Human whole-exome genotype data for Alzheimer’s disease
(2024) Nature Communications, 15 (1), art. no. 684, .
Leung, Y.Y.a , Naj, A.C.a b , Chou, Y.-F.a , Valladares, O.a , Schmidt, M.c d , Hamilton-Nelson, K.c d , Wheeler, N.e f , Lin, H.g , Gangadharan, P.a , Qu, L.a , Clark, K.a , Kuzma, A.B.a , Lee, W.-P.a , Cantwell, L.a , Nicaretta, H.a , van der Lee, S.p , English, A.q , Kalra, D.q , Muzny, D.q , Skinner, E.q , Doddapeneni, H.q , Dinh, H.q , Hu, J.q , Santibanez, J.q , Jayaseelan, J.q , Worley, K.q , Gibbs, R.A.q , Lee, S.q , Dugan-Perez, S.q , Korchina, V.q , Nasser, W.q , Liu, X.q , Han, Y.q , Zhu, Y.q , Liu, Y.q , Khan, Z.q , Zhu, C.j , Sun, F.J.j , Jun, G.R.j , Chung, J.j , Farrell, J.j , Zhang, X.j , Banks, E.r , Gupta, N.r , Gabriel, S.r , Butkiewicz, M.e f , Benchek, P.e f , Smieszek, S.e f , Song, Y.e f , Vardarajan, B.n , Reitz, C.n , Reyes-Dumeyer, D.n , Tosto, G.n , De Jager, P.L.n , Barral, S.n , Ma, Y.n , Beiser, A.i , Liu, C.T.i , Dupuis, J.i , Lunetta, K.i , Cupples, L.A.i , Choi, S.H.i , Chen, Y.i , Mez, J.o , Vanderspek, A.s , Ikram, M.A.s , Ahmad, S.s , Faber, K.t , Foroud, T.t , Mlynarski, E.u , Schmidt, H.v , Schmidt, R.v , Kunkle, B.c d , Rajabli, F.c d , Beecham, G.c d , Vance, J.M.c d , Adams, L.D.c d , Cuccaro, M.c d , Mena, P.c d , Booth, B.M.w , Renton, A.x , Goate, A.x , Marcora, E.x , Stine, A.y , Feolo, M.y , Launer, L.J.z , Koboldt, D.C.aa , Wilson, R.K.aa , van Duijn, C.ab , Amin, N.ab , Kapoor, M.ac , Salerno, W.ac , Bennett, D.A.ad , Xia, L.C.ae , Malamon, J.af , Mosley, T.H.ag , Satizabal, C.k , Jan Bresslerk , Jian, X.k , Nato, A.Q., Jrah , Horimoto, A.R.ah , Wang, B.ah , Psaty, B.ah , Witten, D.ah , Tsuang, D.ah , Blue, E.ah , Wijsman, E.ah , Sohi, H.ah , Nguyen, H.ah , Bis, J.C.ah , Rice, K.ah , Brown, L.ah , Dorschner, M.ah , Saad, M.ah , Navas, P.ah , Nafikov, R.ah , Thornton, T.ah , Day, T.ah , Haut, J.b , Sha, J.b , Zhang, N.b , Iqbal, T.b , Zhao, Y.a , Below, J.E.ai , Larson, D.E.m , Appelbaum, E.m , Waligorski, J.m , Antonacci-Fulton, L.m , Fulton, R.S.m , Haines, J.e f , Farrer, L.h i , Seshadri, S.j k , Brkanac, Z.l , Cruchaga, C.m , Pericak-Vance, M.c d , Mayeux, R.P.n , Bush, W.S.e f , Destefano, A.i o , Martin, E.c d , Schellenberg, G.D.a , Wang, L.-S.a
a Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
c Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, United States
d The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, United States
e Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
f Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
g Department of Medicine, UMass Chan Medical School, Boston, MA, United States
h Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
i Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
j Boston University School of Medicine, Boston, MA, United States
k The Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, United States
l Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
m Washington University School of Medicine, St. Louis, MO, United States
n Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center, Columbia University and the New York Presbyterian Hospital, New York, NY, United States
o Department of Neurology, Boston University School of Medicine, Boston, MA, United States
p Amsterdam UMC, Amsterdam, Netherlands
q Baylor College of Medicine, Houston, TX, United States
r Broad Institute of MIT and Harvard, Cambridge, MA, United States
s Erasmus Medical University, Rotterdam, Netherlands
t Indiana University, Fort Wayne, IN, United States
u Johnson & Johnson, Horsham, PA, United States
v Medical University Graz, Graz, Austria
w MITRE, McLean, VA, United States
x Mount Sinai School of Medicine New York, New York, NY, United States
y National Center Biotechnology Information, Bethesda, MD, United States
z National Institute on Aging, Bethesda, MD, United States
aa Nationwide Children’s, Columbus, OH, United States
ab Oxford University, Oxford, United Kingdom
ac Regeneron, Tarrytown, NY, United States
ad Rush University, Chicago, IL, United States
ae Stanford University, Stanford, CA, United States
af University of Colorado, Boulder, CO, United States
ag University of Mississippi, Oxford, MS, United States
ah University of Washington, Seattle, WA, United States
ai Vanderbilt University, Nashville, TN, United States
Abstract
The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer’s Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community. © 2024, The Author(s).
