Neighborhood ‘Disamenities’: local barriers and cognitive function among Black and white aging adults
(2023) BMC Public Health, 23 (1), art. no. 197, .
Yu, W.a b , Esposito, M.b c , Li, M.a b , Clarke, P.b d , Judd, S.e , Finlay, J.b d
a Program in Survey and Data Science, Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, MI 48104, United States
b Social Environment and Health, Survey Research Center, Institute for Social Research, University of Michigan 426 Thompson Street, Ann Arbor, MI 48104, United States
c Department of Sociology, Washington University in St. Louis, St. Louis, MO 63130, United States
d Center for Social Epidemiology and Population Health, Department of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States
e School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35233, United States
Abstract
Background: This study examined the association between cognitive function and three neighborhood ‘disamenities’ that may pose local barriers to utilizing community resources and increase risk for cognitive decline. Method: Using national data from 21,165 urban- and suburban-dwelling Black and white adults (mean age: 67 years) in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, we assessed global cognitive function through a factor score of five cognitive screening tests. General Additive Mixed Models (GAMM) tested whether residing in areas with more polluting sites, highways, and limited walkability was associated with worse cognitive function. Results: Limited walkability and the presence of polluting sites had a significant negative association with cognitive function after controlling for individual and neighborhood factors. Conclusion: Neighborhood disamenities may be linked to cognitive function among aging residents. Identifying neighborhood factors that pose barriers to accessing community resources may inform upstream policy applications to reduce risk for cognitive decline. © 2023, The Author(s).
Author Keywords
Aging; Cognitive function; Neighborhood; Urban health
Funding details
National Institutes of Health
U.S. Department of Health and Human Services
National Institute on Aging
National Institute of Neurological Disorders and Stroke
Document Type: Article
Publication Stage: Final
Source: Scopus
Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain
(2023) Nature Communications, 14 (1), art. no. 453, .
Pan, S.a , Yang, P.H.a , DeFreitas, D.a , Ramagiri, S.a , Bayguinov, P.O.b , Hacker, C.D.a , Snyder, A.Z.c d , Wilborn, J.a , Huang, H.c e , Koller, G.M.a , Raval, D.K.a , Halupnik, G.L.a , Sviben, S.b , Achilefu, S.f , Tang, R.c , Haller, G.a d g , Quirk, J.D.c , Fitzpatrick, J.A.J.b h i , Esakky, P.a , Strahle, J.M.a j k
a Department of Neurosurgery, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
b Washington University Center for Cellular Imaging, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Radiology, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
d Department of Neurology, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
f Department of Biomedical Engineering, UT Southwestern Medical Center, Dallas, TX 75390, United States
g Department of Genetics, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
h Department of Neuroscience, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
i Department of Cell Biology and Physiology, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
j Department of Orthopedic Surgery, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
k Department of Pediatrics, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate CSF-parenchymal interactions involving 24 functional-anatomic cell groupings in the brain and spinal cord. CSF distribution to these areas is largely restricted to early development and is altered in posthemorrhagic hydrocephalus. Our study also presents particle size-dependent CSF circulation patterns through the CNS including interaction between neurons and small CSF tracers, but not large CSF tracers. These findings have implications for understanding the biological basis of normal brain development and the pathogenesis of a broad range of disease states, including hydrocephalus. © 2023, The Author(s).
Funding details
National Institutes of Health
Washington University in St. Louis
Foundation for Barnes-Jewish Hospital
University of Washington
McDonnell Center for Systems Neuroscience
Center for Cellular Imaging, Washington University
Hydrocephalus Association
St. Louis Children’s Hospital
Document Type: Article
Publication Stage: Final
Source: Scopus
Multivariate EEG activity reflects the Bayesian integration and the integrated Galilean relative velocity of sensory motion during sensorimotor behavior
(2023) Communications Biology, 6 (1), art. no. 113, .
Jeong, W.a b , Kim, S.a c , Park, J.J.a d , Lee, J.a c e
a Center for Neuroscience Imaging Research, Institute for Basic Science (IBS), Suwon, 16419, South Korea
b Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, United States
c Department of Biomedical Engineering, Sungkyunkwan University, Suwon, 16419, South Korea
d Division of Biology and Biomedical Sciences, Program in Neurosciences, Washington University in St. Louis, St. Louis, MO 63130, United States
e Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, 16419, South Korea
Abstract
Humans integrate multiple sources of information for action-taking, using the reliability of each source to allocate weight to the data. This reliability-weighted information integration is a crucial property of Bayesian inference. In this study, participants were asked to perform a smooth pursuit eye movement task in which we independently manipulated the reliability of pursuit target motion and the direction-of-motion cue. Through an analysis of pursuit initiation and multivariate electroencephalography activity, we found neural and behavioral evidence of Bayesian information integration: more attraction toward the cue direction was generated when the target motion was weak and unreliable. Furthermore, using mathematical modeling, we found that the neural signature of Bayesian information integration had extra-retinal origins, although most of the multivariate electroencephalography activity patterns during pursuit were best correlated with the retinal velocity errors accumulated over time. Our results demonstrated neural implementation of Bayesian inference in human oculomotor behavior. © 2023, The Author(s).
