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up to 32% (Winchester et al., 1974). Others have
found an increase in B-cells (Mellbye et al., 1972).
The lymphocytes in RA synovial membranes, as
distinct from the synovial fluid, are predominantly
T-cells (Loewi, 1975).
There may be a marked diminution in responsive-
ness of synovial lymphocytes of RA patients to
Accepted for publication 19 December 1978.
Correspondence
to
Dr
Mary
Norval,
Department
of
Bacteriology,
University
of Edinburgh
Medical
School,
Teviot Place, Edinburgh EH8 9AG.
various mitogens,
especially PHA (Stratton and
Peter, 1972; Panayi, 1973; Holborow et al., 1975)
but reports are not consistent. Also the reactivity of
peripheral blood lymphocytes in mixed lumphocyte
culture may be depressed (Astorga and Williams,
1969). It is possible that the cells may already be
activated or that the receptor sites for the antigen
may be blocked; such effects might be virally induced.
In view of these pointers to disordered lymphocyte
function
in RA we decided
to
investigate RA
synovial and
peripheral
blood lymphocytes
for
evidence of viral infection or of viral gene products.
We were particularly interested in the association of
retroviruses (type C or oncoviruses) with lympho-
cytes. This interaction has been well studied in
various mice strains in which the immune response
to endogenous viruses is modified by genetic factors
involved with infectivity and expression (review,
Ihle and Hanna, 1977). In human beings there have
been
extensive
attempts
to
detect
retroviruses,
especially in association with leukaemia or lym-
phoma. Several isolations have been made, one of
which was from cultured myeloid leukaemia cells.
This virus was closely related to simian sarcoma
virus and baboon endogenous virus (Reitz et al.,
1976), and it can be established as a chronic in-
fection in various cell lines (Teich et al., 1975).
A range of different cell-virus relationships exists
with retroviruses and extends from productive in-
fection to an integrated 'silent' genome. In addition


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some viruses are unable to replicate in cells of the
same species from which they have been derived
(xenotropic viruses). During the course of this study
we used methods described by other workers for
507


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Characterization of an air-liquid interface primary human vaginal epithelium to study Ebola virus infection and testing of antiv\
irals


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Characterization of an air-liquid interface primary human vaginal 
epithelium to study Ebola virus infection and testing of antivirals
Olivier Escaffrea,c,*, Vsevolod Popova,b,c, Eldridge Hagera, Alexander N. Freiberga,b,c,**
aDepartment of Pathology, USA
bCenter for Biodefense and Emerging Infectious Diseases, USA
cInstitute for Human Infections & Immunity and Sealy & Smith Foundation, University of Texas 
Medical Branch, Galveston, TX, 77555, USA
Abstract
Ebola virus (EBOV) is the causative agent of the often-fatal Ebola virus disease (EVD) 
characterized by hemorrhagic fever in humans and non-human primates. Sexual transmission 
from male survivors has been at the origin of multiple outbreak flare-ups between 2015 and 
2021. However, this route is still poorly understood and the resulting EVD from it is also 
understudied. To support epidemiological studies documenting sexual transmission to women, 
and as a transition from previously using monolayer vaginal epithelial cells (VK2/E6E7), we 
first determined the biological relevance of two similar air-liquid interface models of the human 
vaginal epithelium (VEC and VLC Epivaginal™) and then characterized their susceptibility 
to EBOV and virus-induced inflammation. Finally, we evaluated toxicity of Polyphenylene 
Carboxymethylene (PPCM) microbicide in VLC and reassessed its antiviral effect.
As expected, the VEC, but also VLC model showed stratified layers including a lamina propria 
under an epithelial structure similar to the full thickness of the human vaginal epithelium. 
However, we could not detect the immune cells featured in the most relevant model (VLC) of 
the vaginal epithelium using the dendritic cell CD1a and CD11c markers. Consistent with our 
previous work using the VK2/E6E7 cell line, infectious virus was detected from the apical side 
of both primary human cell systems, but only when using a high infective dose, with titers 
remaining at a constant level of 103–4 pfu/ml over 7 days suggesting lasting infectious virus


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shedding. In addition, infection caused disruption of the epithelium of both models and virus 
antigen was found from the apical superficial layers down to the lamina propria suggesting full 
virus penetration and overall confirming the susceptibility of the human vaginal tissue for EBOV. 
Just like previously seen in VK2/E6E7 cells, VLC infection also caused significant increase 
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
*Corresponding author. Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 
77555-0609, USA. olescaff@utmb.edu (O. Escaffre). **Corresponding author. Department of Pathology, University of Texas Medical 
Branch, 301 University Boulevard, Galveston, TX, 77555-0609, USA. anfreibe@utmb.edu (A.N. Freiberg). 
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to 
influence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.antiviral.2023.105551.
HHS Public Access
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Antiviral Res. Author manuscript; available in PMC 2023 June 22.
Published in final edited form as:
Antiviral Res. 2023 March ; 211: 105551. doi:10.1016/j.antiviral.2023.105551.
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Omnipresence of the sensorimotor-association axis topography 
in the human connectome
Karl-Heinz Nenninga,*, Ting Xub, Alexandre R. Francoa,b,f, Khena M. Swallowc, Arielle 
Tambinia,f, Daniel S. Marguliesd, Jonathan Smallwoode, Stanley J. Colcombea,f, Michael 
P. Milhama,b
aNathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, United States
bChild Mind Institute, New York, NY, United States
cCornell University, Ithaca, NY, United States
dCNRS and Université de Paris, Paris, France
eQueen’s University, Kingston, Ontario, Canada
fNew York University, New York, NY, United States
Abstract
Low-dimensional representations are increasingly used to study meaningful organizational 
principles within the human brain. Most notably, the sensorimotor-association axis consistently 
explains the most variance in the human connectome as its so-called principal gradient, 
suggesting that it represents a fundamental organizational principle. While recent work indicates 
these low dimensional representations are relatively robust, they are limited by modeling 
only certain aspects of the functional connectivity structure. To date, the majority of studies 
have restricted these approaches to the strongest connections in the brain, treating weaker 
or negative connections as noise despite evidence of meaningful structure among them. The 
present work examines connectivity gradients of the human connectome across a full range 
of connectivity strengths and explores the implications for outcomes of individual differences, 
identifying potential dependencies on thresholds and opportunities to improve prediction tasks. 
Interestingly, the sensorimotor-association axis emerged as the principal gradient of the human 
connectome across the entire range of connectivity levels. Moreover, the principal gradient of 
connections at intermediate strengths encoded individual differences, better followed individual-
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)


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*Corresponding author. karl-heinz.nenning@nki.rfmh.org (K.-H. Nenning). 
Declaration of Competing Interest None.
Credit authorship contribution statement
Karl-Heinz Nenning: Conceptualization, Formal analysis, Methodology, Software, Visualization, Writing – original draft, Writing – 
review & editing. Ting Xu: Conceptualization, Methodology, Writing – review & editing. Alexandre R. Franco: Resources, Writing 
– review & editing. Khena M. Swallow: Writing – review & editing. Arielle Tambini: Writing – review & editing. Daniel S. 
Margulies: Writing – review & editing. Jonathan Smallwood: Writing – review & editing. Stanley J. Colcombe: Conceptualization, 
Funding acquisition, Resources, Writing – review & editing. Michael P. Milham: Conceptualization, Funding acquisition, Resources, 
Writing – review & editing.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.neuroimage.2023.120059.
HHS Public Access
Author manuscript
Neuroimage. Author manuscript; available in PMC 2023 June 22.
Published in final edited form as:
Neuroimage. 2023 May 15; 272: 120059. doi:10.1016/j.neuroimage.2023.120059.
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Annals of the Rheumatic Diseases 1989; 48: 958-961
Hypothesis
Osteoarthritis: The cause not result of joint failure?
Osteoarthritis is an enigmatic condition as it is at
once simple and complex. It seems simple as trauma
is sufficient to produce its major features, but it
becomes complex when we try to understand both
'primary' osteoarthritis and why the processes that
are features of osteoarthritis develop. An enormous
amount of information is available on the epidemi-
ology, clinical picture, pathology, and biochemistry
of osteoarthritis, but the problem
is to see the
patterns linking that information. Observation has
established a set of features of osteoarthritis that any
satisfactory hypothesis needs to explain.
Osteoarthritis is characterised by joint destruction
with cartilage loss and occasional gross derange-
ment of the
joint's
integrity. 1
Osteoarthritis
is
homogeneous, ubiquitous, and related to age.2 3
The anatomical, histological, and biochemical fea-
tures are present and constant to a remarkable
degree in osteoarthritis at different sites and in
different animals and animal models, though they
may
vary
quantitatively.
Paradoxically
also,
although osteoarthritis shows extraordinary diver-
sity, it is heterogeneous, and this is shown in its
aetiology.
Joint
insult of almost any kind may
produce osteoarthritis. Cartilage abnormality from
amino acid metabolism in ochronosis, trauma, and
pre-existing
inflammatory
osteoarthritis may
all
produce this seemingly common pathway of a joint
reacting to 'failure'. The clinical picture, pathology,
and natural history are also very varied."4
Osteoarthritis has a characteristic joint distribu-
tion that is both spatial and temporal. Joints that are
frequently involved
include
the
first
metatarso-
phalangeal,
first
carpometacarpal,
distal
inter-
phalangeal, knee, and the apophyseal joints of the
spine
at the thoracolumbar and thoracocervical
junctions. Conversely, others, such as the wrist,
elbow, shoulder, ankle, and tarsal joints, are rarely


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involved. Usually the features are seen first at the
metatarsophalangeal joint, and the sequence
of
involvement reflects the common site distribution.2 5
Remarkably, osteoarthritis is an anabolic as well
as a destructive process. Bone sclerosis, capsular
fibrosis, and osteophyte formation are the result of
active turn on of systems producing tissue growth.
The biochemistry of experimental osteoarthritis and
of pathological specimens reflects this anabolism
in an increase
in
cell activity and proteoglycan
turnover.7 8 More remarkably, the proteoglycans
are qualitatively different from those produced with
aging; they are similar to the profile of 'juvenile'
young cartilage.9-i
Finally, to make the whole process seem totally
contradictory some of its features may occur in
isolation. Fibrillation of cartilage and 'age related
osteophytes', which are features of osteoarthritis,
may occur alone.i 12
Can a hypothesis be constructed to link these
features? The primary approach is to see osteo-
arthritis as joint failure. If the joint is considered as
a mechanical system, which it is, this allows an
analogy with man-made machines. Joint failure is
thus a function of use, material, and design, and this
concept goes some way towards explaining the
observed features. The heterogeneity reflects the
multiple combinations of factors that interact to
produce the osteoarthritic process. The distribution
and age association reflect underdesign of joints. i3
The homogeneity results from the triggering of the
same
final common pathway,
the
osteoarthritic
process itself 6 (Fig. 1), and the anabolic response is
then seen as an attempt at repair. i4 15
The model though is not sufficient as it does not
explain the nature of the anabolic response or why
some features like osteophytes occur in isolation. It
also gives no explanation for primary osteoarthritis.
Is it simply that the aetiological factors are unidenti-
fied, or could the process develop in some other
way? Possibly the process is a result of the failure of


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the normal maintenance of the joint-that is, a
failure of remodelling.'6 17 This concept can be
taken further; rather than the process being driven
Multiple aetiological factors
Joint malfunction
Osteoarthritic response
Joint failure
Fig.
1
The osteoarthritic process.
958


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Advances toward precision medicine for bipolar disorder: 
mechanisms & molecules
Stephen J. Haggarty1, Rakesh Karmacharya2,3, Roy H. Perlis4
(1)Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General 
Hospital, Departments of Psychiatry & Neurology, Harvard Medical School, Boston, USA
(2)Center for Genomic Medicine, Massachusetts General Hospital, Department of Psychiatry, 
Harvard Medical School Boston, Boston, USA
(3)Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, USA
(4)Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, 
Massachusetts General Hospital, Harvard Medical School, Boston, USA
Abstract
Given its chronicity, contribution to disability and morbidity, and prevalence of more than 2%, 
the effective treatment, and prevention of bipolar disorder represents an area of significant 
unmet medical need. While more than half a century has passed since the introduction of 
lithium into widespread use at the birth of modern psychopharmacology, that medication 
remains a mainstay for the acute treatment and prevention of recurrent mania/hypomania and 
depression that characterize bipolar disorder. However, the continued limited understanding of 
how lithium modulates affective behavior and lack of validated cellular and animal models have 
resulted in obstacles to discovering more effective mood stabilizers with fewer adverse side 
effects. In particular, while there has been progress in developing new pharmacotherapy for 
mania, developing effective treatments for acute bipolar depression remain inadequate. Recent 
large-scale human genetic studies have confirmed the complex, polygenic nature of the risk 
architecture of bipolar disorder, and its overlap with other major neuropsychiatric disorders. Such 
discoveries have begun to shed light on the pathophysiology of bipolar disorder. Coupled with 
broader advances in human neurobiology, neuropharmacology, noninvasive neuromodulation, and


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clinical trial design, we can envision novel therapeutic strategies informed by defined molecular 
mechanisms and neural circuits and targeted to the root cause of the pathophysiology. Here, we 
review recent advances toward the goal of better treatments for bipolar disorder, and we outline 
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Author manuscript
Mol Psychiatry. Author manuscript; available in PMC 2023 June 24.
Published in final edited form as:
Mol Psychiatry. 2021 January ; 26(1): 168–185. doi:10.1038/s41380-020-0831-4.
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Sex specificity of pancreatic cancer cachexia phenotypes, mechanisms, and treatment in mice and humans: role of Activin


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Sex speciﬁcity of pancreatic cancer cachexia
phenotypes, mechanisms, and treatment in mice and
humans: role of Activin
Xiaoling Zhong1,2, Ashok Narasimhan1, Libbie M. Silverman1, Andrew R. Young1, Saﬁ Shahda3†, Sheng Liu4,5, Jun Wan4,5,6,
Yunlong Liu4,5,6,7, Leonidas G. Koniaris1,2,6,7 & Teresa A. Zimmers1,2,5,6,7*
1Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 2Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA;
3Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; 4Department of Medical and Molecular Genetics, Indiana University School of
Medicine, Indianapolis, IN, USA; 5Center for Computational Biology and Bioinformatics, Indianapolis, IN, USA; 6Indiana University Melvin and Bren Simon Comprehensive
Cancer Center, Indianapolis, IN, USA; 7Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA
Abstract
ORIGINAL ARTICLE
Background
Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma
(PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting
was clinically tested for cancer cachexia therapy. However, sex-speciﬁc manifestations and mechanisms are poorly un-
derstood, constraining development of effective treatments.
Methods
Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc
were assessed in LSL-KrasG12D/+, LSL-Trp53R172H/+, and Pdx-1-Cre (KPC) mice with autochthonic PDAC. Effects of
PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC-cell conditioned medium (CM)
and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients
with PDAC.
Results
Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed
earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior


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muscles were reduced (21.7%, 18.9%, and 20.8%, respectively, all P < 0.001), with only gastrocnemius reduced
in females (16%, P < 0.01). Sex differences disappeared in late PDAC. Plasma Activin A was similarly elevated be-
tween sexes throughout, while oestrogen and testosterone levels suggested a virilizing effect of PDAC in females. Estra-
diol partially protected myotubes from KPC-CM induced atrophy and promoted expression of the potential Activin in-
hibitor Fstl1. Early-stage female mice showed greater muscle expression of Activin inhibitors Fst, Fstl1, and Fstl3; this
sex difference disappeared by late-stage PDAC. ACVR2B/Fc initiated in early PDAC preserved muscle and fat only in
male KPC mice, with increases of 41.2%, 52.6%, 39.3%, and 348.8%, respectively, in gastrocnemius, quadriceps,
tibialis, and fat pad weights vs. vehicle controls, without effect on tumour. No protection was observed in females.
At protein and RNA levels, pro-atrophy pathways were induced more strongly in early-stage males, with sex differences
less evident in late-stage disease. As with mass, ACVR2B/Fc blunted atrophy-associated pathways only in males. In pa-
tients with resectable PDAC, muscle expression of Activin inhibitors FSTL1, FSLT3, and WFIKKN2/GASP2 were higher
in women than men. Overall, among 124 patients on ﬁrst-line gemcitabine/nab-paclitaxel for PDAC, only men
displayed muscle loss (P < 0.001); average muscle wasting in men was greater (6.63 ± 10.70% vs.
1.62 ± 12.00% mean ± SD, P = 0.038) and more rapid (0.0098 ± 0.0742%/day vs. 0.0466 ± 0.1066%/day,
P = 0.017) than in women.
Conclusions
Pancreatic ductal adenocarcinoma cachexia displays sex-speciﬁc phenotypes in mice and humans, with
Activin a preferential driver of muscle wasting in males. Sex is a major modulator of cachexia mechanisms. Consider-
ation of sexual dimorphism is essential for discovery and development of effective treatments.


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© 2022 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 2022; 13: 2146–2161
Published online 5 May 2022 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jcsm.12998


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Rift Valley fever in animals and humans: Current perspectives
Cynthia M. McMillen,
Amy L. Hartman*
Center for Vaccine Research, Department of Infectious Diseases and Microbiology, University of 
Pittsburgh Graduate School of Public Health, USA
Abstract
Rift Valley fever (RVF) is an ecologically complex emerging arboviral disease that causes 
significant illness in both livestock and people. This review article is designed to assist the 
reader in understanding the varied aspects of RVF disease in animals and humans. The historical 
facets of RVF disease, including the evolution of human outbreaks, are presented and discussed. 
The different clinical presentations of human RVF disease and the underlying causes are then 
addressed. We explore the exposure and transmission potential of RVF in animals and people. In 
the concluding section, we discuss the historical role of RVF as a biological weapon. We conclude 
with an outline of the important unanswered questions for ongoing research into this important 
zoonotic disease.
1. Introduction
Rift Valley fever (RVF) is a veterinary disease of livestock in Africa, and as such it 
exemplifies the One Health concept, in which animal and human health are inextricably 
intertwined. Infection of domesticated livestock (sheep, cattle, and goats) with RVF virus 
(RVFV) causes a highly lethal illness that results in dire economic consequences in affected 
regions. Initially a disease of the Rift Valley in eastern Africa, RVFV has spread through 
continental Africa as well as to Madagascar and the Arabian Peninsula. The World Health 
Organization (WHO)’s first Workshop on Prioritization of Pathogens assigned RVF to the 
list of “severe emerging diseases with potential to generate a public health emergency, 
and for which no, or insufficient, preventive and curative solutions exist” (World Health 
Organization, 2015, 2017). RVF remains on the World Organization for Animal Health 
(OIE)’s list of notifiable animal diseases of concern World Organization for Animal Health


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(OIE), 2018. Veterinary and human vaccination strategies and development of therapeutic 
interventions are the key to limiting spread and alleviating disease burden. Both have 
recently been comprehensively reviewed (Dungu et al., 2018; Atkins and Freiberg, 2017) 
and are not discussed here. Instead, this review article is designed to assist laboratory 
researchers, clinicians, and public health practitioners in understanding the manifold aspects 
of RVF disease in animals and humans. We first provide a historical perspective on the 
*Corresponding author. 8038 Biomedical Science Tower 3, 3501 Fifth Ave, Pittsburgh, PA 15213, USA. Hartman2@pitt.edu (A.L. 
Hartman). 
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.antiviral.2018.05.009.
HHS Public Access
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Antiviral Res. Author manuscript; available in PMC 2023 July 03.
Published in final edited form as:
Antiviral Res. 2018 August ; 156: 29–37. doi:10.1016/j.antiviral.2018.05.009.
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Risk of Hepatocellular Carcinoma After Spontaneous Clearance of Hepatitis C Virus and in Noncirrhosis Chronic Hepatitis C Patients With Sustained Virological Response: A Systematic Review


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Risk of Hepatocellular Carcinoma After Spontaneous 
Clearance of Hepatitis C Virus and in Noncirrhosis 
Chronic Hepatitis C Patients With Sustained Virological 
Response: A Systematic Review
Christine C. Hsu,1,a Harish Gopalakrishna,1,a Maria Mironova,1 Mei-Hsuan Lee,2 Chien-Jen Chen,3 Hwai-I Yang,3 Manfred Wiese,4,b Kyong-Mi Chang,5,6
Elizabeth C. Wright,7 Tomilowo Abijo,7 Jordan J. Feld,8,9 and David E. Kaplan5,6
1Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA; 2Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei, 
Taiwan; 3Genomics Research Center, Academia Sinica, Taipei, Taiwan; 4Department of Hepatology, University Hospital Leipzig, East German HCV Study Group, Leipzig, Germany; 5Division of 
Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA; 6Division of Gastroenterology and Hepatology, Corporal Michael J. Crescenz VA Medical Center, 
Philadelphia, Pennsylvania, USA; 7Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA; 8Department of Medicine, Division of 
Gastroenterology, Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; and 9Toronto Viral Hepatitis Care Network, Toronto, Canada
In a hepatitis C virus (HCV)–controlled human infection model (CHIM), healthy volunteers are inoculated with HCV and then 
treated. Residual hepatocellular carcinoma (HCC) risk after viral clearance is an important consideration when evaluating the 
CHIM. We estimate HCC risk in spontaneously cleared HCV and in noncirrhosis after sustained virological response (SVR) to 
HCV treatment in a systematic review and using data from 3 cohorts: German anti-D, Taiwan, and US Veterans Affairs (VA). 
For noncirrhosis SVR, the overall HCC rate is 0.33 per 100 patient-years in meta-analysis. HCC rates for the German, Taiwan,


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and US Veterans Affairs cohorts are 0, 0.14, and 0.02 per 100 patient-years, respectively. Past hepatitis B virus exposure was not 
accounted for in the Taiwan cohort, while VA patients were likely tested based on liver disease/risk factors, which may 
confound HCC outcomes. The German cohort with no HCC after 44 years is most comparable to the CHIM participants. 
Although it is difficult to precisely estimate HCC risk from an HCV CHIM, the data suggest the risk to be very low or negligible.
Keywords. hepatocellular carcinoma risk; hepatitis C; noncirrhosis.
aC. C. H. and H. G. contributed equally to this work.
bEast German HCV Study Group members include K. Ende (Erfurt), U. Göbel (Cottbus), 
T. Heuchel (Chemnitz), U. Kullig (Dresden), K. Stein (Magdeburg), M. Wiese (Leipzig), 
S. Wollschläger (Dresden).
Correspondence: Christine C. Hsu, Liver Disease Branch, National Institute of Diabetes and 
Digestive and Kidney Diseases, 10 Center Drive, 10N248B, Bethesda, MD 20892 (christine. 
hsu@nih.gov ). J. Feld, Toronto Centre for Liver Disease (TCLD), Francis Family Liver Clinic, 
Department of Medicine, Division of Gastroenterology, Toronto General Hospital, 9EN-225, 
200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada (jordan.feld@uhn.ca).
Clinical Infectious Diseases®
2023;77(S3):S245–56 
Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023. 
This work is written by (a) US Government employee(s) and is in the public domain in the US.
https://doi.org/10.1093/cid/ciad380
Hepatitis C virus (HCV) is a single-stranded RNA virus trans-
mitted to humans primarily via direct blood inoculation or trau-
matic percutaneous exposure [1]. About 25%–30% of acutely 
infected individuals spontaneously clear the virus within 6–12 
months of infection, while the majority progress to develop 
chronic HCV infection, after which spontaneous clearance is 
exceedingly rare [2]. Unlike chronic HCV that may cause pro-
gressive liver damage, ultimately leading to cirrhosis, transient


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HCV infection is not associated with persistent liver injury 
or fibrosis. In patients with chronic infection who progress 
to cirrhosis, there is an increased risk of hepatocellular 
carcinoma (HCC), which is reduced but not eliminated with 
treatment-induced sustained virological response (SVR) [3]. 
There is no known risk of HCC after spontaneously resolving 
acute HCV; however, data are limited. Recent studies have 
shown that HCV infection is associated with epigenetic changes 
in the host genome, leading to increased expression of cancer- 
related genes that persist even after viral clearance [4–6]. 
These epigenetic changes were present in acute and chronic in-
fections; they were demonstrated in patients with chronic HCV 
infections (the majority with significant fibrosis or F2-F4 fibro-
sis) but also in in vitro cell culture studies after hepatoma cell 
lines were briefly infected for 1–2 weeks and in primary human 
hepatocytes after shorter durations of infections [4, 6]. 
Epigenetic alterations similar to those seen in cell culture were 
present in an 8-gene risk set associated with HCC in 7 liver bi-
opsy samples from patients with active chronic HCV infection 
and were also present in 4 liver biopsy samples from patients 
cured of HCV with direct-acting antivirals (DAAs), raising con-
cern that HCV infection may lead to a persistent change in cells 
that could predispose to cancer [6]. However, it is notable that 
HCV-related HCC almost exclusively occurs in patients with 
cirrhosis, including in all cases of HCC described by Perez 
and colleagues and by Hamdane and colleagues [4, 6, 7]. It is fea-
sible that the epigenetic changes can lead to pathways involved 
in hepatocarcinogenesis; however, these data suggest that 
Hepatocellular Carcinoma Risk and Hepatitis C • CID 2023:77 (Suppl 3) • S245
Clinical Infectious Diseases                                          
S U P P L E M E N T  A R T I C L E


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Broadly neutralizing humanized SARS-CoV-2 antibody binds to a conserved epitope on Spike and provides antiviral protection through inhalation-based delivery in non-human primates


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RESEARCH ARTICLE
Broadly neutralizing humanized SARS-CoV-2
antibody binds to a conserved epitope on
Spike and provides antiviral protection
through inhalation-based delivery in non-
human primates
Paule HermetID1, Benoıˆt Delache2, Cecile Herate2, Esther Wolf3, Gaily Kivi1,
Erkki Juronen1, Karl Mumm1, Eva Zˇusinaite4, Denis Kainov5, Eve Sankovski1,
Kai Viruma¨e1, Anu Planken1, Andres Merits4, Jessica E. Besaw6, Ai Woon Yee6,
Takefumi Morizumi6, Kyumhyuk Kim6, Anling Kuo6, Asma Berriche2, Nathalie Dereuddre-
Bosquet2, Quentin Sconosciuti2, Thibaut Naninck2, Francis Relouzat2,
Mariangela Cavarelli2, Mart Ustav1, Derek Wilson3, Oliver P. Ernst6,7, Andres Ma¨nnik1,
Roger LeGrand2, Mart Ustav, Jr.ID1*
1 Icosagen Cell Factory OU¨ ; Tartu, Estonia, 2 Universite´ Paris-Saclay, Inserm, CEA, Center for Immunology
of Viral, Auto-immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT); Fontenay-aux-Roses,
France, 3 York University; Toronto, Canada, 4 University of Tartu; Tartu, Estonia, 5 NTNU; Trondheim,
Norway, 6 Department of Biochemistry, University of Toronto; Toronto, Canada, 7 Department of Molecular
Genetics, University of Toronto; Toronto, Canada
* mart.ustav.jr@icosagen.com
Abstract
The COVID-19 pandemic represents a global challenge that has impacted and is expected
to continue to impact the lives and health of people across the world for the foreseeable
future. The rollout of vaccines has provided highly anticipated relief, but effective therapeu-
tics are required to further reduce the risk and severity of infections. Monoclonal antibodies
have been shown to be effective as therapeutics for SARS-CoV-2, but as new variants of
concern (VoC) continue to emerge, their utility and use have waned due to limited or no effi-
cacy against these variants. Furthermore, cumbersome systemic administration limits easy
and broad access to such drugs. As well, concentrations of systemically administered anti-
bodies in the mucosal epithelium, a primary site of initial infection, are dependent on neona-


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tal Fc receptor mediated transport and require high drug concentrations. To reduce the viral
load more effectively in the lung, we developed an inhalable formulation of a SARS-CoV-2
neutralizing antibody binding to a conserved epitope on the Spike protein, ensuring pan-
neutralizing properties. Administration of this antibody via a vibrating mesh nebulization
device retained antibody integrity and resulted in effective distribution of the antibody in the
upper and lower respiratory tract of non-human primates (NHP). In comparison with intrave-
nous administration, significantly higher antibody concentrations can be obtained in the
lung, resulting in highly effective reduction in viral load post SARS-CoV-2 challenge. This
approach may reduce the barriers of access and uptake of antibody therapeutics in real-
PLOS PATHOGENS
PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011532
August 2, 2023
1 / 32
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OPEN ACCESS
Citation: Hermet P, Delache B, Herate C, Wolf E,
Kivi G, Juronen E, et al. (2023) Broadly neutralizing
humanized SARS-CoV-2 antibody binds to a
conserved epitope on Spike and provides antiviral
protection through inhalation-based delivery in
non-human primates. PLoS Pathog 19(8):
e1011532. https://doi.org/10.1371/journal.
ppat.1011532
Editor: Alexander E. Gorbalenya, Leiden University
Medical Center: Leids Universitair Medisch
Centrum, NETHERLANDS
Received: December 22, 2022
Accepted: July 3, 2023
Published: August 2, 2023
Copyright: © 2023 Hermet 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 available
in the main text or the supplementary materials.
The X-ray diffraction data and X-ray crystal
structure have been deposited in PDB under
accession code 8EL2. The cryo-EM map has been


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deposited in EMDB under accession code EMD-
28228. The cryo-EM structure has been deposited
in PDB under accession code 8ELJ.


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The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and diseas\
e susceptibility


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The microgenderome revealed: sex differences in bidirectional 
interactions between the microbiota, hormones, immunity and 
disease susceptibility
Ravichandra Vemuri1, Kristyn E. Sylvia2, Sabra L. Klein2, Samuel C. Forster3,4, Magdalena 
Plebanski1,5, Raj Eri1, and Katie L. Flanagan1,5,6
1School of Health Sciences, College of Health and Medicine, University of Tasmania, Hobart, 
Tasmania, Australia
2The W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns 
Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
3Microbiota and Systems Biology Laboratory, Centre for Innate Immunity and Infectious Diseases, 
Hudson Institute of Medical Research, Melbourne, Victoria, Australia
4Department of Molecular and Translational Sciences, Monash University, Melbourne, Victoria, 
Australia
5School of Health and Biomedical Science, RMIT University, Melbourne, Victoria, Australia
6Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia
Abstract
Sex differences in immunity are well described in the literature and thought to be mainly driven by 
sex hormones and sex-linked immune response genes. The gastrointestinal tract (GIT) is one of the 
largest immune organs in the body and contains multiple immune cells in the GIT-associated 
lymphoid tissue, Peyer’s patches and elsewhere, which together have profound effects on local and 
systemic inflammation. The GIT is colonised with microbial communities composed of bacteria, 
fungi and viruses, collectively known as the GIT microbiota. The GIT microbiota drives multiple 
interactions locally with immune cells that regulate the homeostatic environment and systemically 
in diverse tissues. It is becoming evident that the microbiota differs between the sexes, both in 
animal models and in humans, and these sex differences often lead to sex-dependent changes in 
local GIT inflammation, systemic immunity and susceptibility to a range of inflammatory


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diseases. The sexually dimorphic microbiome has been termed the ‘microgenderome’. Herein, we 
review the evidence for the microgenderome and contemplate the role it plays in driving sex 
differences in immunity and disease susceptibility. We further consider the impact that biological 
sex might play in the response to treatments aimed at manipulating the GIT microbiota, such as 
prebiotics, live biotherapeutics, (probiotics, synbiotics and bacteriotherapies) and faecal microbial 
transplant. These alternative therapies hold potential in the treatment of both psychological (e.g., 
Katie L. Flanagan, katie.flanagan@ths.tas.gov.au. 
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
HHS Public Access
Author manuscript
Semin Immunopathol. Author manuscript; available in PMC 2019 May 04.
Published in final edited form as:
Semin Immunopathol. 2019 March ; 41(2): 265–275. doi:10.1007/s00281-018-0716-7.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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The effect of erenumab on brain network function in episodic migraine patients: a randomized, placebo-controlled clinical trial \(RESET BRAIN\


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Vol:.(1234567890)
Journal of Neurology (2023) 270:5600–5612
https://doi.org/10.1007/s00415-023-11879-9
1 3
ORIGINAL COMMUNICATION
The effect of erenumab on brain network function in episodic 
migraine patients: a randomized, placebo‑controlled clinical trial 
(RESET BRAIN)
Massimo Filippi1,2,3,4,5  · Roberta Messina1,2,5 · Marta Bartezaghi6 · Ilaria Cetta1,2,5 · Bruno Colombo2 · 
Licia Grazzi7 · Daniele Martinelli8,9 · Raffaele Ornello10 · Anna Pichiecchio9,11 · Debora Raimondi6 · Antonio Russo12 · 
Simona Sacco10 · Alessandra Splendiani10 · Cristina Tassorelli8,9 · Renato Turrini6 · Paola Valsasina1 · 
Maria Assunta Rocca1,2,5 · RESET BRAIN Study Group
Received: 8 June 2023 / Revised: 12 July 2023 / Accepted: 12 July 2023 / Published online: 8 August 2023 
© The Author(s) 2023
Abstract
Background We aimed to explore whether erenumab, a monoclonal antibody targeting the calcitonin gene-related peptide 
receptor, could exert a central effect on brain network function in migraine, and investigate the persistence of such an effect 
following treatment discontinuation.
Methods This was a randomized, double-blind, placebo-controlled, multicenter trial with a crossover design performed in 
adult episodic migraine patients with previous treatment failure. Patients were randomized (1:1) to 12 weeks of erenumab 
140 mg or placebo, followed by a 12-week crossover. Resting state (RS) functional connectivity (FC) changes of brain net-
works involved in migraine were investigated using a seed-based correlation approach.
Results Sixty-one patients were randomized to treatment. In each treatment sequence, 27 patients completed the visit at 
week 12. Forty-four enrolled patients, 22 in each treatment sequence, completed the study procedures with no major proto-
col violations. We observed a carry-over effect of erenumab during the placebo treatment and therefore data analysis was 
performed as a parallel comparison of erenumab vs placebo of the first 12 weeks of treatment. From baseline to week 12,


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compared to placebo, patients receiving erenumab showed RS FC changes within the cerebellar, thalamic and periaqueductal 
gray matter networks, significantly associated with clinical improvement. Compared to non-responders, patients achieving a 
50% reduction in migraine days had distinct patterns of thalamic and visual network RS FC. Brain RS FC changes reversed 
when erenumab was stopped. A lower baseline RS FC of the pontine network identified patients responding to erenumab.
Conclusion Erenumab modulates RS FC of networks involved in migraine pathophysiology. In line with clinical response, 
erenumab-induced brain RS FC changes tend to reverse when treatment is stopped.
Keywords Headache · Prevention · Therapy · Neuroimaging
Introduction
Migraine is a common and highly disabling neurological 
disease [1]. Increased recognition of the huge personal and 
social impact of migraine has increased interest in the devel-
opment of new treatments. Based on evidence supporting 
a key role of calcitonin gene-related peptide (CGRP) in 
migraine neurobiology, new migraine-specific preventive 
drugs targeting the CGRP pathway have been developed 
[2]. Erenumab is a monoclonal antibody (mAb) targeting 
the CGRP receptor. Previous randomized controlled trials 
(RCTs) showed the efficacy, safety and tolerability of ere-
numab in episodic and chronic migraine [3–5]. Erenumab 
is believed to exert its antimigraine effect in the periphery, 
more precisely at the trigeminovascular level. This belief 
is sustained by the large size of anti-CGRP mAbs and their 
poor blood–brain barrier (BBB) penetrability (1:1000 ratio) 
[6]. In this context, modulation of the trigeminal ganglion 
and fibers may limit the recruitment of pain signaling at 
the meningeal tissues and inhibit pain transmission at the 
trigeminal ganglion and nucleus [2]. On the other hand, the 
Members of the RESET BRAIN Study Group are present in the 
Acknowledgement section.
Extended author information available on the last page of the article


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Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments


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Potential Anti-Mpox Virus Activity of Atovaquone, 
Mefloquine, and Molnupiravir, and Their Potential  
Use as Treatments
Daisuke Akazawa,1,a Hirofumi Ohashi,1,a Takayuki Hishiki,1,b Takeshi Morita,1,b Shoya Iwanami,2,c Kwang Su Kim,2,3,4,c Yong Dam Jeong,2,4,c Eun-Sil Park,5
Michiyo Kataoka,6 Kaho Shionoya,7,8 Junki Mifune,1 Kana Tsuchimoto,1 Shinjiro Ojima,1 Aa Haeruman Azam,1 Shogo Nakajima,7 Hyeongki Park,2
Tomoki Yoshikawa,9 Masayuki Shimojima,9 Kotaro Kiga,1 Shingo Iwami,2,10,11,12,13,14,15 Ken Maeda,5 Tadaki Suzuki,6 Hideki Ebihara,9
Yoshimasa Takahashi,1 and Koichi Watashi1,2,7,8,15
1Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, Japan; 2Interdisciplinary Biology Laboratory, Graduate School of Science, Nagoya University, 
Nagoya, Japan; 3Department of Science System Simulation, Pukyong National University, Busan, South Korea; 4Department of Mathematics, Pusan National University, Busan, South Korea; 
5Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan; 6Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan; 7Department of 
Virology II, National Institute of Infectious Diseases, Tokyo, Japan; 8Department of Applied Biological Science, Tokyo University of Science, Noda, Japan; 9Department of Virology I, National 
Institute of Infectious Diseases, Tokyo, Japan; 10Institute of Mathematics for Industry, Kyushu University, Fukuoka, Japan; 11Institute for the Advanced Study of Human Biology, Kyoto University, 
Kyoto, Japan; 12Interdisciplinary Theoretical and Mathematical Sciences Program, RIKEN, Saitama, Japan; 13NEXT-Ganken Program, Japanese Foundation for Cancer Research, Tokyo, Japan; 
14Science Groove, Inc, Fukuoka, Japan; and 15MIRAI, Japan Science and Technology Agency, Saitama, Japan
Background. Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and


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brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, 
by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts 
by mathematical modeling.
Methods. We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential 
drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron 
microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and 
examined combination treatment.
Results. Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 
0.51–5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and 
molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate 
dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative 
mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug 
concentrations.
Conclusions. These data suggest that atovaquone would be a potential candidate for treating mpox.
Keywords. mpox; antiviral; atovaquone; dihydroorotate dehydrogenase; mefloquine; molnupiravir; pan-orthopoxvirus.
Received 23 November 2022; editorial decision 28 February 2023; accepted 08 March 2023; 
published online 9 March 2023
aD. A. and H. O. contributed equally.
bT. H. and T. M. contributed equally.
cS. I., K. S. K., and Y. D. J contributed equally.
Correspondence: Koichi Watashi, PhD, Research Center for Drug and Vaccine Development, 
National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan 
(kwatashi@niid.go.jp).
The Journal of Infectious Diseases®
2023;228:591–603


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© The Author(s) 2023. 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/jiad058
Mpox virus (MPXV) is a zoonotic virus classified in the 
Orthopoxvirus genus of the Poxviridae family that causes 
smallpox-like diseases including rash, scab, fever, and head 
and body aches in humans [1–3]. After the first cases of human 
infection were reported in Congo in 1970, mpox cases have 
been primarily reported in Central and West African countries, 
with rare reports in other countries that have been linked with 
importation and travel from endemic African regions. In May 
2022, an outbreak of human mpox was reported and involved 
more than 80 000 cases in over 100 countries, mainly in Europe 
and North America at the time of writing of this article [4]. The 
World Health Organization declared this mpox outbreak a 
global health emergency on 23 July 2022.
Tecovirimat and brincidofovir are approved by the US Food 
and Drug Administration (FDA) for the treatment of smallpox 
[5]. Tecovirimat targets the viral-encoded VP37 protein to in-
hibit the envelopment of intracellular mature virions, whereas 
brincidofovir is a lipid conjugate prodrug of the nucleotide an-
alogue cidofovir, which inhibits viral DNA replication [6–8]. 
Although these 2 drugs have been approved for smallpox 
Anti-Mpox Virus Activity of Atovaquone • JID 2023:228 (1 September) • 591
The Journal of Infectious Diseases                                
M A J O R  A R T I C L E


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Annals of the Rheumatic Diseases, 1977, 36, 360-364
Discordance for ankylosing spondylitis in
monozygotic twins
C. J. EASTMOND* AND J. C. WOODROW
From the Nuffield Unit ofMedical Genetics, Department of Medicine, University ofLiverpool, Ashton Street,
P.O. Box 147, Liverpool L69 3BX
SUMMARY
Three monozygotic twin pairs, each over the age of 45 years, with ankylosing spondylitis
are described. In two pairs there is discordance for this disease and in the third pair there is a marked
difference in the severity of this disease. These findings provide evidence that environmental factors
are necessary not only for the initial development of ankylosing spondylitis, but possibly also for
determining its future severity.
Genetic factors are known to be important in the
aetiology
of
the
seronegative
spondarthritides
(Emery and Lawrence, 1967; Moll and Wright, 1973;
Lawrence,
1974).
The
finding
of an
increased
frequency of the histocompatibility antigen B27 in
ankylosing spondylitis by Brewerton et al. (1973a)
and Schlosstein et al. (1973) suggested that at least
part of the genetic
susceptibility
to ankylosing
spondylitis is due to genes in the HLA chromosomal
region. Associations have also been found between
HLA B27 and Reiter's syndrome (Brewerton et al.,
1973b; Woodrow et
al.,
1974) and the reactive
arthropathies (Aho
et
al.,
1973). While genetic
factors are known to be important in predisposing
to Reiter's syndrome (Lawrence,
1974) and the
reactive arthropathies, there is also evidence that
infective micro-organisms
are necessary
for the
initial development of these diseases. Similar direct
evidence of an environmental factor being necessary
for the development of ankylosing spondylitis
is
Fig. 1
Pedigree offamily
P showing discordance for
ankylosing spondylitis in
monozygotic twins.
II
All, B12
A9, BD
lacking. Moesmann (1960), reviewing the published
data on monozygous twins and ankylosing spondy-
litis, found nine reported twin pairs of which three
t
t
2
\~~~~2
II
/
A2,9; B7, 27
Fig. 2
Pedigree offamily


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R showing discordance for
ankylosing spondylitis in
monozygotic twins.
t
I
t
2
II
A2, B27
,A2Bw15
III
A2, B27
/A2, B27
A9, Bw 17
A 2, Bw IS
[J Ankylosing spondylitis
[
Radiological socroiliitic
F
Uveitis
Accepted for publication November 20, 1977
* Present address: Department of Rheumatology & Rehabili-
Filg 3
Pedigree offamily E showing concordance for
tation, School of Medicine,
36 Clarendon Road, Leeds
radiological sacroilitis and discordance for clinical
LS2 9PJ
ankylosing spondylitis and anterior uveitis in
Correspondence to Dr. J. C. Woodrow
monozygotic twins.
360