Funding details
National Institute on AgingNIA
University of PennsylvaniaU24-AG041689
Document Type: Article
Publication Stage: Final
Source: Scopus
Barriers and facilitators to a task-shifted stroke prevention program for children with sickle cell anemia in a community hospital: a qualitative study
(2024) Implementation Science Communications, 5 (1), art. no. 10, .
Bello-Manga, H.a , Haliru, L.b , Ahmed, K.b , Ige, S.c , Musa, H.d , Muhammad-Idris, Z.K.e , Monday, B.d , Sani, A.M.f , Bonnet, K.g , Schlundt, D.G.g , Varughese, T.h , Tabari, A.M.i , DeBaun, M.R.j , Baumann, A.A.k , King, A.A.h k
a Department of Haematology and Blood Transfusion, Barau Dikko Teaching Hospital/Kaduna State University, Kaduna, Nigeria
b Department of Paediatrics, Barau Dikko Teaching Hospital/Kaduna State University, Kaduna, Nigeria
c Yusuf Dantsoho Memorial Hospital, Kaduna State Ministry of Health, Kaduna, Nigeria
d Department of Library and Information Science, Ahmadu Bello University, Zaria, Nigeria
e Department of Community Medicine, Kaduna State University, Kaduna, Nigeria
f Research Office, Barau Dikko Teaching Hospital, Kaduna, Nigeria
g Department of Psychology, Vanderbilt University, Nashville, TN, United States
h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
i Department of Radiology, Barau Dikko Teaching Hospital/Kaduna State University, Kaduna, Nigeria
j Department of Pediatrics, Division of Pediatric Neurology, Vanderbilt University of School of Medicine, Nashville, TN, United States
k Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Children with sickle cell anemia (SCA) are at high risk for stroke. Protocols for stroke prevention including blood transfusions, screening for abnormal non-imaging transcranial Doppler (TCD) measurements, and hydroxyurea therapy are difficult to implement in low-resource environments like Nigeria. This study aimed to examine the contextual factors around TCD screening in a community hospital in Nigeria using qualitative interviews and focus groups. Methods: We conducted a descriptive qualitative study in a community hospital in Kaduna, Nigeria, using focus groups and interviews. Interview guides and analysis were informed by the Consolidated Framework for Implementation Research (CFIR) framework and the Theory of Planned Behavior. Transcripts were coded and analyzed using an iterative deductive (CFIR)/Inductive (transcribed quotes) qualitative methodology. Results: We conducted two focus groups and five interviews with health care workers (nurses and doctors) and hospital administrators, respectively. Themes identified key elements of the inner setting (clinic characteristics, resource availability, implementation climate, and tension for change), characteristics of individuals (normative, control, and behavioral beliefs), and the implementation process (engage, implement, and adopt), as well as factors that were influenced by external context, caregiver needs, team function, and intervention characteristics. Task shifting, which is already being used, was viewed by providers and administrators as a necessary strategy to implement TCD screening in a clinic environment that is overstressed and under-resourced, a community stressed by poverty, and a nation with an underperforming health system. Conclusion: Task shifting provides a viable option to improve health care by making more efficient use of already available human resources while rapidly expanding the human resource pool and building capacity for TCD screening of children with SCD that is more sustainable. Trial registration: NCT05434000. © 2024, The Author(s).
Author Keywords
Implementation; Sickle cell anemia; Stroke; Task shifting; Transcranial Doppler
Funding details
National Institutes of HealthNIH
Fogarty International CenterFIC
National Institute of Neurological Disorders and StrokeNINDS1K24 HL14830, K43TW011583
Document Type: Article
Publication Stage: Final
Source: Scopus
Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons
(2024) Journal of Neuroinflammation, 21 (1), art. no. 24, .
Cain, M.D.a b , Klein, N.R.b , Jiang, X.a b , Salimi, H.a b , Wu, Q.a b , Miller, M.J.b , Klimstra, W.B.e , Klein, R.S.a b c d
a Center for Neuroimmunology & Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Departments of Neurosciences, Washington University School of Medicine, St. Louis, MO, United States
e Department of Immunology and Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States
Abstract
Background: Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. Methods: We utilized an established murine model of intranasal infection with VEEV and a repository of scRNAseq data from IFN-treated OSN to assess the cellular targets and IFN signaling responses after VEEV exposure. Results: We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 h during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. Conclusions: Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures. © 2024, The Author(s).