Funding details
Institute for Basic Science
Document Type: Article
Publication Stage: Final
Source: Scopus
Lateral line ablation by ototoxic compounds results in distinct rheotaxis profiles in larval zebrafish
(2023) Communications Biology, 6 (1), art. no. 84, .
Newton, K.C.a e , Kacev, D.b , Nilsson, S.R.O.c , Saettele, A.L.a , Golden, S.A.c , Sheets, L.a d
a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
b Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, United States
c Department of Biological Structure, University of Washington, Seattle, WA, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Fisheries, Wildlife and Conservation Sciences, Coastal Oregon Marine Experiment Station, Oregon State University, Hatfield Marine Science Center, Newport, OR, United States
Abstract
The zebrafish lateral line is an established model for hair cell organ damage, yet few studies link mechanistic disruptions to changes in biologically relevant behavior. We used larval zebrafish to determine how damage via ototoxic compounds impact rheotaxis. Larvae were treated with CuSO4 or neomycin to disrupt lateral line function then exposed to water flow stimuli. Their swimming behavior was recorded on video then DeepLabCut and SimBA software were used to track movements and classify rheotaxis behavior, respectively. Lateral line-disrupted fish performed rheotaxis, but they swam greater distances, for shorter durations, and with greater angular variance than controls. Furthermore, spectral decomposition analyses confirmed that lesioned fish exhibited ototoxic compound-specific behavioral profiles with distinct changes in the magnitude, frequency, and cross-correlation between fluctuations in linear and angular movements. Our observations demonstrate that lateral line input is needed for fish to hold their station in flow efficiently and reveals that commonly used lesion methods have unique effects on rheotaxis behavior. © 2023, The Author(s).
Funding details
National Institute on Drug Abuse
National Institute on Deafness and Other Communication Disorders
National Alliance for Research on Schizophrenia and Depression
Document Type: Article
Publication Stage: Final
Source: Scopus
Semantic wikis as flexible database interfaces for biomedical applications
(2023) Scientific Reports, 13 (1), art. no. 1095, .
Falda, M.a , Atzori, M.a b c , Corbetta, M.a c d
a Neuroscience Department, University of Padova, Padova, Italy
b Institute of Information Systems, University of Applied Sciences Western Switzerland (HES-SO Valais), Sierre, Switzerland
c Padova Neuroscience Center (PNC), Clinica Neurologica, and Venetian Institute of Molecular Medicine, VIMM, Padova, Italy
d Department of Neurology, Radiology, Neuroscience Washington University School of Medicine, St. Louis, MO, United States
Abstract
Several challenges prevent extracting knowledge from biomedical resources, including data heterogeneity and the difficulty to obtain and collaborate on data and annotations by medical doctors. Therefore, flexibility in their representation and interconnection is required; it is also essential to be able to interact easily with such data. In recent years, semantic tools have been developed: semantic wikis are collections of wiki pages that can be annotated with properties and so combine flexibility and expressiveness, two desirable aspects when modeling databases, especially in the dynamic biomedical domain. However, semantics and collaborative analysis of biomedical data is still an unsolved challenge. The aim of this work is to create a tool for easing the design and the setup of semantic databases and to give the possibility to enrich them with biostatistical applications. As a side effect, this will also make them reproducible, fostering their application by other research groups. A command-line software has been developed for creating all structures required by Semantic MediaWiki. Besides, a way to expose statistical analyses as R Shiny applications in the interface is provided, along with a facility to export Prolog predicates for reasoning with external tools. The developed software allowed to create a set of biomedical databases for the Neuroscience Department of the University of Padova in a more automated way. They can be extended with additional qualitative and statistical analyses of data, including for instance regressions, geographical distribution of diseases, and clustering. The software is released as open source-code and published under the GPL-3 license at https://github.com/mfalda/tsv2swm. © 2023, The Author(s).
Funding details
Ministero dell’Istruzione, dell’Università e della Ricerca
Document Type: Article
Publication Stage: Final
Source: Scopus
TRPA1 is involved in the inhibitory effect of Ke-teng-zi on allergic contact dermatitis via MAPK and JAK/STAT3 signaling pathways
(2023) Journal of Ethnopharmacology, 307, art. no. 116182, .
