-Related Axon Loss and Visual Deficits


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Cellular/Molecular
Insufficient Oligodendrocyte Turnover in Optic Nerve
Contributes to Age-Related Axon Loss and Visual Deficits
Jun-Jie Zhi,1,2p Shuang-Ling Wu,2,3p Hao-Qian Wu,1,2p Qi Ran,1,2 Xing Gao,2 Jing-Fei Chen,2 Xing-Mei Gu,2,4
Tao Li,2 Fei Wang,2
Lan Xiao,2 Jian Ye,1 and Feng Mei2,3
1Department of Ophthalmology and Institute of Surgery Research, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing,
400042, China, 2Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Brain and Intelligence Research Key Laboratory of
Chongqing Education Commission, Third Military Medical University (Army Medical University), Chongqing, 400038, China, 3School of Medicine,
Chongqing University, Chongqing, 400030, China, and 4Department of Medical English Teaching and Research, Third Military Medical University (Army
Medical University), Chongqing, 400038, China
Age-related decline in visual functions is a prevalent health problem among elderly people, and no effective therapies are available
up-to-date. Axon degeneration and myelin loss in optic nerves (ONs) are age-dependent and become evident in middle-aged (13-
18months) and old (20-22months) mice of either sex compared with adult mice (3-8months), accompanied by functional deficits.
Oligodendrocyte (OL) turnover is actively going on in adult ONs. However, the longitudinal change and functional significance of OL
turnover in aging ONs remain largely unknown. Here, using cell-lineage labeling and tracing, we reported that oligodendrogenesis dis-
played an age-dependent decrease in aging ONs. To understand whether active OL turnover is required for maintaining axons and
visual function, we conditionally deleted the transcription factor Olig2 in the oligodendrocyte precursor cells of young mice.
Genetically dampening OL turnover by Olig2 ablation resulted in accelerated axon loss and retinal degeneration, and subsequently


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impaired ON signal transmission, suggesting that OL turnover is an important mechanism to sustain axon survival and visual func-
tion. To test whether enhancing oligodendrogenesis can prevent age-related visual deficits, 12-month-old mice were treated with clem-
astine, a pro-myelination drug, or induced deletion of the muscarinic receptor 1 in oligodendrocyte precursor cells. The clemastine
treatment or muscarinic receptor 1 deletion significantly increased new OL generation in the aged ONs and consequently preserved
visual function and retinal integrity. Together, our data indicate that dynamic OL turnover in ONs is required for axon survival and
visual function, and enhancing new OL generation represents a potential approach to reversing age-related declines of visual function.
Key words: clemastine; myelin; myelination; oligodendrogenesis; OPC; RGC
Significance Statement
Oligodendrocyte (OL) turnover has been reported in adult optic nerves (ONs), but the longitudinal change and functional sig-
nificance of OL turnover during aging remain largely unknown. Using cell-lineage tracing and oligodendroglia-specific manip-
ulation, this study reported that OL generation was active in adult ONs and the efficiency decreased in an age-dependent
manner. Genetically dampening OL generation by Olig2 ablation resulted in significant axon loss and retinal degeneration,
along with delayed visual signal transmission. Conversely, pro-myelination approaches significantly increased new myelin
generation in aging ONs, and consequently preserved retinal integrity and visual function. Our findings indicate that promot-
ing OL generation might be a promising strategy to preserve visual function from age-related decline.
Introduction
Age-related decline in visual functions emerges irreversibly in
the elder population, such as impaired visual acuity and contrast
sensitivity to visual signals (C. Zhang et al., 2008). The pathologic
changes underlying the functional damages are complicated and


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remain elusive. The optic nerve (ON) is mainly made up of the
axons of the retinal ganglion cells (RGCs) from the retina. The
axons are susceptible to age and undergo irreversible degenera-
tion with a ;40% decrease in axon number throughout the life-
span regardless of species (Cavallotti et al., 2002; Neufeld and
Gachie, 2003; Harwerth et al., 2008; Calkins, 2013; Fortune et al.,
Received Nov. 16, 2022; revised Jan. 16, 2023; accepted Jan. 27, 2023.
Author contributions: J.-J.Z., S.-L.W., H.-Q.W., Q.R., X.G., J.-F.C., T.L., F.W., and F.M. performed research; J.-J.Z.,
S.-L.W., H.-Q.W., Q.R., T.L., and F.W. analyzed data; H.-Q.W., X.-M.G., L.X., J.Y., and F.M. edited the paper; X.G., X.-M.G.,
T.L., L.X., and J.Y. contributed unpublished reagents/analytic tools; F.M. designed research; F.M. wrote the paper.
This work was supported by the STI 2030–Major Projects (2021ZD0201702), National Natural Science Foundation of
China (82171417, 81901378, 32000723, 31921003), Chongqing Education Commission Fund (CXQT19009), and Young Elite
Scientists Sponsorship Program by CAST (YESS 2019QNRC001). We thank Drs. J. Josh Lawrence (Texas Tech University) and
Susumu Tonegawa (Massachusetts Institute of Technology) for the M1R floxed mice; Dr. Richard Lu (University of
Cincinnati) for the Olig2 floxed mice; and Dr. Sonia Mayoral (Brown University) for critical reading of the manuscript.
*J.-J.Z., S.-L.W., and H.-Q.W. contributed equally to this work.
The authors declare no competing financial interests.
Correspondence should be addressed to Jian Ye at yejian1979@163.com or Feng Mei at meif@tmmu.edu.cn.
https://doi.org/10.1523/JNEUROSCI.2130-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, March 15, 2023 • 43(11):1859–1870 • 1859


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Cerebral blood flow and cardiovascular risk effects on resting 
brain regional homogeneity
Bhim M. Adhikaria, L. Elliot Honga, Zhiwei Zhaob, Danny J.J. Wangc, Paul M. Thompsond, 
Neda Jahanshadd, Alyssa H. Zhud, Stefan Holigae, Jessica A. Turnerf, Theo G.M. van 
Erpg,h, Vince D. Calhounf,i, Kathryn S. Hatcha, Heather Brucea, Stephanie M. Harea, Joshua 
Chiappellia, Eric L. Goldwasera, Mark D. Kvartaa, Yizhou Maa, Xiaoming Dua, Thomas E. 
Nicholsj, Alan R. Shuldinerk, Braxton D. Mitchellk, Juergen Dukartl,m, Shuo Chena, Peter 
Kochunova,∗
aMaryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School 
of Medicine, Baltimore, MD 21228
bUniversity of Maryland, College Park, MD 20742
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
∗ Corresponding author at: Maryland Psychiatry Research Center, Department of Psychiatry, University of Maryland School of 
Medicine, Baltimore, MD 21228. pkochunov@som.umaryland.edu (P. Kochunov). 
Credit authorship contribution statement
B. M. Adhikari: Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review and editing.
P. Kochunov, L. E. Hong: Conceptualization, Research design and data acquisition, Funding acquisition and project administration, 
Writing – review and editing.
S. Chen, Z. Zhao: Data analysis, Methodology, Writing – review and editing
D. J. J. Wang, P. M. Thompson, N. Jahanshad, A. H. Zhu, J. A. Turner, T. G. M. van Erp, V. D. Calhoun, K. S. Hatch, H. Bruce, S. M. 
Hare, J. Chiappelli, E. L. Goldwaser, M. D. Kvarta, Y. Ma, X. Du, T. E. Nichols, A. R. Shuldiner, B. D. Mitchell: Writing – review and 
editing
J. Dukart, S. Holiga: Resources, Writing – review and editing
Data and code availability
Relevant data are made available in the manuscript. Imaging data and relevant codes will be made available upon request.
Competing Interests


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LEH has received or plans to receive research funding or consulting fees on research projects from Mitsubishi, Your Energy Systems 
LLC, Neuralstem, Taisho, Heptares, Pfizer, Luye Pharma, Sound Pharma, Takeda, and Regeneron. None was involved in the design, 
analysis or outcomes of the study. NJ and PT received a research grant from Biogen, Inc., for research unrelated to this project. All 
other authors declare no conflicts of interest.
Credit authorship contribution statement
Bhim M. Adhikari: Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – 
review & editing. L. Elliot Hong: Conceptualization, Investigation, Funding acquisition, Project administration, Supervision, Writing 
– review & editing. Zhiwei Zhao: Formal analysis, Methodology, Writing – review & editing. Danny J.J. Wang: Writing – review 
& editing. Paul M. Thompson: Writing – review & editing. Neda Jahanshad: Writing – review & editing. Alyssa H. Zhu: Writing 
– review & editing. Stefan Holiga: Resources, Writing – review & editing. Jessica A. Turner: Writing – review & editing. Theo 
G.M. van Erp: Writing – review & editing. Vince D. Calhoun: Writing – review & editing. Kathryn S. Hatch: Writing – review & 
editing. Heather Bruce: Writing – review & editing. Stephanie M. Hare: Writing – review & editing. Joshua Chiappelli: Writing 
– review & editing. Eric L. Goldwaser: Writing – review & editing. Mark D. Kvarta: Writing – review & editing. Yizhou Ma: 
Writing – review & editing. Xiaoming Du: Writing – review & editing. Thomas E. Nichols: Writing – review & editing. Alan R. 
Shuldiner: Writing – review & editing. Braxton D. Mitchell: Writing – review & editing. Juergen Dukart: Resources, Writing 
– review & editing. Shuo Chen: Formal analysis, Methodology, Writing – review & editing. Peter Kochunov: Conceptualization, 
Investigation, Funding acquisition, Project administration, Supervision, Writing – review & editing.
Supplementary materials


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Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2022.119555.
HHS Public Access
Author manuscript
Neuroimage. Author manuscript; available in PMC 2023 March 28.
Published in final edited form as:
Neuroimage. 2022 November 15; 262: 119555. doi:10.1016/j.neuroimage.2022.119555.
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Biomimetic natural biomaterials for tissue engineering and regenerative medicine: new biosynthesis methods, recent advances, and emerging applications


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Liu et al. Military Medical Research           (2023) 10:16  
https://doi.org/10.1186/s40779-023-00448-w
REVIEW
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.
Biomimetic natural biomaterials for tissue 
engineering and regenerative medicine: 
new biosynthesis methods, recent advances, 
and emerging applications
Shuai Liu1, Jiang‑Ming Yu2, Yan‑Chang Gan1, Xiao‑Zhong Qiu1, Zhe‑Chen Gao2, Huan Wang3*, 
Shi‑Xuan Chen4*, Yuan Xiong5, Guo‑Hui Liu5, Si‑En Lin6, Alec McCarthy7, Johnson V. John8, Dai‑Xu Wei2,9,10* and 
Hong‑Hao Hou1*   
Abstract 
Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering (TE) and 
regenerative medicine. In contrast to conventional biomaterials or synthetic materials, biomimetic scaffolds based 
on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo


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extracellular matrix (ECM). Additionally, such materials have mechanical adaptability, microstructure interconnectivity, 
and inherent bioactivity, making them ideal for the design of living implants for specific applications in TE and regen‑
erative medicine. This paper provides an overview for recent progress of biomimetic natural biomaterials (BNBMs), 
including advances in their preparation, functionality, potential applications and future challenges. We highlight 
recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs 
with various biological and physicochemical characteristics of native ECM. Moreover, we offer an overview of recent 
key advances in the functionalization and applications of versatile BNBMs for TE applications. Finally, we conclude by 
offering our perspective on open challenges and future developments in this rapidly‑evolving field.
Keywords Biomimic, Scaffold, Biosynthesis, Natural biomaterial, Tissue engineering
*Correspondence:
Huan Wang
wangh679@mail.sysu.edu.cn
Shi‑Xuan Chen
chensx@ucas.ac.cn
Dai‑Xu Wei
daviddxwei@163.com
Hong‑Hao Hou
ss.hhh89@hotmail.com
1 Guangdong Provincial Key Laboratory of Construction and Detection 
in Tissue Engineering, The Fifth Affiliated Hospital, School of Basic Medical 
Science, Southern Medical University, Guangzhou 510900, China
2 Department of Orthopedics, Tongren Hospital, Shanghai Jiao Tong 
University, Shanghai 200336, China
3 The Eighth Affiliated Hospital, Sun Yat‑Sen University, Shenzhen 518033, 
Guangdong, China
4 Engineering Research Center of Clinical Functional Materials 
and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou 
Institute, University of Chinese Academy of Sciences, Wenzhou 325011, 
Zhejiang, China
5 Department of Orthopedics, Union Hospital, Tongji Medical College, 
Huazhong University of Science and Technology, Wuhan 430022, China
6 Department of Orthopaedics and Traumatology, Faculty of Medicine,


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the Chinese University of Hong Kong, Hong Kong SAR 999077, China
7 Department of Functional Materials, Terasaki Institute for Biomedical 
Innovation, Los Angeles, CA 90064, USA
8 Mary & Dick Holland Regenerative Medicine Program, College 
of Medicine, University of Nebraska Medical Center, Omaha, NE 68130, 
USA
9 Zigong Affiliated Hospital of Southwest Medical University, Zigong 
Psychiatric Research Center, Zigong Institute of Brain Science, 
Zigong 643002, Sichuan, China
10 Key Laboratory of Resource Biology and Biotechnology in Western 
China, Ministry of Education, School of Medicine, Department of Life 
Sciences and Medicine, Northwest University, Xi’an 710127, China


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Visual Characteristics of Adults with Long-Standing History of Dietary Exposure to Mercury in Grassy Narrows First Nation, Canada


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Citation: Tousignant, B.; Chatillon,
A.; Philibert, A.; Da Silva, J.; Fillion,
M.; Mergler, D. Visual Characteristics
of Adults with Long-Standing
History of Dietary Exposure to
Mercury in Grassy Narrows First
Nation, Canada. Int. J. Environ. Res.
Public Health 2023, 20, 4827. https://
doi.org/10.3390/ijerph20064827
Academic Editor: Paul B. Tchounwou
Received: 31 January 2023
Revised: 23 February 2023
Accepted: 7 March 2023
Published: 9 March 2023
Copyright:
© 2023 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
Environmental Research
and Public Health
Article
Visual Characteristics of Adults with Long-Standing History
of Dietary Exposure to Mercury in Grassy Narrows First
Nation, Canada
Benoit Tousignant 1,2,*
, Annie Chatillon 1, Aline Philibert 3, Judy Da Silva 4, Myriam Fillion 3,5
and Donna Mergler 3
1
School of Optometry, Université de Montréal, 3744 Jean-Brillant, Montreal, QC H3T 1P1, Canada
2
Department of Social and Preventive Medicine, School of Public Health, Université de Montréal,
7101 Avenue du Parc, Montreal, QC H3N 1X9, Canada
3
Centre de Recherche Interdisciplinaire sur le Bien-être, la Santé, la Société et L’environnement (Cinbiose),
Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC H3C 3P8, Canada
4
Grassy Narrows First Nation, General Delivery, Grassy Narrows, ON P0X 1B0, Canada
5
Département Science et Technologie, Université TÉLUQ, 5800, Rue Saint-Denis, Bureau 1105,
Montréal, QC H2S 3L5, Canada
*
Correspondence: benoit.tousignant@umontreal.ca
Abstract: Since the 1960s, Grassy Narrows First Nation (Ontario, Canada) has been exposed to methyl
mercury (Hg) through ﬁsh consumption, resulting from industrial pollution of their territorial waters.
This cross-sectional study describes the visual characteristics of adults with documented Hg exposure


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between 1970 and 1997. Oculo-visual examinations of 80 community members included visual acuity,
automated visual ﬁelds, optical coherence tomography [OCT], color vision and contrast sensitivity.
Median age was 57 years (IQR 51–63) and 55% of participants were women. Median visual acuity was
0.1 logMAR (Snellen 6/6.4; IQR 0–0.2). A total of 26% of participants presented a Visual Field Index
inferior to 62%, and qualitative losses assessment showed concentric constriction (18%), end-stage
concentric loss (18%), and complex defects (24%). On OCT, retinal nerve ﬁber layer scans showed
74% of participants within normal/green range. For color testing with the Hardy, Rand, and Rittler
test, 40% presented at least one type of color defect, and with the Lanthony D-15 test, median color
confusion index was 1.59 (IQR 1.33–1.96). Contrast sensitivity showed moderate loss for 83% of
participants. These ﬁndings demonstrate important loss of visual ﬁeld, color vision, and contrast
sensitivity in older adults in a context of long-term exposure to Hg in Grassy Narrows First Nation.
Keywords: methyl mercury; visual ﬁeld; optical coherence tomography; color vision; contrast
sensitivity; Indigenous peoples
1. Introduction
For many Indigenous communities around the world, ﬁsh is an important component
of traditional food systems [1]; for some, ﬁsh is not only a nutritious food [2], but also the
heart of their culture and identity [3,4]. Colonization and dispossession have resulted in
land degradation and pollution, with profound impacts on Indigenous food systems [5,6].
Mercury (Hg), from local and global sources, has polluted lakes, rivers, and oceans, bioac-
cumulating and biomagnifying through the aquatic food chain [7]. While the beneﬁts of
ﬁsh consumption have been widely documented [8,9], coastal and riverside Indigenous
communities who rely on ﬁsh for sustenance are often at risk from the toxic effects of
methyl Hg exposure [3,10,11]. In Northern Ontario, Canada, the Asubpeeschoseewagong


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Anishinabek (also known as Grassy Narrows First Nation) people have been exposed to
Hg for 60 years through ﬁsh consumption. Between 1962 and 1975, a chloralkali plant of a
pulp and paper mill discharged almost 10 tons of Hg into the ﬂuvial lake system on their
traditional territories. In 1970, ﬁsh was a dietary mainstay [12] and blood Hg concentrations
Int. J. Environ. Res. Public Health 2023, 20, 4827. https://doi.org/10.3390/ijerph20064827
https://www.mdpi.com/journal/ijerph


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Changes Caused by Bisphenols in the Chemical Coding of Neurons of the Enteric Nervous System of Mouse Stomach


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Citation: Makowska, K.; Gonkowski,
S. Changes Caused by Bisphenols in
the Chemical Coding of Neurons of
the Enteric Nervous System of Mouse
Stomach. Int. J. Environ. Res. Public
Health 2023, 20, 5125. https://
doi.org/10.3390/ijerph20065125
Academic Editor: María
Gemma Albendín
Received: 25 January 2023
Revised: 4 March 2023
Accepted: 13 March 2023
Published: 14 March 2023
Copyright:
© 2023 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
Environmental Research
and Public Health
Article
Changes Caused by Bisphenols in the Chemical Coding of
Neurons of the Enteric Nervous System of Mouse Stomach
Krystyna Makowska 1,*
and Slawomir Gonkowski 2
1
Department of Clinical Diagnostics, Faculty of Veterinary Medicine, University of Warmia and Mazury in
Olsztyn, Oczapowskiego 14, 10-957 Olsztyn, Poland
2
Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in
Olsztyn, Oczapowskiego 13, 10-957 Olsztyn, Poland
*
Correspondence: krystyna.makowska@uwm.edu.pl
Abstract: Bisphenol A (BPA), an organic chemical compound which is widely used in the production
of plastics, can severely damage live organisms. Due to these ﬁndings, the plastic industry has
started to replace it with other substances, most often with bisphenol S (BPS). Therefore, during
the present investigation, with the use of double immunoﬂuorescence labeling, we compared the
effect of BPA and BPS on the enteric nervous system (ENS) in the mouse corpus of the stomach. The
obtained results show that both studied toxins impact the amount of nerve cells immunoreactive to
substance P (SP), galanin (GAL), vesicular acetylcholine transporter (VAChT is used here as a marker
of cholinergic neurons) and vasoactive intestinal polypeptide (VIP). Changes observed under the


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impact of both bisphenols depended on the neuronal factor, the type of the enteric ganglion and the
doses of bisphenols studied. Generally, the increase in the percentage of neurons immunoreactive
to SP, GAL and/or VIP, and the decrease in the percentage of VAChT-positive neurons, was noted.
Severity of changes was more visible after BPA administration. However, the study has shown that
long time exposure to BPS also signiﬁcantly affects the ENS.
Keywords: bisphenol A; bisphenol S; mice; enteric nervous system; stomach; neuroplasticity;
immunoﬂuorescence labeling
1. Introduction
Bisphenol A (BPA) is an organic chemical compound of the phenol family that is
widely used in the production of plastics [1]. However, more and more studies have shown
the many negative effects of BPA on the living organism. Until now, the harmful effects of
this substance have been noticed in almost every internal system of the organism, ﬁrst of
all including the endocrine, reproductive and nervous systems [2].
These allegations have led to different ways of reducing the use of BPA in the plastic
industry. Therefore, many countries have introduced various restrictions on the use of
BPA [1,3] and several substitutes of BPA have been implemented for the plastic production.
The substitute that is most commonly used is bisphenol S (BPS) [4]. Although at ﬁrst
BPS seemed safe for living organisms, more and more studies have featured its harmful
effects on humans and animals [4–6]. It has been discovered that, as with BPA, BPS is also
an endocrine disruptor with a negative impact on endocrine, digestive and reproductive
systems [7].
Bisphenols can get to the organism through several routes, namely through the di-
gestive tract, airway or skin [8]. The main route of exposure is the gastrointestinal tract,
which is connected with the penetration of bisphenols from food containers and bottles to
food and drinking water [1]. In the living organism, every alimentary toxin has to cross the


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intestinal barrier formed with the immune system and enteric nervous system (ENS) [9].
Therefore, the ﬁrst subclinical signs of bisphenol intoxication can involve disturbances in
the digestive tract.
Int. J. Environ. Res. Public Health 2023, 20, 5125. https://doi.org/10.3390/ijerph20065125
https://www.mdpi.com/journal/ijerph


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Repeatability and reproducibility of various 4D Flow CMR postprocessing software programs in a multi-software and multi-vendor cross-over comparison study


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Oechtering et al. 
Journal of Cardiovascular Magnetic Resonance           (2023) 25:22  
https://doi.org/10.1186/s12968-023-00921-4
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.
Journal of Cardiovascular
Magnetic Resonance
Repeatability and reproducibility of various 
4D Flow MRI postprocessing software programs 
in a multi-software and multi-vendor cross-over 
comparison study
Thekla H. Oechtering1,2,3*  , André Nowak1,2, Malte M. Sieren1,2, Andreas M. Stroth1,2, Nicolas Kirschke1,2, 
Franz Wegner1,2, Maren Balks1,2, Inke R. König4, Ning Jin5, Joachim Graessner6, Hendrik Kooijman‑Kurfuerst7, 
Anja Hennemuth8,9, Jörg Barkhausen1,2 and Alex Frydrychowicz1,2 
Abstract 
Background Different software programs are available for the evaluation of 4D Flow cardiovascular magnetic reso‑
nance (CMR). A good agreement of the results between programs is a prerequisite for the acceptance of the method.


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Therefore, the goal was to compare quantitative results from a cross‑over comparison in individuals examined on two 
scanners of different vendors analyzed with four postprocessing software packages.
Methods Eight healthy subjects (27 ± 3 years, 3 women) were each examined on two 3T CMR systems (Ingenia, 
Philips Healthcare; MAGNETOM Skyra, Siemens Healthineers) with a standardized 4D Flow CMR sequence. Six manu‑
ally placed aortic contours were evaluated with Caas (Pie Medical Imaging, SW‑A), cvi42 (Circle Cardiovascular Imag‑
ing, SW‑B), GTFlow (GyroTools, SW‑C), and MevisFlow (Fraunhofer Institute MEVIS, SW‑D) to analyze seven clinically 
used parameters including stroke volume, peak flow, peak velocity, and area as well as typically scientifically used wall 
shear stress values. Statistical analysis of inter‑ and intrareader variability, inter‑software and inter‑scanner comparison 
included calculation of absolute and relative error  (ER), intraclass correlation coefficient (ICC), Bland–Altman analysis, 
and equivalence testing based on the assumption that inter‑software differences needed to be within 80% of the 
range of intrareader differences.
Results SW‑A and SW‑C were the only software programs showing agreement for stroke volume (ICC = 0.96; 
 ER = 3 ± 8%), peak flow (ICC: 0.97;  ER = −1 ± 7%), and area (ICC = 0.81;  ER = 2 ± 22%). Results from SW‑A/D and SW‑C/D 
were equivalent only for area and peak flow. Other software pairs did not yield equivalent results for routinely used 
clinical parameters. Especially peak maximum velocity yielded poor agreement (ICC ≤ 0.4) between all software pack‑
ages except SW‑A/D that showed good agreement (ICC = 0.80). Inter‑ and intrareader consistency for clinically used 
parameters was best for SW‑A and SW‑D (ICC = 0.56–97) and worst for SW‑B (ICC = ‑0.01–0.71). Of note, inter‑scanner 
differences per individual tended to be smaller than inter‑software differences.


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Conclusions Of all tested software programs, only SW‑A and SW‑C can be used equivalently for determination of 
stroke volume, peak flow, and vessel area. Irrespective of the applied software and scanner, high intra‑ and interreader 
*Correspondence:
Thekla H. Oechtering
Thekla.Oechtering@uksh.de
Full list of author information is available at the end of the article


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Strategies for modelling endometrial diseases
Alina R. Murphy,
Hannes Campo,
J. Julie Kim
Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, 
Northwestern University, Chicago, IL, USA.
Abstract
Each month during a woman’s reproductive years, the endometrium undergoes vast changes to 
prepare for a potential pregnancy. Diseases of the endometrium arise for numerous reasons, many 
j-kim4@northwestern.edu .
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Endocrinology thanks Caroline Gargett, Virginia Pensabene and the other, anonymous, reviewer(s) for their 
contribution to the peer review of this work.
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other 
rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such 
publishing agreement and applicable law.
Organoids
3D cellular aggregates that self-assemble and form structural units that partially resemble the organ in both structure and function.
Microphysiological systems
Integrative, microfabricated platforms designed to recapitulate functional units of human organs in vitro; also known as organ-on-a-
chip technology.
Thermoplastics
A class of polymer that can be permanently deformed through the application of heat.
Curettage
Scraping or removal of endometrial tissue for diagnostic or therapeutic purposes.
Spheroids
3D, simple clusters of cells that lack self-assembly or organization.
Sampson’s retrograde menstruation theory
Theory to explain the aetiology of endometriosis in which retrograde flow of sloughed endometrial cells during menstruation occurs 
through the fallopian tubes into the pelvic cavity promoting the establishment of ectopic lesions.
Chorioallantoic membrane


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(CAM). A membrane in bird eggs that is the site of gas exchange for the embryo.
Transwell
A commercially available Boyden chamber device with a microporous membrane that inserts into a standard cell culture well and 
provides a second compartment.
Micropatterned
Seeding and controlling the geometry and location of cells at the microscale level.
Müllerian remnants
Pluripotent remains of the embryonic precursor to the uterus, which could undergo metaplasia into endometrial tissue during the 
development of adenomyosis.
Biobanking
Creating a repository of biological samples for use in future research.
HHS Public Access
Author manuscript
Nat Rev Endocrinol. Author manuscript; available in PMC 2023 March 29.
Published in final edited form as:
Nat Rev Endocrinol. 2022 December ; 18(12): 727–743. doi:10.1038/s41574-022-00725-z.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


key: title
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Using mesoscopic tract-tracing data to guide the estimation of fiber orientation distributions in the mouse brain from diffusion\
 MRI


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Using mesoscopic tract-tracing data to guide the estimation of 
fiber orientation distributions in the mouse brain from diffusion 
MRI
Zifei Liang,
Tanzil Mahmud Arefin,
Choong H. Lee,
Jiangyang Zhang*
Department of Radiology, Bernard and Irene Schwartz Center for Biomedical Imaging, New York 
University School of Medicine, 660 First Ave, New York, NY 10016, USA
Abstract
Diffusion MRI (dMRI) tractography is the only tool for non-invasive mapping of macroscopic 
structural connectivity over the entire brain. Although it has been successfully used to reconstruct 
large white matter tracts in the human and animal brains, the sensitivity and specificity of 
dMRI tractography remained limited. In particular, the fiber orientation distributions (FODs) 
estimated from dMRI signals, key to tractography, may deviate from histologically measured 
fiber orientation in crossing fibers and gray matter regions. In this study, we demonstrated that 
a deep learning network, trained using mesoscopic tract-tracing data from the Allen Mouse 
Brain Connectivity Atlas, was able to improve the estimation of FODs from mouse brain dMRI 
data. Tractography results based on the network generated FODs showed improved specificity 
while maintaining sensitivity comparable to results based on FOD estimated using a conventional 
spherical deconvolution method. Our result is a proof-of-concept of how mesoscale tract-tracing 
data can guide dMRI tractography and enhance our ability to characterize brain connectivity.
Keywords
Diffusion MRI; Tractography; Mouse brain; Deep learning; Fiber orientation distribution; 
Connectivity
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
*Corresponding author. Jiangyang.zhang@nyulangone.org (J. Zhang). 
Credit author statement
The project was conceived by Z.L. and J.Z.. T.A. was involved in discussion and tractography. C.L. acquired and analyzed most MR 
images. Z.L. and J.Z. wrote and prepared the paper, C.L. and T.A. edited the paper.


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Declaration of Competing Interest
The authors declare no competing interest related to the work presented here.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2023.119999.
HHS Public Access
Author manuscript
Neuroimage. Author manuscript; available in PMC 2023 April 15.
Published in final edited form as:
Neuroimage. 2023 April 15; 270: 119999. doi:10.1016/j.neuroimage.2023.119999.
Author Manuscript
Author Manuscript
Author Manuscript
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Multiregion transcriptomic profiling of the primate brain reveals signatures of aging and the social environment


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Multiregion transcriptomic profiling of the primate brain reveals 
signatures of aging and the social environment
Kenneth L. Chiou1,2,3,4,28, Alex R. DeCasien5,6,28, Katherina P. Rees2, Camille Testard7, 
Cailyn H. Spurrell8, Aishwarya A. Gogate8,9, Hannah A. Pliner8, Sébastien Tremblay7, 
Arianne Mercer3, Connor J. Whalen5, Josué E. Negrón-Del Valle2, Mareike C. Janiak10, 
Samuel E. Bauman Surratt11, Olga González12, Nicole R. Compo11, Michala K. Stock13, 
Angelina V. Ruiz-Lambides11, Melween I. Martínez11,
Cayo Biobank Research Unit*,
Melissa A. Wilson1,2, Amanda D. Melin14,15,16, Susan C. Antón5,6, Christopher S. Walker17, 
Jérôme Sallet18, Jason M. Newbern2, Lea M. Starita8,19, Jay Shendure8,19,20,21, James P. 
Higham5,6, Lauren J. N. Brent22, Michael J. Montague7, Michael L. Platt7,23,24, Noah Snyder-
Mackler1,2,3,4,25,26,27
1Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA.
2School of Life Sciences, Arizona State University, Tempe, AZ, USA.
3Department of Psychology, University of Washington, Seattle, WA, USA.
*A list of authors and their affiliations appears at the end of the paper.
Reprints and permissions information is available at www.nature.com/reprints.
Correspondence and requests for materials should be addressed to Kenneth L. Chiou, Alex R. DeCasien or Noah Snyder-Mackler. 
chiou@asu.edu; alex.decasien@nyu.edu; nsnyderm@asu.edu.
Author contributions
N.S.-M., M.L.P., M.J.M., J.P.H., L.J.N.B., K.L.C. and A.R.D. conceptualized the research. N.S.-M., J. Shendure, M.L.P., M.J.M., 
L.M.S. and K.L.C. conceptualized the single-cell sequencing studies. M.J.M., N.S.-M., K.L.C., A.R.D., O.G., N.R.C., S.E.B.S., 
M.C.J., C.J.W. and S.T. collected brain tissue, facilitated by M.I.M., A.V.R.-L., J. Sallet, C.S.W., S.C.A., M.K.S., A.D.M., J.P.H., 
M.L.P. and CBRU. M.A.W. contributed data. K.L.C., A.R.D., A.M. and C.H.S. performed genomic lab work. J.E.N.-D.V. collected


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behavioral data using a protocol designed by L.J.N.B. K.L.C., A.R.D., C.H.S., A.A.G. and H.A.P. performed genomic analysis 
with input from N.S.-M. and J. Shendure. C.T. and L.J.N.B. performed behavioral analysis. K.P.R. and J.M.N. performed protein 
experiments and analysis. K.L.C., A.R.D. and N.S.-M. wrote the manuscript. All authors reviewed and revised the manuscript. Full 
membership of the CBRU: S. C. Antón, L. J. N. Brent, J. P. Higham, M. I. Martínez, A. D. Melin, M. J. Montague, M. L. Platt, J. 
Sallet and N. Snyder-Mackler
Competing interests
J. Shendure is a scientific advisory board member, consultant and/or cofounder of Cajal Neuroscience, Guardant Health, Maze 
Therapeutics, Camp4 Therapeutics, Phase Genomics, Adaptive Biotechnologies, Scale Biosciences and Sixth Street Capital. M.L.P. 
is a scientific advisory board member, consultant and/or cofounder of Blue Horizons International, NeuroFlow, Amplio, Cogwear 
Technologies, Burgeon Labs and Ashurst Cognitive Health and receives research funding from AIIR Consulting, the SEB Group, Mars 
Inc., Slalom Inc., the Lefkort Family Research Foundation, Sisu Capital and Benjamin Franklin Technology Partners. All other authors 
declare no competing interests.
Extended data is available for this paper at https://doi.org/10.1038/s41593-022-01197-0.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/
s41593-022-01197-0.
Reporting summary
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Online content
Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, 
acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code 
availability are available at https://doi.org/10.1038/s41593-022-0n97-0.
HHS Public Access
Author manuscript
Nat Neurosci. Author manuscript; available in PMC 2023 June 01.


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Published in final edited form as:
Nat Neurosci. 2022 December ; 25(12): 1714–1723. doi:10.1038/s41593-022-01197-0.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability


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https://doi.org/10.1093/brain/awac031
BRAIN 2023: 146; 359–371 | 359
Stem cell-derived sensory neurons modelling 
inherited erythromelalgia: normalization of 
excitability
Matthew Alsaloum,1,2,3,4,5 Julie I. R. Labau,1,2,3,6,7 Shujun Liu,1,2,3 Philip R. Effraim2,3,8 
and Stephen G. Waxman1,2,3
Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic ap-
proaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of 
NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree 
of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered ques-
tion important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem 
cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused 
by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs as-
sociated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show 
that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.
1
Department of Neurology, Yale School of Medicine, New Haven, CT 06510, USA
2
Center for Neuroscience and Regeneration Research, Yale University, West Haven, CT 06516, USA
3
Center for Rehabilitation Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA
4
Yale Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06510, USA
5
Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USA
6
Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University 
Medical Centre, Maastricht, The Netherlands
7
Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
8


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8
Department of Anesthesiology, Yale School of Medicine, New Haven, CT 06510, USA
Correspondence to: Stephen G. Waxman  
Center for Neuroscience and Regeneration Research  
950 Campbell Ave, Building 34, West Haven, CT 06516, USA  
E-mail: Stephen.waxman@yale.edu
Keywords: Inherited erythromelalgia; Nav1.7; dynamic clamp; iPSC; stem cell-derived sensory neurons
Received October 17, 2021. Revised December 30, 2021. Accepted January 6, 2022. Advance access publication January 28, 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: 
journals.permissions@oup.com
Introduction
Chronic pain affects a significant percentage of the global 
population1–3 and contributes to multiple comorbidities and 
an impaired quality of life.4–6 Unfortunately, most pharma-
cotherapies are only partially effective or ineffective and may 
be associated with significant adverse effects.7–9 The develop-
ment of improved pain therapeutics is an urgent healthcare 
need.
Voltage-gated sodium (NaV) channels have emerged as promis-
ing targets for the development of novel pain therapeutics. Nine 
different NaV channels (NaV1.1–NaV1.9) have been described in hu-
mans.10,11 Of these nine NaV channel isoforms, three—NaV1.7, 
NaV1.8, and NaV1.9—are preferentially expressed in dorsal root 
ganglion (DRG) neurons, primary afferents responsible for trans-
mitting pain information into the spinal cord.12 Hyperexcitability 
of DRG neurons is known to underlie the development and


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https://doi.org/10.1093/brain/awac339
BRAIN 2023: 146; 20–41 | 20
Temporopolar regions of the human brain
M.-Marsel Mesulam
Following prolonged neglect during the formative decades of behavioural neurology, the temporopolar region has be-
come a site of vibrant research on the neurobiology of cognition and conduct. This turnaround can be attributed to in-
creasing recognition of neurodegenerative diseases that target temporopolar regions for peak destruction. The 
resultant syndromes include behavioural dementia, associative agnosia, semantic forms of primary progressive aphasia 
and semantic dementia. Clinicopathological correlations show that object naming and word comprehension are critically 
dependent on the language-dominant (usually left) temporopolar region, whereas behavioural control and non-verbal 
object recognition display a more bilateral representation with a rightward bias. Neuroanatomical experiments in maca-
ques and neuroimaging in humans show that the temporoparietal region sits at the confluence of auditory, visual and 
limbic streams of processing at the downstream (deep) pole of the ‘what’ pathway. The functional neuroanatomy of 
this region revolves around three axes, an anterograde horizontal axis from unimodal to heteromodal and paralimbic cor-
tex; a radial axis where visual (ventral), auditory (dorsal) and paralimbic (medial) territories encircle temporopolar cortex 
and display hemispheric asymmetry; and a vertical depth-of-processing axis for the associative elaboration of words, ob-
jects and interoceptive states. One function of this neural matrix is to support the transformation of object and word re-
presentations from unimodal percepts to multimodal concepts. The underlying process is likely to start at canonical 
gateways that successively lead to generic (superordinate), specific (basic) and unique levels of recognition. A first sign 
of left temporopolar dysfunction takes the form of taxonomic blurring where boundaries among categories are preserved


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but not boundaries among exemplars of a category. Semantic paraphasias and coordinate errors in word–picture verifi-
cation tests are consequences of this phenomenon. Eventually, boundaries among categories are also blurred and com-
prehension impairments become more profound. The medial temporopolar region belongs to the amygdalocentric 
component of the limbic system and stands to integrate exteroceptive information with interoceptive states underlying 
social interactions. Review of the pertinent literature shows that word comprehension and conduct impairments caused 
by temporopolar strokes and temporal lobectomy are far less severe than those seen in temporopolar atrophies. One ex-
planation for this unexpected discrepancy invokes the miswiring of residual temporopolar neurons during the many 
years of indolently progressive neurodegeneration. According to this hypothesis, the temporopolar regions become 
not only dysfunctional but also sources of aberrant outputs that interfere with the function of areas elsewhere in the lan-
guage and paralimbic networks, a juxtaposition not seen in lobectomy or stroke.
Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of 
Medicine, Chicago, IL 60611, USA
Correspondence to: M. Mesulam  
330 East Superior St, Tarry-8, Chicago, IL 60611, USA  
E-mail: mmesulam@northwestern.edu
Keywords: temporal pole; semantics; word comprehension; object recognition; dementia; aphasia; TDP-C
Received April 8, 2022. Revised July 26, 2022. Accepted August 29, 2022. Advance access publication November 4, 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: 
journals.permissions@oup.com
Introduction
In 1934, Karl Kleist1 published a detailed functional localization 
map where every nook and cranny of the cerebral cortex but one 
was assigned a consequential task. The temporopolar region was


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the sole exception (Fig. 1A). A similar verdict came from Bogen 
and Bogen,2 who wrote: ‘If you have … a cerebral lesion that pro-
duces a loss of language … it is rather unlikely that the lesion will


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The anti-immune dengue subgenomic flaviviral RNA is present in vesicles in mosquito saliva and is associated with increased infectivity


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RESEARCH ARTICLE
The anti-immune dengue subgenomic
flaviviral RNA is present in vesicles in
mosquito saliva and is associated with
increased infectivity
Shih-Chia Yeh1☯¤a, Tania Strilets2☯, Wei-Lian Tan1, David Castillo3, Hacène Medkour4,
Fe´lix Rey-Cadilhac4, Idalba M. Serrato-Pomar4, Florian Rachenne4, Avisha Chowdhury5¤b,
Vanessa Chuo1, Sasha R. Azar6, Moirangthem Kiran Singh2, Rodolphe Hamel4,
Dorothe´e Misse´ 4, R. Manjunatha Kini5,7, Linda J. Kenney2, Nikos Vasilakis6,8,9,10,11,12,13,
Marc A. Marti-Renom3,14,15,16, Guy Nir2, Julien Pompon1,4‡*, Mariano A. Garcia-
BlancoID1,2,17,18‡*
1 Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 2 Department of
Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of
America, 3 CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and
Technology (BIST), Barcelona, Spain, 4 MIVEGEC, Univ. Montpellier, IRD, CNRS, Montpellier, France,
5 Department of Biological Sciences, National University of Singapore, Singapore, 6 Department of
Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America, 7 Department
of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 8 Center
for Biodefense and Emerging Infectious Diseases, University of University of Texas Medical Branch,
Galveston, Texas, United States of America, 9 Center for Tropical Diseases, University of University of Texas
Medical Branch, Galveston, Texas, United States of America, 10 Institute for Human Infection and Immunity,
University of University of Texas Medical Branch, Galveston, Texas, United States of America, 11 Center for
Vector-Borne and Zoonotic Diseases, University of University of Texas Medical Branch, Galveston, Texas,
United States of America, 12 Department of Preventive Medicine and Population Health, University of
University of Texas Medical Branch, Galveston, Texas, United States of America, 13 World Reference