Funding details
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Final
Source: Scopus
Associations between COVID-19 and putative markers of neuroinflammation: A diffusion basis spectrum imaging study
(2024) Brain, Behavior, and Immunity – Health, 36, art. no. 100722, .
Zhang, W.a , Gorelik, A.J.b , Wang, Q.a , Norton, S.A.b , Hershey, T.a b c d , Agrawal, A.c , Bijsterbosch, J.D.a , Bogdan, R.b
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
COVID-19 remains a significant international public health concern. Yet, the mechanisms through which symptomatology emerges remain poorly understood. While SARS-CoV-2 infection may induce prolonged inflammation within the central nervous system, the evidence primarily stems from limited small-scale case investigations. To address this gap, our study capitalized on longitudinal UK Biobank neuroimaging data acquired prior to and following COVID-19 testing (N = 416 including n = 224 COVID-19 cases; Mage = 58.6). Putative neuroinflammation was assessed in gray matter structures and white matter tracts using non-invasive Diffusion Basis Spectrum Imaging (DBSI), which estimates inflammation-related cellularity (DBSI-restricted fraction; DBSI-RF) and vasogenic edema (DBSI-hindered fraction; DBSI-HF). We hypothesized that COVID-19 case status would be associated with increases in DBSI markers after accounting for potential confound (age, sex, race, body mass index, smoking frequency, and data acquisition interval) and multiple testing. COVID-19 case status was not significantly associated with DBSI-RF (|β|’s < 0.28, pFDR >0.05), but with greater DBSI-HF in left pre- and post-central gyri and right middle frontal gyrus (β′s > 0.3, all pFDR = 0.03). Intriguingly, the brain areas exhibiting increased putative vasogenic edema had previously been linked to COVID-19-related functional and structural alterations, whereas brain regions displaying subtle differences in cellularity between COVID-19 cases and controls included regions within or functionally connected to the olfactory network, which has been implicated in COVID-19 psychopathology. Nevertheless, our study might not have captured acute and transitory neuroinflammatory effects linked to SARS-CoV-2 infection, possibly due to symptom resolution before the imaging scan. Future research is warranted to explore the potential time- and symptom-dependent neuroinflammatory relationship with COVID-19. © 2024 The Authors
Author Keywords
COVID-19; DBSI; Diffusion basis spectrum imaging; Long COVID; Neuroimaging; Neuroinflammation; UK biobank
Funding details
National Science FoundationNSFDGE-213989
National Institutes of HealthNIHHD070855, NS109487, R01 AG061162, R01 DA054750, R01 DK126826, R21 AA027827, U01 DA055367
National Institute of Mental HealthNIMHR01 MH128286
Washington University in St. LouisWUSTL
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Factors Associated With Interest in Engaging in Psychological Interventions for Pain Management
(2024) Clinical Journal of Pain, 40 (2), pp. 67-71.
Miller-Matero, L.R.a b , Yaldo, M.b , Chohan, S.c , Zabel, C.b , Patel, S.a , Chrusciel, T.e f , Salas, J.d e , Wilson, L.d , Sullivan, M.D.i , Ahmedani, B.K.a b , Lustman, P.J.h , Scherrer, J.F.d e g
a Henry Ford Health, Behavioral Health Services, United States
b Henry Ford Health, Center for Health Policy and Health Services Research, United States
c Wayne State University School of Medicine, Detroit, MI, United States
d Department of Family and Community Medicine, Saint Louis University School of Medicine, United States
e Advanced HEAlth Data (AHEAD) Research Institute, Saint Louis University School of Medicine, United States
f Department of Health and Clinical Outcomes Research, Saint Louis University School of Medicine, United States
g Department of Psychiatry and Behavioral Neuroscience, Saint Louis University School of Medicine, United States
h Department of Psychiatry, Washington University School of Medicine, St. Louis, MS, United States
i Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, United States
Abstract
Objective: Engagement in evidence-based psychological interventions for pain management is low. Identifying characteristics associated with interest in interventions can inform approaches to increase uptake and engagement. The purpose of this study was to examine factors associated with interest in psychological interventions among persons with chronic noncancer pain receiving prescription opioids. Methods: Participants with chronic noncancer pain and a new 30 to 90 day opioid prescription were recruited from 2 health systems. Participants (N = 845) completed measures regarding pain, opioid use, psychiatric symptoms, emotional support, and interest in psychological interventions for pain management. Results: There were 245 (29.0%) participants who reported a high interest in psychological interventions for pain management. In bivariate analyses, variables associated with interest included younger age, female sex, greater pain severity, greater pain interference, greater number of pain sites, lower emotional support, depression, anxiety, and post-traumatic stress disorder (P < 0.05). In a multivariate model, greater pain severity (odds ratio [OR] = 1.17; CI: 1.04-1.32), depression (OR = 2.10; CI: 1.39-3.16), post-traumatic stress disorder (OR = 1.85; CI: 1.19-2.95), and lower emotional support (OR = 0.69; CI: 0.5-0.97) remained statistically significant. Discussion: The rate of interest in psychological interventions for pain management was low, which may indicate that patients initiating opioid treatment of chronic noncancer pain have low interest in psychological interventions. Greater pain severity and psychiatric distress were related to interest, and patients with these characteristics may especially benefit from psychological interventions. Providers may want to refer to psychological interventions before or when opioids are initiated. Additional work is needed to determine whether this would reduce long-term opioid use. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Author Keywords
opioid use; pain; psychiatric symptoms; psychological treatments
Funding details
National Institute on Drug AbuseNIDAR01DA043811
Document Type: Article
Publication Stage: Final
Source: Scopus
Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations
(2024) The Journal of Experimental Medicine, 221 (2), .