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Endocrinology, 2022, 163, 1–8
https://doi.org/10.1210/endocr/bqab254
Advance access publication 20 December 2021
Mini-Review
Sex and Gender Differences in Lung Cancer and Chronic 
Obstructive Lung Disease
Jill M. Siegfried,
1Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA, and 
2Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Correspondence: Jill M. Siegfried, PhD, Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church, Street SE, Minneapolis MN 
55455, USA. Email: jsiegfri@umn.edu.
Abstract
Two highly prevalent pulmonary diseases, lung cancer and chronic obstructive lung disease (COPD), show both sex and gender differences in their 
presentations and outcomes. Sex differences are defined as biological differences associated with the male vs female genotype, and gender differ-
ences are defined as behavioral or social differences that primarily arise because of gender identity. The incidence of both lung cancer and COPD has 
increased dramatically in women over the past 50 years, and both are associated with chronic pulmonary inflammation. Development of COPD is also 
a risk factor for lung cancer. In this review, the main differences in lung cancer and COPD biology observed between men and women will be sum-
marized. Potential causative factors will be discussed, including the role of estrogen in promoting pro-growth and inflammatory phenotypes which 
may contribute to development of both lung cancer and COPD. Response of the innate and adaptive immune system to estrogen is a likely factor in 
the biology of both lung cancer and COPD. Estrogen available from synthesis by reproductive organs as well as local pulmonary estrogen synthesis 
may be involved in activating estrogen receptors expressed by multiple cell types in the lung. Estrogenic actions, although more pronounced in


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women, may also have importance in the biology of lung cancer and COPD in men. Effects of estrogen are also timing and context dependent; the 
multiple cell types that mediate estrogen action in the lungs may confer both positive and negative effects on disease processes.
Key Words: lung cancer, chronic obstructive pulmonary disease, estrogen, estrogen receptor, sex difference, gender difference
Abbreviations: COC, combined oral contraceptive; COPD, chronic obstructive pulmonary disease; EGFR, epidermal growth factor receptor; ERβ, estrogen re-
ceptor beta; HRT, hormone replacement therapy; TAM, tumor-associated macrophage; TP53, tumor protein 53.
Lung cancer has been the number 1 cause of death from cancer 
in U.S. women as well as men for over a decade (1), and chronic 
obstructive lung disease (COPD) has now emerged as the number 
one overall cause of death in U.S. women who smoke (2-4). COPD 
is also the second largest cause of death in men who smoke, be-
hind heart disease (4, 5). Although the disease burden in women 
occurred in parallel with increased female smoking rates since the 
mid-twentieth century, for both COPD and lung cancer, the disease 
arising in women shows distinctions from disease arising in men. 
To better inform screening and treatment for individual patients, 
it is important to appreciate both the scope of burden in women 
from these 2 diseases, and how the presentation and outcome for 
lung cancer and COPD differs between men and women. In the 
preparation of this review, a PubMed literature search was con-
ducted for articles from 1990 onward using terms such as lung 
cancer, chronic obstructive pulmonary disease, COPD, emphy-
sema, women, female, sex difference, gender difference, estrogen 
receptor, and inflammation; this was followed by a selection, 
based on expert opinion, of the relevance, soundness, and import-
ance of the studies for inclusion in a mini-review. Relevant refer-
ences cited by selected publications were also included.
Differences in Lung Cancer Presentation


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Between Women and Men
For both lung cancer and COPD, diagnosis is more frequent at 
a younger age in women than in men (1, 6-10), and diagnosis 
is also associated with lower exposure to tobacco in women 
than in men (7-13). Population studies show in general a 20% 
to 25% lower average pack-years of smoking for women 
diagnosed with COPD (9, 10, 13) or lung cancer (11, 12) 
compared with men, and comparisons in early onset or low 
exposure groups show similar associations (13). Examination 
of age-specific incidence of lung cancer in U.S.  men and 
women diagnosed before age 50 showed a crossover to an 
increase in diagnoses in women born since 1965, even though 
smoking prevalence and number of cigarettes per day among 
women remained lower than that of men (7). There has also 
been a specific increase in lung cancer incidence rates in pre-
menopausal women (7, 14). Rising trends are found in the 
proportion of new lung cancer diagnoses in never smokers 
(increasing to 15% in 2011-2013 from 8% in 1990-1995), 
with twice the rate of new diagnosis in women compared to 
men (7, 8). In general, both COPD and lung cancer diagnosed 
in never smokers is more common in women than in men 
(15-17). These differences, as well as those discussed below, 
are summarized in Table 1.
For lung cancer, histological presentation in women is more 
frequently adenocarcinoma (2:1 ratio of adenocarcinoma to 
squamous cell carcinoma), while men show a much higher 
prevalence of squamous cell carcinoma (1:1 ratio) (18). 
Adenocarcinoma of the lung in general is less associated with 
smoking than other histological types, and risk for adeno-
carcinoma also declines more slowly after smoking cessation 
Received: 17 May 2021. Editorial Decision: 11 December 2021. Corrected and Typeset: 13 January 2022
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: 
journals.permissions@oup.com


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Downloaded from https://academic.oup.com/endo/article/163/2/bqab254/6470418 by guest on 15 August 2023


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Gestational ethanol exposure impairs motor skills in female mice through dysregulated striatal dopamine and acetylcholine function


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ARTICLE
OPEN
Gestational ethanol exposure impairs motor skills in female
mice through dysregulated striatal dopamine and acetylcholine
function
Sebastiano Bariselli
1✉, Yolanda Mateo1, Noa Reuveni1 and David M. Lovinger1
This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023
Fetal alcohol exposure has deleterious consequences on the motor skills of patients affected by Fetal Alcohol Spectrum Disorder
(FASD) and in pre-clinical models of gestational ethanol exposure (GEE). Deﬁcits in striatal cholinergic interneurons (CINs) and
dopamine function impair action learning and execution, yet the effects of GEE on acetylcholine (ACh) and striatal dopamine
release remain unexplored. Here, we report that alcohol exposure during the ﬁrst ten postnatal days (GEEP0-P10), which mimics
ethanol consumption during the last gestational trimester in humans, induces sex-speciﬁc anatomical and motor skill deﬁcits in
female mice during adulthood. Consistent with these behavioral impairments, we observed increased stimulus evoked-dopamine
levels in the dorsolateral striatum (DLS) of GEEP0-P10 female, but not male, mice. Further experiments revealed sex-speciﬁc deﬁcits in
β2-containing nicotinic ACh receptor (nAChR)-modulation of electrically evoked dopamine release. Moreover, we found a reduced
decay of ACh transients and a decreased excitability of striatal CINs in DLS of GEEP0-P10 females, indicating striatal CIN dysfunctions.
Finally, the administration of varenicline, a β2-containing nAChR partial agonist, and chemogenetic-mediated increase in CIN
activity improved motor performance in adult GEEP0-P10 females. Altogether, these data shed new light on GEE-induced striatal
deﬁcits and establish potential pharmacological and circuit-speciﬁc interventions to ameliorate motor symptoms of FASD.
Neuropsychopharmacology (2023) 48:1808–1820; https://doi.org/10.1038/s41386-023-01594-4
INTRODUCTION
Alcohol exposure during development leads to heterogeneous


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anatomical and neurobehavioral conditions, collectively known as
Fetal Alcohol Spectrum Disorder (FASD) [1]. While a signiﬁcant
number of women with Alcohol Use Disorder (AUD) abstain
during early pregnancy, a large proportion of them report alcohol
use during perinatal periods [2, 3]. The teratogenic effects of
ethanol include impaired cognitive ﬂexibility and motor deﬁcits
[4, 5], severely affecting patient’s everyday life and resulting in
high socioeconomic costs [6]. Despite a reduced overall survival
rate and higher prevalence of FASD in males during infancy [7],
the higher severity of dysmorphology and cognitive symptoms
reported in females [8] points to sex-related differences in the
neurobehavioral effects of FASD.
In animal models of gestational ethanol exposure (GEE), female
offspring show decreased behavioral inhibition [9] and impaired
extinction of aversive memories compared to males [10]. While GEE
interferes with cognitive and motor skill learning [11–14], sex-speciﬁc
effects on motor function remain unclear. Considering the high rate
of alcohol relapse during perinatal periods [2] and the developmental
similarities between the last trimester of human pregnancy and the
ﬁrst 10 postnatal days (P0-P10) in mice [15], we implemented a
mouse model of binge-like and late-term gestational ethanol
exposure that would cover this developmental period (GEEP0-P10).
We have previously hypothesized that the behavioral deﬁcits
induced by GEE might derive from synaptic and circuit deﬁcits in the
striatum [16], a brain region involved in cognitive and motor function
[17–19] and particularly vulnerable to the teratogenic effects of fetal
alcohol exposure [13, 20]. Dorsal striatal circuits contain different
neuronal populations, including medium spiny neurons (MSNs), the
primary striatal projection neurons, acetylcholine (ACh)-releasing
interneurons (CINs), as well as dopaminergic inputs from the
midbrain. Recent simultaneous in vivo ﬁber photometry experiments


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revealed coordinated ACh and dopamine signaling during decision-
making [21] and spontaneous locomotion [22, 23] in the dorsal
striatum. These data support previous evidence that ACh dysregula-
tion impairs cognitive function and motor skills [24–26], the latter
typically assessed with rotarod tasks in rodents. Moreover, Fast Scan
Cyclic Voltammetry (FSCV) experiments demonstrate that pre-
synaptic nAChR and glutamatergic receptor activation modulates
electrically evoked or ACh-driven striatal dopamine release [27–30].
While previous experiments show that GEE impairs dopamine
receptor expression and binding in rodents [31, 32] and monkeys
[33], whether GEE alters striatal dopamine dynamics remains an open
question.
In addition to striatal dopamine dysregulation, GEE impairs ACh
function
in
several
brain
regions.
In
rats,
GEE
alters
the
developmental expression of choline acetyltransferase (ChAT)
[34], the enzyme that catalyzes ACh synthesis, with no obvious
changes in the expression of acetylcholinesterase (AChE), the
enzyme that catalyzes ACh degradation, in nucleus basalis of
Meynert (NBM), neocortex, or striatum [35, 36]. Along with
Received: 14 December 2022 Revised: 29 March 2023 Accepted: 21 April 2023
Published online: 15 May 2023
1Laboratory for Integrative Neuroscience (LIN), NIH-NIAAA, 5625 Fishers Lane, Bethesda, MD 20892, USA. ✉email: sebastiano.bariselli@nih.gov
www.nature.com/npp
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Taking stock of value in the orbitofrontal cortex
Eric B. Knudsen1, Joni D. Wallis2
1Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California, USA.
2Department of Psychology and Helen Wills Neuroscience Institute, University of California 
Berkeley, Berkeley, California, USA.
Abstract
People with damage to the orbitofrontal cortex (OFC) have specific problems making decisions, 
whereas their other cognitive functions are spared. Neurophysiological studies have shown that 
OFC neurons fire in proportion to the value of anticipated outcomes. Thus, a central role of the 
OFC is to guide optimal decision-making by signalling values associated with different choices. 
Until recently, this view of OFC function dominated the field. New data, however, suggest that the 
OFC may have a much broader role in cognition by representing cognitive maps that can be used 
to guide behaviour and that value is just one of many variables that are important for behavioural 
control. In this Review, we critically evaluate these two alternative accounts of OFC function and 
examine how they might be reconciled.
In the 1990s, Damasio brought attention to the fascinating deficits exhibited by people with 
damage to the orbitofrontal cortex (OFC)1. These individuals would make terrible choices 
and their everyday lives lurched from one catastrophic decision to another, yet they would 
perform normally on standard laboratory tests of cognition2. Damasio developed new tests 
based on real-world decision-making3. Participants were given play money and had to make 
choices across a series of gambles based on reward history. People with OFC damage 
performed poorly, quickly losing all their money as they failed to learn from the outcomes 
associated with each gamble. These impairments had gone unnoticed for years, simply 
because no one thought to assess individuals’ decision-making in a neuropsychological 
exam. Inspired by Damasio’s findings, many labs started to record OFC neurons in non-


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human primates during decision-making tasks. In a seminal study, Padoa-Schioppa and 
Assad presented monkeys with choices between different amounts of various juices4. OFC 
neurons encoded the amount of juice, weighted by how much the monkey liked it, consistent 
with how valuable the option was to the animal. This made a neat and compelling story: 
individuals with OFC damage made poor decisions because they were missing the neurons 
that would signal the value of each option.
wallis@berkeley.edu .
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
HHS Public Access
Author manuscript
Nat Rev Neurosci. Author manuscript; available in PMC 2023 September 20.
Published in final edited form as:
Nat Rev Neurosci. 2022 July ; 23(7): 428–438. doi:10.1038/s41583-022-00589-2.
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REVIEW ARTICLE
OPEN
Knife’s edge: Balancing immunogenicity and reactogenicity in
mRNA vaccines
Jisun Lee1,6, Matthew C. Woodruff2,3,6, Eui Ho Kim4✉ and Jae-Hwan Nam
1,5✉
© The Author(s) 2023
Since the discovery of messenger RNA (mRNA), there have been tremendous efforts to wield them in the development of
therapeutics and vaccines. During the COVID-19 pandemic, two mRNA vaccines were developed and approved in record-breaking
time, revolutionizing the vaccine development landscape. Although ﬁrst-generation COVID-19 mRNA vaccines have demonstrated
over 90% efﬁcacy, alongside strong immunogenicity in humoral and cell-mediated immune responses, their durability has lagged
compared to long-lived vaccines, such as the yellow fever vaccine. Although worldwide vaccination campaigns have saved lives
estimated in the tens of millions, side effects, ranging from mild reactogenicity to rare severe diseases, have been reported. This
review provides an overview and mechanistic insights into immune responses and adverse effects documented primarily for
COVID-19 mRNA vaccines. Furthermore, we discuss the perspectives of this promising vaccine platform and the challenges in
balancing immunogenicity and adverse effects.
Experimental & Molecular Medicine (2023) 55:1305–1313; https://doi.org/10.1038/s12276-023-00999-x
INTRODUCTION
For more than 100 years, public vaccination campaigns have
remained our most successful interdictions into the prevention of
human infectious diseases. Prophylactic vaccination has been
implemented to increase life expectancy and improve public
health, thereby saving countless lives1,2. However, while vaccine
technology has signiﬁcantly advanced over the past century3, the
conceptualization of an “optimal” vaccine has only grown more
complicated with the rapid progress in our understanding of the
cellular components associated with protective immunity. Con-
ventional vaccines have often failed against difﬁcult-to-target and
antigenically variable viruses such as human immunodeﬁciency


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virus (HIV) and hepatitis C virus (HCV)4, and due to both the time
required for development processes and rapid mutation of the
viral genome, some traditional vaccine technologies are poorly
suited for sudden outbreaks that threaten global health and
security, such as the recent coronavirus disease (COVID-19)
pandemic. Considering these constraints, messenger RNA (mRNA)
vaccines have represented an attractive alternative to conven-
tional
vaccines
due
to
their
cell-free,
rapid,
and
scalable
development and production5.
mRNA vaccine technology has been extensively studied for
cancer treatment owing to its ability to trigger a potent T-cell
response, well-tolerated nature, and suitability for personalized
design. The details of mRNA-based cancer vaccine development
are comprehensively described in recent reviews6–8. However, it
was the COVID-19 pandemic that incited interest in mRNA for
medical application, leading to expedited licensure of two mRNA
vaccines9,10, with several others at various stages of development
or in clinical trials11. The unprecedented pace of the SARS-CoV-2
vaccine rollout was accomplishable only because of the unique
properties of mRNA vaccine platforms. Tremendous advance-
ments have been made in the efﬁcient delivery and expression of
antigenic mRNA for current COVID-19 mRNA vaccines. Modiﬁca-
tions such as N1-methylpseudouridine, 5′ capping, and codon
optimization have been used to optimize mRNA production to
maximize antigen availability12,13. To enable efﬁcient delivery of
mRNA to the cytosol of target cells, lipid nanoparticles (LNPs)
comprised of ionizable cationic lipids, cholesterol, phospholipids,
and polyethylene glycol (PEG) have been used. The LNP–mRNA
complex is neutral at physiological pH but becomes positively
charged when the LNP is sequestered and acidiﬁed in the
endosome; this process is followed by fusion with the endosomal
membrane and the release of mRNA into the cytosol13–15.
Composed
solely
of
modiﬁed
mRNA
encapsulated
by
an


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by
an
engineered LNP16, this approach eliminates the need for the
massive pathogen culturing efforts required for attenuated or
killed/split vaccines, such as the polio17 or inﬂuenza vaccine18. De
novo DNA template synthesis and basic molecular biology
propagation allow this technology to signiﬁcantly outpace even
protein subunit-based approaches, resulting in nimble, cost-
effective platforms capable of rapidly deploying to the front line
to improve public health19.
The COVID-19 pandemic has allowed for a real-time assessment
of the strong potential of mRNA vaccines to rapidly reshape the
worldwide landscape of a deadly emerging infectious disease.
First-generation SARS-CoV-2 vaccines were fully designed within a
few weeks of the publication of the full-length Wuhan strain spike
Received: 30 November 2022 Revised: 26 February 2023 Accepted: 27 March 2023
Published online: 10 July 2023
1Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Republic of Korea. 2Department of Medicine, Division of
Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA. 3Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
4Viral Immunology Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea. 5BK Plus Department of Biotechnology, The Catholic University of Korea, Bucheon,
Gyeonggi-do 14662, Republic of Korea. 6These authors contributed Equally: Jisun Lee, Matthew C. Woodruff. ✉email: euiho.kim@ip-korea.org; jhnam@catholic.ac.kr
www.nature.com/emm
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Pathological Bergmann glia alterations and disrupted calcium dynamics in ataxic Canavan disease mice


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Pathological Bergmann glia alterations and disrupted calcium 
dynamics in ataxic Canavan disease mice
Vanessa L. Hull1,2, Yan Wang1,2, Travis Burns1,2, Sarah Sternbach3, Shuaishuai Gong1,2, 
Jennifer McDonough3, Fuzheng Guo1,2, Laura N. Borodinsky2,4, David Pleasure1,2
1Department of Neurology, University of California Davis School of Medicine, Sacramento, 
California, USA
2Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children, Sacramento, 
California, USA
3Department of Biological Sciences, Kent State University, Kent, Ohio, USA
4Department of Physiology & Membrane Biology, University of California Davis School of 
Medicine, Sacramento, California, USA
Abstract
Canavan disease (CD) is a recessively inherited pediatric leukodystrophy resulting from 
inactivating mutations to the oligodendroglial enzyme aspartoacylase (ASPA). ASPA is 
responsible for hydrolyzing the amino acid derivative N-acetyl-L-aspartate (NAA), and without 
it, brain NAA concentrations increase by 50% or more. Infants and children with CD present with 
progressive cognitive and motor delays, cytotoxic edema, astroglial vacuolation, and prominent 
spongiform brain degeneration. ASPA-deficient CD mice (Aspanur7/nur7) present similarly with 
elevated NAA, widespread astroglial dysfunction, ataxia, and Purkinje cell (PC) dendritic atrophy. 
Bergmann glia (BG), radial astrocytes essential for cerebellar development, are intimately 
intertwined with PCs, where they regulate synapse stability, functionality, and plasticity. BG 
damage is common to many neurodegenerative conditions and frequently associated with PC 
dysfunction and ataxia. Here, we report that, in CD mice, BG exhibit significant morphological 
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.


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Correspondence Vanessa L. Hull and David Pleasure, Institute for Pediatric Regenerative Medicine, UC Davis, c/o Shriners Hospital 
for Children, 2425 Stockton Blvd, Sacramento, CA 95817, USA. vhull@mednet.ucla.edu and depleasure@ucdavis.edu.
AUTHOR CONTRIBUTIONS
David Pleasure and Vanessa Hull conceived and designed the study. Vanessa Hull performed the immunohistochemistry, confocal 
imaging, morphological analyses and calcium imaging/analysis. Yan Wang performed the qPCR. Yan Wang and Vanessa Hull 
completed the cell culture experiments with help from Shuaishuai Gong. Fuzheng Guo provided required materials and guidance for 
qPCR and cell culture experiments. Laura Borodinsky designed the calcium imaging experiments and provided required materials and 
equipment. Sarah Sternbach and Jenny McDonough performed and analyzed NAA assays. Travis Burns performed rotarod testing. 
Vanessa Hull and David Pleasure wrote the manuscript. All authors reviewed and approved the manuscript.
Present address
Vanessa L. Hull, Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, 
California, USA.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.
CONFLICT OF INTEREST STATEMENT
None.
HHS Public Access
Author manuscript
Glia. Author manuscript; available in PMC 2023 December 01.
Published in final edited form as:
Glia. 2023 December ; 71(12): 2832–2849. doi:10.1002/glia.24454.
Author Manuscript
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1478  ｜NEURAL REGENERATION RESEARCH｜Vol 18｜No. 7｜July 2023
NEURAL REGENERATION RESEARCH
www.nrronline.org
Review
Abstract  
Alteration of the outer retina leads to various diseases such as age-related macular degeneration 
or retinitis pigmentosa characterized by decreased visual acuity and ultimately blindness. Despite 
intensive research in the field of retinal disorders, there is currently no curative treatment. Several 
therapeutic approaches such as cell-based replacement and gene therapies are currently in 
development. In the context of cell-based therapies, different cell sources such as embryonic stem 
cells, induced pluripotent stem cells, or multipotent stem cells can be used for transplantation. In the 
vast majority of human clinical trials, retinal pigment epithelial cells and photoreceptors are the cell 
types considered for replacement cell therapies. In this review, we summarize the progress made in 
stem cell therapies ranging from the pre-clinical studies to clinical trials for retinal disease.
Key Words: age-related macular degeneration; cell transplantation; clinical trial; retinal disease; 
retinal dystrophy; stem cell
Introduction 
The progressive degeneration of photoreceptors characterizes various 
retinal diseases such as age-related macular degeneration (AMD) and 
retinitis pigmentosa (RP), leading to progressive vision and visual field 
loss and ultimately to blindness (Verbakel et al., 2018; Voisin et al., 2022). 
In AMD, there is geographic atrophy (called atrophic AMD form) and 
abnormal and excessive growth of blood vessels in the eye called choroidal 
neovascularization (the exudative AMD form). Anti-vascular endothelial 
growth factor intravitreal therapy, which is the only effective treatment for 
exudative AMD, targets choroidal neovascularization but not the disease 
itself. To date, aside from some positive advances in gene therapy for very 
few particular forms of retinal dystrophy (i.e., voretigene neparvovec), there


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is no curative treatment for these retinal diseases (Stingl et al., 2022). In this 
context, over the past two decades, the development of cell-based therapy 
has been investigated as a means of replacing apoptotic or dystrophic cells 
and restoring visual function. Mammalian retinas have limited regenerative 
capacity, and stem cells in regenerative strategy seem to be a promoting 
approach (Salas et al., 2021). Despite encouraging results, stem cell therapy 
needs to be optimized to improve its effectiveness in the treatment of retinal 
diseases. This review focuses on the retinal dystrophies and the different stem 
cell populations and their use for transplantation in retinal diseases. 
Search Strategy and Selection Criteria
Studies cited in this review were published between 2000 and 2022 and 
searched from PubMed or Google Scholar databases. The following keywords 
were used for this research: stem cell transplantation, retinal disease, retinal 
degeneration, retinal dystrophy, stem cell therapy, age-related macular 
degeneration, retina, retinitis pigmentosa, Stargardt disease, bone marrow-
derived stem cells, retinal precursor cells, clinical trials, retinal pigment 
epithelial cells, mesenchymal stem cells, embryonic stem cells, and induced 
pluripotent stem cells.
1Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, INSERM 1084, Poitiers, France; 2Department of Ophthalmology, CHU Poitiers, Poitiers, France; 
3Laboratoires Thea, Clermont-Ferrand, France
*Correspondence to: Audrey Voisin, PhD, audrey.voisin@univ-poitiers.fr.
https://orcid.org/0000-0002-9766-5759 (Audrey Voisin) 
How to cite this article: Voisin A, Pénaguin A, Gaillard A, Leveziel N (2023) Stem cell therapy in retinal diseases. Neural Regen Res 18(7):1478-1485. 
From the Contents
Introduction
1478
Search Strategy and Selection Criteria
1478
Retinal Degeneration
1478
Cell-Based Therapy
1479
Cell Source
1479
Preclinical Model 
1480
Clinical Trials
1481
Conclusion
1483
Stem cell therapy in retinal diseases


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https://doi.org/10.4103/1673-5374.361537
Date of submission: July 27, 2022 
Date of decision: September 14, 2022 
Date of acceptance: October 24, 2022 
Date of web publication: November 25, 2022 
Audrey Voisin1, 2, *, Amaury Pénaguin1, 3, Afsaneh Gaillard1, Nicolas Leveziel1, 2
Retinal Degeneration
The human adult retina is organized in ten histological layers with one glial 
cell type, the Müller glial cells, and six major types of neurons: two main cell 
types of photoreceptors (PRs; rods and cones), bipolar cells, amacrine cells, 
horizontal cells, and ganglion cells. Retinal cell bodies are organized into three 
layers from apical to basal; the outer nuclear layer, the inner nuclear layer, and 
the ganglion cell layer. Aside from these layers, the outer and inner plexiform 
layers contain axons and dendrites of neuronal cells. The outer part of the 
retina is limited by the retinal pigment epithelium (RPE) layer. These cells 
fulfill many functions such as epithelial transport, visual cycle, phagocytosis, 
secretion, and immune modulation (Voisin et al., 2019). 
Recessive Stargardt macular degeneration
Recessive Stargardt macular degeneration (STGD1) is common retinal 
dystrophy of varying severity, the most common and severe form during 
childhood, and the less common form during adulthood (Tanna et al., 2017). 
STGD1 is an autosomal recessive disease with an incidence of 1:8000 to 
1:10,000, caused by mutations in the ATP binding cassette subfamily A 
member 4 (ABCA4) gene (Spiteri Cornish et al., 2017; Cicinelli et al., 2019). The 
protein encoded by ABCA4 is involved in the visual cycle and localized in the 
photoreceptor outer segments. The disease is characterized by choriocapillaris 
atrophy and by accumulation of lipofuscin, an age-related pigment, in RPE, 
leading to PR degeneration (Figure 1A). Patients affected by STGD1 usually 
experience a rapid bilateral central visual loss with dyschomatopsia and central 
scotoma. Disease-causing variants of ABCA4 are also associated with cone, rod,


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and rod-cone dystrophies (Cremers et al., 2020).
RP 
RP is the most frequent hereditary (30–40% autosomal dominant, 40–60% 
autosomal recessive, and 5–15% X-linked) retinal disease with an incidence 
of approximately 1:4000 (Verbakel et al., 2018). Patients suffering from RP 
frequently report night blindness and progressive visual field loss beginning 
around the age of 20–30 years, and finally are complete blindness at the 
late stage. The disease is characterized by primary degeneration of PR rods 
(eventually secondary degeneration of cones in case of complete blindness) 
(Ali et al., 2017). At fundus examination, the disease is clinically characterized 
by dark bone-spicule pigmentation and attenuated blood vessels (Figure 1B; 
Verbakel et al., 2018). 
AMD
AMD is a complex multifactorial disease characterized by degeneration of the 
macula usually preceded by drusen formation made up of the extracellular 
accumulation of proteins and lipids (Voisin et al., 2022). The disease usually 
affects older adult individuals and is the leading cause of blindness in 
industrialized countries. The pathogenesis of this retinal disease is associated 
with both genetic (CFH, ARMS2, etc.) and environmental factors (smoking 
and light exposure). AMD is classified in an atrophic form (Figure 1C) with the 
progressive development of macular atrophy and an exudative form (Figure 
1D) with the development of choroidal neovascularization (Nashine, 2021). 
Both forms are clinically characterized by visual acuity decrease, central 
scotoma, and metamorphopsia.


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Sex Differences in Gene Expression and Regulatory Networks 
across 29 Human Tissues
Camila M. Lopes-Ramos1, Cho-Yi Chen2, Marieke L. Kuijjer3, Joseph N. Paulson4, Abhijeet 
R. Sonawane5, Maud Fagny6, John Platig5, Kimberly Glass1,5, John Quackenbush1,5,7,*, 
Dawn L. DeMeo5,8,9,*
1Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
2Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
3Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, 
Oslo, Norway
4Department of Biostatistics, Product Development, Genentech Inc., San Francisco, CA, USA
5Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s 
Hospital and Harvard Medical School, Boston, MA, USA
6Genetique Quantitative et Evolution-Le Moulon, Universite Paris-Saclay, Institut National de 
Recherche pour l’Agriculture, l’Alimentation et l’Environnement, Centre National de la Recherche 
Scientifique, AgroParisTech, Gif-sur-Yvette, France
7Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, 
MA, USA
8Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, 
USA
9Lead Contact
SUMMARY
Sex differences manifest in many diseases and may drive sex-specific therapeutic responses. To 
understand the molecular basis of sex differences, we evaluated sex-biased gene regulation by 
constructing sample-specific gene regulatory networks in 29 human healthy tissues using 8,279 
whole-genome expression profiles from the Genotype-Tissue Expression (GTEx) project. We find 
sex-biased regulatory network structures in each tissue. Even though most transcription factors 
*Correspondence: johnq@hsph.harvard.edu (J.Q.), dawn.demeo@channing.harvard.edu (D.L.D.).
AUTHOR CONTRIBUTIONS
Conceptualization, C.M.L.-R., C.-Y.C., M.L.K., J.N.P., A.R.S., M.F., J.P., K.G., J.Q., and D.L.D.; Methodology, C.M.L.-R., C.-Y.C.,


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M.L.K., K.G., J.Q., and D.L.D.; Formal Analysis, C.M.L.-R. and C.-Y.C.; Investigation, C.M.L.-R. and C.-Y.C.; Resources, J.Q. and 
D.L.D.; Data Curation, J.N.P. and J.Q.; Writing – Original Draft, C.M.L.-R. and C.-Y.C.; Writing – Review & Editing, C.M.L.-R., C.-
Y.C., M.L.K., J.N.P., A.R.S., M.F., J.P., K.G., J.Q., and D.L.D.; Visualization, C.M.L.-R. and C.-Y.C.; Supervision, J.Q. and D.L.D.; 
Funding Acquisition, M.L.K., K.G., J.Q., and D.L.D.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.celrep.2020.107795.
DECLARATION OF INTERESTS
The authors declare no competing interests.
HHS Public Access
Author manuscript
Cell Rep. Author manuscript; available in PMC 2021 February 22.
Published in final edited form as:
Cell Rep. 2020 June 23; 31(12): 107795. doi:10.1016/j.celrep.2020.107795.
Author Manuscript
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Altered behavior, brain structure, and neurometabolites in a rat model of autism-specific maternal autoantibody exposure


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ARTICLE
OPEN
Altered behavior, brain structure, and neurometabolites in a rat
model of autism-speciﬁc maternal autoantibody exposure
Matthew R. Bruce
1, Amalie C. M. Couch2, Simone Grant3, Janna McLellan1, Katherine Ku3, Christina Chang3, Angelica Bachman3,
Matthew Matson3, Robert F. Berman4,5, Richard J. Maddock
3, Douglas Rowland
6, Eugene Kim
7, Matthew D. Ponzini7,
Danielle Harvey8, Sandra L. Taylor8, Anthony C. Vernon
2,9,10, Melissa D. Bauman3,5,10 and Judy Van de Water
1,5✉
© The Author(s) 2023
Maternal immune dysregulation is a prenatal risk factor for autism spectrum disorder (ASD). Importantly, a clinically relevant
connection exists between inﬂammation and metabolic stress that can result in aberrant cytokine signaling and autoimmunity. In
this study we examined the potential for maternal autoantibodies (aAbs) to disrupt metabolic signaling and induce
neuroanatomical changes in the brains of exposed offspring. To accomplish this, we developed a model of maternal aAb exposure
in rats based on the clinical phenomenon of maternal autoantibody-related ASD (MAR-ASD). Following conﬁrmation of aAb
production in rat dams and antigen-speciﬁc immunoglobulin G (IgG) transfer to offspring, we assessed offspring behavior and brain
structure longitudinally. MAR-ASD rat offspring displayed a reduction in pup ultrasonic vocalizations and a pronounced deﬁcit in
social play behavior when allowed to freely interact with a novel partner. Additionally, longitudinal in vivo structural magnetic
resonance imaging (sMRI) at postnatal day 30 (PND30) and PND70, conducted in a separate cohort of animals, revealed sex-speciﬁc
differences in total and regional brain volume. Treatment-speciﬁc effects by region appeared to converge on midbrain and
cerebellar structures in MAR-ASD offspring. Simultaneously, in vivo 1H magnetic resonance spectroscopy (1H-MRS) data were
collected to examine brain metabolite levels in the medial prefrontal cortex. Results showed that MAR-ASD offspring displayed


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decreased levels of choline-containing compounds and glutathione, accompanied by increased taurine compared to control
animals. Overall, we found that rats exposed to MAR-ASD aAbs present with alterations in behavior, brain structure, and
neurometabolites; reminiscent of ﬁndings observed in clinical ASD.
Molecular Psychiatry (2023) 28:2136–2147; https://doi.org/10.1038/s41380-023-02020-3
INTRODUCTION
Autism spectrum disorder (ASD) is clinically deﬁned by a collection
of symptoms including alterations in social, communicative, and
stereotyped behaviors [1]. Despite these well-deﬁned behaviorally
diagnostic criteria, the molecular basis of these behaviors remains
unclear.
However,
evidence
exists
for the dysregulation
of
important brain signaling molecules and pathways in ASD etiology;
including imbalances in key neurotransmitters, gamma aminobu-
tyric acid (GABA) and glutamate [2], or alterations in cellular
metabolism including mitochondrial function [3] and one-carbon
signaling [4]. Understanding which physiological systems and
related signaling molecules are impacted, as well as the roles of
developmental timing and biological sex on individual outcomes
will aid in early diagnosis and therapeutic strategies in ASD.
Genetic inﬂuence is also an important factor in ASD, and studies
investigating genetic risk have identiﬁed a multitude of candidate
gene networks associated with diagnosis [5]. These include gene
networks important for synaptic function [6], cellular metabolism
[7], and immune signaling [8, 9]. The development of ASD,
however, likely results from a combination of genetic and
environmental factors, with early-life exposure to environmental
insults playing an important role in some cases [10, 11]. In support
of this view, numerous studies provide evidence that changes in
maternal immune signaling during pregnancy associate with ASD
diagnosis in offspring [12–15]. Prominent among these ﬁndings is
that ~20% of mothers of children subsequently diagnosed with


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ASD possess circulating aAbs directed against proteins known to
be important for early development. This phenomenon has been
termed maternal autoantibody-related (MAR) ASD [16, 17]. We
have previously shown that exposure to clinically relevant patterns
of these aAbs results in changes to behavior, brain structure (as
measured by sMRI), and neural progenitor cell proliferation in
mice [18–20]. What remains to be understood are the effects of
MAR-ASD aAb exposure on offspring across the lifespan, the
impact of aAbs on cell signaling and target proteins, and the
inﬂuence of sex as a biological variable.
Received: 15 August 2022 Revised: 23 February 2023 Accepted: 27 February 2023
Published online: 27 March 2023
1Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA. 2Department of Basic and Clinical
Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. 3Department of Psychiatry and Behavioral Sciences, University of
California, Davis, CA, USA. 4Department of Neurological Surgery, University of California, Davis, CA, USA. 5MIND Institute, University of California, Davis, CA, USA. 6Center for
Molecular and Genomic Imaging, University of California, Davis, CA, USA. 7Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College
London, London, UK. 8Department of Public Health Sciences, University of California, Davis, CA, USA. 9MRC Centre for Neurodevelopmental Disorders, King’s College London,
London, UK. 10These authors contributed equally: Anthony C. Vernon, Melissa D. Bauman. ✉email: javandewater@ucdavis.edu
www.nature.com/mp
Molecular Psychiatry
1234567890();,:


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Resource
Caloric Restriction Engages Hepatic RNA Processing
Mechanisms in Rhesus Monkeys
Graphical Abstract
Highlights
d Caloric restriction reprograms hepatic metabolism in
monkeys independently of aging
d The response to CR involves recruitment of RNA processing
mechanisms
d Integrative analysis reveals a multi-pathway core CR
metabolic network
d The core CR metabolic network is regulated at the level of
RNA processing
Authors
Timothy W. Rhoads,
Maggie S. Burhans, Vincent B. Chen, ...,
Joshua J. Coon, Ricki J. Colman,
Rozalyn M. Anderson
Correspondence
rozalyn.anderson@wisc.edu
In Brief
Rhoads et al. use multi-platform high-
resolution molecular proﬁling to
demonstrate that caloric restriction (CR)
reprograms hepatic metabolism in rhesus
monkeys. They identify a role for RNA
processing in the mechanisms of CR and
show that the CR metabolic network is
subject to substantial regulation at the
RNA level.
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O
O
O
O
O
O
O
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Acetylation
Hepatic CR-responsive
molecular network
mRNA
metabolites
lipids
proteins
PTMs
Rhoads et al., 2018, Cell Metabolism 27, 677–688
March 6, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.cmet.2018.01.014


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Meng et al. BMC Neurosci            (2020) 21:2  
https://doi.org/10.1186/s12868-020-0550-4
RESEARCH ARTICLE
Proteomics profiling and pathway analysis 
of hippocampal aging in rhesus monkeys
Shu Meng1†, Wenchao Xia1†, Meng Pan1†, Yangjie Jia1†, Zhanlong He2* and Wei Ge1,3* 
Abstract 
Background: Aged rhesus monkeys exhibit deficits in memory mediated by the hippocampus. Although extensive 
research has been carried out on the characteristics of human hippocampal aging, there is still very little scientific 
understanding of the changes associated with hippocampal aging in rhesus monkeys. To explore the proteomics 
profiling and pathway-related changes in the rhesus hippocampus during the aging process, we conducted a high 
throughput quantitative proteomics analysis of hippocampal samples from two groups of rhesus macaques aged 
6 years and 20 years, using 2-plex tandem mass tag (TMT) labeling. In addition, we used a comprehensive bioinfor-
matics analysis approach to investigate the enriched signaling pathways of differentially expressed proteins (the ratios 
of 20-years vs. 6-years, ≥ 1.20 or ≤ 0.83).
Results: In total, 3260 proteins were identified with a high level of confidence in rhesus hippocampus. We found 
367 differentially expressed proteins related to rhesus hippocampus aging. Based on biological pathway analysis, we 
found these aging-related proteins were predominantly enriched in the electron transport chain, NRF2 pathway, focal 
adhesion–PI3K–AKT–mTOR signaling pathway and cytoplasmic ribosome proteins. Data are available via ProteomeX-
change with identifier PXD011398.
Conclusion: This study provides a detail description of the proteomics profile related to rhesus hippocampal aging. 
These findings should make an important contribution to further mechanistic studies, marker selection and drug 
development for the prevention and treatment of aging or age-related neurodegeneration.
Keywords: Aging, Proteomics, Hippocampus, Rhesus monkey, Neurodegeneration


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© The Author(s) 2020. 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.
Background
Rhesus macaques are a nonhuman primate species that 
is closely related to humans and share a common ances-
tor that lived over 25 million years ago [1–3]. Rhesus 
macaques are also one of the most commonly used ani-
mal models in basic and applied biomedical research on 
human disease [1, 2]. Previous research has also estab-
lished that rhesus macaques and humans share approxi-
mately 95% genetic homology and have very similar 
age-associated conditions including diabetes, osteoar-
thritis, endometriosis, visual accommodation, hyper-
tension, osteoporosis, and amyloidosis [2]. The brain 
architecture of the rhesus macaque is also very similar to 
that in humans and displays comparable age-related cog-
nitive decline [2–4]. Investigating the molecular mecha-
nism of the normal aging of rhesus brain has received 
considerable critical attention.
The hippocampus plays a pivotal role in cerebral learn-


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ing and memory and is particularly susceptible to normal 
Open Access
BMC Neuroscience
*Correspondence:  hzl612@126.com; wei.ge@chem.ox.ac.uk
†Shu Meng, Wenchao Xia, Meng Pan and Yangjie Jia contributed equally 
to this work
1 State Key Laboratory of Medical Molecular Biology & Department 
of Immunology, Institute of Basic Medical Sciences Chinese Academy 
of Medical Sciences, School of Basic Medicine Peking Union Medical 
College, Dongdan Santiao 5# Dongcheng District, Beijing 100005, China
2 Yunnan Key Laboratory of Vaccine Research and Development 
on Severe Infectious Disease, Institute of Medical Biology, Chinese 
Academy of Medical Sciences and Peking Union Medical College, 
Kunming 650118, Yunnan, China
Full list of author information is available at the end of the article


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Article
3D Genome of macaque fetal brain reveals
evolutionary innovations during primate
corticogenesis
Graphical Abstract
Highlights
d Construction of a high-resolution Hi-C map of macaque
fetal brain
d Cross-species 3D genome analyses uncover human-speciﬁc
chromatin structures
d The subplate lamina shows human-speciﬁc regulatory
changes during corticogenesis
d The human-speciﬁc loop regulating EPHA7 affects neuron
dendrite development
Authors
Xin Luo, Yuting Liu, Dachang Dang, ...,
Shihua Zhang, Cheng Li, Bing Su
Correspondence
zsh@amss.ac.cn (S.Z.),
cheng_li@pku.edu.cn (C.L.),
sub@mail.kiz.ac.cn (B.S.)
In Brief
High-resolution map of developing
rhesus macaque brain genome
architecture during corticogenesis
reveals human-speciﬁc chromatin
structure and regulatory changes that
impact dendrite development.
Luo et al., 2021, Cell 184, 723–740
February 4, 2021 ª 2021 Elsevier Inc.
https://doi.org/10.1016/j.cell.2021.01.001
ll


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Alzheimer’s Association Report
2019 Alzheimer’s disease facts and ﬁgures
Alzheimer’s Association*
Abstract
This article describes the public health impact of Alzheimer’s disease (AD), including incidence
and prevalence, mortality and morbidity, use and costs of care, and the overall impact on caregivers
and society. The Special Report examines the use of brief cognitive assessments by primary care
physicians as a tool for improving early detection of dementia. An estimated 5.8 million Americans
have Alzheimer’s dementia. By mid-century, the number of people living with Alzheimer’s dementia
in the United States may grow to 13.8 million, fueled in large part by the aging baby boom generation.
In 2017, ofﬁcial death certiﬁcates recorded 121,404 deaths from AD, making AD the sixth leading
cause of death in the United States and the ﬁfth leading cause of death among Americans age
65 years. Between 2000 and 2017, deaths resulting from stroke, heart disease, and prostate cancer
decreased, whereas reported deaths from AD increased 145%. In 2018, more than 16 million family
members and other unpaid caregivers provided an estimated 18.5 billion hours of care to people
with Alzheimer’s or other dementias. This care is valued at nearly $234 billion, but its costs extend
to family caregivers’ increased risk for emotional distress and negative mental and physical health
outcomes. Average per-person Medicare payments for services to beneﬁciaries age 65 years with
Alzheimer’sorotherdementiasaremorethanthreetimesasgreataspaymentsforbeneﬁciarieswithout
these conditions. Total payments in 2019 for health care, long-term care and hospice services for peo-
ple age 65 years with dementia are estimated to be $290billion. Early detection of Alzheimer’s offers
numerous medical, emotional and ﬁnancial beneﬁts—beneﬁts that accrue to affected individuals and
their families as well as to society at large. Alzheimer’s Association surveys regarding brief cognitive


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assessments for detection of dementia found that while a large majority of seniors and primary care
physicians say the assessments are important, only half of seniors have received an assessment, and
only 16 percent of seniors receive regular cognitive assessments. Many educational opportunities exist
to facilitate increased use of brief cognitive assessments in the primary care setting.
Keywords:
Alzheimer’s disease; Alzheimer’s dementia; Dementia; Diagnostic criteria; Risk factors; Prevalence; Incidence;
Mortality; Morbidity; Caregivers; Family caregiver; Spouse caregiver; Health care professional; Health care costs;
Health care expenditures; Long-term care costs; Medicare spending; Medicaid spending; Brief cognitive assess-
ment; Primary care physician; Medicare Annual Wellness Visit; Early detection
1. About this report
2019 Alzheimer’s Disease Facts and Figures is a
statistical resource for U.S. data related to Alzheimer’s
disease, the most common cause of dementia. Background
and context for interpretation of the data are contained in
the overview. Additional sections address prevalence,
mortality and morbidity, caregiving and use and costs of
health care, long-term care and hospice. A Special
Report discusses Alzheimer’s detection in the primary care
setting.
1.1. Speciﬁc information in this report
Speciﬁc information in this year’s Alzheimer’s Disease
Facts and Figures includes:
 Brain changes that occur with Alzheimer’s disease.
 Risk factors for Alzheimer’s disease.
 Number of Americans with Alzheimer’s dementia
nationally and for each state.
 Lifetime risk for developing Alzheimer’s dementia.
 Proportion of women and men with Alzheimer’s and
other dementias.
*Tel.: 11-312-335-5893; Fax: 11-866-521-8007.
E-mail address: sciencestaff@alz.org
https://doi.org/10.1016/j.jalz.2019.01.010
1552-5260
Alzheimer’s & Dementia 15 (2019) 321-387


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Sex Differences in Lifespan
Steven N. Austad1,* and Kathleen E. Fischer1
1Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294-1170, USA
SUMMARY
Sex differences in longevity can provide insights into novel mechanisms of aging, yet they have 
been little studied. Surprisingly, sex-specific longevity patterns are better known in wild animals. 
Evolutionary hypotheses accounting for longevity patterns in natural populations include 
differential vulnerability to environmental hazards, differential intensity of sexual selection and 
distinct patterns of parental care. Mechanistic hypotheses focus on asymmetric inheritance of sex 
chromosomes and mitochondria. Virtually all intensively studied species show conditional sex 
differences in longevity. Humans are the only species in which one sex is known to have a 
ubiquitous survival advantage. Paradoxically, although women live longer, they suffer greater 
morbidity particularly late in life. This mortality-morbidity paradox may be a consequence of 
greater connective tissue responsiveness to sex hormones in women. Human females’ longevity 
advantage may result from hormonal influences on inflammatory and immunological responses, or 
greater resistance to oxidative damage; current support for these mechanisms is weak.
 INTRODUCTION
The vast majority of animal species have two sexes and those sexes often differ in many 
aspects of their biology. Most obviously, males range from a tiny fraction of the size of 
females to considerably larger and live considerably shorter to substantially longer lives 
(Austad, 2006; Finch, 1990). Sex differences in longevity can potentially be exploited to 
help understand mechanisms underlying variation in longevity within a species. Yet these 
differences remain little studied despite considerable variation among different genotypes of 
commonly used laboratory species such as C. elegans (McCulloch and Gems, 2003), 
Drosophila melanogaster (Malick and Kidwell, 1966), and Mus musculus (Austad, 2011).