Ju, Y.a , Luo, M.a , Yan, T.a , Zhou, Z.a , Zhang, M.a , Zhao, Z.b c , Liu, X.a , Mei, Z.a d , Xiong, H.a
a School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China
b Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, United States
c Barnes-Jewish Hospital, St Louis, MO 63110, United States
d College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, 430074, China
Abstract
Ethnopharmacological relevance: The seeds of Entada phaseoloides (Linn.) Merr. commonly named “Ke-teng-zi” is a traditional Chinese folk medicine and reported to treat dermatitis, spasm, and headache. However, the exact effect and the mechanism of Ke-teng-zi on the treatment of dermatitis is unclear. Aim of the study: To elucidate the antipruritic effect and molecular mechanisms of Ke-teng-zi on the treatment of allergic contact dermatitis (ACD). Materials and methods: The main components of the n-butanol fraction of 70% ethanol extract from Ke-teng-zi (abbreviated as KB) were analyzed by HPLC. The chloroquine (CQ)-induced acute itch and squaraine dibutyl ester (SADBE)-induced ACD chronic itch in mice was established, and the TNF-α/IFN-γ stimulated Human keratinocytes (HaCaT) were used to evaluate the antipruritic and anti-inflammatory effects of KB. Behavioral tests, lesion scoring, and histology were also examined. The expression levels of molecules in MAPK and JAK/STAT3 pathways, the mRNA levels of chemokines and cytokines in both the skin of ACD mice and the HaCaT cells were detected by western blot and qPCR. Furthermore, whole-cell patch-clamp recordings in TRPA1-tranfected HEK293T cells were used to elucidate the effect of KB on TRPA1 channels. TRPA1 siRNA was used to evaluate the role of TRPA1 in the anti-inflammatory effect of KB in keratinocytes. Results: The main compounds in KB could bind to the active sites of TRPA1 mainly through hydrogen bond and hydrophobic bond interactions. KB could inhibit the scratching behavior in CQ-induced acute itch, and the inhibitory effect of KB was blocked by TRPA1 inhibitor HC-030031. In addition, KB significantly decreased the scratching bouts of ACD mice, reduced the skin lesion scores, mast cells degranulation, and epidermal thickening, inhibited the production of inflammatory chemokines/cytokines and CGRP, and down-regulated the levels of p-ERK1/2, p-p38, and p-STAT3, compared to the ACD mice. Moreover, continuous application of KB induced the desensitization of TRPA1 channels. Also, KB inhibited the expression of p-ERK1/2, p-p38, and p-STAT3, and down-regulated the expression of inflammatory chemokines and cytokines in vitro, which were reversed by the TRPA1 siRNA. Conclusions: KB alleviated the pruritus and skin inflammation in ACD mice through TRPA1 channels desensitization and down-regulation of intracellular MAPK and JAK/STAT3 signaling pathways. Our results suggested that Ke-teng-zi is a potential drug for the treatment of inflammatory skin diseases such as ACD. © 2023 Elsevier B.V.
Author Keywords
Allergic contact dermatitis; Entada phaseoloides (Linn.) Merr.; TRPA1
Funding details
National Key Research and Development Program of China
Hebei Provincial Key Research Projects
Document Type: Article
Publication Stage: Final
Source: Scopus
The Spectrum of Quantitative EEG Utilization Across North America: A Cross-Sectional Survey
(2023) Pediatric Neurology, 141, pp. 1-8.
Benedetti, G.M.a , Morgan, L.A.a , Sansevere, A.J.b , Harrar, D.B.b , Guerriero, R.M.c , Wainwright, M.S.a , LaRovere, K.L.d , Kielian, A.d , Ganesan, S.L.e f , Press, C.A.g , Pediatric Quantitative EEG Strategic Taskforce (PedQuEST)h
a Division of Pediatric Neurology, Department of Neurology, University of Washington School of Medicine, Seattle, WA, United States
b Department of Neurology, Children’s National Hospital and Departments of Neurology and Pediatrics, George Washington University School of Medicine, Washington, District of Columbia, United States
c Division of Pediatric and Developmental Neurology, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States
d Department of Neurology, Harvard Medical School and Boston Children’s Hospital, Boston, Massachusetts, United States
e Paediatric Critical Care Medicine, Children’s Hospital of Western Ontario, London Health Sciences Centre, London, ON, Canada
f Department of Paediatrics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
g Departments of Neurology and Pediatrics, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States
Abstract
Background: Continuous electroencephalography (cEEG) is commonly used for neuromonitoring in pediatric intensive care units (PICU); however, there are barriers to real-time interpretation of EEG data. Quantitative EEG (qEEG) transforms the EEG signal into time-compressed graphs, which can be displayed at the bedside. A survey was designed to understand current PICU qEEG use. Methods: An electronic survey was sent to the Pediatric Neurocritical Care Research Group and Pediatric Status Epilepticus Research Group, and intensivists in 16 Canadian PICUs. Questions addressed demographics, qEEG acquisition and storage, clinical use, and education. Results: Fifty respondents from 39 institutions completed the survey (response rate 53% [39 of 74 institutions]), 76% (37 of 50) from the United States and 24% (12 of 50) from Canada. Over half of the institutions (22 of 39 [56%]) utilize qEEG in their ICUs. qEEG use was associated with having a neurocritical care (NCC) service, ≥200 NCC consults/year, ≥1500 ICU admissions/year, and ≥4 ICU EEGs/day (P < 0.05 for all). Nearly all users (92% [24 of 26]) endorsed that qEEG enhanced care of children with acute neurological injury. Lack of training in qEEG was identified as a common barrier [85% (22 of 26)]. Reviewing and reporting of qEEG was not standard at most institutions. Training was required by 14% (three of 22) of institutions, and 32% (seven of 22) had established curricula. Conclusions: ICU qEEG was used at more than half of the institutions surveyed, but review, reporting, and application of this tool remained highly variable. Although providers identify qEEG as a useful tool in patient management, further studies are needed to define clinically meaningful pediatric trends, standardize reporting, and enhance educate bedside providers. © 2023 Elsevier Inc.