Cadiz, M.P.a b , Gibson, K.A.a , Todd, K.T.a , Nascari, D.G.a c d , Massa, N.a b , Lilley, M.T.b , Olney, K.C.a , Al-Amin, M.M.e , Jiang, H.f , Holtzman, D.M.f , Fryer, J.D.a b c d
a Department of Neuroscience, Mayo Clinic, Scottsdale, AZ, United States
b Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Scottsdale, AZ, United States
c Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Scottsdale, AZ, United States
d MD/PhD Training Program, Mayo Clinic, Scottsdale, AZ, United States
e Department of Medical and Molecular Genetics, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Aducanumab, an anti-amyloid immunotherapy for Alzheimer’s disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy. © 2024 Cadiz et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Gene-environment interactions and risk of pediatric-onset multiple sclerosis associated with time spent outdoors
(2024) Multiple Sclerosis and Related Disorders, 82, art. no. 105351, .
Nasr, Z.a , Virupakshaiah, A.a , Schoeps, V.A.a , Cherbuin, N.b , Casper, T.C.c , Waltz, M.c , Hart, J.a , Rodriguez, M.d , Gorman, M.P.e , Benson, L.A.e , Chitnis, T.f , Rensel, M.g , Abrams, A.g , Krupp, L.h , Waldman, A.T.i , Lotze, T.j , Aaen, G.S.k , Mar, S.l , Schreiner, T.m , Wheeler, Y.n , Rose, J.o , Shukla, N.M.p , Barcellos, L.F.q , Lucas, R.r , Waubant, E.a
a UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United States
b Centre for Research on Ageing, Health and Wellbeing, Australian National University, Canberra, Australia
c University of Utah School of Medicine, Salt Lake City, UT, United States
d Mayo Clinic, Rochester, MN, United States
e Boston Childrens Hospital, Boston, MA, United States
f Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
g Cleveland Clinic, Cleveland, OH, United States
h New York University Medical Center, New York City, NY, United States
i Division of Child Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
j Texas Children’s Hospital, Houston, TX, United States
k Loma Linda University Children’s Hospital, Loma Linda, CA, United States
l Washington University in St. Louis, St Louis, MO, United States
m Childrens Hospital Colorado/University of Colorado, Aurora, CO, United States
n Children’s Hospital of Alabama, Birmingham, AL, United States
o George E. Wahlen Department of Veterans Affairs Medical Center, University of Utah, Salt Lake City, UT, United States
p Baylor College of Medicine/Texas Children’s Hospital, Neurology and Developmental Neuroscience, Houston, TX, United States
q Genetic Epidemiology and Genomics Laboratory, Divisions of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, United States
r National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australia
Abstract
Background: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. Methods: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). Results: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56–0.78, p < 0.001; OR 0.78, 95 % CI 0.62–0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. Conclusions: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may. © 2023
Author Keywords
Gene-environment interactions; Multiple sclerosis; Risk factors; Time spent outdoors
Funding details
National Institutes of HealthNIH
National Multiple Sclerosis SocietyNMSSHC-1509-06233
Multiple Sclerosis International FederationMSIF
Document Type: Article
Publication Stage: Final
Source: Scopus
APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread
(2024) Cell, 187 (2), pp. 428-445.e20.
Chen, Y.a b , Song, S.a , Parhizkar, S.a c d , Lord, J.a , Zhu, Y.a , Strickland, M.R.a , Wang, C.a , Park, J.a , Tabor, G.T.a , Jiang, H.a c d , Li, K.a , Davis, A.A.a c , Yuede, C.M.a c d e f , Colonna, M.b c , Ulrich, J.D.a c d , Holtzman, D.M.a c d
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
d Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer’s Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy. © 2023 Elsevier Inc.