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Surprisingly, much more has been reported about sex differences in longevity among wild 
populations than among captive populations because numerous long-term field studies have 
tried to understand the evolutionary forces underlying sex differences in behavior and a host 
of life history traits such as rates of development, mating systems, and reproductive patterns. 
Thus we know that female short-finned pilot whales live nearly twice as long as males 
(Kasuya and Marsh, 1984); and that female African lions, red deer, black-tailed prairie dogs, 
*Correspondence: austad@uab.edu. 
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our 
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of 
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be 
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
HHS Public Access
Author manuscript
Cell Metab. Author manuscript; available in PMC 2017 June 14.
Published in final edited form as:
Cell Metab. 2016 June 14; 23(6): 1022–1033. doi:10.1016/j.cmet.2016.05.019.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Neuroscience
 and
 Biobehavioral
 Reviews
 39
 (2014)
 34–50
Contents
 lists
 available
 at
 ScienceDirect
Neuroscience
 and
 Biobehavioral
 Reviews
journal
 h
 om
 epa
 ge:
 www.elsevier.com/locate/neubiorev
A
 meta-analysis
 of
 sex
 differences
 in
 human
 brain
 structure
Amber
 N.V.
 Ruigrok a,∗,  Gholamreza
 Salimi-Khorshidi b,  Meng-Chuan
 Lai a,c,
Simon
 Baron-Cohen a,d, Michael
 V.
 Lombardo a,e,  Roger
 J.  Tait f,g,  John
 Suckling d,f,g
a Autism
 Research
 Centre,
 Department
 of
 Psychiatry,
 University
 of
 Cambridge,
 Douglas
 House,
 18B
 Trumpington
 Road,
 Cambridge
 CB2
 8AH,
 United
 Kingdom
b Centre
 for
 Functional
 MRI
 of
 the
 Brain
 (FMRIB),
 Nufﬁeld
 Department
 of
 Clinical
 Neurosciences,
 University
 of
 Oxford,
 John
 Radcliffe
 Hospital,
 Oxford
 OX3
9DU,
 United
 Kingdom
c Department
 of
 Psychiatry,
 College
 of
 Medicine,
 National
 Taiwan
 University,
 No.
 1
 Jen-Ai
 Road
 Section
 1,
 Taipei
 10051,
 Taiwan
d Cambridgeshire
 and
 Peterborough
 NHS
 Foundation
 Trust,
 Elizabeth
 House,
 Fulbourn
 Hospital,
 Cambridge
 CB21
 5EF,
 United
 Kingdom
e Department
 of
 Psychology,
 University
 of
 Cyprus,
 P.O.
 Box
 20537,
 CY
 1678
 Nicosia,
 Cyprus
f Brain
 Mapping
 Unit,
 School
 of
 Clinical
 Medicine,
 University
 of
 Cambridge,
 Herchel
 Smith
 Building,
 Robinson
 Way,
 Cambridge
 CB2
 0SP,
 United
 Kingdom
g Behavioural
 and
 Clinical
 Neuroscience
 Institute,
 Department
 of
 Psychology,
 University
 of
 Cambridge,
 Downing
 Street,
 Cambridge
 CB2
 3EB,
 United
 Kingdom
a
 r  t
 i c  l e  
i  n  f  o
Article
 history:
Received
 15
 June
 2013
Received
 in
 revised
 form
13
 December
 2013
Accepted
 17
 December
 2013
Keywords:
Brain
Sex
 differences
Meta-analysis
Gaussian-process
 regression
 (GPR)
Voxel-based
 morphometry
Volume
a
 b
 s
 t  r  a
 c  t
The  prevalence,
 age  of onset,
 and  symptomatology
 of  many  neuropsychiatric
 conditions
 differ
 between
males
 and
 females.
 To  understand
 the  causes  and  consequences
 of  sex  differences
 it is  important


key: chroma:document
string_value:
to  estab-
lish
 where
 they  occur
 in  the  human  brain.  We  report  the  ﬁrst  meta-analysis
 of  typical  sex  differences
 on
global
 brain
 volume,
 a  descriptive
 account
 of the  breakdown
 of studies
 of  each
 compartmental
 volume
by
 six  age  categories,
 and
 whole-brain
 voxel-wise
 meta-analyses
 on  brain
 volume  and  density.  Gaussian-
process
 regression
 coordinate-based
 meta-analysis
 was  used  to examine  sex  differences
 in voxel-based
regional
 volume
 and  density.  On  average,
 males  have  larger  total
 brain
 volumes
 than
 females.
 Exami-
nation
 of the  breakdown
 of  studies
 providing
 total
 volumes
 by  age  categories
 indicated  a bias  towards
the
 18–59  year-old
 category.
 Regional
 sex  differences
 in  volume
 and  tissue  density
 include  the  amyg-
dala,
 hippocampus
 and  insula,
 areas  known
 to be  implicated
 in  sex-biased
 neuropsychiatric
 conditions.
Together,
 these  results  suggest
 candidate
 regions
 for  investigating
 the  asymmetric
 effect  that
 sex  has  on
the
 developing
 brain,
 and
 for  understanding
 sex-biased
 neurological
 and  psychiatric
 conditions.
©
 2014  The  Authors.  Published
 by  Elsevier
 Ltd.
 All  rights
 reserved.
Contents
1.
 
Introduction
 . . .  . . .  . . . . .  . . . .  . . .  .  . . .  . . .  .  .  . .  .  . . . . . . .  .  . . .  . . .  .  . . .  .  .  . .  . . . .  . . . . .  . . .  .  . . .  . . . .  . .  .  . .  . . .  . . .  . . . .  .  . .  .  .  . .  .  . . .  . . .  . . .  .  . . .  .  . . . . .  . . . .  . . .
 .  .  .  . . . . . . . . . .  .  .  .  .  
35
2.
 
Methods.  .  . .  .  . .  .  . . . .  .  . . .  .  . . .  .  . . .  .  . . .  .  . . .  . . . .  .  . . .  . . .  .  . . .  .  . . .  .  . . .  . . .  .  . . .  . . . .  . . .  .  . .  . . . .  . . .  .  . . . .  .  . . .  .  .  . . .  .  . . .  . . . .  . . .  . . . .  . . .  .  . . . . . .  . .  .  . .  .  . . . . .
 .  .  . . .  . . .  . . . .  .  .  
35
2.1.
 
Systematic
 literature
 search


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search
 . . .  . . .  . . . .  .  . . . .  . . .  .  . . .  . . .  .  . . .  . . .  .  .  . . .  . .  . . .  . .  .  . .  .  . .  . . .  . . . .  .  . .  .  .  .  . .  . . .  .  .  . . .  . . . . .  . .  . .  .  .  . . .  .  . . .  .  . . .  . . . . .
 .  .  . . .  .  .  .
 . . .  . . .  
35
2.2.
 
Selection
 criteria  . . . .  . . . . . . . .  . . . .  . . .  .  .  . .  .  . . .  .  . . .  . . . .  . . .  . . .  .  . . .  .  . . .  . .  .  .  . . .  . . .  . . . .  .  .  . . . .  . .  . . .  .  .  .  . .  . . .  .  . . . .  . .  .  . .  .  . . .  .  . . .  .  .  . . .  .  . . . . .  .  . . .  .  .  .  . . .  .  . . .  .  
35
2.3.
 
Data analysis
 . .  .  . . .  .  . . .  .  . . .  . . . . . . .  . . .  .  . . .  .  . . . .  . . .  .  . . .  . . .  . . . .  . . .  . . . .  . . .  .  . . .  . . . .  . .  . . .  . . .  . . .  . . .  .  .  . . .  . . . .  .  . .  . . .  . . .  . . . .  .  . .  .  .  .  . . .  .  . . .  .  .  .  . . . . . . . . . .  . . . 
36
2.3.1.
 
Overall
 volumes
 meta-analysis
 . . . . .  .  . . .  .  . . .  . . . .  . . .  . . . .  . . . . . .  .  . .  . . . . . .  . . .  .  .  . .  .  .  .  . .  . . .  .  .  . . .  . . . . . . .  . . . .  . . .  .  .  . .  .  . . .  .  .  . .  .  .  . . . .
 .  .  . . .  .  . .  .  .  
36
2.3.2.
 
Regional
 coordinate-based
 meta-analysis
 . .  .  . .  .  . . .  . .  . .  .  . .  .  . . .  . . . . .  . . .  .  . . .  . . . . .  . .  . . .  .  . . .  .  . . .  .  . . . .  . . . . .  . . .  . .  . . .  .  . . . . .
 .  .  . . .  .  .  .  . . .  .  .  . .  . 
36
3.
 
Results
 . . . . .  . . . .  . .  .  . . . .  .  . . . .  . . . .  . . .  .  . . .  .  . . .  .  . . .  .  . .  .  . . .  .  . .  .  .  . .  .  .  .  .  .  . .  .  . . .  .  . .  . .  . . .  .  .  . . . .  . . .  . . . .  . .  . . .  .  .  . . .  .  . . .  . . . .  . .  .  . .  .  . . .  .  . . .  .  . . .  .  .  .  . . .  .  . . . . .  .  . . .  .  .  .  . . .  .  
37
3.1.
 
Literature
 search


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search
 . . .  . . . . . . . .  . . . .  . . .  .  .  . .  .  . . .  . . .  .  . . .  .  . . .  .  . .  .  .  . .  . . .  .  .  . . .  .  . . .  . . . .  . .  .  . .  .  . .  . . .  . . . .  .  . . .  .  .  . .  .  . . .  .  . . .  . . . . . . . .  . .  . . . .  .  .  .
 .  . .  . . .  .  .  . .  . . .  .  . . . . 
37
3.2.
 
Sex  differences
 in  overall  volumes
 . . .  . . . .  .  . . .  . . . .  . . . . . .  . . . .  .  . . .  .  . .  . . . .  . . .  . .  . . .  . . . .  .  .  . .  . . .  . . .  . . . .  .  . .  .  .  . . .  . .  .  . . .  . . . . . .  . . . .  . . .
 .  . .  . . . . . . . .  . . .  .  .  .  . 
37
3.2.1.
 
Breakdown
 of  studies  looking  at  overall  volume
 .  . . .  . . .  . . . .  . . .  . . .  . . .  . . . .  .  . .  . . .  .  . . . .  . . .  . . . . .  . . .  . . . .  . . .  .  . . .  .  .  .  . . . . . . . . .  .  . . .  .  .  .  . . . .  .  . .  
37
3.3.
 
Regional
 sex differences
 in  volume
 and  tissue  density.  .  .  .  . . .  .  . .  .  .  . . .  .  . .  . .  . . .  .  .  . . .  . . .  . . .  . . .  .  . . .  .  .  . . .  . . .  .  .  . . .  . . . .  . . .  .  . . . . .  . . .  .  .  .  .  . . . . . .  . . . .  . .  .  
41
3.3.1.
 
Regional
 volume
 meta-analysis
 . . . . .  . . . .  .  . .  . . . .  . . .  . . . . . . .  .  .  . .  . . .  .  .  .  . . . .  . . . . . . .  .  . .  . . .  .  . . . .  . .  .  . .  . . . .  .  . . .  .  . . . .  .  . . .  .  .  . . . . .  .  . . . .  .  .  . .  . .  . . .  
41
3.3.2.
 
Regional
 tissue  density
 meta-analysis
 . .  .  .  . . .  .  .  . .  . . .  .  .  . . .  . .  .  .  . . .  . . .  . . . .  . . .  . . .  .  . . . .  . . .  . . . .  .  . .  .  . . .  . . .  .  . . .  .  . .  .  . . .  . . .  .  . . . . . .  .  . .  .  . .  .  . .  .  . . 
43
4.
 
Discussion


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. .  .  . . . .  .  . . .  . .  .  .  . .  .  . . .  .  . . . . . . . . . .  . . .  .  . . .  .  .  . .  .  . .  .  .  . .  . .  . .  .  . .  .  .  .  . . .  . . . .  . .  .  . .  .  .  . . .  . . . . .  . . .  . .  .  . .  . .  .  . . .  . . . .  .  . .  . .  . . .  . . .  . .  . . .  . . . .  . .  . . . .  .  .  .  .  . .  .
 . . . .  . . . 
43
4.1.  
Brain  development
 . .  .  . .  . . . .  . . . .  . . . .  . . .  .  . . .  .  . . .  .  . . .  .  . . .  . . .  . . .  .  . . . .  . .  .  . . .  .  . . .  . . . . .  . . .  . .  .  . .  . .  . . .  . . .  . .  .  . . . .  .  . . .  .  . . .  . . .  . .  . . .  .  .  . . .  .  .  .
 .  . .  . . . . . . .  . . .  . .  
43
 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.
∗ Corresponding
 author.
 Tel.:
 +44
 1223
 746030/746057;
 fax:
 +44
 1223
 746033.
E-mail
 address:
 ar560@cam.ac.uk
 (A.N.V.
 Ruigrok).
0149-7634/$
 –
 see
 front
 matter
 ©
 2014
 The
 Authors.
 Published
 by
 Elsevier
 Ltd.
 All
 rights
 reserved.
http://dx.doi.org/10.1016/j.neubiorev.2013.12.004


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Annals ofthe Rheumatic Diseases, 1978, 37, 277-280
Case report
Polymyositis in Chagas's disease
W. COSSERMELLI, H. FRIEDMAN, E. H. PASTOR, M. R. NOBRE,
A. MANZIONE, M. E. CAMARGO, AND M. SHIROMA
From the Rheumatology Research Unit and Department of Pathology, Faculty of Medicine, University of
Sao Paulo, Brazil
suMMARY
Polymyositis marked the clinical onset of Chagas's disease in a patient with rheumatoid
arthritis. This is unusual, although clinically unimportant muscle involvement in trypanosomiasis
has been described. The plasma cell infiltrate and vascular deposition of IgM and C3 suggest that
the humoral immune system may play a role in the pathogenesis of chagasic polymyositis. It is not
known whether the rheumatoid diseases predisposed to the polymyositis.
There are few reports of myositis
in Chagas's
disease, although this is commonly seen in experi-
mental models (Wolf et al., 1952; Andrade and
Andrade,
1968).
Myositis
associated
with
the
presence of parasites was demonstrated by Ponce
(1972) in sequential biopsies of the gastrocnemius
muscle in patients with chronic and acute Chagas's
disease and cardiopathy. Cenget and Rojas (1959)
observed deltoid myositis in 96-3% of 27 chagasic
patients, but did not mention parasites in the muscle
lesions.
Cossio et al. (1974a, b) described a circulating
autoantibody that reacts against endocardium, as
well as vessels and interstitium of skeletal muscle
and myocardium and interacts with complement
(EVI antibody). It was found in 95% ofpatients with
Chagas's heart disease and in 45 % of asymptomatic
individuals infected with Trypanosoma cruzi. In the
early stage of acute heart disease EVI antibody is of
IgM class but one month later both IgM and IgG
antibodies are found. We report a patient with
definite rheumatoid arthritis who developed chagasic
polymyositis.
Case report
A 43-year-old
white female had
suffered from
rheumathoid arthritis from age 17 years. Early in
the course of the disease she received gold salts with
remarkable improvement. After a 15-year period


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without symptoms, she then started to complain of
Accepted for publication September 5, 1977
Correspondence
to
Dr W.
Cossermelli,
Faculdade
de
Medicina, Universidade de Sao Paulo, SP 2921, Sao Paulo-
SP Brazil.
joint pain in both hands, shoulders, and knees, with
morning stiffness and fever of 38°C. Nonsteroidal
anti-inflammatory drugs provided some relief. At
this time she had her tonsils removed. Postoperatively
she received 500 ml of fresh blood. 10 days after
surgery her joint pains increased and were accom-
panied by muscle weakness and pain in the shoulders,
thighs, and legs, fever of 40°C ,and tachycardia. She
was wholly incapacitated by the muscle weakness.
Raised values of transaminases and LDH isoenzymes
and positive antinuclear factor were recorded. Pred-
nisone 80 mg bd was started, but 20 days later she
was no better and was admitted to the Hospital das
Clinicas da Universidade de Sao Paulo.
Her general condition was fair, blood pressure
110/70 mmHg, pulse rate 100/min, respiratory rate
30/min, and temperature 38°C. No cardiac murmurs
or changes in heart sounds or rhythm disturbances
were found. The lungs were normal on examination.
The spleen was not palpable, but the liver was
enlarged about 3 cm. There was pain on joint move-
ment in both hands, shoulders, knees, and ankles.
The left ankle was swollen without limited movement.
Muscle
weakness
in
a
symmetrical,
proximal
distribution was the prominent feature, and the
affected muscles were tender to pressure. Tendon
reflexes were well preserved.
The erythrocyte sedimentation rate was 49 mm/h,
RA latex fixation test 1:80, negative LE-cell test,
antinuclear antibodies (ANA) positive at a 1:5000
dilution (rat liver preparation),
total haemolytic
complement 15 U (normal: 166-333), C3 0-6 g/l
(normal 0 8-1 * 2 g/l). Total protein measured 102 g/l,
gammaglobulin 44 g/l. Serum muscle enzymes were
markedly raised:
creatine phosphokinase (CPK)
277


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Aging hallmarks exhibit organ-specific temporal signatures
Nicholas Schaum1,#, Benoit Lehallier2,#, Oliver Hahn2,#, Róbert Pálovics2, Shayan 
Hosseinzadeh3, Song E. Lee2, Rene Sit3, Davis P. Lee4, Patricia Morán Losada2, Macy E. 
Zardeneta4, Tobias Fehlmann5, James Webber3, Aaron McGeever3, Kruti Calcuttawala2, Hui 
Zhang4, Daniela Berdnik4, Vidhu Mathur2, Weilun Tan3, Alexander Zee3, Michelle Tan3, The 
Tabula Muris Consortium†, Angela Pisco3, Jim Karkanias3, Norma F. Neff3, Andreas 
Keller2,5,*, Spyros Darmanis3, Stephen R. Quake3,6,*, Tony Wyss-Coray2,4,7,8,*
1Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of 
Medicine, Stanford, California, USA.
2Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 
Stanford, California, USA.
3Chan Zuckerberg Biohub, San Francisco, California, USA.
4Veterans Administration Palo Alto Healthcare System, Palo Alto, California, USA.
5Clinical Bioinformatics, Saarland University, Saarbrücken, Germany.
6Department of Bioengineering, Stanford University, Stanford, California, USA.
7Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, 
California, USA.
8Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, California, 
USA.
Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, 
subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#termsAuthor Information 
Reprints and permissions information is available at www.nature.com/reprints. Readers are welcome to comment on the online version 
of the paper.
*Correspondence to twc@stanford.edu or quake@stanford.edu.
#These authors contributed equally.
†A full list of authors and affiliations appears in the online version of the paper.
Author Contributions


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N.S., B.L., S.R.Q., and T.W.-C. conceptualized the study. N.S., O.H., B.L., R.P., and T.W.-C. conceptualized the analysis. O.H., B.L., 
and R.P. with contributions from A.K., and T.F. conducted the transcriptomic analyses. N.S., S.E.L., D.P.L., M.E.Z., H.Z., and D.B. 
collected samples and extracted RNA. S.H., A.Z., and W.T. conducted cDNA and library preparation. P.M.L. created the Shiny web 
interface. R.S. and M.T. performed sequencing and library quality control. S.H., A.O.P., J.W., and A.M. processed raw sequencing 
data. The Tabula Muris Senis Consortium generated the single-cell sequencing database. N.S. and K.C. performed and analyzed FACS 
and RNAscope experiments. N.S., B.L., O.H., T.W.-C., and S.R.Q. wrote and edited the manuscript. T.W.-C., S.R.Q., S.D., N.F.N. and 
J.K. supervised the work.
Supplementary Information is available in the online version of the paper.
The authors declare no competing financial interests.
Code Availability
All code was limited to the commercial software listed in the methods and reporting summary.
Data Availability
Raw data are available on GEO (GSE132040).
Reviewer Information Nature thanks the anonymous reviewers for their contributions to the peer review of this work.
HHS Public Access
Author manuscript
Nature. Author manuscript; available in PMC 2021 January 15.
Published in final edited form as:
Nature. 2020 July ; 583(7817): 596–602. doi:10.1038/s41586-020-2499-y.
Author Manuscript
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Alzheimer’s Pathogenic Mechanisms and Underlying Sex 
Difference
Donghui Zhu1,2,*, Axel Montagne3,4, Zhen Zhao3,4
1Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, United States
2Neuroscience Graduate Program, Renaissance School of Medicine, Stony Brook University, 
Stony Brook, NY, United States
3Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern 
California, Los Angeles, CA, United States
4Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los 
Angeles, CA, United States
Abstract
Both men and women can have Alzheimer’s disease (AD), and there might be sex differences. 
AD is a neurodegenerative disease, and its frequency is often reported to be higher for women 
than men: almost two-thirds of patients with AD are women. One prevailing view is that women 
live longer than men on average of 4.5 years, plus there are more women aged 85 years or 
older than men in most global subpopulations; and older age is the greatest risk factor for 
AD. However, the differences in the actual risk of developing AD for men and women of 
the same age is difficult to assess, and the findings have been mixed. An increasing body of 
evidence from preclinical and clinical studies as well as the complications in estimating incidence 
support the sex-specific biological mechanisms in diverging AD risk as an important adjunct 
explanation to the epidemiologic perspective. While some of the sex differences in AD prevalence 
are due to differences in longevity, other distinct biological mechanisms increase the risk and 
progression of AD in women. These risk factors include 1) deviations in brain structure and 
biomarkers, 2) psychosocial stress responses, 3) pregnancy, menopause, and sex hormones, 4) 
genetic background (i.e., APOE), 5) inflammation, gliosis, and immune module (i.e., TREM2), 
and 6) vascular disorders. More studies focusing on the underlying biological mechanisms for this


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phenomenon are needed to better understand AD. This review presents the most recent data in 
sex differences in AD – the gateway to precision medicine, therefore, shaping expert perspectives, 
inspiring researchers to go in new directions, and driving development of future diagnostic tools 
and treatments for AD in a more customized way.
Keywords
aging; dementia; gender difference; cognition; hormones; estrogen; menopause
*Corresponding author: Donghui.Zhu@stonybrook.edu (D. Zhu). 
Conflicts of Interest
The authors declare no conflicts of interest.
HHS Public Access
Author manuscript
Cell Mol Life Sci. Author manuscript; available in PMC 2022 January 02.
Published in final edited form as:
Cell Mol Life Sci. 2021 June ; 78(11): 4907–4920. doi:10.1007/s00018-021-03830-w.
Author Manuscript
Author Manuscript
Author Manuscript
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The times they are a-changinâ : a proposal on how brain flexibility goes beyond the obvious to include the concepts of â upwardâ  and â downwardâ  to neuroplasticity


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REVIEW ARTICLE
OPEN
The times they are a-changin’: a proposal on how brain
ﬂexibility goes beyond the obvious to include the concepts
of “upward” and “downward” to neuroplasticity
Cassiano Ricardo Alves Faria Diniz
1,2✉ and Ana Paula Crestani
1,2✉
© The Author(s) 2022
Since the brain was found to be somehow ﬂexible, plastic, researchers worldwide have been trying to comprehend its
fundamentals to better understand the brain itself, make predictions, disentangle the neurobiology of brain diseases, and ﬁnally
propose up-to-date treatments. Neuroplasticity is simple as a concept, but extremely complex when it comes to its mechanisms.
This review aims to bring to light an aspect about neuroplasticity that is often not given enough attention as it should, the fact
that the brain’s ability to change would include its ability to disconnect synapses. So, neuronal shrinkage, decrease in spine
density or dendritic complexity should be included within the concept of neuroplasticity as part of its mechanisms, not as an
impairment of it. To that end, we extensively describe a variety of studies involving topics such as neurodevelopment, aging,
stress, memory and homeostatic plasticity to highlight how the weakening and disconnection of synapses organically permeate
the brain in so many ways as a good practice of its intrinsic physiology. Therefore, we propose to break down neuroplasticity
into two sub-concepts, “upward neuroplasticity” for changes related to synaptic construction and “downward neuroplasticity”
for changes related to synaptic deconstruction. With these sub-concepts, neuroplasticity could be better understood from a
bigger landscape as a vector in which both directions could be taken for the brain to ﬂexibly adapt to certain demands. Such a
paradigm shift would allow a better understanding of the concept of neuroplasticity to avoid any data interpretation bias, once
it makes clear that there is no morality with regard to the organic and physiological changes that involve dynamic biological


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systems as seen in the brain.
Molecular Psychiatry (2023) 28:977–992; https://doi.org/10.1038/s41380-022-01931-x
INTRODUCTION
The etymology of neuroplasticity breaks it down into two basic
morphemes: neuro- plastic; with the “plastic” originally meaning
“suitable for molding” as it comes ﬁrst from the Greek term
“plastikós” and later from the Latin “plasticus”. As a concept,
neuroplasticity means the nervous system’s ability to reorganize its
structure and functioning in response to some stimuli, either
intrinsic or extrinsic [1]. Although simple in deﬁnition, the historical
ground behind this concept relies entirely on the shoulders of
magniﬁcent and pioneering scientists. From a philosophical
perspective, plasticity roots, as a reference to the nervous system,
are still a matter of debate and have been tracked back to Willian
James (1890), Santiago Ramón y Cajal (1894) and Demor (1896) in
the late 1800s or Lugaro (1906) and Minea (1909) in the early 1900s
[2–4]. However, the practical relevance of the neuroplasticity only
began to be unveiled in the mid-20th century by Paul Bach-y-Rita
who built the concept of sensory substitution by proposing that
other brain areas may assume functions previously mediated by a
lost neural tissue [5]. Similarly, based on Wilder Penﬁeld works that
showed a motor and sensory cortical representation of the body [6],
Michael Merzenich noted that the adult brain is actually a dynamic
structure, with the cortical body representations constantly shifting
its boundaries [7]. Intriguing, Merzenich’s ﬁndings were initially
criticized by David Hubel and Torsten Wiesel, two eminent
neuroscientists at Johns Hopkins who had found a critical period
for visual cortex plasticity to allow visual processing input to be
replaced by the non-deprived eye at the expense of the deprived
one [8, 9].
All
the
ﬁeld
advancement
has
not
come
without
the
controversy of the unknown and, not surprisingly, for so long
the adult brain was considered hard-wired, incapable of any


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accommodation. However, after some breakthroughs, neuroplas-
ticity is now well recognized as a fundamental and lifelong brain
property. Although partially compromised, compared to early
neurodevelopment, adult brain remodeling is still salient and
fairly required for learning/experience- and internal milieu-based
behavioral adjustments [10].
Bearing in mind a broader perspective of a ﬂexible brain, we will
go through studies related to early neurodevelopment, aging,
stress, memory, and homeostatic plasticity to propose that brain
ﬂexibility goes beyond the obvious to include the concepts of
“upward” and “downward” to neuroplasticity. Such sub-concepts
aim to clarify how neuroplasticity is not only about building, but
also about dismantling.
Received: 21 September 2022 Revised: 7 December 2022 Accepted: 14 December 2022
Published online: 27 December 2022
1School of Medicine, Campus USP, Ribeirão Preto, SP, Brazil. 2Center for Neuroscience, University of California, Davis, CA, USA. ✉email: crafd87@gmail.com;
paula.crestani@gmail.com
www.nature.com/mp
Molecular Psychiatry
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Chronic intermittent ethanol exposure differentially alters the excitability of neurons in the orbitofrontal cortex and basolate\
ral amygdala that project to the dorsal striatum


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Chronic intermittent ethanol exposure differentially alters the 
excitability of neurons in the orbitofrontal cortex and basolateral 
amygdala that project to the dorsal striatum
Sudarat Nimitvilai-Roberts1, Dominic Gioia1, Marcelo F. Lopez2, Christina M. Glaser1, John 
J. Woodward1,2,*
1Department of Neuroscience
2Department of Psychiatry and Behavioral Sciences, Addiction Sciences Division, Medical 
University of South Carolina, Charleston, SC 29425
Abstract
Alcohol use disorder is associated with altered neuronal function including those in orbitofrontal 
cortex (OFC) and basolateral amygdala (BLA) that send glutamatergic inputs to areas of the dorsal 
striatum (DS) that mediate goal and habit directed actions. Previous studies reported that chronic 
intermittent (CIE) exposure to ethanol alters the electrophysiological properties of OFC and BLA 
neurons, although projection targets for these neurons were not identified. In this study, we used 
male and female mice and recorded current-evoked spiking of retrobead labeled DS-projecting 
OFC and BLA neurons in the same animals following air or CIE treatment. DS-projecting OFC 
neurons were hyperexcitable 3- and 7-days following CIE exposure and spiking returned to 
control levels after 14 days of withdrawal. In contrast, firing was decreased in DS-projecting 
BLA neurons at 3-days withdrawal, increased at 7- and 14-days and returned to baseline at 28 
days post-CIE. CIE exposure enhanced the amplitude and frequency of spontaneous excitatory 
postsynaptic currents (sEPSCs) of DS-projecting OFC neurons but had no effect on inhibitory 
postsynaptic currents (sIPSCs). In DS-projecting BLA neurons, the amplitude and frequency of 
sIPSCs was enhanced 3 days post-CIE with no change in sEPSCs while at 7-days post-withdrawal, 
sEPSC amplitude and frequency were increased and sIPSCs had returned to normal. Finally, 
in CIE-treated mice, acute ethanol no longer inhibited spike firing of DS-projecting OFC and


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BLA neurons. Overall, these results suggest that CIE-induced changes in the excitability of 
DS-projecting OFC and BLA neurons could underlie deficits in behavioral control often observed 
in alcohol-dependent individuals.
Keywords
Orbitofrontal cortex; basolateral amygdala; dorsal medial striatum; chronic ethanol exposure; 
intrinsic excitability; spontaneous postsynaptic currents
*Corresponding author: John J. Woodward, PhD, Dept. of Neuroscience, 30 Courtenay Drive, STB627B, Charleston, SC 29425, Tel: 
843-792-5225, woodward@musc.edu.
Author contributions
Participated in research design: S. Nimitvilai-Roberts, J.J. Woodward; Conducted experiments: S. Nimitvilai-Roberts, D. Gioia, M.F. 
Lopez; C.M. Glaser; Performed data analysis: S. Nimitvilai-Roberts, J.J. Woodward; Wrote or contributed to the writing of the 
manuscript: S. Nimitvilai-Roberts, J.J. Woodward.
HHS Public Access
Author manuscript
Neuropharmacology. Author manuscript; available in PMC 2023 May 01.
Published in final edited form as:
Neuropharmacology. ; 228: 109463. doi:10.1016/j.neuropharm.2023.109463.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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REVIEW ARTICLE
OPEN
Synthetic biology-inspired cell engineering in diagnosis,
treatment, and drug development
Ninglin Zhao1, Yingjie Song2, Xiangqian Xie3, Ziqi Zhu1, Chenxi Duan1, Cheng Nong1, Huan Wang
3✉ and Rui Bao
1✉
The fast-developing synthetic biology (SB) has provided many genetic tools to reprogram and engineer cells for improved
performance, novel functions, and diverse applications. Such cell engineering resources can play a critical role in the research and
development of novel therapeutics. However, there are certain limitations and challenges in applying genetically engineered cells
in clinical practice. This literature review updates the recent advances in biomedical applications, including diagnosis, treatment,
and drug development, of SB-inspired cell engineering. It describes technologies and relevant examples in a clinical and
experimental setup that may signiﬁcantly impact the biomedicine ﬁeld. At last, this review concludes the results with future
directions to optimize the performances of synthetic gene circuits to regulate the therapeutic activities of cell-based tools in speciﬁc
diseases.
Signal Transduction and Targeted Therapy  (2023) 8:112 
; https://doi.org/10.1038/s41392-023-01375-x
INTRODUCTION
Modern science is becoming highly multidisciplinary to promote
the innovation of new theories and technologies. Synthetic biology
(SB) is one of the fastest-growing and most dynamic multi-
disciplinary ﬁelds comprising different projects, approaches, and
deﬁnitions.1–3 SB applies engineering principles to genetically
design and transform cells or living organisms by constructing
biological functional components, devices, and systems, creating or
reinventing biological modules to meet human needs, or even
creating novel biological systems.4 SB-inspired cell factory engi-
neering for industrial applications, in a narrow concept, is about
using renewable biomass resources as raw materials and synthetic
assembly of existing components from microbial or animal cells to


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produce various products.5–7 Engineered and standardized func-
tional modules are the strengths of SB. Appropriate interface design
makes modules detachable, improving their stability and compat-
ibility in different environments. Whole-genome synthesis, redesign,
and reconstruction allow generating of artiﬁcial biomimetic/
minimal cells, while atomic or module/domain-level protein
engineering offers high speciﬁcity and controllability over more
complex functions. Meanwhile, innovative modiﬁcation and crea-
tive assembly of signaling and communication systems can further
optimize cell engineering. In addition, mathematical models for
functional module simulation and prediction help streamline circuit
design for the development of invaluable research tools.8–10
Engineered cells can have various applications, including the
production of industrial or pharmaceutical compounds and
increasing agricultural productivity by alleviating pathogens and
environmental challenges.11,12 SB-inspired cell engineering can be
commercialized for medical and healthcare. The main goal of
medical SB is to genetically modify cells and redesign/synthesize
regulatory systems to assist in disease diagnosis and treat-
ment.13,14 Such cell-based sensors and therapies could achieve
more speciﬁc detection and treat diseases on a much broader
scale.12,15,16 Medical SB utilizes rationally designed therapeutic
gene circuits, which can be implanted into the human body via
vectors to correct the targeted defect. SB-inspired cell engineering
with efﬁcient design, speciﬁcity, and control can maximize
therapeutic effects while minimizing side effects.
There are several reviews on SB technologies for developing
therapeutic strategies or improving clinical effectiveness; most of
them covered different aspects or speciﬁc approaches of SB in
medical applications (Fig. 1).17–26 The ongoing development of
engineered cells-derived tools has attracted substantial public
attention.
Accordingly,
this
review
summarizes
the
recent


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recent
preclinical, clinical, and experimental data to discuss the beneﬁts
and
limitations
of SB
techniques
in
cell
engineering
and
biomedical research. Here, we elaborate on various SB-driven cell
devices in diagnosis, treatment, and drug development. Also, we
address the current and potential future challenges for SB and cell
engineering in medical applications.
ENGINEERED CELLS FOR DIAGNOSIS
Accurate disease characterization and monitoring are critical for
therapeutic planning and epidemiological records. However, most
traditional diagnostic procedures involving pathological examina-
tion of biopsies cannot precisely detect the disease state in real-
time and are time-consuming. Thus, there is an urgent need to
enhance current medical diagnostics capabilities. SB-inspired cell
engineering and programmable biosensors have focused on high-
throughput biomolecular/pathogens identiﬁcation and probing,
Received: 5 September 2022 Revised: 31 January 2023 Accepted: 15 February 2023
1Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China; 2College of Life
Science, Sichuan Normal University, Chengdu, China and 3State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center of Nanjing University,
Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
Correspondence: Huan Wang (wanghuan@nju.edu.cn) or Rui Bao (baorui@scu.edu.cn)
These authors contributed equally: Ninglin Zhao, Yingjie Song, Xiangqian Xie.
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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Distinct platelet crosstalk with adaptive and innate immune&nbsp;cells after adenoviral and mRNA vaccination against SARS-CoV-2


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Acute histologic chorioamnionitis independently and directly increases the risk for brain abnormalities seen on MRI in very pret\
erm infants


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Acute histologic chorioamnionitis independently and directly 
increases the risk for brain abnormalities seen on MRI in very 
preterm infants
Viral G Jain, MD1,2, Julia E. Kline, PhD2, Lili He, PhD2, Beth Kline-Fath, MD3,4, Mekibib 
Altaye, PhD5, Louis J. Muglia, MD PhD2,6,7, Emily A DeFranco, DO8, Namasivayam 
Ambalavanan, MD1, Nehal A. Parikh, DO, MS*,2,7,9,
Cincinnati Infant Neurodevelopment Early Prediction Study (CINEPS) Investigators
1.Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, 
Birmingham, AL
2.Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
3.Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
4.Department of Radiology, University of Cincinnati, College of Medicine, Cincinnati, OH
5.Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, 
Cincinnati, OH
6.Burroughs Wellcome Fund, Research Triangle Park, NC
7.Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH
8.Department of Obstetrics & Gynecology, University of Cincinnati, College of Medicine, 
Cincinnati, OH
9.Center for Prevention of Neurodevelopmental Disorders, Cincinnati Children’s Hospital Medical 
Center, Cincinnati, OH
Abstract
Background: The independent risk for neurodevelopmental impairments attributed to 
chorioamnionitis in premature infants remains controversial. Delayed brain maturation or injury 
identified on magnetic resonance imaging (MRI) at term-equivalent age can be used as a surrogate 
measure of neurodevelopmental impairments that is less confounded by post neonatal intensive 
care unit (NICU) environmental factors to more clearly investigate this relationship.
*Correspondence: Nehal A. Parikh, DO, MS, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 7009, 
Cincinnati, OH, 45229, United States, nehal.parikh@cchmc.org, Phone: 513.636.7584.
Author Contribution Statement


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Conceptualization - VGJ, NAP. Methodology – NAP, VGJ, EAD, NA, LJM. Formal Analysis - VGJ, NAP, MA, JK, LH, BKF. Data 
curation & Investigation – NAP, JK, BFK, LH. Writing- Original draft preparation - VGJ. Writing-Reviewing and Editing – NAP, MA, 
EAD, NM, LJM. Supervision - NAP. All authors have reviewed and approved the final version of this manuscript.
Conflict of Interest: None declared
Publisher's Disclaimer: This is a PDF fle 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
Am J Obstet Gynecol. Author manuscript; available in PMC 2023 October 01.
Published in final edited form as:
Am J Obstet Gynecol. 2022 October ; 227(4): 623.e1–623.e13. doi:10.1016/j.ajog.2022.05.042.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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REVIEW ARTICLE
OPEN
Activation of immune signals during organ transplantation
Qingwen Li1,2 and Peixiang Lan1,2✉
The activation of host’s innate and adaptive immune systems can lead to acute and chronic graft rejection, which seriously impacts
graft survival. Thus, it is particularly signiﬁcant to clarify the immune signals, which are critical to the initiation and maintenance of
rejection generated after transplantation. The initiation of response to graft is dependent on sensing of danger and stranger
molecules. The ischemia and reperfusion of grafts lead to cell stress or death, followed by releasing a variety of damage-associated
molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs) of host immune cells to activate
intracellular immune signals and induce sterile inﬂammation. In addition to DAMPs, the graft exposed to ‘non-self’ antigens
(stranger molecules) are recognized by the host immune system, stimulating a more intense immune response and further
aggravating the graft damage. The polymorphism of MHC genes between different individuals is the key for host or donor immune
cells to identify heterologous ‘non-self’ components in allogeneic and xenogeneic organ transplantation. The recognition of ‘non-
self’ antigen by immune cells mediates the activation of immune signals between donor and host, resulting in adaptive memory
immunity and innate trained immunity to the graft, which poses a challenge to the long-term survival of the graft. This review
focuses on innate and adaptive immune cells receptor recognition of damage-associated molecular patterns, alloantigens and
xenoantigens, which is described as danger model and stranger model. In this review, we also discuss the innate trained immunity
in organ transplantation.
Signal Transduction and Targeted Therapy  (2023) 8:110 
; https://doi.org/10.1038/s41392-023-01377-9
INTRODUCTION
Transplantation rejection has always been the most critical
problem affecting the long-term survival of allografts, which