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Center for Emerging Viruses and Arboviruses, University of University of Texas Medical Branch, Galveston,
Texas, United States of America, 14 Centre for Genomic Regulation (CRG), Barcelona Institute of Science
and Technology (BIST), Barcelona, Spain, 15 Universitat Pompeu Fabra (UPF), Barcelona, Spain,
16 ICREA, Barcelona, Spain, 17 Department of Internal Medicine, University of Texas Medical Branch,
Galveston, Texas, United States of America, 18 Department of Microbiology, Immunology and Cancer
Biology, University of Virginia, Charlottesville, Virginia, United States of America
☯ These authors contributed equally to this work.
¤a Current address: Cancer Science Institute of Singapore, National University of Singapore, Singapore
¤b Current address: Toronto Centre for Liver Disease, University Health Network, Princess Margaret Cancer
Research Tower, Toronto, Canada
‡ JP and MAG-B also contributed equally to this work.
* julien.pompon@ird.fr (JP); marianogb@virginia.edu, maragarc@utmb.edu (MAGB)
Abstract
Mosquito transmission of dengue viruses to humans starts with infection of skin resident
cells at the biting site. There is great interest in identifying transmission-enhancing factors in
mosquito saliva in order to counteract them. Here we report the discovery of high levels of
the anti-immune subgenomic flaviviral RNA (sfRNA) in dengue virus 2-infected mosquito
saliva. We established that sfRNA is present in saliva using three different methods: north-
ern blot, RT-qPCR and RNA sequencing. We next show that salivary sfRNA is protected in
detergent-sensitive compartments, likely extracellular vesicles. In support of this
PLOS PATHOGENS
PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011224
March 30, 2023
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OPEN ACCESS
Citation: Yeh S-C, Strilets T, Tan W-L, Castillo D,
Medkour H, Rey-Cadilhac F, et al. (2023) The anti-
immune dengue subgenomic flaviviral RNA is
present in vesicles in mosquito saliva and is


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associated with increased infectivity. PLoS Pathog
19(3): e1011224. https://doi.org/10.1371/journal.
ppat.1011224
Editor: Amy L. Hartman, University of Pittsburgh,
UNITED STATES
Received: August 4, 2022
Accepted: February 20, 2023
Published: March 30, 2023
Copyright: © 2023 Yeh 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: All relevant data are
within the manuscript and its Supporting
Information files. The link https://github.com/
Garcia-BlancoGroup/Yehetal2022 describes in
house macros.
Funding: Support for this research came from a
fellowship from the McLauglin Family Foundation
to TS, scholarships from the Fondation pour la
Recherche Me´dicale (FRM project
SPF202110013925) to HM, from the Institut


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Vector-based SARS-CoV-2 vaccination is associated with improved T-cell responses in hematological neoplasia


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Vector-based SARS-CoV-2 vaccination is associated with improved
T-cell responses in hematological neoplasia
Robby Engelmann,1 Nadja Jaekel,2 Sabrina Jotschke,3 Beatrice Ludwig-Kraus,4 Frank Bernhard Kraus,4 Neha Kumari,1 Susann Schulze,3
Michael Hecker,5 Christina Zahn,2 Haifa Kathrin Al-Ali,3 Christian Junghanss,1 and Sebastian Böttcher1
1Clinic III—Hematology, Oncology, and Palliative Care, Rostock University Medical Center, Rostock, Germany; 2University Clinic and Outpatient Clinic for Internal Medicine IV,
3Krukenberg Cancer Center Halle and 4Central Laboratory, University Hospital Halle (Saale), Halle (Saale), Germany; and 5Division of Neuroimmunology, Department of
Neurology, Rostock University Medical Center, Rostock, Germany
Key Points
• Vector-based SARS-
CoV-2 vaccines are
advantageous for the
generation of T-cell
responses in patients
with hematological
neoplasia.
• CD4+ and CD8+ T-cell
responses cooccur in
hematological
neoplasms, whereas
IgG titers are CD4+ T
cells associated in
myeloid neoplasia only.
In order to elucidate mechanisms for severe acute respiratory syndrome coronavirus
2 vaccination success in hematological neoplasia, we, herein, provide a
comprehensive characterization of the spike-speciﬁc T-cell and serological immunity
induced in 130 patients in comparison with 91 healthy controls. We studied 121
distinct T-cell subpopulations and the vaccination schemes as putative response
predictors. In patients with lymphoid malignancies an insufﬁcient immunoglobulin G
(IgG) response was accompanied by a healthy CD4+ T-cell function. Compared with
controls, a spike-speciﬁc CD4+ response was detectable in fewer patients with myeloid
neoplasia whereas the seroconversion rate was normal. Vaccination-induced CD4+
responses were associated to CD8+ and IgG responses. Vector-based AZD1222 vaccine
induced more frequently detectable speciﬁc CD4+ responses in study participants
across all cohorts (96%; 27 of 28), whereas fully messenger RNA-based vaccination


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schemes resulted in measurable CD4+ cells in only 102 of 168 participants (61%;
P < .0001). A similar beneﬁt of vector-based vaccination was observed for the
induction of spike-speciﬁc CD8+ T cells. Multivariable models conﬁrmed vaccination
schemes that incorporated at least 1 vector-based vaccination as key feature to mount
both a spike-speciﬁc CD4+ response (odds ratio, 10.67) and CD8+ response (odds ratio,
6.56). Multivariable analyses identiﬁed a speciﬁc CD4+ response but not the vector-
based immunization as beneﬁcial for a strong, speciﬁc IgG titer. Our study reveals
factors associated with a T-cell response in patients with hematological neoplasia and
might pave the way toward tailored vaccination schemes for vaccinees with these
diseases. The study was registered at the German Clinical Trials Register as
#DRKS00027372.
Submitted 29 September 2022; accepted 13 March 2023; prepublished online on
Blood
Advances
First
Edition
22
March
2023.
https://doi.org/10.1182/
bloodadvances.2022009054.
All R scripts and accompanying raw data are available upon reasonable request to the
corresponding author, Sebastian Böttcher (sebastian.boettcher@med.uni-rostock.de).
The full-text version of this article contains a data supplement.
© 2023 by The American Society of Hematology. Licensed under Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0),
permitting only noncommercial, nonderivative use with attribution. All other rights
reserved.
REGULAR ARTICLE
25 JULY 2023 • VOLUME 7, NUMBER 14
3403


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ARTICLE
OPEN
Pramipexole modulates fronto-subthalamic pathway
in sequential working memory
Marcus Heldmann1,2, Eliana Mönch1, Antonia Kesseböhmer1, Norbert Brüggemann1,3, Thomas F. Münte1,2✉ and Zheng Ye4✉
© The Author(s) 2022
Brain dopamine may regulate the ability to maintain and manipulate sequential information online. However, the precise role of
dopamine remains unclear. This pharmacological fMRI study examined whether and how the dopamine D2/3 receptor agonist
pramipexole modulates fronto-subthalamic or fronto-striatal pathways during sequential working memory. This study used a
double-blind, randomized crossover design. Twenty-two healthy male volunteers completed a digit ordering task during fMRI
scanning after receiving a single oral dose of 0.5-mg pramipexole or placebo. The pramipexole effects on task performance,
regional activity, activity pattern similarity, and functional connectivity were analyzed. Pramipexole impaired task performance,
leading to less accurate and slower responses in the digit ordering task. Also, it downregulated the maintenance-related
subthalamic and dorsolateral prefrontal activity, increasing reaction times for maintaining sequences. In contrast, pramipexole
upregulated the manipulation-related subthalamic and dorsolateral prefrontal activity, increasing reaction time costs for
manipulating sequences. In addition, it altered the dorsolateral prefrontal activity pattern similarity and fronto-subthalamic
functional connectivity. Finally, pramipexole reduced maintenance-related striatal activity, which did not affect the behavior. This
study conﬁrms the role of the fronto-subthalamic pathway in sequential working memory. Furthermore, it shows that D2
transmission can regulate sequential working memory by modulating the fronto-subthalamic pathway.
Neuropsychopharmacology (2023) 48:716–723; https://doi.org/10.1038/s41386-022-01494-z
INTRODUCTION
Brain dopamine is known to regulate visuospatial working memory
[1–3]. It may also regulate sequential working memory as patients


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with Parkinson’s disease (PD) exhibit difﬁculties in arranging items
in a speciﬁc order [4, 5], understanding stories that are told
backward [6, 7], and planning sequential steps to achieve goals
[8–10]. To better understand the role of dopaminergic innervation,
this study investigates whether and how the D2/3 receptor agonist
pramipexole modulates the fronto-subthalamic hyperdirect or
fronto-striatal indirect pathway during sequential working memory.
In visuospatial working memory, the dual-state theory of prefrontal
dopamine function [11] assumes that a cortical D2-dominated state
(e.g., D2 receptor activation) facilitates ﬂexible manipulation, whereas
a cortical D1-dominated state (e.g., D2 receptor blockade) favors
persistent maintenance of information. The tonic-phasic dopamine
hypothesis emphasizes a balance of tonic and phasic dopamine
function in the frontal and subcortical regions [12, 13]. Namely,
increased phasic and reduced tonic dopamine transmission sub-
cortically and reduced dopamine concentration cortically (i.e.,
increased D2 and reduced D1 transmission) may facilitate ﬂexible
manipulation but impair persistent maintenance of information. In
contrast, reduced phasic and increased tonic dopamine transmission
subcortically and increased dopamine concentration cortically (i.e.,
increased D1 and reduced D2 transmission) may have opposite
effects on visuospatial working memory [14].
Distinct roles of D1 versus D2 transmission in sequential working
memory are less understood. Human pharmacological and genetic
studies had inconsistent ﬁndings. In healthy adults, the D2 receptor
antagonist sulpiride (D2 receptor blockade) can improve perfor-
mance in reordering sequential items [15] but impair performance
in planning sequential steps [16, 17]. In patients with PD, both the
D2 receptor agonist bromocriptine (predominant D2 receptor
activation) and levodopa (predominant D1 receptor activation)
can improve performance in maintaining or reordering sequential


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items [18, 19]. The Val allele of the COMT Val158Met polymorphism
(high COMT activity, increased D2 and reduced D1 transmission)
improves performance in planning sequential steps [20]. But the Val
allele of the BDNF Val66Met polymorphism (high BDNF secretion
and increased D3 transmission) impairs performance in planning
sequential steps [21]. These ﬁndings don’t ﬁt well with current
dopaminergic models of visuospatial working memory.
We have put forward a fronto-basal ganglia model for sequential
working memory [22]. We assume that the prefrontal cortex encodes
and retrieves sequential items through a competitive queuing
mechanism [23–25]. The competitive queuing mechanism comprises
a parallel planning layer, which represents the serial position of items
as the relative strength of node activations, and a competitive choice
layer, which forms reciprocal connections which the parallel
planning layer and selects the node with the strongest activation.
The basal ganglia may interact with the competitive choice layer to
Received: 20 June 2022 Revised: 23 October 2022 Accepted: 26 October 2022
Published online: 9 November 2022
1Department of Neurology, University of Lübeck, Lübeck 23538, Germany. 2Institute of Psychology II, University of Lübeck, Lübeck 23538, Germany. 3Institute of Neurogenetics,
University of Lübeck, Lübeck 23538, Germany. 4Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences,
Shanghai 200031, China. ✉email: thomas.muente@neuro.uni-luebeck.de; yez@ion.ac.cn
www.nature.com/npp
1234567890();,:


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Correction: A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque \(Macaca mulatta\) model


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CORRECTION
Correction: A time-course comparative clinical
and immune response evaluation study
between the human pathogenic Orientia
tsutsugamushi strains: Karp and Gilliam in a
rhesus macaque (Macaca mulatta) model
Manutsanun Inthawong, Piyanate Sunyakumthorn, Sirima Wongwairot,
Tippawan Anantatat, Susanna J. Dunachie, Rawiwan Im-Erbsin, James W. Jones, Carl
J. Mason, Luis A. Lugo, Stuart D. Blacksell, Nicholas P. J. Day, Piengchan Sonthayanon,
Allen L. Richards, Daniel H. Paris
There is an error in the affiliation order for author Manutsanun Inthawong. The correct affilia-
tion order is:
Manutsanun Inthawong1,2
1 Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine,
Mahidol University, Bangkok, Thailand
2 Department of Veterinary Medicine, United States Army Medical Directorate, Armed
Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok, Thailand
Reference
1.
Inthawong M, Sunyakumthorn P, Wongwairot S, Anantatat T, Dunachie SJ, Im-Erbsin R, et al. (2022) A
time-course comparative clinical and immune response evaluation study between the human patho-
genic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model.
PLoS Negl Trop Dis 16(8): e0010611. https://doi.org/10.1371/journal.pntd.0010611 PMID: 35925895
PLOS NEGLECTED TROPICAL DISEASES
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0011277
April 12, 2023
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Citation: Inthawong M, Sunyakumthorn P,
Wongwairot S, Anantatat T, Dunachie SJ, Im-
Erbsin R, et al. (2023) Correction: A time-course
comparative clinical and immune response
evaluation study between the human pathogenic
Orientia tsutsugamushi strains: Karp and Gilliam in
a rhesus macaque (Macaca mulatta) model. PLoS
Negl Trop Dis 17(4): e0011277. https://doi.org/
10.1371/journal.pntd.0011277
Published: April 12, 2023
Copyright: This is an open access article, free of all
copyright, and may be freely reproduced,


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distributed, transmitted, modified, built upon, or
otherwise used by anyone for any lawful purpose.
The work is made available under the Creative
Commons CC0 public domain dedication.


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Orexinergic neurons in the hypothalami of an Asiatic lion, an African lion, and a Southeast African cheetah


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Received: 1 September 2022
Revised: 17 October 2022
Accepted: 19 October 2022
DOI: 10.1002/cne.25431
R E S E A R C H A R T I C L E
Orexinergic neurons in the hypothalami of an Asiatic lion, an
African lion, and a Southeast African cheetah
Demi Oddes1
Ayanda Ngwenya1
Illke B. Malungo1
Anita Burkevica2
Therese Hård3
Mads. F. Bertelsen4
Muhammad A. Spocter1,5
D. Michael Scantlebury6
Paul R. Manger1
1School of Anatomical Sciences, Faculty of
Health Sciences, University of the
Witwatersrand, Johannesburg, South Africa
2Parken Zoo i Eskilstuna AB, Eskilstuna,
Sweden
3Borås Zoo, Borås, Sweden
4Centre for Zoo and Wild Animal Health,
Copenhagen Zoo, Frederiksberg, Denmark
5Department of Anatomy, Des Moines
University, Des Moines, Iowa, USA
6School of Biological Sciences, Queen’s
University Belfast, Belfast, UK
Correspondence
Paul Manger, School of Anatomical Sciences,
Faculty of Health Sciences, University of the
Witwatersrand, 7 York Road, Parktown,
Johannesburg, 2193, South Africa.
Email: Paul.Manger@wits.ac.za
Funding information
Carnegie Corporation of New York; South
African National Research Foundation;
seed-funding from Queen’s University, Belfast,
and the University of the Witwatersrand
Abstract
Employing orexin-A immunohistochemistry, we describe the distribution, morphology,
and nuclear parcellation of orexinergic neurons within the hypothalami of an Asiatic
lion (Panthera leo subsp. persica), an African lion (Panthera leo subsp. melanochaita),
and a Southeast African cheetah (Acinonyx jubatus subsp. jubatus). In all three felids,
the clustering of large, bipolar, and multipolar hypothalamic orexinergic neurons pri-
marily follows the pattern observed in other mammals. The orexinergic neurons were
found, primarily, to form three distinct clusters—the main, zona incerta, and optic tract
clusters. In addition, large orexinergic neurons were observed in the ventromedial
supraoptic region of the hypothalamus, where they are not typically observed in other


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species. As has been observed in cetartiodactyls and the African elephant, a cluster of
small, multipolar orexinergic neurons, the parvocellular cluster, was observed in the
medial zone of the hypothalamus in all three felids, although this parvocellular cluster
has not been reported in other carnivores. In both subspecies of lions, but not the chee-
tah, potential orexin-immunopositive neurons were observed in the paraventricular
hypothalamic nucleus, supraoptic nucleus, the lateral part of the retrochiasmatic area,
and the inner layer of the median eminence. The distribution and parcellation of orexin-
ergic neurons in the hypothalami of the three felids studied appear to be more complex
than observed in many other mammals and for the two subspecies of lion may be even
more complex. These findings are discussed in terms of potential technical concerns,
phylogenetic variations of this system, and potentially associated functional aspects of
the orexinergic system.
KEY WO RDS
Carnivora, Felidae, hypocretin, immunohistochemistry, orexin, RRID:AB_91545, stereology
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2022 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals LLC.
366
wileyonlinelibrary.com/journal/cne
J Comp Neurol. 2023;531:366–389.


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Received: 23 June 2022
Revised: 25 September 2022
Accepted: 9 October 2022
DOI: 10.1111/andr.13325
O R I G I N A L A R T I C L E
Complete meiosis in rat prepubertal testicular tissue under
in vitro sequential culture conditions
Justine Saulnier1
Mathilde Soirey1
Nasreddine Kébir2
Marion Delessard1
Aurélie Rives-Feraille1
Laura Moutard1
Ludovic Dumont1
Nathalie Rives1
Christine Rondanino1
1INSERM, U1239, Adrenal and Gonadal
Pathophysiology team, Laboratory of
Neuroendocrine Endocrine and Germinal
Differentiation and Communication, Rouen
University Hospital, Rouen Normandy
University, Rouen, France
2Normandie Univ, INSA Rouen Normandie,
Laboratoire PBS, Saint-Etienne-du-Rouvray,
France
Correspondence
Christine Rondanino, INSERM, U1239,
Adrenal and Gonadal Pathophysiology team,
Laboratory of Neuroendocrine Endocrine and
Germinal Differentiation and Communication,
Rouen University Hospital, Rouen Normandy
University, Rouen, France.
Email: christine.rondanino@univ-rouen.fr
Funding information
Rouen Normandy University
Abstract
Background: Testicular tissue cryopreservation before gonadotoxic treatments allows
fertility preservation in children suffering from cancer. Fertility restoration strategies,
in particular in vitro maturation of prepubertal testicular tissue, are being developed
mainly in animal models. The rat, widely used in biomedical research, including in
reproductive biology, is a relevant model.
Objectives: To determine whether sequential two-step culture protocols can improve
the efficiency of rat in vitro spermatogenesis.
Materials and methods: Rat prepubertal testicular tissues were cultured on agarose
gels with either a one-step or two-step protocol with or without polydimethyl-
siloxane (PDMS) ceiling chips. The progression of spermatogenesis, germ/Sertoli
cell ratio, cell proliferation, seminiferous tubule area, and intratubular cell density
were assessed by histological and immunohistochemical analyses. Terminal deoxynu-


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cleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays and Peanut
Agglutinin (PNA) lectin labeling were performed to analyze the Deoxyribonucleic Acid
(DNA) integrity and differentiation step of in vitro-produced spermatids.
Results: Sequential two-step protocols allowed the production of spermatids with
a higher efficiency compared with the one-step culture protocol. However, the effi-
ciency was low, as less than 1.5% of tubules contained spermatids. Most of the in
vitro-produced spermatids contained unfragmented DNA and were at an early step of
differentiation. Rare elongating spermatids could be detected in the cultured explants.
Although complete in vitro spermatogenesis could not be obtained with PDMS ceiling
chips, entry into meiosis was promoted in one-step organotypic cultures.
Discussion and conclusion: Complete in vitro meiosis and the beginning of the elon-
gation phase of spermiogenesis were obtained in a rat model using sequential culture
methods. Because of their low efficiency, further work will be necessary to identify
the culture conditions allowing the completion of spermiogenesis. These optimizations
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. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.
Andrology. 2023;11:167–176.
wileyonlinelibrary.com/journal/andr
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J Physiol 600.23 (2022) pp 5077–5099
5077
The Journal of Physiology
Neuronal activity patterns in microcircuits of the cerebellar
cortical C3 zone during reaching
Nadia L. Cerminara1
, Martin Garwicz2, Henry Darch1, Conor Houghton3
, Dilwyn E. Marple-Horvat4
and Richard Apps1
1School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK
2Neuronano Research Centre and Birgit Rausing Centre for Medical Humanities, Department of Experimental Medical Science, Lund University, Lund,
Sweden
3Department of Computer Science, University of Bristol, Bristol, UK
4Department of Life Sciences, Manchester Metropolitan University, Manchester, UK
Handling Editors: Richard Carson & Vatsala Thirumalai
The peer review history is available in the Supporting Information section of this article
(https://doi.org/10.1113/JP282928#support-information-section).
Nadia Cerminara is a Research Fellow at the University of Bristol, UK. She obtained her PhD in neurophysiology from Monash University, Australia,
in 2002. Using an in vivo systems-level approach, a key aim of her work is to determine the information processing that occurs in cerebellar circuits
during the performance of both new and well-rehearsed movements.
N. L. Cerminara, M. Garwicz, D. E. Marple-Horvat and R. Apps contributed as senior authors.
This article was first published as a preprint. Cerminara NL, Garwicz M, Darch H, Houghton C, Marple-Horvat DE, Apps R. 2020. Action-based
organization and function of cerebellar cortical microcircuits. bioRxiv. https://doi.org/10.1101/2020.04.04.025387
© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
DOI: 10.1113/JP282928
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.


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R E S E A R C H A R T I C L E
Characterizing microglial gene expression in a model
of secondary progressive multiple sclerosis
Ilia D. Vainchtein1
|
Astrid M. Alsema1
|
Marissa L. Dubbelaar1
|
Corien Grit1
|
Jonathan Vinet2
|
Hilmar R. J. van Weering1
|
Sarah Al-Izki3
|
Giuseppe Biagini2
|
Nieske Brouwer1
|
Sandra Amor3,4
|
David Baker3
|
Bart J. L. Eggen1
|
Erik W. G. M. Boddeke1,5
|
Susanne M. Kooistra1
1Department of Biomedical Sciences of Cells &
Systems, Section Molecular Neurobiology,
University of Groningen, University Medical
Center Groningen, Groningen,
The Netherlands
2Department of Biomedical, Metabolic and
Neural Sciences, University of Modena and
Reggio Emilia, Modena, Italy
3Department of Neuroimmunology, Blizard
Institute, Barts and the London School of
Medicine and Dentistry, Queen Mary
University of London, London, UK
4Department of Pathology, VUMC,
Amsterdam, The Netherlands
5Department of Cellular and Molecular
Medicine, Center for Healthy Ageing,
University of Copenhagen, Copenhagen,
Denmark
Correspondence
Ilia D. Vainchtein and Susanne M. Kooistra,
Department of Biomedical Sciences of Cells &
Systems, Section Molecular Neurobiology,
University of Groningen, University Medical
Center Groningen, Groningen,
The Netherlands.
Email: ilia.vainchtein@gmail.com and s.m.
kooistra@umcg.nl
Funding information
Italian MS Foundation, Grant/Award Number:
2011/B/7; Stichting MS Research,
Grant/Award Numbers: 10-723, 16-947
Abstract
Multiple sclerosis (MS) is the most common inflammatory, demyelinating and neuro-
degenerative disease of the central nervous system in young adults. Chronic-
relapsing experimental autoimmune encephalomyelitis (crEAE) in Biozzi ABH mice is
an experimental model of MS. This crEAE model is characterized by an acute phase
with severe neurological disability, followed by remission of disease, relapse of neu-
rological disease and remission that eventually results in a chronic progressive phase
that mimics the secondary progressive phase (SPEAE) of MS. In both MS and SPEAE,


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the role of microglia is poorly defined. We used a crEAE model to characterize micro-
glia in the different phases of crEAE phases using morphometric and RNA sequencing
analyses. At the initial, acute inflammation phase, microglia acquired a pro-
inflammatory phenotype. At the remission phase, expression of standard immune
activation genes was decreased while expression of genes associated with lipid
metabolism and tissue remodeling were increased. Chronic phase microglia partially
regain inflammatory gene sets and increase expression of genes associated with pro-
liferation. Together, the data presented here indicate that microglia obtain different
features at different stages of crEAE and a particularly mixed phenotype in the
chronic stage. Understanding the properties of microglia that are present at the
chronic phase of EAE will help to understand the role of microglia in secondary pro-
gressive MS, to better aid the development of therapies for this phase of the disease.
K E Y W O R D S
experimental autoimmune encephalitis, microglia, RNA sequencing, secondary progressive MS
1
|
INTRODUCTION
Microglia are the tissue-resident macrophages of the central nervous
system
(CNS)
and
recent
genome-wide
association
analysis
(International Multiple Sclerosis Genetics Consortium, 2019) and
Ilia D. Vainchtein and Astrid M. Alsema contributed equally to this study.
Received: 16 March 2022
Revised: 30 September 2022
Accepted: 26 October 2022
DOI: 10.1002/glia.24297
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. GLIA published by Wiley Periodicals LLC.
588
Glia. 2023;71:588–601.
wileyonlinelibrary.com/journal/glia


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Nature Reviews Nephrology
nature reviews nephrology
https://doi.org/10.1038/s41581-023-00704-1
Review article
 Check for updates
Complosome — the intracellular 
complement system
Erin E. West 
   & Claudia Kemper 
   
Abstract
The complement system is a recognized pillar of host defence against 
infection and noxious self-derived antigens. Complement is traditionally 
known as a serum-effective system, whereby the liver expresses and  
secretes most complement components, which participate in the 
detection of bloodborne pathogens and drive an inflammatory reac -
tion to safely remove the microbial or antigenic threat. However, pertur-
bations in normal complement function can cause severe disease and,  
for reasons that are currently not fully understood, the kidney is parti-
cularly vulnerable to dysregulated complement activity. Novel insights  
into complement biology have identified cell-autonomous and intra-
cellularly active complement — the complosome — as an unexpected central 
orchestrator of normal cell physiology. For example, the complo some 
controls mitochondrial activity, glycolysis, oxidative phosphorylation, 
cell survival and gene regulation in innate and adaptive immune cells, and 
in non-immune cells, such as fibroblasts and endothelial and epithelial 
cells. These unanticipated complosome contributions to basic cell 
physiological pathways make it a novel and central player in the control 
of cell homeostasis and effector responses. This discovery, together with 
the realization that an increasing number of human diseases involve 
complement perturbations, has renewed interest in the complement 
system and its therapeutic targeting. Here, we summarize the current 
knowledge about the complosome across healthy cells and tissues, 
highlight contributions from dysregulated complosome activities  
to human disease and discuss potential therapeutic implications.
Sections
Introduction
Classical functions of systemic 
and local extracellular 
complement
Intracellular complement and


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its role in cell physiology
The complosome across cells 
and tissues
The complosome in human 
disease
Therapeutic implications
Conclusions
National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Complement and 
Inflammation Research Section (CIRS), Bethesda, MD, USA. 
 e-mail: claudia.kemper@nih.gov


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Syrian hamster convalescence from prototype SARS-CoV-2 confers measurable protection against the attenuated disease caused by the Omicron variant


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RESEARCH ARTICLE
Syrian hamster convalescence from prototype
SARS-CoV-2 confers measurable protection
against the attenuated disease caused by the
Omicron variant
Kathryn A. RyanID*, Kevin R. Bewley, Robert J. Watson, Christopher Burton,
Oliver Carnell, Breeze E. Cavell, Amy Challis, Naomi S. Coombes, Elizabeth R. Davies,
Jack Edun-Huges, Kirsty Emery, Rachel Fell, Susan A. Fotheringham, Karen E. Gooch,
Kathryn Gowan, Alastair Handley, Debbie J. Harris, Richard Hesp, Laura Hunter,
Richard Humphreys, Rachel Johnson, Chelsea Kennard, Daniel Knott, Sian Lister,
Daniel Morley, Didier Ngabo, Karen L. Osman, Jemma Paterson, Elizabeth J. Penn, Steven
T. Pullan, Kevin S. Richards, Sian Summers, Stephen R. Thomas, Thomas Weldon,
Nathan R. Wiblin, Emma L. Rayner, Richard T. Vipond, Bassam Hallis, Francisco
J. Salguero, Simon G. P. Funnell, Yper Hall
UK Health Security Agency, Salisbury, United Kingdom
* kathryn.ryan@ukhsa.gov.uk
Abstract
The mutation profile of the SARS-CoV-2 Omicron (lineage BA.1) variant posed a concern
for naturally acquired and vaccine-induced immunity. We investigated the ability of prior
infection with an early SARS-CoV-2 ancestral isolate (Australia/VIC01/2020, VIC01) to pro-
tect against disease caused by BA.1. We established that BA.1 infection in naïve Syrian
hamsters resulted in a less severe disease than a comparable dose of the ancestral virus,
with fewer clinical signs including less weight loss. We present data to show that these clini-
cal observations were almost absent in convalescent hamsters challenged with the same
dose of BA.1 50 days after an initial infection with ancestral virus. These data provide evi-
dence that convalescent immunity against ancestral SARS-CoV-2 is protective against
BA.1 in the Syrian hamster model of infection. Comparison with published pre-clinical and
clinical data supports consistency of the model and its predictive value for the outcome in
humans. Further, the ability to detect protection against the less severe disease caused by


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BA.1 demonstrates continued value of the Syrian hamster model for evaluation of BA.1-spe-
cific countermeasures.
Author summary
The Golden Syrian hamster model has proved to be a robust model for SARS-CoV-2, with
clinical signs, pathological changes and viral load outputs providing endpoints for an ani-
mal model of COVID-19, suitable for the assessment of interventions that may serve to
prevent infection, transmission and/or disease. Following wild type virus infection in the
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Citation: Ryan KA, Bewley KR, Watson RJ, Burton
C, Carnell O, Cavell BE, et al. (2023) Syrian hamster
convalescence from prototype SARS-CoV-2
confers measurable protection against the
attenuated disease caused by the Omicron variant.
PLoS Pathog 19(4): e1011293. https://doi.org/
10.1371/journal.ppat.1011293
Editor: Jacob S. Yount, The Ohio State University,
UNITED STATES
Received: August 23, 2022
Accepted: March 11, 2023
Published: April 4, 2023
Copyright: © 2023 Ryan 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: All relevant data are
within the manuscript and its Supporting
Information files.
Funding: This work was funded by the Coalition for
Epidemic Preparedness Innovations’ (CEPI) Agility
Programme. 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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Intranasal booster using an Omicron vaccine confers broad mucosal and systemic immunity against SARS-CoV-2 variants


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ARTICLE
OPEN
Intranasal booster using an Omicron vaccine confers broad
mucosal and systemic immunity against SARS-CoV-2 variants
Qian Wang1, Chenchen Yang2,3, Li Yin4,5, Jing Sun1, Wei Wang3, Hengchun Li4,5, Zhengyuan Zhang4,5, Si Chen3, Bo Liu2,3, Zijian Liu4,5,
Linjing Shi4,5, Xiaolin Liu2,3, Suhua Guan2,3, Chunhua Wang2,3, Linbing Qu4, Ying Feng3, Xuefeng Niu1, Liqiang Feng4,
Jincun Zhao
1,3✉, Pingchao Li4✉, Ling Chen1,3,4✉ and Nanshan Zhong1,3
The highly contagious SARS-CoV-2 Omicron subvariants severely attenuated the effectiveness of currently licensed SARS-CoV-2
vaccines based on ancestral strains administered via intramuscular injection. In this study, we generated a recombinant, replication-
incompetent human adenovirus type 5, Ad5-S-Omicron, that expresses Omicron BA.1 spike. Intranasal, but not intramuscular
vaccination, elicited spike-speciﬁc respiratory mucosal IgA and residential T cell immune responses, in addition to systemic
neutralizing antibodies and T cell immune responses against most Omicron subvariants. We tested intranasal Ad5-S-Omicron as a
heterologous booster in mice that previously received intramuscular injection of inactivated ancestral vaccine. In addition to
inducing serum broadly neutralizing antibodies, there was a signiﬁcant induction of respiratory mucosal IgA and neutralizing
activities against Omicron subvariants BA.1, BA.2, BA.5, BA.2.75, BF.7 as well as pre-Omicron strains Wildtype, Beta, and Delta. Serum
and mucosal neutralizing activities against recently emerged XBB, BQ.1, and BQ.1.1 could also be detected but were much lower.
Nasal lavage ﬂuids from intranasal vaccination contained multimeric IgA that can bind to at least 10 spike proteins, including
Omicron subvariants and pre-Omicron strains, and possessed broadly neutralizing activities. Intranasal vaccination using Ad5-S-
Omicron or instillation of intranasal vaccinee’s nasal lavage ﬂuids in mouse nostrils protected mice against Omicron challenge.


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Taken together, intranasal Ad5-S-Omicron booster on the basis of ancestral vaccines can establish effective mucosal and systemic
immunity against Omicron subvariants and multiple SARS-CoV-2 variants. This candidate vaccine warrants further development as a
safe, effective, and user-friendly infection and transmission-blocking vaccine.
Signal Transduction and Targeted Therapy  (2023) 8:167 
; https://doi.org/10.1038/s41392-023-01423-6
INTRODUCTION
It has been over 3 years since the beginning of the COVID-19
pandemic that is caused by SARS-CoV-2, which is an enveloped
single-stranded RNA virus. Vaccines are the most effective way to
minimize infection and associated morbidity and mortality. The
spike protein of SARS-CoV-2 is the principal target for antibody
and vaccine countermeasures. SARS-CoV-2 enters and replicates in
epithelial cells through the binding of spike with the cell-surface
receptor angiotensin-converting enzyme 2 (ACE2). As of March 06,
2023, over two-thirds of the world’s population has received at
least one dose of a COVID-19 vaccine, and 13.23 billion doses have
been administered globally.1 Although infection or vaccine-
induced neutralizing antibodies can inhibit the binding and
infection of SARS-CoV-2, the virus mutates rapidly. An increasing
list of lineages is designated variants of concern (VOCs) due to
increased transmission and evasion of vaccine-induced immunity,
including Beta, Delta, and Omicron subvariants.
Since the end of 2021, the dominant variants have become and
remained thus far the Omicron subvariants, including BA.1, BA.2,
BA.2.12.1, BA.2.75, BA.4, BA.5, BF.7, BQ.1, BQ.1.1, and XBB. These
subvariants contain multiple mutations with the capability of
strong immune escape and rapid transmission. The effectiveness
of the 2-dose mRNA-1273 vaccine against Omicron infection was
30.4% between 14–90 days and declined to 0% by 180 days post-
vaccination.2 Even with the 4th dose of mRNA vaccine of ancestral
strain, vaccine efﬁcacy against symptomatic infection was 30% for


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BNT162b2 and 11% for mRNA-1273, and people had a high viral
load in the nasopharyngeal tract that can be highly transmissible.3
The outcome of reduced vaccine efﬁcacy against new variants and
lack of mucosal immunity may provide conditions for further
selection of highly resistant and transmissible variants in the
upper airway. Thus, there is a need to establish an immune barrier
that can provide front-line immunity to block infection and
transmission of Omicron subvariants.
SARS-CoV-2 infection starts in the upper respiratory system,
where the nasopharyngeal tract is at the forefront. To prevent
viruses from attaching and replicating at the mucosal epithelium,
effective mucosal immunity in the airway is critically important.
Earlier studies have shown that mucosal booster vaccination with
adenovirus-vectored ancestral vaccines after mRNA priming can
Received: 26 November 2022 Revised: 14 March 2023 Accepted: 22 March 2023
1State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Afﬁliated Hospital of Guangzhou Medical University, Guangzhou, China;
2Guangzhou nBiomed Ltd., Guangzhou, China; 3Guangzhou Laboratory & Bioland Laboratory, Guangzhou, China; 4Guangdong Laboratory of Computational Biomedicine,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China and 5University of Chinese Academy of Sciences, Beijing, China
Correspondence: Jincun Zhao (zhaojincun@gird.cn) or Pingchao Li (li_pingchao@gibh.ac.cn) or Ling Chen (chen_ling@gibh.ac.cn)
These authors contributed equally: Qian Wang, Chenchen Yang, Li Yin, Jing Sun, Wei Wang.
The original online version of this article was revised: The error in


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Nature Reviews Immunology
nature reviews immunology
https://doi.org/10.1038/s41577-023-00858-w
Review article
 Check for updates
Antiviral neutralizing antibodies: 
from in vitro to in vivo activity
Dennis R. Burton 
  1,2 
Abstract
Neutralizing antibodies (nAbs) are being increasingly used as passive 
antiviral reagents in prophylactic and therapeutic modalities and to 
guide viral vaccine design. In vivo, nAbs can mediate antiviral functions 
through several mechanisms, including neutralization, which is defined 
by in vitro assays in which nAbs block viral entry to target cells, and 
antibody effector functions, which are defined by in vitro assays that 
evaluate nAbs against viruses and infected cells in the presence of 
effector systems. Interpreting in vivo results in terms of these  
in vitro assays is challenging but important in choosing optimal passive 
antibody and vaccine strategies. Here, I review findings from many 
different viruses and conclude that, although some generalizations are 
possible, deciphering the relative contributions of different antiviral 
mechanisms to the in vivo efficacy of antibodies currently requires 
consideration of individual antibody–virus interactions.
Sections
Introduction
Mechanisms of neutralization 
in vitro
Neutralization stoichiometry
Antibody effector assays
Antiviral antibody activities 
in vivo
Concluding remarks
1Department of Immunology and Microbiology, Consortium for HIV/AIDS Vaccine Development, International 
AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA. 2Ragon 
Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, 
Cambridge, MA, USA. 
 e-mail: burton@scripps.edu


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The E2 glycoprotein holds key residues for Mayaro virus adaptation to the urban Aedes aegypti mosquito


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RESEARCH ARTICLE
The E2 glycoprotein holds key residues for
Mayaro virus adaptation to the urban Aedes
aegypti mosquito
Chelsea Cereghino1,2☯, Ferdinand Roesch3,4☯, Lucı´a Carrau3,5, Alexandra Hardy3, Helder
V. Ribeiro-Filho6, Annabelle Henrion-Lacritick7, Cassandra Koh7, Jeffrey M. Marano1,8,
Tyler A. Bates1, Pallavi Rai1, Christina Chuong1, Shamima Akter1,9, Thomas Vallet3,
Herve´ Blanc7, Truitt J. Elliott10,11,12, Anne M. Brown10, Pawel Michalak1,13,14,15,
Tanya LeRoith1, Jesse D. Bloom16,17, Rafael Elias Marques6, Maria-Carla Saleh7,
Marco Vignuzzi3, James Weger-LucarelliID1,2,3*
1 Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine,
Virginia Tech, Blacksburg, Virginia, United States of America, 2 Center for Emerging, Zoonotic, and
Arthropod-borne Pathogens, Virginia Tech, Blacksburg, Virginia, United States of America, 3 Institut Pasteur,
Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris,
France, 4 UMR 1282 ISP, INRAE Centre Val de Loire, Nouzilly, France, 5 Department of Microbiology, New
York University Langone Medical Center, New York, New York, United States of America, 6 Brazilian
Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials (CNPEM),
Campinas, São Paulo, Brazil, 7 Institut Pasteur, Viruses and RNA Interference Unit, Centre National de la
Recherche Scientifique UMR 3569, Paris, France, 8 Translational Biology, Medicine, and Health Graduate
Program, Virginia Tech, Roanoke, Virginia, United States of America, 9 Department of Bioinformatics and
Computational Biology, School of Systems Biology, George Mason University, Fairfax, Virginia, United States
of America, 10 Program in Genetics, Bioinformatics, and Computational Biology (GBCB), Virginia Tech,
Blacksburg, Virginia, United States of America, 11 Research and Informatics, University Libraries, Virginia
Tech, Blacksburg, Virginia, United States of America, 12 Department of Biochemistry, Virginia Tech,


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Blacksburg, Virginia, United States of America, 13 Edward Via College of Osteopathic Medicine, Monroe,
Louisiana, United States of America, 14 Center for One Health Research, VA-MD Regional College of
Veterinary Medicine, Blacksburg, Virginia, Untied States of Ameria, 15 Institute of Evolution, University of
Haifa, Haifa, Israel, 16 Basic Sciences Division and Computational Biology Program, Fred Hutchinson
Cancer Research Center, Seattle, Washington, United States of America, 17 Howard Hughes Medical
Institute, Chevy Chase, Maryland, United States of America
☯ These authors contributed equally to this work.
* weger@vt.edu
Abstract
Adaptation to mosquito vectors suited for transmission in urban settings is a major driver in
the emergence of arboviruses. To better anticipate future emergence events, it is crucial to
assess their potential to adapt to new vector hosts. In this work, we used two different exper-
imental evolution approaches to study the adaptation process of an emerging alphavirus,
Mayaro virus (MAYV), to Ae. aegypti, an urban mosquito vector of many other arboviruses.
We identified E2-T179N as a key mutation increasing MAYV replication in insect cells and
enhancing transmission after escaping the midgut of live Ae. aegypti. In contrast, this muta-
tion decreased viral replication and binding in human fibroblasts, a primary cellular target of
MAYV in humans. We also showed that MAYV E2-T179N generates reduced viremia and
displays less severe tissue pathology in vivo in a mouse model. We found evidence in
mouse fibroblasts that MAYV E2-T179N is less dependent on the Mxra8 receptor for replica-
tion than WT MAYV. Similarly, exogenous expression of human apolipoprotein receptor 2
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Citation: Cereghino C, Roesch F, Carrau L, Hardy
A, Ribeiro-Filho HV, Henrion-Lacritick A, et al.
(2023) The E2 glycoprotein holds key residues for