Funding details
National Institutes of HealthNIHRF1AG047644, RF1NS090934
Alzheimer’s AssociationAAAARF-21-850865
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
University of WashingtonUW
Center for Cellular Imaging, Washington UniversityWUCCI
Document Type: Article
Publication Stage: Final
Source: Scopus
Structural and functional basis of VLDLR usage by Eastern equine encephalitis virus
(2024) Cell, 187 (2), pp. 360-374.e19.
Adams, L.J.a , Raju, S.a , Ma, H.a b , Gilliland, T., Jr.c , Reed, D.S.c , Klimstra, W.B.c , Fremont, D.H.a d e , Diamond, M.S.a b d f g
a Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15261, United States
d Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
f Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, United States
g Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
The very-low-density lipoprotein receptor (VLDLR) comprises eight LDLR type A (LA) domains and supports entry of distantly related alphaviruses, including Eastern equine encephalitis virus (EEEV) and Semliki Forest virus (SFV). Here, by resolving multiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously. However, no single LA domain is necessary or sufficient to support efficient EEEV infection. Whereas all EEEV strains show conservation of two VLDLR-binding sites, the EEEV PE-6 strain and a few other EEE complex members feature a single amino acid substitution that enables binding of LA domains to an additional site on the E2 B domain. These structural and functional analyses informed the design of a minimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge. © 2023 Elsevier Inc.
Author Keywords
alphavirus; cryo-electron microscopy; encephalitis; mice; pathogenesis; receptor; therapeutic
Funding details
National Institutes of HealthNIHAI201800001, R01 AI141436, U19 AI142790
National Institute of Allergy and Infectious DiseasesNIAID75N93022C00035, R01AI095436
Defense Threat Reduction AgencyDTRAMCDC2103-011
Vir Biotechnology
Document Type: Article
Publication Stage: Final
Source: Scopus
Targeting cell-type-specific, choroid-peripheral immune signaling to treat age-related macular degeneration
(2024) Cell Reports Medicine, 5 (1), art. no. 101353, .
Lin, J.B.a b , Santeford, A.a , Colasanti, J.J.a c , Lee, Y.a , Shah, A.V.a , Wang, T.J.a , Ruzycki, P.A.a , Apte, R.S.a d e f
a John F. Hardesty, MD, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
b Neurosciences Graduate Program, Roy and Diana Vagelos Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
c Molecular Cell Biology Graduate Program, Roy and Diana Vagelos Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness featuring pathogenic neovascularization of the choroidal vasculature (CNV). Although systemic immunity plays a role in AMD, the ocular signals that recruit and activate immune cells remain poorly defined. Using single-cell RNA sequencing, we prospectively profile peripheral blood mononuclear cells from 65 individuals including AMD and controls, which we integrate with existing choroid data. We generate a network of choroid-peripheral immune interactions dysregulated in AMD, including known AMD-relevant gene vascular endothelial growth factor (VEGF) receptor 2. Additionally, we find CYR61 is upregulated in choroidal veins and may signal to circulating monocytes. In mice, we validate that CYR61 is abundant in endothelial cells within CNV lesions neighboring monocyte-derived macrophages. Mechanistically, CYR61 activates macrophage anti-angiogenic gene expression, and ocular Cyr61 knockdown increases murine CNV size, indicating CYR61 inhibits CNV. This study highlights the potential of multi-tissue human datasets to identify disease-relevant and potentially therapeutically modifiable targets. © 2023 The Authors
Author Keywords
angiogenesis; choroid; CYR61; macrophage; neovascularization
Funding details
National Institutes of HealthNIHEY02687, R01 EY019287
Research to Prevent BlindnessRPBF30 DK130282
BrightFocus FoundationBFF
Washington University in St. LouisWUSTLT32 GM07200
Institute of Clinical and Translational SciencesICTSUL1 TR002345
Carl Marshall and Mildred Almen Reeves Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
Purposeful and purposeless aging: Structural issues for sense of purpose and their implications for predicting life outcomes
(2024) Developmental Psychology, 60 (1), pp. 75-93.