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involves many biological processes. During transplantation, the
graft experiences hypoxia/ischemia during preservation, leading
to dysmetabolism and stress response. On the one hand, it
induces the production of mediators related to inﬂammation and
expands the inﬂammatory damage of cells. On the other hand, it
mediates cells death. Damage-associated molecular patterns
(DAMPs) from cells are exposed on the cell surface or released
extracellular due to cellular stress or death. Graft reperfusion
allows exposed DAMPs to be recognized by pattern recognition
receptors (PRRs) of the host circulating immune cells. The
interaction between DAMPs and PRRs activates PRRs, transmits
activation signals intracellular, and stimulates immune cells to
secrete pro-inﬂammatory cytokines and chemokines, resulting in
aggravated graft injury. In addition to inducing innate immune
response, the DAMPs produced by ischemia/reperfusion can be
involved in the initiation of adaptive immunity as signal 0 via
Dendritic cells (DCs).1 However, it is important to note that
compared to allogeneic transplantation, DAMPs from syngeneic
graft induce DCs production and promote T lymphocyte cloning
and proliferation, but they are not enough to induce DCs to
produce IL-12 and cannot drive T cells to differentiate into
lymphocytes capable of producing IFN-γ.2,3 Therefore, it’s not
sufﬁcient to activate adaptive immune signals.
The host immune system distinguishes self and ‘non-self’
components, tolerates its healthy cells, and eliminates cells with
‘non-self’ antigens, which inevitably lead to graft rejection. To
recognition of ‘non-self’ antigens, the host immune system
requires the participation of receptors of immune cells. TCR of T
and BCR of B lymphocytes can recognize allogeneic ‘non-self’ MHC
antigens, leading to the activation of T and B lymphocyte-
mediated rejection. However, the mere involvement of adaptive
immune cells in recognizing ‘non-self’ MHC molecules cannot
explain the fact that the depletion of lymphocytes still produces


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immune rejection of ‘non-self’ antigens.3 Multiple evidences reveal
that receptors expressed in innate immune NK and myeloid cells
can also recognize allogeneic antigens. These receptors belong to
a family of immunoglobulin-like receptors (ILRs), which recognize
MHC molecules including classical and non-classical MHC and are
involved in the regulation of transplant tolerance and immune
response. Based on the release of DAMPs induced by metabolic
reprogramming and stress responses during transplantation, as
well as the exposure of allogenic molecules to the host, this review
mainly discusses the role of DAMPs, allogenic and xenogeneic
‘non-self’ component in immune recognition and induction of
positive immune signals during transplantation.
HISTORY OF ORGAN TRANSPLANTATION RESEARCH
The history of organ transplantation is inevitably associated with
the development of immunology. Advancements in our under-
standing of immune rejection have also driven clinical application
of organ transplantation. Organ transplantation, as a powerful
treatment for end-stage diseases, has gone through a long and
Received: 26 October 2022 Revised: 10 February 2023 Accepted: 15 February 2023
1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China and 2Key Laboratory of Organ
Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan,
China
Correspondence: Peixiang Lan (lansong9783@126.com)
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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Cellular/Molecular
Opioid Withdrawal Abruptly Disrupts Amygdala Circuit
Function by Reducing Peptide Actions
Gabrielle C. Gregoriou, Sahil D. Patel, Sebastian Pyne,
Bryony L. Winters, and Elena E. Bagley
Sydney Pharmacy School, Faculty of Medicine and Health and Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia, 2111
While the physical signs of opioid withdrawal are most readily observable, withdrawal insidiously drives relapse and contrib-
utes to compulsive drug use, by disrupting emotional learning circuits. How these circuits become disrupted during with-
drawal is poorly understood. Because amygdala neurons mediate relapse, and are highly opioid sensitive, we hypothesized
that opioid withdrawal would induce adaptations in these neurons, opening a window of disrupted emotional learning circuit
function. Under normal physiological conditions, synaptic transmission between the basolateral amygdala (BLA) and the neigh-
boring main island (Im) of GABAergic intercalated cells (ITCs) is strongly inhibited by endogenous opioids. Using patch-clamp
electrophysiology in brain slices prepared from male rats, we reveal that opioid withdrawal abruptly reduces the ability of these
peptides to inhibit neurotransmission, a direct consequence of a protein kinase A (PKA)-driven increase in the synaptic activity
of peptidases. Reduced peptide control of neurotransmission in the amygdala shifts the excitatory/inhibitory balance of inputs
onto accumbens-projecting amygdala cells involved in relapse. These findings provide novel insights into how peptidases control
synaptic activity within the amygdala and presents restoration of endogenous peptide activity during withdrawal as a viable option
to mitigate withdrawal-induced disruptions in emotional learning circuits and rescue the relapse behaviors exhibited during opioid
withdrawal and beyond into abstinence.
Key words: addiction; amygdala; opioids; peptidase; withdrawal
Significance Statement


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We find that opioid withdrawal dials down inhibitory neuropeptide activity in the amygdala. This disrupts both GABAergic
and glutamatergic transmission through amygdala circuits, including reward-related outputs to the nucleus accumbens. This
likely disrupts peptide-dependent emotional learning processes in the amygdala during withdrawal and may direct behavior
toward compulsive drug use.
Introduction
Opioid addiction is characterized by cycles of compulsive drug-
use, withdrawal and relapse (Koob and Volkow, 2016). During
withdrawal, relapse is strongly motivated by disrupted emotional
learning processes. Maladaptive reinforcement mechanisms drive
relapse triggered by the desire to alleviate the aversive withdrawal
state (Wikler and Pescor, 1967; Kenny et al., 2006) and by expo-
sure to cues/contexts previously associated with drug use or with-
drawal (Wikler and Pescor, 1967; Childress et al., 1993; Hellemans
et al., 2006; Crombag et al., 2008). Then, if opioid reuse during
withdrawal does occur, disrupted reward learning processes ele-
vate the incentive value of opiates, which persistently escalates
reward-seeking and taking behaviors (Hutcheson et al., 2001;
Wassum et al., 2016). The cellular adaptions that underlie these
disruptions likely develop in the basolateral amygdala (BLA), as
neural circuits within this area are associated with reinforce-
ment-driven relapse (Stinus et al., 1990; Fuchs and See, 2002;
Frenois et al., 2005) and disrupted reward learning during with-
drawal (Wassum et al., 2016).
Endogenous opioids acting at m-opioid receptors (MORs) in the
BLA mediate the aversive opioid withdrawal state (Frenois et al.,
2002) and learning changes in incentive value during withdrawal
(Wassum et al., 2016). While their involvement in cue/context-
induced reinstatement of opiates is unresolved, endogenous opioids
are also implicated in cue/context-driven relapse to other drugs
such as nicotine (Liu et al., 2009), alcohol (Ciccocioppo et al., 2002),


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and cocaine (Burattini et al., 2008). This suggests that changes to en-
dogenous opioid activity in the BLA during withdrawal may under-
lie the disruptions to emotional learning processes that support and
escalate drug use. Whether BLA endogenous opioid actions are
changed by opioid withdrawal is unknown.
The endogenous opioids that disrupt BLA processes during
opioid withdrawal are likely sourced from neighboring GABAergic
Received July 3, 2022; revised Oct. 18, 2022; accepted Nov. 21, 2022.
Author contributions: E.E.B. designed research; G.C.G., S.D.P., S.P., B.L.W., and E.E.B. performed research;
G.C.G., S.D.P., S.P., and B.L.W. analyzed data; G.C.G. wrote the first draft of the paper; G.C.G. and E.E.B. edited
the paper; E.E.B. wrote the paper.
This work was supported by the National Health and Medical Research Council Grant APP1047372.
The authors declare no competing financial interests.
Correspondence should be addressed to Elena E. Bagley at elena.bagley@sydney.edu.au.
https://doi.org/10.1523/JNEUROSCI.1317-22.2022
Copyright © 2023 the authors
1668 • The Journal of Neuroscience, March 8, 2023 • 43(10):1668–1681


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Systems/Circuits
Model-Based Approach Shows ON Pathway Afferents Elicit a
Transient Decrease of V1 Responses
David St-Amand and Curtis L. Baker Jr
McGill Vision Research Unit, Department of Ophthalmology & Visual Sciences, McGill University, Montreal, Quebec H3G 1A4, Canada
Neurons in the primary visual cortex (V1) receive excitation and inhibition from distinct parallel pathways processing light-
ness (ON) and darkness (OFF). V1 neurons overall respond more strongly to dark than light stimuli, consistent with a pre-
ponderance of darker regions in natural images, as well as human psychophysics. However, it has been unclear whether this
“dark-dominance” is because of more excitation from the OFF pathway or more inhibition from the ON pathway. To under-
stand the mechanisms behind dark-dominance, we record electrophysiological responses of individual simple-type V1 neurons
to natural image stimuli and then train biologically inspired convolutional neural networks to predict the neurons’ responses.
Analyzing a sample of 71 neurons (in anesthetized, paralyzed cats of either sex) has revealed their responses to be more
driven by dark than light stimuli, consistent with previous investigations. We show that this asymmetry is predominantly
because of slower inhibition to dark stimuli rather than to stronger excitation from the thalamocortical OFF pathway.
Consistent with dark-dominant neurons having faster responses than light-dominant neurons, we find dark-dominance to
solely occur in the early latencies of neurons’ responses. Neurons that are strongly dark-dominated also tend to be less orien-
tation-selective. This novel approach gives us new insight into the dark-dominance phenomenon and provides an avenue to
address new questions about excitatory and inhibitory integration in cortical neurons.
Key words: dark dominance; neurophysiology; receptive field; system identification; V1; visual cortex
Significance Statement


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Neurons in the early visual cortex respond on average more strongly to dark than to light stimuli, but the mechanisms behind
this bias have been unclear. Here we address this issue by combining single-unit electrophysiology with a novel machine
learning model to analyze neurons’ responses to natural image stimuli in primary visual cortex. Using these techniques, we
find slower inhibition to light than to dark stimuli to be the leading mechanism behind stronger dark responses. This slower
inhibition to light might help explain other empirical findings, such as why orientation selectivity is weaker at earlier response
latencies. These results demonstrate how imbalances in excitation versus inhibition can give rise to response asymmetries in
cortical neuron responses.
Introduction
The early thalamocortical visual system is separated into two dis-
tinct pathways: an ON pathway, which responds more to lighter
parts of images; and an OFF pathway, which encodes darker
image regions. Neurons in primary visual cortex (V1) combine
inputs from these two pathways, but the nature of this integra-
tion is still poorly understood.
V1 neurons evidently receive asymmetrical inputs from the
two pathways, since they are on average more responsive to dark
than light stimuli (Jin et al., 2008; Yeh et al., 2009), especially at
low spatial frequencies (Kremkow et al., 2014; Jansen et al., 2019)
and shorter time latencies (Komban et al., 2014). This asymmetry
is presumably adaptive because of the preponderance of dark
regions in natural images (Ratliff et al., 2010), which is also more
pronounced at lower spatial frequencies (Cooper and Norcia,
2015). These asymmetries may influence human perception,
since dark stimuli are processed faster and more reliably than
light stimuli (Buchner and Baumgartner, 2007; Komban et al.,
2011).
There are more OFF than ON excitatory inputs from the
LGN to layer 4 of V1, which could help explain why responses to
dark stimuli are stronger in V1 (Jin et al., 2008). However, this


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does not explain why more dark-dominant neurons are found in
layers 2/3 than in layer 4 (Yeh et al., 2009). This discrepancy
could be explained by stronger ON than OFF intracortical
Received June 21, 2022; revised Jan. 29, 2023; accepted Jan. 30, 2023.
Author contributions: D.S.-A. and C.L.B. designed research; D.S.-A. performed research; D.S.-A. analyzed
data; D.S.-A. wrote the first draft of the paper; D.S.-A. and C.L.B. edited the paper.
This work was supported by Canadian Institutes of Health Research Grant MOP-119498 to C.L.B. We thank
Guangxing Li for contributions to software and technical support in experiments; and Philippe Nguyen and
Amol Gharat for important contributions to data collection and spike-sorting.
The authors declare no competing financial interests.
Correspondence should be addressed to Curtis L. Baker at curtis.baker@mcgill.ca.
https://doi.org/10.1523/JNEUROSCI.1220-22.2023
Copyright © 2023 the authors
1920 • The Journal of Neuroscience, March 15, 2023 • 43(11):1920–1932


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Axial Shortening in Myopic Children after Repeated Low-Level Red-Light Therapy: Post Hoc Analysis of a Randomized Trial


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ORIGINAL RESEARCH
Axial Shortening in Myopic Children after Repeated
Low-Level Red-Light Therapy: Post Hoc Analysis
of a Randomized Trial
Wei Wang . Yu Jiang . Zhuoting Zhu . Shiran Zhang .
Meng Xuan . Xingping Tan . Xiangbin Kong . Hui Zhong .
Gabriella Bulloch . Ruilin Xiong . Yixiong Yuan . Yanping Chen .
Jian Zhang . Junwen Zeng . Ian G. Morgan . Mingguang He
Received: January 1, 2023 / Accepted: January 31, 2023 / Published online: February 15, 2023
 The Author(s) 2023
ABSTRACT
Introduction: Axial length (AL) elongation in
myopia is considered irreversible. We aimed to
systemically report unexpected AL shortening
observed in a randomized clinical trial (RCT)
after repeated low-level red-light (RLRL) therapy.
Methods: This is a post hoc analysis of a multi-
center, single-masked RCT. Two hundred sixty-
four myopic children aged 8–13 years allocated
to RLRL treatment (intervention group) or a sin-
gle vision spectacle (SVS, control group) were
included. AL was measured using an IOL-master
500 at baseline, 1-, 3-, 6-, and 12-month follow-
up visits. AL shortening was deﬁned as AL
reduction from baseline to follow-up visits at
three
cutoffs: [ 0.05 mm, [ 0.10 mm,
and [
0.20 mm. Frequency of AL shortening at differ-
ent cutoffs was calculated. Analysis was done
with intent to treat (ITT).
Results: At 12-months follow up, frequency of
AL shortening [ 0.05 mm was 26/119 (21.85%)
Wei Wang, Yu Jiang, Zhuoting Zhu, and Shiran Zhang
contributed equally and share the ﬁrst authorship.
Supplementary Information
The online version
contains supplementary material available at https://
doi.org/10.1007/s40123-023-00671-7.
W. Wang  Y. Jiang  Z. Zhu  S. Zhang  M. Xuan 
R. Xiong  Y. Yuan  Y. Chen  J. Zhang  J. Zeng 
M. He
State Key Laboratory of Ophthalmology, Zhongshan
Ophthalmic Center, Sun Yat-Sen University,
Guangzhou, China
Z. Zhu  G. Bulloch  M. He (&)
Centre for Eye Research Australia, Royal Victorian
Eye and Ear Hospital, University of Melbourne,
Level 7, 32 Gisborne Street, East Melbourne, VIC


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3004, Australia
e-mail: mingguang.he@unimelb.edu.au
X. Tan
Ophthalmology, Xiangya Hospital, Central South
University, Changsha, Hunan, China
X. Kong
Ophthalmology, Department of Surgery, The
Second People’s Hospital of Foshan, Foshan,
Guangdong, China
H. Zhong
Department of Ophthalmology, Shenzhen
Children’s Hospital, Shenzhen, Guangdong, China
G. Bulloch  M. He
Ophthalmology, Department of Surgery, University
of Melbourne, Melbourne, Australia
I. G. Morgan
Research School of Biology, Australian National
University, Canberra, Australia
Ophthalmol Ther (2023) 12:1223–1237
https://doi.org/10.1007/s40123-023-00671-7


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Vol.:(0123456789)
1 3
Current Neurology and Neuroscience Reports (2023) 23:33–48 
https://doi.org/10.1007/s11910-023-01252-8
Advances in the Rehabilitation of Hemispatial Inattention
Neena R. Singh1,2 · Alexander P. Leff1 
Accepted: 22 December 2022 / Published online: 4 March 2023 
© The Author(s) 2023
Abstract
Purpose of Review There continue to be a plethora of approaches to the rehabilitation of hemispatial inattention, from dif-
ferent forms of sensory stimulation (visual, auditory and somatosensory feedback), through all major modes of non-invasive 
brain stimulation to drug therapies. Here we summarise trials published in the years 2017–2022 and tabulate their effect 
sizes, with the aim of drawing on common themes that may serve to inform future rehabilitative studies.
Recent Findings Immersive virtual reality approaches to visual stimulation seem well tolerated, although they have yet to 
yield any clinically relevant improvements. Dynamic auditory stimulation looks very promising and has high potential for 
implementation. Robotic interventions are limited by their cost and are perhaps best suited to patients with a co-occurring 
hemiparesis. Regarding brain stimulation, rTMS continues to demonstrate moderate effects but tDCS studies have yielded 
disappointing results so far. Drugs, primarily aimed at the dopaminergic system, often demonstrate beneficial effects of a 
medium size, but as with many of the approaches, it seems difficult to predict responders and non-responders.
Summary Our main recommendation is that researchers consider incorporating single-case experimental designs into their 
studies as rehabilitation trials are likely to remain small in terms of patient numbers, and this is the best way to deal with all 
the factors that cause large between-subject heterogeneity.
Keywords Hemispatial inattention · Neglect · Sensory stimulation · Brain stimulation · Dopaminergic therapy · 
Rehabilitation
Introduction
Hemispatial inattention, also known as ‘neglect’, is an


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acquired neurological deficit affecting attention with a bias 
towards one side of space. This is usually manifested in 
extra-personal space but can also affect the patient’s own 
body parts or intra-personal space. This causes significant 
disability and, when stroke is the cause, often reduces the 
effectiveness of attempts to rehabilitate co-occurring deficits 
such as hemiparesis, causing increased in-patient stays and 
reduced functional independence [1]. It occurs in 25–30% 
of people hospitalised by a stroke and despite a degree of 
spontaneous recovery it can persist into the chronic phase 
(>3 months) in a third of cases [2].
Given its significant impact on stroke recovery, there 
has been a considerable focus on the rehabilitation of hem-
ispatial inattention, with a variety of approaches trialled 
over the past 60 years employing either sensory stimula-
tion, indirect brain stimulation, or drugs. Here we review 
the most recent studies in the field. Given the diversity 
of approaches, it can be challenging to compare results 
across studies. This is compounded by the lack of stand-
ardisation of outcome measures (summarised in Table 1). 
We have addressed this by tabulating unstandardised (raw) 
and standardised (usually Cohen’s d) effects for all the 
reviewed studies, where these have been reported or can be 
calculated from the data or figures provided (Table 2). We 
have limited ourselves to primary outcome measures in the 
main text and split these into measures of impairment (e.g. 
cancellation tasks) or function (e.g. the Catherine Bergego 
Scale (CBS)). There is no accepted Minimally Important 
Clinical Difference (MICD) for cancellation tasks. For the 
CBS, a reduction of four points is considered meaningful 
[3].
 * Alexander P. Leff 
 
a.leff@ucl.ac.uk
1 
UCL Queen Square institute of Neurology, University 
College London, London, UK
2 
Department of Neurology, Neurosciences Institute, Cleveland 
Clinic London, London, UK


key: title
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Clinically Significant Axial Shortening in Myopic Children After Repeated Low-Level Red Light Therapy: A Retrospective Multicenter Analysis


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ORIGINAL RESEARCH
Clinically Signiﬁcant Axial Shortening in Myopic
Children After Repeated Low-Level Red Light Therapy:
A Retrospective Multicenter Analysis
Wei Wang . Yu Jiang . Zhuoting Zhu . Shiran Zhang .
Meng Xuan . Yanping Chen . Ruilin Xiong . Gabriella Bulloch .
Junwen Zeng . Ian G. Morgan . Mingguang He
Received: October 22, 2022 / Accepted: December 14, 2022 / Published online: January 7, 2023
 The Author(s) 2023
ABSTRACT
Introduction: Myopia is recognized as a pro-
gressive eye disease. The aim of this study was to
evaluate the frequency and associated factors of
clinically signiﬁcant axial length (AL) shorten-
ing among myopic children following repeated
low-level red light (RLRL) therapy.
Methods: The clinical data that were collected
for the myopic children aged 3–17 years who
received an RLRL therapy delivered by home-
use desktop light device that emitted light at
650 nm for at least 1 year, were reviewed. The
clinical data included AL, spherical equivalent
refraction (SER), and visual acuity measured at
baseline and follow-up. The primary outcomes
were
frequency
of
AL
shortening
of [ 0.05 mm, [ 0.10 mm, and [ 0.20 mm per
year, and associated factors of AL shortening per
year.
Results: A total of 434 myopic children with at
least 12 months of follow-up data were inclu-
ded. The mean age of participants was 9.7 (2.6)
years with SER of -3.74 (2.60) diopters. There
were 115 (26.50%), 76 (17.51%), and 20 (4.61%)
children with AL shortening based on cutoffs of
0.05 mm/year,
0.10 mm/year,
and
0.20 mm/
year, respectively. In the multivariable model,
AL shortening was signiﬁcantly associated with
older baseline age, female gender, and longer
baseline AL
or greater spherical
equivalent
Wei Wang, Yu Jiang, Zhuoting Zhu, and Shiran Zhang
contributed equally.
Supplementary Information
The online version
contains supplementary material available at https://
doi.org/10.1007/s40123-022-00644-2.
W. Wang  Y. Jiang  Z. Zhu  S. Zhang  M. Xuan 
Y. Chen  R. Xiong  J. Zeng  M. He (&)


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State Key Laboratory of Ophthalmology,
Guangdong Provincial Key Laboratory of
Ophthalmology and Visual Science, Zhongshan
Ophthalmic Center, Sun Yat-Sen University,
Guangzhou 510060, China
e-mail: mingguang.he@unimelb.edu.au
G. Bulloch  M. He
Centre for Eye Research Australia, Royal Victorian
Eye and Ear Hospital, University of Melbourne,
Level 7, 32 Gisborne Street, East Melbourne, VIC
3004, Australia
I. G. Morgan
Research School of Biology, Australian National
University, Canberra, Australia
M. He
Ophthalmology, Department of Surgery, University
of Melbourne, Melbourne, Australia
Ophthalmol Ther (2023) 12:999–1011
https://doi.org/10.1007/s40123-022-00644-2


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Neisseria gonorrhoeae co-opts C4b-binding protein to enhance complement-independent survival from neutrophils


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RESEARCH ARTICLE
Neisseria gonorrhoeae co-opts C4b-binding
protein to enhance complement-independent
survival from neutrophils
Lacie M. Werner1, Allison Alcott1¤a, Frida Mohlin2, Jocelyn C. Ray1, Meagan Belcher
Dufrisne3, Asya Smirnov1¤b, Linda Columbus3, Anna M. Blom2, Alison K. CrissID1*
1 Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville,
Virginia, United States of America, 2 Department of Translational Medicine, Lund University, Malmo,
Sweden, 3 Department of Chemistry, University of Virginia, Charlottesville, Virginia, United States of America
¤a Current address: Thermo Fisher Scientific, Gaithersburg, Maryland, United States of America
¤b Current address: Department of Molecular Microbiology, Washington University School of Medicine,
St. Louis, Missouri, United States of America
* akc2r@virginia.edu
Abstract
Neisseria gonorrhoeae (Gc) is a human-specific pathogen that causes the sexually transmit-
ted infection gonorrhea. Gc survives in neutrophil-rich gonorrheal secretions, and recovered
bacteria predominantly express phase-variable, surface-expressed opacity-associated
(Opa) proteins (Opa+). However, expression of Opa proteins like OpaD decreases Gc sur-
vival when exposed to human neutrophils ex vivo. Here, we made the unexpected observa-
tion that incubation with normal human serum, which is found in inflamed mucosal
secretions, enhances survival of Opa+ Gc from primary human neutrophils. We directly
linked this phenomenon to a novel complement-independent function for C4b-binding pro-
tein (C4BP). When bound to the bacteria, C4BP was necessary and sufficient to suppress
Gc-induced neutrophil reactive oxygen species production and prevent neutrophil phagocy-
tosis of Opa+ Gc. This research identifies for the first time a complement-independent role
for C4BP in enhancing the survival of a pathogenic bacterium from phagocytes, thereby
revealing how Gc exploits inflammatory conditions to persist at human mucosal surfaces.
Author summary


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Gonorrhea is considered an urgent threat to public health with an estimated 87 million
cases occurring annually worldwide, growing antimicrobial resistance, and the absence of
a gonococcal vaccine. Currently, we do not understand how N. gonorrhoeae expressing
opacity (Opa) proteins survive neutrophil defenses and are recovered viable from infected
patients.
Here, we investigated how soluble elements of gonorrhea infection, present in human
serum, contribute to N. gonorrhoeae survival from neutrophils. We found that the serum
component C4b-binding protein (C4BP) protects N. gonorrhoeae from neutrophil killing
and suppresses neutrophil activation. C4BP limited neutrophil phagocytosis of N.
PLOS PATHOGENS
PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011055
March 2, 2023
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OPEN ACCESS
Citation: Werner LM, Alcott A, Mohlin F, Ray JC,
Belcher Dufrisne M, Smirnov A, et al. (2023)
Neisseria gonorrhoeae co-opts C4b-binding protein
to enhance complement-independent survival from
neutrophils. PLoS Pathog 19(3): e1011055. https://
doi.org/10.1371/journal.ppat.1011055
Editor: H. Steven Seifert, Northwestern University
Feinberg School of Medicine, UNITED STATES
Received: December 8, 2022
Accepted: February 7, 2023
Published: March 2, 2023
Copyright: © 2023 Werner 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: Data for the results
presented in this manuscript are deposited in the
Open Science Framework repository: https://osf.io/
6smfu/?view_only=f870019813d04cd38b6f89a94
21f3788. Raw imaging flow cytometry data are
uploaded to the MyFlowCyt repository as follows:
Phagocytosis and association of bacteria with
neutrophils: https://flowrepository.org/id/RvFrI1
RnnCQSpSV7q5tLgTflvbNzVfC8Edq5I9pyOU8


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BOPRNuxMrLinIOVpmKGZ2 Detecting C4BP on
the bacterial surface: https://flowrepository.org/id/
RvFrDE8iJvnxTCQOq0MD65s5vgpRts4oRz1oo7C


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REVIEW ARTICLE
OPEN
Metabolic landscape in cardiac aging: insights into molecular
biology and therapeutic implications
Saiyang Xie1, Si-Chi Xu2, Wei Deng
3 and Qizhu Tang1✉
Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic
microenvironment has been identiﬁed as a hallmark of malignancy, but recent studies have shed light on its role in cardiovascular
diseases (CVDs). Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging
heart. Metabolic alteration is a common process throughout cardiac degeneration. Importantly, the involvement of cellular
senescence in cardiac injuries, including heart failure and myocardial ischemia and infarction, has been reported. However,
metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility.
Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in
cardiac aging, including autophagy, oxidative stress, epigenetic modiﬁcations, chronic inﬂammation, and myocyte systolic
phenotype regulation. In addition, metabolic status is involved in crucial aspects of myocardial biology, from ﬁbrosis to hypertrophy
and chronic inﬂammation. However, further elucidation of the metabolism involvement in cardiac degeneration is still needed.
Thus, deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the
novel interventions to protect or even restore cardiac function in aging hearts. Here, we summarize emerging concepts about
metabolic landscapes of cardiac aging, with speciﬁc focuses on why metabolic proﬁle alters during cardiac degeneration and how
we could utilize the current knowledge to improve the management of cardiac aging.
Signal Transduction and Targeted Therapy  (2023) 8:114 
; https://doi.org/10.1038/s41392-023-01378-8
INTRODUCTION


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In the past few decades, improved pharmacological and surgical
treatments have contributed to increased life expectancy and
an aging population in certain industrialized countries.1 In
addition, the proportion of the retired population is rapidly
increasing; retirees are much more likely to slide into sedentary
lifestyles,
which
further
accelerates
cardiac
aging.2–5
The
incidence of age-associated disorders, especially cardiovascular
diseases (CVDs), has increased dramatically; in elderly indivi-
duals, these age-related disorders correlate with high hospita-
lization, increased mortality rates, as well as elevated cost.4,5
Even without disease, aging is accompanied with functional
decline of multiple organs. It is characterized by unique
histological and biochemical features, including oxidative stress,
protein misfolding, cell death, and mitochondrial abnormal-
ities.6,7 Similar to other group of organs, the heart function
declines gradually with age, which is evident by the reduced
pump function and myocardial compliance resulting from
increased afterload and insufﬁcient coronary perfusion/oxyge-
nation.8–10 Conventional wisdom suggests that the aging heart
manifests increased left ventricular mass, while considerable
evidence from autopsies and magnetic resonance imaging
demonstrate that cardiac mass tends to be decreased in older
adults and remain the same in women in the absence of
hypertension.11,12 In line with the reduced performance of other
organ systems, the age-related cardiac decline dramatically
accelerates after 50 years of age.10
In elderly individuals, the metabolic landscape during cellular
senescence can increase the risk of cardiac function dysregulation
and cardiac repair dysfunction.13 For example, the stroke volume of
the aging heart is mildly increased during moderate aerobic
exercise. This is partly due to the strength of the Frank-Starling
mechanism (cardiac preload), in which the metabolic demand of the
work rate is substantially enhanced.14,15 In addition, a recent study


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involving metabolic proﬁling of serum and urine in healthy subjects
suggested that aging induces impaired catabolism in glycoproteins,
amino acids, and several lipids, among which cumulative metabo-
lites contribute to the cardiac aging process.16 Importantly,
accumulated evidence from multiomics exploration has highlighted
the complex alterations of metabolic status during aging. In this
regard, we review and outline the recent advancements of the
mechanisms and therapeutic implications of the metabolic land-
scape in aging hearts since this information inﬂuences the
progression of the cardiac dysfunction and lifespan.
DISTINCT SUBSTRATE METABOLISM DURING CARDIAC AGING
Aging hearts are accompanied by several pathological changes in
metabolism (Fig. 1). Below, we outline the major alterations in
metabolism and their involvement in developing cardiac aging.
Received: 12 September 2022 Revised: 6 February 2023 Accepted: 20 February 2023
1Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Cardiovascular Research Institute of Wuhan
University, Wuhan, PR China; 2State Key Laboratory of Complex Severe and Rare Diseases, Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of
Medical Science and Peking Union Medical College, Beijing, PR China and 3Department of Cardiology, Renmin Hospital of Wuhan University, Department of Cardiology, The Fifth
Afﬁliated Hospital of Xinjiang Medical University, Ürümqi, PR China
Correspondence: Qizhu Tang (qztang@whu.edu.cn)
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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Time-resolved transcriptomic profiling of the developing rabbits lungs: impact of premature birth and implications for modelling bronchopulmonary dysplasia


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Storti et al. Respiratory Research           (2023) 24:80  
https://doi.org/10.1186/s12931-023-02380-y
RESEARCH
© 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.
Open Access
Respiratory Research
Time-resolved transcriptomic profiling 
of the developing rabbit’s lungs: impact 
of premature birth and implications 
for modelling bronchopulmonary dysplasia
Matteo Storti1, Maria Laura Faietti2, Xabier Murgia3, Chiara Catozzi1, Ilaria Minato4,5, Danilo Tatoni4,9, 
Simona Cantarella4,8, Francesca Ravanetti6, Luisa Ragionieri6, Roberta Ciccimarra6, Matteo Zoboli6, 
Mar Vilanova7, Ester Sánchez‑Jiménez7, Marina Gay7, Marta Vilaseca7, Gino Villetti1, Barbara Pioselli2, 
Fabrizio Salomone1, Simone Ottonello4,5, Barbara Montanini4,5* and Francesca Ricci1,10* 
Abstract 
Background Premature birth, perinatal inflammation, and life‑saving therapies such as postnatal oxygen and 
mechanical ventilation are strongly associated with the development of bronchopulmonary dysplasia (BPD); these


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risk factors, alone or combined, cause lung inflammation and alter programmed molecular patterns of normal lung 
development. The current knowledge on the molecular regulation of lung development mainly derives from mecha‑
nistic studies conducted in newborn rodents exposed to postnatal hyperoxia, which have been proven useful but 
have some limitations.
Methods Here, we used the rabbit model of BPD as a cost‑effective alternative model that mirrors human lung 
development and, in addition, enables investigating the impact of premature birth per se on the pathophysiology of 
BPD without further perinatal insults (e.g., hyperoxia, LPS‑induced inflammation). First, we characterized the rabbit’s 
normal lung development along the distinct stages (i.e., pseudoglandular, canalicular, saccular, and alveolar phases) 
using histological, transcriptomic and proteomic analyses. Then, the impact of premature birth was investigated, 
comparing the sequential transcriptomic profiles of preterm rabbits obtained at different time intervals during their 
first week of postnatal life with those from age‑matched term pups.
Results Histological findings showed stage‑specific morphological features of the developing rabbit’s lung and 
validated the selected time intervals for the transcriptomic profiling. Cell cycle and embryo development, oxidative 
phosphorylation, and WNT signaling, among others, showed high gene expression in the pseudoglandular phase. 
Autophagy, epithelial morphogenesis, response to transforming growth factor β, angiogenesis, epithelium/endothe‑
lial cells development, and epithelium/endothelial cells migration pathways appeared upregulated from the 28th 
day of gestation (early saccular phase), which represents the starting point of the premature rabbit model. Premature 
birth caused a significant dysregulation of the inflammatory response. TNF‑responsive, NF‑κB regulated genes were 
*Correspondence:
Barbara Montanini
barbara.montanini@unipr.it
Francesca Ricci
F.RICCI@chiesi.com


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ARTICLE
OPEN
A new generation Mpro inhibitor with potent activity against
SARS-CoV-2 Omicron variants
Chong Huang1, Huiping Shuai2,3, Jingxin Qiao1, Yuxin Hou2,3, Rui Zeng1, Anjie Xia
1, Lingwan Xie1, Zhen Fang
1, Yueyue Li1,
Chaemin Yoon2,3, Qiao Huang4, Bingjie Hu2,3, Jing You1, Baoxue Quan1, Xiu Zhao1, Nihong Guo4, Shiyu Zhang4, Ronggang Ma1,
Jiahao Zhang1, Yifei Wang1, Ruicheng Yang1, Shanshan Zhang1, Jinshan Nan1, Haixing Xu1, Falu Wang1, Jian Lei
1✉,
Hin Chu
2,3✉ and Shengyong Yang1✉
Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health.
Small molecule antivirals are an effective treatment strategy to ﬁght against the virus. However, the ﬁrst-generation antivirals either
show limited clinical efﬁcacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these
drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new
generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This
compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but
also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2
mouse model, oral treatment with SY110 signiﬁcantly lowered the viral burdens in lung and alleviated the virus-induced pathology.
Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding
safety proﬁle. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation
provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.
Signal Transduction and Targeted Therapy  (2023) 8:128 
; https://doi.org/10.1038/s41392-023-01392-w
INTRODUCTION


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Since the outbreak of the Coronavirus Disease 2019 (COVID-19)
pandemic
due
to
the
severe
acute
respiratory
syndrome
coronavirus 2 (SARS-CoV-2) in late 2019, more than three years
have passed.1,2 In the battle against this virus, vaccines have
played a decisive role. However, continuous viral mutations, from
Alpha, Beta, to the latest Omicron, bring challenges to the
protection effect of existing vaccines.3–7 Especially, the Omicron
variant and its sublineages have more than 30 mutations on the
spike protein, which is the main target of vaccines, and have
shown much higher transmissibility and escape of immune
elicited by natural infection or vaccines than other SARS-CoV-2
variants.8–11 Furthermore, historical experiences tell us that the
long-term existence of SARS-CoV-2 is perhaps inevitable.12 There-
fore, besides vaccines, effective antivirals are also an important
strategy to address the current epidemic and future threats.
SARS-CoV-2 is a positive-sense single stranded (+ss) RNA
virus.2,13 It belongs to the genus β-coronavirus of the family
Coronaviridae.2 The SARS-CoV-2 genome encodes 14 open reading
frames (ORFs) with a length of around 30 kb. These ORFs encodes
two long polyproteins, pp1a and pp1ab, four structural proteins
and nine accessory proteins. The two polyproteins, pp1a and
pp1ab, are self-catalyzed and cleaved into 16 non-structural
proteins (NSPs) by two cysteine proteases, the main protease
(Mpro, also referred to as 3CLpro) and the papain-like protease
(PLpro).14,15 Mpro is a conserved gene in SARS-CoV-2 and its
variants, as well as other highly pathogenic coronavirus, including
SARS-CoV-1, MERS-CoV.15–18 This protease is responsible for the
generation of 13 NSPs by cleaving pp1a and pp1ab, including
RNA-dependent RNA polymerase (RdRp), helicase, exoribonu-
cleases, 2′-O-methyltransferase and uridine-speciﬁc endoribonu-
clease.15,19 Of note is that Mpro recognizes and cleaves amino acid
sequence of the substrate with speciﬁcity and its most cleavage


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sites at sequences Leu-Gln ↓ (Ser, Ala, or Gly) (↓ represents the
cleavage site), while no known human proteases have the similar
speciﬁcity.20 The critical role of Mpro in viral replication and its high
conservation, combined with no known human proteases with
similar cleavage speciﬁcity, render it an attractive target for the
development of antivirals. The RdRp, a highly versatile enzyme
that assists in RNA synthesis by catalyzing the RNA-template-
dependent
formation
of
phosphodiester
bonds,
is
another
important
antiviral
target,
and
has
also
been
extensively
studied.18,19
Currently, several small-molecule antivirals targeting Mpro or
RdRp have been approved to use in some countries and regions
worldwide. For example, three small-molecule antivirals, Remde-
sivir, Molnupiravir, and Paxlovid (a combination of Nirmatrelvir
and Ritonavir), have been approved to use clinically by US Food
Received: 4 February 2023 Revised: 27 February 2023 Accepted: 5 March 2023
1State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041,
China; 2State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region,
China; 3Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China and 4Key
Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
Correspondence: Jian Lei (leijian@scu.edu.cn) or Hin Chu (hinchu@hku.hk) or Shengyong Yang (yangsy@scu.edu.cn)
These authors contributed equally: Chong Huang, Huiping Shuai, Jingxin Qiao, Yuxin Hou, Rui Zeng, Anjie Xia, Lingwan Xie, Zhen Fang
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex


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Vol.:(0123456789)
1 3
Acta Neuropathologica (2023) 145:439–459 
https://doi.org/10.1007/s00401-023-02541-9
ORIGINAL PAPER
Associations of psychiatric disease and ageing with FKBP5 expression 
converge on superficial layer neurons of the neocortex
Natalie Matosin1,2,3  · Janine Arloth1,4 · Darina Czamara1 · Katrina Z. Edmond2,3 · Malosree Maitra6 · 
Anna S. Fröhlich1,5 · Silvia Martinelli1,5 · Dominic Kaul2,3 · Rachael Bartlett2,3 · Amber R. Curry2,3 · Nils C. Gassen1,8 · 
Kathrin Hafner1 · Nikola S. Müller4 · Karolina Worf4 · Ghalia Rehawi1,4 · Corina Nagy6,9 · Thorhildur Halldorsdottir7 · 
Cristiana Cruceanu1,20 · Miriam Gagliardi10 · Nathalie Gerstner1,4,5 · Maik Ködel1 · Vanessa Murek1,10 · 
Michael J. Ziller1,10 · Elizabeth Scarr11,17 · Ran Tao12 · Andrew E. Jaffe12 · Thomas Arzberger13,14 · Peter Falkai1,13 · 
Joel E. Kleinmann12,15 · Daniel R. Weinberger12,15 · Naguib Mechawar6,9 · Andrea Schmitt13,16 · Brian Dean11,17 · 
Gustavo Turecki6,9,18 · Thomas M. Hyde12,15 · Elisabeth B. Binder1,19
Received: 19 December 2022 / Revised: 18 January 2023 / Accepted: 19 January 2023 / Published online: 2 February 2023 
© The Author(s) 2023
Abstract
Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with 
decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a 
therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expres-
sion is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical 
areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, 
we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 
and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With


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an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and 
protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, 
ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently 
heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. 
Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established 
that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons 
of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found 
that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated 
with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in 
BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 
drug development to treat cognitive symptoms in psychiatric disorders.
Keywords FKBP5 · FKBP51 · Psychosis · Depression · Ageing · Stress · Single cell · Postmortem brain
Introduction
Severe psychiatric disorders—including schizophrenia, 
major depression and bipolar disorder—present a huge 
burden for individuals, society and the healthcare system. 
While there are efficacious treatments, relapse, resistance 
and chronicity are common, and cognitive symptoms in par-
ticular are not adequately treated [28, 58]. A major issue 
is that the approved use of available drugs and treatments 
for specific psychiatric diagnoses, and their prescription 
 * Natalie Matosin 
 
nmatosin@uow.edu.au
 * Elisabeth B. Binder 
 
binder@psych.mpg.de
Extended author information available on the last page of the article


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Biotypes of Central Nervous System Complications in People With Human Immunodeficiency Virus: Virology, Immunology, and Neuropathology


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The Journal of Infectious Diseases                                
S U P P L E M E N T  A R T I C L E
Biotypes of Central Nervous System Complications in 
People With Human Immunodeficiency Virus: 
Virology, Immunology, and Neuropathology
Sarah B. Joseph,1,a, Sara Gianella,2,a Tricia H. Burdo,3 Paola Cinque,4 Magnus Gisslen,5,6 Scott Letendre,2 Avindra Nath,7, Susan Morgello,8
Lishomwa C. Ndhlovu,9,b and Serena Spudich10,b
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; 2Department of Medicine, Division of Infectious Disease and Global 
Public Health, University of California, San Diego, La Jolla, California, USA; 3Department of Microbiology, Immunology and Inflammation, Center for NeuroVirology and Gene Editing, Lewis Katz 
School of Medicine, Temple University, Philadelphia, Pennsylvania, USA; 4Unit of Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy; 5Department of Infectious Diseases, Institute of 
Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 6Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, 
Sweden; 7National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA; 8Departments of Neurology, Neuroscience, and Pathology, Icahn School 
of Medicine at Mount Sinai, New York, New York, USA; 9Department of Medicine, Division of Infectious Diseases, Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, 
USA; and 10Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA
Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to 
experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health 
disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of