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Mayaro virus adaptation to the urban Aedes aegypti
mosquito. PLoS Pathog 19(4): e1010491. https://
doi.org/10.1371/journal.ppat.1010491
Editor: Thomas E. Morrison, University of Colorado
Denver, UNITED STATES
Received: April 4, 2022
Accepted: March 13, 2023
Published: April 5, 2023
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
process; therefore, we enable the publication of
all of the content of peer review and author
responses alongside final, published articles. The
editorial history of this article is available here:
https://doi.org/10.1371/journal.ppat.1010491
Copyright: © 2023 Cereghino 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: Raw sequencing data
was deposited under the Sequence Read Archive
(SRA, NCBI) under bioproject number


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Evaluation of Oral V2043 in a Mouse Model of SARS-CoV-2 Infection and Synthesis and Antiviral Evaluation of Additional Phospholipid Esters with Enhanced Anti-SARS-CoV-2 Activity


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1‑O‑Octadecyl-2‑O‑benzyl-sn-glyceryl-3-phospho-GS-441524
(V2043). Evaluation of Oral V2043 in a Mouse Model of SARS-CoV‑2
Infection and Synthesis and Antiviral Evaluation of Additional
Phospholipid Esters with Enhanced Anti-SARS-CoV‑2 Activity
Aaron F. Carlin,# James R. Beadle,# Alex E. Clark, Kendra L. Gully, Fernando R. Moreira, Ralph S. Baric,
Rachel L. Graham, Nadejda Valiaeva, Sandra L. Leibel, William Bray, Rachel E. McMillan,
Jonathan E. Freshman, Aaron F. Garretson, Rachael N. McVicar, Tariq Rana, Xing-Quan Zhang,
Joyce A. Murphy, Robert T. Schooley, and Karl Y. Hostetler*
Cite This: J. Med. Chem. 2023, 66, 5802−5819
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sı
Supporting Information
ABSTRACT: Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease caused
by COVID-19. An orally bioavailable RDV analog may facilitate earlier treatment of non-hospitalized COVID-19 patients. Here we
describe the synthesis and evaluation of alkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which
allow for oral bioavailability and stability in plasma. Oral treatment of SARS-CoV-2-infected BALB/c mice with 1-O-octadecyl-2-O-
benzyl-sn-glyceryl-3-phospho-RVn (60 mg/kg orally, once daily for 5 days starting 12h after infection) reduced lung viral load by
1.5 log10 units versus vehicle at day 2 and to below the limit of detection at day 5. Structure/activity evaluation of additional analogs
that have hydrophobic ethers at the sn-2 of glycerol revealed improved in vitro antiviral activity by introduction of a 3-fluoro-4-
methoxy-substituted benzyl or a 3- or 4-cyano-substituted benzyl. Collectively, our data support the development of RVn
phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections.
■ INTRODUCTION
Since its emergence in late 2019, SARS-CoV-2 has resulted in
the deaths of more than a million people in the United States


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and over 6.5 million people globally.1 Despite the dramatic
impact of SARS-CoV-2 vaccines on COVID-19-related
morbidity, COVID-19 remains the third most frequent cause
of death in the U.S. behind only cardiovascular disease and
cancer.2 The emergence of novel SARS-CoV-2 variants
coupled with the natural decay of coronavirus immunity has
contributed to successive waves of new and breakthrough
infections since the advent of COVID-19 vaccines. Vaccine
hesitancy and the partial vaccine protection provided to older
and immunocompromised populations further compromise
vaccine efficacy at the population level.3−5 Viral evolution has
also severely compromised the efficacy of all currently available
SARS-CoV-2-specific monoclonal antibodies for the preven-
tion or treatment of the infection.6
Two orally bioavailable antiviral drugs are currently
available, nirmatrelvir/ritonavir and molnupiravir.7,8 Nirma-
trelvir/ritonavir reduces hospitalization and death, but the
substantial number of ritonavir-related drug−drug interactions
related to its effects on hepatic metabolism and gut transport
mechanisms, as well as the physician reticence to dose-adjust
other medications in patients who are otherwise stable,
Received:
January 9, 2023
Published: April 11, 2023
Article
pubs.acs.org/jmc
© 2023 The Authors. Published by
American Chemical Society
5802
https://doi.org/10.1021/acs.jmedchem.3c00046
J. Med. Chem. 2023, 66, 5802−5819


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Longitudinal analyses using 18F-Fluorodeoxyglucose positron emission tomography with computed tomography as a measure of COVID-19 severity in the aged, young, and humanized ACE2 SARS-CoV-2 hamster models


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Efficient and Precise Processing of the Optimized Primary Artificial MicroRNA in a Huntingtin-Lowering Adeno-Associated Viral Gene Therapy In Vitro and in Mice and Nonhuman Primates


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Efﬁcient and Precise Processing of the Optimized Primary
Artiﬁcial MicroRNA in a Huntingtin-Lowering Adeno-Associated
Viral Gene Therapy In Vitro and in Mice and Nonhuman Primates
Wei Wang,1,{,{ Pengcheng Zhou,1,{,x Xin Wang,1 Fen Chen,1,** Emily Christensen,1,{{ Jeffrey Thompson,1
Xiaoqin Ren,1 Adrian Kells,1,{{ Lisa Stanek,2,xx Todd Carter,1 Jay Hou,1,*** and Dinah W.Y. Sah1,*,i
1Voyager Therapeutics, Cambridge, Massachusetts, USA; 2Sanoﬁ-Genzyme, Framingham, Massachusetts, USA.
{Both these authors are co-ﬁrst authors.
Current afﬁliations: {Tome Biosciences, Cambridge, Massachusetts, USA.
xFrontera Therapeutics, Bedford, Massachusetts, USA.
**Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
{{IDEXX Laboratories, Westbrook, Maine, USA.
{{Asklepios BioPharmaceutical, Columbus, Ohio, USA.
xxAfﬁnia Therapeutics, Waltham, Massachusetts, USA.
***Skyline Therapeutics, Shanghai, China.
iORCID ID (https://orcid.org/0000-0003-2598-5881).
Huntington’s disease is a fatal neurodegenerative disorder caused by an inherited mutation in the huntingtin (HTT) gene
comprising an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat sequence that results in a pathogenic hun-
tingtin protein. Adeno-associated viral (AAV) gene therapy containing a primary artiﬁcial microRNA (pri-amiRNA)
speciﬁcally targeting HTT messenger RNA (mRNA) has the potential to provide long-lasting therapeutic beneﬁt, through
durable reduction of mutant HTT expression after a single administration. The efﬁciency and precision of processing of the
pri-amiRNA precursor to the mature guide (G) strand by transduced cells are critical for speciﬁc and potent HTT mRNA
lowering. The selection of the optimized pri-amiRNA comprised a series of in vitro studies followed by in vivo studies in
small and then large mammals. Our studies demonstrate the predictivity of certain cell culture systems and rodent models for
nonhuman primates with respect to some, but not all key features of pri-amiRNA processing. In addition, our results show


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that the processing of pri-amiRNAs to the mature guide strand can differ greatly across different scaffolds and sequences
while providing the same levels of target lowering. Importantly, our data demonstrate that there is a combinatorial effect of
guide and passenger (P) strand sequences, together with the scaffold, on pri-amiRNA processing, with different guide and
passenger strand sequences within the same scaffold dramatically altering pri-amiRNA processing. Taken together, our
results highlight the importance of optimizing not only target lowering but also the efﬁciency and precision of pri-amiRNA
processing in vitro, in rodents and in large mammals to identify the most potent and selective AAV gene therapy that
harnesses the endogenous microRNA (miRNA) biogenesis pathway for target lowering without perturbing the endogenous
cellular miRNA proﬁle. The optimized pri-amiRNA was selected with this focus on efﬁciency and precision of pri-amiRNA
processing in addition to its pharmacological activity on HTT mRNA lowering and general tolerability in vivo.
Keywords: RNAi, artiﬁcial microRNA, Huntington’s disease, huntingtin lowering, in vivo
INTRODUCTION
HUNTINGTON’S DISEASE (HD) is a rare, autosomal-dominant,
debilitating, and fatal neurodegenerative disorder charac-
terized by progressive motor, cognitive, and neuropsychi-
atric impairment. There are no effective therapies. Clinical
onset based on motor diagnosis occurs at *40 years of age
on average, with death typically 15–20 years later, preceded
by profound physical deterioration and dementia.
HD is caused by a mutation in the huntingtin (HTT)
gene, in which an expansion of more than *39 cytosine
*Correspondence: Dr. Dinah W.Y. Sah, Voyager Therapeutics, 75 Sidney Street, Cambridge, MA 02139, USA. E-mail: dinah@vygr.com
The abstract portion of this article was presented at the ESGCT XXV Anniversary Congress in Collaboration with the German Society for Gene Therapy October 17–20, 2017


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Berlin, Germany; and also presented at the 21st Annual ASGCT Meeting, May 16–19, 2018, Chicago, IL, USA.
ª Wei Wang et al., 2021; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License [CC-BY]
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
HUMAN GENE THERAPY, VOLUME 33, NUMBERS 1–2
DOI: 10.1089/hum.2021.221 j 37
Mary Ann Liebert, Inc.


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Non-Lactobacillus-Dominant and Polymicrobial Vaginal Microbiomes Are More Common in Younger South African Women and Predictive of Increased Risk of Human Immunodeficiency Virus Acquisition


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Clinical Infectious Diseases                                          
M A J O R  A R T I C L E
Non-Lactobacillus-Dominant and Polymicrobial Vaginal 
Microbiomes Are More Common in Younger South 
African Women and Predictive of Increased Risk of 
Human Immunodeficiency Virus Acquisition
Yiran Wang,1,a Laura Noël-Romas,1,2,a Michelle Perner,3,a Samantha Knodel,1,2,a Refilwe Molatlhegi,4 Sarah Hoger,5 Kenzie Birse,1,2 Christina Farr Zuend,1
Lyle R. McKinnon,5 and Adam D. Burgener1,2,6
1Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; 2Department of Obstetrics and Gynecology, University of Manitoba, Winnipeg, 
Canada; 3Sexually Transmitted Infectious and Bloodborne Pathogens Section, JC Wilt Infectious Disease Research Center, Public Health Agency of Canada, Winnipeg, Canada; 4Department of 
Medical Microbiology, University of KwaZulu-Natal, Durban, South Africa; 5Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada; and 6Unit of 
Infectious Diseases, Department of Medicine Solna, Center for Molecular, Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Background. Adolescent girls and young women aged 15‒24 years in sub-Saharan Africa are at disproportionate risk of human 
immunodeficiency virus (HIV) infection. Given the known association between vaginal microbial dysbiosis and HIV susceptibility, we 
performed an age-stratified analysis of the vaginal microbiome in South African women and compared this to their risk of HIV acquisition.
Methods. Vaginal microbiome data were generated by mass spectrometry–based proteomic analysis of cervicovaginal lavages 
collected from participants (n = 688) in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial. 
Participants were grouped by age (18–19 years, n = 93; 20–24 years, n = 326; 25–41 years, n = 269).


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Results. Four microbiome types were identified based on predominant taxa, including Lactobacillus crispatus (CST-LC, 12.2%), 
Lactobacillus iners (CST-LI, 43.6%), Gardnerella vaginalis (CST-GV, 26.6%), or polymicrobial (CST-PM, 15.1%). Women aged 18– 
19 and 20–24 years had increased CST-PM and a non-Lactobacillus-dominant microbiome compared to those 25–41 years (odds 
ratio [OR], 3.14 [95% confidence interval {CI}, 1.12–7.87], P = .017; OR, 2.81 [95% CI, 1.07–7.09], P = .038, respectively; and OR, 
1.65 [95% CI, 1.02–2.65], P = .028; OR, 1.40 [95% CI, 1.01–1.95], P = .030, respectively). The HIV incidence rate of women with 
CST-PM microbiome was 7.19-fold higher compared to women with CST-LC (hazard ratio [HR], 7.19 [95% CI, 2.11–24.5], P = 
.00162), which was also consistent in women aged 20–24 years (HR, 4.90 [95% CI, 1.10–21.9], P = .0375).
Conclusions. Younger women were more likely to have a higher-risk polymicrobial microbiome suggesting that vaginal 
microbiota are contributing to increased HIV-1 susceptibility in this group.
Clinical Trials Registration. NCT00441298.
Keywords. HIV transmission; vaginal microbiome; young women.
Received 02 September 2022; editorial decision 04 December 2022; published online 12 
December 2022
aY. W., L. N.-R., M. P., and S. K. contributed equally to this work.
Correspondence: A. Burgener, Center for Global Health and Diseases, Case Western Reserve 
University, 2109 Adelbert Rd, Biomedical Research Bldg, Cleveland, OH 44106 (adam. 
burgener@case.edu).
Clinical Infectious Diseases®
2023;76(8):1372–81 
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases 
Society of America. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution- 
NonCommercial-NoDerivs 
licence 
(https://creativecommons.org/licenses/by-nc-nd/4.0/), 
which permits non-commercial reproduction and distribution of the work, in any medium, pro-


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vided the original work is not altered or transformed in any way, and that the work is properly 
cited. For commercial re-use, please contact journals.permissions@oup.com
https://doi.org/10.1093/cid/ciac938
In sub-Saharan Africa, adolescent girls and young women 
(AGYW) aged 15–24 years are twice as likely to have human 
immunodeficiency virus (HIV) than males of the same age 
[1]. Compared to their male counterparts, they acquire HIV in-
fection at least 5–7 years earlier [1]. AGYW aged 15–19 years 
are especially vulnerable to becoming infected [2, 3]. In high- 
burden areas within South Africa, new infections are alarming-
ly high in AGYW, including 7.8% in those 15–19 years and 
8.6% in those 20–24 years of age based on a recent meta- 
analysis [4]. Antiretroviral agents formulated as vaginal gels 
[5], rings [6, 7], and pills [8–10] have shown lower efficacy in 
those with lower adherence, and lower adherence rates are 
common in younger age groups [6, 11]. Recent trials of newer 
technologies such as long-acting injectables, including HIV 
Prevention Trials Network study 084, have shown high efficacy 
[12] and provide further HIV prevention options for AGYW. 
Nevertheless, intensifying HIV prevention efforts, specifically 
in young women, could have significant public health impact, 
and lessons learned in studying young women would have rel-
evance for epidemic regions like these in Africa and the global 
effort to stop HIV. Although social, high-risk behavior, access 
to or utilization of healthcare services, and economic factors 
may all contribute to increased susceptibility to HIV infection 
1372 • CID 2023:76 (15 April) • Wang et al


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Evaluating the seroprevalence of SARS-CoV-2 IgG in five different districts of Bangladesh. A seroepidemiological study


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Male-selective effects of oxytocin agonism on alcohol intake: behavioral assessment in socially housed prairie voles and involvement of RAGE


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ARTICLE
OPEN
Male-selective effects of oxytocin agonism on alcohol intake:
behavioral assessment in socially housed prairie voles and
involvement of RAGE
Sheena Potretzke1, Yangmiao Zhang1, Ju Li1, Kristopher M. Fecteau2, David W. Erikson2, Marcel Hibert3 and Andrey E. Ryabinin
1✉
© The Author(s) 2022
Targeting the oxytocin (OXT) peptide system has emerged as a promising new approach for the treatment of alcohol use disorder
(AUD). However, further advancements in this development depend on properly modeling various complex social aspects of AUD
and its treatment. Here we examined behavioral and molecular underpinnings of OXT receptor (OXTR) agonism in prairie voles, a
rodent species with demonstrated translational validity for neurobiological mechanisms regulating social afﬁliations. To further
improve translational validity of these studies, we examined effects of intranasal (IN) OXT administration in male and female prairie
voles socially housed in the presence of untreated cagemates. IN OXT selectively inhibited alcohol drinking in male, but not female,
animals. Further, we conﬁrmed that exogenously administered OXT penetrates the prairie vole brain and showed that Receptor for
Advanced Glycation End-products assists this penetration after IN, but not intraperitoneal (IP), OXT administration. Finally, we
demonstrated that IP administration of LIT-001, a small-molecule OXTR agonist, inhibits alcohol intake in male, but not female,
prairie voles socially housed in the presence of untreated cagemates. Taken together, results of this study support the promise of
selectively targeting OXTR for individualized treatment of AUD.
Neuropsychopharmacology (2023) 48:920–928; https://doi.org/10.1038/s41386-022-01490-3
INTRODUCTION
The prevalence and negative impacts of alcohol use disorder
(AUD) demand efﬁcacious treatment options. Currently approved
AUD pharmacotherapies show limited success clinically [1–4],
despite demonstrated efﬁcacy in preclinical models [5–10].


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Oxytocin (OXT), a hormone with essential roles in social behaviors
[11, 12], has drawn interest as a potential pharmacotherapy for
AUD. Previous research indicated a role for OXT in mediating the
processes associated with alcohol use [13]. In particular, OXT’s
social effects [14, 15] may serve to bolster abstinence through
social support—a key mediator of treatment outcomes [16, 17].
This idea is in line with the previously proposed overarching role
of OXT in the regulation of social-cue saliency [18].
Optimization of animal models for testing pharmacotherapies
for AUD may help to bridge the gap between preclinical and
clinical efﬁcacy. In the current studies, we administered OXT
intranasally (IN)—a translationally relevant route exclusively used
in clinical trials in human patients. Among the obstacles in
development of efﬁcacious therapies for AUD that current
therapies have inadequately addressed are the complex interac-
tions of alcohol-related behaviors with the social environment
[19–21]. Here we examined the effect of pharmacologically
targeting the OXT system in socially housed prairie voles given
unrestricted access to the other animals in the cage and alcohol in
a continuous-access two-bottle choice paradigm (CA-2BC). Prairie
voles are facultatively monogamous rodents with demonstrated
translational validity for mechanisms regulating social behaviors,
in which the OXT system has been extensively explored [22–24].
As animals that voluntarily consume alcohol, and show social
inﬂuences on alcohol consumption similar to humans, prairie voles
serve as an ideal animal model for these studies [25, 26]. Finally,
we used a mixed-cage design, with treated and control animals in
the same cage. This design better recapitulates scenarios human
patients experience during medication-assisted maintenance of
abstinence from alcohol.
Despite previous demonstrations of OXT’s efﬁcacy in decreasing
measures associated with AUD preclinically [27–32] and clinically


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[33–35], the molecular mechanisms of OXT’s effects remain elusive
including its transport into the brain. OXT is thought to cross the
blood-brain barrier (BBB) [36]. Evidence indicates that OXT acts
centrally to inhibit alcohol intake. In rats, centrally administered
OXT decreased reinstatement of alcohol self-administration, and
central, but not peripheral, administration of a BBB non-penetrant
oxytocin receptor (OXTR) antagonist prevented OXT’s inhibitory
effects on alcohol self-administration [31, 33]. In mice, a centrally-
but not peripherally acting- OXTR antagonist prevented a
decrease in alcohol intake following chemogenetic activation of
hypothalamic OXT neurons [37]. Recent studies in rodents and
non-human
primates
(NHPs)
showed
small
proportions
of
exogenous OXT in the brain when administered peripherally,
Received: 3 August 2022 Revised: 20 October 2022 Accepted: 25 October 2022
Published online: 11 November 2022
1Department of Behavioral Neuroscience, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA. 2Endocrine Technologies Core, Oregon National
Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA. 3Laboratoire d’Innovation Thérapeutique, Faculté de Pharmacie,
UMR7200 CNRS/Université de Strasbourg, 74 Route du Rhin, F-67412 Illkirch, France. ✉email: ryabinin@ohsu.edu
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Systemic kappa opioid receptor antagonism accelerates reinforcement learning via augmentation of novelty processing in male mice


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ARTICLE
OPEN
Systemic kappa opioid receptor antagonism accelerates
reinforcement learning via augmentation of novelty processing
in male mice
Zahra Z. Farahbakhsh1, Keaton Song1, Hannah E. Branthwaite1, Kirsty R. Erickson
1, Snigdha Mukerjee1, Suzanne O. Nolan
1 and
Cody A. Siciliano
1✉
© The Author(s) 2023
Selective inhibition of kappa opioid receptors (KORs) is highly anticipated as a pharmacotherapeutic intervention for substance use
disorders and depression. The accepted explanation for KOR antagonist-induced amelioration of aberrant behaviors posits that
KORs globally function as a negative valence system; antagonism thereby blunts the behavioral inﬂuence of negative internal states
such as anhedonia and negative affect. While effects of systemic KOR manipulations have been widely reproduced, explicit
evaluation of negative valence as an explanatory construct is lacking. Here, we tested a series of falsiﬁable hypotheses generated a
priori based on the negative valence model by pairing reinforcement learning tasks with systemic pharmacological KOR blockade in
male C57BL/6J mice. The negative valence model failed to predict multiple experimental outcomes: KOR blockade accelerated
contingency learning during both positive and negative reinforcement without altering innate responses to appetitive or aversive
stimuli. We next proposed novelty processing, which inﬂuences learning independent of valence, as an alternative explanatory
construct. Hypotheses based on novelty processing predicted subsequent observations: KOR blockade increased exploration of a
novel, but not habituated, environment and augmented the reinforcing efﬁcacy of novel visual stimuli in a sensory reinforcement
task. Together, these results revise and extend long-standing theories of KOR system function.
Neuropsychopharmacology (2023) 48:857–868; https://doi.org/10.1038/s41386-023-01547-x
INTRODUCTION
Central and peripheral kappa opioid receptors (KORs) are targets
of a wide variety of pharmacotherapeutics. Most currently


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approved compounds are multi-target drugs, with varying
pharmacodynamic actions and selectivity for KORs. These drugs
are used for the treatment of a diverse array of disorders
including, but not limited to, nalfuraﬁne for pruritus [1],
alfentanil for nociceptive [2] and levorphanol for neuropathic
pain [3], naltrexone for substance use disorders [4], and
eluxadoline for irritable bowel syndrome [5, 6]. Development
of selective KOR compounds has been a longstanding goal in
medicinal chemistry and recent breakthroughs have produced
clinically viable, highly selective KOR agonists and antagonists,
several of which are in various stages of clinical evaluation
(National Clinical Trial number: NCT02800928, NCT02218736,
NCT01913535, NCT02641028, NCT02475447) [1, 7, 8]. In parti-
cular, clinically viable selective KOR antagonists have been
highly anticipated due to wide consensus in the preclinical
literature that systemic blockade of KORs holds great promise
for the treatment of several neuropsychiatric disorders including
depression, substance use disorders, and anxiety [9–12].
In preclinical models, KOR activity has been causally linked to
the underlying behavioral symptomatology of multiple neuropsy-
chiatric diseases. For example, systemic administration of KOR
antagonists in model species reliably reverses escalated drug and
alcohol consumption resulting from chronic exposure [13–17],
ameliorates depression-like phenotypes [18, 19], and can prevent
the behavioral consequences of chronic stress [20–23]. It is
thought that KOR modulation of addiction-, depression-, and
anxiety-related behaviors stems from its endogenous function as a
negative valence system. Indeed, the prevailing and widely
accepted model of KOR’s role in neuropsychiatric disease posits
that acute activation of KORs produces dysphoria and that
experience-dependent upregulation of this system drives aberrant
behavioral states such as anhedonia in depression and negative
affect during periods of drug abstinence in addiction [24–41]. This


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model of the KOR’s primary role in neurobehavioral processes
centers on negative valence processing and motivated behaviors
driven by aversive internal states, which are both critical but latent
constructs (i.e., cannot be directly observed). Though the latent
nature of the variables involved does not allow for a straightfor-
ward operationalized deﬁnition, the theory has been semantically
formalized by multiple literatures. The theory states that KOR
activity is involved in negative valence domains (e.g., acute threat,
potential threat, sustained threat, loss, and frustrative nonreward)
and is critical for the development of subsequent behavioral
responses to aversive stimuli, such as negative reinforcement
[12, 22, 25, 42, 43]. The role of KORs in these constructs are
Received: 13 September 2022 Revised: 20 January 2023 Accepted: 2 February 2023
Published online: 17 February 2023
1Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN 37232, USA.
✉email: cody.siciliano@vanderbilt.edu
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Iron and the Pathophysiology of Diabetes
Alexandria V Harrison1, Felipe Ramos Lorenzo1,2, Donald A. McClain1,2
1Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, 
North Carolina, USA
2Department of Veterans Affairs, W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury, 
North Carolina, USA
Abstract
High iron is a risk factor for type 2 diabetes mellitus (T2DM) and affects most of its cardinal 
features: decreased insulin secretion, insulin resistance, and increased hepatic gluconeogenesis. 
This is true across the normal range of tissue iron levels and in pathologic iron overload. Because 
of iron’s central role in metabolic processes (e.g., fuel oxidation) and metabolic regulation (e.g., 
hypoxia sensing), iron levels participate in determining metabolic rates, gluconeogenesis, fuel 
choice, insulin action, and adipocyte phenotype. The risk of diabetes related to iron is evident 
in most or all tissues that determine diabetes phenotypes, with the adipocyte, beta cell, and liver 
playing central roles. Molecular mechanisms for these effects are diverse, although there may be 
integrative pathways at play. Elucidating these pathways has implications not only for diabetes 
prevention and treatment, but also for the pathogenesis of other diseases that are, like T2DM, 
associated with aging, nutrition, and iron.
Keywords
diabetes; iron; hepcidin; hemochromatosis; adipocyte; insulin
1. INTRODUCTION
Macronutrients play an undisputed role in conferring an increased risk of type 2 diabetes 
mellitus (T2DM), but the micronutrient iron is also a risk determinant, not only in pathologic 
excess or deficiency, but also within its very broad range of normal levels. This review 
addresses the evidence for a connection between iron and diabetes risk, first providing a 
brief review of iron homeostasis and the evidence linking tissue iron levels with diabetes 
in humans. Because in many cases the aforementioned topics have been the subject of


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detailed reviews, this review concentrates on mechanistic studies addressing how iron 
This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, 
and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party 
material in this article for license information.
dmcclain@wakehealth.edu . 
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the 
objectivity of this review.
HHS Public Access
Author manuscript
Annu Rev Physiol. Author manuscript; available in PMC 2023 May 05.
Published in final edited form as:
Annu Rev Physiol. 2023 February 10; 85: 339–362. doi:10.1146/annurev-physiol-022522-102832.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Fourth mRNA vaccination increases cross-neutralizing antibody titers against SARS-CoV-2 variants, including BQ.1.1 and XBB, in a very elderly population


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Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain


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Article
Molecular and cognitive signatures of ageing
partially restored through synthetic delivery of IL2
to the brain
Pierre Lemaitre1,2,†
, Samar HK Tareen3,†, Emanuela Pasciuto1,2,†
, Loriana Mascali1,2,
Araks Martirosyan1,4, Zsuzsanna Callaerts-Vegh5
, Suresh Poovathingal1, James Dooley3,6
,
Matthew G Holt1,4,7,*,‡
, Lidia Yshii1,2,4,**,‡
& Adrian Liston1,2,3,6,***,‡
Abstract
Cognitive decline is a common pathological outcome during aging,
with an ill-defined molecular and cellular basis. In recent years,
the concept of inflammaging, defined as a low-grade inflammation
increasing with age, has emerged. Infiltrating T cells accumulate in
the brain with age and may contribute to the amplification of
inflammatory cascades and disruptions to the neurogenic niche
observed with age. Recently, a small resident population of regula-
tory T cells has been identified in the brain, and the capacity of
IL2-mediated expansion of this population to counter neuroinflam-
matory disease has been demonstrated. Here, we test a brain-
specific IL2 delivery system for the prevention of neurological
decline in aging mice. We identify the molecular hallmarks of
aging in the brain glial compartments and identify partial restora-
tion of this signature through IL2 treatment. At a behavioral level,
brain IL2 delivery prevented the age-induced defect in spatial
learning, without improving the general decline in motor skill or
arousal. These results identify immune modulation as a potential
path to preserving cognitive function for healthy aging.
Keywords Aging; Brain; Gene Therapy; Interleukin 2; Regulatory T cells
Subject Categories Immunology; Neuroscience
DOI 10.15252/emmm.202216805 | Received 28 August 2022 | Revised 8 March
2023 | Accepted 10 March 2023 | Published online 28 March 2023
EMBO Mol Med (2023) 15: e16805
Introduction
Aging is an irreversible process associated with physical deteriora-
tion and hence especially noticeable in organs containing mainly
postmitotic cells, such as the brain. The progressive decline in mem-


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ory, orientation, attention, motivation, and cognition seen in
humans is thought to stem largely from aging-related processes (Hof
& Morrison, 2004). Although cognitive aging research generally
focuses on neurons, which are widely held to be the computational
units of the brain, there is an increasing realization that reciprocal
interactions between neurons and non-neuronal cells (collectively
referred to as glia) play key roles in all aspects of nervous system
function. These include the regulation of synapse formation and
function by astrocytes, as well as myelination and provision of tro-
phic support to neurons by oligodendrocytes. Once thought of as
solely immune cells, which protect the CNS against injury and dis-
ease, there is increasing evidence that the same systems used by
microglia to remove invading pathogens from the brain have also
been co-opted to remove weak and/or inappropriate neuronal syn-
apses, establishing precise patterns of neuronal connectivity in the
brain (Allen & Lyons, 2018). It should not be surprising, therefore,
that aging-related cognitive decline has been associated with several
molecular processes, including chronic inflammation, impaired
autophagy, macromolecular damage, and mitochondrial dysfunction
and senescence (Hou et al, 2019), which impact the function of all
CNS cell types (Jurk et al, 2012; Bussian et al, 2018; Chinta
et al, 2018; Ogrodnik et al, 2019).
In addition to the shared cellular phenotypes of aging, unique
phenotypes emerge among the individual glial cell types with aging.
1
VIB Center for Brain and Disease Research, Leuven, Belgium
2 Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
3 Immunology Programme, The Babraham Institute, Babraham, UK
4 Department of Neurosciences, KU Leuven, Leuven, Belgium
5 Laboratory of Biological Psychology, Faculty of Psychology, KU Leuven, Leuven, Belgium
6 Department of Pathology, The University of Cambridge, Cambridge, UK


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7 Instituto de Investigaçao e Inovaçao em Saude (i3S), University of Porto, Porto, Portugal
*Corresponding author. Tel: +351 226 074 900; E-mail: mholt@i3s.up.pt
**Corresponding author. Tel: +32 16 32 33 67; E-mail: lidia.yshii@kuleuven.be
***Corresponding author. Tel: +44 1223 333690; E-mail: al989@cam.ac.uk
†These authors contributed equally to this work
‡These authors contributed equally to this work
 2023 The Authors. Published under the terms of the CC BY 4.0 license
EMBO Molecular Medicine
15: e16805 | 2023
1 of 18


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Nature Neuroscience | Volume 26 | May 2023 | 850–857
850
nature neuroscience
Article
https://doi.org/10.1038/s41593-023-01307-6
Computational complexity drives  
sustained deliberation
Tao Hong 
  1,2,3 & William R. Stauffer 
  1,2,3 
Economic deliberations are slow, effortful and intentional searches for 
solutions to difficult economic problems. Although such deliberations are 
critical for making sound decisions, the underlying reasoning strategies and 
neurobiological substrates remain poorly understood. Here two nonhuman 
primates performed a combinatorial optimization task to identify valuable 
subsets and satisfy predefined constraints. Their behavior revealed 
evidence of combinatorial reasoning—when low-complexity algorithms 
that consider items one at a time provided optimal solutions, the animals 
adopted low-complexity reasoning strategies. When greater computational 
resources were required, the animals approximated high-complexity 
algorithms that search for optimal combinations. The deliberation 
times reflected the demands created by computational complexity—
high-complexity algorithms require more operations and, concomitantly, 
the animals deliberated for longer durations. Recurrent neural networks 
that mimicked low- and high-complexity algorithms also reflected the 
behavioral deliberation times and were used to reveal algorithm-specific 
computations that support economic deliberation. These findings reveal 
evidence for algorithm-based reasoning and establish a paradigm for 
studying the neurophysiological basis for sustained deliberation.
Difficult economic decisions—whether to buy a house or not, what to 
study at school or how to invest for retirement—require slow, effortful 
and intentional consideration1. Decision-makers must determine the 
best outcomes by considering combinations of economic factors, 
including immediate needs, available resources, environmental con-
straints and future consequences. These combinatorial considera-


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tions generate substantial computational demands and render the 
finding of satisfactory solutions to a hard problem. Economic delib-
eration is, therefore, a cognitive process of identifying subjectively 
optimal solutions to hard economic problems. This mode of slow 
and effortful thinking is rarely evoked with traditional neuroeco-
nomic paradigms. Even when choosing between items with similar 
values, a context that is considered to drive hard economic choices, 
both human and nonhuman primate (NHP) neuronal and behavioral 
responses evolve in hundreds of milliseconds2,3. In contrast to stand-
ard neuroeconomic tasks, combinatorial optimization problems 
require extended deliberations. These problems can be designed to 
reflect the combinatorial nature of difficult economic decisions, as 
defined above, and possess a normative scale of difficulty—compu-
tational complexity. Recent studies of human decision-makers have 
shown that computational complexity modulates effort, response 
times (RTs) and performance4,5. Thus, combinatorial optimization 
tasks have the capacity to model difficult economic decisions, and 
to reveal the mental algorithms for economic deliberation.
Computational difficulty, or complexity, is manifested in numer-
ous routine tasks, including scheduling, route planning and, as men-
tioned above, economic decision making6. Therefore, understanding 
how the brain manages computational complexity is vital for build-
ing computationally plausible models of cognition and behavior7,8. 
Computational complexity theory is a branch of computer science 
that focuses on characterizing the difficulty of solving computational 
problems9, defining the complexity of individual problems10 and 
Received: 26 April 2022
Accepted: 16 March 2023
Published online: 24 April 2023
 Check for updates
1Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA. 2Program in Neural Computation, Carnegie Mellon University, Pittsburgh, PA,


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Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines


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REVIEW ARTICLE
OPEN
Targetable elements in SARS-CoV-2 S2 subunit for the design
of pan-coronavirus fusion inhibitors and vaccines
Liyan Guo1, Sheng Lin1, Zimin Chen1, Yu Cao1,2, Bin He1✉ and Guangwen Lu
1✉
The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2
(SARS‐CoV‐2), has caused devastating impacts on the public health and the global economy. Rapid viral antigenic evolution has led
to the continual generation of new variants. Of special note is the recently expanding Omicron subvariants that are capable of
immune evasion from most of the existing neutralizing antibodies (nAbs). This has posed new challenges for the prevention and
treatment of COVID-19. Therefore, exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In
sharp contrast to the massive accumulation of mutations within the SARS-CoV-2 receptor-binding domain (RBD), the S2 fusion
subunit has remained highly conserved among variants. Hence, S2-based therapeutics may provide effective cross-protection
against new SARS-CoV-2 variants. Here, we summarize the most recently developed broad-spectrum fusion inhibitors (e.g., nAbs,
peptides, proteins, and small-molecule compounds) and candidate vaccines targeting the conserved elements in SARS-CoV-2 S2
subunit. The main focus includes all the targetable S2 elements, namely, the fusion peptide, stem helix, and heptad repeats 1 and 2
(HR1-HR2) bundle. Moreover, we provide a detailed summary of the characteristics and action-mechanisms for each class of cross-
reactive fusion inhibitors, which should guide and promote future design of S2-based inhibitors and vaccines against new
coronaviruses.
Signal Transduction and Targeted Therapy  (2023) 8:197 
; https://doi.org/10.1038/s41392-023-01472-x
INTRODUCTION
Coronaviruses
(CoVs)
are
enveloped,
positive-sense,
single-
stranded RNA viruses, classiﬁed in the family of Coronaviridae.1
They exist widely in nature and can infect humans, other


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mammals, or various avian species, causing different acute and
chronic diseases.2,3 Coronaviruses are a highly diverse family
comprising four genera: alphacoronavirus (α-CoV), betacorona-
virus (β-CoV), gammacoronavirus (γ-CoV) and deltacoronavirus (δ-
CoV).4 The four annually circulating human coronaviruses (HCoVs),
namely HCoV-229E and HCoV-NL63 of α-CoV and HCoV-OC43 and
HCoV-HKU1 of β-CoV, are endemic to humans and generally cause
mild upper respiratory illness.5–8 However, there are also three
highly pathogenic β-CoVs, including severe acute respiratory
syndrome coronavirus (SARS-CoV), Middle East respiratory syn-
drome coronavirus (MERS-CoV), and severe acute respiratory
syndrome
coronavirus
2
(SARS‐CoV‐2).9–11
All
three
highly
pathogenic HCoVs can cause severe pneumonia in humans and
have led to numerous infections and deaths worldwide.12–14 The
astonishingly high transmissibility of SARS-CoV-2 has resulted in a
global coronavirus disease 2019 (COVID-19) pandemic that
signiﬁcantly impacted the global economy and public health,
causing more than 763,740,140 conﬁrmed infections and over
6,908,554 deaths as of 19 April 2023 (https://covid19.who.int).
Coronavirus infection begins with virus entry, which depends
on the intact trimetric spike (S) protein located on the surface of
the virion.15–19 The S protein, a class I viral fusion glycoprotein, is
functionally
divided
into
S1
and
S2
subunits,
which
are
responsible for receptor binding and membrane fusion, respec-
tively. Speciﬁcally, S1 relies on receptor-binding domain (RBD) to
interact with human angiotensin-converting enzyme 2 (ACE2).16,20
As a major antigenic determinant, RBD is a critical target for the
development of vaccines and fusion inhibitors. Currently, most
therapeutic neutralizing antibodies (nAbs) and promising vaccine
candidates are designed to target the RBD or use RBD as the sole
antigen.21–25 However, RBD is poorly conserved, with the newly
emerged Omicron subvariants harboring multiple mutations in


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RBD that are capable of immune evasion from the majority of
existing neutralizing antibodies (nAbs). Consequently, vaccine
efﬁcacy has markedly reduced, thus, posing new challenges for
the prevention and treatment of SARS-CoV-2.26–30 Although
efforts have been made to design nAbs and vaccines against
Omicron subvariants, new variants might continue to emerge due
to the progressive accumulation of mutations and the increasing
immune selective pressure.31 Moreover, SARS-CoV-2 and MERS-
CoV coinfection has been reported and may occur more
frequently as the virus evolves.32 Given that β-CoVs infect the
same target cells and use identical transcriptional regulatory
sequences, genetic recombination between coronaviral coinfec-
tion
in
COVID-19
may
result
in
new
clades
with
higher
transmissibility and lethality.33 Although many nAbs and vaccines
against each class of β-CoVs have been developed with proven
efﬁcacy, they show weak cross-neutralization activity, thus, limit-
ing their ability to prevent or treat highly pathogenic new HCoV
infections.34,35
Received: 18 February 2023 Revised: 4 April 2023 Accepted: 23 April 2023
1Department of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China and 2Disaster Medicine
Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Correspondence: Bin He (hb40400387@163.com) or Guangwen Lu (lugw@scu.edu.cn)
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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HIV replication and latency in monocytes and macrophages
Rebecca T. Veenhuisa, Celina M. Abreua, Erin N. Shirka, Lucio Gamaa,d, Janice E. 
Clementsa,b,c,*
aDepartment of Molecular and Comparative Biology, Johns Hopkins University School of 
Medicine, Baltimore, MD, United States
bDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United 
States
cDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United 
States
dVaccine Research Center, NIAID, NIH, Bethesda, MD, United States
Abstract
The relevance of monocyte and macrophage reservoirs in virally suppressed people with HIV 
(vsPWH) has previously been debatable. Macrophages were assumed to have a moderate life 
span and lack self-renewing potential. However, recent studies have challenged this dogma and 
now suggest an important role of these cell as long-lived HIV reservoirs. Lentiviruses have a 
long-documented association with macrophages and abundant evidence exists that macrophages 
are important target cells for HIV in vivo. A critical understanding of HIV infection, replication, 
and latency in macrophages is needed in order to determine the appropriate method of measuring 
and eliminating this cellular reservoir. This review provides a brief discussion of the biology and 
acute and chronic infection of monocytes and macrophages, with a more substantial focus on 
replication, latency and measurement of the reservoir in cells of myeloid origin.
Keywords
Macrophages; HIV; SIV; Latency; Replication
1. Introduction
Since the emergence of AIDS, it was demonstrated that both CD4 + T cells and 
macrophages were susceptible to HIV infection and were involved in disease progression. 
Early studies classified the virus as macrophage tropic, as it was able to induce syncytia 
in culture [1]. HIV isolates that could infect healthy donor CD4 + T cells in vitro were 
also able to infect tissue macrophages in several organs, including brain and lung [2,3].