Pfund, G.N.a , Olaru, G.b , Allemand, M.c , Hill, P.L.d
a Department of Medical Social Sciences, Northwestern University
b Department of Developmental Psychology, Tilburg University
c Department of Psychology, University Research Priority Program “Dynamics of Healthy Aging”, University of Zurich
d Department of Psychological and Brain Sciences, Washington University in St. Louis
Abstract
Despite the value of sense of purpose during older adulthood, this construct often declines with age. With some older adults reconsidering the relevance of purpose later in life, the measurement of purpose may suffer from variance issues with age. The current study investigated whether sense of purpose functions similarly across ages and evaluated if the predictive power of purpose on mental, physical, cognitive, and financial outcomes changes when accounting for a less age-affected measurement structure. Utilizing data from two nationwide panel studies (Health and Retirement Study: n = 14,481; Midlife in the United States: n = 4,030), the current study conducted local structural equation modeling and found two factors for the positively and negatively valenced purpose items in the Purpose in Life subscale (Ryff, 1989), deemed the purposeful and purposeless factor. These factors become less associated with each other at higher ages. When reproducing past findings with this two-factor structure, the current study found that the purposeful and purposeless factors predicted these outcomes in the same direction as would be suggested by past research, but the magnitude of these effects differed for some outcomes. The discussion focuses on the implications of what this means for our understanding of sense of purpose across the lifespan. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Document Type: Article
Publication Stage: Final
Source: Scopus
Hormonal basis of sex differences in anesthetic sensitivity
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (3), art. no. e2312913120, .
Wasilczuk, A.Z.a b c , Rinehart, C.a b , Aggarwal, A.a b d , Stone, M.E.a b d , Mashour, G.A.e , Avidan, M.S.f , Kelz, M.B.a b d g , Proekt, A.a b d g
a Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, United States
b Neuroscience of Unconsciousness and Reanimation Research Alliance, Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, United States
c Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, United States
d Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, United States
e Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48105, United States
f Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
g Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
Abstract
General anesthesia-a pharmacologically induced reversible state of unconsciousness- enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females. © 2024 the Author(s).
Author Keywords
behavior; EEG; hormones; sex differences; whole brain c-Fos imaging
Funding details
National Institutes of HealthNIHR01 GM088156, R01 GM124023, R01 GM144377, R01 GM151556, T32 HL007953, T32 NS091006
James S. McDonnell FoundationJSMF
University of Pennsylvania
Document Type: Article
Publication Stage: Final
Source: Scopus
Neural mechanisms of face familiarity and learning in the human amygdala and hippocampus
(2024) Cell Reports, 43 (1), art. no. 113520, . Cited 1 time.
Cao, R.a b , Wang, J.b , Brunner, P.c , Willie, J.T.c , Li, X.b , Rutishauser, U.d , Brandmeir, N.J.e , Wang, S.a b c
a Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
b Lane Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV 26506, United States
c Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO 63110, United States
d Departments of Neurosurgery and Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
e Department of Neurosurgery, West Virginia University, Morgantown, WV 26506, United States
Abstract
Recognizing familiar faces and learning new faces play an important role in social cognition. However, the underlying neural computational mechanisms remain unclear. Here, we record from single neurons in the human amygdala and hippocampus and find a greater neuronal representational distance between pairs of familiar faces than unfamiliar faces, suggesting that neural representations for familiar faces are more distinct. Representational distance increases with exposures to the same identity, suggesting that neural face representations are sharpened with learning and familiarization. Furthermore, representational distance is positively correlated with visual dissimilarity between faces, and exposure to visually similar faces increases representational distance, thus sharpening neural representations. Finally, we construct a computational model that demonstrates an increase in the representational distance of artificial units with training. Together, our results suggest that the neuronal population geometry, quantified by the representational distance, encodes face familiarity, similarity, and learning, forming the basis of face recognition and memory. © 2023 The Author(s)
Author Keywords
amygdala; CP: Neuroscience; face; familiarity; hippocampus; human single-neuron recordings; learning; representational distance; similarity
Funding details
National Science FoundationNSFBCS-1945230, IIS-2114644
National Institutes of HealthNIHP41EB018783, R01EB026439, R01MH120194, R01MH129426, R21NS128307, U01NS108916, U01NS128612, U24NS109103
Air Force Office of Scientific ResearchAFOSRFA9550-21-1-0088
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
A critical period for developing face recognition
(2024) Patterns, art. no. 100895, . Cited 1 time.
Wang, J.a , Cao, R.a b , Chakravarthula, P.N.b , Li, X.a c , Wang, S.a b
a Lane Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV 26506, United States
b Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Computer Science, University at Albany, Albany, NY 12222, United States
Abstract
Face learning has important critical periods during development. However, the computational mechanisms of critical periods remain unknown. Here, we conducted a series of in silico experiments and showed that, similar to humans, deep artificial neural networks exhibited critical periods during which a stimulus deficit could impair the development of face learning. Face learning could only be restored when providing information within the critical period, whereas, outside of the critical period, the model could not incorporate new information anymore. We further provided a full computational account by learning rate and demonstrated an alternative approach by knowledge distillation and attention transfer to partially recover the model outside of the critical period. We finally showed that model performance and recovery were associated with identity-selective units and the correspondence with the primate visual systems. Our present study not only reveals computational mechanisms underlying face learning but also points to strategies to restore impaired face learning. © 2023 The Author(s)
Author Keywords
attention transfer; autism spectrum disorder; critical period; deep neural network; DSML2: Proof-of-Concept: Data science output has been formulated, implemented, and tested for one domain/problem; eyes; faces; facial landmarks; knowledge distillation; learning; mouth
Funding details
National Science FoundationNSFBCS-1945230, IIS-2114644
National Institutes of HealthNIHR01MH129426
Air Force Office of Scientific ResearchAFOSRFA9550-21-1-0088
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Transcription factor interactions explain the context-dependent activity of CRX binding sites
(2024) PLoS Computational Biology, 20 (1), art. no. e1011802, .