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mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and 
effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on 
underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the 
Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and 
guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from 
people with HIV on and off ART.
Keywords. HIV-associated cognitive disorder; HAND; neuroHIV; biomarkers; inflammation; biotype.
aS. B. J. and S. G. contributed equally to this work (shared first authors).
bL. C. N. and S. S. contributed equally to this work (shared last authors).
Correspondence: Sarah B. Joseph, PhD, Department of Microbiology and Immunology, 
University of North Carolina at Chapel Hill, 22-062 Lineberger Comprehensive Cancer Center 
CB# 7295, Chapel Hill, NC 27510 (sbjoseph@email.unc.edu).
The Journal of Infectious Diseases®
2023;227(S1):S3–15 
© The Author(s) 2023. 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, provided 
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/jiac370
Human immunodeficiency virus type 1 (HIV) can be detected 
in the central nervous system (CNS) days after infection [1] and 
is associated with cognitive, neurological, and mental health 
complications [2]. Antiretroviral therapy (ART) has dramat-


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ically reduced CNS morbidity; however, many people with 
HIV (PWH) continue to experience CNS complications, pri-
marily in the form of mild cognitive impairment and mental 
health disorders (eg, depression, anxiety, other neuropsychi-
atric problems) [3–5]. Understanding the complex relation-
ship between HIV infection and neuropathogenesis remains 
a research priority even though ART that suppresses HIV 
replication reduces how HIV directly and indirectly affects 
the CNS.
Decades-long research efforts have not generated a complete 
understanding of the mechanisms by which HIV infection gen-
erates and maintains CNS complications during ART, and no 
effective therapies exist to reverse these complications. 
Inflammation has long been viewed as one of the primary driv-
ers of CNS complications. While an early-stage study aimed at 
reducing monocyte activation in the CNS showed promise for 
improving cognition in PWH [6], several clinical trials aimed at 
reducing neuroinflammation in ART-treated PWH generated 
minimal or no improvement in cognition [7, 8]. Such findings 
may be explained by the following, not mutually exclusive, pos-
sibilities: (1) neuroinflammation is not the exclusive driver of 
adverse CNS outcomes; (2) clinical trials included interven-
tions that were unable to sufficiently inhibit the type of inflam-
mation responsible for CNS complications; (3) participants had 
accumulated irreversible CNS damage prior to the intervention 
(so-called legacy effect); (4) these trials only examined differ-
ences in specific subgroups, which might not be representative 
of the entire populations of PWH; and/or (5) most studies fo-
cused on global cognition and it is possible that certain drugs 
influence some, but not all, domains. These findings highlight 
the need for new approaches for studying neuroHIV.
Biotypes of CNS Complications in People With HIV • JID 2023:227 (Suppl 1) • S3


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Annals of the Rheumatic Diseases, 1978, 37, 89-92
Sulindac
Trials of a new anti-inflammatory drug
E. C. HUSKISSON AND JANE SCOTT
From the Department ofRheumatology, St Bartholomew's Hospital, London ECI
SUMMARY
Trials in patients with rheumatoid arthritis and osteoarthritis showed sulindac to be an
analgesic with anti-inflammatory properties and at least as effective as aspirin. It was effective
within 24 hours in doses of 300-400 mg daily. It had the advantages of twice daily administration
and a lower incidence of gastric side effects than aspirin. Constipation, usually mild, occurred in
20-30% of cases. Like other anti-inflammatory drugs, it was effective in only a proportion of the
patients.
There is no shortage of nonsteroidal anti-inflamma-
tory drugs. A new compound should therefore have
some advantage to justify its introduction. Sulindac
is related to indomethacin and would have such an
advantage
if
it combined the anti-inflammatory
activity of indomethacin with a more acceptable
incidence ofside effects.
Sulindac is an indene analogue of indomethacin
with similar anti-inflammatory potency in animal
models but less tendency to cause gastric bleeding
and ulceration (Van Arman et al., 1972). It is well
absorbed after oral administration with a plasma
half,life of about 8 hours, it is excreted mainly in
the urine as unchanged drug and sulphone metabo-
lite.
Another
metabolite,
the
sulphide,
can
be
detected in plasma and has a long half-life of about
18 hours. It is more active than sulindac in animal
models of inflammation and may account for a
major part of the anti-inflammatory effect (Hucker
etal., 1973).
Methods
Three double-blind trials were carried out, a short-
term
three-way
crossover
trial
in
rheumatoid
arthritis (RA) and long-term studies in both RA and
osteoarthritis (OA).
CROSSOVER STUDY
Twenth-four outpatients with RA entered a cross-
over study, each receiving one week of treatment
with aspirin (3-6 g daily in 4 divided doses), sulindac
Accepted for publication June 20, 1977


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Correspondence to Dr E. C. Huskisson
(400 mg daily in 2 divided doses), and placebo. The
order of treatment was randomised and balanced.
Measurements made at the end of each week of
treatment by a single observer included pain (visual
analogue
scale),
duration
of morning
stiffness,
proximal
interphalangeal
joint
circumference
(Boardman and Hart, 1967), articular index (Ritchie
et al., 1968), and drug preference. The patients com-
pleted a daily visual analogue pain relief scale which
was used to determine the time course of the actions
of the drugs.
LONG-TERM STUDY IN OA
Thirty outpatients with OA of the hip or knee were
allocated randomly to two treatment groups.
14
patients received sulindac in an initial dose of 100 mg
twice daily with the possibility of increasing up to a
total daily dose of 400 mg.
16 patients received
aspirin in an initial dose of 500 mg four times daily
with the possibility of increasing up to a total daily
dose of 4 g. Measurements were made by a single
observer before the start of treatment and after 1, 2,
3, 4, 6, and 8 weeks of treatment. They included pain
severity (visual analogue scale), duration of stiffness
after inactivity, and side effects. The dose of trial
drugs was noted at each visit and checked by
returned tablet counting. Side effects were recorded,
scored as either mild (1), moderate (2), or severe (3),
and used to calculate side effect scores. The side
effect score represented the sum of all side effects at
all assessment visits. Urinalysis and full haematolo-
gical and biochemical monitoring were performed.
An
electrocardiogram
and
an
ophthalmological
assessment were carried out at the beginning and
end of the study.
89


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Potential RNA-dependent RNA polymerase \(RdRp\) inhibitors as prospective drug candidates for SARS-CoV-2


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Altered dendritic morphology in dorsolateral prefrontal cortex of nonhuman primates prenatally exposed to maternal immune activa\
tion


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Altered dendritic morphology in dorsolateral prefrontal cortex 
of nonhuman primates prenatally exposed to maternal immune 
activation
Kari L. Hansona,b,1, Ruth K. Weirc,1, Ana-Maria Iosifd, Judy Van de Waterb,f, Cameron S. 
Cartera,g, A. Kimberley McAllisterg, Melissa D. Baumana,b,e,*, Cynthia M. Schumanna,b,*
aDepartment of Psychiatry and Behavioral Sciences, University of California, Davis School of 
Medicine, United States
bMIND Institute, University of California, Davis, United States
cInnovation & Enterprise Department, University College London, United Kingdom
dDivision of Biostatistics, Department of Public Health Sciences, University of California, Davis, 
United States
eCalifornia National Primate Research Center, University of California, Davis, United States
fRheumatology/Allergy and Clinical Immunology, University of California, Davis, United States
gCenter for Neuroscience, University of California, Davis, United States
Abstract
Women who contract a viral or bacterial infection during pregnancy have an increased risk of 
giving birth to a child with a neurodevelopmental or psychiatric disorder. The effects of maternal 
infection are likely mediated by the maternal immune response, as preclinical animal models have 
confirmed that maternal immune activation (MIA) leads to long lasting changes in offspring brain 
and behavior development. The present study sought to determine the impact of MIA-exposure 
during the first or second trimester on neuronal morphology in dorsolateral prefrontal cortex 
(DLPFC) and hippocampus from brain tissue obtained from MIA-exposed and control male rhesus 
monkey (Macaca mulatta) during late adolescence. MIA-exposed offspring display increased 
neuronal dendritic branching in pyramidal cells in DLPFC infra- and supragranular layers relative 
to controls, with no significant differences observed between offspring exposed to maternal 
infection in the first and second trimester. In addition, the diameter of apical dendrites in DLPFC


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infragranular layer is significantly decreased in MIA-exposed offspring relative to controls, 
irrespective of trimester exposure. In contrast, alterations in hippocampal neuronal morphology 
of MIA-exposed offspring were not evident. These findings demonstrate that a maternal immune 
*Corresponding authors at: Department of Psychiatry and Behavioral Sciences, University of California, Davis School of Medicine, 
United States. mdbauman@ucdavis.edu (M.D. Bauman), cschumann@ucdavis.edu (C.M. Schumann).
1Authors contributed equally.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to 
influence the work reported in this paper.
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Brain Behav Immun. Author manuscript; available in PMC 2023 March 18.
Published in final edited form as:
Brain Behav Immun. 2023 March ; 109: 92–101. doi:10.1016/j.bbi.2023.01.003.
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The Neural Basis for Biased Behavioral Responses Evoked by Galvanic Vestibular Stimulation in Primates


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Systems/Circuits
The Neural Basis for Biased Behavioral Responses Evoked by
Galvanic Vestibular Stimulation in Primates
Patrick A. Forbes,1p Annie Kwan,2p Diana E. Mitchell,3 Jean-Sébastien Blouin,4 and
Kathleen E. Cullen3,5,6,7,8
1Department of Neuroscience, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands, 2Departments of
Biomedical Engineering and, 3Physiology, McGill University, Montréal, Québec H3G 1Y6, Canada, 4School of Kinesiology, University of British
Columbia, Vancouver, British Colombia V6T 1Z1, Canada, 5Departments of Biomedical Engineering, 6Otolaryngology-Head and Neck Surgery, and,
7Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, and 8Kavli Neuroscience Discovery Institute, Johns Hopkins University,
Baltimore, Maryland 21205
Noninvasive electrical stimulation of the vestibular system in humans has become an increasingly popular tool with a broad
range of research and clinical applications. However, common assumptions regarding the neural mechanisms that underlie
the activation of central vestibular pathways through such stimulation, known as galvanic vestibular stimulation (GVS), have
not been directly tested. Here, we show that GVS is encoded by VIIIth nerve vestibular afferents with nonlinear dynamics
that differ markedly from those predicted by current models. GVS produced asymmetric activation of both semicircular canal
and otolith afferents to the onset versus offset and cathode versus anode of applied current, that in turn produced asymmet-
ric eye movement responses in three awake-behaving male monkeys. Additionally, using computational methods, we demon-
strate that the experimentally observed nonlinear neural response dynamics lead to an unexpected directional bias in the net
population response when the information from both vestibular nerves is centrally integrated. Together our findings reveal
the neural basis by which GVS activates the vestibular system, establish that neural response dynamics differ markedly from


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current predictions, and advance our mechanistic understanding of how asymmetric activation of the peripheral vestibular
system alters vestibular function. We suggest that such nonlinear encoding is a general feature of neural processing that will
be common across different noninvasive electrical stimulation approaches.
Key words: asymmetry; galvanic vestibular stimulation; modeling; nonlinear; vestibular afferent
Significance Statement
Here, we show that the application of noninvasive electrical currents to the vestibular system (GVS) induces more complex
responses than commonly assumed. We recorded vestibular afferent activity in macaque monkeys exposed to GVS using a
setup analogous to human studies. GVS evoked notable asymmetries in irregular afferent responses to cathodal versus anodal
currents. We developed a nonlinear model explaining these GVS-evoked afferent responses. Our model predicts that GVS
induces directional biases in centrally integrated head motion signals and establishes electrical stimuli that recreate physiolog-
ically plausible sensations of motion. Altogether, our findings provide new insights into how GVS activates the vestibular sys-
tem, which will be vital to advancing new clinical and biomedical applications.
Introduction
Vestibular sensory signals encode head movement and orienta-
tion in space to shape our actions and perception in everyday life
as we move and interact within our environment. During such
self-motion, the vestibular system is inevitably activated in con-
cert with other sensory modalities (e.g., vision, proprioception).
As such, studying the vestibular system requires techniques that
allow for independent investigation from other sources of sen-
sory feedback. A promising approach to target and understand
the functional role of the vestibular system is the application of
localized currents via surface electrodes placed bilaterally behind
the ears on the mastoid process (Fitzpatrick and Day, 2004;
Forbes et al., 2015; Dlugaiczyk et al., 2019). This noninvasive


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Received May 23, 2022; revised Jan. 25, 2023; accepted Jan. 30, 2023.
Author contributions: P.A.F., A.K., J.-S.B., and K.E.C. designed research; P.A.F., A.K., and D.E.M. performed
research; P.A.F. and A.K. analyzed data; and P.A.F., A.K., J.-S.B., and K.E.C. wrote the paper.
This work was supported by National Institutes of Health–National Institute on Deafness and Other
Communication Disorders Grants R01-DC002390, R01-DC013069, and 1UF1NS111695 to K.E.C. P.A.F. was
supported by Dutch Research Council Grants 016.Veni.188.049 and VI.Vidi.203.066, and J.-S.B. was supported
by Natural Sciences and Engineering Research Council of Canada Grant RGPIN-2020-05438. We thank Maurice
Chacron for critical feedback on the manuscript.
*P.A.F. and A.K. contributed equally to this work.
The authors declare no competing financial interests.
Correspondence should be addressed to Kathleen E. Cullen at kathleen.cullen@jhu.edu.
https://doi.org/10.1523/JNEUROSCI.0987-22.2023
Copyright © 2023 the authors
The Journal of Neuroscience, March 15, 2023 • 43(11):1905–1919 • 1905


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ZIKV RNA and IgM Persistence in blood compartments and body fluids: a\nprospective observational study


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ZIKV RNA and IgM Persistence in blood compartments and body 
fluids: a prospective observational study
Mars Stone, PhD1,2, Sonia Bakkour, PhD1,2, Marion C. Lanteri, PhD1,2, Donald Brambilla, 
PhD3, Prof. Graham Simmons, PhD1,2, Roberta Bruhn, PhD1,2, Zhanna Kaidarova, PhD1, 
Tzong-Hae Lee, MD1, Jose Orlando Alsina, MS4, Phillip C. Williamson, PhD5, Susan A. 
Galel, MD6, Lisa Lee Pate, MD6, Jeffrey M. Linnen7, Prof. Steve Kleinman, MD8, Prof. 
Michael P. Busch, MD1,2,
NHLBI Recipient Epidemiology Donor Evaluation Study REDS-III Program
1.Vitalant Research Institute (formerly Blood Systems Research Institute), San Francisco, CA, 
United States.
2.Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, 
United States
3.RTI International, Rockville, MD, United States
4.Banco de Sangre de Servicios Mutuos, San Juan, Puerto Rico, United States
5.Creative Testing Solutions, Tempe, AZ, United States
6.Roche Molecular Systems, Inc., Pleasanton, CA, United States
7.Grifols Diagnostic Solutions Inc., San Diego, CA, United States
8.Department of Pathology, University of British Columbia, Victoria, British Columbia, Canada
Abstract
Background: Characterization of the dynamics of Zika virus (ZIKV) persistence following acute 
infection is needed to inform blood donor and diagnostic testing policies and understand the 
natural history of ZIKV infection. We characterized the natural history, persistence, and clinical 
outcomes of ZIKV infection through prospective study of initially asymptomatic ZIKV RNA+ 
blood donors.
Corresponding author: Mars Stone PhD. Address: Vitalant Research Institute, 270 Masonic Avenue, San Francisco, CA, United States 
94118. Phone: 1-415-354-1389. Fax: 1-415-567-5899. mstone@vitalant.org. 
Conflicts of interest
Dr Linnen is an employee of Grifols Diagnostic Solutions Inc. and shareholder of Grifols. Drs Galel and Lee are employees and 
shareholder of Roche Diagnostics, which sponsored the clinical trial that identified the potential subjects for this study.


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Conflicts of interest
Dr Linnen is an employee of Grifols Diagnostic Solutions Inc. and shareholder of Grifols. Drs Galel and Lee are employees of Roche 
Molecular Systems. The remaining coauthors declare no conflicts of interest.
MCL is now an employee of Cerus Corporation
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.
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Author manuscript
Lancet Infect Dis. Author manuscript; available in PMC 2023 March 21.
Published in final edited form as:
Lancet Infect Dis. 2020 December ; 20(12): 1446–1456. doi:10.1016/S1473-3099(19)30708-X.
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Vol:.(1234567890)
Journal of Clinical Immunology (2023) 43:882–893
https://doi.org/10.1007/s10875-023-01459-x
1 3
ORIGINAL ARTICLE
Neutrophil Activation and Immune Thrombosis Profiles Persist 
in Convalescent COVID‑19
Hakim Hocini1 · Aurélie Wiedemann1 · Fabiola Blengio1 · Cécile Lefebvre1 · Minerva Cervantes‑Gonzalez4,5,6 · 
Emile Foucat1 · Pascaline Tisserand1 · Mathieu Surenaud1 · Séverin Coléon1 · Mélanie Prague1,2 · Lydia Guillaumat1 · 
Corinne Krief1 · Craig Fenwick3 · Cédric Laouénan4,5 · Lila Bouadma5,6 · Jade Ghosn5,7 · Giuseppe Pantaleo1,8 · 
Rodolphe Thiébaut1,2,9 · the French COVID cohort study group · Yves Lévy1,10 
Received: 23 December 2022 / Accepted: 24 February 2023 / Published online: 21 March 2023 
© The Author(s) 2023, corrected publication 2023
Abstract
Purpose Following a severe COVID-19 infection, a proportion of individuals develop prolonged symptoms. We investigated 
the immunological dysfunction that underlies the persistence of symptoms months after the resolution of acute COVID-19.
Methods We analyzed cytokines, cell phenotypes, SARS-CoV-2 spike-specific and neutralizing antibodies, and whole 
blood gene expression profiles in convalescent severe COVID-19 patients 1, 3, and 6 months following hospital discharge.
Results We observed persistent abnormalities until month 6 marked by (i) high serum levels of monocyte/macrophage and 
endothelial activation markers, chemotaxis, and hematopoietic cytokines; (ii) a high frequency of central memory  CD4+ and 
effector  CD8+ T cells; (iii) a decrease in anti-SARS-CoV-2 spike and neutralizing antibodies; and (iv) an upregulation of 
genes related to platelet, neutrophil activation, erythrocytes, myeloid cell differentiation, and RUNX1 signaling. We identi-
fied a “core gene signature” associated with a history of thrombotic events, with upregulation of a set of genes involved in 
neutrophil activation, platelet, hematopoiesis, and blood coagulation.


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Conclusion The lack of restoration of gene expression to a normal profile after up to 6 months of follow-up, even in asymp-
tomatic patients who experienced severe COVID-19, signals the need to carefully extend their clinical follow-up and propose 
preventive measures.
Keywords COVID-19 disease · post-acute COVID-19 syndrome · thrombosis
Introduction
Following a severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection, a significant proportion of individ-
uals develop prolonged symptoms, including predominantly 
fatigue, headache, and upper respiratory and multi-system 
 * Yves Lévy 
 
yves.levy@aphp.fr
1 
Vaccine Research Institute, Université Paris-Est Créteil,  
Faculté de Médecine, INSERM U955, Team 16, Créteil, 
France
2 
Department of Public Health, Univ. Bordeaux, Inserm 
Bordeaux Population Health Research Centre, Inria SISTM, 
UMR 1219, Bordeaux, France
3 
Service of Immunology and Allergy, Department 
of Medicine, Lausanne University Hospital and University 
of Lausanne, Lausanne, Switzerland
4 
Département Épidémiologie Biostatistiques Et Recherche 
Clinique, AP-HP, Hôpital Bichat, INSERM, Centre 
d’Investigation Clinique-Epidémiologie Clinique 1425, 
75018 Paris, France
5 
UMR 1137, Université de Paris, INSERM, IAME, 
75018 Paris, France
6 
APHP- Hôpital Bichat – Médecine Intensive et Réanimation 
des Maladies Infectieuses, Paris, France
7 
AP-HP, Hôpital Bichat, Service de Maladies Infectieuses Et 
Tropicales, 75018 Paris, France
8 
Swiss Vaccine Research Institute, Lausanne University 
Hospital, University of Lausanne, Lausanne, Switzerland
9 
CHU de Bordeaux, Pôle de Santé Publique, Service 
d’Information Médicale, Bordeaux, France
10 Assistance Publique-Hôpitaux de Paris, Service Immunologie 
Clinique, Groupe Henri-Mondor Albert-Chenevier, Créteil, France


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Severe COVID-19 versus multisystem inflammatory syndrome: comparing two critical outcomes of SARS-CoV-2 infection


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Severe COVID-19 versus multisystem inflammatory syndrome:
comparing two critical outcomes of SARS-CoV-2 infection
Rupsha Fraser1, Aurelio Orta-Resendiz
2, David Dockrell1, Michaela Müller-Trutwin2 and
Alexander Mazein3
1The University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK.
2Institut Pasteur, Université Paris Cité, HIV,
Inflammation and Persistence Unit, Paris, France. 3Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux,
Luxembourg.
Corresponding author: Rupsha Fraser (rupsha.fraser@ed.ac.uk)
Shareable abstract (@ERSpublications)
Development of severe COVID-19 versus multisystem inflammatory syndrome relies on distinct
aetiological factors that lead to variable host immune responses and inflammatory manifestations,
despite following a common trajectory of immune dysregulation. https://bit.ly/3Xtsa7P
Cite this article as: Fraser R, Orta-Resendiz A, Dockrell D, et al. Severe COVID-19 versus multisystem
inflammatory syndrome: comparing two critical outcomes of SARS-CoV-2 infection. Eur Respir Rev
2023; 32: 220197 [DOI: 10.1183/16000617.0197-2022].
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with diverse host
response immunodynamics and variable inflammatory manifestations. Several immune-modulating risk
factors can contribute to a more severe coronavirus disease 2019 (COVID-19) course with increased
morbidity and mortality. The comparatively rare post-infectious multisystem inflammatory syndrome (MIS)
can develop in formerly healthy individuals, with accelerated progression to life-threatening illness. A
common trajectory of immune dysregulation forms a continuum of the COVID-19 spectrum and MIS;
however, severity of COVID-19 or the development of MIS is dependent on distinct aetiological factors
that produce variable host inflammatory responses to infection with different spatiotemporal manifestations,
a comprehensive understanding of which is necessary to set better targeted therapeutic and preventative


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strategies for both.
Introduction
The management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, causing the
coronavirus disease 2019 (COVID-19) pandemic, has been a major new challenge to healthcare and
research. SARS-CoV-2 infection is associated with diverse host response immunodynamics with variable
inflammatory manifestations. The development of severe COVID-19 can typically be linked to a number of
risk factors (e.g. age-related susceptibility, pre-existing chronic diseases or an immunosuppressed status,
amongst others) that cause altered immune profiles [1–7], while another potentially fatal syndrome can
develop in previously
healthy individuals following SARS-CoV-2 infection, termed multisystem
inflammatory syndrome (MIS) [8–10]. Despite a significant overlap in their dysregulated immune
responses, these two hyperinflammatory disease phenotypes can be distinguished by a range of distinct
spatiotemporal adaptations and clinical profiles. Understanding how different aetiological factors underpin
the immunopathogenic pathways and timeline of events in the development of severe COVID-19 and MIS
will guide patient stratification and more targeted therapeutic or vaccination strategies. Here, we pinpoint
severe COVID-19 as an early acute hyperinflammatory response predominantly affecting the respiratory
tract, but also with systemic involvement that is influenced by various risk factors to cause impairment of
the primary innate response to infection, as well as dysregulation of downstream innate and adaptive
defence mechanisms, and MIS as a delayed acute hyperinflammatory response to SARS-CoV-2 infection
with systemic but minimal or no respiratory symptoms and low pulmonary viral loads, which might
develop due to genetic susceptibility traits that trigger the activation of systemic autoimmune and
hyperinflammatory pathways upon SARS-CoV-2 infection.
Copyright ©The authors 2023
This version is distributed under
the terms of the Creative
Commons Attribution Non-


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Commercial Licence 4.0. For
commercial reproduction rights
and permissions contact
permissions@ersnet.org
Received: 14 Oct 2022
Accepted: 31 Dec 2022
https://doi.org/10.1183/16000617.0197-2022
Eur Respir Rev 2023; 32: 220197
EUROPEAN RESPIRATORY REVIEW
REVIEW
R. FRASER ET AL.


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The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota


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The balance between protective and pathogenic immune 
responses to pneumonia in the neonatal lung is enforced by gut 
microbiota
Joseph Stevens1,2, Shelby Steinmeyer3,4, Madeline Bonfield1, Laura Peterson3,4, Timothy 
Wang3,4, Jerilyn Gray3, Ian Lewkowich4,5, Yan Xu3,4,6, Yina Du3, Minzhe Guo3,4, James 
L. Wynn7, William Zacharias3,4, Nathan Salomonis4,6, Lisa Miller8,9, Claire Chougnet4,5, 
Dennis Hartigan O’Connor9,10,11, Hitesh Deshmukh3,4,5,*
1Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 
45229, USA.
2Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 
45267, USA.
3Division of Neonatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, 
USA.
4Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, 
USA.
5Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, 
USA.
6Division of Bioinformatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, 
USA.
7Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
8Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University 
of California, Davis, Davis, CA 95616, USA.
9California National Primate Research Center, Davis, CA 95616, USA.
10Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA 
95616, USA.
*Corresponding author. hitesh.deshmukh@cchmc.org.
Author contributions: H.D., J.G., C.C., L.M., and D.H.O. designed the experiments. I.L. and W.Z. provided tools. J.L.W. provided 
the patient-related metadata. N.S., J.S., Y.X., Y.D., M.G., L.P., and H.D. analyzed the single-cell and bulk transcriptomic data. J.G. 
and H.D. analyzed the cytometry data. J.S., S.S., T.W., M.B., and H.D. wrote the manuscript with inputs from M.G., Y.X., C.C., I.L., 
J.L.W., D.H.O., and L.M.
Competing interests: The authors declare that they have no competing interests.


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SUPPLEMENTARY MATERIALS
www.science.org/doi/10.1126/scitranslmed.abl3981 
Materials and Methods 
Figs. S1 to S12
Tables S1 to S33
MDAR Reproducibility Checklist 
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Sci Transl Med. Author manuscript; available in PMC 2023 March 22.
Published in final edited form as:
Sci Transl Med. 2022 June 15; 14(649): eabl3981. doi:10.1126/scitranslmed.abl3981.
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A Modular Approach to Vocal Learning: Disentangling the 
Diversity of a Complex Behavioral Trait
Morgan Wirthlin1, Edward F. Chang2, Mirjam Knörnschild3, Leah A. Krubitzer4,5, Claudio V. 
Mello6, Cory T. Miller7, Andreas R. Pfenning1, Sonja C. Vernes8,9, Ofer Tchernichovski10, 
Michael M. Yartsev11
1.Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA
2.Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 
USA
3.Animal Behavior Lab, Free University Berlin, Takustrasse 6, 14195, Berlin, Germany
4.Center for Neuroscience, University of California, Davis, CA, USA
5.Department of Psychology, University of California, Davis, CA, USA
6.Department of Behavioral Neuroscience, OHSU, Portland, OR, USA
7.Cortical Systems and Behavior Laboratory, Neurosciences Graduate Program, University of 
California San Diego, La Jolla, CA, USA
8.Neurogenetics of Vocal Communication Group, Max Planck Institute for Psycholinguistics, 
Nijmegen, The Netherlands
9.Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
10.Department of Psychology, Hunter College, The City University of New York, New York, NY, 
USA
11.Helen Wills Neuroscience Institute and Department of Bioengineering, UC Berkeley, Berkeley, 
CA USA
Abstract
Vocal learning is a behavioral trait in which the social and acoustic environment shapes the vocal 
repertoire of individuals. Over the past century, the study of vocal learning has progressed at the 
intersection of neuroscience, genomics, molecular biology, physiology, ecology, and evolution. 
Yet, despite the complexity of this trait, vocal learning is most frequently described as a binary 
trait, with species being classified as either vocal learners or vocal non-learners. As a result, 
studies have largely focused on a handful of vocal learner species. Recent studies, however, 
suggest a continuum in vocal learning capacity across taxa. Here, we further suggest that


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vocal learning is a multidimensional behavioral phenotype comprised of distinct, interconnected 
modules. Discretizing the vocal learning phenotype into its constituent components would 
facilitate integration of findings across a diversity of species, taking advantage of the ways in 
which each excels in a particular component, or in a specific combination of features. Such 
comparative studies can improve understanding of the mechanisms and evolutionary origins of 
vocal learning. We propose an initial set of vocal learning modules supported by behavioral 
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Neuron. Author manuscript; available in PMC 2023 April 01.
Published in final edited form as:
Neuron. 2019 October 09; 104(1): 87–99. doi:10.1016/j.neuron.2019.09.036.
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Broadly neutralizing antibodies to SARS-related viruses can be 
readily induced in rhesus macaques
Wan-ting He1,2,3,†, Meng Yuan4,†, Sean Callaghan1,2,3,†, Rami Musharrafieh1,2,3, Ge 
Song1,2,3, Murillo Silva3,5, Nathan Beutler1, Wen-Hsin Lee4, Peter Yong1,2,3, Jonathan 
L. Torres4, Mariane Melo3,5, Panpan Zhou1,2,3, Fangzhu Zhao1,2,3, Xueyong Zhu4, 
Linghang Peng1, Deli Huang1, Fabio Anzanello1,2,3, James Ricketts1, Mara Parren1, Elijah 
Garcia1, Melissa Ferguson6, William Rinaldi6, Stephen A. Rawlings7, David Nemazee1, 
Davey M. Smith7, Bryan Briney1,2,3, Yana Safonova8, Thomas F. Rogers1,7, Jennifer M. 
Dan7,9, Zeli Zhang9, Daniela Weiskopf9, Alessandro Sette7,9, Shane Crotty3,7,9, Darrell 
J. Irvine3,5,10,11,12, Andrew B. Ward2,3,4, Ian A. Wilson2,3,4,13,*, Dennis R. Burton1,2,3,12,*, 
Raiees Andrabi1,2,3,*
1Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 
92037, USA.
2IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
3Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La 
Jolla, CA 92037, USA.
4Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 
La Jolla, CA 92037, USA.
5Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 
Cambridge, MA 02139, USA.
This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, 
distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit 
http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the 
article that is credited to a third party; obtain authorization from the rights holder before using this material. The Authors, some rights 
reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.


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Distributed under a Creative Commons Attribution License 4.0 (CC BY).
*Corresponding author. wilson@scripps.edu (I.A.W.); burton@scripps.edu, (D.R.B.); andrabi@scripps.edu (R.A.).
†These authors contributed equally to this work.
Author contributions: W.-t.H., M.Y., S. Callaghan, S. Crotty, D.J.I., A.B.W., I.A.W., D.R.B., and R.A. conceived and designed 
the study. W.-t.H., S. Callaghan, G.S., D.H., M.F., and W.R. conducted animal immunization studies. M.S. and M.M. prepared 
the SMNP adjuvant. N.B., J.R., M.P., E.G., S.A.R., D.M.S., T.F.R., J.M.D., Z.Z., D.W., A.S., and S. Crotty recruited donors and 
collected and processed plasma samples. W.-t.H., S. Callaghan, R.M., G.S., F.A., P.Y., and P.Z. performed BLI assays, ELISAs, virus 
preparations, neutralization assays, and isolation and characterization of monoclonal antibodies. F.Z. prepared the human antibodies. 
L.P. and D.H. prepared virus mutant plasmids. R.M., B.B., and Y.S. performed immunogenetic analysis of the antibodies. W.-H.L. and 
J.L.T. conducted nSEM studies. M.Y. and X.Z. determined the crystal structures of the antibody-antigen complexes. W.-t.H., M.Y., 
S. Callaghan, R.M., G.S., N.B., W.-H.L., P.Y., J.L.T., P.Z., X.Z., L.P., D.H., F.A., D.N., B.B., Y.S., T.F.R., S. Crotty, D.J.I., A.B.W., 
I.A.W., D.R.B., and R.A. designed the experiments or analyzed the data. W.-t.H., M.Y., R.M., I.A.W., D.R.B., and R.A. wrote the 
paper, and all authors reviewed and edited the paper.
Competing interests: W.-t.H., M.Y., S. Callaghan, I.A.W., D.R.B., and R.A. are listed as inventors on a pending patent application 
describing the macaque sarbecovirus bnAbs reported in this study. D.J.I., S. Crotty, and M.S. are inventors on a patent filed by MIT 
and the La Jolla Institute for Immunology relating to the SMNP adjuvant. A.S. is a consultant for Gritstone Bio, Flow Pharma, 
ImmunoScape, Avalia, Moderna, Fortress, Repertoire, Gerson Lehrman Group, RiverVest, MedaCorp, and Guggenheim. S. Crotty has


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consulted for GSK, JP Morgan, Citi, Morgan Stanley, Avalia NZ, Nutcracker Therapeutics, University of California, California State 
Universities, United Airlines, Adagio, and Roche. D.R.B. is a consultant for IAVI, Adagio, Adimab, Mabloc, VosBio, Nonigenex, and 
Radiant. The other authors declare that they have no competing interests.
HHS Public Access
Author manuscript
Sci Transl Med. Author manuscript; available in PMC 2023 August 10.
Published in final edited form as:
Sci Transl Med. 2022 August 10; 14(657): eabl9605. doi:10.1126/scitranslmed.abl9605.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Kuburas and Russo  
The Journal of Headache and Pain           (2023) 24:34  
https://doi.org/10.1186/s10194-023-01569-2
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.
The Journal of Headache
                           and Pain
Shared and independent roles of CGRP 
and PACAP in migraine pathophysiology
Adisa Kuburas1 and Andrew F. Russo1,2* 
Abstract 
The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypep-
tide (PACAP) have emerged as mediators of migraine pathogenesis. Both are vasodilatory peptides that can cause 
migraine-like attacks when infused into people and migraine-like symptoms when injected into rodents. In this 
narrative review, we compare the similarities and differences between the peptides in both their clinical and preclini-
cal migraine actions. A notable clinical difference is that PACAP, but not CGRP, causes premonitory-like symptoms


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in patients. Both peptides are found in distinct, but overlapping areas relevant to migraine, most notably with the 
prevalence of CGRP in trigeminal ganglia and PACAP in sphenopalatine ganglia. In rodents, the two peptides share 
activities, including vasodilation, neurogenic inflammation, and nociception. Most strikingly, CGRP and PACAP cause 
similar migraine-like symptoms in rodents that are manifested as light aversion and tactile allodynia. Yet, the peptides 
appear to act by independent mechanisms possibly by distinct intracellular signaling pathways. The complexity of 
these signaling pathways is magnified by the existence of multiple CGRP and PACAP receptors that may contribute to 
migraine pathogenesis. Based on these differences, we suggest PACAP and its receptors provide a rich set of targets 
to complement and augment the current CGRP-based migraine therapeutics.
Keywords CGRP, PACAP, Migraine, Intracellular signaling, Receptors
Background
Migraine is one of the most disabling neurological dis-
orders in the world [1]. It affects over one billion people 
with 3:1 prevalence in women. Migraine is a headache 
lasting 4–72  h with characteristics that often include 
unilateral pulsating pain of moderate to severe intensity 
that is aggravated by routine physical activity and is asso-
ciated with vomiting or nausea and/or photophobia and 
phonophobia [2]. While the mechanisms of migraine are 
still poorly understood, insights from clinical and pre-
clinical studies over the past three decades have focused 
attention on two neuropeptides: calcitonin gene-related 
peptide (CGRP) and pituitary adenylate cyclase-activat-
ing polypeptide (PACAP).
The importance of CGRP in migraine was first real-
ized in reports that CGRP is upregulated during migraine 
attacks and between attacks in chronic migraine patients 
[3–5], although this is not seen in all studies [6–8]. Even 
more striking was the finding that infusion of CGRP can 
induce migraine-like attacks in migraine patients, as


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described below. The importance of CGRP has been fully 
established over the past 5 years with the efficacy of eight 
FDA approved CGRP-based therapeutics [9–13]. These 
drugs include monoclonal antibodies against CGRP or its 
receptor and small molecule receptor antagonists that are 
effective for prevention and treatment of migraine. How-
ever, in general only about 40–60% of migraine patients 
are significantly helped by these agents [12, 14, 15], which 
suggests involvement of other factors beyond CGRP in 
migraine pathophysiology, such as PACAP [16]. In this 
*Correspondence:
Andrew F. Russo
andrew-russo@uiowa.edu
1 Department of Molecular Physiology and Biophysics and Department 
of Neurology, University of Iowa, Iowa City, IA 52242, USA
2 Veterans Affairs Medical Center, Iowa City, IA 52246, USA


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Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome in patients with COVID-19 infection: is there a link? A systematic review and case report analysis


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Vol:.(1234567890)
Journal of Neurology (2023) 270:2826–2852
https://doi.org/10.1007/s00415-023-11684-4
1 3
REVIEW
Posterior reversible encephalopathy syndrome and reversible cerebral 
vasoconstriction syndrome in patients with COVID‑19 infection: 
is there a link? A systematic review and case report analysis
Adriano Bonura1,2 · Gianmarco Iaccarino1,2 · Sergio Soeren Rossi1,2 · Fioravante Capone1,2 · Francesco Motolese1,2 · 
Rosalinda Calandrelli3 · Vincenzo Di Lazzaro1,2 · Fabio Pilato1,2 
Received: 15 January 2023 / Revised: 26 February 2023 / Accepted: 21 March 2023 / Published online: 4 April 2023 
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2023
Abstract
During the SARS-CoV2 pandemic, several cases of Posterior Reversible Encephalopathy Syndrome (PRES) and of Revers-
ible Cerebral Vasoconstriction Syndrome (RCVS) in COVID-19 patients have been reported, but the link between these 
syndromes and COVID-19 is unclear. We performed a systematic review, according to the Preferred Reporting Items for 
Systematic Reviews and Meta-Analyses (PRISMA) statement to evaluate whether SARS-CoV2 infection or the drugs used 
to treat it could be deemed potential risk factors for PRES or RCVS. We performed a literature search. We found 70 articles 
(60 on PRES and 10 on RCVS) concerning n = 105 patients (n = 85 with PRES, n = 20 with RCVS). We analyzed the clinical 
characteristics of the two populations separately, then performed an inferential analysis to search for other independent risk 
factors. We found fewer than usual PRES-related (43.9%) and RCVS-related (45%) risk factors in patients with COVID-
19. Such a low incidence of risk factors for PRES and RCVS might suggest the involvement of COVID-19 as an additional 
risk factor for both diseases due to its capability to cause endothelial dysfunction. We discuss the putative mechanisms of 
endothelial damage by SARS-CoV2 and antiviral drugs which may underlie the development of PRES and RCVS.