Author Keywords
Continuous EEG; Critical care; Neuromonitoring; Pediatric neurocritical care; Quantitative EEG; Seizure; Spectral analysis
Funding details
National Institutes of Health
National Center for Advancing Translational Sciences
Document Type: Article
Publication Stage: Final
Source: Scopus
Making the invisible visible: Using a qualitative system dynamics model to map disparities in cumulative environmental stressors and children’s neurodevelopment
(2023) Environmental Research, 221, art. no. 115295, .
Payne-Sturges, D.C.a , Ballard, E.b , Cory-Slechta, D.A.c , Thomas, S.B.d , Hovmand, P.e
a Maryland Institute for Applied Environmental Health, University of Maryland School of Public Health, 255 Valley Drive, College Park, MD 20742, United States
b Brown School of Social Work and Director of the Social System Design Lab, Washington University, Campus Box 1196, One Brookings Dr, St. Louis, MO 63130, United States
c University of Rochester School of Medicine, Box EHSC, Rochester, NY 14642, United States
d Department of Health Policy and Management and Director of Maryland Center for Health Equity, University of Maryland School of Public Health, 255 Valley Drive, College Park, MD 20742, United States
e Center for Community Health Integration, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-7136, United States
Abstract
Background: The combined effects of multiple environmental toxicants and social stressor exposures are widely recognized as important public health problems, likely contributing to health inequities. However, US policy makers at state and federal levels typically focus on one stressor exposure at a time and have failed to develop comprehensive strategies to reduce multiple co-occurring exposures, mitigate cumulative risks and prevent harm. This research aimed to move from considering disparate environmental stressors in isolation to mapping the links between environmental, economic, social and health outcomes as a dynamic complex system using children’s exposure to neurodevelopmental toxicants as an illustrative example. Such a model can be used to support a broad range of child developmental and environmental health policy stakeholders in improving their understanding of cumulative effects of multiple chemical, physical, biological and social environmental stressors as a complex system through a collaborative learning process. Methods: We used system dynamics (SD) group model building to develop a qualitative causal theory linking multiple interacting streams of social stressors and environmental neurotoxicants impacting children’s neurodevelopment. A 2 1/2-day interactive system dynamics workshop involving experts across multiple disciplines was convened to develop the model followed by qualitative survey on system insights. Results: The SD causal map covered seven interconnected themes: environmental exposures, social environment, health status, education, employment, housing and advocacy. Potential high leverage intervention points for reducing disparities in children’s cumulative neurotoxicant exposures and effects were identified. Workshop participants developed deeper level of understanding about the complexity of cumulative environmental health risks, increased their agreement about underlying causes, and enhanced their capabilities for integrating diverse forms of knowledge about the complex multi-level problem of cumulative chemical and non-chemical exposures. Conclusion: Group model building using SD can lead to important insights to into the sociological, policy, and institutional mechanisms through which disparities in cumulative impacts are transmitted, resisted, and understood. © 2023
Author Keywords
Chemicals; Cumulative risk; Environmental exposures; Group model building; Neurodevelopment; System dynamics
Funding details
National Institute of Environmental Health Sciences
Document Type: Article
Publication Stage: Final
Source: Scopus
Charge-voltage curves of Shaker potassium channel are not hysteretic at steady state
(2023) The Journal of General Physiology, 155 (3), .
Cowgill, J., Chanda, B.