Loell, K.J.a b , Friedman, R.Z.a b , Myers, C.A.c , Corbo, J.C.c , Cohen, B.A.a b , White, M.A.a b
a Department of Genetics, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
b The Edison Family Center for Genome Sciences & Systems Biology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
The effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs. © 2024 Loell 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.
Document Type: Article
Publication Stage: Final
Source: Scopus
Predictors and outcomes of fluctuations in the clinical dementia rating scale
(2024) Alzheimer’s and Dementia, .
Wilks, H.a b , Benzinger, T.L.S.b c , Schindler, S.E.b , Cruchaga, C.b d , Morris, J.C.b , Hassenstab, J.a b
a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine, 1 Barnes Jewish Hospital Plaza, St. Louis, MO, United States
Abstract
INTRODUCTION: Reversion, or change in cognitive status from impaired to normal, is common in aging and dementia studies, but it remains unclear what factors predict reversion. METHODS: We investigated whether reverters, defined as those who revert from a Clinical Dementia Rating® (CDR®) scale score of 0.5 to CDR 0) differed on cognition and biomarkers from unimpaired participants (always CDR 0) and impaired participants (converted to CDR > 0 and had no reversion events). Models evaluated relationships between biomarker status, apolipoprotein E (APOE) ε4 status, and cognition. Additional models described predictors of reversion and predictors of eventual progression to CDR > 0. RESULTS: CDR reversion was associated with younger age, better cognition, and negative amyloid biomarker status. Reverters that eventually progressed to CDR > 0 had more visits, were older, and were more likely to have an APOE ε4 allele. DISCUSSION: CDR reversion occupies a transitional phase in disease progression between cognitive normality and overt dementia. Reverters may be ideal candidates for secondary prevention Alzheimer’s disease (AD) trials. Highlights: Reverters had more longitudinal cognitive decline than those who remained cognitively normal. Predictors of reversion: younger age, better cognition, and negative amyloid biomarker status. Reverting from CDR 0.5 to 0 is a risk factor for future conversion to CDR > 0. CDR reversion may be a transitional phase in Alzheimer’s Disease progression. CDR reverters may be ideal for Alzheimer’s disease secondary prevention trials. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer disease; biomarkers; clinical dementia rating scale; clinical reversion; cognition; dementia
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Early Emotion Development Intervention Improves Mental Health Outcomes in Low-Income, High-Risk Community Children
(2024) Child Psychiatry and Human Development, .
Hennefield, L.a f , Gilbert, K.a , Donohue, M.R.a , Tillman, R.a , McCoy, A.b , Diggs, G.c , Paul, Z.A.d , Kohl, P.L.a e , Luby, J.L.a
a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
b Saint Louis University, The Jennings School District, Jennings, MO, United States
c Head Start/Early Head Start at the Urban League of Metropolitan, Saint Louis, MO, United States
d Department of Counselor Education and Counseling Psychology, College of Education, Marquette University, Milwaukee, WI, United States
e The Brown School of Social Work, Washington University in Saint Louis, Saint Louis, MO, United States
f Department of Psychiatry, Washington University School of Medicine, 4444 Forest Park, Suite 2100, Saint Louis, MO, United States
Abstract
Children living in poverty and facing related forms of adversity are at higher risk for experiencing concurrent and later psychopathology. Although negative psychological outcomes can be improved by enhancing sensitive and responsive caregiving early in development, interventions targeting the caregiver–child dyad are not readily accessible. The present study investigated the feasibility and effectiveness of delivering a shortened eight-session form of Parent–Child Interaction Therapy-Emotion Development (PCIT-ED) in-person or remotely as an early intervention for 3–6-year-old children (N = 62) at elevated risk for psychopathology who were growing up in low-income communities. Caregiver–child dyads were randomized to eight-sessions of PCIT-ED or online parenting education. Relative to parenting education, children receiving PCIT-ED exhibited lower externalizing symptoms and functional impairment and more positive peer relationships following the intervention. Findings support the effectiveness of this shortened form of PCIT-ED, delivered in-person or remotely, as an early intervention to improve symptoms of psychopathology and functioning in high-risk children living in poverty. Trial registration Clinicaltrials.gov; NCT04399629. © 2024, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Adversity; Early intervention; Online intervention; PCIT; PCIT-ED
Funding details
National Institute of Mental HealthNIMHK01 MH127412, K23 MH115074, K23 MH125023
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Estrogen-induced glial IL-1β mediates extrinsic retinal ganglion cell vulnerability in murine Nf1 optic glioma
(2024) Annals of Clinical and Translational Neurology, .