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Keywords RCVS · PRES · SARS-CoV2 · COVID-19 · Antiviral drugs · Endothelial dysfunction
Introduction
COVID-19 is a disease caused by Severe Acute Respiratory 
Syndrome Corona Virus 2 (SARS-CoV2), a single-stranded 
RNA beta coronavirus. Most patients develop mild to mod-
erate respiratory symptoms, while others require medi-
cal assistance and hospitalization due to respiratory tract 
involvement. Several long-term complications have been 
reported including diabetes mellitus, kidney injury, myo-
carditis, heart failure, and venous thromboembolism [1, 2]. 
Neurological complications have been described as well: 
myalgia, dizziness, headache, anosmia, ageusia, encepha-
litis, stroke, seizures, and myelitis [3–5] but also Posterior 
Reversible Encephalopathy Syndrome (PRES) and Revers-
ible Cerebral Vasoconstriction Syndrome (RCVS) [6–8].
PRES and RCVS [9–11] are relatively new clinical-radio-
logical syndromes. More and more cases of these syndromes 
have been described so far, mainly due to increased aware-
ness of their clinical signs and the widespread use of MRI 
that allows catching their signs at an early stage. Although 
their etiologies remain unclear, several studies pointed out 
the role of intracranial vessels and endothelium in their 
development [12].
PRES, first described by Hinchey et al. in 1996 [13], 
causes encephalopathy, disorders of consciousness, seizures, 
visual disturbances, and headache [14]. It is more common 
in females and the most frequently recognized risk factors 
are: hypertension, pre-eclampsia, renal disease, immuno-
suppressive state, infections, steroids, dialysis, and blood 
 * Fabio Pilato 
 
f.pilato@policlinicocampus.it
1 
Department of Medicine and Surgery, Unit of Neurology, 
Neurophysiology, Neurobiology and Psychiatry, Università 
Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 
00128 Rome, Italy
2 
Institute of Neurology, Fondazione Policlinico Universitario 
Campus Bio-Medico, Via Alvaro del Portillo, 200, 
00128 Rome, Italy
3


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3 
Institute of Radiology, Fondazione Policlinico Universitario 
Agostino Gemelli IRCCS, Largo A. Gemelli, 1, 00168 Rome, 
Italy


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Forever Connected: The Lifelong Biological Consequences of Fetomaternal and Maternofetal Microchimerism


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Forever Connected: The Lifelong Biological Consequences of 
Fetomaternal and Maternofetal Microchimerism
Diana W. Bianchia,*, Kiarash Khosrotehranib, Sing Sing Wayc, Tippi C. MacKenzied, 
Ingeborg Bajemae, Keelin O’Donoghuef
aNational Human Genome Research Institute and Eunice Kennedy Shriver National Institute of 
Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA;
bExperimental Dermatology Group, The University of Queensland, UQ Diamantina Institute, 
Brisbane, Queensland, Australia;
cDivision of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children’s 
Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA;
dCenter for Maternal-Fetal Precision Medicine and the Department of Surgery, University of 
California, San Francisco, CA, USA;
eDepartment of Pathology, Leiden University Medical Center, Leiden, The Netherlands;
fIrish Centre for Maternal and Child Health (INFANT), University College Cork, Cork, Ireland.
Abstract
BACKGROUND: Originally studied as a mechanism to understand eclampsia-related deaths 
during pregnancy, fetal cells in maternal blood have more recently garnered attention as a 
noninvasive source of fetal material for prenatal testing. In the 21st century, however, intact 
fetal cells have been largely supplanted by circulating cell-free placental DNA for aneuploidy 
screening. Instead, interest has pivoted to the ways in which fetal cells influence maternal biology. 
In parallel, an increasing appreciation of the consequences of maternal cells in the developing 
fetus has occurred.
CONTENT: In this review, we highlight the potential clinical applications and functional 
consequences of the bidirectional trafficking of intact cells between a pregnant woman and her 
fetus. Fetal cells play a potential role in the pathogenesis of maternal disease and tissue repair. 
Maternal cells play an essential role in educating the fetal immune system and as a factor in


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transplant acceptance. Naturally occurring maternal microchimerism is also being explored as a 
source of hematopoietic stem cells for transplant in fetal hematopoietic disorders.
*Address correspondence to this author at: Eunice Kennedy Shriver National Institute of Child Health and Human Development, 31 
Center Drive, Room 2A03, National Institutes of Health, Bethesda, MD 20892, USA. Fax 301-402-1104; Diana.Bianchi@nih.gov.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the 
following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation 
of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be 
accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are 
appropriately investigated and resolved.
K. Khosrotehrani, administrative support, provision of study material or patients; I. Bajema, provision of study material or patients; K. 
O’Donoghue, administrative support, provision of study material or patients.
Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
HHS Public Access
Author manuscript
Clin Chem. Author manuscript; available in PMC 2023 April 04.
Published in final edited form as:
Clin Chem. 2021 January 30; 67(2): 351–362. doi:10.1093/clinchem/hvaa304.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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NEURAL REGENERATION RESEARCH｜Vol 18｜No. 7｜July 2023｜1397
NEURAL REGENERATION RESEARCH
www.nrronline.org
Review
Abstract  
As the average age of the world population increases, more people will face debilitating aging-
associated conditions, including dementia and stroke. Not only does the incidence of these conditions 
increase with age, but the recovery afterward is often worse in older patients. Researchers and 
health professionals must unveil and understand the factors behind age-associated diseases to 
develop a therapy for older patients. Aging causes profound changes in the immune system including 
the activation of microglia in the brain. Activated microglia promote T lymphocyte transmigration 
leading to an increase in neuroinflammation, white matter damage, and cognitive impairment in both 
older humans and rodents. The presence of T and B lymphocytes is observed in the aged brain and 
correlates with worse stroke outcomes. Preclinical strategies in stroke target either microglia or the 
lymphocytes or the communications between them to promote functional recovery in aged subjects. 
In this review, we examine the role of the microglia and T and B lymphocytes in aging and how they 
contribute to cognitive impairment. Additionally, we provide an important update on the contribution 
of these cells and their interactions in preclinical aged stroke.
Key Words: age; B lymphocytes; brain; central nervous system; cognition; inflammation; microglia; 
middle cerebral artery occlusion; neuroinflammation; stroke; T lymphocytes; white matter injury
Introduction 
The advancement of technology and medicine increased the individual’s 
average age. With a decreasing fertility and mortality rate, a significant 
proportion of the population is becoming older (Kowal et al., 2016). Older 
individuals are more susceptible to age-associated diseases including stroke, 
dementia, diabetes, cardiovascular disease, and cancer (Jaul and Barron, 
2017). The anatomy and homeostasis of the brain change with aging (Juraska


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and Lowry, 2012) and the aged brain respond differently to injury and stress 
than the brain of a young adult. Interestingly, the neuronal density remains 
stable throughout the lifespan however, 30% of individuals suffer from severe 
cognitive impairment without meeting the criteria of Alzheimer’s disease (AD) 
or dementia (Harada et al., 2013). Results from MRI and histological analysis 
studies demonstrate a decline in white matter volume which corroborated 
with cognitive impairment in healthy aged individuals (Fjell and Walhovd, 
2010; Coelho et al., 2021). The myelin sheath damage leads to white matter 
vulnerability resulting in axonal damage producing disconnect that could 
attribute to cognitive impairment (Kohama et al., 2012; Peters and Kemper, 
2012; Faizy et al., 2020). A complex interplay between myelin plasticity, 
oligodendrocyte maturation, removal and clearance of myelin debris, and 
remyelination supports myelin maintenance and homeostasis and these 
processes decline with age (Soreq et al., 2017; Spitzer et al., 2019; Sams, 
2021). Experimental studies have shown that oligodendrocyte precursor 
cells fail to mature into myelinating oligodendrocytes and aged animals 
demonstrate limited ability to replenish oligodendrocyte precursor cells pool 
thus is partially responsible for age-related reduced remyelination and myelin 
repair (Shields et al., 2000; Neumann et al., 2019; Ito et al., 2021). Microglia 
plays an important role in oligodendrocyte precursor cell differentiation 
into mature oligodendrocytes, removes myelin debris, and promotes 
remyelination, however, this function declines with age (Kalafatakis and 
Karagogeos, 2021; Luan et al., 2021), thus prompting cognitive dysfunction. 
Several genes are expressed by microglia that promote lymphocyte infiltration 
in the aged brain exacerbating the white matter injury and contributing 
to cognitive impairments in aged individuals. Thus an interplay between 
microglia and lymphocytes not only contributes to age-associated brain injury


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but their precise role in stroke pathophysiology in older subjects has not been 
fully explored. 
The objective of this review is to summarize the evidence that both microglia 
and lymphocytes are involved in the process of aging. The interplay of 
microglia and lymphocytes negatively modulates cognition in older subjects 
after stroke. Finally, we present the studies targeting therapeutic strategies 
toward microglia or lymphocytes in older animals after stroke. The review will 
aid in better understanding the contribution of microglia and lymphocytes in 
post-stroke functional outcomes that happen to be a major concern in older 
individuals. 
Retrieval Strategy 
The studies cited in this review were retrieved from Google scholar and 
PubMed databases. The relevant literature published from January 1994 
to September 2022 was screened. A combination of the following words 
(MeSH terms) was used to maximize search specificity and sensitivity: age, 
cognition, microglia, T lymphocytes, B lymphocytes, stroke, white matter, 
neuroinflammation, and brain. The results were further screened by title 
and abstract and studies exploring the relationship between microglia, and 
lymphocytes in aging were included. Furthermore, the role of microglia and 
lymphocytes and their contribution to stroke neuroinflammation was included. 
No language or study type restrictions were applied. Articles involving studies 
investigating the contribution of young microglia and lymphocytes in stroke 
were excluded. No limit was used on the year of publication or authorship. 
Aged Microglia Contributes to Cognitive 
Impairment
One of the cell types that is profoundly affected by age is brain resident 
macrophages- microglia. Microglia are primary immune cells that constitute 
10% of all cells in the adult brain (Pessac et al., 2001). Microglia acquire 
a dystrophic and dysfunctional phenotype with age (Safaiyan et al., 2016; 
Cantuti-Castelvetri et al., 2018; Deczkowska et al., 2018). A multitude


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of factors including cellular aging, transcriptomic changes, senescence-
associated secretory phenotype, dysregulated microglia metabolism, and 
the milieu that these cells reside could influence the microglia behavior 
(Minhas et al., 2021). Activated microglia secrete multiple pro-inflammatory 
1University of Texas McGovern Medical School at Houston, Houston, TX, USA; 2Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA
*Correspondence to: Anjali Chauhan, PhD, anjali.chauhan@uth.tmc.edu. 
https://orcid.org/0000-0002-9825-8100 (Anjali Chauhan)
Funding: This work was supported by 16POST27490032 American Heart Association post-doctoral fellowship and National Institute of Neurological Disorders and Stroke Exploratory 
Neuroscience Research Grant R21 NS114836-01A1 (to AC).
How to cite this article: Nguyen JN, Chauhan A (2023) Bystanders or not? Microglia and lymphocytes in aging and stroke. Neural Regen Res 18(7):1397-1403. 
From the Contents
Introduction
1397
Retrieval Strategy
1397
Aged Microglia Contributes to Cognitive Impairment
1397
Microglia and Lymphocytes Interact with Age
1398
Role of T Lymphocytes in Aging and Cognition
1398
Role of B Lymphocytes in Aging
1399
Aged Microglia in Stroke
1399
T and B Lymphocytes in Aged Stroke
1400
Conclusion
1400
Bystanders or not? Microglia and lymphocytes in aging 
and stroke
https://doi.org/10.4103/1673-5374.360345
Date of submission: September 17, 2022 
Date of decision: October 18, 2022 
Date of acceptance: October 24, 2022
Date of web publication: November 9, 2022 
Justin N. Nguyen1, Anjali Chauhan2, *


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A whole blood intracellular cytokine assay optimised for field site studies demonstrates polyfunctionality of CD4+ T cells in acute scrub typhus


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RESEARCH ARTICLE
A whole blood intracellular cytokine assay
optimised for field site studies demonstrates
polyfunctionality of CD4+ T cells in acute scrub
typhus
Manutsanun InthawongID1,2,3, Nattapon Pinthong4, Areerat Thaiprakhong2,
Tri Wangrangsimakul2,5, Piyanate Sunyakumthorn3, Jennifer Hill5,
Piengchan Sonthayanon1,2, Daniel H. Paris2,6,7, Susanna J. Dunachie2,5,
Barbara KronsteinerID2,5*
1 Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University,
Bangkok, Thailand, 2 Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Faculty of Tropical
Medicine, Mahidol University, Bangkok, Thailand, 3 Department of Veterinary Medicine, United States Army
Medical Directorate, Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS), Bangkok,
Thailand, 4 Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Bangkok,
Thailand, 5 NDM Center for Global Health Research, Nuffield Dept. of Clinical Medicine, University of Oxford,
Oxford, United Kingdom, 6 Department of Medicine, Swiss Tropical and Public Health Institute, Allschwil,
Switzerland, 7 Department of Clinical Research, University of Basel, Basel, Switzerland
* barbara.kronsteiner-dobramysl@ndm.ox.ac.uk
Abstract
Background
Assessment of cellular immune responses by combining intracellular cytokine staining and
immunophenotyping using flow cytometry enables the simultaneous measurement of T cell
phenotype and effector function in response to pathogens and vaccines. The use of whole
blood samples rather than peripheral blood mononuclear cells avoids both the need for
immediate processing and loss of functional antigen presenting cells due to processing and
cryopreservation. Using whole blood provides the possibility to stimulate peripheral T cells
in situ, and is more suitable for studies where sample volume is limited, such as those involv-
ing children, the elderly and critically ill patients. The aim of this study was to provide a robust


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tool for the assessment of antigen-specific T cell responses in a field site setting with limited
resources.
Methodology/principle findings
We optimised a flow cytometry-based whole blood intracellular cytokine assay (WBA) with
respect to duration of antigen stimulation and intracellular protein retention time. We demon-
strate the ability of the WBA to capture polyfunctional T cell responses in the context of
acute scrub typhus infection, by measuring IFN-γ, TNF and IL-2 in CD4+ and CD8+ T cells
in response to the causative agent O. tsutsugamushi (OT). Using an optimised OT antigen
preparation, we demonstrate the presence of polyfunctional antigen-specific memory CD4+
T cells in the blood of scrub typhus patients.
PLOS NEGLECTED TROPICAL DISEASES
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0010905
March 24, 2023
1 / 19
a1111111111
a1111111111
a1111111111
a1111111111
a1111111111
OPEN ACCESS
Citation: Inthawong M, Pinthong N, Thaiprakhong
A, Wangrangsimakul T, Sunyakumthorn P, Hill J, et
al. (2023) A whole blood intracellular cytokine
assay optimised for field site studies demonstrates
polyfunctionality of CD4+ T cells in acute scrub
typhus. PLoS Negl Trop Dis 17(3): e0010905.
https://doi.org/10.1371/journal.pntd.0010905
Editor: Allen L. Richards, Uniformed Services
University of the Health Sciences, UNITED STATES
Received: October 28, 2022
Accepted: February 25, 2023
Published: March 24, 2023
Copyright: This is an open access article, free of all
copyright, and may be freely reproduced,
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: The data that support
the findings of this study are publicly available from
Mendeley Data under https://data.mendeley.com/
datasets/4jj4dfd6b7/1.
Funding: MI, BK and SJD were funded by the
Wellcome Trust (WT100174/Z/12/Z awarded to
SJD, https://wellcome.org/). JH, BK and SJD are


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supported by the NIHR Global Research
Professorship (NIHR300791 awarded to SJD,
https://www.nihr.ac.uk/). MI, NP, AT, TW, PSu and


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Received: 4 April 2022
-
Revised: 1 July 2022
-
Accepted: 3 August 2022
DOI: 10.1002/rmv.2385
R E V I E W
Safety and immunogenicity of Zika virus vaccine:
A systematic review of clinical trials
Mahmuda Yeasmin1
|
Md. Maruf Ahmed Molla1,2
|
H. M. Abdullah Al Masud3
|
K. M. Saif‐Ur‐Rahman4,5,6
1Department of Virology, National Institute of
Laboratory Medicine and Referral Center,
Dhaka, Bangladesh
2College of Graduate Studies, State University
of New York Upstate Medical University,
Syracuse, New York, USA
3Department of Microbiology, Faculty of
Biological Sciences, University of Chittagong,
Chattogram, Bangladesh
4Health Systems and Population Studies
Division, icddr, b, Dhaka, Bangladesh
5Evidence Synthesis Ireland and Cochrane
Ireland, Galway, Ireland
6College of Medicine, Nursing and Health
Sciences, National University of Ireland,
Galway, Ireland
Correspondence
K. M. Saif‐Ur‐Rahman, College of Medicine,
Nursing and Health Sciences, National
University of Ireland, Galway, Ireland and
Health Systems and Population Studies
Division, icddr, b, Dhaka, Bangladesh.
Email: su.rahman@icddrb.org
Funding information
Open access funding provided by IReL.
Abstract
Several phase‐1 clinical trials have been performed to evaluate the safety and effi-
cacy of candidate anti‐Zika vaccines. In this systematic review, we systematically
evaluated the safety and immunogenicity of candidate vaccines, which would aid
researchers in formulating an effective vaccination strategy for phase‐2 trials based
on current evidence. A literature search was conducted using the electronic data-
bases MEDLINE through Pubmed, Web of Science, and Cochrane Database for
relevant studies on candidate anti‐zika vaccines. Studies on animal models were
excluded from our study. Healthy individuals who were administered candidate Zika
vaccines to evaluate the immune response and adverse events (AEs) compared to
placebo were considered. Data were extracted, tabulated, and analysed using


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Microsoft Excel, while the risk of bias plots were generated using tidyverse and
Robvis packages in R‐studio. A total of five phase‐1 clinical trials were included in our
analysis comprising of studies on inactivated, viral vector, and DNA vaccines.
Immunogenicity ranged from 10% to 100% after vaccination with the lowest sero-
conversion rate (10%) and geometric mean titre (GMT) (6.3; 95% confidence interval
(CI):3.7–10.8) observed among recipients of single‐dose inactivated anti‐zika vaccine
(ZPIV). For DNA vaccines, the seroconversion rate ranged from 60% to 100% with
the highest seroconversion rate (100%) and GMT (2871; 95% CI:705.3–11688)
observed among recipients of three shots of high dose GLS‐5700 vaccine. For viral
vector vaccine (Ad26.ZIKV.001) seroconversion rate (100%) and GMT peaked after
two shots with both low and high‐dose vaccines. In all those studies AEs were mostly
local including injection site pain, erythema, and itching. The most common systemic
AEs included fever, myalgia, nausea, and fatigue. In phase‐1 clinical trials, all candi-
date vaccines were found to be highly immunogenic and relatively safe, especially
when administered in higher doses and with the help of needle‐free devices.
Abbreviations: AE, Adverse Event; COVID‐19, Coronavirus Disease 2019; CZS, Congenital Zika Syndrome; ELISPOT, Enzyme‐linked Immune Absorbent Spot; GBS, Gullain Barrie Syndrome;
GMT, Geometric Mean Titre; HD, Higher dose; LD, Lower Dose; MN50, 50% Microneutralisation; NHP, Nonhuman primtaes; PL, Placebo; PRISMA, Preferred Reporting Project for Systematic
Evaluation and Meta‐Analysis; RCT, Randomised Controlled Trial; SARS‐CoV‐2, Severe Acute Respiratory Syndrome Coronavirus‐2; ZPIV, Zika Virus Purified Inactivated Vaccine.
Mahmuda Yeasmin, Md. Maruf Ahmed Molla contributed equally.
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any


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medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.
Rev Med Virol. 2023;33:e2385.
wileyonlinelibrary.com/journal/rmv
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1 of 10
https://doi.org/10.1002/rmv.2385


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Porcine reproductive and respiratory syndrome virus infection triggers autophagy via ER stress-induced calcium signaling to facilitate virus replication


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RESEARCH ARTICLE
Porcine reproductive and respiratory
syndrome virus infection triggers autophagy
via ER stress-induced calcium signaling to
facilitate virus replication
Feifei Diao1, Chenlong Jiang1, Yangyang Sun1, Yanni Gao1, Juan Bai1,2, Hans Nauwynck3,
Xianwei Wang1,2, Yuanqi Yang1, Ping Jiang1,2*, Xing LiuID1,2*
1 Key Laboratory of Animal Disease Diagnostics and Immunology, Ministry of Agriculture, MOE International
Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine,
Nanjing Agricultural University, Nanjing, PR China, 2 Jiangsu Co-innovation Center for Prevention and
Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, PR China,
3 Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
* jiangp@njau.edu.cn (PJ); xingliu@njau.edu.cn (XL)
Abstract
Calcium (Ca2+), a ubiquitous second messenger, plays a crucial role in many cellular func-
tions. Viruses often hijack Ca2+ signaling to facilitate viral processes such as entry, replica-
tion, assembly, and egress. Here, we report that infection by the swine arterivirus, porcine
reproductive and respiratory syndrome virus (PRRSV), induces dysregulated Ca2+ homeo-
stasis, subsequently activating calmodulin-dependent protein kinase-II (CaMKII) mediated
autophagy, and thus fueling viral replication. Mechanically, PRRSV infection induces endo-
plasmic reticulum (ER) stress and forms a closed ER–plasma membrane (PM) contacts,
resulting the opening of store operated calcium entry (SOCE) channel and causing the ER
to take up extracellular Ca2+, which is then released into the cytoplasm by inositol trispho-
sphate receptor (IP3R) channel. Importantly, pharmacological inhibition of ER stress or
CaMKII mediated autophagy blocks PRRSV replication. Notably, we show that PRRSV pro-
tein Nsp2 plays a dominant role in the PRRSV induced ER stress and autophagy, interacting


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with stromal interaction molecule 1 (STIM1) and the 78 kDa glucose-regulated protein 78
(GRP78). The interplay between PRRSV and cellular calcium signaling provides a novel
potential approach to develop antivirals and therapeutics for the disease outbreaks.
Author summary
Porcine reproductive and respiratory syndrome virus (PRRSV) infection results in a seri-
ous swine disease and causes a severe economic threat to the global swine industry. How-
ever, commercial vaccines do not provide satisfactory protection against PRRSV due to its
genetic variation. Well understanding the mechanism of PRRSV replication is helpful to
develop the effective strategies to control the disease. Calcium signaling has been reported
to play an important role in the life cycles of viruses. In this study, we describe the picture
PLOS PATHOGENS
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March 27, 2023
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OPEN ACCESS
Citation: Diao F, Jiang C, Sun Y, Gao Y, Bai J,
Nauwynck H, et al. (2023) Porcine reproductive
and respiratory syndrome virus infection triggers
autophagy via ER stress-induced calcium signaling
to facilitate virus replication. PLoS Pathog 19(3):
e1011295. https://doi.org/10.1371/journal.
ppat.1011295
Editor: Balaji Manicassamy, University of Iowa,
UNITED STATES
Received: August 28, 2022
Accepted: March 13, 2023
Published: March 27, 2023
Copyright: © 2023 Diao 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: The authors confirm
that all data underlying the findings are fully
available without restriction. All relevant data are
within the paper and its Supporting Information
files.
Funding: This work was supported by the National
Natural Science Foundation (32230103), the
Earmarked Fund for CARS-35, the Jiangsu


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Systemic inflammation exacerbates developmental neurotoxicity induced by sevoflurane in neonatal rats


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Systemic inﬂammation exacerbates developmental neurotoxicity
induced by sevoﬂurane in neonatal rats
Nemanja Useinovic1,*, Stefan Maksimovic1, Cole Liechty1, Omar H. Cabrera1,
Nidia Quillinan1,2 and Vesna Jevtovic-Todorovic1,3
1Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2Neuronal Injury
and Plasticity Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA and 3Department of
Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
*Corresponding author. E-mail: nemanja.useinovic@cuanschutz.edu
Abstract
Background: General anaesthesia in the neonatal period has detrimental effects on the developing mammalian brain.
The impact of underlying inﬂammation on anaesthesia-induced developmental neurotoxicity remains largely unknown.
Methods: Postnatal day 7 (PND7) rats were randomly assigned to receive sevoﬂurane (3 vol% for 3 h) or carrier gas 12 h
after bacterial lipopolysaccharide (LPS; 1 mg g1) or vehicle injection. Pharmacological inhibition of caspase-1 by Vx-765
(two doses of 50 mg g1 body weight) was used to investigate mechanistic pathways of neuronal injury. Histomorpho-
logical injury and molecular changes were quantiﬁed 2 h after the end of anaesthesia. Long-term functional deﬁcits were
tested at 5e8 weeks of age using a battery of behavioural tests in the memory and anxiety domains.
Results: Sevoﬂurane or LPS treatment increased activated caspase-3 and caspase-9 expression in the hippocampal
subiculum and CA1, which was greater when sevoﬂurane was administered in the setting of LPS-induced inﬂammation.
Neuronal injury induced by LPSþsevoﬂurane treatment resulted in sex-speciﬁc behavioural outcomes when rats were
tested at 5e8 weeks of age, including learning and memory deﬁcits in males and heightened anxiety-related behaviour in
females. Hippocampal caspase-1 and NLRP1 (NLR family pyrin domain containing 1), but not NLRP3, were upregulated by


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LPS or LPSþsevoﬂurane treatment, along with related proinﬂammatory cytokines, interleukin (IL)-1b, and IL-18. Pre-
treatment with Vx-765, a selective caspase-1 inhibitor, led to reduced IL-1b in LPS and LPSþsevoﬂurane groups. Caspase-
1 inhibition by Vx-765 signiﬁcantly decreased activated caspase-3 and caspase-9 immunoreactivity in the subiculum.
Conclusions: Systemic inﬂammation promotes developmental neurotoxicity by worsening anaesthesia-induced
neuronal damage with sex-speciﬁc behavioural outcomes. This highlights the importance of studying anaesthesia-
induced neurotoxicity in more clinically relevant settings.
Keywords: apoptosis; caspase-1; hippocampus; inﬂammasome; inﬂammation; lipopolysaccharide; neonatal anaesthesia
Editor’s key points
 General anaesthetics alone can enhance apoptotic
neuronal and glial death and produce long-term
behavioural deﬁcits in animal models, but whether
this
is
modiﬁed
by
underlying
inﬂammation
is
unclear.
 Systemic inﬂammation induce with bacterial lipo-
polysaccharide (LPS) worsened neuroapoptosis and
sex-speciﬁc behavioural deﬁcits produced by sevo-
ﬂurane anaesthesia exposure in neonatal rats.
 These ﬁndings demonstrate effects of both sex and
systemic inﬂammation on developmental anaes-
thetic neurotoxicity in rats.
 These ﬁndings highlight the potential impact of un-
derlying pathological conditions on developmental
anaesthetic neurotoxicity, which will require clinical
validation.
Received: 21 September 2021; Accepted: 8 May 2022
© 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com
555
British Journal of Anaesthesia, 129 (4): 555e566 (2022)
doi: 10.1016/j.bja.2022.05.008
Advance Access Publication Date: 11 June 2022
Neuroscience and Neuroanaesthesia


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Scientific rationale for the use of Î±2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders


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EXPERT REVIEW
OPEN
Scientiﬁc rationale for the use of α2A-adrenoceptor agonists in
treating neuroinﬂammatory cognitive disorders
Amy F. T. Arnsten
1✉, Yumiko Ishizawa2 and Zhongcong Xie2
© The Author(s) 2023
Neuroinﬂammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This
includes such challenging disorders as delirium, perioperative neurocognitive disorder, and the sustained cognitive deﬁcits from
“long-COVID” or traumatic brain injury. There are no FDA-approved treatments for these symptoms; thus, understanding their
etiology is important for generating therapeutic strategies. The current review describes the molecular rationale for why PFC circuits
are especially vulnerable to inﬂammation, and how α2A-adrenoceptor (α2A-AR) actions throughout the nervous and immune
systems can beneﬁt the circuits in PFC needed for higher cognition. The layer III circuits in the dorsolateral PFC (dlPFC)
that generate and sustain the mental representations needed for higher cognition have unusual neurotransmission and
neuromodulation. They are wholly dependent on NMDAR neurotransmission, with little AMPAR contribution, and thus are
especially vulnerable to kynurenic acid inﬂammatory signaling which blocks NMDAR. Layer III dlPFC spines also have unusual
neuromodulation, with cAMP magniﬁcation of calcium signaling in spines, which opens nearby potassium channels to rapidly
weaken connectivity and reduce neuronal ﬁring. This process must be tightly regulated, e.g. by mGluR3 or α2A-AR on spines, to
prevent loss of ﬁring. However, the production of GCPII inﬂammatory signaling reduces mGluR3 actions and markedly diminishes
dlPFC network ﬁring. Both basic and clinical studies show that α2A-AR agonists such as guanfacine can restore dlPFC network ﬁring
and cognitive function, through direct actions in the dlPFC, but also by reducing the activity of stress-related circuits, e.g. in the


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locus coeruleus and amygdala, and by having anti-inﬂammatory actions in the immune system. This information is particularly
timely, as guanfacine is currently the focus of large clinical trials for the treatment of delirium, and in open label studies for the
treatment of cognitive deﬁcits from long-COVID.
Molecular Psychiatry; https://doi.org/10.1038/s41380-023-02057-4
INTRODUCTION
Stress and inﬂammation can profoundly alter the nervous and
immune systems, creating long-term impairments in cognitive
functioning. In particular, the cognitive functions of the prefrontal
cortex (PFC) are impaired in a wide range of neuroinﬂammatory
disorders, including in Alzheimer’s disease (AD) [1], traumatic brain
injury (TBI) [2], and perioperative neurocognitive disorder (PND)
[3]. The PFC subserves abstract reasoning and the executive
functions, where deﬁcits can be remarkably debilitating, interfer-
ing with the ability to work or care for families [4]. There is a great
need for treatment, especially in the wake of COVID-19 infection,
where cognitive deﬁcits from “long-COVID” are prevalent [5].
However, there are no FDA-approved medications for treating
neuroinﬂammatory cognitive disorders.
New research has shown that the recently evolved circuits in
the primate PFC have unusual molecular needs that support
higher cognitive operations, but render these circuits particularly
vulnerable to disruption from neuroinﬂammation [6]. In particular,
these circuits express the molecular machinery for cAMP to
magnify calcium signaling to help sustain prolonged neuron
ﬁring needed to represent information without sensory stimula-
tion. However, magniﬁed cAMP-calcium signaling is readily
dysregulated by stress and inﬂammation, leading to atrophy, tau
phosphorylation and impaired PFC cognitive functioning. Thus,
medications that can restore regulation of cAMP-calcium signaling
may be especially helpful in restoring cognitive abilities.
As will be described in detail below, research has shown that


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the selective noradrenergic α2A-adrenoceptor (α2A-AR) agonist,
guanfacine,
can
strengthen
PFC
network
connections
and
improve PFC cognitive functioning by regulating cAMP-calcium
signaling [7]. Based on this research, extended release guanfacine
was approved by the FDA in 2009 for the treatment of Attention
Deﬁcit Hyperactivity Disorder, which is characterized by PFC
deﬁcits. Guanfacine is also being used off-label and/or being
tested to treat cognitive deﬁcits in a variety of neuroinﬂammatory
disorders including traumatic brain injury (TBI), delirium (post-
anesthetic or infectious), and cognitive deﬁcits from long-COVID
(“brain fog”). However, the scientiﬁc bases for guanfacine’s actions
in these disorders are generally not understood, as this research
has arisen from multiple, and often disparate, disciplines. While
many scientists and physicians are aware of how stimulation of
presynaptic α2A-AR autoreceptors reduces NE release from the
sympathetic nervous system [8], they are often unaware of
important,
post-synaptic
α2A-AR
actions
in
brain
that
are
Received: 20 November 2022 Revised: 22 March 2023 Accepted: 24 March 2023
1Department Neuroscience, Yale University School of Medicine, New Haven, CT 056510, USA. 2Department Anesthesiology, Critical Care and Pain Medicine, Massachusetts
General Hospital, Harvard Medical School, Boston, MA 02114, USA. ✉email: amy.arnsten@yale.edu
www.nature.com/mp
Molecular Psychiatry
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Viral vectored vaccines: design, development, preventive and therapeutic applications in human diseases


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REVIEW ARTICLE
OPEN
Viral vectored vaccines: design, development, preventive and
therapeutic applications in human diseases
Shen Wang1, Bo Liang1, Weiqi Wang1,2, Ling Li3, Na Feng1, Yongkun Zhao1, Tiecheng Wang1, Feihu Yan1✉, Songtao Yang1✉ and
Xianzhu Xia1✉
Human diseases, particularly infectious diseases and cancers, pose unprecedented challenges to public health security and the
global economy. The development and distribution of novel prophylactic and therapeutic vaccines are the prioritized
countermeasures of human disease. Among all vaccine platforms, viral vector vaccines offer distinguished advantages and
represent prominent choices for pathogens that have hampered control efforts based on conventional vaccine approaches.
Currently, viral vector vaccines remain one of the best strategies for induction of robust humoral and cellular immunity against
human diseases. Numerous viruses of different families and origins, including vesicular stomatitis virus, rabies virus, parainﬂuenza
virus, measles virus, Newcastle disease virus, inﬂuenza virus, adenovirus and poxvirus, are deemed to be prominent viral vectors
that differ in structural characteristics, design strategy, antigen presentation capability, immunogenicity and protective efﬁcacy. This
review summarized the overall proﬁle of the design strategies, progress in advance and steps taken to address barriers to the
deployment of these viral vector vaccines, simultaneously highlighting their potential for mucosal delivery, therapeutic application
in cancer as well as other key aspects concerning the rational application of these viral vector vaccines. Appropriate and accurate
technological advances in viral vector vaccines would consolidate their position as a leading approach to accelerate breakthroughs
in novel vaccines and facilitate a rapid response to public health emergencies.
Signal Transduction and Targeted Therapy  (2023) 8:149 
; https://doi.org/10.1038/s41392-023-01408-5
INTRODUCTION
The outbreak of infectious diseases and the occurrence of


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cancers cause a huge impact on humans throughout history.
Hemorrhagic fever, including Ebola, Marburg, and Lassa fever,
cause fatality rates of up to 50%.1–3 In addition, there have been
three waves of beta coronavirus emergence since 2003, of which
coronavirus disease 2019 (COVID-19) has caused billions of
conﬁrmed cases and millions of deaths since 2019.4–6 Globally,
an estimated 19.3 million new cancer cases and almost 10.0
million cancer deaths occur every year,7 which pose as the
leading health threat.
For infectious diseases, vaccination and establishment of herd
immunity
are
of
primary
importance.
Among
all
vaccine
technologies, recombinant viral vectors represent promising
vaccine platforms due to their ability to express heterologous
antigens and induction of cellular immune responses and
humoral immune responses without exogenous adjuvants. Viral
vector vaccines consist of viral particles whose genomes have
been modiﬁed to contain one or more foreign genes encoding
the targeted antigens. The rationale for using viruses to deliver
the ‘vaccine gene’ is in several folds. Viral vectored vaccines are
safe and induce both arm of innate and adaptive immune
responses without involvement of the complete hazardous
pathogen.8 Moreover, viral vectors have intrinsic adjuvant proper-
ties due to the expression of diverse pathogen-associated
molecular
patterns
(PAMPs)
and
the
activation
of
innate
immunity.9 In addition, viral vectors can be engineered to deliver
antigens to speciﬁc cells or tissues. Similarly, they can be rendered
replication-competent or replication-deﬁcient to increase their
safety and reduce reactogenicity. Notably, the viral vector vaccine
can recapitulate the natural infection process of speciﬁc patho-
gens, thus triggering classical acute inﬂammation and immune
detection through the natural production of PAMPs, enabling
mucosal delivery and induction of local-mucosal and systemic
immunity. Several viral vector-based prophylactic vaccines have


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entered Phase III clinical trials or have been approved.10–15 In the
ﬁeld of cancers, viral vectors are ideal oncolytic viruses (OVs)
since they can trigger cellular immunity and could be armed,
shielded and targeting tumor cells. The release of tumorasso-
ciated antigens (TAAs) could activate and regulate the anti-tumor
immune response. Several OV preparations have been approved
for marketing, which present promising directions for immu-
notherapy of tumors.
Nevertheless, the systematic and comparative review of these
viral vectors is less well established. Moreover, the generality and
individuality of these viral vectors are not fully elucidated. In this
review, the general overview of vesicular stomatitis virus (VSV),
rabies virus (RABV), parainﬂuenza virus (PIV), measles virus (MeV),
Newcastle disease virus (NDV), inﬂuenza virus (IFV), adenovirus
(AdV), and poxvirus vector vaccines was summarized in terms of
Received: 8 November 2022 Revised: 6 March 2023 Accepted: 14 March 2023
1Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China;
2College of Veterinary Medicine, Jilin University, Changchun, China and 3China National Research Center for Exotic Animal Diseases, China Animal Health and Epidemiology
Center, Qingdao, China
Correspondence: Feihu Yan (yanfh1990@163.com) or Songtao Yang (yst62041@163.com) or Xianzhu Xia (xiaxzh@cae.cn)
These authors contributed equally: Shen Wang, Bo Liang, Weiqi Wang, Ling Li
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
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RESEARCH ARTICLE
Frequent first-trimester pregnancy loss in
rhesus macaques infected with African-
lineage Zika virus
Jenna R. RosinskiID1☯, Lauren E. Raasch1☯, Patrick Barros Tiburcio1, Meghan
E. Breitbach1, Phoenix M. Shepherd1, Keisuke Yamamoto1, Elaina Razo2, Nicholas
P. Krabbe2, Mason I. Bliss3, Alexander D. Richardson3, Morgan A. Einwalter3, Andrea
M. Weiler3, Emily L. Sneed3, Kerri B. Fuchs3, Xiankun Zeng4, Kevin K. Noguchi5, Terry
K. Morgan6,7, Alexandra J. Alberts1, Kathleen M. Antony8, Sabrina Kabakov9, Karla
K. Ausderau9,10, Ellie K. Bohm11, Julia C. Pritchard11, Rachel V. Spanton9, James N. Ver
Hoove12, Charlene B. Y. Kim12, T. Michael Nork12, Alex W. Katz12, Carol A. Rasmussen12,
Amy Hartman13, Andres Mejia3, Puja Basu3, Heather A. Simmons3, Jens C. Eickhoff14,
Thomas C. Friedrich15, Matthew T. Aliota11, Emma L. Mohr2, Dawn M. Dudley1, David
H. O’Connor1,3‡, Christina M. Newman1‡*
1 Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison; Madison, Wisconsin,
Unites States of America, 2 Department of Pediatrics, University of Wisconsin-Madison; Madison, Wisconsin,
Unites States of America, 3 Wisconsin National Primate Research Center, University of Wisconsin-Madison;
Madison, Wisconsin, Unites States of America, 4 United States Army Medical Research Institute of Infectious
Diseases; Fort Detrick, Maryland, Unites States of America, 5 Department of Psychiatry, Washington
University School of Medicine; St. Louis, Washington, Unites States of America, 6 Department of Pathology,
Oregon Health and Science University; Portland, Oregon, Unites States of America, 7 Department of
Obstetrics and Gynecology, Oregon Health and Science University; Portland, Oregon, Unites States of
America, 8 Department of Obstetrics and Gynecology, University of Wisconsin-Madison; Madison,
Wisconsin, Unites States of America, 9 Department of Kinesiology, University of Wisconsin-Madison;
Madison, Wisconsin, Unites States of America, 10 Waisman Center, University of Wisconsin-Madison;


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Madison, Wisconsin, Unites States of America, 11 Department of Veterinary and Biomedical Science,
University of Minnesota; St. Paul, Minnesota, Unites States of America, 12 Department of Ophthalmology
and Visual Sciences, University of Wisconsin-Madison; Madison, Wisconsin, Unites States of America,
13 Department of Communication Sciences and Disorders, University of Wisconsin-Madison; Madison,
Wisconsin, Unites States of America, 14 Department of Biostatistics & Medical Informatics, University of
Wisconsin-Madison; Madison, Wisconsin, Unites States of America, 15 Department of Pathobiological
Sciences, University of Wisconsin-Madison; Madison, Wisconsin, Unites States of America
☯ These authors contributed equally to this work.
‡ DHO and CMN also contributed equally to this work.
* ccondon2@wisc.edu
Abstract
In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects sur-
faced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy.
Less is known about the impacts of gestational African-lineage ZIKV infections. Given high
human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circu-
lates, we evaluated whether pregnant rhesus macaques infected with simian immunodefi-
ciency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects.
Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused
a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings sug-
gest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection
PLOS PATHOGENS
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March 28, 2023
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Citation: Rosinski JR, Raasch LE, Barros Tiburcio
P, Breitbach ME, Shepherd PM, Yamamoto K, et al.
(2023) Frequent first-trimester pregnancy loss in
rhesus macaques infected with African-lineage Zika


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virus. PLoS Pathog 19(3): e1011282. https://doi.
org/10.1371/journal.ppat.1011282
Editor: Helen M. Lazear, University of North
Carolina at Chapel Hill School of Medicine, UNITED
STATES
Received: January 11, 2023
Accepted: March 8, 2023
Published: March 28, 2023
Copyright: This is an open access article, free of all
copyright, and may be freely reproduced,
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 relevant data are
within the manuscript and the Supporting
Information files. Primary data that support this
study are also available at GitHub https://github.
com/lraasch/Frequent-first-trimester-pregnancy-
loss-in-rhesus-macaques-infected-with-African-
lineage-Zika-virus. ISH images are available at
https://go.wisc.edu/23d838.
Funding: This work was supported by NIH Grants
R01AI138647, P01AI132132, K08AI139341,


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Targeted isolation of panels of diverse human protective broadly neutralizing antibodies against SARS-like viruses


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Targeted isolation of panels of diverse human protective broadly 
neutralizing antibodies against SARS-like viruses
Wan-ting He1,2,3,†, Rami Musharrafieh1,2,3,†, Ge Song1,2,3,†, Katharina Dueker1,2,3,†, 
Longping V. Tse4, David R. Martinez4, Alexandra Schäfer4, Sean Callaghan1,2,3, Peter 
Yong1,2,3, Nathan Beutler1, Jonathan L. Torres5, Reid M. Volk5, Panpan Zhou1,2,3, Meng 
Yuan5, Hejun Liu5, Fabio Anzanello1,2,3, Tazio Capozzola1,2,3, Mara Parren1, Elijah Garcia1, 
Stephen A. Rawlings6, Davey M. Smith6, Ian A. Wilson2,3,5,7, Yana Safonova8, Andrew 
B. Ward2,3,5, Thomas F. Rogers1,6, Ralph S. Baric4,9,*, Lisa E. Gralinski4,*, Dennis R. 
Burton1,2,3,10,*, Raiees Andrabi1,2,3,*
1Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 
92037, USA.
2IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA
3Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La 
Jolla, CA 92037, USA.
4Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 
27599, USA.
5Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 
La Jolla, CA 92037, USA.
6Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La 
Jolla, CA 92037, USA.
7Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 9203
8Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA
9Departments of Microbiology and Immunology, The University of North Carolina at Chapel Hill, 
Chapel Hill, NC 27599, USA.
*Corresponding author. rbaric@email.unc.edu (R.S.B.); lgralins@email.unc.edu (L.E.G.); burton@scripps.edu (D.R.B.); 
andrabi@scripps.edu (R.A.).
†These authors contributed equally to this work.
Author contributions
W.H., R.M., G.S., K.D., D.R.B. and R.A. conceived and designed the study. N.B., M.P., E.G., S.A.R., D.M.S., and T.F.R. recruited


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donors and collected and processed plasma and PBMC samples. W.H., R.M., G.S., K.D., S.C., P.Y. and F.A. performed BLI, ELISA, 
virus preparation, neutralization and isolation and characterization of monoclonal antibodies. Y.S. performed immunogenetic analysis 
of antibodies. P.Z. prepared virus mutant plasmids. J.L.T. and R.M.V. conducted negative stain electron microscopy studies. M.Y. and 
H.L. generated antibody-antigen structural models. L.V.T. performed live virus neutralizations assays and L.V.T., D.R.M., A.S., and 
L.E.G. conducted in vivo animal protection studies. W.H., R.M., G.S., K.D., L.V.T., D.R.M., A.S., S.C., P.Y., N.B., J.L.T., R.M.V., 
P.Z., M.Y. H.L., F.A., M.P., E.G., I.A.W., A.B.W., T.F.R., R.S.B., L.E.G., D.R.B. and R.A. designed the experiments and/or analyzed 
the data. W.H., R.M., D.R.B. and R.A. wrote the paper, and all authors reviewed and edited the paper.
Competing interests: W.H., R.M., G.S., K.D., T.F.R., D.R.B. and R.A. are listed as inventors on pending patent applications describing 
the sarbecovirus broadly neutralizing antibodies isolated in this study. A.B.W, I.A.W and D.R.B. receive research funding from 
Adagio. RSB and LEG have ongoing collaborations with Adagio. All other authors have no competing interests to declare.
HHS Public Access
Author manuscript
Nat Immunol. Author manuscript; available in PMC 2023 April 09.
Published in final edited form as:
Nat Immunol. 2022 June ; 23(6): 960–970. doi:10.1038/s41590-022-01222-1.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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J Physiol 601.1 (2023) pp 37–50
37
The Journal of Physiology
REVIEW-SYMPOSIUM
The ventromedial prefrontal cortex and emotion
regulation: lost in translation?
Laith Alexander1,2
, Christian M. Wood3,4
and Angela C. Roberts3,4
1St Thomas’ Hospital, London, UK
2Department of Psychological Medicine, School of Academic Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London,
London, UK
3Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
4Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
Edited by: Ian Forsythe & Michael Okun
The peer review history is available in the Supporting information section of this article
(https://doi.org/10.1113/JP282627#support-information-section).
Abstract Neuroimaging studies implicate the ventromedial prefrontal cortex (vmPFC) in a wide
range of emotional and cognitive functions, and changes in activity within vmPFC have been
This symposium review forms part of the ’Decoding Prefrontal Cortical Physiology: Circuits of Cognition’ symposium held at Physiology 2021 in
July 2021, and organised by Professor Matt Jones.
© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
DOI: 10.1113/JP282627
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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Chronic immune activation and gut barrier dysfunction is associated with neuroinflammation in ART-suppressed SIV+ rhesus macaques