Departments of Anesthesiology, Neuroscience, Biochemistry and Molecular Biophysics, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Charge-voltage curves of many voltage-gated ion channels exhibit hysteresis but such curves are also a direct measure of free energy of channel gating and, hence, should be path-independent. Here, we identify conditions to measure steady-state charge-voltage curves and show that these are curves are not hysteretic. Charged residues in transmembrane segments of voltage-gated ion channels (VGICs) sense and respond to changes in the electric field. The movement of these gating charges underpins voltage-dependent activation and is also a direct metric of the net free-energy of channel activation. However, for most voltage-gated ion channels, the charge-voltage (Q-V) curves appear to be dependent on initial conditions. For instance, Q-V curves of Shaker potassium channel obtained by hyperpolarizing from 0 mV is left-shifted compared to those obtained by depolarizing from a holding potential of -80 mV. This hysteresis in Q-V curves is a common feature of channels in the VGIC superfamily and raises profound questions about channel energetics because the net free-energy of channel gating is a state function and should be path independent. Due to technical limitations, conventional gating current protocols are limited to test pulse durations of <500 ms, which raises the possibility that the dependence of Q-V on initial conditions reflects a lack of equilibration. Others have suggested that the hysteresis is fundamental thermodynamic property of voltage-gated ion channels and reflects energy dissipation due to measurements under non-equilibrium conditions inherent to rapid voltage jumps (Villalba-Galea. 2017. Channels. https://doi.org/10.1080/19336950.2016.1243190). Using an improved gating current and voltage-clamp fluorometry protocols, we show that the gating hysteresis arising from different initial conditions in Shaker potassium channel is eliminated with ultra-long (18-25 s) test pulses. Our study identifies a modified gating current recording protocol to obtain steady-state Q-V curves of a voltage-gated ion channel. Above all, these findings demonstrate that the gating hysteresis in Shaker channel is a kinetic phenomenon rather than a true thermodynamic property of the channel and the charge-voltage curve is a true measure of the net-free energy of channel gating. © 2023 Cowgill and Chanda.
Document Type: Article
Publication Stage: Final
Source: Scopus
CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity
(2023) Neurology(R) Neuroimmunology & Neuroinflammation, 10 (2), .
Gupta, S., Simic, M., Sagan, S.A., Shepherd, C., Duecker, J., Sobel, R.A., Dandekar, R., Wu, G.F., Wu, W., Pak, J.E., Hauser, S.L., Lim, W., Wilson, M.R., Zamvil, S.S.
From the Department of Neurology (S.G., S.A.S., C.S., R.D., S.L.H., M.R.W., S.S.Z.), Weill Institute for Neurosciences, University of California San Francisco, CA; Department of Cellular Molecular Pharmacology (M.S., J.D., W.L.), University of California San Francisco Cell Design Institute, CA; Veterans Affairs Health Care System (R.A.S.), Department of Pathology, Stanford University School of Medicine, CA; Departments of Neurology and Pathology and Immunology (G.F.W.), Washington University in St. Louis, MO; and Chan Zuckerberg Biohub (W.W., J.E.P.), San Francisco, CA
Abstract
BACKGROUND AND OBJECTIVES: Anti-CD20 monoclonal antibody (mAb) B-cell depletion is a remarkably successful multiple sclerosis (MS) treatment. Chimeric antigen receptor (CAR)-T cells, which target antigens in a non-major histocompatibility complex (MHC)-restricted manner, can penetrate tissues more thoroughly than mAbs. However, a previous study indicated that anti-CD19 CAR-T cells can paradoxically exacerbate experimental autoimmune encephalomyelitis (EAE) disease. We tested anti-CD19 CAR-T cells in a B-cell-dependent EAE model that is responsive to anti-CD20 B-cell depletion similar to the clinical benefit of anti-CD20 mAb treatment in MS. METHODS: Anti-CD19 CAR-T cells or control cells that overexpressed green fluorescent protein were transferred into C57BL/6 mice pretreated with cyclophosphamide (Cy). Mice were immunized with recombinant human (rh) myelin oligodendrocyte protein (MOG), which causes EAE in a B-cell-dependent manner. Mice were evaluated for B-cell depletion, clinical and histologic signs of EAE, and immune modulation. RESULTS: Clinical scores and lymphocyte infiltration were reduced in mice treated with either anti-CD19 CAR-T cells with Cy or control cells with Cy, but not with Cy alone. B-cell depletion was observed in peripheral lymphoid tissue and in the CNS of mice treated with anti-CD19 CAR-T cells with Cy pretreatment. Th1 or Th17 populations did not differ in anti-CD19 CAR-T cell, control cell-treated animals, or Cy alone. DISCUSSION: In contrast to previous data showing that anti-CD19 CAR-T cell treatment exacerbated EAE, we observed that anti-CD19 CAR-T cells ameliorated EAE. In addition, anti-CD19 CAR-T cells thoroughly depleted B cells in peripheral tissues and in the CNS. However, the clinical benefit occurred independently of antigen specificity or B-cell depletion. Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Document Type: Article
Publication Stage: Final
Source: Scopus
Novel LIAS variants in a patient with epilepsy and profound developmental disabilities
(2023) Molecular Genetics and Metabolism, 138 (3), art. no. 107373, .