Tang, Y.a b , Chatterjee, J.a , Wagoner, N.a , Bozeman, S.a , Gutmann, D.H.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Optic pathway gliomas (OPGs) arising in children with neurofibromatosis type 1 (NF1) can cause retinal ganglion cell (RGC) dysfunction and vision loss, which occurs more frequently in girls. While our previous studies demonstrated that estrogen was partly responsible for this sexually dimorphic visual impairment, herein we elucidate the underlying mechanism. In contrast to their male counterparts, female Nf1OPG mice have increased expression of glial interleukin-1β (IL-1β), which is neurotoxic to RGCs in vitro. Importantly, both IL-1β neutralization and leuprolide-mediated estrogen suppression decrease IL-1β expression and ameliorate RGC dysfunction, providing preclinical proof-of-concept evidence supporting novel neuroprotective strategies for NF1-OPG-induced vision loss. © 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Eye InstituteNEIP30EY002687
National Institute of Neurological Disorders and StrokeNINDSR25‐NS090978
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exploration of Resveratrol as a Potent Modulator of α-Synuclein Fibril Formation
(2023) ACS Chemical Neuroscience, .
Illes-Toth, E., Rempel, D.L., Gross, M.L.
Department of Chemistry, Washington University in St Louis, St Louis, MO 63130, United States
Abstract
The molecular determinants of amyloid protein misfolding and aggregation are key for the development of therapeutic interventions in neurodegenerative disease. Although small synthetic molecules, bifunctional molecules, and natural products offer a potentially advantageous approach to therapeutics to remodel aggregation, their evaluation requires new platforms that are informed at the molecular level. To that end, we chose pulsed hydrogen/deuterium exchange mass spectrometry (HDX-MS) to discern the phenomena of aggregation modulation for a model system of alpha synuclein (αS) and resveratrol, an antiamyloid compound. We invoked, as a complement to HDX, advanced kinetic modeling described here to illuminate the details of aggregation and to determine the number of oligomeric populations by kinetically fitting the experimental data under conditions of limited proteolysis. The misfolding of αS is most evident within and nearby the nonamyloid-β component region, and resveratrol significantly remodels that aggregation. HDX distinguishes readily a less solvent-accessible, more structured oligomer that coexists with a solvent-accessible, more disordered oligomer during aggregation. A view of the misfolding emerges from time-dependent changes in the fractional species across the protein with or without resveratrol, while details were determined through kinetic modeling of the protected species. A detailed picture of the inhibitory action of resveratrol with time and regional specificity emerges, a picture that can be obtained for other inhibitors and amyloid proteins. Moreover, the model reveals that new states of aggregation are sampled, providing new insights on amyloid formation. The findings were corroborated by circular dichroism and transmission electron microscopy. © 2024 American Chemical Society.
Author Keywords
amyloid formation; kinetic modeling of aggregation; limited proteolysis; modulator of alpha-synuclein; protein aggregation; pulsed hydrogen/deuterium exchange; resveratrol
Funding details
National Institutes of HealthNIHP41GM103422, R24GM136766
American Parkinson Disease AssociationAPDA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Evolving Barriers to Clinical Trial Enrollment and Clinical Care in Neuro-oncology in the Face of COVID-19
(2024) Seminars in Neurology, 44 (1), pp. 47-52.
Grandhi, N.a , Zhou, A.Y.a , Johnson, M.O.b , Butt, O.H.a
a Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University in Saint Louis, St. Louis, MO, United States
b Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, United States
Abstract
The lack of treatments with durable response in neuro-oncology highlights the critical need for clinical trials to advance patient care. The intersection of relatively low incidence, evolving classification schema, and entrenched community, healthcare provider, and organizational factors have been historic challenges against successful trial enrollment and implementation. The additional need for multidisciplinary, often tertiary-level care, further magnifies latent national and international health inequities with rural and under-served populations. The COVID-19 pandemic both unveiled fundamental weaknesses in historical approaches and prompted the necessity of new approaches and systems for conducting clinical trials. Here, we provide an overview of traditional barriers to clinical trial enrollment in neuro-oncology, the effect of COVID-19 on these barriers, and the discovery of additional systemic weaknesses. Finally, we discuss future directions by reflecting on lessons learned with strategies to broaden access of care and streamline clinical trial integration into clinical practice. © 2024 Thieme Medical Publishers, Inc.. All rights reserved.
Author Keywords
barriers; clinical trials; COVID-19; inequities; neuro-oncology
Document Type: Article
Publication Stage: Final
Source: Scopus