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Indeed, some of the direct manifestations of viral pathogenesis were directly associated with 
infection of tissue macrophages, leading to neurological and lung symptoms. Combined 
*Corresponding author at: Department of Molecular and Comparative Biology, Johns Hopkins University School of Medicine, 733 N. 
Broadway, Baltimore, MD, 21205, United States. jclements@jhmi.edu (J.E. Clements). 
HHS Public Access
Author manuscript
Semin Immunol. Author manuscript; available in PMC 2023 May 10.
Published in final edited form as:
Semin Immunol. 2021 January ; 51: 101472. doi:10.1016/j.smim.2021.101472.
Author Manuscript
Author Manuscript
Author Manuscript
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An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor-binding domain vaccine in aged mice


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An aluminum hydroxide:CpG adjuvant enhances protection 
elicited by a SARS-CoV-2 receptor-binding domain vaccine in 
aged mice
Etsuro Nanishi1,2,†, Francesco Borriello1,2,3,19,†, Timothy R. O’Meara1,‡, Marisa E. 
McGrath4,‡, Yoshine Saito1, Robert E. Haupt4, Hyuk-Soo Seo5,6, Simon D. van Haren1,2, 
Cecilia B. Cavazzoni7, Byron Brook1,2, Soumik Barman1,2, Jing Chen8, Joann Diray-
Arce1,2, Simon Doss-Gollin1, Maria De Leon1, Alejandra Prevost-Reilly1, Katherine Chew1, 
Manisha Menon1, Kijun Song5, Andrew Z. Xu5, Timothy M. Caradonna9, Jared Feldman9, 
Blake M. Hauser9, Aaron G. Schmidt9,10, Amy C. Sherman1,11, Lindsey R. Baden11, 
Robert K. Ernst12, Carly Dillen4, Stuart M. Weston4, Robert M. Johnson4, Holly L. 
Hammond4, Romana Mayer13, Allen Burke13, Maria E. Bottazzi14,15, Peter J. Hotez14,15, 
Ulrich Strych14,16, Aiquan Chang17, Jingyou Yu17, Peter T. Sage7, Dan H. Barouch17, Sirano 
Dhe-Paganon5,6, Ivan Zanoni2,3, Al Ozonoff1,2, Matthew B. Frieman4,§, Ofer Levy1,2,18,§, 
David J. Dowling1,2,§,*
1Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, 
MA, USA 02115.
2Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115.
3Division of Immunology, Boston Children’s Hospital, Boston, MA, USA 02115.
4Department of Microbiology and Immunology, University of Maryland School of Medicine, 
Baltimore, MD, USA 21201.
*Corresponding author: David J. Dowling, Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital; 
Harvard Medical School, Rm 842, Boston, MA 02115, USA. Tel: +1 617-919-6890. david.dowling@childrens.harvard.edu.
†These authors contributed equally to this manuscript.
§Co-senior authors.
‡These authors contributed equally to this manuscript.
AUTHOR CONTRIBUTIONS
EN and FB conceived, designed, performed, analyzed the experiments and wrote the paper; TRO performed mouse serological 
assays, splenocyte restimulation, human in vitro experiments and their analysis; YS performed mouse in vivo experiments, serological


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readouts, splenocyte restimulation; BB, MDL, APR, KC, MM, SDG, and SDvH performed in vitro PBMC or T cell co-culture 
experiments; SB performed splenocyte restimulation; JC and JD-A performed the analysis of the qPCR data; KS, AZX, HSS, SDP, 
TMC, JF, BMH, and AGS expressed and purified SARS-CoV-2 RBD and spike protein; MEM, REH, CD, SMW, RMJ, HLH, 
RM, AB, and MBF performed and analyzed SARS-CoV-2 neutralization experiments and mouse challenge study; AC, JY, and 
DHB performed and analyzed pseudovirus neutralization experiments; ACS and LRB contributed to the human older adult in vitro 
analysis; CBC and PTS performed and analyzed lymph node immunophenotyping; MEB, PJH, and US edited and critically reviewed 
the manuscript; RKE and IZ contributed to the design of experiments; AO provided study design feedback and contributed to the 
statistical analysis; OL and DJD conceived the project, designed the experiments, and wrote the manuscript.
COMPETING INTERESTS STATEMENT
EN, FB, TRO, YS, SVH, IZ, OL and DJD are named inventors on vaccine adjuvant patents assigned to Boston Children’s Hospital 
(“Adjuvants For Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV) Vaccines”, PCT/US21/34919). FB has signed 
consulting agreements with Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc.), Sana Biotechnology, Inc., and F. 
Hoffmann-La Roche Ltd. IZ reports compensation for consulting services with Implicit Biosciences. MF is on the advisory board 
of Aikido Pharma. The Baylor College of Medicine (BCM) authors declare they are developers of a recombinant RBD technology. 
BCM recently licensed the technology to Biological E, an Indian manufacturer, for advancement and licensure. OL served as a paid 
consultant to Moody’s analytics. These commercial or financial relationships are unrelated to the current study.
HHS Public Access
Author manuscript
Sci Transl Med. Author manuscript; available in PMC 2023 May 12.
Published in final edited form as:


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Sci Transl Med. 2022 January 26; 14(629): eabj5305. doi:10.1126/scitranslmed.abj5305.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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7ournal ofNeurology, Neurosurgery, and Psychiaty 1993;56:788-792
Paroxysmal alien hand syndrome
Ramon Leiguarda, Sergio Starkstein, Martin Nogues, Marcelo Berthier, Roberto Arbelaiz
Abstract
Four patients are described who presen-
ted with a paroxysmal form of the alien
hand syndrome. Two patients with dam-
age to one frontomedial cortex had brief
episodes of abnormal motor behaviour of
the contralateral arm that featured grop-
ing, grasping, and apparently purposeful
but
perseverative
movements,
which
both
patients
interpreted
as
alien
or
foreign. The other two patients, with
posterior parietal damage, reported a
paroxysmal feeling of unawareness of the
location of the contralateral arm, lack of
recognition of the arm as their own, pur-
poseless movements, and personification
of the arm. These cases represent a new
form of the alien hand syndrome mani-
fested by
brief, paroxysmal
episodes,
which may be due to ictal mechanisms.
(7 Neurol Neurosurg Psychiatty 1993;56:788-792)
with an infarction in the territory of the right
posterior
cerebral
artery spontaneous arm
movements such as those related to gestures
or postural adjustment, are felt as out of con-
trol due to opticosensory ataxia and as alien
due to the severe sensory loss." The alien
hand syndrome in patients with unilateral
hemispheric lesions, unlike those with callosal
damage, is always present in the hand con-
tralateral to the lesion, regardless of the pat-
tern of cerebral speech dominance and not
necessarily triggered by volitional movements
of the normal hand.4 69
The alien hand syndrome may last for days
or weeks but has not been described as a
paroxysmal manifestation. We
report four
patients who showed a paroxysmal alien hand
syndrome probably caused by seizures origi-
nating in the contralateral frontomedial cor-
tex (two patients) and in the contralateral
posterior parietal region (two patients).
Institute of
Neurological Research
Rafil Carrea, Buenos
Aires, Argentina
Ram6n Leiguarda
Sergio Starkstein
Martin Nogues
Marcelo Berthier


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Roberto Arbelaiz
Correspondence to:
Dr Leiguarda, Fleni,
Ayacucho 2166, (1112)
Buenos Aires, Argentina.
Received 23 June 1992
and in revised form
13 October 1992.
Accepted 16 October 1992
The alien hand sign or syndrome is a psy-
chomotor disorder characterised by a dissoci-
ation between intention and action. One of
the patient's hands performs apparently pur-
poseful movements, which are independent of
volitional control, as if the hand is driven by
an
external
agent.'-9 The
symptoms
vary
according to location of the lesion. In patients
with either surgical
or spontaneous lesions
restricted to the corpus callosum, the hand
ipsilateral to the language and motor domi-
nant hemisphere acts in a manner opposite to
what the patient voluntarily does with the
dominant
hand,
a
phenomenon
called
diagonistic dyspraxia by Akelaitis' and inter-
manual conflict by Bogen.3 This abnormal
motor behaviour is always triggered by voli-
tional movements of the normal hand.58'0
When a medial callosal lesion affects adjacent
parietotemporal
regions,
the non-dominant
arm may not be recognised as the patient's
own when held by the
contralateral
arm
behind the back in the absence of sensory
loss7 or, altematively, the hand "behaves in a
way which the patient finds 'foreign', 'alien'
or
at
least uncooperative".'
Patients
with
medial frontal lobe damage affecting the sup-
plementary
motor
area and
the
cingulate
gyrus may show a seemingly purposeful and
uncontrollable tendency of the hand
con-
tralateral
to the lesion to grope and grasp
objects, sometimes accompanied by motor
perseveration or compulsive manipulation of
tools placed before them.469 Among patients
Case reports
Case 1
A 65 year old right handed man reported the
following: "While I was travelling on a bus I
noticed that a hand was approaching me on
the right from behind, trying to catch me.
After grasping my trouser leg, the hand did
not release it. First, I thought somebody was
assaulting me, but then I realised that it was
my own right hand, although I did not feel it


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belonged to me. Thereafter, the fingers devel-
oped
creeping movements,
and
repetitive
jerks involving the whole arm soon followed. I
was unable to control my right hand and I
had to grasp and hold it with my left hand.
My right arm felt heavy and awkward.
I was
very anguished, anxious and frightened, and
had palpitations.
. ." The episode lasted for a
few
minutes,
and
recurred
briefly
that
evening at the patient's home: "I couldn't
sleep at all that night because I was terrified
my right hand would assault me while sleep-
ing."
Neurological,
neuropsychiatric,
and
general examinations yielded normal results.
Laboratory analyses (haemoglobin concentra-
tion, white 7 blood cell count, erythrocyte
sedimentation
rate,
blood
glucose,
blood
urea,
plasma
electrolytes,
calcium
ions,
Venereal Disease Research Laboratory test,
lipids,
liver
function
test,
protein
elec-
trophoresis, coagulation studies, T3 and T4,
urinalysis, electrocardiography, doppler ultra-
sound
of
neck
and
intracranial
vessels,
echocardiogram,
and
interictal
electroen-
cephalography) also yielded normal results.
788


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7Journal of Neurology, Neurosurgery, and Psychiatry 1992;55:768-773
Regional cerebral blood flow abnormalities in
depressed patients with cognitive impairment
R J Dolan, C J Bench, R G Brown, L C Scott, K J Friston, R S J Frackowiak
Academic Department
of Psychiatry, Royal
Free Hospital and
School of Medicine,
London
R J Dolan*
C J Bench*
L C Scott
MRC Cyclotron Unit,*
Hammersmith
Hospital, London
K J Friston
R S J Frackowiak
MRC Human
Movement and
Balance Unit, National
Hospital for Neurology
and Neurosurgery,
London
R G Brown
Academic Department
of Psychiatry,
Westminster and
Charing Cross
Medical School,
London
K J Friston
National Hospital for
Neurology and
Neurosurgery, London
R J Dolan
R S J Frackowiak
Correspondence to:
Dr Dolan, Royal Free
Hospital School of
Medicine, Rowland Hill
Street, London NW3 2PF,
UK.
Received 30 September
1991
and in final revised form
5 March 1992.
Accepted 16 March 1992
Abstract
Depression with cognitive impairment, so
called
depressive
pseudodementia,
is
commonly mistaken for a neurodegener-
ative dementia. Using positron emission
tomography (PET) derived measures of
regional cerebral blood flow (rCBF) a
cohort of 33 patients with major depres-
sion was studied. Ten patients displayed
significant
and
reversible
cognitive
impairment. The patterns of rCBF of
these
patients
were compared
with
a
cohort of equally depressed non-cogni-
tively impaired depressed patients. In the
depressed cognitively impaired patients a
profile of rCBF abnormalities was identi-
fied consisting of decreases in the left
anterior medial prefrontal
cortex and
increases in the cerebellar vermis. These
changes were additional to those seen in
depression alone and are distinct from
those
described
in
neurodegenerative
dementia. The cognitive impairment seen
in a proportion
of depressed patients
would seem to be associated with dysfimc-
tion of neural systems distinct from those
implicated in depression alone or the
neurodegenerative dementias.
(7 Neurol Neurosurg Psychiatry 1992;55:768-773)


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Primary depression with significant cognitive
impairment, commonly referred to as depres-
sive
pseudodementia
or
the
dementia
of
depression, may be mistaken for a progressive
neurodegenerative
dementia. 1
Depression
itself may also be a concomitant of a progres-
sive degenerative dementia, particularly in its
early phases.2 The conjunction of depression
and cognitive impairment frequently poses a
clinical diagnostic problem which may hamper
patient management. Recognition of a primary
depression masquerading as a neurodegener-
ative dementia is clinically important because
of its treatability. Depression with cognitive
impairment can lead to misdiagnosis of pri-
mary degenerative dementia even in specialist
centres.3 Misdiagnosis, more common in the
elderly, may also occur in the presenium.4
The extent of misdiagnosis may be inferred
from
a study which reported
that 8%
of
patients with an index diagnosis of dementia
were rediagnosed as depression on subsequent
admission.6 Depressed patients with cognitive
impairment demonstrate a significant improve-
ment on quantitative assessments of cognition
following treatment or on follow-up.78
The
neurobiological
basis
of depression
related cognitive impairment remains obscure.
Distinct patterns of focal cerebral metabolic
abnormalities have been described in primary
depression.9"0 The most consistent change
described is a decrease in rCBF or metabolism
in
the
left
dorsolateral
prefrontal
cortex
(DLPFC). We report a study of depressed
patients,
using PET
derived
measures
of
rCBF, which reveals a profile of abnormality,
distinct from that seen in depression alone, in
depression related cognitive impairment.
Subjects and methods
Patients included in the study were recruited
from
district
psychiatric
services
in
north
London and the National Hospital for Neurol-
ogy and Neurosurgery. Potential participants
indicating willingness to cooperate with the
study and ability to give informed consent were
administered The Schedule for Affective Dis-
orders and Schizophrenia (SADS).


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" Patients
who
met
Research
Diagnostic
Criteria
(RDC)12 for major depressive disorder were
considered further. Exclusion criteria were a
past or present history of neurological disease,
drug or alcohol abuse (based on the SADS) or
any significant past medical illness. Subjects
were also excluded if they scored over 4 on the
Hachinski ischaemic scale.13 Patients on psy-
chotropic medication (19 of the 33) entered
the study on the hypothesis that patterns of
rCBF would reflect their depressed mental
state rather than medication. The study was
approved by the
ethical committees of all
referring hospitals and by the local committee
ofthe Hammersmith Hospital, where the scans
were performed.
Permission
to
administer
"5Oxygen was granted by the Administration of
Radioactive Substances Advisory Committee
(ARSAC). All subjects gave informed written
consent.
A total of 33 patients met entry criteria for
the study. All patients had moderate to severe
depression as rated on the 17 item Hamilton
Rating Scale for Depression14 (range 17-32,
mean = 25). Cognitive finction, assessed using
a clinical neuropsychological battey as well as
the Mini Mental State Examination (MMSE)
and CAMCOG
scale
of the CAMDEX,
showed that 10 patients had marked cognitive
impairment and scored in the impaired range.
Cognitive impairment was determined using
cut-points of < 25 on the MMSE and < 85 on
the CAMCOG."5 16 Subsequent follow up of
these patients revealed a clinical course con-
768


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NEURAL REGENERATION RESEARCH｜Vol 18｜No. 7｜July 2023｜1521
NEURAL REGENERATION RESEARCH
www.nrronline.org
Research Article
Transient neurogenesis in ischemic cortex from Sox2+ 
astrocytes
Abstract  
The adult cortex has long been regarded as non-neurogenic. Whether injury can induce neurogenesis in the adult cortex is still controversial. Here, we report 
that focal ischemia stimulates a transient wave of local neurogenesis. Using 5′-bromo-2′-deoxyuridine labeling, we demonstrated a rapid generation of 
doublecortin-positive neuroblasts that died quickly in mouse cerebral cortex following ischemia. Nestin-CreER-based cell ablation and fate mapping showed a 
small contribution of neuroblasts by subventricular zone neural stem cells. Using a mini-photothrombotic ischemia mouse model and retrovirus expressing 
green fluorescent protein labeling, we observed maturation of locally generated new neurons. Furthermore, fate tracing analyses using PDGFRα-, GFAP-, 
and Sox2-CreER mice showed a transient wave of neuroblast generation in mild ischemic cortex and identified that Sox2-positive astrocytes were the major 
neurogenic cells in adult cortex. In addition, a similar upregulation of Sox2 and appearance of neuroblasts were observed in the focal ischemic cortex of Macaca 
mulatta. Our findings demonstrated a transient neurogenic response of Sox2-positive astrocytes in ischemic cortex, which suggests the possibility of inducing 
neuronal regeneration by amplifying this intrinsic response in the future.  
Key Words: adult; astrocyte; cortex; fate-mapping; ischemia; local neurogenesis; neural stem cells; Sox2
https://doi.org/10.4103/1673-5374.357910
Date of submission: April 20, 2022 
Date of decision: June 23, 2022 
Date of acceptance: August 23, 2022 
Date of web publication: October 13, 2022 
Introduction 
Once development ends, the neurogenic potential of the neocortex becomes 
latent. Because of the importance of the neocortex in brain function and


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its vulnerability to injuries (such as ischemia), extensive investigations have 
been conducted to seek and promote neurogenesis in adult cortex after 
injury (Kernie and Parent, 2010; Ceanga et al., 2021). In the past decade, 
several studies have documented cortical neurogenesis under physiological 
and pathophysiological conditions, particularly following cerebral ischemia, 
whereas others have detected no neurogenesis in adult cortex (Jiang et 
al., 2001; Pekcec et al., 2006; Kernie and Parent, 2010; Ohira et al., 2010; 
Vessal and Darian-Smith, 2010; Ohira, 2011; Huttner et al., 2014). Cortical 
neurogenesis, if indeed occurs, is minimal. Adult neural stem cells (aNSCs) in 
the subventricular zone (SVZ) respond to cerebral ischemia, so it is generally 
thought that the observed cortical neurogenesis is mainly derived from SVZ 
aNSCs (Li et al., 2010). 
Some studies have indicated that there may exist potential neurogenic 
cells in the cortex, such as GABAnergic progenitors (Ohira et al., 2010), 
oligodendrocyte progenitors (Guo et al., 2010) and reactive astrocytes (Buffo 
et al., 2008). In particular, reactive astrocytes have been speculated to be 
neurogenic because (1) SVZ aNSCs and hippocampal aNSCs are astrocyte-like 
cells, and (2) reactive astrocytes can upregulate neural progenitor markers, 
form neurospheres, and are multi-potent in vitro (Robel et al., 2011; Shimada 
et al., 2012; Gotz et al., 2015). Recent studies have reported that in the 
striatum, where postischemic neurogenesis is thought to be solely derived 
from SVZ aNSCs, local astrocytes also give rise to neurons (Luzzati et al., 2014; 
Magnusson et al., 2014). These observations indicate the possibility of cortical 
neurogenesis from local astrocytes. However, in vivo neurogenic evidence is 
still lacking.
Recently, Chunli Zhang’s group reported that a subpopulation of cortical 
astrocytes maintains a low level of Sox2 expression (Chen et al., 2019). Our 
previous study revealed that Sox2-positive glia in dorsal root ganglion give rise


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to nociceptive neurons under chronic pain (Zhang et al., 2019). In the present 
study, using 5′-bromo-2′-deoxyuridine (BrdU) labeling, retrovirus expressing 
green fluorescent protein (GFP; Retro-GFP) labeling and Cre-mediated cell 
fate tracing, we demonstrated transient neurogenesis in adult mouse cortex 
after ischemia and further explored the neurogenic potential of Sox2-positive 
astrocytes. 
1Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi Province, China; 2China National Clinical 
Research Center for Neurological Diseases, Department of Neurology, Beijing Tiantan Hospital, Beijing, China; 3Department of Neurology, The Second Affiliated Hospital of Xi’an 
Jiaotong University, Xi’an, Shaanxi Province, China; 4State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan 
University, Shanghai, China; 5Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, 
Chinese Academy of Sciences, Kunming, Yunnan Province, China
*Correspondence to: Ya-Zhou Wang, PhD, yazhouw@fmmu.edu.cn; Ying-Zhou Hu, PhD, huyingzhou@mail.kiz.ac.cn; Kun Zhang, PhD, Kunyang1028@126.com.
https://orcid.org/0000-0002-7116-2395 (Ya-Zhou Wang); https://orcid.org/0000-0001-7220-7607 (Ying-Zhou Hu); https://orcid.org/0000-0003-2928-8178 (Kun Zhang)
#These authors contribute equally to the work. 
Funding: This work was supported by the National Natural Science Foundation of China, Nos. 82171346 (to YZW), 82171269 (to JLY), 82171471 (to HF); Beijing Nova Program, No. 
Z201100006820076 (to JLY).
How to cite this article: Yang JL, Fan H, Fu FF, Guo BL, Huang Y, Sun L, Wang WT, Xing JL, Hu XT, Ding YQ, Zhang K, Hu YZ, Wang YZ (2023) Transient neurogenesis in ischemic cortex 
from Sox2+ astrocytes. Neural Regen Res 18(7):1521-1526. 
Graphical Abstract
Transient wave of local neurogenesis
From the Contents
Introduction


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1521
Methods  
1522
Results
1523
Discussion
1526
Jia-Lei Yang1, 2, #, Hong Fan1, 3, #, Fan-Fan Fu1, #, Bao-Lin Guo1, Ying Huang4, Li Sun1, Wen-Ting Wang1, Jun-Ling Xing1, Xin-Tian Hu5, 
Yu-Qiang Ding4, Kun Zhang1, *, Ying-Zhou Hu5, *, Ya-Zhou Wang1, *


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Vol.:(0123456789)
1 3
Angiogenesis 
https://doi.org/10.1007/s10456-023-09878-5
REVIEW PAPER
Damage to endothelial barriers and its contribution to long COVID
Xiaoming Wu1 · Mengqi Xiang1 · Haijiao Jing1 · Chengyue Wang1 · Valerie A. Novakovic2 · Jialan Shi1,2,3 
Received: 1 August 2022 / Accepted: 16 April 2023 
© The Author(s), under exclusive licence to Springer Nature B.V. 2023
Abstract
The world continues to contend with COVID-19, fueled by the emergence of viral variants. At the same time, a subset 
of convalescent individuals continues to experience persistent and prolonged sequelae, known as long COVID. Clinical, 
autopsy, animal and in vitro studies all reveal endothelial injury in acute COVID-19 and convalescent patients. Endothelial 
dysfunction is now recognized as a central factor in COVID-19 progression and long COVID development. Different organs 
contain different types of endothelia, each with specific features, forming different endothelial barriers and executing different 
physiological functions. Endothelial injury results in contraction of cell margins (increased permeability), shedding of 
glycocalyx, extension of phosphatidylserine-rich filopods, and barrier damage. During acute SARS-CoV-2 infection, damaged 
endothelial cells promote diffuse microthrombi and destroy the endothelial (including blood–air, blood–brain, glomerular 
filtration and intestinal–blood) barriers, leading to multiple organ dysfunction. During the convalescence period, a subset 
of patients is unable to fully recover due to persistent endothelial dysfunction, contributing to long COVID. There is still an 
important knowledge gap between endothelial barrier damage in different organs and COVID-19 sequelae. In this article, 
we mainly focus on these endothelial barriers and their contribution to long COVID.
Keywords Long COVID · Endothelial barrier · Vaccination · Antithrombotic therapy
Abbreviations
ACE2 
 Angiotensin converting enzyme 2
AKI 
 Acute kidney injury
APCs 
 Antigen presenting cells
BBB 
 Blood–brain barrier


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BAL 
 Bronchoalveolar lavage
CNS 
 Central nervous system
DOAC 
 Direct oral anticoagulation
ECs 
  Endothelial cells
eGFR 
 Estimated glomerular filtration rate
FCV 
 Forced vital capacity
FEV1 
 Forced expiratory volume in the first 
second
GFB 
 Glomerular filtration barrier
GIS 
 Gastrointestinal symptoms
RBC 
 Erythrocyte
RBD 
 Receptor-binding domain
RCT 
 Randomized clinical trial
VE-cadherin  Vascular endothelial cadherin
VE-PTP 
  Vascular endothelial-protein tyrosine 
phosphatase
VEGF 
 Vascular endothelial growth factor
VEGF A 
 Vascular endothelial growth factor A
ZO 
 Zonula occludens
Introduction
As of March 3, 2023, more than 758 million confirmed cases 
of COVID-19 have been reported to WHO [1]. Although 
most patients return to their baseline state of health after 
infection, a subset of patients have ongoing health prob-
lems, known as post-acute sequelae of COVID-19 or long 
COVID. The WHO defines long COVID as the continuation 
or development of new symptoms 3 months after the initial 
SARS-CoV-2 infection, with these symptoms lasting for at 
least 2 months without other explanation [2]. The persis-
tent symptoms can occur even after an oligosymptomatic 
infection [3]. These symptoms include fatigue, shortness of 
 * Jialan Shi 
 
jialan_shi@dfci.harvard.edu; shi73661@gmail.com
1 
Department of Hematology,  The First Hospital, Harbin 
Medical University, 150001 Harbin, China
2 
Department of Research, VA Boston Healthcare System, 
Harvard Medical School, Boston, MA, USA
3 
Department of Medical Oncology, Dana-Farber Cancer 
Institute, Harvard Medical School, MA, Boston, USA


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Antiretroviral drug exposure in urethral and glans surface 
sampling of the penis
Richard E. Haaland1,*, Jeffrey Fountain1, Chuong Dinh1, L. Davis Lupo1, Amy Martin1, 
Christopher Conway-Washington2, LaShonda Hall2, Colleen F. Kelley2,3, J. Gerardo Garcia-
Lerma1, Walid Heneine1
1Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA;
2The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of 
Medicine, Emory University School of Medicine, Atlanta, GA, USA;
3Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 
USA
Abstract
Background: HIV exposure to penile tissues provides a risk of acquisition among men, yet 
studies evaluating penile antiretroviral (ARV) drug distribution have been lacking. We measured 
ARVs on urethral and glans surface swabs collected following a dose of tenofovir alafenamide, 
emtricitabine, elvitegravir, darunavir and cobicistat.
Methods: Thirty-five HIV-negative male participants provided urethral swabs, glans swabs, rectal 
swabs, blood and urine up to 96 h following a single dose of tenofovir alafenamide/emtricitabine/
elvitegravir/cobicistat and darunavir. ARVs were measured by liquid chromatography–mass 
spectrometry with a lower limit of detection (LOD) of 1 ng/swab for swabs and 10 ng/mL for 
plasma and urine. Concentrations are reported as median and range.
Results: Urethral swab emtricitabine and darunavir concentrations peaked at 4 h for 
emtricitabine (36 ng/swab; 3–307 ng/swab) and 8 h for darunavir (25 ng/swab; 2–52 ng/swab). 
Glans swab emtricitabine and darunavir concentrations peaked 24 h after dosing (emtricitabine 
14 ng/swab, <LOD–328 ng/swab; darunavir 6 ng/swab, <LOD–149 ng/swab). Estimated peak 
urethral secretion emtricitabine and darunavir concentrations are between 10 and 20 lg/mL, similar 
to rectal secretions, 4-fold greater than in plasma, but 2-fold lower than in urine. Tenofovir and


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elvitegravir were detected on less than 20% of urethral or glans swabs collected within 24 h of 
dosing.
This work is written by (a) US Government employee(s) and is in the public domain in the US.
*Corresponding author. hyw9@cdc.gov. 
Transparency declarations
J.G.G.-L. and W.H. are named in a US Government patent application related to methods for HIV prophylaxis. All other authors: none 
to declare.
Disclaimer
The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the 
United States Centers for Disease Control and Prevention or the Department of Health and Human Services.
HHS Public Access
Author manuscript
J Antimicrob Chemother. Author manuscript; available in PMC 2023 April 27.
Published in final edited form as:
J Antimicrob Chemother. 2021 August 12; 76(9): 2368–2374. doi:10.1093/jac/dkab155.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Journal ofNeurology, Neurosurgery, and Psychiatry 1993;56:31 1-313
SHORT REPORT
Post-ictal Kliuver-Bucy syndrome after temporal
lobectomy
John A Anson, Donald T Kuhlman
Abstract
In both animals and humans, Kluver-
Bucy syndrome is produced by bilateral
temporal lobectomy. It is characterised
by hypersexuality, visual agnosia, strong
oral
tendencies,
dietary
changes,
and
hypermetamorphosis. Recurrent, postic-
tal
Kluver-Bucy
syndrome
occurred
transiently after seizures in a female who
had
undergone
unilateral
temporal
lobectomy.
The
pathophysiological
mechanism may have been postictal dys-
function of the remaining temporal lobe,
producing a transient functional bilateral
temporal lobectomy.
(7 Neurol Neurosurg Psychiatry 1993;56:31 1-313)
Division of
Neurological Surgery,
University of
New Mexico Hospital,
Albuquerque, New
Mexico, USA
J A Anson
Department of
Neurology, Mt Sinal
Hospital, Chicago,
Illinois, USA
J D T Kuhlman
Correspondence to:
Dr Anson, c/o Division of
Neurosurgery, University of
New Mexico Hospital, 2211
Lomas NE, Albuquerque,
New Mexico 87131, USA
Received 8 April 1992
and in revised form
16 June 1992.
Accepted 7 July 1992
In 1939, Kliiver and Bucy described a behav-
ioural syndrome in rhesus monkeys that fol-
lowed
bilateral
temporal
lobectomy.'
The
syndrome
was
characterised by prominent
and indiscriminate hypersexuality, excessive
oral tendencies, loss of normal fear and anger,
hypermetamorphosis (excessive attentiveness
to visual stimuli), psychic blindness (inability
to recognise objects without loss of gross visu-
al discrimination), and dietary changes.
In 1955 Terzian
first reported the same
syndrome in humans after bilateral temporal
lobectomy.
Kliiver-Bucy syndrome
is
also
associated with a variety of neurological disor-
ders, including herpes encephalitis, Pick's dis-
ease,
Alzheimer's
disease,
cerebrovascular
accidents, cerebral trauma, and temporal lobe
epilepsy. The common feature of all aetiolo-
gies
was
bilateral
mesial
temporal
lobe
destruction or dysfunction.


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We report an unusual
case of recurrent
transient Kluver-Bucy syndrome
that
only
occurred during the
postictal
period
in
a
patient who had occasional seizures after a
unilateral temporal lobectomy.
Case report
In 1984 a 24 year old female sought treat-
ment
after generalised
seizures
followed
a.
week-long fever. A CT scan showed a nonen-
hancing radioluscent
area between the
left
medial temporal lobe and the
left cerebral
peduncle that suggested atrophy of the left
medial
temporal
lobe
(Fig). Two
lumbar
punctures
were normal.
She
continued
to
have frequent seizures and a week later devel-
oped
status
epilepticus
despite
therapeutic
levels of phenytoin, phenobarbitone, and val-
proic acid. A 24 hour EEG demonstrated that
bilateral frontotemporal
ictal patterns were
occurring every 30 minutes and lasting 70 to
90 seconds. These EEG patterns were associ-
ated with
the
clinically observed
seizures.
Eighty one per cent of the ictal events origi-
nated from the left side.
MRI showed increased signal intensity of
the left temporal lobe. Status epilepticus was
persistent and refractory to maximal medical
therapy. The patient therefore had a left tem-
poral craniotomy 2 weeks after admission.
Electrocorticography showed many indepen-
dent spike discharges from the inferior and
middle temporal gyri. A temporal lobectomy
removed the anterior 4 cm of the left tempo-
ral lobe, the amygdala, and the anterior 1 to
1g5 cm of the hippocampus.
Postoperatively, the patient did well. She
experienced no further seizures while receiv-
ing phenytoin, phenobarbitone, and carba-
mazepine in the hospital. An EEG showed
spike and wave complexes and sharp waves
from the left frontotemporal region. Because
of the unusual need for temporal lobectomy
to control status epilepticus, this case was
reported
in the neurosurgical
literature
in
1986.3 The patient was then lost to follow up
several months after surgery.
Five years later after a generalised seizure,
the patient sought treatment in a local emer-


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gency room. On examination, she was lethar-
gic and unresponsive but medically stable
without further seizure activity. She was left
unattended in an examination room. About
30 minutes later, she was found in an adja-
cent room performing fellatio on an elderly
male cardiac patient. The patient was easily
led back to her room. She was placid and
apparently did not recognise family members
who arrived soon after. An hour later she was
alert and neurologically intact with no memo-
ry of the episode.
When
questioned,
the
patient's
family
revealed that she still had occasional seizures
despite the temporal lobectomy. Typically,
the seizures occurred after she had run out of
anticonvulsant medication. After the seizures,
the family reported that she exhibited abnor-
mal sexual behaviour, which included mastur-
bating in public and
soliciting intercourse
with family members and neighbours. During
these episodes, she did not recognise family
members and was subdued and apathetic.
She also exhibited bulimia, eating voraciously
whatever food was available. These behav-
ioural changes lasted 1 to 2 hours; afterwards,
she was amnestic for the entire event. During
31


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Journal ofNeurology, Neurosurgery, and Psychiatty 1993;56:799-807
Smooth pursuit eye movement deficits after
pontine nuclei lesions in humans
B Gaymard, C Pierrot-Deseilligny, S Rivaud, S Velut
Abstract
Eye movements were recorded electro-
oculographically
in four patients with
basal pontine lesions, demonstrated by
MRI. The most prominent eye move-
ment abnormality observed was mild to
severe impairment
of smooth pursuit
and optokinetic nystagmus, mainly ipsi-
lateral to the lesion. This abnormality is
thought to result from damage to the
pontine
nuclei, which form a
crucial
relay between the cerebral cortex and the
cerebellum controlling smooth pursuit.
Abnormalities
of
saccades
and
the
vestibulo-ocular reflex in one patient are
also discussed.
(9Neurol Neurosurg Psychiatry 1993;56:799-807)
Clinique Neurologique
and Unit6 INSERM
289, Hopital de la
Salpetriere, Paris, and
Service de
Neurochirurgie,
H6pital Bretonneau,
Tours, France
B Gaymard
C Pierrot-Deseilligny
S Rivaud
S Velut
Correspondence to:
B Gaymard, INSERM 289,
H6pital de la Salpetriere, 47
Bd de l'H6pital, 75651
Paris, Cedex 13, France
Received 30 March 1992
and in revised from
11 August 1992.
Accepted 25 September 1992
The pontine nuclei (PN) consist of several
groups of neurons in the basis pontis relaying
signals from the cerebral cortex towards the
cerebellum. Some of them, namely the dorso-
lateral, the lateral, and the dorsomedian PN,
could be specifically involved in smooth pur-
suit eye movements, and represent a crucial
link in the corticopontine pathways mediating
this eye movement.'23 However, the location
and function of the PN involved in smooth
pursuit still have to be precisely determined
in humans. The first human case with a selec-
tive PN lesion and including eye movement
recordings was recently reported.4 It provided
data consistent with the results of experimen-
tal lesion studies involving the dorsolateral
pontine nuclei (DLPN) in the monkey. We
report
four patients with
diverse vascular


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lesions affecting the basis pontis, resulting in
various impairments of smooth pursuit and
optokinetic nystagnus (OKN). The relation
between smooth pursuit impairment and the
location of the lesions is discussed.
Case reports
PATENT 1
A 73 year old woman had been complaining
for a year and a half of a right trigeminal neu-
ralgia despite carbamazepine
therapy.
She
thus agreed to a neurosurgical procedure, and
a microvascular decompression of the fifth
nerve
was
performed.
After
surgery,
the
patient awoke with left hemiplegia.
There
was no cerebellar symptoms, no sensory loss,
and no diplopia. MRI showed a right pontine
lesion, compatible with a haematoma (fig 1).
This lesion was located along the lateral edge
of the basis pontis, and affected about two
thirds of the rostrocaudal extent of the pons
(fig 2). When eye movement recordings were
made, one week after surgery, the left hemi-
plegia had not improved, though the patient
was alert and cooperative.
PATENT 2
A 59 year old woman was hospitalised after
the sudden onset of right hemiplegia. On ini-
tial examination, severe right hemiplegia was
observed. On the left side, strength was nor-
mal but there was dysmetria in the finger to
nose test. All sensory examination was nor-
mal. MRI showed a left pontine lesion, com-
patible with an infarct (fig 3). A transverse
section showed that the lesion affected almost
all the left basis pontis, and slightly crossed
the midline (fig 3A). The pontine tegmentum
was spared, excepc-for a limited part of the
median structures, on which a very narrow
posterior extent of the lesion impinged (fig 2).
Sagittal
sections
clearly
showed
that
the
lesion had a short rostrocaudal extent, and
consisted of a thin horizontal slice (about
5 mm) at the mid-pons level (fig 3B). MRI
did not show any lesions in the superior or
inferior cerebellar peduncles or in the cerebel-
lum. Eye movement recordings were per-
formed five months after the stroke. At that
time, the motor deficit and the cerebellar
syndrome persisted. The patient was
alert


key: chroma:document
string_value:
alert
and cooperative.
PATENT 3
A 34 year old woman with no medical back-
ground was
hospitalised
after the sudden
onset of pure left hemiparesis. MRI showed a
lesion restricted to the basis pontis, compati-
ble with an infarct. It was located just below
the mid-pons level, along the midline, with a
limited extent on the right side (fig 2). On
sagittal sections,
it occupied approximately
30% of the whole rostrocaudal extent of the
pons. Eye movement recordings were per-
formed one month after the stroke. At that
time, there was no improvement in the motor
deficit, though
the
patient was
alert and
cooperative.
PATINT 4
A 66 year old woman with a long history of
hypertension suddenly experienced isolated
left hemiplegia. MRI showed a lesion com-
patible with an infarct, located on the right
side of the brainstem, at the mid-pons level.
The lesion was restricted to the basis pontis,
799


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Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation


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Impact of GVHD prophylaxis on CMV reactivation and disease after
HLA-matched peripheral blood stem cell transplantation
Masumi Ueda Oshima,1,2 Hu Xie,1 Danniel Zamora,1,3 Mary E. Flowers,1,2 Geoffrey R. Hill,1,2 Marco B. Mielcarek,1,2
Brenda M. Sandmaier,1,2 Ted A. Gooley,1 and Michael J. Boeckh1,3
1Fred Hutchinson Cancer Center, Seattle, WA; 2Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; and 3Division of Allergy and
Infectious Diseases, University of Washington, Seattle, WA
Key Points
• Despite higher risk of
early CMV reactivation
using PTCy, 1-year viral
burden and CMV
disease are
comparable with MTX-
based prophylaxis.
• MMF is associated
with higher risk of early
and late CMV
reactivation and higher
1-year viral burden than
MTX-based
prophylaxis.
The kinetics of early and late cytomegalovirus (CMV) reactivation after hematopoietic cell
transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are
poorly deﬁned. We retrospectively compared CMV reactivation and disease among 780
seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and
calcineurin inhibitor plus posttransplantation cyclophosphamide (PTCy; n = 44),
mycophenolate mofetil (MMF; n = 414), or methotrexate (MTX; n = 322). Transplantation
occurred between 2007 and 2018; CMV monitoring/management followed uniform standard
practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves
were ﬁt over average daily viral load and areas under the curve (AUC) within 1 year were
calculated. PTCy and MMF were associated with an increased risk of early (day ≤100) CMV
reactivation ≥250 IU/mL after multivariate adjustment. The viral load AUC at 1 year was
highest with MMF (mean difference = 0.125 units vs MTX group) and similar between PTCy
and MTX (mean difference = 0.016 units vs MTX group). CMV disease risk was similar across
groups. There was no interaction between GVHD prophylaxis and CMV reactivation on


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chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the
CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast,
MMF was associated with higher overall CMV viral burden in the 1 year posttransplant.
Although different mechanisms of immunosuppressive agents may affect CMV reactivation
risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate
infection risk over time.
Introduction
Cytomegalovirus (CMV) reactivation at any level after allogeneic stem cell transplantation is strongly
associated with inferior overall and nonrelapse mortality. The differential impact of various pharmaco-
logic graft-versus-host disease (GVHD) prophylaxis regimens on CMV infection is poorly deﬁned. In
recent years, the use of posttransplantation cyclophosphamide (PTCy) has been shown to signiﬁcantly
reduce both severe acute and chronic GVHD risk after HLA-haploidentical (haplo)1 and HLA-matched
related and unrelated donor stem cell transplantation.2 Single-center retrospective studies have
reported a higher incidence of CMV infection after haplo transplantation using PTCy than historically
Submitted 23 December 2022; accepted 28 December 2022; prepublished
online on Blood Advances First Edition 3 January 2023. https://doi.org/10.1182/
bloodadvances.2022009112.
Data are available on request from the corresponding author, Masumi Ueda Oshima
(mueda@fredhutch.org).
The full-text version of this article contains a data supplement.
© 2023 by The American Society of Hematology. Licensed under Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0),
permitting only noncommercial, nonderivative use with attribution. All other rights
reserved.
TRANSPLANTATION
1394
25 APRIL 2023 • VOLUME 7, NUMBER 8


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Effect of antiplatelet agents and tyrosine kinase inhibitors on oxLDL-mediated procoagulant platelet activity


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Effect of antiplatelet agents and tyrosine kinase inhibitors on
oxLDL-mediated procoagulant platelet activity
Tony J. Zheng,1 Tia C. L. Kohs,1 Paul A. Mueller,2 Jiaqing Pang,1 St´ephanie E. Reitsma,1 Iv´an Parra-Izquierdo,1,2 Alexander R. Melrose,2
Liping Yang,3 Jaewoo Choi,4 Keith D. Zientek,5 Denis O. Sviridov,6 Mark K. Larson,7 Craig D. Williams,8 Nathalie Pamir,2
Joseph J. Shatzel,1,9 Ashok P. Reddy,5 Paul Kievit,4 Alan T. Remaley,6 Jan F. Stevens,8,10 Monica T. Hinds,1 Owen J. T. McCarty,1,9,11 and
Joseph E. Aslan1,2,12
1Department of Biomedical Engineering and 2Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR; 3Department of Chemistry, Oregon State
University, Corvallis, OR; 4Oregon National Primate Research Center and 5Proteomics Shared Resource, Oregon Health & Science University, Portland, OR; 6Lipoprotein
Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; 7Department of
Biology, Augustana University, Sioux Falls, SD; 8College of Pharmacy, Oregon State University, Corvallis, OR; 9Division of Hematology & Medical Oncology, Oregon Health &
Science University, Portland, OR; 10Linus Pauling Institute, Oregon State University, Corvallis, OR; and 11Department of Cell, Developmental & Cancer Biology and
12Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR
Key Points
• OxLDL enhances
GPVI-driven platelet
procoagulant activity
ex vivo.
• P2YR antagonists and
tyrosine kinase
inhibitors may reduce
oxLDL-enhanced
platelet procoagulant
activity more so than
aspirin.
Low-density lipoprotein (LDL) contributes to atherogenesis and cardiovascular disease through
interactions with peripheral blood cells, especially platelets. However, mechanisms by which
LDL affects platelet activation and atherothrombosis, and how to best therapeutically target
and safely prevent such responses remain unclear. Here, we investigate how oxidized low-