Wongkittichote, P.a b , Chhay, C.c , Zerafati-Jahromi, G.d , Weisenberg, J.L.d , Mian, A.e , Jensen, L.T.d , Grange, D.K.a
a Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
b Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
c Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
d Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
Abstract
Multiple mitochondrial enzymes employ lipoic acid as a coenzyme. Pathogenic variants in LIAS, encoding lipoic acid synthase (LIAS), are associated with autosomal recessive LIAS-related disorder (OMIM# 614462). This disorder is characterized by infantile-onset hypotonia, profound psychomotor delay, epileptic encephalopathy, nonketotic hyperglycinemia, and lactic acidosis. We present the case of a 20-year-old female who experienced developmental deficits at the age of 6 months and began to have seizures at 3 years of age. Exome sequencing revealed compound heterozygous novel variants in LIAS, designated c.277delC (p.Leu93Ter) and c.542A > T (p.Asp181Val). The p.Leu93Ter variant is predicted to cause loss of function due to the severe truncation of the encoded protein. To examine the p.Asp181Val variant, functional analysis was performed using Baker’s yeast (Saccharomyces cerevisiae) lacking LIP5, the homologue of human LIAS. Wild-type LIAS promoted oxidative growth of the lip5∆ yeast strain. In contrast, lip5∆ yeast expressing p.Asp181Val exhibited poor growth, similar to known pathogenic variants, p.Asp215Glu and p.Met310Thr. Our work has expanded the phenotypic and genotypic spectrum of LIAS-related disorder and established the use of the yeast model as a system for functional study of novel missense variants in LIAS. © 2023 Elsevier Inc.
Author Keywords
Developmental delay; Epilepsy; LIAS-related disorder; Lipoic acid biosynthesis; Mitochondrial disorder; Nonketotic hyperglycinemia
Funding details
Faculty of Science, Mahidol University
Document Type: Article
Publication Stage: Final
Source: Scopus
Characterizing the Pain Experience of Children with Acute Gastroenteritis Based on Identified Pathogens
(2023) Journal of Pediatric Gastroenterology and Nutrition, 76 (2), pp. 160-165.
Ma, K.a , Ali, S.b c , Xie, J.d , Maki, C.b , Lee, B.b c , Chui, L.e f , Pang, X.-L.e f , Zhuo, R.f , Parsons, B.f , Vanderkooi, O.g , Poonai, N.h , Macdonald, S.E.i j , Tarr, P.k , Freedman, S.B.l
a Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Canada
b Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
c Women and Children’s Health Research Institute (WCHRI), Edmonton, Canada
d Section of Pediatric Emergency Medicine, Alberta Children’s Hospital, Cumming School of Medicine, University of Calgary, Calgary, Canada
e Alberta Precision Laboratories-ProvLab, Edmonton, Canada
f Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
g Department of Pediatrics, Microbiology, Immunology and Infectious Diseases, Pathology and Laboratory Medicine and Community Health Sciences, The Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
h Department of Emergency Medicine, Section of Pediatric Emergency Medicine, Schulich School of Medicine and Dentistry, Western University, London, Canada
i Faculty of Nursing, University of Alberta, Edmonton, Canada
j Department of Pediatrics, University of Calgary, Calgary, Canada
k Division of Gastroenterology, Washington University, St. Louis, MO, United States
l Sections of Pediatric Emergency Medicine and Gastroenterology, Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
Abstract
Objectives: Pain is common with acute gastroenteritis (AGE) yet little is known about the severity associated with specific enteropathogens. We sought to explore the correlation of pain severity with specific enteropathogens in children with AGE. Methods: Participants were prospectively recruited by the Alberta Provincial Pediatric EnTeric Infection TEam at 2 pediatric emergency departments (EDs) (December 2014-August 2018). Pain was measured (by child and/or caregiver) using the 11-point Verbal Numerical Rating Scale. Results: We recruited 2686 participants; 46.8% (n = 1256) females, with median age 20.1 months (interquartile range 10.3, 45.3). The mean highest pain scores were 5.5 [standard deviation (SD) 3.0] and 4.2 (SD 2.9) in the 24 hours preceding the ED visit, and in the ED, respectively. Prior to ED visit, the mean highest pain scores with bacterial detection were 6.6 (SD 2.5), compared to 5.5 (SD 2.9) for single virus and 5.5 (SD 3.1) for negative stool tests. In the ED, the mean highest pain scores with bacterial detection were 5.5 (SD 2.7), compared to 4.1 (SD 2.9) for single virus and 4.2 (SD 3.0) for negative stool tests. Using multivariable modeling, factors associated with greater pain severity prior to ED visit included older age, fever, illness duration, number of diarrheal or vomiting episodes in the preceding 24 hours, and respiratory symptoms, but not enteropathogen type. Conclusion: Children with AGE experience significant pain, particularly when the episode is associated with the presence of a bacterial enteric pathogen. However, older age and fever appear to influence children’s pain experiences more than etiologic pathogens. © 2023 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
Emergency department; Enteric infection; Enteric pathogen; Pediatric
Funding details
Women and Children’s Health Research Institute
Alberta Children’s Hospital Research Institute
Alberta Innovates – Health Solutions
Alberta Children’s Hospital Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing
(2023) Nature Genetics, 55 (2), pp. 291-300. .