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RESEARCH ARTICLE
Chronic immune activation and gut barrier
dysfunction is associated with
neuroinflammation in ART-suppressed SIV+
rhesus macaques
Sarah J. Byrnes1, Kathleen Busman-Sahay2,3, Thomas A. Angelovich1,4,5,
Skyler Younger2, Sol Taylor-Brill2, Michael Nekorchuk2, Stephen Bondoc2,
Rachel Dannay2, Margaret Terry2, Catherine R. Cochrane1, Trisha A. Jenkins1,
Michael Roche1,5, Claire Deleage6, Steven E. Bosinger7,8, Mirko Paiardini7,8, Bruce
J. Brew9, Jacob D. Estes1,2,3☯, Melissa J. ChurchillID1,4,10☯*
1 School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia, 2 Vaccine & Gene
Therapy Institute, Oregon Health & Science University, Portland, Oregon, United States of America,
3 Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health &
Science University, Portland, Oregon, United States of America, 4 Life Science, Burnet Institute, Melbourne,
Australia, 5 Department of Infectious Diseases, The Peter Doherty Institute for Infection and Immunity, The
University of Melbourne, Melbourne, Australia, 6 AIDS and Cancer Virus Program, Leidos Biomedical
Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of
America, 7 Division of Microbiology and Immunology, Emory National Primate Research Center, Emory
University, Atlanta, Georgia, United States of America, 8 Department of Pathology and Laboratory Medicine,
Emory University School of Medicine, Atlanta, Georgia, United States of America, 9 Peter Duncan
Neurosciences Unit, Departments of Neurology and Immunology St Vincent’s Hospital, University of New
South Wales and University of Notre Dame, Sydney, New South Wales, Australia, 10 Departments of
Microbiology and Medicine, Monash University, Clayton, Australia
☯ These authors contributed equally to this work.
* melissa.churchill@rmit.edu.au
Abstract
HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people


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with HIV (PWH), however, the precise viral dependent and independent changes to the
brain are unclear. Here we characterized the CNS reservoir and immune environment of
SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic (n = 12) or ART-sup-
pressed SIV infection (n = 11). Multiplex immunofluorescence for markers of SIV infection
(vRNA/vDNA) and immune activation was performed on frontal cortex and matched colon
tissue. SIV+ animals contained detectable viral DNA+ cells that were not reduced in the
frontal cortex or the gut by ART, supporting the presence of a stable viral reservoir in these
compartments. SIV+ animals had impaired blood brain barrier (BBB) integrity and height-
ened levels of astrocytes or myeloid cells expressing antiviral, anti-inflammatory or oxidative
stress markers which were not abrogated by ART. Neuroinflammation and BBB dysfunction
correlated with measures of viremia and immune activation in the gut. Furthermore, SIV-
uninfected animals with experimentally induced gut damage and colitis showed a similar
immune activation profile in the frontal cortex to those of SIV-infected animals, supporting
the role of chronic gut damage as an independent source of neuroinflammation. Together,
these findings implicate gut-associated immune activation/damage as a significant
PLOS PATHOGENS
PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011290
March 29, 2023
1 / 26
a1111111111
a1111111111
a1111111111
a1111111111
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OPEN ACCESS
Citation: Byrnes SJ, Busman-Sahay K, Angelovich
TA, Younger S, Taylor-Brill S, Nekorchuk M, et al.
(2023) Chronic immune activation and gut barrier
dysfunction is associated with neuroinflammation
in ART-suppressed SIV+ rhesus macaques. PLoS
Pathog 19(3): e1011290. https://doi.org/10.1371/
journal.ppat.1011290
Editor: Daniel C. Douek, Vaccine Research Center,
UNITED STATES
Received: August 11, 2022
Accepted: March 10, 2023
Published: March 29, 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 relevant data are
within the manuscript and its Supporting
Information files.
Funding: This research was funded by National
Health and Medical Research Council, Australia
grant 1157988 (M.J.C, J.D.E, T.A.A; https://www.
nhmrc.gov.au/funding) and National Institutes of
Health, USA grants https://www.nih.gov/grants-
funding): R01AI143411 (J.D.E), P51OD011092
(Oregon National Primate Research Center),


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J Physiol 601.1 (2023) pp 25–35
25
The Journal of Physiology
REVIEW-SYMPOSIUM
Cortico-thalamocortical interactions for learning, memory
and decision-making
Brook A. L. Perry1
, Juan Carlos Mendez1,2
and Anna S. Mitchell1
1Department of Experimental Psychology, University of Oxford, Oxford, UK
2College of Medicine and Health, University of Exeter, Exeter, UK
Handling Editors: Ian Forsythe & Richard Carson
The peer review history is available in the Supporting information section of this article
(https://doi.org/10.1113/JP282626#support-information-section).
Abstract
The thalamus and cortex are interconnected both functionally and anatomically
and share a common developmental trajectory. Interactions between the mediodorsal thalamus
(MD) and different parts of the prefrontal cortex are essential in cognitive processes, such as
learning and adaptive decision-making. Cortico-thalamocortical interactions involving other
dorsal thalamic nuclei, including the anterior thalamus and pulvinar, also influence these
cognitive processes. Our work, and that of others, indicates a crucial influence of these inter-
dependent cortico-thalamocortical neural networks that contributes actively to the processing
of information within the cortex. Each of these thalamic nuclei also receives potent subcortical
This symposium review forms part of the ‘Decoding Prefrontal Cortical Physiology: Circuits of Cognition’ symposium held at Physiology 2021 in July
2021, and organized by Professor Matt Jones.
© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
DOI: 10.1113/JP282626
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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Review Article
Major haemorrhage: past, present and future
A. Shah,1
V. Kerner,2
S. J. Stanworth3
and S. Agarwal4
1 NIHR Academic Clinical Lecturer, Nufﬁeld Department of Clinical Neurosciences, University of Oxford, Oxford, UK
2 Specialist Registrar, Nufﬁeld Department of Anaesthesia, Oxford University Hospitals NHS Foundation Trust,
Oxford, UK
3 Professor, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
4 Consultant, Department of Anaesthesia, Manchester University NHS Foundation Trust, Manchester, UK
Summary
Major haemorrhage is a leading cause of morbidity and mortality worldwide. Successful treatment requires
early recognition, planned responses, readily available resources (such as blood products) and rapid access to
surgery or interventional radiology. Major haemorrhage is often accompanied by volume loss, haemodilution,
acidaemia, hypothermia and coagulopathy (factor consumption and ﬁbrinolysis). Management of major
haemorrhage over the past decade has evolved to now deliver a `package´ of haemostatic resuscitation
including: surgical or radiological control of bleeding; regular monitoring of haemostasis; advanced critical
care support; and avoidance of the lethal triad of hypothermia, acidaemia and coagulopathy. Recent trial data
advocate for a more personalised approach depending on the clinical scenario. Fresh frozen plasma should be
given as early as possible in major trauma in a 1:1 ratio with red blood cells until the results of coagulation tests
are available. Tranexamic acid is a cheap, life-saving drug and is advocated in major trauma, postpartum
haemorrhage and surgery, but not in patients with gastrointestinal bleeding. Fibrinogen levels should be
maintained > 2 g.l1 in postpartum haemorrhage and > 1.5 g.l1 in other haemorrhage. Improving outcomes
after major traumatic haemorrhage is now driving research to include extending blood-product resuscitation
into prehospital care.


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.................................................................................................................................................................
Correspondence to: A. Shah
Email: akshay.shah@linacre.ox.ac.uk
Accepted: 29 August 2022
Keywords: crystalloid resuscitation: coagulopathy; major haemorrhage; transfusion; trauma
Twitter: @DocAShah; @OxCPD; @SimonStanworth; @SeemaMosca
Introduction
A person dies from injury nearly every 3 min, and 40% of
these deaths are due to major haemorrhage or its
consequences [1]. Death from haemorrhage is early, with
up to 60% of deaths occurring within the ﬁrst 3 h of injury
[2]. Haemorrhage continues to be the leading cause of
maternal death globally [3]. Causes of haemorrhage may
also vary geographically. In high-resource settings, the most
common indications for massive transfusion are major
surgery (61.2%) followed by trauma (15.4%), whereas
obstetric bleeding only constitutes 1.8% of cases [4].
Since the publication of major haemorrhage guidelines
from the British Society of Haematology in 2015 and
Association of Anaesthetists in 2016, there have been
numerous randomised controlled trials in this ﬁeld. A
summary of these trials is displayed in Table 1.
The aims of this article are to: describe the deﬁnitions of
major haemorrhage; brieﬂy recap the mechanisms and
pathophysiology of bleeding; provide a contemporary
narrative review of transfusion support during major
haemorrhage across a range of clinical indications; and
highlight ongoing trials and areas of uncertainty.
© 2022 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.
93
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.
Anaesthesia 2023, 78, 93–104
doi:10.1111/anae.15866


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The current status of stem cell-based therapies during ex vivo graft perfusion: an integrated review of four organs 


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Am J Transplant. 2022;22:2723–2739. 
 
 | 2723
AJT
amjtransplant.com
Received: 3 May 2022 | Revised: 26 June 2022 | Accepted: 15 July 2022
DOI: 10.1111/ajt.17161  
M I N I R E V I E W
The current status of stem cell- based therapies during ex vivo 
graft perfusion: An integrated review of four organs
Stefan H. Luijmes1
 |   Monique M. A. Verstegen1
 |   Martin J. Hoogduijn2
 |    
Leonard Seghers3
 |   Robert C. Minnee1
 |   Edris A. F. Mahtab4
 |    
Yannick J. H. J. Taverne4
 |   Marlies E. J. Reinders2
 |   Luc J. W. van der Laan1
 |   
Jeroen de Jonge1
1Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, 
Rotterdam, The Netherlands
2Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam, 
Rotterdam, The Netherlands
3Department of Pulmonology, Thorax Center, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
4Department of Cardiothoracic Surgery, Thorax Center, Erasmus MC Transplant Institute, University Erasmus Medical Center Rotterdam, Rotterdam, The 
Netherlands
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. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the 
American Society of Transplant Surgeons.
Abbreviations: ADAR, adenosine deaminase, RNA- specific; AFC, alveolar fluid clearance; AKT1, v- akt murine thymoma viral oncogene homolog 1; AKT3, v- akt murine thymoma viral


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oncogene homolog 3; ALP, alkaline phosphatase; ALT, alanine aminotransferase; A- MSC, adipose- derived mesenchymal stromal cell; ANG- 1, angiopoietin 1; AOX1, aldehyde oxidase 1; 
AST, aspartate aminotransferase; ATP, adenosine triphosphate; ATP6V0D2, vacuolar H + - ATPase d2 Subunit; BALF, bronchoalveolar lavage fluid; BCL2L11, BCL2- like 11; BICC1, 
bicaudal C homolog 1 gene; BID, BH3- interacting domain death agonist; BIRC5, baculoviral IAP repeat- containing 5; BM- MSC, bone marrow- derived mesenchymal stromal cell; BTLA, 
B-  and T- lymphocyte attenuator; BW, bodyweight; CALB1, calbindin 1; CASP2, caspase- 2; CASP8, caspase- 8; CAT, catalase; CCL11, chemokine (C − C motif) ligand 11; CD40LG, CD40 
ligand; CFTR, cystic fibrosis transmembrane conductance regulator; CXCL2, chemokine C- X- C motif ligand 2; CXCL3, chemokine C- X- C motif ligand 3; CXCR4, C- X- C chemokine 
receptor type 4; CXCR5, C- X- C chemokine receptor type 5; CXCR7, C- X- C chemokine receptor type 7; DCDC2, doublecortin domain- containing protein 2; DHCR24, 
24- Dehydrocholesterol reductase; DNM2, dynamin 2; dP/dtmax, maximal slope of systolic pressure increment; dP/dtmin, maximal slope of diastolic pressure decrement; E.coli, Escherichia 
coli; EB, endobronchially; ECD, extended criteria donor; EGF, endothelial growth factor; EPX, eosinophil peroxidase; EV, extracellular vesicle; EVHP, ex vivo heart perfusion; EVLP, ex 
vivo lung perfusion; FADD, fas (TNFRSF6) associated via death domain; FASLG, Fas ligand; FBS, fetal bovine serum; FGF- 1, fibroblast growth factor- 1; FGF- 2, fibroblast growth factor- 2; 
FLT- 3 L, FMS- like tyrosine kinase 3 ligand; FOXG1, forkhead box G1; GCP, Good Clinical Practice; G- CSF, granulocyte colony- stimulating factor; GGT, gamma- glutamyltransferase; 
GITR, glucocorticoid- induced tumor necrosis factor receptor; GM- CSF, granulocyte- macrophage colony- stimulating factor; GPX, glutathione peroxidase; GPX4, anti- glutathione


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peroxidase 4; GRB2, growth factor receptor- bound protein 2; GSH, glutathione; GZMB, granzyme B; HA, hyaluronic acid; HGF, hepatocyte growth factor; HIF1A, hypoxia- inducible 
factor 1- α; HLA- G5, human leukocyte antigen- G5; HLSC, human liver stem cell; HLSC- EV, human liver stem cell extracellular vesicle; HMGB1, high- mobility group box 1; HMP, 
hypothermic machine perfusion; HO- 1, heme oxygenase 1; HO- 1/BMMSC, heme oxygenase 1- modified bone marrow- derived mesenchymal stromal cell; HOPE, hypothermic 
oxygenated perfusion; HSP70, heat shock protein 70; HYOU1, hypoxia upregulated 1; IA, intra- arterially; ICAM- 1, intercellular adhesion molecule 1; IDH2, isocitrate dehydrogenase 2; 
IDO, Indolamine- 2,3- dioxygenase; IFN- γ, interferon- gamma; IGF, insulin- like growth factor; IH, intrahepatic; IL, interleukin; IL- 1- RA, interleukin- 1 receptor antagonist; IP- 10, 
interferon- inducible protein 10; IT, intratracheal; IV, intravenous; KRT19, cytokeratin- 19; KRT7, cytokeratin- 7; LDH, lactate dehydrogenase; LLL, left lower lobe; MAPC, multipotent 
adult progenitor cell; MAPK3, mitogen- activated protein kinase 3; MAPK4, extracellular signal- regulated kinase 4; MCP- 1, monocyte chemoattractant protein- 1; MCP- 3, monocyte 
chemoattractant protein- 3; M- CSF, macrophage colony- stimulating factor; MDA, malondialdehyde; MDC, macrophage- derived chemokine; MIP, macrophage inflammatory protein; MP, 
machine perfusion; MPO, myeloperoxidase; MSC, mesenchymal stromal cell; MSC- CM, mesenchymal stromal cell- conditioned medium; MSC- EV, mesenchymal stem cell- derived 
extracellular vesicle; mTOR, mechanistic target of rapamycin; MV, microvesicle; MVB, multivesicular body; NDUFS8, NADH dehydrogenase Fe- S protein 8; NGAL, neutrophil 
gelatinase- associated lipocalin; NK, natural killer; NMP, normothermic machine perfusion; NO, nitric oxide; NOX4, NADPH oxidase 4; NOXO1, NADPH oxidase organizer; PAK1, p21


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protein (Cdc42/Rac)- activated kinase; PAP, pulmonary arterial pressure; PAR, pulmonary artery resistance; PBG, peribiliary gland; PCNA, proliferating cell nuclear antigen; PD- 1, 
programmed cell death protein- 1; PDHB, pyruvate dehydrogenase beta; PGE2, prostaglandin E2; PTGS2, prostaglandin- endoperoxide synthase 2; PV, portal vein; PVR, pulmonary 
vascular resistance; RAI, rejection activity index; RANTES, regulated on activation, normal T expressed and secreted; RBC, red blood cell; RML, right middle lobe; RNA, ribonucleic acid; 
ROS, reactive oxidative species; SDF- 1α, stromal cell- derived factor- 1α; Serpinb1b, Serine (or cysteine) peptidase inhibitor, clade B, member 1b; SLC16A1, monocarboxylate transporter 
1; sNMP, subnormothermic machine perfusion; SOCS3, suppressor of cytokine signaling 3; SOD, superoxide dismutase; SOD2, superoxide dismutase 2, mitochondrial; SOX4, 
sex- determining region Y- related high- mobility group box transcription factor 4; STC- 1, stanniocalcin- 1; STIP1, transformation- sensitive protein IEF SSP 3521; Tau- w, time constant of 
the left ventricular pressure decay; TCL1a, T- cell leukemia/lymphoma 1A; TGF, transforming growth factor; TIMP- 1, tissue inhibitor of metalloproteinase- 1; TNF- α, tumor necrosis 
factor- α; TPN, total parenteral nutrition; TPO, thyroid peroxidase; TPVR, total pulmonary vascular resistance; T- reg, regulatory T cell; TUNEL, terminal deoxynucleotidyl transferase 
dUTP nick end labeling; TXNRD2, thioredoxin reductase 2; UC- MSC, umbilical cord- derived mesenchymal stromal cell; UW- MPS, University of Wisconsin machine perfusion solution; 
VEGF, vascular endothelial growth factor.


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R E V I E W A R T I C L E
Neural bases of the bodily self as revealed by electrical brain
stimulation: A systematic review
Zoé Dary1
|
Bigna Lenggenhager2,3
|
Stanislas Lagarde4,5
|
Samuel Medina Villalon4,5
|
Fabrice Bartolomei4,5
|
Christophe Lopez1
1Aix Marseille University, CNRS, LNC, FR3C,
Marseille, France
2Department of Psychology, University of
Zurich, Zurich, Switzerland
3Department of Psychology, University of
Konstanz, Konstanz, Germany
4Aix Marseille University, APHM, Inserm, INS,
Timone Hospital, Marseille, France
5APHM, Timone Hospital, Epileptology and
Cerebral Rhythmology, Marseille, France
Correspondence
Christophe Lopez, Laboratoire de
Neurosciences Cognitives – UMR 7291, Aix
Marseille University & Centre National de la
Recherche Scientifique (CNRS), Centre Saint-
Charles, Fédération de Recherche 3C – Case
B. 3, Place Victor Hugo. 13331 Marseille
Cedex 03, France.
Email: christophe.lopez@univ-amu.fr
Funding information
Agence Nationale de la Recherche,
Grant/Award Number: ANR-19-CE37-0027
Abstract
An increasing amount of recent research has focused on the multisensory and neural
bases of the bodily self. This pre-reflective form of self is considered as multifaceted,
incorporating phenomenal components, such as self location, body ownership, first-
person perspective, agency, and the perceptual body image. Direct electrical brain
stimulation (EBS) during presurgical evaluation of epilepsy and brain tumor re-
section is a unique method to causally relate specific brain areas to the various phe-
nomenal components of the bodily self. We conducted a systematic review of the
literature describing altered phenomenal experience of the bodily self evoked by
EBS. We included 42 articles and analyzed self reports from 221 patients. Three-
dimensional density maps of EBS revealed that stimulation in the middle cingulum,
inferior parietal lobule, supplementary motor area, posterior insula, hippocampal
complex/amygdala, and precuneus most consistently altered one or several compo-


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nents of the bodily self. In addition, we found that only EBS in the parietal cortex
induced disturbances of all five components of the bodily self considered in this
review article. These findings inform current neuroscientific models of the bodily self.
K E Y W O R D S
self consciousness, bodily self, electrical brain stimulation, epilepsy, parietal cortex
1
|
INTRODUCTION
The functionality, morphology, and state of our body have shown to
play a major role in many cognitive, affective, and social processes
and crucially define our self consciousness. Such bodily self is consid-
ered to result from a constant multisensory integration and fine-
tuning of bottom-up signals (visual, somatosensory, interoceptive, and
vestibular
signals)
and
top-down
expectancy
(Blanke,
2012;
Lenggenhager & Lopez, 2015; Park & Blanke, 2019; Tsakiris, 2010).
Various phenomenal components of the bodily self have been
described in the literature, of which five main components will be
differentiated in the present review article: self location, body owner-
ship, the first-person perspective, the sense of agency, and the per-
ceptual body image (Table 1). Self location refers to the experience of
occupying a volume of space, typically localized within one's own
physical body boundaries (Blanke & Metzinger, 2009). Body owner-
ship is the experience of owning a physical body (Tsakiris et al., 2007).
The first-person perspective refers to “the experience from where I
perceive the world” (Blanke, 2012). The first-person perspective is
usually centered on the body and corresponds to an egocentric per-
spective/viewpoint (Vogeley & Fink, 2003). Agency is the sense of
being in control of one's own actions (Jeannerod, 2006). The
Received: 17 October 2022
Revised: 8 February 2023
Accepted: 13 February 2023
DOI: 10.1002/hbm.26253
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any


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medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.
2936
Hum Brain Mapp. 2023;44:2936–2959.
wileyonlinelibrary.com/journal/hbm


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Single-Administration Long-Acting Microarray Patch with Ultrahigh Loading Capacity and Multiple Releases of Thermally Stable Antibodies


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Single-Administration Long-Acting Microarray Patch with Ultrahigh
Loading Capacity and Multiple Releases of Thermally Stable
Antibodies
Khanh T. M. Tran, Thinh T. Le, Vivek Agrahari, M. Melissa Peet, Louise A. Ouattara,
Sharon M. Anderson, Trang Huyen Le-Kim, Onkar N. Singh, Gustavo F. Doncel,*
and Thanh D. Nguyen*
Cite This: Mol. Pharmaceutics 2023, 20, 2352−2361
Read Online
ACCESS
Metrics & More
Article Recommendations
*
sı
Supporting Information
ABSTRACT: Current antibody (Ab) therapies require development of
stable formulations and an optimal delivery system. Here, we present a new
strategy to create a single-administration long-lasting Ab-delivery microarray
(MA) patch, which can carry high doses of thermally stabilized Abs. The
MA fabricated by an additive three-dimensional manufacturing technology
can be fully embedded into the skin via a single application to deliver doses
of Abs at multiple programmable time points, thus sustaining Ab
concentrations in systemic circulation. We developed an MA formulation
that stabilized and delivered human immunoglobulins (hIg) in a time-controlled manner while maintaining their structure and
functionality. As an example, the b12 Aba broadly neutralizing Ab against HIV-1maintained antiviral activity in vitro after MA
manufacturing and heat exposure. Pharmacokinetic studies of MA patch-delivered hIg in rats successfully provided a proof of
concept for concurrent and time-delayed Ab delivery. These MA patches codeliver different Abs, providing a tool for expanded
protection against viral infections or combination HIV therapy and prevention.
KEYWORDS: microarray patch, fabrications, therapeutic antibodies, protein stabilization, long-acting delivery
1. INTRODUCTION
Antibodies (Abs) are an important class of therapeutic agents
and are being used to treat a wide variety of diseases including
cancer, autoimmune disorders, and infectious diseases.1 More
than 100 monoclonal Ab (mAb)-based therapeutics have been
approved by regulatory authorities for treatment of cancer, skin


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disorders, human immunodeficiency virus (HIV-1), COVID-
19, Alzheimer’s, and other diseases,2 and several others are
actively under clinical development.3 Specifically, potent
broadly neutralizing antibodies (bnAbs) have emerged as
potential alternatives or adjuvants to HIV antiretroviral therapy
(ART).4 Although combination ART is highly effective, it
requires lifelong medication, which is associated with
significant side effects.5 In contrast, bnAbs uniquely target
and bind to specific parts of the HIV envelope, preventing new
infections through a different mechanism of action, and thus
can be used to suppress viral rebound in the absence of
ART.6,7 As such, Ab treatments are being explored as
alternative/supplementary tools to antiretrovirals (ARVs) for
the long-acting treatment or prevention of HIV infection.8
Additionally, administration of a combination of bnAbs
targeting different neutralizing epitopes could expand
protection and treatment effectiveness.9 However, the delivery
of Abs into the human body faces many challenges that have
yet to be overcome.
The efficacy of therapeutic or prophylactic Abs is critically
dependent on circulatings serum concentrations, which are
difficult to maintain at high levels for a long period. In order to
achieve high and persistent serum levels of Abs for optimal
efficacy, Ab therapies typically require frequent and repeated
administrations of relatively large doses (subgrams or grams).10
Intravenous infusion remains the most popular delivery route
of choice; however, it involves pain, discomfort, high costs,
repeated visits to medical facilities, intervention of highly
trained personnel, and use of hypodermic needles, which cause
stress on patients, ultimately resulting in a high burden on the
healthcare system, especially in resource-constrained regions of
the world.11 While there is an unmet need for minimally
invasive, controlled-release, and easy-to-administer delivery
systems for mAb-based therapies, protein-based therapeutic


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agents frequently suffer from formulation challenges, and Abs
are no exception. Formulations of Abs in polymeric carriers
often include the use of organic solvents or high-temperature
Received:
November 2, 2022
Revised:
March 15, 2023
Accepted:
March 15, 2023
Published: April 4, 2023
Article
pubs.acs.org/molecularpharmaceutics
© 2023 The Authors. Published by
American Chemical Society
2352
https://doi.org/10.1021/acs.molpharmaceut.2c00919
Mol. Pharmaceutics 2023, 20, 2352−2361


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Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization


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Analysis of antibodies from HCV elite neutralizers identifies 
genetic determinants of broad neutralization
Timm Weber1,16, Julian Potthoff1,16, Sven Bizu2, Maurice Labuhn3, Leona Dold1,4,5, 
Till Schoofs1,17, Marcel Horning1, Meryem S. Ercanoglu1, Christoph Kreer1, Lutz 
Gieselmann1,5, Kanika Vanshylla1, Bettina Langhans4,5, Hanna Janicki1, Luisa J. Ströh9, 
Elena Knops6, Dirk Nierhoff7, Ulrich Spengler4,5, Rolf Kaiser5,6, Pamela J. Bjorkman8, 
Thomas Krey9,10,11,12,13, Dorothea Bankwitz3, Nico Pfeifer2, Thomas Pietschmann3,13,14, 
Andrew I. Flyak8, Florian Klein1,5,6,15,18,*
1Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University 
Hospital Cologne, University of Cologne, 50931 Cologne, Germany
2Methods in Medical Informatics, Department of Computer Science, University of Tübingen, 
72076 Tübingen, Germany
3Twincore, Centre for Experimental and Clinical Infection Research, Institute of Experimental 
Virology, 30625 Hannover, Germany
4Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany
5German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 50931 Cologne, 
Germany
6Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 
50931 Cologne, Germany
7Department of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital 
Cologne, 50931 Cologne, Germany
8Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 
91125, USA
9Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
10Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Lübeck, 
23562 Luebeck, Germany
11Centre for Structural Systems Biology (CSSB), 22607 Hamburg, Germany
*Correspondence: florian.klein@uk-koeln.de.
AUTHOR CONTRIBUTIONS
Conceptualization, T.W., T.P., A.I.F., and F.K.; methodology, T.W., J.P., S.B., M.L., L.D., T.S., M.H., M.S.E., C.K., L.G., K.V., P.J.B.,


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T.K., D.B., N.P., T.P., A.I.F., and F.K.; investigation, T.W., J.P., S.B., M.L., L.D., T.S., M.H., M.S.E., C.K., L.G., K.V., H.J., D.B., and 
A.I.F.; software, S.B., C.K., and N.P.; formal analysis, T.W., J.P., L.D., T.S., M.H., C.K., N.P., A.I.F., and F.K.; resources, B.L., L.S., 
E.K., D.N., U.S., R.K., P.J.B., T.K., T.P., and F.K.; writing–original draft, T.W., J.P., A.I.F., and F.K.; supervision, P.J.B., T.K., N.P., 
T.P., and F.K.
SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.immuni.2021.12.003.
DECLARATION OF INTERESTS
Reported antibodies are in the process of being patented.
HHS Public Access
Author manuscript
Immunity. Author manuscript; available in PMC 2023 April 11.
Published in final edited form as:
Immunity. 2022 February 08; 55(2): 341–354.e7. doi:10.1016/j.immuni.2021.12.003.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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RESEARCH ARTICLE
Regional Precuneus Cortical
Hyperexcitability in Alzheimer’s Disease
Patients
Elias P. Casula, PhD
,1,2 Ilaria Borghi, MSc,1,3 Michele Maiella, MSc,1
Maria C. Pellicciari, PhD,1 Sonia Bonnì, PhD,1 Lucia Mencarelli, PhD,1
Martina Assogna, MD,1 Alessia D’Acunto, BSc,1 Francesco Di Lorenzo, MD,1
Danny A. Spampinato, PhD,1 Emiliano Santarnecchi, PhD,4
Alessandro Martorana, MD, PhD,5 and Giacomo Koch, MD, PhD
1,6
Objective: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in
Alzheimer’s disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining trans-
cranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain
areas known to be directly involved in AD pathology.
Methods: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left pos-
terior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n = 65)
that were compared with a group of age-matched healthy controls (n = 21).
Results: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to
some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over
the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability
was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with
corticospinal ﬂuid levels of Aβ42.
Interpretation: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic
dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel prom-
ising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to
stage disease severity and evaluate response to novel therapies.


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ANN NEUROL 2023;93:371–383
Abbreviations
Aβ
amyloid beta
AD
Alzheimer’s disease
CDR
clinical dementia score
ChAT
choline acetyltransferase
CSF
cerebrospinal ﬂuid
DLPFC
dorso-lateral prefrontal cortex
DMN
default mode network
E/I
excitation/inhibition
EEG
electroencephalography
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.26514
Received Jun 10, 2022, and in revised form Sep 5, 2022. Accepted for publication Sep 12, 2022.
Address correspondence to Dr Koch, Experimental Neuropsychophysiology Lab, Department of Behavioral and Clinical Neurology, Santa Lucia Founda-
tion IRCCS, Via Ardeatina, 306, 00179, Rome, Italy. E-mail: g.koch@hsantalucia.it
From the 1Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy; 2Department of Psychology, La Sapienza
University, Rome, Italy; 3Center for Translational Neurophysiology of Speech and Communication (CTNSC), Italian Institute of Technology (IIT), Ferrara,
Italy; 4Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 5Memory
Clinic, Department of Systems Medicine, University of Tor Vergata, Rome, Italy; and 6Department of Neuroscience and Rehabilitation, University of
Ferrara, Ferrara, Italy
© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
371
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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J Physiol 601.3 (2023) pp 435–449
435
The Journal of Physiology
REVIEW-SYMPOSIUM
The role of oestrogen in determining sexual dimorphism in
energy balance
Anne Nicole De Jesus and Belinda A. Henry
Metabolism, Obesity and Diabetes Program, Biomedicine, Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria,
Australia
Handling Editors: Laura Bennet & Janna Morrison
The peer review history is available in the Supporting information section of this article
(https://doi.org/10.1113/JP279501#support-information-section).
Sexual dimorphism in
adipose tissue distribution
Women in the
reproductive years
Shift in adipose tissue distribution
Gynoid
Android
Post-menopausal
women
Men
Gynoid body shape
Android body shape
Android body shape
Oestrogen
Physical activity
Adaptive thermogenesis
Cardiometabolic
diseases
Oestrogen
Physical activity
Adaptive thermogenesis
Cardiometabolic
diseases
Resting energy 
expenditure
Cardiometabolic
diseases
Abstract
Energy balance is determined by caloric intake and the rate at which energy
is expended, with the latter comprising resting energy expenditure, physical activity and
adaptive thermogenesis. The regulation of both energy intake and expenditure exhibits clear
Anne Nicole De Jesus is a doctoral student under the supervision of Dr Belinda Henry. She received a
double degree BA extended major in Psychology (2019) and BSc (Hons) major in Physiology (2020) at
Monash University. Her current work explores the role of female sex hormones on brown fat activity and
glucose metabolism in women across different stages of reproductive live. Belinda Henry is the Director
of the Biomedicine Discovery Institute Graduate School and a Senior Lecturer within the Department of
Physiology at Monash University, Australia. She is the head of the Metabolic Neuroendocrinology Group.
Her research centres on the discovery of novel means of altering energy expenditure through modulation


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of the brain as a mechanism for prevention or treatment of obesity. Her work is particularly focused on
the process of thermogenesis and the mechanisms that underpin this process in brown adipose tissue and
skeletal muscle. She has strong expertise in utilising large animal models for neuroendocrine research and she has recently established the Translational
Metabolic and Exercise laboratory.
This review was presented at the Australian Physiological Society Diamond Jubilee Conference ‘Sex differences in Physiology’, which took place at
Griffith University, Gold Coast QLD, Australia, 22 November 2021.
© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
DOI: 10.1113/JP279501
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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Australian Fertility Preservation Guidelines for People with Cancer 2022: Review and Recommendations


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Perspectives
MJA 217 (11) ▪ 12 December 2022
564
Australian fertility preservation guidelines 
for people with cancer 2022: review and 
recommendations
Best practice in oncofertility care requires structured referral pathways, with access to 
fertility preservation counselling and technology
F
ertility preservation is a rapidly advancing 
field, and new strategies are continuously being 
developed and refined.1 These strategies include 
oocyte and embryo cryopreservation, ovarian tissue 
cryopreservation and subsequent autografting for 
females, and sperm cryopreservation and testicular 
biopsy for males. Fertility preservation treatment is 
often urgent to prevent a delay in commencing cancer 
treatments. It requires effective communication and 
referral pathways between multidisciplinary teams, 
so that provision of fertility preservation care can be 
delivered consistently.1
In Australia, cancer incidence and survival have 
both increased.2 In 2022, it is projected that over 
8200 Australians under the age of 40 years will be 
diagnosed with cancer, with an incidence of 60.7 cases 
per 100 000 population.2 This has nearly doubled from 
4277 cases diagnosed per year in 1982.2 The 5- year 
survival rate from all cancers has also improved in 
both the paediatric and young adult populations aged 
0– 19 years (75.5% survival in 1988 v 86.1% in 2017) and 
in the adult population aged 20– 39 years (78.7% in 1988 
v 88.6% in 2017).2
Currently, fertility preservation care is often 
underimplemented.3 The barriers to overcome include 
limited models of care and uneven access due to cost, 
low health literacy, and patient education.3 As the use 
of fertility preservation increases, further reporting 
on outcomes data is required.1 In order to improve 
the quality of care, data collection by national and 
international registries is vital to identify the short 
and long term outcomes of fertility preservation 
interventions.1
As the Clinical Oncology Society of Australia (COSA)


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Fertility Preservation Taskforce, we have developed 
the 2022 guidelines,4 with updates in management 
including:
• oocyte and embryo cryopreservation;
• ovarian tissue cryopreservation and 
transplantation;
• testicular sperm extraction; and
• testicular tissue cryopreservation in pre- pubertal 
boys.
The interdisciplinary working group designed 
clinically focused questions on important aspects of 
fertility for patients with cancer to inform guideline 
development. The draft guidelines were released for 
public consultation by professional societies and other 
interest groups in Australia from 2 to 28 June 2021, 
involving stakeholder input from the public. Using 
the National Health and Medical Research Council 
Levels of Evidence and grades for recommendations,5 
we made 26 evidence- based recommendations, with 
six consensus statements and two practice points.6 The 
full COSA guidelines for fertility preservation for people 
with cancer can be accessed at www.cancer.org.au/clini 
cal-guide lines/ cancer-ferti lity-prese rvation.
Impact of cancer on fertility and discussing risk 
and referrals
Future fertility and the opportunity to have a 
family are among the most important concerns of 
people with cancer.3 There is a wide variation in 
the awareness of health care professionals of the 
need for timely fertility discussion with people 
diagnosed with cancer.3 The treatment of cancer 
in premenopausal women of childbearing age is 
associated with both decreased pregnancy and 
live birth rates7 (Box 1). Women who receive cancer 
treatment may be more likely to have reduced ovarian 
reserve than those who have not undergone cancer 
treatment.8 Furthermore, sperm quality is reduced 
in men previously treated for cancer compared with 
the general population.9 Azoospermia may occur 
after cancer treatment including chemotherapy and 
radiation.
The lack of knowledge of current fertility preservation 
options is a barrier to this discussion. Optimising 
education and training of health care providers and


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implementing a formal oncofertility service reduces 
the risk of patient decisional conflict and regret 
regarding fertility preservation options.10 Referral 
of patients with cancer to a fertility preservation 
specialist does not always occur, despite being 
acknowledged internationally as an important part of 
early cancer management3 (Box 2).
The provision of a fertility preservation program 
within a multidisciplinary team is associated 
with improved referral pathways and timely 
fertility preservation discussion and treatment if 
required,3,10 with guidance available from both the 
Australasian Oncofertility Consortium Charter11 
and the International Oncofertility Competency 
Framework.12 Fertility counselling and the 
opportunity for fertility preservation are both 
associated with increased quality of life, including 
better physical, social and psychological health, and 
lower decisional regret. Studies evaluating decision 
aids have shown reduced decisional conflict and 
improved education in people with cancer and 
parents of patients with cancer.13
1 University of 
Melbourne,  
Melbourne, VIC. 
2 Royal Women’s 
Hospital, Melbourne, VIC. 
3 Clinical Oncology 
Society of, Australia, 
Sydney, NSW. 
4 Queensland University 
of Technology,  
Brisbane, QLD. 
5 Peter MacCallum 
Cancer Centre, 
Melbourne, VIC. 
6 Royal Hospital for 
Women, Sydney, NSW. 
7 University of New 
South, Wales,  
Sydney, NSW. 
Violet Kieu1,2
Catharyn Stern1,2
Jessica Harris3
Yasmin Jayasinghe1,2
Natalie Bradford4
Wanyuan Cui5
Rebecca Deans6,7
Tamara Hunter8
Catherine Allingham9
Stefan C Kane1,2
Lei Shong Lau7
Shanna Logan7
Robert McLachlan10
Kristen Neville4,7
Michelle Peate1,2
Marianne Phillips11
Carla Saunders12
Marianne Tome13
Rita Upreti10,14
Kate White15
Antoinette 
Anazodo16,17
Roger J Hart8,18


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Citation: Romney, C.E.; Arroyo, A.C.;
Robles, T.F.; Zawadzki, M.J. Hugs
and Cortisol Awakening Response
the Next Day: An Ecological
Momentary Assessment Study. Int. J.
Environ. Res. Public Health 2023, 20,
5340. https://doi.org/10.3390/
ijerph20075340
Academic Editor: Paul B. Tchounwou
Received: 1 February 2023
Revised: 14 March 2023
Accepted: 16 March 2023
Published: 30 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
Hugs and Cortisol Awakening Response the Next Day:
An Ecological Momentary Assessment Study
Chelsea E. Romney 1,*
, Amber Carmen Arroyo 2, Theodore F. Robles 3 and Matthew J. Zawadzki 2
1
Department of Psychology, Brigham Young University, Provo, UT 84602, USA
2
Department of Psychological Sciences, University of California Merced, Merced, CA 95343, USA
3
Department of Psychology, University of California Los Angeles, Los Angeles, CA 90095, USA
*
Correspondence: chelsea_romney@byu.edu; Tel.: +1-801-422-3280
Abstract: Previous research suggests that affectionate touch such as hugs might downregulate stress
systems such as the hypothalamic pituitary adrenal (HPA) axis. However, the current literature lacks
in generalizability beyond the laboratory setting and outside the context of romantic relationships.
The cortisol awakening response (CAR) is a measure of the HPA axis and is responsive to daily
ﬂuctuations in stress and social information. However, associations between affectionate touch and
the CAR have never been assessed. This study used ecological momentary assessment (EMA) to
measure daily hugging behaviors in 104 ﬁrst-year college students and salivary cortisol to assess
the CAR. Participants who reported more daily hugs in their social interactions had signiﬁcantly


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smaller CARs the next morning compared to days they reported fewer hugs. This study contributes
to the literature on social interactions and stress responsive systems and emphasizes the importance
of assessing affectionate touch behaviors such as hugs that can be exchanged outside the context of
romantic relationships.
Keywords: cortisol awakening response; affectionate touch; hugging; ecological momentary assessment
1. Introduction
Affectionate touch such as hugs can be used in social settings to communicate greetings,
excitement, support, and friendship. From Harry Harlow’s (1965) seminal work with
rhesus monkeys, we know that a lack of contact comfort may result in major issues with
psychological and physical development [1]. In the recent context of social distancing in
response to the COVID-19 pandemic, the study of in-person affectionate touch is timely,
especially as many of us are re-entering the social space and deciding whether it is safe to
engage in affectionate touch behaviors.
Affectionate touch is physical touch interactions that are intended to demonstrate
positivity toward another person (e.g., love, care, fondness, and appreciation) [2]. Jakubiak
and Feeney (2016) posit a model in which affectionate touch is processed through relational–
cognitive and neurobiological pathways to impact relational, psychological, and physical
well-being [3]. They assert that stress responses are inﬂuenced by affectionate touch receipt.
Laboratory research suggests that affectionate touch may blunt the hypothalamic–pituitary–
adrenal (HPA) axis response to stress that produces the hormone cortisol. In a study
of couples in the laboratory, women who received affectionate touch through neck and
shoulder massage before a stressor had signiﬁcantly lower cortisol and other physiological
stress responses, such as heart rate, to the Trier Social Stress Test (TSST), compared to
women who received verbal social support or no social interaction with their partner [4].