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density lipoprotein (oxLDL) enhances glycoprotein VI (GPVI)-mediated platelet hemostatic and
procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-
enhanced platelet procoagulant activity ex vivo. Human platelets were treated with oxLDL and
the GPVI-speciﬁc agonist, crosslinked collagen-related peptide, and assayed for hemostatic and
procoagulant responses in the presence of inhibitors of purinergic receptors (P2YR),
cyclooxygenase (COX), and tyrosine kinases. Ex vivo, oxLDL enhanced GPVI-mediated platelet
dense granule secretion, α-granule secretion, integrin activation, thromboxane generation and
aggregation, as well as procoagulant phosphatidylserine exposure and ﬁbrin generation.
Studies of washed human platelets, as well as platelets from mouse and nonhuman primate
models of hyperlipidemia, further determined that P2YR antagonists (eg, ticagrelor) and Bruton
tyrosine kinase inhibitors (eg, ibrutinib) reduced oxLDL-mediated platelet responses and
procoagulant activity, whereas COX inhibitors (eg, aspirin) had no signiﬁcant effect. Together,
our results demonstrate that oxLDL enhances GPVI-mediated platelet procoagulant activity in a
manner that may be more effectively reduced by P2YR antagonists and tyrosine kinase
inhibitors compared with COX inhibitors.
Introduction
Dyslipidemia and lipoprotein accumulation drive atherogenesis and cardiovascular disease, a leading
preventable cause of mortality worldwide.1-3 Lipoprotein levels are established risk factors for
Submitted 28 January 2022; accepted 11 September 2022; prepublished online on
Blood
Advances
First
Edition
11
October
2022.
https://doi.org/10.1182/
bloodadvances.2022007169.
Full material/reagents list and reproducible methods are provided in supplemental
Methods.
Data are available on request from the corresponding author, Joseph E. Aslan (aslanj@
ohsu.edu).
The full-text version of this article contains a data supplement.
Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0


key: chroma:document
string_value:
International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use
with attribution.
REGULAR ARTICLE
1366
25 APRIL 2023 • VOLUME 7, NUMBER 8


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54ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:854-856
SHORT REPORT
Lacunar thalamic stroke with pure cerebellar and
proprioceptive deficits
Jose A Gutrecht, Amir A Zamani, Deepak N Pandya
Abstract
Case reports of two patients with cere-
bellar ataxia and proprioceptive sensory
loss
are presented. MRI of the brain
revealed lesions of the ventroposterior
part of the thalamus. These patients illus-
trate clinically the anatomical independ-
ence ofcerebelkar and sensory pathways in
the thalamus. We suggest that the ataxic
deficit is caused by interruption of cere-
bellar outflow pathways in the thalamus
and not secondary to sensory deaffer-
entation.
(3 Neurol Neurosurg Psychiatry 1992;55:854-856)
Department of
Neurology, Lahey
Clinic Medical Center,
Burlington,
Massachusetts
J A Gutrecht
Department of
Radiology, Brigham
and Women's Hospital,
Boston, Massachusetts
A A Zamani
Department of
Anatomy and
Neurology, Boston
University Medical
School, Boston,
Massachusetts, and
the Bedford Veterans
Administration
Hospital, Bedford,
Massachusetts, USA
D N Pandya
Correspondence to:
Dr Gutrecht, Department of
Neurology, Lahey Clinic
Medical Center, 41 Mall
Road, Burlington, MA
01805.
Received 12 September
1991
and in revised form
6 December 1991.
Accepted 18 December
1991
Ischaemic lacunar strokes occur frequently in
the thalamus.' 2 Small haemorrhages in the
thalamus may also produce lacunar strokes3 4
with similar clinical deficits.5 The lateral syn-
drome is the most common and has one of the
best known cluster of findings of the thalamic
syndromes.6This syndrome and its anatomical
location of the responsible lesion were first
described by Dejerine and Roussy7 in 1906.
Reported cases of "pure" thalamic
syn-
dromes with deficits in only one or two tracts
or systems deficits are rare.8-" We report two
cases of lacunar thalamic stroke that produced
a contralateral combination of a cerebellar
deficit and proprioceptive sensory loss.
Case reports
A 63 year old right handed man was seen at the


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Lahey Clinic Medical Center because of the
sudden onset of dysaesthesia of the right side
of the face and distal right limbs and an
inability to walk that lasted for one hour. Three
days earlier, he had had an episode of nausea,
decreased concentration, and an inability to
read that lasted for a few hours. The patient has
diabetes mellitus and hypertension, and he was
taking tolbutamide and metoprolol. Neuro-
logical examination demonstrated dysdiado-
chokinesis and dysmetria with terminal tremor
in the right limbs that did not worsen with
closed eyes. A mild subjective decreased pain
sensation was observed in the right side of the
face and right hand, but touch, position, and
temperature sensation were normal. Two-point
discrimination and stereognosis were greatly
decreased in the right hand. No weakness was
noted. Stretch reflexes were hypoactive but
symmetrical.
Plantar reflexes were normal.
MRI of the brain showed a small lesion in the
lateral posterior aspect of the left thalamus (fig
1). No source of an embolus was found.
Cerebral angiography was not performed. The
deficits abated in several days.
A 74 year old right handed man complained
of sudden onset of inability to control the right
arm and leg despite normal strength, unsteadi-
ness, and a "frozen feeling" in the right side of
the face and right hand. History included
hypertension
treated with methyldopa and
triamterene/hydrochlorothiazide. Mild dysar-
thria, inconsistently decreased pain sensation,
dysdiadochokinesis,
and
decomposition
of
movements in the right limbs were noted. CT
of the head showed a small left lateral thalamic
haemorrhage. The findings improved in a few
weeks. Neurological examination at the Lahey
Clinic seven months
later revealed
slightly
decreased touch and pain sensations but nor-
mal temperature sensation and position sense
with moderately diminished two-point
dis-
crimination and graphaesthesia in the right
hand. Mild dysmetria, terminal tremor, and
decreased finger and foot tapping ability were


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present on the right side. No weakness was
present,
and
the
stretch
reflexes
were
normoactive and symmetrical. Plantar reflexes
were normal. MRI of the brain performed
.5
.
*A4~~~~~~~~~~~..
...
....S.
...S..;...:
Figure 1
(Case 1). Coronal T,-weighted (Magneton 1 *0
T, TR 065 s, TE 17 ms, 3 mm slice) image through
posterior thalamic regions demonstrates a well-defined
irregular area of low intensity in the lateral portion of the
left thalamus.
854


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The Orienting Reflex Reveals Behavioral States Set by Demanding Contexts: Role of the Superior Colliculus


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Behavioral/Cognitive
The Orienting Reflex Reveals Behavioral States Set by
Demanding Contexts: Role of the Superior Colliculus
Ji Zhou, Sebastian Hormigo,
Natan Busel, and
Manuel A. Castro-Alamancos
Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut 06001
Sensory stimuli can trigger an orienting reflex (response) by which animals move the head to position their sensors (e.g., eyes,
pinna, whiskers). Orienting responses may be important to evaluate stimuli that call for action (e.g., approach, escape, ignore),
but little is known about the dynamics of orienting responses in the context of goal-directed actions. Using mice of either sex, we
found that, during a signaled avoidance action, the orienting response evoked by the conditioned stimulus (CS) consisted of a
fast head movement containing rotational and translational components that varied substantially as a function of the behavioral
and underlying brain states of the animal set by different task contingencies. Larger CS-evoked orienting responses were associ-
ated with high-intensity auditory stimuli, failures to produce the appropriate signaled action, and behavioral states resulting from
uncertain or demanding situations and the animal’s ability to cope with them. As a prototypical orienting neural circuit, we con-
firmed that the superior colliculus controls and codes the direction of spontaneous exploratory orienting movements. In addition,
superior colliculus activity correlated with CS-evoked orienting responses, and either its optogenetic inhibition or excitation
potentiated CS-evoked orienting responses, which are likely generated downstream in the medulla. CS-evoked orienting responses
may be a useful probe to assess behavioral and related brain states, and state-dependent modulation of orienting responses may
involve the superior colliculus.
Key words: avoidance; behavioral states; escape; midbrain; orienting
Significance Statement


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Humans and other animals produce an orienting reflex (also known as orienting response) by which they rapidly orient their
head and sensors to evaluate novel or salient stimuli. Spontaneous orienting movements also occur during exploration of the
environment in the absence of explicit, salient stimuli. We monitored stimulus-evoked orienting responses in mice perform-
ing signaled avoidance behaviors and found that these responses reflect the behavioral state of the animal set by contextual
demands and the animal’s ability to cope with them. Various experiments involving the superior colliculus revealed a well-
established role in spontaneous orienting but only an influencing effect over orienting responses. Stimulus-evoked orienting
responses may be a useful probe of behavioral and related brain states.
Introduction
In alert animals, an unexpected, novel, or salient sensory stimu-
lus leads to a well-known orienting response by which animals
move their head and sensors in an apparent effort to evaluate the
stimulus (Sokolov, 1963). Spontaneous orienting also occurs dur-
ing active exploration of the environment in the absence of sa-
lient overt stimuli, but it is not clear whether stimulus-evoked
and spontaneous orienting share the same neural substrate. Since
Pavlov identified orienting responses, they have been intensely
investigated in humans as a functional unconditioned response
system that comprises numerous motor and physiological (e.g.,
vascular, respiratory, skin conductance, EEG) reactions (e.g.,
Ranganath and Rainer, 2003; Friedman et al., 2009). However,
less is known about stimulus-evoked orienting responses in
mice, an animal model amenable to studying the underlying
neural circuits.
A decision to act usually follows stimulus-evoked orienting
responses. For instance, during a learned sensory guided loco-
motor behavior in rodents, known as signaled active avoidance,
the conditioned stimulus (CS) onset typically evokes a head ori-
enting response that is dissociable from the ensuing avoidance


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action (e.g., Hormigo et al., 2021b; Zhou et al., 2022). However,
little is known about CS-evoked orienting responses in the con-
text of signaled avoidance behaviors. One possibility is that ori-
enting responses adapt to changes in the meaning of the evoking
CS, reflecting the significance of the stimulus. Alternatively, ori-
enting responses may vary in relation to the demands of the
Received Aug. 29, 2022; revised Jan. 26, 2023; accepted Feb. 1, 2023.
Author contributions: J.Z., S.H., N.B., and M.A.C.-A. performed research; J.Z., S.H., and M.A.C.-A. analyzed
data; J.Z., S.H., N.B., and M.A.C.-A. edited the paper; M.A.C.-A. designed research; M.A.C.-A. wrote the first
draft of the paper; M.A.C.-A. wrote the paper.
This work was supported by National Institutes of Health grants R35 NS097272 and R01 NS104810 to M.A.C.-A.
The authors declare no competing financial interests.
Correspondence should be addressed to Manuel A. Castro-Alamancos at mcastro@uchc.edu.
https://doi.org/10.1523/JNEUROSCI.1643-22.2023
Copyright © 2023 the authors
1778 • The Journal of Neuroscience, March 8, 2023 • 43(10):1778–1796


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Horizontal Transmission of Cytomegalovirus in a Rhesus Model Despite High-Level, Vaccine-Elicited Neutralizing Antibody and T-Cell Responses


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string_value:
Horizontal Transmission of Cytomegalovirus in a Rhesus
Model Despite High-Level, Vaccine-Elicited Neutralizing
Antibody and T-Cell Responses
Julia Li,1 Sabine Wellnitz,1 Xiaoyuan S. Chi,1 Yujuan Yue,2 Kimberli A. Schmidt,3 Nancy Nguyen,3 Wei Chen,1 Irina Yurgelonis,1 Eduardo Rojas,1
Yuhang Liu,3 Jakob Loschko,1 Eneida Pollozi,1 Yury V. Matsuka,1 Elie Needle,1 Eugene Vidunas,1 Robert G. K. Donald,1 Justin Moran,1
Kathrin U. Jansen,1 Philip R. Dormitzer,1 Peter A. Barry,2,4,5 and Xinzhen Yang1
1Vaccine Research and Development, Pﬁzer, Inc, Pearl River, New York, USA; 2Center for Comparative Medicine, University of California Davis, Davis, California, USA; 3Groton Center for Chemistry,
Pﬁzer, Inc, Groton, Connecticut, USA; 4Department of Pathology and Laboratory Medicine, University of California Davis, Davis, California, USA; and 5California National Primate Research Center,
University of California Davis, Davis, California, USA
The development of a vaccine to prevent congenital human cytomegalovirus (HCMV) disease is a public health priority. We tested
rhesus CMV (RhCMV) prototypes of HCMV vaccine candidates in a seronegative macaque oral challenge model. Immunogens
included a recombinant pentameric complex (PC; gH/gL/pUL128/pUL130/pUL131A), a postfusion gB ectodomain, and a DNA
plasmid that encodes pp65-2. Immunization with QS21-adjuvanted PC alone or with the other immunogens elicited neutralizing
titers comparable to those elicited by RhCMV infection. Similarly, immunization with all 3 immunogens elicited pp65-speciﬁc
cytotoxic T-cell responses comparable to those elicited by RhCMV infection. RhCMV readily infected immunized animals and
was detected in saliva, blood, and urine after challenge in quantities similar to those in placebo-immunized animals. If HCMV
evades vaccine-elicited immunity in humans as RhCMV evaded immunity in macaques, a HCMV vaccine must elicit immunity
superior to, or different from, that elicited by the prototype RhCMV vaccine to block horizontal transmission.
Keywords.


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Keywords.
cytomegalovirus; vaccine; neutralizing antibody; protective efﬁcacy; rhesus macaque; RhCMV.
Human
cytomegalovirus
(HCMV)
infection
of
immune-
competent individuals generally manifests with an acute phase
followed by a life-long latent phase and is often asymptomatic.
However, new infection or reactivation from latent HCMV infec-
tion in immunosuppressed patients, such as transplant recipients
or those with AIDS, can cause serious disease and even death.
Primary HCMV infection of a seronegative pregnant woman re-
sults in transmission to her fetus in approximately 30% of cases
[1, 2]. Approximately 10% of congenitally infected infants will
have symptoms at birth, with approximately 30%–40% of those
exhibiting severe disease, which can include hearing loss, vision
loss, microcephaly, and developmental delay. Nonprimary infec-
tion of a seropositive pregnant woman or reactivation of her la-
tent HCMV also can result in transplacental transmission. The
probability of transmission to the fetus and severe sequelae
may be substantially lower after nonprimary maternal infection,
though studies of the outcomes of nonprimary maternal infection
are inconsistent [1, 2]. A prophylactic HCMV vaccine is urgently
needed to prevent congenital HCMV disease, as well as HCMV
disease in immunosuppressed patients.
At least 3 viral glycoproteins or glycoprotein complexes me-
diate HCMV entry into cells: glycoprotein B (gB), which is re-
quired for CMV entry into all target cells [3]; the gH/gL/
pUL128/pUL130/pUL131 heteropentamer complex (PC) [3],
which is important for entry into epithelial and endothelial
cells; and gH/gL/gO, which is important for entry into ﬁbro-
blasts [4–7]. The viral fusion glycoprotein, gB, transitions
from a metastable prefusion conformation to a stable postfu-
sion conformation as it fuses membranes during cell entry [8,
9]. Postfusion gB has been isolated in a well-characterized
form stable enough to test its immunogenicity. Postfusion gB
elicits strong nonneutralizing antibody responses, strong


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complement-dependent neutralizing responses, and much
weaker complement-independent neutralizing responses [10,
11]. A subunit vaccine candidate containing an adjuvanted, re-
combinant, postfusion CMV gB antigen has demonstrated stat-
istically signiﬁcant protection from horizontal transmission of
CMV to seronegative new mothers [12], and a trend toward
protection of seronegative adolescent girls [13]. Although the
observed level of protection was insufﬁcient to justify further
development of a postfusion gB-based vaccine, the ﬁndings
suggest that mechanisms other than virus neutralization may
have some protective capacity. Prefusion HCMV gB has been
Received 07 December 2021; editorial decision 01 March 2022; accepted 07 April 2022;
published online 12 April 2022
Correspondence: Xiaoyuan S. Chi, PhD, Pﬁzer Vaccine Research and Development, 401
N. Middletown Road, Pearl River, NY 10965 (schi01@yahoo.com).
The Journal of Infectious Diseases®
2022;226:585–94
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases
Society of America. All rights reserved. For permissions, please e-mail: journals.permissions
@oup.com
https://doi.org/10.1093/infdis/jiac129
CMV Infection Despite Vaccination • JID 2022:226 (15 August) • 585
The Journal of Infectious Diseases
M A J O R A R T I C L E


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Episodic memory deficit in HIV infection: common phenotype with Parkinsons disease, different neural substrates


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Vol.:(0123456789)
1 3
Brain Structure and Function (2023) 228:845–858 
https://doi.org/10.1007/s00429-023-02626-x
ORIGINAL ARTICLE
Episodic memory deficit in HIV infection: common phenotype 
with Parkinson’s disease, different neural substrates
Rosemary Fama1,2  · Eva M. Müller‑Oehring1,2  · Taylor F. Levine3  · Edith V. Sullivan1  · 
Stephanie A. Sassoon2  · Priya Asok1,2 · Helen M. Brontë‑Stewart3,4  · Kathleen L. Poston3,4  · Kilian M. Pohl1,2  · 
Adolf Pfefferbaum1,2  · Tilman Schulte2,5 
Received: 3 November 2022 / Accepted: 3 March 2023 / Published online: 18 April 2023 
© The Author(s) 2023
Abstract
Episodic memory deficits occur in people living with HIV (PLWH) and individuals with Parkinson’s disease (PD). Given 
known effects of HIV and PD on frontolimbic systems, episodic memory deficits are often attributed to executive dysfunc-
tion. Although executive dysfunction, evidenced as retrieval deficits, is relevant to mnemonic deficits, learning deficits may 
also contribute. Here, the California Verbal Learning Test-II, administered to 42 PLWH, 41 PD participants, and 37 controls, 
assessed learning and retrieval using measures of free recall, cued recall, and recognition. Executive function was assessed 
with a composite score comprising Stroop Color-Word Reading and Backward Digit Spans. Neurostructural correlates were 
examined with MRI of frontal (precentral, superior, orbital, middle, inferior, supplemental motor, medial) and limbic (hip-
pocampus, thalamus) volumes. HIV and PD groups were impaired relative to controls on learning and free and cued recall 
trials but did not differ on recognition or retention of learned material. In no case did executive functioning solely account 
for the observed mnemonic deficits or brain-performance relations. Critically, the shared learning and retrieval deficits in 
HIV and PD were related to different substrates of frontolimbic mnemonic neurocircuitry. Specifically, diminished learning


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and poorer free and cued recall were related to smaller orbitofrontal volume in PLWH but not PD, whereas diminished learn-
ing in PD but not PLWH was related to smaller frontal superior volume. In PD, poorer recognition correlated with smaller 
thalamic volume and poorer retention to hippocampal volume. Although memory deficits were similar, the neural correlates 
in HIV and PD suggest different pathogenic mechanisms.
Keywords HIV infection · Episodic memory processes · Regional brain volume · Parkinson’s disease
Introduction
Even in the current era of antiretroviral therapies (ART), 
mild to moderate cognitive deficits can be observed in peo-
ple living with HIV infection (PLWH) (Heaton et al. 2010). 
As PLWH live longer, the most susceptible cognitive defi-
cits to the progression of impairment in aging include epi-
sodic memory and motor functions, which may be associ-
ated with hippocampal (Maki et al. 2009) and basal ganglia 
(Goodkin et al. Sep 2017) dysfunction. The behavioral- and 
brain-related impairments observed in HIV infection are 
more often consistent with age-related diseases that affect 
subcortical regions such as Parkinson’s disease (PD) than 
age-related diseases that affect cortical regions, such as Alz-
heimer’s disease (Scott et al. Aug 2011), although the his-
torical and heuristic dissociation between “subcortical” and 
“cortical” dementia has continued to diminish. For example, 
Rosemary Fama and Eva M. Müller-Oehring are the Joint first 
authorship.
 * Eva M. Müller-Oehring 
 
evamoe@stanford.edu
1 
Department of Psychiatry and Behavioral Sciences, Stanford 
University School of Medicine, 401 Quarry Rd, Stanford, 
CA 94305, USA
2 
Neuroscience Program, Center for Health Sciences, 
Bioscience Division, SRI International, 333 Ravenswood 
Ave, Menlo Park, CA 94025, USA
3 
Department of Neurology and Neurological Sciences, 
Stanford University School of Medicine, Stanford, 
CA 94305, USA
4 
Department of Neurosurgery, Stanford University School 
of Medicine, Stanford, CA 94305, USA
5


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An RBD virus-like particle vaccine for SARS-CoV-2 induces cross-variant antibody responses in mice and macaques


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LETTER
OPEN
An RBD virus-like particle vaccine for SARS-CoV-2 induces
cross-variant antibody responses in mice and macaques
Signal Transduction and Targeted Therapy  (2023) 8:173 
; https://doi.org/10.1038/s41392-023-01425-4
Dear Editor,
Since early 2020, severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) has spread globally infecting over 500 million
people and causing over 6 million deaths. The massive worldwide
immunisation programmes and the arising clinical trial data
present a unique opportunity to compare the vaccines and
various delivery platforms (i.e. viral vector platform, mRNA
platform and virus-like particle platform). As reviewed from the
published clinical data,1 it is evident that the mRNA vaccines
(mRNA-1273 from Moderna, BNT162b2 from Pﬁzer) and subunit
protein/adjuvant vaccine (NVAX-CoV2373 from Novavax) were
able to induce an average 2–4 fold greater neutralizing antibody
(nAb) titer as compared to the human convalescent serum (HCS)
control.
On
the
other
hand,
the
viral
vectored
vaccines
(Ad26.COV2.S from Johnson & Johnson, ChAdOx1 nCoV-19 from
AstraZeneca) and the inactivated vaccine (CoronaVac from
Sinovac) induced less nAb than the HCS. Interestingly, CoVLP
from Medicago, which uses a plant-based virus-like particle (VLP)
platform technology, was able to induce a >10-fold increase in the
nAb response as compared to HCS;2 suggesting VLP vaccine or
arrayed antigen delivery is highly immunogenic.
We designed a vaccine, named RBDM, targeting the receptor-
binding domain (RBD) of the SARS-CoV-2 Spike glycoprotein (S-
protein), whereby the wild-type (WT; Wuhan strain) RBD is
delivered in an array on a VLP (an RBD-VLP vaccine) produced
using a split protein Tag/Catcher technology as described
previously.3 The RBD protein and VLP carrier, depicted in Fig. 1a,
were expressed at high titres in CHO cells (>4 g/L) and E. coli BL21
(DE3) cells (>3 g/L) respectively. Using a good manufacturing
practice (GMP) compatible puriﬁcation process, RBDM achieved a


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purity of >95% and endotoxin level of <5EU/mL (Fig. 1b).
Furthermore, RBDM robustly formed particles as conﬁrmed by
dynamic
light
scattering
(DLS)
reading
at
35.86 nm;
high-
performance liquid chromatography size exclusion chromatogra-
phy (HPLC-SEC) analysis at 26.4 min retention time; as well as
transmission electron microscopy (TEM) analysis (Fig. 1c, d, e). The
afﬁnity between RBD antigen and human Angiotensin-converting
enzyme 2 (hACE2) was measured in vitro using a Biolayer
Interferometry (BLI) assay. RBDM demonstrated the strongest
binding afﬁnity constant to hACE2 among all other designs, likely
due to the avidity of the interaction when arraying antigen on a
VLP (Supplementary Fig. S1). The S protein trimer (S-trimer),
depicted in Fig. 1a, was selected as a “reference vaccine” since
most ﬁrst-generation SARS-CoV-2 subunit vaccines were designed
based on S-protein antigen.
We
immunised
BALB/c
mice
with
two
doses
of
RBDM
formulated in Alhydrogel to evaluate its immunogenicity (Fig.
1f). RBDM was able to induce a signiﬁcantly higher IgG response
as compared to the soluble RBD; although it was not signiﬁcantly
different as compared to the larger S-trimer immunogen at each
timepoint (Supplementary Fig. S2a). RBD-speciﬁc IgG subclasses
were also measured in day 28 samples. Here, RBDM induced a
signiﬁcantly higher and more balanced IgG1, IgG2a and IgG2b
response than the soluble RBD. A similar trend was observed
when compared to S-trimer (Supplementary Fig. S2b). Neutralizing
antibody (nAb) was measured using an ACE2-RBD binding
competition ELISA. RBDM induced signiﬁcantly higher nAb
responses against most variants (Fig. 1g). For RBDM, the reduction
of nAb titers from WT to variants were no more than 3-fold, expect
for Omicron BA.1 where a >20-fold reduction was observed
(Fig. 1g). To understand if the higher nAb response of the RBDM
group was solely due to a higher total IgG response as
demonstrated in the endpoint titre ELISA (Supplementary Fig
S2a), we calculated the ratio of ELISA-measured nAb to IgG


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endpoint titer for individual animals. Per unit of endpoint titer,
there were signiﬁcantly more anti-WT, Alpha, Beta, Delta and
Lambda nAbs in the RBDM vaccinated group than the S-trimer
group. The nAb response against Gamma and Omicron BA.1
variant followed the same trend but was not statistically different
(Fig. 1h). These data indicate the RBDM vaccine induced a
qualitatively superior antibody response against most variants in
our study.
To test if RBDM is effective against viral challenges, K18-hACE2
transgenic mice were immunised three times with 10 μg or 20 μg
RBDM formulated in Alhydrogel adjuvant on days 0, 21 and 42 as
depicted in Fig. 1i. Serum from individual mice was taken on days
21, 42 and 49. The IgG titers were measured and the vaccines at
both doses induced signiﬁcantly higher IgG response as compared
to the saline and adjuvant control groups; while no signiﬁcant
difference
was
observed
between
the
two
vaccine
doses
(Supplementary
Fig.
S3a).
Neutralizing
antibody
(nAb)
was
measured by pseudovirus assay and the nAb response against
both the WT and Delta stains of pseudovirus were detected
(Supplementary Fig. S3b, c). The mice were then challenged with
the WT or Delta variant of SARS-CoV-2 live virus on day 49
followed by dissection on day 52. The viral loads in the lung tissue
were measured by plaque assay and no live virus was detected in
any of the vaccinated groups challenged with either strain of
SARS-CoV-2 (Fig. 1k).
To test if RBDM is immunogenic in non-human primates (NHP),
rhesus macaques were immunised three times with 50 or 25 μg
RBDM or adjuvant control on days 0, 28 and 56; the immunisation
strategy is depicted in Fig. 1j. The anti-Spike glycoprotein IgG was
measured by ELISA and both dosage groups induced high
antibody titers with similar trend, and both peaked after the
second immunisation (Fig. 1l). Pseudovirus neutralization assay
(Supplementary Fig. S4a) and live virus neutralization assay
(Fig. 1m) were performed. Both tests conﬁrmed induction of high


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nAb titers against the WT and Delta variant of SARS-CoV-2. The live
virus
neutralization
assay
against
WT
SARS-CoV-2
revealed
relatively high nAb responses, with a geometric mean titer
(GMT) of 3547 on day 56 after two vaccinations and 5552 on day
Received: 18 November 2022 Revised: 15 March 2023 Accepted: 29 March 2023
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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Vol.:(0123456789)
1 3
World Journal of Pediatrics (2023) 19:417–424 
https://doi.org/10.1007/s12519-022-00619-0
REVIEW ARTICLE
Biliatresone: progress in biliary atresia study
Jia‑Jie Zhu1 · Yi‑Fan Yang1 · Rui Dong1 · Shan Zheng1 
Received: 24 March 2022 / Accepted: 5 September 2022 / Published online: 27 September 2022 
© The Author(s) 2022
Abstract
Background Biliary atresia (BA) is one of the main causes of neonatal end-stage liver disease. Without timely diagnosis 
and treatment, most children with BA will develop irreversible liver fibrosis within the first two months. While current 
theorized causes of BA include viral infection, immune disorders, and genetic defects, the comprehensive etiology is still 
largely unknown. Recently, biliatresone attracted much interest for its ability to induce BA in both zebrafish and mice, so we 
summarized the latest progress of biliatresone research in BA and tried to answer the question of whether it could provide 
further clues to the etiology of human BA.
Data sources We conducted a PubMed search for any published articles related to the topic using search terms including 
“biliary atresia”, “biliatresone”, “GSH”, and “HSP90”. Relevant data were extracted from the original text or supplementary 
materials of the corresponding articles.
Results Biliatresone had shown its unique toxicity in multiple species such as zebrafish and mice, and pathogenic factors 
involved included glutathione (GSH), heat shock protein 90 (HSP90) and the related pathways. In combination with epide-
miological evidence and recent studies on the intestinal flora in biliary atresia, a new pathogenic hypothesis that the occur-
rence of biliary atresia is partly due to biliatresone or its structure-like compounds depositing in human body via vegetables 
or/and the altered intestinal flora structure can be tentatively established.
Conclusions Based on the existing evidence, we emphasized that GSH and HSP90 are involved in the development of BA,


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and the maternal diet, especially higher vegetable intake of Asian women of childbearing age, accompanied by the altered 
intestinal flora structure, may contribute to the occurrence of biliary atresia and the higher incidence in the Asia group. 
However, the evidence from large sample epidemiological research is necessary.
Keywords Biliary atresia · Biliatresone · Glutathione · Gut flora
Introduction
Biliary atresia (BA), characterized by fibro-inflammation 
and obstruction of extrahepatic bile ducts (EHBD) that can 
lead to liver fibrosis [1], remains the most common reason 
for liver transplantation in infants, and its clinical presen-
tations include high levels of direct or conjugated serum 
bilirubin, acholic stool, dark urine, and progressive hepatic 
failure [2]. Typical pathophysiological features of BA liv-
ers include EHBD obstruction, portal tract fibrosis, ductular 
proliferation, and cholestasis with the appearance of bile 
plugs [3]. BA occurs variably worldwide, affecting all ethnic 
groups, and has a higher incidence in Asia and the Pacific 
region [4, 5]. To date, there are still no consistently cura-
tive treatment options for BA, and nearly 70% of children 
still cannot escape the fate of requiring liver transplantation 
even after undergoing a Kasai portoenterostomy (KPE), a 
procedure that removes fibrotic EHBD and reestablishes the 
bile drainage pathway [6]. Therefore, to transfer from effec-
tive but symptom-only treatments (such as KPE) to origin-
related treatment and/or prevention methods, unraveling the 
etiology of BA must be a top priority.
Studies conducted on specimen samples (acquired dur-
ing surgery or tissue biopsy) or experimental animal mod-
els, especially the Rhesus rotavirus (RRV)-induced mouse 
model, which replicates the key pathological features of 
human BA, such as EHBD damage, portal tract fibrosis and 
ductular proliferation [7], are trying to answer the ques-
tion of what causes BA, and some of the factors have been 
 * Shan Zheng 
 
szheng@shmu.edu.cn
1


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1 
Department of Pediatric Surgery, Shanghai Key Laboratory 
of Birth Defect, and Key Laboratory of Neonatal Disease, 
Ministry of Health, Children’s Hospital of Fudan University, 
399 Wan Yuan Road, Shanghai 201102, China


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A replicon RNA vaccine can induce durable protective immunity from SARS-CoV-2 in nonhuman primates after neutralizing antibodies have waned


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RESEARCH ARTICLE
A replicon RNA vaccine can induce durable
protective immunity from SARS-CoV-2 in
nonhuman primates after neutralizing
antibodies have waned
Megan A. O’Connor1,2, David W. Hawman3,4, Kimberly Meade-White3, Shanna Leventhal3,
Wenjun Song5, Samantha Randall1,6, Jacob Archer1,6, Thomas B. Lewis1,2,
Brieann Brown1,2, Megan N. Fredericks1,2, Kaitlin R. Sprouse7, Hillary C. Tunggal1,2,
Mara Maughan1,2, Naoto Iwayama2, Chul Ahrens2, William Garrison2, Solomon Wangari2,
Kathryn A. Guerriero2, Patrick Hanley4, Jamie Lovaglio4, Greg Saturday4, David Veesler7,
Paul T. Edlefsen5, Amit P. Khandhar6, Heinz Feldmann3, Deborah
Heydenburg FullerID1,2*, Jesse H. ErasmusID1,6*
1 Department of Microbiology, University of Washington, Seattle, Washington, United States of America,
2 Washington National Primate Research Center, University of Washington, Seattle, Washington, United
States of America, 3 Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United
States of America, 4 Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute
of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton,
Montana, United States of America, 5 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer
Research Center, Seattle, Washington, United States of America, 6 HDT Bio, Seattle, Washington, United
States of America, 7 Department of Biochemistry, University of Washington, United States of America
* fullerdh@uw.edu (DHF); jesse.erasmus@hdt.bio (JHE)
Abstract
The global SARS-CoV-2 pandemic prompted rapid development of COVID-19 vaccines.
Although several vaccines have received emergency approval through various public health
agencies, the SARS-CoV-2 pandemic continues. Emergent variants of concern, waning
immunity in the vaccinated, evidence that vaccines may not prevent transmission and ineq-


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uity in vaccine distribution have driven continued development of vaccines against SARS-
CoV-2 to address these public health needs. In this report, we evaluated a novel self-ampli-
fying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19
disease. We found that this vaccine elicited strong binding and neutralizing antibody
responses against homologous virus. We also observed broad binding antibody against het-
erologous contemporary and ancestral strains, but neutralizing antibody responses were
primarily targeted to the vaccine-homologous strain. While binding antibody responses
were sustained, neutralizing antibody waned to undetectable levels in some animals after
six months but were rapidly recalled and conferred protection from disease when the ani-
mals were challenged 7 months after vaccination as evident by reduced viral replication and
pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower
concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demon-
strate in pigtail macaques that a self-amplifying replicon RNA vaccine can elicit durable and
protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence
PLOS PATHOGENS
PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011298
April 19, 2023
1 / 24
a1111111111
a1111111111
a1111111111
a1111111111
a1111111111
OPEN ACCESS
Citation: O’Connor MA, Hawman DW, Meade-
White K, Leventhal S, Song W, Randall S, et al.
(2023) A replicon RNA vaccine can induce durable
protective immunity from SARS-CoV-2 in
nonhuman primates after neutralizing antibodies
have waned. PLoS Pathog 19(4): e1011298.
https://doi.org/10.1371/journal.ppat.1011298
Editor: Alexander Bukreyev, University of Texas
Medical Branch / Galveston National Laboratory,
UNITED STATES
Received: September 5, 2022
Accepted: April 11, 2023
Published: April 19, 2023
Copyright: This is an open access article, free of all
copyright, and may be freely reproduced,


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distributed, transmitted, modified, built upon, or
otherwise used by anyone for any lawful purpose.
The work is made available under the Creative
Commons CC0 public domain dedication.
Data Availability Statement: All data are available
in the main text or the supplementary materials.
Funding: This work was supported in part by the
Intramural Research Program of NIAID/NIH to HF
and by the National Institute of Health (NIH) (P51
OD010425 to DHF and MAO; 27220140006C to
JHE; K01-MH123258 to MAO; U42OD011123),
and HDT Bio internal funds. JHE, APK, SR, JA
receive salary from HDT Bio.The funders had no


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Fiber photometry in striatum reflects primarily nonsomatic 
changes in calcium
Alex A. Legaria1, Bridget A. Matikainen-Ankney2, Ben Yang3, Biafra Ahanonu4, Julia A. 
Licholai5, Jones G. Parker3,✉, Alexxai V. Kravitz1,2,6,✉
1Department of Neuroscience, Washington University School of Medicine, St Louis, MO, USA.
2Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
3Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, 
USA.
4Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
5Department of Neuroscience, Brown University, Providence, RI, USA.
6Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA.
Abstract
Fiber photometry enables recording of population neuronal calcium dynamics in awake mice. 
While the popularity of fiber photometry has grown in recent years, it remains unclear whether 
photometry reflects changes in action potential firing (that is, ‘spiking’) or other changes in 
neuronal calcium. In microscope-based calcium imaging, optical and analytical approaches can 
help differentiate somatic from neuropil calcium. However, these approaches cannot be readily 
applied to fiber photometry. As such, it remains unclear whether the fiber photometry signal 
reflects changes in somatic calcium, changes in nonsomatic calcium or a combination of the two. 
✉Correspondence and requests for materials should be addressed to Jones G. Parker or Alexxai V. Kravitz. 
jones.parker@northwestern.edu; alexxai@wustl.edu.
Author contributions
A.A.L. contributed to conceptualization, methodology, software, formal analysis, investigation, data curation, writing of the original 
draft, reviewing and editing the article and visualization. B.A.M.-A. contributed to the investigation and reviewing and editing the 
article. B.Y. contributed to data curation and formal analysis. B.A. contributed to software, methodology and reviewing and editing the


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article. J.A.L. contributed to conceptualization and the methodology. J.G.P. contributed to the methodology, data curation, writing of 
the original draft, reviewing and editing the article, resources and supervision. A.V.K. contributed to conceptualization, investigation, 
writing of the original draft, reviewing and editing the article, resources and supervision.
Competing interests
The authors declare no competing interests.
Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this 
article.
Code availability
All custom code generated to analyze the datasets used in the current study are available in the Open Science Framework repository, at 
https://osf.io/8j7g2/.
Extended data is available for this paper at https://doi.org/10.1038/s41593-022-01152-z.
Peer review information Nature Neuroscience thanks Bernardo Sabatini, Garret Stuber, and the other, anonymous, reviewer(s) for 
their contribution to the peer review of this work.
Reprints and permissions information is available at www.nature.com/reprints.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/
s41593-022-01152-z.
HHS Public Access
Author manuscript
Nat Neurosci. Author manuscript; available in PMC 2023 May 02.
Published in final edited form as:
Nat Neurosci. 2022 September ; 25(9): 1124–1128. doi:10.1038/s41593-022-01152-z.
Author Manuscript
Author Manuscript
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REVIEW ARTICLE
OPEN
G protein-coupled receptors in neurodegenerative diseases and
psychiatric disorders
Thian-Sze Wong1,2, Guangzhi Li3, Shiliang Li
4,5, Wei Gao1,5, Geng Chen1, Shiyi Gan1, Manzhan Zhang4,5, Honglin Li
4,5✉,
Song Wu3,6✉ and Yang Du
1✉
Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging
because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing
understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of
molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review
provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the
emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.
Signal Transduction and Targeted Therapy  (2023) 8:177 
; https://doi.org/10.1038/s41392-023-01427-2
INTRODUCTION
The nervous system employs membrane receptors to detect
extracellular stimuli and transmit signals across the cell mem-
brane. As the largest membrane protein family, G protein-coupled
receptors (GPCRs) allow the nervous system to respond accurately
to external stimuli and internal states. GPCRs are structurally
similar transmembrane proteins containing seven transmembrane
(TM) α-helices linked by three extracellular loops and three
intracellular loops.1 The unique ligand binding pockets formed by
the 7TM regions allow the receptor to engage with various stimuli,
including neurotransmitters, nucleotides, amines, peptides, cyto-
kines, and hormones in the extracellular environment (Fig. 1).2
Through expressing GPCRs with different ligand-recognizing
abilities, the nervous system could ﬁlter and select particular
signals to respond.3 Furthermore, the intrinsic ligand selectivity of


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neuronal GPCRs allows crosstalk and proper integration between
signal transduction pathways. GPCRs drive signal transduction via
two major modulators: heterotrimeric G protein and arrestins.
Characterizing the physiological functions of GPCRs in the nervous
system and pathological mechanisms in disease models could
accelerate GPCR-targeted drug development.
The progressive dysfunction of neural tissues in the central and
peripheral nervous systems is the hallmark feature of neurode-
generative diseases. Neurodegenerative diseases are increasing in
the elderly population.4 It is estimated that neurodegenerative
diseases affect over
50 million people across the globe.5
Alzheimer’s disease, Huntington’s disease, Parkinson’s disease,
and Multiple sclerosis are representative examples. Currently,
there is no effective cure. The pathogenesis and underlying
mechanisms
of
neurodegenerative
diseases
remain
poorly
understood. At present, symptom control is the primary treatment
objective.6 It is estimated that neurodegenerative diseases will
become the second most common cause of death.7
Alzheimer’s disease and dementias are in the top-ten ranking
leading cause of death globally.8 Deposition of the insoluble and
phosphorylated β-amyloid peptide (derived from amyloid precursor
protein) in the brain parenchyma of Alzheimer’s disease patients
affects functions/regeneration of various forms of neurons.9 The
resulting widespread neuron damage affects synaptic communication
leading to cognitive deﬁcits, regional brain shrinkage, and brain
atrophy;10 Huntington’s disease could appear in childhood or
adolescence. Aberrant expansion of DNA segment containing CAG
trinucleotide repeats in the huntingtin gene is a hallmark feature.11
Large CAG repeat is associated with early symptoms manifestation.12
Symptoms include poor coordination, chorea (involuntary dance-like
movements), slow movement, seizures, and slurred speech; Parkin-
son’s disease affects motion control. Rigidity, tremor, and slow