Chen, F.a , Wang, X.a , Jang, S.-K.b , Quach, B.C.c , Weissenkampen, J.D.d e , Khunsriraksakul, C.f , Yang, L.a , Sauteraud, R.a , Albert, C.M.g h , Allred, N.D.D.i , Arnett, D.K.j , Ashley-Koch, A.E.k l m , Barnes, K.C.n , Barr, R.G.o , Becker, D.M.p , Bielak, L.F.q , Bis, J.C.r , Blangero, J.s t , Boorgula, M.P.n , Chasman, D.I.h u , Chavan, S.n , Chen, Y.-D.I.v , Chuang, L.-M.w , Correa, A.x , Curran, J.E.s t , David, S.P.y z , Fuentes, L.aa , Deka, R.ab , Duggirala, R.s t , Faul, J.D.ac , Garrett, M.E.k l , Gharib, S.A.r ad , Guo, X.v , Hall, M.E.ae , Hawley, N.L.af , He, J.ag , Hobbs, B.D.u ah ai , Hokanson, J.E.aj , Hsiung, C.A.ak , Hwang, S.-J.al am , Hyde, T.M.an ao ap , Irvin, M.R.aq , Jaffe, A.E.an ao ar as , Johnson, E.O.c , Kaplan, R.at au , Kardia, S.L.R.q , Kaufman, J.D.av , Kelly, T.N.ag , Kleinman, J.E.an ao , Kooperberg, C.aw , Lee, I.-T.ax , Levy, D.al , Lutz, S.M.ay , Manichaikul, A.W.az , Martin, L.W.ba , Marx, O.bb , McGarvey, S.T.bc , Minster, R.L.bd , Moll, M.ah ai , Moussa, K.A.be , Naseri, T.bf , North, K.E.bg , Oelsner, E.C.o , Peralta, J.M.s t , Peyser, P.A.q , Psaty, B.M.r bh bi , Rafaels, N.n , Raffield, L.M.bj , Reupena, M.S.bk , Rich, S.S.az , Rotter, J.I.v , Schwartz, D.A.bl , Shadyab, A.H.bm , Sheu, W.H.-H.bn , Sims, M.ae , Smith, J.A.q ac , Sun, X.ag , Taylor, K.D.v , Telen, M.J.l , Watson, H.bo , Weeks, D.E.bd , Weir, D.R.ac , Yanek, L.R.p , Young, K.A.aj , Young, K.L.bg , Zhao, W.q ac , Hancock, D.B.c , Jiang, B.a , Vrieze, S.b , Liu, D.J.a
a Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, United States
b Department of Psychology, University of Minnesota, Minneapolis, MN, United States
c RTI International, Research Triangle, NC, United States
d Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States
e Department of Psychology, Penn State College of Medicine, Hershey, PA, United States
f Deparment of Bioinformatics and Genomics, Penn State College of Medicine, Hershey, PA, United States
g Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
h Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, United States
i Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, United States
j College of Public Health, University of Kentucky, Lexington, KY, United States
k Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States
l Department of Medicine, Duke University Medical Center, Durham, NC, United States
m Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, NC, United States
n Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Center, Aurora, CO, United States
o Department of Medicine, Columbia University Medical Center, New York, NY, United States
p Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
q Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States
r Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, United States
s Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, United States
t South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, United States
u Harvard Medical School, Boston, MA, United States
v Department of Pediatrics, Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
w Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
x Department of Medicine, Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, United States
y University of Chicago, Chicago, IL, United States
z NorthShore University Health System, Evanston, IL, United States
aa Department of Medicine, Division of Biostatistics and Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States
ab Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
ac Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, MI, United States
ad Computational Medicine Core at Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, United States
ae Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States
af Department of Epidemiology (Chronic Disease), School of Public Health, Yale University, New Haven, CT, United States
ag Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States
ah Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
ai Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, United States
aj Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
ak Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
al The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
am The Framingham Heart Study, Framingham, MA, United States
an Lieber Institute for Brain Development, Baltimore, MD, United States
ao Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
ap Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
aq Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States
ar Department of Mental Health and Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
as Department of Human Genetics and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
at Department of Epidemiology and Population Health, Albert Einstein College of Medicine, The Bronx, NY, United States
au Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
av Departments of Environmental & Occupational Health Sciences, Medicine, and Epidemiology, University of Washington Seattle, Seattle, WA, United States
aw Fred Hutchinson Cancer Center, Seattle, WA, United States
ax Department of Internal Medicine, Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taichung, Taiwan
ay Department of Population Medicine, Harvard Pilgrim Health Care, Boston, MA, United States
az Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
ba Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
bb Department of Biomedical Sciences, Penn State College of Medicine, Hershey, PA, United States
bc Department of Epidemiology, International Health Institute, Brown University School of Public Health, Providence, RI, United States
bd Department of Human Genetics and Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, United States
be Penn State Huck Institutes of Life Sciences, Penn State College of Medicine, University Park, PA, United States
bf Ministry of Health, Government of Samoa, Apia, Samoa
bg Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
bh Department of Epidemiology, University of Washington, Seattle, WA, United States
bi Department of Health Systems and Population Health, University of Washington, Seattle, WA, United States
bj Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
bk Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa
bl Department of Medicine, University of Colorado, Aurora, CO, United States
bm Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La JollaCA, United States
bn Taipei Veterans General Hospital, Taipei, Taiwan
bo Faculty of Medical Sciences, University of the West Indies, Cave Hill Campus, Barbados
Abstract
Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction. © 2023, The Author(s).