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In another TSST study in couples, both men and women had lower physiological stress
response markers (i.e., lower cardiovascular reactivity) when they had a 10 min period
of handholding and a 20 s hug before the stressor, compared to people who received no
partner interaction [5].
Int. J. Environ. Res. Public Health 2023, 20, 5340. https://doi.org/10.3390/ijerph20075340
https://www.mdpi.com/journal/ijerph


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Citation: Héroux, P.; Belyaev, I.;
Chamberlin, K.; Dasdag, S.; De Salles,
A.A.A.; Rodriguez, C.E.F.; Hardell, L.;
Kelley, E.; Kesari, K.K.;
Mallery-Blythe, E.; et al. Cell Phone
Radiation Exposure Limits and
Engineering Solutions. Int. J. Environ.
Res. Public Health 2023, 20, 5398.
https://doi.org/10.3390/
ijerph20075398
Academic Editors: Daniela Varrica
and Lingxin Chen
Received: 20 January 2023
Revised: 17 March 2023
Accepted: 31 March 2023
Published: 4 April 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
Review
Cell Phone Radiation Exposure Limits and Engineering Solutions
Paul Héroux 1,*
, Igor Belyaev 2
, Kent Chamberlin 3, Suleyman Dasdag 4
, Alvaro Augusto Almeida De Salles 5,
Claudio Enrique Fernandez Rodriguez 6
, Lennart Hardell 7,8
, Elizabeth Kelley 9, Kavindra Kumar Kesari 10
,
Erica Mallery-Blythe 11,12,13, Ronald L. Melnick 14,15, Anthony B. Miller 16, Joel M. Moskowitz 17
and on behalf of
the International Commission on the Biological Effects of Electromagnetic Fields (ICBE-EMF) †
1
Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University,
Montreal, QC H3A 1G1, Canada
2
Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences,
814 38 Bratislava, Slovakia
3
Department of Electrical and Computer Engineering, University of New Hampshire, Durham, NH 03824, USA
4
Biophysics Department, Medical School, Istanbul Medeniyet University, Istanbul 34700, Turkey
5
Graduate Program on Electrical Engineering (PPGEE), Federal University of Rio Grande do Sul (UFRGS),
Porto Alegre 90010-150, Brazil
6
Division of Electrical and Electronics Engineering, Federal Institute of Rio Grande do Sul (IFRS),
Canoas 92412-240, Brazil
7


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7
Department of Oncology, Orebro University Hospital, 701 85 Orebro, Sweden (Retired)
8
The Environment and Cancer Research Foundation, 702 17 Orebro, Sweden
9
ICBE-EMF and International EMF Scientist Appeal, and Electromagnetic Safety Alliance, Tempe, AZ 85282, USA
10
Department of Applied Physics, School of Science, Aalto University, 02150 Espoo, Finland
11
Physicians’ Health Initiative for Radiation and Environment, East Sussex TN6, UK
12
British Society of Ecological Medicine, London W1W 6DB, UK
13
Oceania Radiofrequency Scientiﬁc Advisory Association, Scarborough, QLD 4020, Australia
14
National Toxicology Program (Retired), National Institute of Environmental Health Sciences,
Research Triangle Park, Durham, NC 27709, USA
15
Ron Melnick Consulting LLC, North Logan, UT 84341, USA
16
Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
17
School of Public Health, University of California, Berkeley, CA 94704, USA
*
Correspondence: paul.heroux@mcgill.ca; Tel.: +1-514-767-5556
†
Membership of the Working Group is provided in the Acknowledgments.
Abstract: In the 1990s, the Institute of Electrical and Electronics Engineers (IEEE) restricted its risk
assessment for human exposure to radiofrequency radiation (RFR) in seven ways: (1) Inappropriate
focus on heat, ignoring sub-thermal effects. (2) Reliance on exposure experiments performed over
very short times. (3) Overlooking time/amplitude characteristics of RFR signals. (4) Ignoring
carcinogenicity, hypersensitivity, and other health conditions connected with RFR. (5) Measuring
cellphone Speciﬁc Absorption Rates (SAR) at arbitrary distances from the head. (6) Averaging SAR
doses at volumetric/mass scales irrelevant to health. (7) Using unrealistic simulations for cell phone
SAR estimations. Low-cost software and hardware modiﬁcations are proposed here for cellular phone
RFR exposure mitigation: (1) inhibiting RFR emissions in contact with the body, (2) use of antenna


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patterns reducing the Percent of Power absorbed in the Head (PPHead) and body and increasing the
Percent of Power Radiated for communications (PPR), and (3) automated protocol-based reductions of
the number of RFR emissions, their duration, or integrated dose. These inexpensive measures do not
fundamentally alter cell phone functions or communications quality. A health threat is scientiﬁcally
documented at many levels and acknowledged by industries. Yet mitigation of RFR exposures to
users does not appear as a priority with most cell phone manufacturers.
Keywords: cellular phone; SAR; cancer; electromagnetic hypersensitivity; radiofrequency radiation;
antennas
Int. J. Environ. Res. Public Health 2023, 20, 5398. https://doi.org/10.3390/ijerph20075398
https://www.mdpi.com/journal/ijerph


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Systemic inflammation enhances stimulant-induced striatal 
dopamine elevation in tobacco smokers
Yasmin Zakiniaeiza,b,1,*, Jocelyn Hoyeb,c,1, Joseph Ryan Petrullib,c, Brittany LeVasseura, 
Gelsina Stanleyb,c, Hong Gaob,c, Soheila Najafzadehb,c, Jim Ropchanb,c, Nabeel Nabulsib,c, 
Yiyun Huangb,c, Ming-Kai Chenb,c, David Matuskeya,b,c, Daniel S. Barrona,d,e, Benjamin 
Kelmendia, Robert K. Fulbrightc, Michelle Hampsona,c,f, Kelly P. Cosgrovea,b, Evan D. 
Morrisa,b,c,d
aDepartment of Psychiatry, Yale School of Medicine, New Haven, CT, USA
bYale Positron Emission Tomography (PET) Center, Yale School of Medicine, New Haven, CT, 
USA
cDepartment of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, 
USA
dDepartment of Psychiatry, Brigham & Women’s Hospital, Boston, MA, USA
eDepartment of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women’s Hospital, 
Boston, MA, USA
fDepartment of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA
Abstract
Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide 
(LPS)-induced systemic inflammation produces effects on reward-related brain regions and the 
dopamine system. We previously showed that LPS amplifies dopamine elevation induced by 
methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects 
of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 
1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal 
of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to 
examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect 
size determination. Eight smokers were each scanned with [11C]raclopride positron emission 
tomography three times—at baseline, after administration of LPS (0.8 ng/kg, intravenously) and 
MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized


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order. Dopamine elevation was quantified as change in [11C]raclopride binding potential (ΔBPND) 
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
*Corresponding author at: 40 Temple Street, Suite 7C, New Haven, CT 06511, USA. yasmin.zakiniaeiz@yale.edu (Y. Zakiniaeiz).
1These authors contributed equally to this work.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to 
influence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbi.2022.08.016.
HHS Public Access
Author manuscript
Brain Behav Immun. Author manuscript; available in PMC 2023 April 12.
Published in final edited form as:
Brain Behav Immun. 2022 November ; 106: 262–269. doi:10.1016/j.bbi.2022.08.016.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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Journal of Neurology, Neurosurgery, and Psychiatry 1983 ;46:561-563
Short report
Hemiataxia and crural hemiparesis following
capsular infarct
E DE RENZI,* P NICHELLI,* G CRISIt
From Clinica Neurologica* and Istituto di Radiologiat Universita di Modena, Modena, Italy
SUMMARY Two patients presenting with hemiataxia and hemiparesis on the same side are
described. Both had cr scan evidence of an infarct located in the posterior limb of the con-
tralateral internal capsule.
The association of cerebellar ataxia and pyramidal
signs involving the limbs of the same side was first
described by Fisher and Cole' in 1965, who tenta-
tively located the lesion in the posterior limb of the
internal capsule. Subsequently ataxic hemiparesis
has been reported in six patients with lesion in the
basis pontis contralateral to the involved limb,25 in
a patient with a ventrolateral midbrain lesion6 and in
three patients showing CT scan evidence of an
infarct of the posterior limb of the internal cap-
sule.7-9 We report two more cases of ataxia and
homolateral crural paresis. In both patients a lesion
located in the posterior limb of the internal capsule
was identified on the CT scan.
Case I
A 45-year-old man was admitted to the wards after the
sudden onset of a right hemiparesis. On neurological
examination he was alert and oriented. Speech and cranial
nerves were normal. There was slight right-sided weakness
of the peroneal muscles with minimal weakness of the
extensor muscles of the right arm. Tendon reflexes on the
right were slightly brisker than those on the left and the
right plantar response was extensor. On standing with the
feet together the patient fell to the right. There was a
severe dysmetria on both finger-to-nose and heel-to-knee
tests. Rapid alternating movements were slow and clumsy
on the right side. Sensory functions and visual fields were
normal. Weakness and ataxia increased in a step-wise fash-
ion in the next two days. Weakness was greater in the
proximal muscles of the upper limb and in the distal mus-


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cles of the lower limb. At the end of the fourth week of
illness the right arm had completely recovered its strength,
Address
for
reprint
requests:
Dr
Ennio De
Renzi,
Clinica
Neurologica Via del Pozzo 71, 41100 Modena, Italy.
Received 21 October 1982 and in revised form 9 January 1983.
Accepted 1 February 1983
but both upper and lower right extremities were still dys-
metric and the right lower limb was still moderately weak
particularly in the hamstrings and peroneal muscles. Four
and a half months after the onset of disease, ataxia per-
sisted with only minimal improvement, while weakness of
the left hamstrings had almost completely recovered.
CT scan one day after admission revealed
a small
decreased density area in the left posterior limb of the
internal capsule with possible involvement of the adjacent
thalamus. One month after the onset of illness CT scan
(Fig la) showed a clear-cut hypodensity area in the two
middle quarters of the posterior limb of the left internal
capsule. The lesion extended upward from a midthalamic
to a high thalamic level, but spared the corona radiata and
that most superior part of internal capsule which
is
immediately adjacent to corona radiata.
Case 2
A 55-year-old man, with a long history of hypertension
and diabetes, suddenly noticed dragging of his left leg and
loss of motor power and tingling of his left arm. On admis-
sion the patient was alert and fully oriented. Visual fields
were intact. There was moderate left central facial weak-
ness and a gross left hemiparesis which in the upper limb,
mainly affected the proximal muscles. Tendon reflexes
were slightly brisker on the left side. The left plantar
response was extensor. Light touch and joint position sense
were slightly impaired on the left. At that time tests of
coordination could not be carried out, because of the
severe motor weakness. Computed tomography revealed a
low density area occupying a great part of the posterior
limb of the internal capsule with involvement of the most


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lateral part of the thalamus. The corona radiata also was
involved (Fig lb). The patient's paralysis began to improve
after two weeks, and after a month the muscle power of
arm and forearm flexors and extensors had recovered to
the point of permitting finger-to-nose and finger-to-finger
testing. The latter manoeuvre was carried out holding the
examiner's thumb at the same horizontal level as the
patient's hand, so that no movement of the shoulder mus-
cles, which were still weak, was required. These tests dis-
561


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https://doi.org/10.1093/brain/awac436
BRAIN 2023: 146; 1243–1266 | 1243
Quantitative myelin imaging with MRI 
and PET: an overview of techniques  
and their validation status
Chris W. J. van der Weijden,1 
Emma Biondetti,2 Ingomar W. Gutmann,3 
Hildebrand Dijkstra,4 Rory McKerchar,5 
Daniele de Paula Faria,6 Erik F. J. de Vries,1 
Jan F. Meilof,7,8 Rudi A. J. O. Dierckx,1 Valentin H. Prevost9 and 
Alexander Rauscher5
Myelin is the protective sheath wrapped around axons, consisting of a phospholipid bilayer with water between the 
wraps. The measurement of damage to the myelin sheaths, the evaluation of the efficacy of therapies aiming to pro-
mote remyelination and monitoring the degree of brain maturation in children all require non-invasive quantitative 
myelin imaging methods. To date, various myelin imaging techniques have been developed. Five different MRI ap-
proaches can be distinguished based on their biophysical principles: (i) imaging of the water between the lipid bi-
layers directly (e.g. myelin water imaging); (ii) imaging the non-aqueous protons of the phospholipid bilayer 
directly with ultra-short echo-time techniques; (iii) indirect imaging of the macromolecular content (e.g. magnetiza-
tion transfer; inhomogeneous magnetization transfer); (iv) mapping of the effects of the myelin sheath’s magnetic 
susceptibility on the MRI signal (e.g. quantitative susceptibility mapping); and (v) mapping of the effects of the myelin 
sheath on water diffusion. Myelin imaging with PET uses radioactive molecules with high affinity to specific myelin 
components, in particular myelin basic protein. This review aims to give an overview of the various myelin imaging 
techniques, their biophysical principles, image acquisition, data analysis and their validation status.
1
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center 
Groningen, 9713 GZ Groningen, The Netherlands
2


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2
Department of Neuroscience, Imaging, and Clinical Sciences, Institute for Advanced Biomedical Technologies, ‘G. 
d’Annunzio’ University of Chieti-Pescara, 66100 Chieti, Italy
3
Faculty of Physics, University of Vienna, 1090 Vienna, Austria
4
Department of Radiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The 
Netherlands
5
Department of Pediatrics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
6
Department of Radiology and Oncology, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo 05403- 
911, Brazil
7
Department of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center 
Groningen, 9713 GZ Groningen, The Netherlands
8
Department of Neurology, Martini Ziekenhuis, 9728 NT Groningen, The Netherlands
9
CT-MR Planning division department, Canon Medical Systems Corporation, Tochigi 324-8550, Japan
Correspondence to: Chris W. J. van der Weijden  
Department of Nuclear Medicine and Molecular Imaging, UMCG  
Hanzeplein 1, 9713 GZ Groningen  
The Netherlands  
E-mail: c.w.j.van.der.weijden@umcg.nl
Received June 10, 2022. Revised September 30, 2022. Accepted November 07, 2022. Advance access publication November 21, 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. 
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


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Correction: Mitigation of endemic GI-tract pathogen-mediated inflammation through development of multimodal treatment regimen and its impact on SIV acquisition in rhesus macaques


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CORRECTION
Correction: Mitigation of endemic GI-tract
pathogen-mediated inflammation through
development of multimodal treatment
regimen and its impact on SIV acquisition in
rhesus macaques
Rachele M. Bochart, Kathleen Busman-Sahay, Stephen Bondoc, David W. Morrow,
Alexandra M. Ortiz, Christine M. Fennessey, Miranda B. Fischer, Oriene Shiel,
Tonya Swanson, Christine M. Shriver-Munsch, Hugh B. Crank, Kimberly M. Armantrout,
Aaron M. Barber-Axthelm, Charlotte Langner, Cassandra R. Moats, Caralyn S. Labriola,
Rhonda MacAllister, Michael K. Axthelm, Jason M. Brenchley, Brandon F. Keele, Jacob
D. Estes, Scott G. Hansen, Jeremy V. Smedley
The published article [1] presents data from two separate animal studies. The first study con-
ducted at the National Cancer Institute (NCI) comprised an 18-rhesus macaque (RM) intrar-
ectal dose titration experiment to determine appropriate dosing of SIVmac239X for use in
viral transmission/early necropsy studies. This notice addresses errors in the methodological
description for the initial NCI study: in these animals, the authors did not assess gastrointesti-
nal pathogens, microbiome, immunology, or mucosal barrier integrity, and the handling and
treatment of the animals differed from that employed in the subsequent study conducted at
Oregon National Primate Research Center (ONPRC). The originally published Materials and
Methods section incorrectly reported some similarities between the animal handling and treat-
ment regimens used in the two studies. This Correction provides amended methodological
information, including that the multimodal therapeutic regimen for the NCI study included
only metronidazole and fenbendazole, while the regimen for the ONPRC study included enro-
floxacin, paromomycin, fenbendazole, and azithromycin.
Initial dose titration study at NCI
The terms “proof of concept study” and “proof of concept animals” are inaccurate and are
replaced in all instances with “initial dose titration study at NCI” and “initial NCI dose titra-


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tion study animals”, respectively.
In the Materials and Methods section originally titled Proof of concept study assessing the
impact of the multimodal treatment regimen on acquisition of SIVmac239X, the correct text is
as follows:
Initial dose titration study at NCI assessing the impact of the multimodal treatment regi-
men on acquisition of SIVmac239X
A total of 18 male Indian-origin rhesus macaques between 2.6 and 13.4 years of age were
used in accordance with the policies of the Animal Care and Use Committee at the NCI, an
AAALAC-accredited institution, which abides by the USDA Animal Welfare Regulations [38]
and the Guide for the Care and Use of Laboratory Animals [37]. Animals were singly housed
in accordance with the IACUC-approved protocol and facility practices for the NIH facilities
where the work was conducted (NIH main campus, Bethesda, MD or NIH Animal Center,
PLOS PATHOGENS
PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1011343
April 19, 2023
1 / 6
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OPEN ACCESS
Citation: Bochart RM, Busman-Sahay K, Bondoc S,
Morrow DW, Ortiz AM, Fennessey CM, et al. (2023)
Correction: Mitigation of endemic GI-tract
pathogen-mediated inflammation through
development of multimodal treatment regimen and
its impact on SIV acquisition in rhesus macaques.
PLoS Pathog 19(4): e1011343. https://doi.org/
10.1371/journal.ppat.1011343
Published: April 19, 2023
Copyright: © 2023 Bochart 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.


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REVIEW
Human monkeypox infection threat: A
comprehensive overview
Yue Kang1, Yue Yu2, Silu XuID3*
1 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China, 2 School of
Pharmacy, Fujian Medical University, Fuzhou, Fujian China, 3 Department of Pharmacy, Jiangsu Cancer
Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical
University, Nanjing, Jiangsu, China
* jsszlyy_xusilu@sina.com
Abstract
Background
AU : Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly:
In addition to the COVID-19 waves, the globe is recently facing global monkeypox (MPX)
outbreak. As the daily confirmed cases of MPX infection across epidemic and nonepidemic
countries are increasing, taking measures to control global pandemic remains crucial.
Therefore, this review aimed to provide fundamental knowledge for the prevention and con-
trol of future outbreaks of this emerging epidemic.
Methods
The review was conducted using PubMed and Google Scholar databases; the search terms
used were “monkeypox,” “MPX tropism,” “replication signaling of MPX,” “biology and patho-
genicity of MPX,” “diagnosis of MPX,” “treatment of MPX,” “prevention of MPX,” etc. The
update epidemic data were collected from the websites of the World Health Organization
(WHO), United States Centers for Disease Control and Prevention (CDC), and Africa Center
for Disease Control and Prevention (ADCC). High-quality research results published in
authoritative journals were summarized and preferred cited. Excluding all duplicates, non-
English published references, and irrelevant literature, totally 1,436 articles were assessed
for eligibility.
Results
It is still difficult to diagnose the patient as MPX simply based on clinical manifestations;
therefore, under this situation, employing polymerase chain reaction (PCR) technology to
provide confirmed evidence for the diagnosis of MPX seems to be the preferred and indis-
pensable strategy. The treatment approach for MPX infection is mainly symptomatic and


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supportive; anti-smallpox virus drugs including tecovirimat, cidofovir, and brincidofovir can
be employed in severe cases. Timely identification and isolation of confirmed cases, cutting
off dissemination routes, and vaccination of close contacts are effective measures to control
MPX. Also, smallpox vaccines (JYNNEOS, LC16m8, and ACAM2000) can be under consid-
eration due to their immunological cross-protection among Orthopoxvirus. NeverthelessAU : Pleasech
,
given the low quality and scarcity of relevant evidence of current antiviral drugs and
PLOS NEGLECTED TROPICAL DISEASES
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0011246
April 20, 2023
1 / 22
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OPEN ACCESS
Citation: Kang Y, Yu Y, Xu S (2023) Human
monkeypox infection threat: A comprehensive
overview. PLoS Negl Trop Dis 17(4): e0011246.
https://doi.org/10.1371/journal.pntd.0011246
Editor: Zvi Bentwich, Ben-Gurion University of the
Negev, ISRAEL
Published: April 20, 2023
Copyright: © 2023 Kang 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.
Funding: The author(s) received no specific
funding for this work.
Competing interests: The authors disclose no
conflict of interest.


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Signaling pathways in vascular function and hypertension: molecular mechanisms and therapeutic interventions


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REVIEW ARTICLE
OPEN
Signaling pathways in vascular function and hypertension:
molecular mechanisms and therapeutic interventions
Jun Ma
1, Yanan Li1, Xiangyu Yang1, Kai Liu1, Xin Zhang1, Xianghao Zuo1, Runyu Ye1, Ziqiong Wang1, Rufeng Shi1,
Qingtao Meng1✉ and Xiaoping Chen1✉
Hypertension is a global public health issue and the leading cause of premature death in humans. Despite more than a century of
research, hypertension remains difﬁcult to cure due to its complex mechanisms involving multiple interactive factors and our
limited understanding of it. Hypertension is a condition that is named after its clinical features. Vascular function is a factor that
affects blood pressure directly, and it is a main strategy for clinically controlling BP to regulate constriction/relaxation function of
blood vessels. Vascular elasticity, caliber, and reactivity are all characteristic indicators reﬂecting vascular function. Blood vessels are
composed of three distinct layers, out of which the endothelial cells in intima and the smooth muscle cells in media are the main
performers of vascular function. The alterations in signaling pathways in these cells are the key molecular mechanisms underlying
vascular dysfunction and hypertension development. In this manuscript, we will comprehensively review the signaling pathways
involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway,
various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system,
oxidative stress-related signaling pathway, immunity/inﬂammation pathway, etc. Meanwhile, we will also summarize the treatment
methods of hypertension that targets vascular function regulation and discuss the possibility of these signaling pathways being
applied to clinical work.
Signal Transduction and Targeted Therapy  (2023) 8:168 
; https://doi.org/10.1038/s41392-023-01430-7
INTRODUCTION
Hypertension represents a signiﬁcant risk factor for cardiovascular


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and cerebrovascular diseases (CVDs) and remains the primary
cause of premature mortality on a global scale.1 The estimated
number
of
people
aged
30–79-year-old
with
hypertension
doubled from 648 million in 1990 to 1.27 billion in 2019.2 The
prevention and control of hypertension represent a crucial global
public health strategy in the effort to reduce premature mortality
from CVDs.3
Blood pressure (BP) is deﬁned as the lateral pressure exerted on
the walls of blood vessels per unit area during the ﬂow of blood.
Hypertension is characterized by an increase in systolic BP and/or
diastolic BP. There are two primary factors that directly affect BP:
the volume of intravascular ﬂuid and the capacity for vasodilation.
The amount of ﬂuid in the blood vessels is mainly related to the
everyday intake and output volume. Vasodilatation is the basic
function of blood vessels.4 The capacity for vasodilation is
inﬂuenced by vascular elasticity, caliber, and reactivity. Poorer
the vasodilatation capacity, higher the BP. The disturbance of
vascular contraction and/or relaxation function exerts a great
inﬂuence on the onset and progression of hypertension. As
vasodilatation capacity plays a crucial role in regulating BP, it has
garnered signiﬁcant attention in the ﬁeld of vascular biology
research.5
Changes in signaling pathways in vascular endothelial cells
(ECs) and vascular smooth muscle cells (VSMCs) are key molecular
mechanisms which trigger vascular dysfunction and promote the
development of hypertension. Here, we reviewed all key signaling
pathways in vascular function and hypertension, as well as their
treatment application value in clinical settings.
VASCULAR STRUCTURE AND FUNCTIONS OF EACH LAYER
Blood vessels are composed of three distinct layers, including
intima, media, and adventitia (Fig. 1). The intima is mainly
composed of ECs, which organize themselves into a continuous
monolayer, allowing blood perfusion. On their surface, ECs form a
surrounding extracellular matrix (ECM) known as the glycocalyx,


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which extends beyond the cell surface into the vascular lumen.
This structure plays a crucial role in providing a barrier function for
ECs, preventing the transmural migration of leukocytes and
platelet adhesion.6,7 Intima is the “sensor” of vessels, as it can
sense various stimuli (such as ﬂuid shear force, cytokines, etc.) in
the blood and actively control the degree of vascular relaxation
and contraction. This active regulation is mainly achieved through
the secretion of various mediators from ECs.8 ECs serve not only as
a barrier-forming cell population, acting as a responsive interface,
but also actively regulate their microenvironment, serving as
gatekeepers of organ development, homeostasis, and tissue
regeneration.9 ECs dysfunction has been regarded as a pivotal
mechanism in early pathogenesis of hypertension.10 Generalized
deﬁnition of ECs function or endothelial function involves barrier,
Received: 9 November 2022 Revised: 3 March 2023 Accepted: 31 March 2023
1Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan 610041, People’s Republic of China
Correspondence: Qingtao Meng (mengqingtao9@163.com) or Xiaoping Chen (xiaopingchen23@163.com)
These authors contributed equally: Jun Ma, Yanan Li, Xiangyu Yang
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
© The Author(s) 2023
1234567890();,:


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https://doi.org/10.1007/s00259-022-06073-4
REVIEW ARTICLE
PET imaging of animal models with depressive‑like phenotypes
Daniel Aaron Vazquez‑Matias  · Erik F. J. de Vries  · Rudi A. J. O. Dierckx  · Janine Doorduin
1
1
1
1 
Received: 8 July 2022 / Accepted: 3 December 2022 
© The Author(s) 2023
Abstract
Major depressive disorder is a growing and poorly understood pathology. Due to technical and ethical limitations, a significant 
proportion of the research on depressive disorders cannot be performed on patients, but needs to be investigated in animal 
paradigms. Over the years, animal studies have provided new insight in the mechanisms underlying depression. Several of 
these studies have used PET imaging for the non-invasive and longitudinal investigation of the brain physiology. This review 
summarises the findings of preclinical PET imaging in different experimental paradigms of depression and compares these 
findings with observations from human studies. Preclinical PET studies in animal models of depression can be divided into 
three main different approaches: (a) investigation of glucose metabolism as a biomarker for regional and network involve-
ment, (b) evaluation of the availability of different neuroreceptor populations associated with depressive phenotypes, and 
(c) monitoring of the inflammatory response in phenotypes of depression. This review also assesses the relevance of the use 
of PET imaging techniques in animal paradigms for the understanding of specific aspects of the depressive-like phenotypes, 
in particular whether it might contribute to achieve a more detailed characterisation of the clinical depressive phenotypes 
for the development of new therapies for depression.
Keywords Major depressive disorder · Depressive-like behaviour · Preclinical imaging · Neuroreceptor · PET · Animal 
models
Introduction
Major depressive disorder (MDD) is one of the most prev-
alent psychiatric disorders worldwide [1]. It presents a 
clinical course characterised by a broad and heterogenous


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constellation of symptoms, which may lead to harmful con-
sequences, such as prolonged periods of disability, or even 
suicidal behaviour. According to data from the World Health 
Organisation (WHO), around 300 million people worldwide 
are affected by depression and it is predicted that this dis-
order will become the first cause of incapacity in terms of 
disability-adjusted life years (DALYs) by 2030 [1]. This lack 
of understanding entails a major challenge to both clinicians 
and fundamental researchers, and may hamper the selec-
tion of effective therapeutic schemes, and slow down the 
development of new therapies. One of the most notorious 
examples of these knowledge-gaps is the lack of reliable 
diagnostic auxiliary tools to stage severity and monitor the 
clinical course of MDD in the managing protocols [2].
Currently, there are no reliable diagnostic biomarkers avail-
able to stage patients with MDD or predict the outcome of 
treatment [3]. Present MDD management protocols are largely 
based on antidepressant drugs. The use of these antidepres-
sants began as a serendipitous finding after these drugs were 
prescribed to patients with different illnesses, and improve-
ments in the affective state were found as a side effect [4, 5]. 
MMD standard treatment includes drugs like selective and 
non-selective serotonin and norepinephrine reuptake inhibi-
tors, which are used as first line of treatment. However, about 
50–70% of MDD patients experience incomplete remission of 
symptoms after receiving standard antidepressant treatment 
[6–8]. In view of the high rates of treatment failure with stand-
ard antidepressant therapy, and the limited understanding of 
the pathophysiology, it is necessary to fill the knowledge gaps 
regarding MDD in order to develop and prescribe more effec-
tive treatments. New insights could be obtained from clinical 
studies, but these studies are expensive, time-consuming and 
This article is part of the Topical Collection on Preclinical Imaging.
 * Janine Doorduin


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j.doorduin@umcg.nl
1 
Department of Nuclear Medicine and Molecular Imaging, 
University Medical Centre Groningen, University 
of Groningen, Groningen, the Netherlands
European Journal of Nuclear Medicine and Molecular Imaging (2023) 50:1564–1584
/ Published online: 16 January 2023
1 3


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Vol:.(1234567890)
Neurotherapeutics (2023) 20:140–153
https://doi.org/10.1007/s13311-023-01348-6
1 3
REVIEW
Preclinical Interventions in Mouse Models of Frontotemporal 
Dementia Due to Progranulin Mutations
Shreya N. Kashyap1 · Nicholas R. Boyle1 · Erik D. Roberson1 
Accepted: 20 January 2023 / Published online: 13 February 2023 
© The Author(s) 2023
Abstract
Heterozygous loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia (FTD), a leading cause 
of early-onset dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-
approved therapeutics for FTD-GRN, but this has been an active area of investigation, and several approaches are now in 
clinical trials. Here, we review preclinical development of therapies for FTD-GRN with a focus on testing in mouse models. 
Since most FTD-GRN-associated mutations cause progranulin haploinsufficiency, these approaches focus on raising pro-
granulin levels. We begin by considering the disorders associated with altered progranulin levels, and then review the basics 
of progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models 
of progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These 
include approaches to raise progranulin expression from the normal allele or facilitate progranulin production by the mutant 
allele, as well as approaches to directly increase progranulin levels by delivery across the blood–brain barrier or by gene 
therapy. Several of these approaches have entered clinical trials, providing hope that new therapies for FTD-GRN may be 
the next frontier in the treatment of neurodegenerative disease.
Keywords Frontotemporal dementia · Neurodegeneration · Progranulin · Haploinsufficiency · Lysosome · Gene therapy
The approval of the first amyloid immunotherapies by the 
US Food and Drug Administration for patients with Alzhei-


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mer’s disease, although not without controversy, marks the 
beginning of a new era in the treatment of neurodegenera-
tive dementias. Therapeutics targeting one of the primary 
disease-associated molecules are now approved, and a neu-
ropathological hallmark of neurodegenerative dementia can 
be substantially eliminated from the brains of those affected. 
Following aducanumab, lecanemab, and other amyloid 
immunotherapies likely to follow, treatments targeting pro-
granulin for frontotemporal dementia (FTD) may be among 
the next round of disease-modifying neurodegenerative dis-
ease therapeutics.
One advantage in the pursuit of progranulin-targeted 
therapeutics is that, unlike amyloid-beta, tau, and other 
proteins associated with neurodegenerative diseases that 
have gain-of-function effects, the mechanism of progran-
ulin-related disease is clearly loss-of-function. Thus, 
the approach to progranulin therapeutics can focus on 
boosting levels of progranulin, which, while not trivial, 
is likely more straightforward than identifying specific 
downstream gain-of-function effects along with strategies 
to selectively block them. Indeed, several progranulin-
targeting therapies have already entered clinical trials. 
Such progress, of course, comes on the heels of rigorous 
preclinical studies, many of which have utilized mouse 
models.
Our goal here is to review data from preclinical testing of 
potential treatments for progranulin-related FTD in mouse 
models. Before considering studies on specific therapeutic 
approaches, we begin with a review of the neurologic disor-
ders caused by progranulin insufficiency and other diseases 
associated with progranulin, key features of progranulin 
biology, and the currently available mouse models and out-
come measures used in preclinical studies on progranulin 
therapeutics.
Shreya N. Kashyap and Nicholas R. Boyle are equal contributors.
 * Erik D. Roberson 
 
eroberson@uabmc.edu
1 
Center for Neurodegeneration and Experimental


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Therapeutics, Alzheimer’s Disease Center, Medical Scientist 
Training Program, Department of Neurology, University 
of Alabama at Birmingham, Birmingham, AL 35294, USA


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Animal Models of Childhood Exposure to Lead or Manganese: Evidence for Impaired Attention, Impulse Control, and Affect Regulation and Assessment of Potential Therapies


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Vol.:(0123456789)
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Neurotherapeutics (2023) 20:3–21 
https://doi.org/10.1007/s13311-023-01345-9
REVIEW
Animal Models of Childhood Exposure to Lead or Manganese: 
Evidence for Impaired Attention, Impulse Control, and Affect 
Regulation and Assessment of Potential Therapies
Donald R. Smith1  · Barbara J. Strupp2
Accepted: 18 January 2023 / Published online: 28 February 2023 
© The Author(s) 2023
Abstract
Behavioral disorders involving attention and impulse control dysfunction, such as ADHD, are among the most prevalent 
disorders in children and adolescents, with significant impact on their lives. The etiology of these disorders is not well 
understood, but is recognized to be multifactorial, with studies reporting associations with polygenic and environmental 
risk factors, including toxicant exposure. Environmental epidemiological studies, while good at establishing associations 
with a variety of environmental and genetic risk factors, cannot establish causality. Animal models of behavioral disorders, 
when properly designed, can play an essential role in establishing causal relationships between environmental risk factors 
and a disorder, as well as provide model systems for elucidating underlying neural mechanisms and testing therapies. Here, 
we review how animal model studies of developmental lead or manganese exposure have been pivotal in (1) establishing a 
causal relationship between developmental exposure and lasting dysfunction in the domains of attention, impulse control, 
and affect regulation, and (2) testing the efficacy of specific therapeutic approaches for alleviating the lasting deficits. The 
lead and manganese case studies illustrate how animal models can advance knowledge in ways that are not possible in human 
studies. For example, in contrast to the Treatment of Lead Poisoned Children (TLC) human clinical trial evaluating succimer 
chelation efficacy to improve cognitive functioning in lead-exposed children, our developmental lead exposure animal model


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showed that succimer chelation can produce lasting cognitive benefits if chelation sufficiently reduces brain lead levels. In 
addition, this study revealed that succimer treatment in the absence of lead exposure produces lasting cognitive dysfunction, 
highlighting potential risks of chelation in off-label uses, such as the treatment of autistic children without a history of lead 
exposure. Our animal model of developmental manganese exposure has demonstrated that manganese can cause lasting 
attentional and sensorimotor deficits, akin to an ADHD-inattentive behavioral phenotype, thereby providing insights into 
the role of environmental exposures as contributors to ADHD. These studies have also shown that oral methylphenidate 
(Ritalin) can fully alleviate the deficits produced by early developmental Mn exposure. Future work should continue to focus 
on the development and use of animal models that appropriately recapitulate the complex behavioral phenotypes of behav-
ioral disorders, in order to determine the mechanistic basis for the behavioral deficits caused by developmental exposure to 
environmental toxicants, and the efficacy of existing and emerging therapies.
Keywords Attention deficit · ADHD · Neurotoxicity · Lead · Manganese · Animal model
Introduction
Behavioral disorders, particularly those involving learn-
ing, attention, and impulse control, are among the most 
prevalent disorders in children [1]. While the etiologies of 
behavioral disorders are often poorly understood, they are 
generally recognized to be multifactorial in nature, with 
epidemiological studies providing evidence for both genetic 
and environmental risk factors. For example, substantial evi-
dence has emerged over the past several decades supporting 
 * Donald R. Smith 
 
drsmith@ucsc.edu
1 
Department of Microbiology and Environmental Toxicology, 
University of California, Santa Cruz, CA 95060, USA
2 
Division of Nutritional Sciences and Department 
of Psychology, Cornell University, Ithaca, NY 14853, USA


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Efficacy of the modified vaccinia Ankara virus vaccine and the replication-competent vaccine ACAM2000 in monkeypox prevention


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Elsevier has created a Monkeypox Information Center in response to the 
declared public health emergency of international concern, with free 
information in English on the monkeypox virus. The Monkeypox Information 
Center is hosted on Elsevier Connect, the company's public news and 
information website.  
  
Elsevier hereby grants permission to make all its monkeypox related 
research that is available on the Monkeypox Information Center - including 
this research content - immediately available in publicly funded 
repositories, with rights for unrestricted research re-use and analyses in 
any form or by any means with acknowledgement of the original source. 
These permissions are granted for free by Elsevier for as long as the 
Monkeypox Information Center remains active.


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Treatment with benznidazole and pentoxifylline regulates microRNA transcriptomic profile in a murine model of Chagas chronic cardiomyopathy


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RESEARCH ARTICLE
Treatment with benznidazole and
pentoxifylline regulates microRNA
transcriptomic profile in a murine model of
Chagas chronic cardiomyopathy
Priscila Silva Grijo´ Farani1,2, Beatriz Iandra da Silva Ferreira1, Khodeza Begum3,
Glaucia Vilar-Pereira2, Isabela Resende Pereira2, Edith A. Ferna´ndez-Figueroa4, Roberto
Alejandro Cardenas-Ovando4, Igor C. Almeida3, Sourav Roy3, Joseli Lannes-Vieira2,
Otacilio Cruz MoreiraID1*
1 Real-Time PCR Platform RPT09A, Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz
Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, 2 Laboratory of Biology of the Interactions,
Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, 3 Border Biomedical Research
Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of
America, 4 Computational and Integrative Genomics, Instituto Nacional de Medicina Geno´mica, Arenal
Tepepan, Mexico City, Mexico
* otacilio@ioc.fiocruz.br
Abstract
Chronic Chagas cardiomyopathy (CCC) is one of the leading causes of morbidity and mor-
tality due to cardiovascular disorders in endemic areas of Chagas disease (CD), a neglected
tropical illness caused by the protozoan parasite Trypanosoma cruzi. CCC is characterized
by parasite persistence and inflammatory response in the heart tissue, which occur parallel
to microRNA (miRNA) alterations. Here, we investigated the miRNA transcriptome profiling
in the cardiac tissue of chronically T. cruzi-infected mice treated with a suboptimal dose of
benznidazole (Bz), the immunomodulator pentoxifylline alone (PTX), or the combination of
both (Bz+PTX), following the CCC onset. At 150 days post-infection, Bz, PTX, and Bz+PTX
treatment regimens improved electrocardiographic alterations, reducing the percentage of
mice afflicted by sinus arrhythmia and second-degree atrioventricular block (AVB2) when
compared with the vehicle-treated animals. miRNA Transcriptome profiling revealed consid-


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erable changes in the differential expression of miRNAs in the Bz and Bz+PTX treatment
groups compared with the control (infected, vehicle-treated) group. The latter showed path-
ways related to organismal abnormalities, cellular development, skeletal muscle develop-
ment, cardiac enlargement, and fibrosis, likely associated with CCC. Bz-Treated mice
exhibited 68 differentially expressed miRNAs related to signaling pathways like cell cycle,
cell death and survival, tissue morphology, and connective tissue function. Finally, the Bz
+PTX-treated group revealed 58 differentially expressed miRNAs associated with key sig-
naling pathways related to cellular growth and proliferation, tissue development, cardiac
fibrosis, damage, and necrosis/cell death. The T. cruzi-induced upregulation of miR-146b-
5p, previously shown in acutely infected mice and in vitro T. cruzi-infected cardiomyocytes,
was reversed upon Bz and Bz+PTX treatment regimens when further experimentally vali-
dated. Our results further our understanding of molecular pathways related to CCC
PLOS NEGLECTED TROPICAL DISEASES
PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0011223
March 27, 2023
1 / 29
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OPEN ACCESS
Citation: Silva Grijo´ Farani P, Iandra da Silva
Ferreira B, Begum K, Vilar-Pereira G, Pereira IR,
Ferna´ndez-Figueroa EA, et al. (2023) Treatment
with benznidazole and pentoxifylline regulates
microRNA transcriptomic profile in a murine model
of Chagas chronic cardiomyopathy. PLoS Negl
Trop Dis 17(3): e0011223. https://doi.org/10.1371/
journal.pntd.0011223
Editor: Armando Jardim, McGill university,
CANADA
Received: September 27, 2022
Accepted: March 7, 2023
Published: March 27, 2023
Copyright: © 2023 Silva Grijo´ Farani 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.


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Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: This work received financial support from
Coordenac¸ão de Aperfeic¸oamento de Pessoal de
Nı´vel Superior Brasil (CAPES - Finance Code 001 to
PSGF and BIFS), Conselho Nacional de
Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq -
OCM is a researcher fellow of CNPq 1D (311539/


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Summary of the joint National Institutes of Health and the Food and Drug Administration workshop titled \215exploring the science s\
urrounding the safe use of bioactive ingredients in infant formula: Considerations for an assessment framework\216


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Summary of the joint National Institutes of Health and the Food 
and Drug Administration workshop titled “exploring the science 
surrounding the safe use of bioactive ingredients in infant 
formula: Considerations for an assessment framework”
Sharon M. Donovan, PhD1, Steven A. Abrams, MD2, Meghan B. Azad, PhD3,4, Mandy B. 
Belfort, MD, MPH5, Lars Bode, PhD6, Susan E. Carlson, PhD7, David C. Dallas, PhD8, 
Kasper Hettinga, PhD9, Kirsi Järvinen, MD, PhD10, Jae H. Kim, MD, PhD11, Carlito B. 
Lebrilla, PhD12, Michelle K. McGuire, PhD13, David A. Sela, PhD14, Josef Neu, MD15
1Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL;
2Department of Pediatrics Dell Medical School, The University of Texas at Austin, Austin, TX;
3Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada;
4Manitoba Interdisciplinary Lactation Centre (MILC), Children’s Hospital Research Institute of 
Manitoba, Winnipeg, Canada;
5Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital and Harvard 
Medical School, Boston, MA;
6Department of Pediatrics and Mother-Milk-Infant Center of Research Excellence (MOMI CORE), 
University of California, San Diego, La Jolla, CA;
7Department of Dietetics and Nutrition, Kansas University Medical Center and The University of 
Kansas, Kansas City, KS;
8Department of Nutrition, Oregon State University, Corvallis, OR;
9Department of Food Sciences and Agrotechnology, Wageningen University, Wageningen, 
Netherlands;
10Department of Pediatrics, Golisano Children’s Hospital and University of Rochester School of 
Medicine and Dentistry, Rochester, NY;
11Perinatal Institute, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and 
University of Cincinnati College of Medicine, Cincinnati, OH;
12Department of Chemistry, University of California, Davis, Davis, CA;
13School of Family and Consumer Sciences, University of Idaho, Moscow, ID;
14Department of Food Science, University of Massachusetts, Amherst, Amherst, MA;


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Reprint requests: Josef Neu, MD, University of Florida. neuj@peds.ufl.edu. 
Affiliations: 1Eunice Kennedy Shrive National Institute of Child Health and Human Development, Bethesda, MD; 2Center for Food 
Safety and Applied Nutrition, College Park, MD; 3Office of Dietary Supplements, National Institutes of Health, Bethesda, MD.
HHS Public Access
Author manuscript
J Pediatr. Author manuscript; available in PMC 2023 April 22.
Published in final edited form as:
J Pediatr. 2023 April ; 255: 30–41.e1. doi:10.1016/j.jpeds.2022.11.027.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript


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TrkC Intracellular Signalling in the Brain Fear Network During the Formation of a Contextual Fear Memory


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Vol.:(0123456789)
1 3
https://doi.org/10.1007/s12035-023-03292-0
TrkC Intracellular Signalling in the Brain Fear Network During 
the Formation of a Contextual Fear Memory
Francisca Silva1,2 · Gianluca Masella1,2 · Maria Francisca Madeira1 · Carlos B. Duarte1,3 · Mónica Santos1,2 
Received: 10 October 2022 / Accepted: 21 February 2023 
© The Author(s) 2023
Abstract
Learned fear is orchestrated by a brain fear network that comprises the amygdala, hippocampus and the medial prefrontal 
cortex. Synaptic plasticity within this network is critical for the formation of proper fear memories. Known for their role 
in the promotion of synaptic plasticity, neurotrophins position as obvious candidates in the regulation of fear processes. 
Indeed, recent evidence from our laboratory and others associates dysregulated signalling through neurotrophin-3 and its 
receptor TrkC with the pathophysiology of anxiety and fear-related disorders. Here, we put wild-type C57Bl/6J mice through 
a contextual fear conditioning paradigm in order to characterize TrkC activation and expression in the main brain regions 
involved in (learned) fear – amygdala, hippocampus, and prefrontal cortex – during the formation of a fear memory. We 
report an overall decreased activation of TrkC in the fear network during fear consolidation and reconsolidation. During 
reconsolidation, hippocampal TrkC downregulation was accompanied by a decrease in the expression and activation of Erk, 
a critical signalling pathway in fear conditioning. Moreover, we did not find evidence that the observed decrease of TrkC 
activation was caused by altered expression of dominant negative form of TrkC, neurotrophin-3, or the PTP1B phosphatase. 
Our results indicate hippocampal TrkC inactivation through Erk signalling as a potential mechanism in the regulation of 
contextual fear memory formation.
Keywords Fear conditioning · Neurotrophin 3 · Erk · Akt · PLC
Introduction
Excessive (learned) fear is a shared feature of anxiety disor-