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movement (bradykinesia) are frequently observed. Risk factors include
genetic polymorphism, chronic inﬂammation, and metabolic dis-
orders.13 Multiple sclerosis is a relapsing-remitting disease caused by
an autoimmune attack in the central nervous system. Damage of
myelin sheath in multiple areas by immune cells causes cognitive
impairment, fatigue, muscle weakness, tremor, and vision problems.14
Brain disorders are frequently associated with mental/psychia-
tric illnesses.15 Mental illness is burdening the healthcare system
with enormous unmet medical needs.16,17 Serious mental illness is
closely linked to reduced life expectancy due to a higher risk of
cardiovascular morbidity and mortality.18 Common mental ill-
nesses include anxiety, depression, bipolar disorder, attention
deﬁcit hyperactivity disorder, and schizophrenia. Both children
Received: 8 July 2022 Revised: 17 February 2023 Accepted: 30 March 2023
1Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong,
518172 Shenzhen, Guangdong, China; 2School of Medicine, Tsinghua University, 100084 Beijing, China; 3Institute of Urology, The Afﬁliated Luohu Hospital of Shenzhen
University, Shenzhen University, 518000 Shenzhen, Guangdong, China; 4Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and
Technology, 200237 Shanghai, China; 5Innovation Center for AI and Drug Discovery, East China Normal University, 200062 Shanghai, China and 6Department of Urology, South
China Hospital, Health Science Center, Shenzhen University, 518116 Shenzhen, Guangdong, China
Correspondence: Honglin Li (hlli@ecust.edu.cn) or Song Wu (wusong@szu.edu.cn) or Yang Du (yangdu@cuhk.edu.cn)
These authors contributed equally: Thian-Sze Wong, Guangzhi Li, Shiliang Li.
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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Lessons from Acquired Natural Immunity and Clinical Trials to Inform Next-Generation Human Cytomegalovirus Vaccine Development


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Lessons from Acquired Natural Immunity and Clinical Trials 
to Inform Next-Generation Human Cytomegalovirus Vaccine 
Development
Xintao Hu1, Hsuan-Yuan Wang1,2, Claire E. Otero1,2, Jennifer A. Jenks2, Sallie R. Permar1
1Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA;
2Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA
Abstract
Human cytomegalovirus (HCMV) infection, the most common cause of congenital disease 
globally, affecting an estimated 1 million newborns annually, can result in lifelong sequelae in 
infants, such as sensorineural hearing loss and brain damage. HCMV infection also leads to 
a significant disease burden in immunocompromised individuals. Hence, an effective HCMV 
vaccine is urgently needed to prevent infection and HCMV-associated diseases. Unfortunately, 
despite more than five decades of vaccine development, no successful HCMV vaccine is available. 
This review summarizes what we have learned from acquired natural immunity, including innate 
and adaptive immunity; the successes and failures of HCMV vaccine human clinical trials; the 
progress in related animal models; and the analysis of protective immune responses during natural 
infection and vaccination settings. Finally, we propose novel vaccine strategies that will harness 
the knowledge of protective immunity and employ new technology and vaccine concepts to inform 
next-generation HCMV vaccine development.
Keywords
human cytomegalovirus; acquired natural immunity; clinical trial; animal model; immune 
correlates of protection; next-generation vaccine
1. INTRODUCTION
Human cytomegalovirus (HCMV), a double-stranded DNA virus with the largest genome 
(around 235 kbp) of known human viruses, belongs to the human betaherpesvirus family (1). 
HCMV infection causes persistent, life-long infection in broad types of host cells mediated 
by four major envelope glycoprotein complexes (GCs): glycoprotein B (gB) oligomer,


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gM/gN dimer, gH/gL/gO trimer, and gH/gL/UL128/UL130/UL131 pentamer complex (PC) 
through distinct entry mechanisms (1, 2).
sallie.permar@med.cornell.edu . 
DISCLOSURE STATEMENT
S.R.P. is a consultant to Moderna, Merck, Pfizer, GSK, Dynavax, and Hoopika CMV vaccine programs and leads sponsored programs 
with Moderna and Merck. S.R.P. also serves on the board of the National CMV Foundation and as an educator on CMV for Medscape. 
The other authors have no financial conflicts of interest.
HHS Public Access
Author manuscript
Annu Rev Virol. Author manuscript; available in PMC 2023 September 29.
Published in final edited form as:
Annu Rev Virol. 2022 September 29; 9(1): 491–520. doi:10.1146/annurev-virology-100220-010653.
Author Manuscript
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REVIEW ARTICLE
OPEN
Single-cell transcriptomics of the ocular anterior segment: a
comprehensive review
Soﬁa Ahsanuddin
1,2,3 and Albert Y. Wu
1✉
© The Author(s) 2023
Elucidating the cellular and genetic composition of ocular tissues is essential for uncovering the pathophysiology of ocular diseases.
Since the introduction of single-cell RNA sequencing (scRNA-seq) in 2009, vision researchers have performed extensive single-cell
analyses to better understand transcriptome complexity and heterogeneity of ocular structures. This technology has revolutionized
our ability to identify rare cell populations and to make cross-species comparisons of gene expression in both steady state and
disease conditions. Importantly, single-cell transcriptomic analyses have enabled the identiﬁcation of cell-type speciﬁc gene
markers and signalling pathways between ocular cell populations. While most scRNA-seq studies have been conducted on retinal
tissues, large-scale transcriptomic atlases pertaining to the ocular anterior segment have also been constructed in the past three
years. This timely review provides vision researchers with an overview of scRNA-seq experimental design, technical limitations, and
clinical applications in a variety of anterior segment-related ocular pathologies. We review open-access anterior segment-related
scRNA-seq datasets and illustrate how scRNA-seq can be an indispensable tool for the development of targeted therapeutics.
Eye (2023) 37:3334–3350; https://doi.org/10.1038/s41433-023-02539-3
INTRODUCTION
Technological advances in mRNA phenotyping methods have
enabled unprecedented access to transcriptomic data in ophthal-
mology [1]. As a proxy to the proteome, the “transcriptome” offers
insight into how gene expression correlates with cellular physiology
and function, thereby revealing previously unknown cellular
dynamics in ensembles of large cell numbers [2, 3]. Prior to
transcriptomics, the earliest applications of immunohistochemistry
in ophthalmic pathology enabled researchers to deﬁne cellular


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phenotype by protein expression, while in-situ hybridization
enabled precise spatial RNA sequence localization in a select tissue
sample [4]. To construct gene expression proﬁles at different time-
points, researchers harnessed subtractive hybridization to create
complementary DNA (cDNA) libraries of various ocular structures
such as retina, retinal pigment epithelial (RPE), and ciliary epithelium
[5–8]. This technique has been demonstrated to be effective for
investigating gene expression in complex disease states such as
uveal melanoma [9].
Expression studies involving differential display, expressed
sequence tags (EST), serial analysis of gene expression (SAGE),
and hybridization-based microarray technologies have similarly
facilitated differentially expressed gene identiﬁcation in ophthal-
mology [10]. Eventually, the development of next-generation
sequencing (NGS) techniques like RNA-sequencing (RNA-Seq)
pooled large cell numbers and allowed researchers to generate
more comprehensive cell atlases comprised of both known and
unknown mRNA transcripts, a feat that was previously limited to
known transcripts [11, 12]. The high throughput of this technology
allowed for novel gene marker detection and provided insight
into alternative splicing as an important regulatory factor of
cellular heterogeneity and pathogenesis in many disease states
[13]. Nonetheless, all of these technologies involve analysis of
large numbers of aggregated cells, which hinders more granular
assessments of gene expression dynamics in highly heterogenous
tissues like those found in the eye. Because it lacks individual cell-
type resolution, pooled RNA-seq analyses also cannot provide
insight into each cell type’s relative abundance and how gene
expression differs by cell type within a sample [14].
Since the ﬁrst single-cell RNA sequencing (scRNA-seq) study was
described by Tang et al. in 2009, the technology has generated
unprecedented levels of interest in the vision research community


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[3, 15]. It has proven to be a versatile and powerful tool for
understanding the transcriptional heterogeneity of ocular tissues
at single-cell resolution. ScRNA-seq studies have rapidly expanded
from proﬁling eight cells to 1.3 million cells [3]. In comparison to
bulk RNA-seq, scRNA-seq enables the identiﬁcation of rare cell
populations, stem cells, novel biomarkers, lineage tracing between
various cellular states, and transcriptional responses to drug
therapy over time, all of which allow researchers to understand
the molecular mechanisms driving disease processes at high-
resolution [16]. Importantly, scRNA-seq has been demonstrated
to be useful for developing targeted therapeutic interventions in
highly heterogenous tissues because it enables investigations
of cell type, monoallelic gene expression, gene co-expression,
splicing patterns, and gene regulatory networks in a parallelized
manner.
In the vision research community, scRNA-seq has primarily been
utilized to elucidate the different cell types in the retina, RPE, and
Received: 21 November 2022 Revised: 7 March 2023 Accepted: 11 April 2023
Published online: 3 May 2023
1Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Stanford, CA, USA. 2Department of Ophthalmology, New York Eye and Ear Inﬁrmary
of Mount Sinai, New York City, NY, USA. 3Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA. ✉email: awu1@stanford.edu
www.nature.com/eye
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Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials


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Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma


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Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 
Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Robert E. Schoen1, Lisa A. Boardman2, Marcia Cruz-Correa3, Ajay Bansal4, David 
Kastenberg5, Chin Hur6, Lynda Dzubinski1, Sharon F. Kaufman2, Luz M. Rodriguez7, Ellen 
Richmond7, Asad Umar7, Eva Szabo7, Andres Salazar8, John McKolanis9, Pamela Beatty9, 
Reetesh K. Pai10, Aatur D. Singhi10, Camille M. Jacqueline9, Riuye Bao11,12, Brenda 
Diergaarde12,13, Ryan P. McMurray2, Carrie Strand2, Nathan R. Foster2, David M. Zahrieh2, 
Paul J. Limburg2, Olivera J. Finn9
Corresponding authors: Robert E. Schoen, MD, MPH. Address: Division of Gastroenterology, Hepatology, and Nutrition, 200 
Lothrop St., Mezzanine Level, C Wing, PUH Pittsburgh, PA 15213-2582 Email: rschoen@pitt.edu, Olivera J. Finn, PhD. Address: 
Department of Immunology, Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA, 15213. ojfinn@pitt.edu.
Study concept and design: RES, LMR, PJL, OJF
Acquisition of data: RES, LAB, MCC, AB, DK, CH, LD, SFK, JM, PB, RP, AS, CMJ, RB, BD, OJF
Analysis and interpretation of data: RES, PB, RKP, ADS, CMJ, RB, BD, RPM, CS, NRF, DMZ, PJL, OJF
Drafting of the manuscript: RES, OJF
Critical revision of the manuscript for important intellectual content: RES, LAB, MCC, AB, DK, CH, LMR, ER, AU, ES, RKP, AS, 
BD, RPM, CS, NRF, DMZ, PJL, OJF
Statistical analysis: RB, RPM, CS, NRF, DMZ
Obtained funding: RES, PJL, OJF
Administrative, technical, or material support: LD, SFK, LMR, ER, AU, ES, AS, JM, PB, RP, ADS, CMJ, RB, BD
Study supervision: LMR, ER, AU, ES, PJL
Disclosures of Potential conflict of interest:
RES: Research support from Freenome, Immunovia, and Exact Sciences
LAB: None
MCC: None
AB: Research support from Freenome and Stella Diagnostics
DK: Consultant Medtronic, Research support - Exact Sciences and Freenome
CH: None
LD: None
SFK: None
LMR: None
ER: None
AU: None
ES: None
AS: Founder, CEO and CSO of Oncovir
JM: None
PB: None
RKP: Consultant for Alimentiv
ADS: None
CMJ: None


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CMJ: None
RB: RB declares patents: (all provisional) PCT/US15/612657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers 
for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof), PCT/US63/055227 (Methods and 
Compositions for Treating Autoimmune and Allergic Disorders)
BD: None
RPM: None
CS: None
NRF: None
DMZ: None
PJL: Chief Medical Officer for Screening at Exact Sciences through a contracted services agreement with the Mayo Clinic. Dr. 
Limburg and Mayo Clinic have contractual rights to receive royalties through this agreement.
OJF: Consultant: PDS Biotech, GeoVax, Immodulon, Ardigen, Invectys, Sparc, Isa Therapeutics
ClinicalTrials.gov Identifier: NCT02134925.
https://clinicaltrials.gov/ct2/show/NCT02134925 
HHS Public Access
Author manuscript
Clin Cancer Res. Author manuscript; available in PMC 2023 November 01.
Published in final edited form as:
Clin Cancer Res. 2023 May 01; 29(9): 1678–1688. doi:10.1158/1078-0432.CCR-22-3168.
Author Manuscript
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Myostatin: A Skeletal Muscle Chalone
Se-Jin Lee1,2
1Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, 
Farmington, Connecticut, USA
2The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
Abstract
Myostatin (GDF-8) was discovered 25 years ago as a new transforming growth factor-β family 
member that acts as a master regulator of skeletal muscle mass. Myostatin is made by skeletal 
myofibers, circulates in the blood, and acts back on myofibers to limit growth. Myostatin appears 
to have all of the salient properties of a chalone, which is a term proposed over a half century ago 
to describe hypothetical circulating, tissue-specific growth inhibitors that control tissue size. The 
elucidation of the molecular, cellular, and physiological mechanisms underlying myostatin activity 
suggests that myostatin functions as a negative feedback regulator of muscle mass and raises the 
question as to whether this type of chalone mechanism is unique to skeletal muscle or whether it 
also operates in other tissues.
Keywords
GDF-8; transforming growth factor-β; activin; latency; growth; tissue size
THE CHALONE HYPOTHESIS FOR THE REGULATION OF TISSUE MASS
Substances of the kind under discussion do not fall within the usual definition 
of a hormone as a systemically distributed chemical substance ‘produced by one 
tissue with the primary function of exerting a specific effect of functional value 
on another tissue’ (Huxley 1935) (1). On the contrary, these are substances each 
of which is produced by a tissue with the primary function of controlling the 
growth, and perhaps the differentiation, of that same tissue…. It is suggested that 
the members of this complex of chemical messengers, which may possibly prove to 
be a family of proteins, should be called chalones.
(2, p. 332)
This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution,


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and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party 
material in this article for license information.
Se-Jin.Lee@jax.org . 
DISCLOSURE STATEMENT
The author is a consultant to Biohaven Pharmaceuticals, Inc., and an inventor on a patent application titled “Therapeutics Targeting 
Transforming Growth Factor Beta Family Signaling.”
HHS Public Access
Author manuscript
Annu Rev Physiol. Author manuscript; available in PMC 2023 May 06.
Published in final edited form as:
Annu Rev Physiol. 2023 February 10; 85: 269–291. doi:10.1146/annurev-physiol-012422-112116.
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REVIEW
Potential Protective Function of Adiponectin
in Diabetic Retinopathy
Hui Deng . Meichen Ai . Yuchen Cao . Liyang Cai . Xi Guo .
Xiongyi Yang . Guoguo Yi . Min Fu
Received: February 15, 2023 / Accepted: March 6, 2023 / Published online: March 31, 2023
 The Author(s) 2023
ABSTRACT
Adiponectin,
one
of
the
most
ubiquitous
adipokines found in the blood, plays a major
role
in
glucolipid
metabolism
and
energy
metabolism and regulation. In recent years, a
growing body of research indicates that adipo-
nectin also plays a signiﬁcant role in diabetic
retinopathy. In the present review, we speciﬁ-
cally
address
the
protective
effects
of
adiponectin on the development and progres-
sion of diabetic retinopathy through improve-
ment
in
insulin
resistance,
alleviation
of
oxidative stress, limiting of inﬂammation, and
prevention of vascular remodeling, with the
aim to explore new potential approaches and
targets for the prevention and treatment of
diabetic retinopathy.
Keywords: Adiponectin; Diabetic retinopathy;
Therapy targets
Hui Deng, Meichen Ai, and Yuchen Cao have
contributed equally to this review.
H. Deng  M. Ai  Y. Cao  L. Cai  X. Yang  M. Fu
(&)
Department of Ophthalmology, Zhujiang Hospital,
Southern Medical University, No. 253, Industrial
Avenue Middle, Haizhu, Guangzhou 510280,
Guangdong, China
e-mail: min_fu1212@163.com
H. Deng  M. Ai  Y. Cao  L. Cai  X. Yang  M. Fu
The Second Clinical School of Southern Medical
University, Guangzhou 510280, Guangdong, China
Y. Cao
Plastic Surgery Hospital, Peking Union Medical
College, Chinese Academy of Medical Sciences,
Beijing 100144, China
X. Guo
School of Rehabilitation Sciences, Southern Medical
University, Guangzhou 510280, Guangdong, China
G. Yi (&)
Department of Ophthalmology, The Sixth Afﬁliated
Hospital of Sun Yat-Sen University, No. 26, Erheng
Road, Yuancun, Tianhe, Guangzhou 510230,
Guangdong, China
e-mail: yigg@mail.sysu.edu.cn
Ophthalmol Ther (2023) 12:1519–1534
https://doi.org/10.1007/s40123-023-00702-3


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World Psychiatry 22:2 - June 2023 
177
SPECIAL ARTICLE
Evolutionary psychiatry: foundations, progress and challenges
Randolph M. Nesse
Departments of Psychiatry and Psychology, University of Michigan, Ann Arbor, MI, USA; Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA
Evolutionary biology provides a crucial foundation for medicine and behavioral science that has been missing from psychiatry. Its absence helps to ex-   
plain slow progress; its advent promises major advances. Instead of offering a new kind of treatment, evolutionary psychiatry provides a scientific foun-
dation useful for all kinds of treatment. It expands the search for causes from mechanistic explanations for disease in some individuals to evolutionary 
explanations for traits that make all members of a species vulnerable to disease. For instance, capacities for symptoms such as pain, cough, anxiety 
and low mood are universal because they are useful in certain situations. Failing to recognize the utility of anxiety and low mood is at the root of 
many problems in psychiatry. Determining if an emotion is normal and if it is useful requires understanding an individual’s life situation. Conducting 
a review of social systems, parallel to the review of systems in the rest of medicine, can help achieve that understanding. Coping with substance abuse 
is advanced by acknowledging how substances available in modern environments hijack chemically mediated learning mechanisms. Understanding 
why eating spirals out of control in modern environments is aided by recognizing the motivations for caloric restriction and how it arouses famine 
protection mechanisms that induce binge eating. Finally, explaining the persistence of alleles that cause serious mental disorders requires evolutionary 
explanations of why some systems are intrinsically vulnerable to failure. The thrill of finding functions for apparent diseases is evolutionary psychiatry’s


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greatest strength and weakness. Recognizing bad feelings as evolved adaptations corrects psychiatry’s pervasive mistake of viewing all symptoms as if 
they were disease manifestations. However, viewing diseases such as panic disorder, melancholia and schizophrenia as if they are adaptations is an 
equally serious mistake in evolutionary psychiatry. Progress will come from framing and testing specific hypotheses about why natural selection left 
us vulnerable to mental disorders. The efforts of many people over many years will be needed before we will know if evolutionary biology can provide 
a new paradigm for understanding and treating mental disorders.
Key words: Evolutionary psychiatry, natural selection, vulnerability to diseases, evolutionary medicine, depression, anxiety, substance use dis ­
orders, eating disorders, schizophrenia
(World Psychiatry 2023;22:177–202)
Calls for new directions in psychiatry have echoed for dec­
ades, but only now is recognition growing that the field has been 
hobbled by using only one half of biology. Almost all effort has 
gone into research on mechanisms, while the rest of medicine 
and behavioral science have long also investigated the evolution­
ary origins and functions of those mechanisms. Evolutionary 
medicine goes further to ask why natural selection left some traits 
vulnerable to malfunction. Evolutionary psychiatry answers that 
question for mental disorders.
Research on animal behavior was transformed when it adopted 
an evolutionary foundation in the final decades of the 20th cen­
tury1­ 4. Recognition that brains are shaped by natural selection to 
maximize gene transmission expanded ethology from a descrip­
tive science to one grounded in theory that predicts behavior. For 
instance, the assumption that birds lay as many eggs as possible 
was replaced when theoretically inspired studies showed that 
birds adjust egg laying in ways that maximize the number of sur­
viving fledglings in the current environment5. Animal behavior


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textbooks are now all grounded on evolutionary biology.
Medicine has long relied on knowledge about adaptive func­
tions as well as mechanisms. Knowing the functions of the pan­
creas, the mitral valve, and the cough reflex is crucial for under­
standing their malfunctions. Internal medicine textbooks describe 
pathology in the context of normal physiological functions. Psy­
chiatry textbooks, instead, describe pathology with little reference 
to normal functions.
Explaining traits that leave a species vulnerable to a disease 
poses special challenges, because most evolutionary explana­
tions describe how traits give advantages. Webbed feet make 
ducks paddle faster. Sweating stabilizes body temperature. Cough 
clears foreign matter from the airways. So, it seems natural to try 
to explain mental disorders by proposing ways they could offer 
advantages. That approach is essential for negative emotions, to 
correct the pervasive error of viewing adaptations as if they were 
diseases. However, viewing true diseases as if they were adapta­
tions is an even more serious error that is common in evolution­
ary psychiatry. It is tempting to try to explain schizophrenia, ano­
rexia nervosa or autism by proposing ways that they might offer 
advantages, but such hypotheses are almost always wrong. Dis­
eases are not adaptations shaped by natural selection. They are 
not universal traits. They harm fitness. Trying to explain diseases 
as if they were somehow useful gives rise to a conceptual fog, 
which will be dispelled, not by global debates about adaptation­
ism, but by systematically considering specific hypotheses in the 
light of rigorous evolutionary theory.
Evolutionary medicine does not explain diseases; it explains 
traits that make bodies vulnerable to disease. Examples include 
the narrow birth canal, the windpipe opening into the pharynx, 
and the tendency for immune responses to attack the body’s own 
tissues. The usual explanation for disease vulnerability has been


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that natural selection cannot prevent all mutations. That is an 
important explanation, but several others are equally important6­ 10. 
Natural selection is too slow to keep up with rapid environmen­
tal change or fast­ evolving pathogens. It can’t start fresh to cor­
rect a suboptimal design. It increases the performance of traits at 
the cost of reduced robustness. It maximizes gene transmission, 
at the expense of health and happiness. And it shapes useful 
defenses such as pain and anxiety that feel awful and are prone 
to excessive expression. Evolutionary medicine frames and tests 
hypotheses based on these explanations.


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1584  ｜NEURAL REGENERATION RESEARCH｜Vol 18｜No. 7｜July 2023
NEURAL REGENERATION RESEARCH
www.nrronline.org
Research Article
Potential application of let-7a antagomir in injured 
peripheral nerve regeneration
Abstract  
Neurotrophic factors, particularly nerve growth factor, enhance neuronal regeneration. However, the in vivo applications of nerve growth factor are largely 
limited by its intrinsic disadvantages, such as its short biological half-life, its contribution to pain response, and its inability to cross the blood-brain barrier. 
Considering that let-7 (human miRNA) targets and regulates nerve growth factor, and that let-7 is a core regulator in peripheral nerve regeneration, we 
evaluated the possibilities of let-7 application in nerve repair. In this study, anti-let-7a was identified as the most suitable let-7 family molecule by analyses of 
endogenous expression and regulatory relationship, and functional screening. Let-7a antagomir demonstrated biosafety based on the results of in vivo safety 
assessments and it entered into the main cell types of the sciatic nerve, including Schwann cells, fibroblasts and macrophages. Use of hydrogel effectively 
achieved controlled, localized, and sustained delivery of let-7a antagomir. Finally, let-7a antagomir was integrated into chitosan conduit to construct a chitosan-
hydrogel scaffold tissue-engineered nerve graft, which promoted nerve regeneration and functional recovery in a rat model of sciatic nerve transection. Our 
study provides an experimental basis for potential in vivo application of let-7a.
Key Words: chitosan; chitosan-hydrogel scaffold; let-7; let-7a antagomir; miRNA; nerve graft; peripheral nerve injury; peripheral nerve regeneration; Schwann 
cells
https://doi.org/10.4103/1673-5374.357914
Date of submission: April 27, 2022 
Date of decision: July 26, 2022 
Date of acceptance: August 23, 2022 
Date of web publication: October 13, 2022 
Introduction 
Peripheral nerve injury is a common clinical problem that affects


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approximately 13–23 per 100,000 persons per year  (Li et al., 2014; Lolis et 
al., 2018). Currently, the gold standard treatment for peripheral nerve injury 
is autologous nerve grafting. The application of autologous nerve grafts, 
however, is largely limited by its intrinsic disadvantages, such as limited donor 
nerve sources, donor nerve functional loss, and size differences between the 
donor nerve and recipient nerve (Gu et al., 2011; Luo et al., 2021). Therefore, 
there is an urgent need to develop and construct tissue-engineered nerve 
grafts with better clinical application to repair injured peripheral nerves.
Tissue-engineered nerve grafts have been designed as a prospective 
alternative for regenerative medicine. Tissue-engineered nerve grafts 
generally contain scaffolds and embedded supporting cells or biological 
cues. Morphological and cellular molecular studies have demonstrated that 
axonal regeneration involves the precise coordination of numerous cells to 
provide an optimal regeneration microenvironment (Wang et al., 2022a). 
Macrophages, fibroblasts, and Schwann cells gather at the injury site to 
perform different functions and help establish a regenerative pathway to 
repair peripheral nerve function (Qian et al., 2018; Wang et al., 2022a). Many 
growth factors with neurotrophic effects, especially nerve growth factor 
(NGF), promote myelin sheath formation, enhance axonal regeneration, and 
have been used in neural tissue engineering (Gu et al., 2011, 2014). However, 
the in vivo applications of these growth factors are largely restricted by their 
low stability, short half-life periods, and high costs (Chen and Mooney, 2003; 
Chen et al., 2012). Recent studies have reported that a variety of microRNAs 
(miRNAs) regulate peripheral nerve injury and regeneration (Li et al., 2015b; 
Ji et al., 2019; Lopez-Leal et al., 2020; Wang et al., 2022c). Therefore, it is 
feasible to incorporate miRNAs into biomaterial scaffolds to reshape the


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microenvironment, so as to promote injured nerve regeneration (Krutzfeldt 
et al., 2005; Gu et al., 2014; Yu et al., 2015; Ou et al., 2019; Leng et al., 2020). 
Many reviews have discussed the possibilities of various miRNA applications, 
especially the therapeutic application of miRNA for tissue engineering 
(Hutchison et al., 2013; Zhao et al., 2014; Caputo et al., 2015; Chew, 2015; 
Li et al., 2015a; Miller et al., 2015; Raschzok et al., 2015; Sabirzhanov et al., 
2016; Yao et al., 2016). 
Let-7, the first identified human miRNA, is involved in many important 
biological processes (Shell et al., 2007; Roush and Slack, 2008; Su et al., 
2012; Yuan et al., 2012). Previous studies showed that decreased let-7 
levels elevated NGF secretion from Schwann cells, increased Schwann cell 
proliferation and migration in vitro, and promoted Schwann cell migration and 
axon outgrowth in vivo (Li et al., 2015b; Zhang et al., 2020). Another study 
showed that let-7 miRNAs were core regulators affecting peripheral nerve 
repair and regeneration (Wang et al., 2019). Considering these studies, we 
selected let-7a as a suitable member of the let-7 family, performed a safety 
assessment for potential application, and investigated its morphological and 
functional effects on peripheral nerve injury repair. 
1State Key Laboratory of Pharmaceutical Biotechnology and Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical 
School, Nanjing University, Nanjing, Jiangsu Province, China; 2NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Key Laboratory of 
Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
*Correspondence to: Shi-Ying Li, PhD, lisy0379@ntu.edu.cn.
http://orcid.org/0000-0001-5150-7299 (Shi-Ying Li)


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Funding: This work was supported by the National Natural Science Foundation of China, No. 31970968 (to SYL), the Collegiate Natural Science Foundation of Jiangsu Province, 
No.16KJA310005 (to SYL), Priority Academic Program Development of Jiangsu Higher Education Institutions [PAPD] and the Natural Science Foundation of Jiangsu Province, No. 
BK20200976 (to XHW).
How to cite this article: Chen QQ, Liu QY, Wang P, Qian TM, Wang XH, Yi S, Li SY (2023) Potential application of let-7a antagomir in injured peripheral nerve regeneration. Neural 
Regen Res 18(7):1584-1590. 
Graphical Abstract
In vivo application of let-7a antagomir in the repair of peripheral nerve injury
From the Contents
Introduction
1584
Methods  
1585
Results
1586
Discussion
1589
Qian-Qian Chen1, 2 Qian-Yan Liu2, Pan Wang2, Tian-Mei Qian2, Xing-Hui Wang2, Sheng Yi2, Shi-Ying Li2, *


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Conservative Management of Alloimmune Hemolysis and Cholestasis With Extreme Laboratory Abnormalities


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Conservative Management of Alloimmune Hemolysis and 
Cholestasis With Extreme Laboratory Abnormalities
Chelsea Kotch, MDa, David F. Friedman, MDa,b,c, Benjamin J. Wilkins, MD,PhDb,c, Benjamin 
J. Samelson-Jones, MD,PhD,FAAPa,c
aDivision of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania;
bDepartment of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, 
Philadelphia, Pennsylvania;
cPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Abstract
Alloimmune hemolytic disease of the fetus or newborn (HDFN) is a rare cause of neonatal 
cholestasis. HDFN-associated cholestasis has most often been reported secondary to anti-D 
alloimmunization. In utero transfusions are also an identified risk factor. A variety of diagnostic 
and therapeutic strategies have been described, mostly in case reports. Here, we report 2 cases 
of HDFN-associated cholestasis that were notable for extreme laboratory abnormalities including 
a peak ferritin of 24 700 ng/mL and a peak alanine aminotransferase of 1406 U/L (33.5-fold 
upper limit of normal). One case was due to alloimmunization other than anti-D. These cases help 
define the range of laboratory derangements that are consistent with HDFN-associated cholestasis, 
including extreme hyperferritinemia. Although in a number of cases, researchers have reported 
the use of iron chelation in these infants, herein, we describe successful management without iron 
chelation.
Alloimmune hemolytic disease of the fetus or newborn (HDFN)1 is a rare cause of 
neonatal cholestasis.2,3 Infants with HDFN and in utero or postnatal red blood cell (RBC) 
transfusions are at increased risk for cholestasis. The diagnostic workup and management 
of these infants relies principally on experiences from case reports and small series (Table 
1).4–23 Herein, we describe the successful management, without iron chelation, of 2 infants 
with HDFN-associated cholestatic liver disease and substantial laboratory abnormalities,


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including extreme hyperferritinemia. One case is also a rare example of cholestasis 
occurring with HDFN not due to anti-D alloimmunization.
Address correspondence to Benjamin J. Samelson-Jones, MD, PhD, FAAP, Children’s Hospital of Philadelphia, 3501 Civic Center 
Blvd, 5028 Colket Translational Research Center, Philadelphia, PA 19104, samelsonjonesb@email.chop.edu.
Drs Kotch and Samelson-Jones conceptualized and designed the report, collected and interpreted data, and drafted and revised the 
manuscript; Drs Friedman and Wilkins collected and interpreted data and critically revised the manuscript; and all authors approved 
the final manuscript as submitted and agree to be accountable for all aspects of the work.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
HHS Public Access
Author manuscript
Pediatrics. Author manuscript; available in PMC 2023 May 10.
Published in final edited form as:
Pediatrics. 2021 February ; 147(2): . doi:10.1542/peds.2019-3367.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Ann. rheum. Dis. (1976), 35, 314
Factors relating to circulating immune
complexes in rheumatoid arthritis
P. J. ROBERTS-THOMSON, B. L. HAZLEMAN,*
I. G. BARNETT,t
I. C. M. MAcLENNAN, AND A. G. MOWAT
From the Nuffield Department of Clinical Medicine, Radcliffe Infirmary, and
the Rheumatology Unit, Nuffield Orthopaedic Centre, Oxford
Roberts-Thomson, P. J., Hazleman, B. L., Barnett,
I. G., MacLennan,
I. C. M., and
Mowat, A. G. (1976). Annals of the Rheumatic Diseases, 35, 314-320. Factors relating
to circulating immune complexes in rheumatoid arthritis. Evidence has been presented
suggesting that circulating immune complexes occur in over half of the sera of patients
with rheumatoid arthritis. These IgG-containing complexes were small, eluting between
IgG and IgM on gel filtration on Sepharose 6B and were not seen in the sera of healthy
control subjects. These complexes were detected in the sera of both seronegative and
seropositive patients and their quantity did not correlate with IgM rheumatoid factor
titre. The quantity of complexed IgG was estimated from a ratio derived from the IgG
profile obtained by gel filtration of the serum. This quantity correlated significantly
with the degree of inhibition by the rheumatoid sera of cytolysis in vitro of IgG sensi-
tized target cells by K cells from human peripheral blood. A significant inverse cor-
relation was observed between the quantity of serum complexes and the chemotactic
index of the circulating polymorphonuclear leucocytes obtained from the same rheuma-
toid patient. It is suggested that ingestion of these complexes may be implicated in the
reduction in chemotaxis observed in patients with rheumatoid arthritis. There was no
correlation between the quantity of the complexes in the sera and other clinical,
haematological, and biochemical measurements.
The presence of circulating IgG complexes of small
size (i.e. sedimenting between 7 and 19S) has now
been shown in the sera of patients with a wide
variety
of
diseases.
These
include
rheumatoid


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arthritis and hypergammaglobulinaemic purpura of
Waldenstrom (Kunkel and others, 1961), systemic
lupus
erythematosus
and
Sj0gren's
syndrome
(Blaylock, Waller, and Normansell, 1974; Alarcon-
Segovia and
others,
1974),
inflammatory
bowel
disease (Jewell and MacLennan, 1973), and some
thyroid disorders (Calder and others,
1974). The
nature
of
these
immune
complexes
and
their
relationship to the pathogenesis of these diseases is
obscure.
In
rheumatoid
arthritis
small immune
complexes
are
frequently
found and
are
often
present in considerable quantity (Winchester and
others, 1971; Norberg, 1974).
In this study two techniques have been used to
detect and quantitate small immune complexes in
the sera of 35 patients with rheumatoid arthritis.
The first technique involves the separation of serum
IgG using Sepharose 6B column chromatography
(Jewell and MacLennan,
1973).
In
this method
complexed IgG separates in higher molecular size
fractions
than noncomplexed
IgG.
The
second
technique is a functional assay which can detect
certain immune complexes and aggregates of IgG.
This technique
is based upon the principle that
antibody-dependent
cell-mediated
cytotoxicity
or
K cell mediated cytotoxicity can be competitively
inhibited
by immune
complexes
occupying
the
receptors for antibody on K cells and so preventing
K cell access to target cells sensitized with antibody.
A ratio derived from gel filtration chromato-
graphy has been described for estimating the amount
of these complexes found circulating in the sera of
Accepted for publication December 21, 1975.
* Present address: Department of Rlleumatology, Addenbrooke's Hospital, Cambridge.
t Deceased.
Correspondence to: Dr. A. G. Mowat, Dept. of Rheumatology, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD.


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HLA-A, B antigens and a1-antitrypsin phenotypes in nodal generalised osteoarthritis and osteoarthritis


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Annals of the Rheumatic Diseases 1989; 48: 470-475
HLA-A, B antigens and a1-antitrypsin phenotypes in
nodal generalised osteoarthritis and erosive
osteoarthritis
MARTIN
PATTRICK,'
ADRIAN
MANHIRE,2
A
MILFORD
WARD,3
AND
MICHAEL DOHERTY1
From the 'Rheumatology
Unit and the 2Radiology Department,
City Hospital, Nottingham; and the
3Department of Immunology, Royal Hallamshire Hospital, Sheffield
SUMMARY
HLA-A, B and a1-antitrypsin phenotypes were studied in 90 unrelated patients with
established nodal generalised osteoarthritis (OA). Compared with standard reference popula-
tions, independently increased frequency of the HLA-A1B8 and MZ ac-antitrypsin phenotypes
were observed (27% v 11-5%, relative risk 2-79, and 12% v 3-6%, relative risk 3.73 respectively).
These associations related to development of nodal generalised OA rather than to severity as
judged by the summated radiographic scores for hand OA. Ten patients had marked subchondral
radiographic erosions and were further classified as erosive OA; these patients had an increased
frequency of the MS a,-antitrypsin phenotype (30% v 9%) and higher radiographic OA scores
corrected for presence of erosions. This first report of two independent genetic markers in nodal
generalised OA is of interest in relation to the increasingly recognised inflammatory component
of the osteoarthritis process.
Symptomatic osteoarthritis (OA) is a common but
ill understood condition with a spectrum of clinical
presentation
and
outcome.' 2
Multiple
factors
(genetic,
constitutional,
environmental) may be
involved
in
its development.-5 To
understand
better its pathogenesis OA has been divided into
subsets on the basis of distribution, radiographic
features, associated crystal deposition, and recog-
nised aetiological factors.2 Nodal generalised OA is
a subset characterised by polyarticular interpha-
langeal and thumb base OA, female preponderance,
early inflammatory component, and Heberden node
formation6; of all OA subsets, familial tendency is
particularly
recognised.4 Erosive OA


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is an un-
common form of generalised OA sharing many
features of nodal generalised OA but differing by
having marked subchondral erosive change and a
florid inflammatory component.7 8
Genetic factors have been extensively studied in
rheumatic diseases4 and may be associated with
either development or severity.9'2 Despite marked
familial predisposition few studies have investigated
Accepted for publication 9 November 1988.
Correspondence to Dr Martin Pattrick. Rheumatology Unit. City
Hospital. Hucknall Road. Nottingham NG5 IPB.
genetic markers in nodal generalised OA.4 Only
four report the frequencies of HLA antigens, with
conflicting
results 1-6:
one
reporting
increased
frequency
of HLA-A1B8, 13
one
an
increased
frequency
of HLA-B8, 14
and
two
finding
no
associations. 15 16 To our knowledge ac-antitrypsin
phenotypes,
well
studied
in
other
rheumatic
diseases,'7-21 have not been examined in OA.
We
therefore
investigated
the
prevalence
of
HLA-A, B antigens and a,-antitrypsin phenotypes
in patients with well characterised nodal generalised
OA to define genetic markers predisposing to either
OA development or severity of radiographic change.
Patients and methods
Ninety unrelated, English born, white patients (79
women, 11 men; mean age 67, range 42-90 years)
presenting
to
the Nottingham
unit
with
nodal
generalised OA were studied. Each had symptoma-
tic polyarticular interphalangeal OA affecting more
than three rays of each hand with Heberden node
formation unrelated to obvious trauma. Each under-
went full clinical and radiographic assessment. All
had radiographic and
in some
cases
additional
clinical evidence of OA
at other
sites, but no
470


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NEURAL REGENERATION RESEARCH｜Vol 18｜No. 7｜July 2023｜1535
NEURAL REGENERATION RESEARCH
www.nrronline.org
Research Article
Emodin attenuates inflammation and demyelination in 
experimental autoimmune encephalomyelitis
Abstract  
Emodin, a substance extracted from herbs such as rhubarb, has a protective effect on the central nervous system. However, the potential therapeutic effect 
of emodin in the context of multiple sclerosis remains unknown. In this study, a rat model of experimental autoimmune encephalomyelitis was established by 
immune induction to simulate multiple sclerosis, and the rats were intraperitoneally injected with emodin (20 mg/kg/d) from the day of immune induction 
until they were sacrificed. In this model, the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the 
microglia exacerbated neuroinflammation, playing an important role in the development of multiple sclerosis. In addition, silent information regulator of 
transcription 1 (SIRT1)/peroxisome proliferator-activated receptor-alpha coactivator (PGC-1α) was found to inhibit activation of the NLRP3 inflammasome, and 
SIRT1 activation reduced disease severity in experimental autoimmune encephalomyelitis. Furthermore, treatment with emodin decreased body weight loss 
and neurobehavioral deficits, alleviated inflammatory cell infiltration and demyelination, reduced the expression of inflammatory cytokines, inhibited microglial 
aggregation and activation, decreased the levels of NLRP3 signaling pathway molecules, and increased the expression of SIRT1 and PGC-1α. These findings 
suggest that emodin improves the symptoms of experimental autoimmune encephalomyelitis, possibly through regulating the SIRT1/PGC-1α/NLRP3 signaling 
pathway and inhibiting microglial inflammation. These findings provide experimental evidence for treatment of multiple sclerosis with emodin, enlarging the 
scope of clinical application for emodin.


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Key Words: demyelination; emodin; experimental autoimmune encephalomyelitis; microglia; multiple sclerosis; neuroinflammation; NLRP3 inflammasome; 
PGC-1α; pyroptosis; SIRT1
https://doi.org/10.4103/1673-5374.358612
Date of submission: May 12, 2022 
Date of decision: August 2, 2022 
Date of acceptance: September 28, 2022 
Date of web publication: October 24, 2022
Introduction 
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central 
nervous system (CNS) (Filippi et al., 2018). MS affects more than two million 
people worldwide (Browne et al., 2014) and is more common in young adults. 
The pathological features of MS include focal demyelinating plaques in the 
brain, spinal cord, and optic nerve, as well as diffuse changes such as axonal 
injury and astrogliosis (Lassmann, 2018). Although the etiology of MS has not 
been fully elucidated, environmental, genetic, and epigenetic factors have 
been implicated in its pathogenesis (Olsson et al., 2017). Existing drugs for 
MS, such as interferon beta, dimethyl fumarate, and fingolimod, have strong 
side effects and cannot reverse the chronic progressive disabilities associated 
with this condition (Tintore et al., 2019; Bhargava, 2021; D’Amico et al., 2022). 
Therefore, there is an urgent need to develop effective and safe therapeutic 
drugs for MS. Experimental autoimmune encephalomyelitis (EAE) is currently 
the most widely used animal model of MS (Lassmann and Bradl, 2017); it 
partially simulates MS pathogenesis and is a useful tool for exploring the 
underlying molecular mechanisms of MS. 
Inflammasomes are signaling complexes that sense injury and stress signals 
and induce inflammatory cytokine maturation and secretion. The nucleotide-
binding domain-like receptor family pyrin domain containing 3 (NLRP3) 
inflammasome is the most widely studied inflammasome and is involved 
in many autoimmune and inflammatory diseases (Duewell et al., 2010; 
Heneka et al., 2013). NLRP3 inflammasome-related molecules are involved


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in MS pathogenesis, as indicated by altered levels of NLRP3 inflammasome 
complex components in patients with MS and in animal knockout models 
(Gris et al., 2010; Walsh et al., 2014; Burm et al., 2016; McKenzie et al., 
2018). Inflammasome component expression is increased in the CNS tissues 
of MS patients. Furthermore, inflammasome activation and pyroptosis occur 
in human glial cells, which may affect the occurrence and development of 
MS. Moreover, abnormal microglial activation leads to demyelination and 
neurodegenerative changes (Baecher-Allan et al., 2018). Microglia, which 
are the intrinsic immune cells of the CNS, can exacerbate neuroinflammation 
by secreting chemokines, which in turn recruit immune cells to the CNS, 
and can also act as antigen-presenting cells to activate immune cells (Ferrari 
et al., 2004; Mallucci et al., 2015). In addition, microglia can be activated 
by pro-inflammatory cytokines such as interleukin (IL)-1β, thus creating a 
vicious cycle (Correale and Farez, 2015). These studies illustrate the key roles 
of inflammasome and microglial activation in MS. In addition, studies have 
demonstrated that silent information regulator of transcription 1 (SIRT1) and 
the downstream molecule peroxisome proliferator-activated receptor-alpha 
coactivator (PGC-1α) can inhibit NLRP3 inflammasome activation (Park et al., 
2020; Wang et al., 2021b; Zhang et al., 2021). Research has shown that SIRT1-
mediated responses are involved in a variety of physiological processes, such 
as oxidative stress, inflammation, and apoptosis (Yang et al., 2022). Several 
studies have reported the inhibitory effect of SIRT1 on the inflammatory 
response (Yeung et al., 2004; Planavila et al., 2011; Bai et al., 2020). These 
results suggest that SIRT1 can reduce neuroinflammation by inhibiting NLRP3 
inflammasome activation. Moreover, related studies have found that activation 
Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China


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*Correspondence to: Juan Feng, MD, PhD, juanfeng@cmu.edu.cn.
https://orcid.org/0000-0002-1815-7036 (Juan Feng)
Funding: This study was supported by the National Natural Science Foundation of China, No. 81771271; Key Research and Development Program of Liaoning Province, No. 
2020JH2/10300047; and Outstanding Scientific Fund of Shengjing Hospital (all to JF).
How to cite this article: Cui YR, Bu ZQ, Yu HY, Yan LL, Feng J (2023) Emodin attenuates inflammation and demyelination in experimental autoimmune encephalomyelitis. Neural Regen 
Res 18(7):1535-1541. 
Graphical Abstract
Emodin inhibits the NLRP3 signaling pathway and suppresses microglial activation in 
experimental autoimmune encephalomyelitis
From the Contents
Introduction
1535
Methods  
1536
Results
1537
Discussion
1539
Yue-Ran Cui, Zhong-Qi Bu, Hai-Yang Yu, Li-Li Yan, Juan Feng*


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Prevalence of Parvovirus B19 Viremia Among German Blood Donations and the Relationship to ABO and Rhesus Blood Group Antigens


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The Journal of Infectious Diseases                                
B R I E F  R E P O R T
Prevalence of Parvovirus B19 Viremia 
Among German Blood Donations and 
the Relationship to ABO and Rhesus 
Blood Group Antigens
Katie Healy,1,2 Linda B. S. Aulin,3,4 Urban Freij,5 Marie Ellerstad,5 Lena Brückle,6
Helen Hillmering,5 Tor-Einar Svae,7 Kristina Broliden,8 and Rasmus Gustafsson5,9
1Division of Clinical Diagnostics and Surgery, Department of Dental Medicine, Karolinska 
Institutet, Stockholm, Sweden; 2Division of Clinical Microbiology, Department of Laboratory 
Medicine, Karolinska Institutet, Stockholm, Sweden; 3Leiden Academic Centre for Drug 
Research, Leiden University, Leiden, The Netherlands; 4Clinical Pharmacy and Biochemistry, 
Freie Universität Berlin, Berlin, Germany; 5Octapharma AB, Stockholm, Sweden; 6Octapharma 
Plasma GmbH, Langenfeld, Germany; 7Octapharma Handelsges.m.b.H, Vienna, Austria; 
8Karolinska Institutet, Department of Medicine Solna, Center for Molecular Medicine, 
Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; 
and 9Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska 
Institutet, Stockholm, Sweden
Background. Asymptomatic blood donors can transmit 
human parvovirus B19 (B19V).
Methods. We assessed the B19V prevalence among a large 
cohort of blood donations collected in Germany during 2015– 
2018.
Results. In total, 167 123 donations were screened for B19V 
deoxyribonucleic acid with 22 cases of viremia identified (0.013% 
positive). Infections peaked at a 4-year interval and the highest 
number of cases occurred in the summer months. All 22 
infections were found in rhesus D-antigen-positive donations, 
suggesting a protective factor in donors who lack this antigen.
Conclusions. These 
findings 
contribute 
to 
our 
understanding of risk factors for B19V infection among central 
European blood and plasma donors.
Keywords. ABO; b19V; blood donations; blood group; 
rhesus.


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rhesus.
Received 01 July 2022; editorial decision 15 November 2022; accepted 18 November 2022; 
published online 21 November 2022
Correspondence: Rasmus Gustafsson, PhD, Octapharma AB, 11251 Stockholm, Sweden 
(Rasmus.Gustafsson@ki.se).
The Journal of Infectious Diseases®
2023;227:1214–8 
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases 
Society of America. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution- 
NonCommercial-NoDerivs 
licence 
(https://creativecommons.org/licenses/by-nc-nd/4.0/), 
which permits non-commercial reproduction and distribution of the work, in any medium, pro-
vided the original work is not altered or transformed in any way, and that the work is properly 
cited. For commercial re-use, please contact journals.permissions@oup.com
https://doi.org/10.1093/infdis/jiac456
The human erythroparvovirus B19 (B19V) is a small, single- 
stranded, nonenveloped deoxyribonucleic acid (DNA) virus 
belonging to the Parvoviridae family. The B19V replicates in 
human progenitor cells, leading to a decline in red blood cells 
that can cause an accompanying anemia [1]. Although it is pri-
marily considered a respiratory disease, B19V can also be 
transmitted through contaminated blood components as well 
as plasma-derived medicinal products [2, 3].
In epidemic seasons, blood and plasma donations with high 
B19V viral load have been reported, posing a risk for vulnerable 
groups and B19V-naive individuals alike [4]. For example, 
B19V infection during pregnancy increases the risk of fetal 
loss, although the incidence rates are low [5]. It is known that 
the risk of infection through blood products and plasma- 
derived medicinal products is correlated to the level of viremia, 
and the exclusion of plasma manufacturing pools containing 
B19V DNA levels above 104 IU/mL prevents transmission 
through the latter products [6].
The primary B19V receptor has been identified as the P


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blood group antigen [7]. Although the P antigen is necessary 
for B19V binding, it alone is not sufficient for viral entry, which 
implies that there is an additional surface coreceptor involved 
[8]. Integrin α5β1 and Ku80 have been suggested as coreceptors, 
but the low expression on B19V-permissive cells indicates that 
the exact mechanisms underlying B19V entry remain to be elu-
cidated [9]. More recently, antibody-mediated mechanisms of 
viral entry have been proposed [10]. However, the exact core-
ceptor that enables B19V entry, and its subsequent endocytosis, 
is not yet known.
Given the importance of the P blood group antigens in B19V 
entry and the well documented importance of ABO and rhesus 
D-antigen [Rh(D)] blood groups in other virus infections in-
cluding norovirus, human immunodeficiency virus (HIV), 
and hepatitis B virus [11], we hypothesized that other blood 
group antigens may play a role in virus susceptibility. In this 
study, we aimed to investigate the relationship between ABO 
blood group, Rh(D), and B19V prevalence in a large cohort 
of blood donations in Germany. Furthermore, we also investi-
gated B19V infection dynamics among these central European 
blood and plasma donations over a 4-year period.
METHODS
Ethical Statement
This study was performed within the ethical standards of the 
Declaration of Helsinki.
All data included in this study were pseudonymized and the 
original donor identities could not be traced back. Therefore, 
no ethical permit was required according to the Regional 
Ethical Review Board in Stockholm.
Human Erythroparvovirus B19 Screening and Blood Group Typing of 
Plasma Donors
At Octapharma AB (Stockholm, Sweden) plasma donations 
(n = 167 123) from Germany were dispensed into 96-well 
1214 • JID 2023:227 (15 May) • BRIEF REPORT


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Nature Reviews Drug Discovery
nature reviews drug discovery
https://doi.org/10.1038/s41573-023-00692-8
Perspective
 Check for updates
Accelerating antiviral drug 
discovery: lessons from COVID-19
Annette von Delft 
  1,2,11 
, Matthew D. Hall 
  3, Ann D. Kwong4, Lisa A. Purcell 
  5, Kumar Singh Saikatendu6, Uli Schmitz7, 
John A. Tallarico8 & Alpha A. Lee9,10,11 
Abstract
During the coronavirus disease 2019 (COVID-19) pandemic, a wave of 
rapid and collaborative drug discovery efforts took place in academia 
and industry, culminating in several therapeutics being discovered, 
approved and deployed in a 2-year time frame. This article summarizes 
the collective experience of several pharmaceutical companies and 
academic collaborations that were active in severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) antiviral discovery. We outline 
our opinions and experiences on key stages in the small-molecule 
drug discovery process: target selection, medicinal chemistry, 
antiviral assays, animal efficacy and attempts to pre-empt resistance. 
We propose strategies that could accelerate future efforts and argue 
that a key bottleneck is the lack of quality chemical probes around 
understudied viral targets, which would serve as a starting point for 
drug discovery. Considering the small size of the viral proteome, 
comprehensively building an arsenal of probes for proteins in viruses 
of pandemic concern is a worthwhile and tractable challenge for the 
community.
Sections
Introduction
Target selection and validation
Clinically validated targets
Targets with chemical probe 
validation
Targets with genetic evidence
Medicinal chemistry
Cell culture models
Animal models
Human viral challenge models
Pre-empting resistance
Concluding remarks
1Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 2Oxford 
Biomedical Research Centre, National Institute for Health Research, University of Oxford, Oxford, UK. 3National


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Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. 4Pardes Biosciences, 
Carlsbad, CA, USA. 5Vir Biotechnology, San Francisco, CA, USA. 6Drug Discovery Sciences, Takeda California, Inc., 
San Diego, CA, USA. 7Gilead Sciences, Inc., Foster City, CA, USA. 8Novartis Institutes for Biomedical Research, 
Cambridge, MA, USA. 9PostEra, Inc., Cambridge, MA, USA. 10Cavendish Laboratory, University of Cambridge, 
Cambridge, UK. 11These authors contributed equally: Annette von Delft, Alpha A. Lee. 
 e-mail: Annette.vondelft@
cmd.ox.ac.uk; alpha.lee@postera.ai


key: title
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Homotopic local-global parcellation of the human cerebral cortex from resting-state functional connectivity


key: chroma:document
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Homotopic local-global parcellation of the human cerebral 
cortex from resting-state functional connectivity
Xiaoxuan Yana,b,c,d, Ru Konga,b,c, Aihuiping Xuea,b,c, Qing Yanga,b,c, Csaba Orbana,b,c, Lijun 
Ana,b,c, Avram J. Holmese, Xing Qiana, Jianzhong Chena,b,c, Xi-Nian Zuof,g, Juan Helen 
Zhoua,b,d, Marielle V Fortierh,i, Ai Peng Tani,j, Peter Gluckmank, Yap Seng Chongi,l, Michael J 
Meaneyi,m, Danilo Bzdokn,o, Simon B. Eickhoffp,q, B.T. Thomas Yeoa,b,c,d,r,*
aCentre for Sleep and Cognition (CSC) & Centre for Translational Magnetic Resonance Research 
(TMR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
bDepartment of Electrical and Computer Engineering, National University of Singapore, 
Singapore
cN.1 Institute for Health and Institute for Digital Medicine (WisDM), National University of 
Singapore, Singapore
dIntegrative Sciences and Engineering Programme (ISEP), National University of Singapore, 
Singapor
eYale University, Departments of Psychology and Psychiatry, New Haven, CT, Unites States of 
America
fState Key Laboratory of Cognitive Neuroscience and Learning/IDG McGovern Institute for Brain 
Research, Beijing Normal University, Beijing, China
gNational Basic Public Science Data Center, China
hDepartment of Diagnostic and Interventional Imaging, KK Women’s and Children’s Hospital, 
Singapore
iSingapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research 
(A*STAR), Singapore
jDepartment of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of 
Singapore, Singapore
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
*Corresponding author. thomas.yeo@nus.edu.sg (B.T.T. Yeo). 
Credit authorship contribution statement
Xiaoxuan Yan: Conceptualization, Methodology, Software, Writing – original draft, Visualization, Ru Kong: Conceptualization, 
Methodology; Aihuiping Xue: Conceptualization, Methodology, Validation; Qing Yang: Methodology; Csaba Orban: Writing,


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Validation Lijun An: Software; Avram J Holmes: Writing, Validation; Xing Qian: Data processing; Jianzhong Chen: Software; 
Xi-Nian Zuo: Writing, Validation; Juan Helen Zhou: Writing, Validation; Marielle V Fortier: Data collection; Ai Peng Tan: 
Data collection; Peter Gluckman: Data collection; Yap Seng Chong: Data collection; Michael J Meaney: Data collection; Danilo 
Bzdok: Writing, Validation; Simon B. Eickhoff: Writing, Validation; B.T. Thomas Yeo: Supervision, Conceptualization, Validation, 
Writing review and editing.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2023.120010.
HHS Public Access
Author manuscript
Neuroimage. Author manuscript; available in PMC 2023 June 01.
Published in final edited form as:
Neuroimage. 2023 June ; 273: 120010. doi:10.1016/j.neuroimage.2023.120010.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Human Cytomegalovirus IE2 Disrupts Neural Progenitor Development and Induces Microcephaly in Transgenic Mouse


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Vol.:(0123456789)
1 3
Molecular Neurobiology (2023) 60:3883–3897 
https://doi.org/10.1007/s12035-023-03310-1
Human Cytomegalovirus IE2 Disrupts Neural Progenitor Development 
and Induces Microcephaly in Transgenic Mouse
Delei Niu1 · Xianjuan Zhang1 · Shuyun Zhang1 · Tianyu Fan2 · Xiaoqiong Zhou1 · Hui Wang3 · Xueming Zhang1 · 
Fulong Nan3 · Shasha Jiang1 · Fengjun Liu3 · Yunyang Wang4 · Bin Wang1,3 
Received: 4 October 2022 / Accepted: 25 February 2023 / Published online: 29 March 2023 
© The Author(s) 2023
Abstract 
Human cytomegalovirus (HCMV) is a significant contributor to congenital birth defects. Limited by the lack of animal mod-
els, the pathogenesis of neurological damage in vivo caused by HCMV infection and the role of individual viral genes remain 
to be elucidated. Immediate early (IE2) protein may play a function in neurodevelopmental problems caused by HCMV 
infection. Here, this study intended to investigate IE2’s long-term effects on development of the brain in IE2-expressing 
transgenic mice (Rosa26-LSL-IE2+/−, Camk2α-Cre) aimed to observe the phenotype of postnatal mice. The expression of 
IE2 in transgenic mice was confirmed by PCR and Western blot technology. We collected mouse brain tissue at 2, 4, 6, 8, 
and 10 days postpartum to analyze the developmental process of neural stem cells by immunofluorescence. We discovered 
that transgenic mice (Rosa26-LSL-IE2+/−, Camk2α-Cre) can reliably produce IE2 in the brain at various postpartum phases. 
Furthermore, we also observed the symptoms of microcephaly in postnatal transgenic mice, and IE2 can damage the amount 
of neural stem cells, prevent them from proliferating and differentiating, and activate microglia and astrocytes, creating an 
unbalanced environment in the brain’s neurons. In conclusion, we demonstrate that long-term expression of HCMV-IE2 
can cause microcephaly through molecular mechanisms affecting the differentiation and development of neural stem cells


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in vivo. This work establishes a theoretical and experimental foundation for elucidating the molecular mechanism of fetal 
microcephaly brought by HCMV infection in throughout the period of neural development of pregnancy.
Keywords Human cytomegalovirus · IE2 · Neural progenitor cells development · Microcephaly · Transgenic mouse
Introduction
Human cytomegalovirus (HCMV), belonging to the 
β-herpesvirus subfamily, is a ubiquitous and adaptable 
human pathogen that can remain latent for life in infected 
individuals [1]. HCMV is a kind of opportunistic pathogens, 
mainly in immunocompromised patients cause significant 
morbidity and mortality. During pregnancy, HCMV can be 
transmitted to the developing fetus, thus globally affecting 
0.5–2% of newborns [2]. Approximately, 10–15% of neo-
nates with congenital HCMV infection are symptomatic at 
birth with defects, such as microcephaly (the most serious 
brain diseases), hearing impairment, mental deficiency, and 
ventricular calcification [3]. However, the mechanism by 
which HCMV affects neuropathogenesis has not yet been 
fully understood.
The correct timing of neural progenitor cell (NPC) pro-
liferation/self-renewal and differentiation, neuronal migra-
tion, and maturation is important for appropriate mammalian 
Delei Niu and Xianjuan Zhang contributed equally to this work.
 * Yunyang Wang 
 
wangyy_09@outlook.com
 * Bin Wang 
 
wangbin532@126.com
1 
Department of Pathogenic Biology, College of Basic 
Medicine, Qingdao University, Qingdao 266000, Shandong, 
China
2 
Department of Immunology, College of Basic Medicine, 
Qingdao University, Qingdao 266000, Shandong, China
3 
Department of Special Medicine, College of Basic Medicine, 
Qingdao University, Qingdao 266000, Shandong, China
4 
Department of Endocrinology and Metabolism, the Affiliated 
Hospital of Qingdao University, Qingdao 266000, Shandong, 
China


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Cell death in the lateral geniculate nucleus, and its possible relationship with nicotinic receptors and sudden infant death syndrome \(SIDS\


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Vol:.(1234567890)
Molecular Neurobiology (2023) 60:4120–4131
https://doi.org/10.1007/s12035-023-03332-9
1 3
ORIGINAL ARTICLE
Cell death in the lateral geniculate nucleus, and its possible 
relationship with nicotinic receptors and sudden infant death 
syndrome (SIDS)
Cynthia Chang1 · Arunnjah Vivekanandarajah2 · Karen A Waters1,3 · Rita Machaalani1,3 
Received: 15 June 2022 / Accepted: 28 March 2023 / Published online: 11 April 2023 
© The Author(s) 2023
Abstract
The role of the lateral geniculate nucleus (LGN) in vision has been extensively studied, yet its extraretinal capacities are 
still being investigated, including its role in arousal from sleep. The β2 nicotinic acetylcholine receptor (nAChR) subunit is 
involved in the laminal organisation of the LGN with magnocellular (MC) and parvocellular (PC) neurons. Sudden infant death 
syndrome (SIDS) occurs during a sleep period and, neuropathologically, is associated with increased neuronal cell death and 
altered nAChRs. A recent qualitative pilot study from our group implicates the possibility of increased neuronal death/apop-
tosis in the SIDS LGN. The present study used quantitative analysis to report the baseline expression of apoptotic and nAChR 
subunits α7 and β2 in the PC and MC layers of the LGN, to determine correlations amongst these markers within layers and 
across layers, and to evaluate changes in the expression of these markers in the LGN of SIDS infants, along with associations 
with SIDS risk factors, such as age, sex, cigarette smoke exposure, bed-sharing, and presence of an upper respiratory tract 
infection (URTI). Tissue was immunohistochemically stained for cell death markers of active caspase-3 (Casp-3) and TUNEL, 
and for the α7 and β2 nAChR subunits. Amongst 43 cases of sudden and unexpected deaths in infancy (SUDI), classifications 
included explained deaths (eSUDI, n = 9), SIDS I (n = 5) and SIDS II (n = 29). Results indicated a strong correlation of the


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apoptotic markers and β2 nAChR subunit between the LGN layers, but not across the markers within the layers. Amongst the 
diagnostic groups, compared to eSUDI, the SIDS II cases had decreased Casp-3 expression while β2 nAChR expression was 
increased in both PC and MC layers. Amongst the SIDS risk factors, URTI and bed-sharing were associated with changes in 
neuronal death but not in the α7 and β2 markers. In conclusion, our findings do not support a role for the α7 and β2 nAChRs in 
apoptotic regulation of the LGN layers during infancy. However, for SIDS victims, an inverse correlation between the changes 
for markers of apoptosis and the β2 nAChR subunit expression suggests altered LGN function.
Keywords Apoptosis · Acetylcholine · Cholinergic · LGN · SUDI · Sleep
Abbreviations
ACh 
 Acetylcholine
Casp-3 
 Caspase 3
LC 
 Locus coeruleus
LGN  
 Lateral Geniculate Nucleus
LSD 
 Least Significant Difference
MC 
 Magnocellular
nAChR 
 Nicotinic acetylcholine receptor
PC 
 Parvocellular
SEM 
 Standard Error of the Mean
SIDS 
 Sudden Infant Death Syndrome
SUDI 
 Sudden Unexpected Death in Infancy
TUNEL  Terminal Deoxynucleotidyl Transferase (Tdt)-
Mediated dUTP Nick End
REM 
 Rapid Eye Movement sleep
URTI 
 Upper Respiratory Tract Infection
 * Rita Machaalani 
 
rita.machaalani@sydney.edu.au
1 
Sydney Medical School, Faculty of Medicine and Health, 
The University of Sydney, Camperdown, NSW 2006, 
Australia
2 
Discipline of Medicine, Central Clinical School, Faculty 
of Medicine and Health, The University of Sydney, 
Camperdown, NSW, Australia
3 
Discipline of Child and Adolescent Health, Children’s 
Hospital at Westmead Clinical School, Faculty of Medicine 
and Health, The University of Sydney, Camperdown, NSW, 
Australia


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Comparison of the Ct-values for genomic and subgenomic SARS-CoV-2 RNA reveals limited predictive value for the presence of replication competent virus


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Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection


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Persistence of Immunogenicity of a Purified Inactivated 
Zika Virus Vaccine Candidate in Healthy Adults:  
2 Years of Follow-up Compared With Natural Infection
Camilo J. Acosta,1 Clemente Diaz,2 Francesco Nordio,1 Htay-Htay Han,1 Kelley J. Moss,1 Kelly Bohning,1 Pradeep Kumar,3 Mengya Liu,1 Hetal Patel,1
Filippo Pacciarini,1 Vincent Mwangi,1 Elke Walter,3 Tim D. Powell,1 Hana M. El Sahly,4 Whitney R. Baldwin,1 Joseph Santangelo,1 Evan J. Anderson,5,
and Gary Dubin3
1Takeda Vaccines Inc, Cambridge, Massachusetts, USA; 2Puerto Rico Clinical and Translational Research Consortium, San Juan, Puerto Rico; 3Takeda Pharmaceuticals International AG, Zürich, 
Switzerland; 4Baylor College of Medicine, Houston, Texas, USA; and 5Emory University School of Medicine, Atlanta, Georgia, USA
Background. We report 2-year persistence of immune response to Takeda’s prophylactic purified formalin-inactivated whole 
Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection.
Methods. A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18–49-year-old 
adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives 
were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to 
flavivirus (FV)–naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary 
vaccination with 10-μg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after 
natural infection.
Results. TAK-426 at 10-μg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. 
Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed 
groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus 
infection.


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Conclusions. These results support the further clinical development of TAK-426 for both FV-naive and FV-primed 
populations.
Clinical Trials Registration. NCT03343626
Keywords. Zika virus; natural infection; neutralizing antibody response; persistence; safety; vaccine.
Received 25 August 2022; editorial decision 01 December 2022; accepted 09 December 
2022; published online 9 December 2022
Presented in part: Eighth Northern European Conference on Travel Medicine, Rotterdam, the 
Netherlands, June 2022 (abstract 4291-A-2209).
Correspondence: Camilo J. Acosta, MD, PhD, MSc, Vaccines Clinical Development, Vaccine 
Business Unit, Takeda Vaccines, 40 Landsdowne St, Cambridge, MA 02139 (camiloj.acosta@ 
takeda.com).
The Journal of Infectious Diseases®
2023;227:1303–12 
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases 
Society of America. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution- 
NonCommercial-NoDerivs 
licence 
(https://creativecommons.org/licenses/by-nc-nd/4.0/), 
which permits non-commercial reproduction and distribution of the work, in any medium, pro-
vided the original work is not altered or transformed in any way, and that the work is properly 
cited. For commercial re-use, please contact journals.permissions@oup.com
https://doi.org/10.1093/infdis/jiac482
Zika virus (ZIKV) is a mosquito and sexually transmitted flavi-
virus (FV) first identified in Uganda in 1947; it has since been 
responsible for sporadic outbreaks of self-limited illness in 
Africa, Asia, and French Polynesia [1–4]. ZIKV spread to 
South and Central America, and circulation has occurred in 
other regions, including the United States and Europe [5, 6]. 
The incidence of ZIKV infections has since declined, but low 
sustained circulation occurs in Thailand [7], India [8], and 
South America [9]. Global awareness of ZIKV increased in 
2015 when clusters of Guillain-Barré syndrome in adults and


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neurological disorders and congenital anomalies in newborns, 
including microcephaly, were temporally associated with a 
large ZIKV outbreak in Northeast Brazil [10] that subsequently 
spread to several countries in the Americas [11]. The World 
Health Organization declared ZIKV a public health emergency 
of international concern in February 2016 [12] and has includ-
ed it as one of the priority diseases listed in its 2018 research 
and development blueprint [13]. Therefore, the threat of dis-
ease caused by ZIKV infection exists not only for human pop-
ulations living in and traveling to currently endemic countries 
but also for those living in nonendemic countries where trans-
mission of disease could occur in the future owing to the pres-
ence of the mosquito vector.
Because there is no effective therapy, a ZIKV vaccine is an 
important unmet medical need both for inhabitants of affected 
regions and for travelers to those countries. Takeda Vaccines is 
developing TAK-426, a purified formalin-inactivated whole 
ZIKV vaccine (PIZV) based on a plaque-purified subisolate 
Zika Virus Vaccine Candidate After 2 Years • JID 2023:227 (1 June) • 1303
The Journal of Infectious Diseases                                
M A J O R  A R T I C L E


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Coordinated reset deep brain stimulation of subthalamic nucleus produces long-lasting, dose-dependent motor improvements in the \
1- methyl -4- phenyl -1,2,3,6-tetrahydropyridine non-human primate model of parkinsonism


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Coordinated reset deep brain stimulation of subthalamic nucleus 
produces long-lasting, dose-dependent motor improvements in 
the 1- methyl -4- phenyl -1,2,3,6-tetrahydropyridine non-human 
primate model of parkinsonism
Jing Wanga, Shane Nebeckb, Abirami Muralidharanc, Matthew D. Johnsond, Jerrold L. 
Viteke, Kenneth B. Bakerf
aDepartment of Neurology, University of Minnesota, Minneapolis, MN, USA 55455
bDepartment of Neurology, University of Minnesota, Minneapolis, MN, USA 55455
cDepartment of Neurology, University of Minnesota, Minneapolis, MN, USA 55455
dDepartment of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA 55455
eDepartment of Neurology, University of Minnesota, Minneapolis, MN, USA 55455
fDepartment of Neuroscience, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA 
44195
Abstract
Background: Novel deep brain stimulation (DBS) paradigms are being explored in an effort to 
further optimize therapeutic outcome for patients with Parkinson’s disease (PD). One approach, 
termed ‘Coordinated Reset’ (CR) DBS, was developed to target pathological oscillatory network 
activity; with desynchronizing effects and associated therapeutic benefit hypothesized to endure 
beyond cessation of stimulus delivery.
Objective: To characterize the acute and carry-over effects of low-intensity CR DBS versus 
traditional DBS (tDBS) in the region of the subthalamic nucleus (STN).
Methods: A within-subjects, block treatment design involving the 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) non-human primate model of parkinsonism was used. Each treatment 
block consisted of five days of daily DBS delivery followed by a one week minimum post-
treatment observation window. Motor behavior was quantified using a modified rating scale for 
both animals combined with an objective, upper-extremity reach task in one animal.
Results: Both animals demonstrated significant motor improvements during acute tDBS;


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however within-session and post-treatment carry-over were limited. Acute motor improvements 
also were observed in response to low-intensity CR DBS, however both within- and between-
session therapeutic carry-over enhanced progressively following each daily treatment. Moreover, 
Corresponding Author: Kenneth B. Baker, Department of Neurology, University of Minnesota, 2873H, 2001 6th St SE, Minneapolis, 
MN 55455, phone: 612-626-8065, fax: 612-626-5685, bakerk6@ccf.org.
Author Contributions:
KBB, JLV and MDJ conceived and designed the experiments. JW, SN, AM, and KBB acquired and analyzed the data. All authors 
were involved in drafting the article and have approved the final version for submission.
HHS Public Access
Author manuscript
Brain Stimul. Author manuscript; available in PMC 2023 May 29.
Published in final edited form as:
Brain Stimul. 2016 ; 9(4): 609–617. doi:10.1016/j.brs.2016.03.014.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Characterization of the expression of gastrin-releasing peptide and its receptor in the trigeminal and spinal somatosensory syst\
ems of Japanese macaque monkeys: Insight into humans


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Characterization of the expression of gastrin-releasing peptide 
and its receptor in the trigeminal and spinal somatosensory 
systems of Japanese macaque monkeys: Insight into humans
Keiko Takanami1,2,3,4, Takumi Oti1,5, Yasuhisa Kobayashi1,6, Koki Hasegawa7,8, Takashi 
Ito1, Naoaki Tsutsui1,9, Yasumasa Ueda10,11, Earl Carstens4, Tatsuya Sakamoto1, Hirotaka 
Sakamoto1
1Ushimado Marine Institute (UMI), Okayama University, Okayama, Japan
2Department of Genetics, Mouse Genomics Resources Laboratory, National Institute of Genetics, 
Sokendai (The Graduate University for Advanced Studies), Shizuoka, Japan
3Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, 
Japan
4Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California, 
USA
5Department of Biological Sciences, Faculty of Science, Kanagawa University, Kanagawa, Japan
6Department of Aquatic Biology, Fisheries, Faculty of Agriculture, Kindai University, Nara, Japan
7Center for Instrumental Analysis, Kyoto Pharmaceutical University, Kyoto, Japan
8Theranostic Pharmaceuticals Laboratory, Department of Radiological Sciences, School of Health 
Sciences, Fukushima Medical University, Fukushima, Japan
9Department of Marine Bioresources, Mie University, Mie, Japan
10Department of Physiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
11Department of Physiology, Kansai Medical University, Osaka, Japan
Abstract
Gastrin-releasing peptide (GRP) and its receptor (GRPR) have been identified as itch mediators 
in the spinal and trigeminal somatosensory systems in rodents. In primates, there are few reports 
of GRP/GRPR expression or function in the spinal sensory system and virtually nothing is known 
This is an open access article under the terms of the Creative Commons Attribution-Noncommercial License, which permits use, 
distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.


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Correspondence: Keiko Takanami, Present address: Department of Environmental Health, Faculty of Human Life and Environmental 
Sciences, Nara Women’s University, Nara, Japan. takanami@cc.nara-wu.ac.jp.
AUTHORS CONTRIBUTION
K.T. and H.S. designed research. K.T., T.O., Y.K., K.H., T.I., N.T., Y.U., and H.S. performed research. K.H., T.S., and H.S. contributed 
new reagents or analytic tools. K.T., T.O., Y.K., K.H., T.I., N.T., Y.U., E.C., T.S., and H.S. analyzed data. K.T. wrote the article with 
assistance from K.H., E.C., T.S., and H.S. The whole study was supervised by K.T. All authors discussed the results and commented 
on the manuscript.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
HHS Public Access
Author manuscript
J Comp Neurol. Author manuscript; available in PMC 2023 May 30.
Published in final edited form as:
J Comp Neurol. 2022 November ; 530(16): 2804–2819. doi:10.1002/cne.25376.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Pathogenicity, tissue tropism and potential vertical transmission of SARSr-CoV-2 in Malayan pangolins


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RESEARCH ARTICLE
Pathogenicity, tissue tropism and potential
vertical transmission of SARSr-CoV-2 in
Malayan pangolins
Xianghui Liang1☯, Xiaoyuan Chen1☯, Junqiong Zhai2☯, Xiaobing Li1,3☯, Xu Zhang1☯,
Zhipeng Zhang1, Ping Zhang1, Xiao Wang1, Xinyuan Cui1, Hai Wang1, Niu Zhou2, Zu-
Jin Chen2, Renwei Su1, Fuqing Zhou4, Edward C. Holmes5, David M. Irwin6,7, Rui-
Ai Chen1,8, Qian He1, Ya-Jiang Wu2, Chen Wang2, Xue-Qing Du2, Shi-Ming Peng2, Wei-
Jun Xie2, Fen Shan2, Wan-Ping Li2, Jun-Wei Dai2, Xuejuan Shen1, Yaoyu Feng1,
Lihua Xiao1, Wu Chen2*, Yongyi ShenID1,9*
1 State Key Laboratory for Animal Disease Control and Prevention, Guangdong Laboratory for Lingnan
Modern Agriculture, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South
China Agricultural University, Guangzhou, China, 2 Guangzhou Zoo & Guangzhou Wildlife Research Center,
Guangzhou, China, 3 College of Life Sciences, Longyan University, Longyan, China, 4 Department of
Radiology, the First Affiliated Hospital, Nanchang University, Nanchang, China, 5 Sydney Institute for
Infectious Diseases, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia,
6 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada, 7 Banting
and Best Diabetes Centre, University of Toronto, Toronto, Canada, 8 Zhaoqing Branch Center of Guangdong
Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing, China, 9 Guangdong
Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
☯ These authors contributed equally to this work.
* guangzhouchenwu@sina.com (WC); shenyy@scau.edu.cn (YS)
Abstract
Malayan pangolin SARS-CoV-2-related coronavirus (SARSr-CoV-2) is closely related to
SARS-CoV-2. However, little is known about its pathogenicity in pangolins. Using CT scans
we show that SARSr-CoV-2 positive Malayan pangolins are characterized by bilateral
ground-glass opacities in lungs in a similar manner to COVID-19 patients. Histological


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examination and blood gas tests are indicative of dyspnea. SARSr-CoV-2 infected multiple
organs in pangolins, with the lungs the major target, and histological expression data
revealed that ACE2 and TMPRSS2 were co-expressed with viral RNA. Transcriptome anal-
ysis indicated that virus-positive pangolins were likely to have inadequate interferon
responses, with relative greater cytokine and chemokine activity in the lung and spleen.
Notably, both viral RNA and viral proteins were detected in three pangolin fetuses, providing
initial evidence for vertical virus transmission. In sum, our study outlines the biological
framework of SARSr-CoV-2 in pangolins, revealing striking similarities to COVID-19 in
humans.
Author summary
SARS-CoV-2 has caused a severe and ongoing global pandemic. To date, bats and pango-
lins are the only groups of mammals known carry SARS-CoV-2-related coronaviruses
PLOS PATHOGENS
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May 17, 2023
1 / 14
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OPEN ACCESS
Citation: Liang X, Chen X, Zhai J, Li X, Zhang X,
Zhang Z, et al. (2023) Pathogenicity, tissue tropism
and potential vertical transmission of SARSr-CoV-2
in Malayan pangolins. PLoS Pathog 19(5):
e1011384. https://doi.org/10.1371/journal.
ppat.1011384
Editor: Vineet D. Menachery, University of Texas
Medical Branch at Galveston, UNITED STATES
Received: January 9, 2023
Accepted: April 24, 2023
Published: May 17, 2023
Copyright: © 2023 Liang 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: All data are in the
manuscript and supporting information files.
Sequence reads generated in this study are
available from the NCBI Sequence Read Archive
(SRA) database under BioProject accession
number PRJNA939083.
Funding: YS is funded by the Guangdong


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Provincial Key R&D Program (2022B1111040001),
Basic and Applied Basic Research Foundation of
Guangdong Province (2020B0301030007),
Laboratory of Lingnan Modern Agriculture Project


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In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury


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RESEARCH ARTICLE
In vitro evidence against productive SARS-
CoV-2 infection of human testicular cells:
Bystander effects of infection mediate
testicular injury
Stefanos Giannakopoulos1, Daniel P. Strange2, Boonyanudh Jiyarom2, Omar Abdelaal3,4,
Aaron W. Bradshaw3,5, Vivek R. Nerurkar2, Monika A. Ward6, Jackson Bakse6,
Jonathan Yap7, Selena Vanapruks7, William A. Boisvert7, Michelle D. Tallquist7,
Cecilia Shikuma2, Hooman Sadri-Ardekani3,5, Philip Clapp3, Sean V. Murphy3,
Saguna VermaID1,2*
1 Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at
Manoa, Honolulu, Hawaii, United States of America, 2 Department of Tropical Medicine, Medical
Microbiology, and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa,
Honolulu, Hawaii, United States of America, 3 Wake Forest Institute for Regenerative Medicine, Wake Forest
School of Medicine, Winston-Salem, North Carolina, United States of America, 4 Department of Urology,
Faculty of Medicine, Zagazig University, Egypt, 5 Department of Urology, Wake Forest School of Medicine,
Winston-Salem, North Carolina, 6 Institute for Biogenesis Research, John A Burns School of Medicine,
University of Hawaii at Manoa, Honolulu, Hawaii, United States of America, 7 Center for Cardiovascular
Research, Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa,
Honolulu, Hawaii, United States of America
* saguna@hawaii.edu
Abstract
The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury
including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2
receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection
and mechanisms of testicular injury are not fully understood. The testicular injury could be
initiated by direct virus infection or exposure to systemic inflammatory mediators or viral
antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D


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culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells
(STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not
productively infect any testicular cell type. However, exposure of STC and HTO to inflamma-
tory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell
viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to
only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects
dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was
observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue archi-
tecture with no evidence of virus replication in the testis that correlated with peak lung
inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in
the serum during the acute stage of the disease. Collectively, these data strongly suggest
that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of
exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel
PLOS PATHOGENS
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May 18, 2023
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Citation: Giannakopoulos S, Strange DP, Jiyarom
B, Abdelaal O, Bradshaw AW, Nerurkar VR, et al.
(2023) In vitro evidence against productive SARS-
CoV-2 infection of human testicular cells:
Bystander effects of infection mediate testicular
injury. PLoS Pathog 19(5): e1011409. https://doi.
org/10.1371/journal.ppat.1011409
Editor: Stanley Perlman, University of Iowa,
UNITED STATES
Received: January 6, 2023
Accepted: May 8, 2023
Published: May 18, 2023
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
process; therefore, we enable the publication of
all of the content of peer review and author
responses alongside final, published articles. The


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editorial history of this article is available here:
https://doi.org/10.1371/journal.ppat.1011409
Copyright: © 2023 Giannakopoulos 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: All relevant data are
within the manuscript and its Supporting
Information files.


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Neurophysiological mechanisms of error monitoring in human 
and non-human primates
Zhongzheng Fu1,2, Amirsaman Sajad3,4,5, Steven P. Errington3,4,5, Jeffrey D. Schall3,5,6,7,8, 
Ueli Rutishauser1,9,10
1Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
2Division of Humanities and Social Sciences, California Institute of Technology, Pasadena, CA, 
USA.
3Center for Integrative & Cognitive Neuroscience, Vanderbilt University, Nashville, TN, USA.
4Vanderbilt Vision Research Center, Vanderbilt University, Nashville, TN, USA.
5Department of Psychology, Vanderbilt University, Nashville, TN, USA.
6Centre for Vision Research, York University, Toronto, Ontario, Canada.
7Vision: Science to Applications (VISTA), York University, Toronto, Ontario, Canada.
8Department of Biology, Faculty of Science, York University, Toronto, Ontario, Canada.
9Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 
USA.
10Center for Neural Science and Medicine, Department of Biomedical Sciences, Cedars-Sinai 
Medical Center, Los Angeles, CA, USA.
Abstract
Performance monitoring is an important executive function that allows us to gain insight into 
our own behaviour. This remarkable ability relies on the frontal cortex, and its impairment is an 
aspect of many psychiatric diseases. In recent years, recordings from the macaque and human 
medial frontal cortex have offered a detailed understanding of the neurophysiological substrate 
that underlies performance monitoring. Here we review the discovery of single-neuron correlates 
of error monitoring, a key aspect of performance monitoring, in both species. These neurons are 
the generators of the error-related negativity, which is a non-invasive biomarker that indexes error 
detection. We evaluate a set of tasks that allows the synergistic elucidation of the mechanisms 
of cognitive control across the two species, consider differences in brain anatomy and testing


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Reprints and permissions information is available at www.nature.com/reprints.
Correspondence should be addressed to Zhongzheng Fu, Jeffrey D. Schall or Ueli Rutishauser. zzbrooksfu@gmail.com; 
schalljd@yorku.edu; rutishauseru@csmc.edu.
Author contributions
The authors all contributed to all aspects of preparing the article.
Competing interests
The authors declare no competing interests.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/
s41583-022-00670-w.
HHS Public Access
Author manuscript
Nat Rev Neurosci. Author manuscript; available in PMC 2023 September 01.
Published in final edited form as:
Nat Rev Neurosci. 2023 March ; 24(3): 153–172. doi:10.1038/s41583-022-00670-w.
Author Manuscript
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https://doi.org/10.1093/brain/awac428
BRAIN 2023: 146; 2524–2534 | 2524
Tau seeds from patients induce progressive 
supranuclear palsy pathology and symptoms 
in primates
Morgane Darricau,1 Taxiarchis Katsinelos,2 Flavio Raschella,3,4,5 
Tomislav Milekovic,3,4,5 Louis Crochemore,1 Qin Li,6 
Grégoire Courtine,3,4,5 
William A. McEwan,2 
Benjamin Dehay,1 
Erwan Bezard1,6,† and Vincent Planche1,7,†
†These authors contributed equally to this work.
Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both mo-
tor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may 
spread in the brain from cell to cell in a ‘prion-like’ manner. However, direct experimental evidence of this phenom-
enon, and its consequences on brain functions, is still lacking in primates.
In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive 
supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, 
the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in 
P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), mis-
folded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally in-
jected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau 
proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features 
revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism 
as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed 
the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected ma-


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caques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear 
palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including glo-
bose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also 
in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thal-
amus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly 
neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease.
Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and 
behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathologic-
al progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy- 
tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurode-
generative disease.
1
University of Bordeaux, CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France
2
UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, CB2 0AH 
Cambridge, UK
3
Swiss Federal Institute of Technology (EPFL), CH-1011 Lausanne, Switzerland
4
Defitech Center for Interventional Neurotherapies (NeuroRestore), CH-1011 Lausanne, Switzerland
Received August 27, 2022. Revised October 26, 2022. Accepted November 04, 2022. Advance access publication November 16, 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: 
journals.permissions@oup.com


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Fatty acid amides as potential circulating biomarkers
for sarcopenia
Ye An Kim1†, Seung Hun Lee2†, Jung-Min Koh2, Seung-hyun Kwon3, Young Lee3, Han Jin Cho4, Hanjun Kim4, Su Jung Kim5,
Ji Hyun Lee1, Hyun Ju Yoo5*† & Je Hyun Seo3*†
1Division of Endocrinology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, South Korea; 2Division of Endocrinology and Metabolism, Asan
Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 3Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, South
Korea; 4Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea; 5Department of Convergence Medicine, Asan Institute for Life
Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
Abstract
Background
Sarcopenia is characterized by a progressive decrease in skeletal muscle mass and function with age.
Given that sarcopenia is associated with various metabolic disorders, effective metabolic biomarkers for its early detec-
tion are required. We aimed to investigate the metabolic biomarkers related to sarcopenia in elderly men and perform
experimental studies using metabolomics.
Methods
Plasma metabolites from 142 elderly men, comprising a sarcopenia group and an age-matched control
group, were measured using global metabolome proﬁling. Muscle and plasma samples from an aging mouse model
of sarcopenia, as well as cell media and cell lysates during myoblast differentiation, were analysed based on targeted
metabolome proﬁling. Based on these experimental results, fatty acid amides were quantiﬁed from human plasma as
well as human muscle tissues. The association of fatty acid amide levels with sarcopenia parameters was evaluated.
Results
Global metabolome proﬁling showed that fatty acid amide levels were signiﬁcantly different in the plasma of
elderly men with sarcopenia (all Ps < 0.01). Consistent with these results in human plasma, targeted metabolome pro-


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ﬁling in an aging mouse model of sarcopenia showed decreased levels of fatty acid amides in plasma but not in muscle
tissue. In addition, the levels of fatty acid amides increased in cell lysates during muscle cell differentiation. Targeted
metabolome proﬁling in men showed decreased docosahexaenoic acid ethanolamide (DHA EA) levels in the plasma
(P = 0.016) but not in the muscle of men with sarcopenia. DHA EA level was positively correlated with sarcopenia pa-
rameters such as skeletal muscle mass index (SMI) and handgrip strength (HGS) (P = 0.001, P = 0.001, respectively).
The area under the receiver-operating characteristic curve (AUC) for DHA EA level ≤ 4.60 fmol/μL for sarcopenia was
0.618 (95% conﬁdence interval [CI]: 0.532–0.698). DHA EA level ≤ 4.60 fmol/μL was associated with a signiﬁcantly
greater likelihood of sarcopenia (odds ratio [OR]: 2.11, 95% CI: 1.03–4.30), independent of HGS. The addition of
DHA EA level to age and HGS signiﬁcantly improved the AUC from 0.620 to 0.691 (P = 0.0497).
Conclusions
Our study demonstrated that fatty acid amides are potential circulating biomarkers in elderly men with
sarcopenia. DHA EA, in particular, strongly related to muscle mass and strength, can be a key metabolite to become
a reliable metabolic biomarker for sarcopenia. Further research on fatty acid amides will provide insights into the
metabolomic changes relevant to sarcopenia from an aging perspective.
Keywords
Aging; Metabolomics; Sarcopenia; Biomarkers; Fatty acid amides
Received: 31 October 2022; Revised: 14 February 2023; Accepted: 3 April 2023
*Correspondence to: Je Hyun Seo, Veterans Medical Research Institute, Veterans Health Service Medical Center, Jinhwangdo-ro 61-gil 53, Gangdong-gu, Seoul 05368, South
Korea. Email: jazmin2@naver.com;
Hyun Ju Yoo, Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Email:
yoohyunju@amc.seoul.kr
†These authors contributed equally to this work.
ORIGINAL ARTICLE


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© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and no modiﬁcations or adaptations are made.
Journal of Cachexia, Sarcopenia and Muscle 2023; 14: 1558–1568
Published online 1 May 2023 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jcsm.13244


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Stress-Induced Biological Aging: A Review and Guide for 
Research Priorities
Lilian R. Polsky1,†, Kelly E. Rentscher, Ph.D.1,2,†,*, Judith E. Carroll1
1Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience & Human 
Behavior, University of California, Los Angeles
2Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin
Abstract
Exposure to chronic adverse conditions, and the resultant activation of the neurobiological 
response cascade, has been associated with an increased risk of early onset of age-related disease 
and, recently, with an older biological age. This body of research has led to the hypothesis that 
exposure to stressful life experiences, when occurring repeatedly or over a prolonged period, may 
accelerate the rate at which the body ages. The mechanisms through which chronic psychosocial 
stress influences distinct biological aging pathways to alter rates of aging likely involve multiple 
layers in the physiological-molecular network. In this review, we integrate research using animal, 
human, and in vitro models to begin to delineate the distinct pathways through which chronic 
psychosocial stress may impact biological aging, as well as the neuroendocrine mediators (i.e., 
norepinephrine, epinephrine, and glucocorticoids) that may drive these effects. Findings highlight 
key connections between stress and aging, namely cellular metabolic activity, DNA damage, 
telomere length, cellular senescence, and inflammatory response patterns. We conclude with a 
guiding framework and conceptual model that outlines the most promising biological pathways 
by which chronic adverse conditions could accelerate aging and point to key missing gaps in 
knowledge where future research could best answer these pressing questions.
Keywords
psychosocial stress; biological aging; cellular senescence; telomere length; DNA damage; 
inflammation
*Corresponding author: Kelly E. Rentscher, Ph.D., Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin,


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Clinical Cancer Center, 1000 N. 92nd St., Milwaukee, WI 53226, Phone: 414-955-4097, krentscher@mcw.edu.
†Co-first authorship
Author Contributions
All authors made substantial contributions to and approved the final version of this manuscript. The manuscript was conceptualized, 
drafted, and revised critically for intellectual content by L.R.P., K.E.R., and J.E.C.
Declarations of Interest
None
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
Brain Behav Immun. Author manuscript; available in PMC 2023 October 23.
Published in final edited form as:
Brain Behav Immun. 2022 August ; 104: 97–109. doi:10.1016/j.bbi.2022.05.016.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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The blue-light-hazard vs. blue-light-hype
Martin A. Mainster, PhD, MD, FRCOphth1, Oliver Findl, MD, MBA, FEBO2, H. Burkhard Dick, 
MD, PhD3, Thomas Desmettre, MD, PhD4, Gerardo Ledesma-Gil, MD, FICO5, Christine A. 
Curcio, PhD, FARVO6, Patricia L. Turner, MD1
1Department of Ophthalmology, University of Kansas School of Medicine, Prairie Village, Kansas, 
USA
2Vienna Institute for Research in Ocular Surgery, A Karl Landsteiner Institute, Hanusch Hospital, 
Vienna, Austria
3Department of Ophthalmology, Ruhr University Eye Hospital, Science, Bochum, Germany
4Centre de Retine Medicale, Marquette-Lez-Lille, France
5Retina Department, Institute of Ophthalmology, Fundación Conde de Valenciana, Mexico City, 
Mexico
6Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, 
Birmingham, Alabama, USA
Abstract
PURPOSE: The blue-light-hazard is the experimental finding that blue light is highly toxic 
to the retina (photic retinopathy), in brief abnormally intense exposures, including sungazing 
or vitreoretinal endoillumination. This term has been misused commercially to suggest, falsely, 
that ambient environmental light exposure causes phototoxicity to the retina, leading to age-
related macular degeneration (AMD). We analyze clinical, epidemiological and biophysical data 
regarding blue-filtering optical chromophores.
DESIGN: Multi-institutional perspective.
METHODS: Analysis and integration of data regarding the blue-light-hazard and blue-blocking 
filters in ophthalmology and related disciplines.
RESULTS: Large epidemiological studies show that blue-blocking intraocular lenses (IOLs) do 
not decrease AMD risk or progression. Blue-filtering lenses cannot reduce disability glare because 
image and glare illumination are decreased in the same proportion. Blue light essential for optimal 
rod and retinal ganglion photoreception is decreased by progressive age-related crystalline lens 
yellowing, pupillary miosis and rod and retinal ganglion photoreceptor degeneration. Healthful


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daily environmental blue light exposure decreases in older adults, especially women. Blue light is 
important in dim environments where inadequate illumination increases risk of falls and associated 
morbidities.
Corresponding author: Martin A. Mainster, PhD, MD, FRCOphth, Department of Ophthalmology, University of Kansas School of 
Medicine, 7400 State Line Road, Prairie Village, Kansas, 66208-3444, USA, mmainste@kumc.edu (no “r” in “mmainste”). 
HHS Public Access
Author manuscript
Am J Ophthalmol. Author manuscript; available in PMC 2023 June 06.
Published in final edited form as:
Am J Ophthalmol. 2022 August ; 240: 51–57. doi:10.1016/j.ajo.2022.02.016.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Coccidioides undetected in soils from agricultural land and uncorrelated with time or the greater soil fungal community on undeveloped land


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RESEARCH ARTICLE
Coccidioides undetected in soils from
agricultural land and uncorrelated with time
or the greater soil fungal community on
undeveloped land
Robert WagnerID1*, Liliam Montoya1, Jennifer R. Head2, Simon Campo3, Justin Remais3,
John W. Taylor1
1 Department of Plant & Microbial Biology, University of California Berkeley, Berkeley, California, United
States of America, 2 Division of Epidemiology, University of California Berkeley, Berkeley, California, United
States of America, 3 Division of Environmental Health Sciences, University of California Berkeley, Berkeley,
California, United States of America
* robwagner@berkeley.edu
Abstract
Coccidioidomycosis is a typically respiratory fungal disease that, in the United States,
occurs primarily in Arizona and California. In California, most coccidioidomycosis cases
occur in the San Joaquin Valley, a primarily agricultural region where the disease poses a
risk for outdoor workers. We collected 710 soil samples and 265 settled dust samples from
nine sites in the San Joaquin Valley and examined how Coccidioides detection varied by
month, site, and the presence and abundance of other fungal species. We detected Cocci-
dioides in 89 of 238 (37.4%) rodent burrow soil samples at five undeveloped sites and were
unable to detect Coccidioides in any of 472 surface and subsurface soil samples at four agri-
cultural sites. In what is the largest sampling effort undertaken on agricultural land, our
results provide no evidence that agricultural soils in the San Joaquin Valley harbor Cocci-
dioides. We found no clear association between Coccidioides and the greater soil fungal
community, but we identified 19 fungal indicator species that were significantly associated
with Coccidioides detection in burrows. We also did not find a seasonal pattern in Cocci-
dioides detection in the rodent burrow soils we sampled. These findings suggest both the
presence of a spore bank and that coccidioidomycosis incidence may be more strongly


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associated with Coccidioides dispersal than Coccidioides growth. Finally, we were able to
detect Coccidioides in only five of our 265 near-surface settled dust samples, one from agri-
cultural land, where Coccidioides was undetected in soils, and four from undeveloped land,
where Coccidioides was common in the rodent burrow soils we sampled. Our ability to
detect Coccidioides in few settled dust samples indicates that improved methods are likely
needed moving forward, though raises questions regarding aerial dispersal in Coccidioides,
whose key transmission event likely occurs over short distances in rodent burrows from soil
to naïve rodent lungs.
PLOS PATHOGENS
PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011391
May 25, 2023
1 / 29
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OPEN ACCESS
Citation: Wagner R, Montoya L, Head JR, Campo
S, Remais J, Taylor JW (2023) Coccidioides
undetected in soils from agricultural land and
uncorrelated with time or the greater soil fungal
community on undeveloped land. PLoS Pathog
19(5): e1011391. https://doi.org/10.1371/journal.
ppat.1011391
Editor: Eva H. Stukenbrock, Max-Planck-Institut fur
Evolutionsbiologie, GERMANY
Received: December 10, 2022
Accepted: April 27, 2023
Published: May 25, 2023
Copyright: © 2023 Wagner 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: All data supporting
the findings of this study have been deposited in
publically available online repositories. All qPCR
data, environmental data and metadata have been
deposited in the Dryad repository (www.datadryad.
org): https://doi.org/10.5061/dryad.p8cz8w9vx. All
DNA sequencing data have been deposited in the
NCBI Sequence Read Archive (www.ncbi.nlm.nih.
gov/sra) with the following accession numbers:
PRJNA736519, PRJNA736167 and PRJNA736543.


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The association between air pollution and the severity at diagnosis and progression of systemic sclerosis-associated interstitial lung disease: results from the retrospective ScleroPol study


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Roeser et al. Respiratory Research          (2023) 24:151  
https://doi.org/10.1186/s12931-023-02463-w
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.
Respiratory Research
The association between air pollution 
and the severity at diagnosis and progression 
of systemic sclerosis-associated interstitial lung 
disease: results from the retrospective ScleroPol 
study
Anaïs Roeser1, Lucile Sese1,9†, Guillaume Chassagnon2†, Benjamin Chaigne3†, Bertrand Dunogue3, 
Stéphane Tran Ba4, Salma Jebri4, Pierre‑Yves Brillet4, Marie Pierre Revel2, Frédérique Aubourg5, Robin Dhote6, 
Frédéric Caux7, Isabella Annesi‑Maesano8†, Luc Mouthon3†, Hilario Nunes1,9† and Yurdagül Uzunhan1,9*† 
Abstract 
Objective To investigate the association of air pollution exposure with the severity of interstitial lung disease (ILD) at 
diagnosis and ILD progression among patients with systemic sclerosis (SSc)‑associated ILD.


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Methods We conducted a retrospective two‑center study of patients with SSc‑associated ILD diagnosed between 
2006 and 2019. Exposure to the air pollutants particulate matter of up to 10 and 2.5 µm in diameter  (PM10,  PM2.5), 
nitrogen dioxide  (NO2), and ozone  (O3) was assessed at the geolocalization coordinates of the patients’ residential 
address. Logistic regression models were used to evaluate the association between air pollution and severity at diag‑
nosis according to the Goh staging algorithm, and progression at 12 and 24 months.
Results We included 181 patients, 80% of whom were women; 44% had diffuse cutaneous scleroderma, and 56% 
had anti‑topoisomerase I antibodies. ILD was extensive, according to the Goh staging algorithm, in 29% of patients. 
 O3 exposure was associated with the presence of extensive ILD at diagnosis (adjusted OR: 1.12, 95% CI 1.05–1.21; p 
value = 0.002). At 12 and 24 months, progression was noted in 27/105 (26%) and 48/113 (43%) patients, respectively. 
 O3 exposure was associated with progression at 24 months (adjusted OR: 1.10, 95% CI 1.02–1.19; p value = 0.02). We 
found no association between exposure to other air pollutants and severity at diagnosis and progression.
Conclusion Our findings suggest that high levels of  O3 exposure are associated with more severe SSc‑associated ILD 
at diagnosis, and progression at 24 months.
†Lucile Sese, Guillaume Chassagnon and Benjamin Chaigne contributed 
equally to this work.
†Isabella Annesi‑Maesano, Luc Mouthon, Hilario Nunes and Yurdagül 
Uzunhan contributed equally to this work.
*Correspondence:
Yurdagül Uzunhan
yurdagul.uzunhan@aphp.fr
Full list of author information is available at the end of the article


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Prenatal delta-9-tetrahydrocannabinol exposure is associated with changes in rhesus macaque DNA methylation enriched for autism genes


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Shorey‑Kendrick et al. Clinical Epigenetics          (2023) 15:104  
https://doi.org/10.1186/s13148‑023‑01519‑4
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.
Clinical Epigenetics
Prenatal delta‑9‑tetrahydrocannabinol 
exposure is associated with changes in rhesus 
macaque DNA methylation enriched for autism 
genes
Lyndsey E. Shorey‑Kendrick1*, Victoria H. J. Roberts2, Rahul J. D’Mello3, Elinor L. Sullivan1,4,5, Susan K. Murphy6, 
Owen J. T. Mccarty7, Danny J. Schust6, Jason C. Hedges2,8, A. J. Mitchell1, Jose Juanito D. Terrobias2, 
Charles A. Easley IV9, Eliot R. Spindel1 and Jamie O. Lo2,3 
Abstract 
Background With the growing availability of cannabis and the popularization of additional routes of cannabis use 
beyond smoking, including edibles, the prevalence of cannabis use in pregnancy is rapidly increasing. However, the 
potential effects of prenatal cannabis use on fetal developmental programming remain unknown.


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Results We designed this study to determine whether the use of edible cannabis during pregnancy is deleterious 
to the fetal and placental epigenome. Pregnant rhesus macaques consumed a daily edible containing either delta‑
9‑tetrahydrocannabinol (THC) (2.5 mg/7 kg/day) or placebo. DNA methylation was measured in 5 tissues collected 
at cesarean delivery (placenta, lung, cerebellum, prefrontal cortex, and right ventricle of the heart) using the Illumina 
MethylationEPIC platform and filtering for probes previously validated in rhesus macaque. In utero exposure to THC 
was associated with differential methylation at 581 CpGs, with 573 (98%) identified in placenta. Loci differentially 
methylated with THC were enriched for candidate autism spectrum disorder (ASD) genes from the Simons Founda‑
tion Autism Research Initiative (SFARI) database in all tissues. The placenta demonstrated greatest SFARI gene enrich‑
ment, including genes differentially methylated in placentas from a prospective ASD study.
Conclusions Overall, our findings reveal that prenatal THC exposure alters placental and fetal DNA methylation at 
genes involved in neurobehavioral development that may influence longer‑term offspring outcomes. The data from 
this study add to the limited existing literature to help guide patient counseling and public health polices focused on 
prenatal cannabis use in the future.
Keywords Delta‑9‑tetrahydrocannabinol (THC), Cannabis, Marijuana, DNA methylation, Prenatal substance use
*Correspondence:
Lyndsey E. Shorey‑Kendrick
shorey@ohsu.edu
Full list of author information is available at the end of the article


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Non-small cell lung cancers \(NSCLCs\) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors


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ARTICLE
OPEN
Non-small cell lung cancers (NSCLCs) oncolysis using
coxsackievirus B5 and synergistic DNA-damage response
inhibitors
Bopei Cui1,2, Lifang Song1,2, Qian Wang1, Kelei Li1,3, Qian He1, Xing Wu1, Fan Gao1, Mingchen Liu1, Chaoqiang An1,3, Qiushuang Gao1,
Chaoying Hu1, Xiaotian Hao1, Fangyu Dong1,4, Jiuyue Zhou4, Dong Liu1,5, Ziyang Song1,6, Xujia Yan1,5, Jialu Zhang1, Yu Bai1,
Qunying Mao1✉, Xiaoming Yang
2,7✉ and Zhenglun Liang1✉
With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising
tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy.
Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of
some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/
Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing
apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated
protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection
triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded
DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting
exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and
inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by
ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred.


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Conclusively, our study identiﬁes an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a
potential therapy for NSCLCs.
Signal Transduction and Targeted Therapy  (2023) 8:366 
; https://doi.org/10.1038/s41392-023-01603-4
INTRODUCTION
The disability-adjusted life years of tumors were approximately
105 million years globally in 2019.1 Currently, immunotherapy is a
hot spot for tumor treatment because of its targeting and security,
including
chimeric
antigen
receptor
T-cell
immunotherapy,
immune checkpoint blockade, and oncolytic virus (OV).2 OVs are
natural or genetically-modiﬁed viruses that can only recognize
and lyse tumor cells, but cannot mire normal cells.3 For instance,
T-vec was constructed to treat melanoma and was approved by
the FDA in 2015.4 Moreover, many types of OVs, including DNA
and RNA viruses, are in the research stage.5
The targeting and potency of an OV depend on many aspects.
On the one hand, it relies on the expression of speciﬁc receptors
on tumors but not on normal cells. However, signaling pathways
can assist or compromise this effect. Furthermore, neutralizing
antibody levels at baseline or primed by OV causes concerns of a
limited “one shot” approach.6,7 Therefore, OV is required to be low
seroprevalent and its deﬁnite receptor and oncolytic mechanism
should be determined.
Recently, oncolytic enteroviruses have been reported to exert an
oncolytic effect on tumor cells in a receptor-dependent manner,
including coxsackievirus A21 (CV-A21), Coxsackievirus B3 (CV-B3), and
Echovirus 7.8–11 For CV-A21, melanoma is the most sensitive cell type
which is highly prevalent in Europe and America, and a phase II
clinical trial has been launched.8,12 Enteroviruses appear to be a safer
modality that replicates in the host cytosol without a DNA phase. As
a result, they are unlike a DNA virus and lack the genotoxicity caused
by the integration of the viral genome into the host DNA.13
Enteroviruses can utilize the internal ribosome entry site to conduct


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cap-independent translation.14 They can replicate rapidly, activate
inﬂammatory responses, upregulate the expression of cytokines and
chemokines, and induce anti-tumor immune responses. However,
enteroviruses are the main pathogens causing hand-foot-and-mouth
disease (HFMD) in infants and children, including Enterovirus A71,
Coxsackievirus A16, Coxsackievirus A6, Coxsackievirus A10, CV-B3,
Coxsackievirus B5 (CV-B5), Echovirus 30, and Echovirus 25, with a
relatively high seroprevalence, which may be an obstacle in its
application.15 Moreover, these common types of tumors in Asia,
Received: 10 January 2023 Revised: 18 July 2023 Accepted: 14 August 2023
1Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research
and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China; 2National Engineering Technology Research
Center for Combined Vaccines, Wuhan, China; 3Beijing Minhai Biotechnology Co., Ltd, Beijing, China; 4Taibang Biologic Group, Beijing, China; 5Changchun Institute of Biological
Products Co., Ltd, Changchun, China; 6Shanghai Institute of Biological Products Co., Ltd, Shanghai, China and 7China National Biotec Group Company Limited, Beijing, China
Correspondence: Qunying Mao (maoqunying@126.com) or Xiaoming Yang (yangxiaoming@sinopharm.com) or Zhenglun Liang (lzhenglun@126.com)
These authors contributed equally: Bopei Cui, Lifang Song
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
1234567890();,:


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exosomebased_regimen_rescues_endometrial_fibrosis_in_intrauterine_adhesions_via_targeting_clinical_fibrosis_biomarkers


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Stem Cells Translational Medicine, 2023, 12, 154–168
https://doi.org/10.1093/stcltm/szad007
Advance access publication 8 March 2023
Original Research
Received: 21 August 2022; Accepted: 17 January 2023.
© The Author(s) 2023. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For 
commercial re-use, please contact journals.permissions@oup.com.
Exosome-Based Regimen Rescues Endometrial Fibrosis 
in Intrauterine Adhesions Via Targeting Clinical Fibrosis 
Biomarkers
Yifeng Lin1,‡, Yaoshen Li2,‡, Panpan Chen1,‡, Yanye Zhang3, Jiwei Sun3, Xiao Sun3, Jiaqun Li3, 
Jiani Jin3, Jinglei Xue3, Junyan Zheng3, Xin-Chi Jiang2,4, Chuan Chen3, Xiaoqing Li3, Yiqing Wu3, 
Wei Zhao3, Juan Liu3, Xiaohang Ye3, Runju Zhang*,1,3, Jianqing Gao*,2,4,5,
, Dan Zhang*,1,3,
1Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang 
University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China
2Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China
3Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, 
Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China
4Dr Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, People’s Republic of China
5Jinhua Institute of Zhejiang University, Jinhua, People’s Republic of China
*Corresponding author: Dan Zhang, PhD, Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology,


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Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310006, People’s Republic of China. Email: zhangdan@zju.edu.cn; 
or, Jianqing Gao, PhD, Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province 310058, People’s 
Republic of China. Email: gaojianqing@zju.edu.cn; or, Runju Zhang, PhD, Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of 
Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310006, People’s Republic of China. 
Email: 5311005@zju.edu.cn
‡Contributed equally as co-first authors.
Abstract 
Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility 
globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endo-
metrium of IUA patients. Mesenchymal stem cell–derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis 
diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, 
herein, we reported an exosome–based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently 
promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and 
COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides 
the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery 
system in IUA patients.
Key words: intrauterine adhesions; endometrial fibrosis; fibrosis biomarkers; exosomes; poloxamer hydrogel.


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association_between_inflammatory_bowel_diseases_and_parkinsons_disease_systematic_review_and_metaanalysis


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344  ｜NEURAL REGENERATION RESEARCH｜Vol 17｜No. 2｜February 2022
Association between inflammatory bowel diseases 
and Parkinson’s disease: systematic review and 
meta-analysis
Yu Zhu#, Min Yuan#, Yue Liu, Fang Yang, Wen-Zhi Chen, Zhen-Zhen Xu, 
Zheng-Bing Xiang*, Ren-Shi Xu*
Abstract  
Growing evidence suggests that there are similar pathological mechanisms and closely 
related pathogenic risk factors for inflammatory bowel disease (IBD) and Parkinson’s 
disease (PD). However, the epidemiological features of these two diseases are different. 
This review systematically evaluated the relationship between inflammatory bowel diseases 
and Parkinson’s disease risk. We searched PubMed, Embase, and Cochrane databases to 
retrieve observational studies of IBD and PD published from inception to October 2019. 
Nine observational studies, involving 12,177,520 patients, were included in the final 
analysis. None of the studies had Newcastle–Ottawa Scale scores that suggested a high 
risk of bias. After adjusting for confounders and excluding heterogeneous studies, the 
overall risk of PD was significantly higher in IBD patients than in the general population 
(adjusted risk ratio [RR] = 1.24, 95% confidence interval [CI]: 1.15–1.34, P < 0.001). A meta-
analysis of the temporal relationship revealed that the incidence of IBD was significantly 
increased before (adjusted hazard ratio [HR] = 1.26, 95% CI: 1.18–1.35, P < 0.001) and 
after (adjusted RR = 1.40, 95% CI: 1.20–1.80, P < 0.001) PD diagnosis. After excluding a 
heterogeneous study, the pooled risk of PD development in patients with ulcerative colitis 
(adjusted HR = 1.25, 95% CI: 1.13–1.38, P < 0.001) or Crohn’s disease (adjusted HR = 
1.33, 95% CI: 1.21–1.45, P < 0.01) was significantly increased. Subgroup analysis revealed 
no significant differences in risk between men (adjusted HR = 1.23, 95% CI: 1.10–1.39) 
and women (adjusted HR = 1.26, 95% CI: 1.10–1.43); however, older (> 65 years old) IBD


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patients (adjusted HR = 1.32, 95% CI: 1.17–1.48) may have a higher risk than younger (≤ 65 
years old) patients (adjusted HR = 1.24, 95% CI: 1.08–1.42). Patients with IBD who were not 
treated with anti-tumor necrosis factor-α or azathioprine had significantly higher PD risk 
(adjusted HR = 1.6, 95% CI: 1.2–2.2). Thus, our meta-analysis indicates a certain correlation 
between IBD and PD, and suggests that IBD may moderately increase PD risk regardless of 
sex, especially in patients over 65 years of age. Moreover, early anti-inflammatory therapies 
for IBD might reduce the risk of developing PD. Our findings suggest an urgent need for 
an individualized screening strategy for patients with IBD. However, most studies included 
in this paper were observational, and more randomized controlled trials are needed to 
confirm the precise association between IBD and PD.
Key Words: brain-gut axis; central nervous system; Crohn’s disease; inflammatory bowel 
diseases; meta-analysis; neurodegenerative disease; neuroinflammation; Parkinson’s 
disease; systematic review; ulcerative colitis 
Chinese Library Classification No. R452; R574; R741.04
https://doi.org/10.4103/1673-5374.317981
Date of submission: October 9, 2020 
Date of decision: October 13, 2020 
Date of acceptance: November 13, 2020 
Date of web publication: July 8, 2021 
Introduction 
Pa r k i n s o n ’s  d i s e a s e  ( P D )  i s  t h e  m o st  co m m o n 
neurodegenerative motor disorder (Park et al., 2020; Thomas 
Broome et al., 2020), with symptoms that include resting 
tremor, dyskinesia, ankylosis, and postural instability. Non-
motor symptoms (e.g., dementia, depression, and sleep 
disorders) also occur, and can arise even before a motor 
diagnosis is made. The pathology of PD is associated with a 
profound loss of dopaminergic neurons in the substantia nigra 
pars compacta, which is accompanied by filamentous protein 
inclusions, termed Lewy bodies, in the surviving neurons. 
Lewy bodies are mainly composed of alpha-synuclein (α-syn),


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and these inclusions are the hallmark pathological feature 
of PD. However, their pathogenic relevance remains under 
debate (Kalinderi et al., 2016; Obergasteiger et al., 2018). 
Much evidence suggests that PD pathology starts from chronic 
low-level inflammation in the gastrointestinal tract, thus 
inducing misfolded α-syn, which then propagates to the brain 
via a dysfunctional blood-brain barrier (BBB) or the vagus 
nerve. This has been widely investigated in studies regarding 
the association between PD and alterations of the intestinal 
environment (Houser and Tansey, 2017; Lionnet et al., 2018; 
Spielman et al., 2018).
Department of Neurology, Jiangxi Provincial People’s Hospital, Affiliated People’s Hospital of Nanchang University, Nanchang, Jiangxi Province, China
*Correspondence to: Ren-Shi Xu, MD, PhD, 13767015770@163.com; Zheng-Bing Xiang, MD, xzbshawn@163.com.
https://orcid.org/0000-0003-0313-3434 (Ren-Shi Xu); https://orcid.org/0000-0001-9003-0489 (Zheng-Bing Xiang)
#Both authors contributed equally to this work.
How to cite this article: Zhu Y, Yuan M, Liu Y, Yang F, Chen WZ, Xu ZZ, Xiang ZB, Xu RS (2022) Association between inflammatory bowel diseases and Parkinson’s 
disease: systematic review and meta-analysis. Neural Regen Res 17(2):344-353. 
Research Article


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Annals of the Rheumatic Diseases, 1978, 37, 225-233
Type C oncornavirus isolation studies in systemic
lupus erythematosus
II. Attempted detection by viral RNA-dependent DNA polymerase assay
PAUL E. PHILLIPS AND RITA HARGRAVE-GRANDA
From the Department ofMedicine, The Hospitalfor Special Surgery, New York Hospitaland Cornell University
Medical College, 535 East 70th Street, New York, NY 10021, USA
SUMMARY
Isolation of type C oncornavirus was attempted from 20 tissues and cell cultures of
patients with systemic lupus erythematosus. Chemical inducers, cocultivation and fusion with cells
from multiple other species, prolonged subculturing, and the RNA-dependent DNA polymerase
assay for virus detection were used. A type C virus was isolated, but was shown to be the endogenous
rat virus. Thus the methods, although generally appropriate, were not specifically permissive for
replication of a human type C virus. This agrees with the failure of other investigators to isolate a
virus of undisputed human origin. Combining available evidence, a fundamental role for type C
viruses in lupus erythematosus remains an attractive hypothesis.
It has been postulated that viruses are involved in the
pathogenesis of systemic lupus erythematosus (SLE)
(reviewed in Phillips and Christian, 1978). Particular
interest has been shown in type C oncornaviruses
because of their role in the animal model of SLE,
New Zealand (NZ) mouse disease (Yoshiki et al.,
1974; Levy et al., 1975). However, the evidence is
conflicting as to whether type C expression is en-
hanced, similar, or absent in SLE patients compared
with other humans (Markenson and Phillips, 1978).
Our earlier study failed to isolate type C, or other
RNA viruses, or mycoplasma from SLE cell cultures
and tissues (Phillips et al., 1976). In this study we
used more sensitive methods previously successful in
isolating type C virsuses from other species, and the
RNA-dependent DNA polymerase (RDDP) assay
for virus detection.
Materials and methods
PATIENTS
We studied


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13 patients with SLE (Cases
1-13,
Table 1) according to the American Rheumatism
Association criteria (Cohen et al., 1971) and 6 with
probable or possible SLE (Cases 14-19). All were
female, aged 15-65 years (mean 33 0 years), and had
Accepted foi publication September 22, 1977
Correspondence to Dr P. E. Phillips
been ill for 0-5-15 years (mean 6 7 years). 7 had
clinically active disease and 12 were receiving pred-
nisone, 1-60 mg daily (mean 27-0 mg); 5 were
receiving
immunosuppressive
drugs.
20
tissues
(Table 1) were studied. Cases 1-5 had also been
tested previously (Cases 2, 3, 5, 6, 7 respectively in
Phillips et al., 1976).
CELL CULTURES
SLE tissues were obtained and the cells cultured as
described (Phillips et al., 1976) except for tissues
from Cases 8 and 17, which were frozen at -70°C
until testing.
31 experiments were done: 5 with
frozen tissue homogenates, the remainder with SLE
cells periodically subcultured for up to 18 months
before testing (6 tested immediately or cultured for
<1 month, 8 cultured for 1-6 months, 7 for 6-12
months, and 5 for 12-18 months; Table 1).
For virus isolation, 6 cell lines from heterologous
species were used: rabbit cornea (SIRC; CCL 60,
American Type Culture Collection, Rockville, MD),
mink lung (Mv 1 Lu; CCL 64), bat lung (Tb 1 Lu;
CCL 88), horse skin (E. Derm.; CCL 57), fetal
rhesus monkey lung (DBS-FRhL-1; from Dr J. C.
Petricciani, Food and Drug Administration, Rock-
ville, MD), and
Harvey
murine sarcoma virus-
transformed
nonvirus-producing
rat
kidney
(H-NRK; from Dr T.
Pincus,
Memorial-Sloan
225


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Annals of the Rheumatic Diseases, 1978, 37, 476-478
Case Report
Systemic lupus erythematosus, repeated abortions, and
thrombocytopenia
M. H. PRITCHARD,
J. D. JESSOP, P. M. TRENCHARD, AND
J. A. WHITTAKER
From the Departments ofRheumatology and Haematology, University Hospital of Wales, Heath Park, Cardiff
SUMMARY A case is described of severe thrombocytopenia in a pregnant patient with mild SLE.
Three previous pregnancies had ended in abortion. Attempts to reverse the thrombocytopenia
with steroids, plasmapheresis, and splenectomy failed, the platelet count returning to normal
immediately after the death of the fetus at 20 weeks gestation.
It is known that patients suffering from systemic
lupus erythematosus (SLE) may show a deterioration
in their disease during pregnancy, and that spontan-
eous abortions are frequent (Grigor et al., 1977).
This report describes a case in which for several
years the only significant symptom of SLE was mild
thrombocytopenia;
however,
during
this time 4
pregnancies ended in spontaneous abortion, and 2
of these were complicated by severe, potentially life
threatening thrombocytopenia.
History
The patient is a 31-year old woman. She gave a
history of 3 previous pregnancies in 1970, 1971, and
1975 all of which ended in spontaneous abortion
between 18 and 24 weeks. The second pregnancy
was
complicated
by
episodes
of
purpura
and
thrombocytopenia with platelet counts of around
20 x
109/l. These responded to oral prednisone.
The platelet counts did not fall significantly during
the first and third pregnancies.
When first seen in Cardiff in December 1973,
SLE had already been diagnosed on the basis of a
positive anti-nuclear factor and a DNA binding of
70%. She had been prescribed 10 mg prednisone
on alternate days with 100 mg azathioprine daily.
The latter was stopped without any ill effects, and her
only symptoms were occasional attacks of arthralgia.
Her platelet count varied between 70 and 140 x 109/l
with occasional episodes of mild purpura.


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She was admitted to hospital in January 1977,
Accepted for publication January 25, 1978
during the 14th week of her fourth pregnancy, at
the request of her obstetrician, because of a steadily
deteriorating thrombocytopenia, which had failed
to respond to raising the prednisone dose to 80 mg
daily. On admission she was found to be in excellent
physical health, there was no bruising, purpura or
bleeding from any source in spite of a platelet count
of 20 x 109/l. It appeared from her notes that the
platelet count 3 weeks earlier had been in the region
of 200 x 109/l, but had shown a steady decline since
then, in spite of massive increases in steroid dosage.
The fetus was
alive, according
to the Sonicaid
findings.
Investigations and management
Investigations showed a haemaglobin (Hb) of 15.2
g/dl, normal urea, electrolytes and liver function
tests, ESR 13 mm/h, DAT 1/32 and an active bone
marrow
with
abundant
megakaryocytes.
Com-
plement studies showed low CH50, C. and C4 but
normal factor B. Complement fixing platelet anti-
bodies were also found (Fig. 1) although, no cryo-
precipitate or anticomplementary activity could be
detected at any time.
The chances of a successful pregnancy in the
presence
of
severe thrombocytopenia
and
high
steroid dosage were considered to be very small.
Two further methods were therefore proposed to
reverse the thrombocytopenia; plasmapheresis to
remove the platelet autoantibodies and splenectomy.
Plasmapheresis was tried first, as it has been success-
fully used in pregnancy for the removal of anti-
Rhesus antibodies with no ill effects on the fetus
476


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Annals of the Rheumatic Diseases, 1979, 38, 507-513
Viruses and lymphocytes in rheumatoid arthritis.
I. Studies on cultured rheumatoid lymphocytes
MARY NORVAL, HELENA HART, AND B. P. MARMION
From the Department ofBacteriology, University ofEdinburgh Medical School, Edinburgh
SUMMARY
Synovial fluid lymphocytes from patients with rheumatoid arthritis have been examined
for evidence of a productive infection with retroviruses by electron microscopy, labelling with
3H-uridine, growth in soft agar, and culturing in conditioned medium. No such viruses were detected.
In addition, the synovial lymphocytes were activated before fusion and cocultivation with several cell
lines which have proved permissive for primate retroviruses. Monitoring these cultures subsequently
by reverse transcriptase assay, labelling with 3H-uridine, and membrane immunofluorescence gave
no indication that retroviruses were present.
A possible viral aetiology for rheumatoid arthritis
(RA) has been much canvassed and investigated
during the last 10 years but with negative results so
far. Much of the search has concentrated on the
fibroblast-like cells cultured from the RA synovial
membrane or synovial fluid effusions and thought
to be derived from type B or C lining cells (Smith
and Hamerman,
1969). However,
there
is
little
evidence for viral genomes, productive viral in-
fection, or neoantigens in such cells. For summaries
and reviews see Hamerman (1975), Marmion and
Mackay (1977), and Marmion (in press).
Less attention has been paid in RA to the possible
production of disease as a result of the interaction
of virus with cells of the immune and immuno-
regulatory system (Denman,
1975;
Talal,
1977;
Marmion and Mackay, 1977; Marmion, in press).
Reports on the relative proportion and classes of
lymphocytes
in
rheumatoid
synovial
fluid
and
peripheral blood vary. Several investigations record
an increase in T-cell numbers, a decrease in B-cell
numbers (Froland et al., 1973; Holborow et al.,
1975), and the presence of a population of null cells,