Funding details
National Institutes of Health
U.S. Department of Health and Human Services
National Heart, Lung, and Blood Institute
Document Type: Article
Publication Stage: Final
Source: Scopus
Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein
(2023) Nature Neuroscience, 26 (2), pp. 213-225.
Zhang, S.a , Zhu, R.a , Pan, B.b , Xu, H.c , Olufemi, M.F.c , Gathagan, R.J.c , Li, Y.a d e , Zhang, L.a , Zhang, J.a , Xiang, W.a , Kagan, E.M.a , Cao, X.f , Yuan, C.g , Kim, S.-J.c , Williams, C.K.h , Magaki, S.h , Vinters, H.V.i , Lashuel, H.A.j , Garcia, B.A.k , James Petersson, E.b , Trojanowski, J.Q.c , Lee, V.M.-Y.c , Peng, C.a l m n
a Department of Neurology, David Geffen School of Medicine, University of California—Los Angeles, Los Angeles, CA, United States
b Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, United States
c The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
d Institute for Cognitive Neurodynamics, East China University of Science and Technology, Shanghai, China
e School of Mathematics, East China University of Science and Technology, Shanghai, China
f Innovent Biologics, Inc., Suzhou, China
g Alexion Pharmaceuticals, Inc., New Haven, CT, United States
h Section of Neuropathology, Department of Pathology and Laboratory Medicine, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, University of California—Los Angeles, Los Angeles, CA, United States
i Section of Neuropathology, Department of Pathology and Laboratory Medicine, Department of Neurology, and Brain Research Institute, Ronald Reagan UCLA Medical Center and David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA, United States
j Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland
k Department of Biochemistry and Molecular Biophysics, Washington University St Louis, St Louis, MO, United States
l Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, United States
m Brain Research Institute, University of California, Los Angeles, 90095, Los Angeles, CA, United States
n Mary S. Easton Center for Alzheimer’s Research, University of California, Los Angeles, Los Angeles, CA 90095, United States
Abstract
Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinsonʼs disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC–MS/MS analyses on soluble α-Syn purified from Parkinsonʼs disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
National Institutes of Health
National Institute on Aging
National Institute of Neurological Disorders and Stroke
Children’s Hospital of Philadelphia
CurePSP
Microscopy Society of America
Document Type: Article
Publication Stage: Final
Source: Scopus
Radiation-induced circulating myeloid-derived suppressor cells induce systemic lymphopenia after chemoradiotherapy in patients with glioblastoma
(2023) Science Translational Medicine, 15 (680), p. eabn6758.
Ghosh, S.a , Huang, J.a b , Inkman, M.a , Zhang, J.a b , Thotala, S.a , Tikhonova, E.c , Miheecheva, N.c , Frenkel, F.c , Ataullakhanov, R.c , Wang, X.a , DeNardo, D.b d , Hallahan, D.a b , Thotala, D.a b
a Department of Radiation Oncology, Washington University School of MedicineMO, United States
b Siteman Cancer Center, Washington University School of MedicineMO, United States
c Waltham, MA, United States
d Department of Medicine, Washington University School of MedicineMO, United States
Abstract
Severe and prolonged lymphopenia frequently occurs in patients with glioblastoma after standard chemoradiotherapy and has been associated with worse survival, but its underlying biological mechanism is not well understood. To address this, we performed a correlative study in which we collected and analyzed peripheral blood of patients with glioblastoma (n = 20) receiving chemoradiotherapy using genomic and immune monitoring technologies. RNA sequencing analysis of the peripheral blood mononuclear cells (PBMC) showed an elevated concentration of myeloid-derived suppressor cell (MDSC) regulatory genes in patients with lymphopenia when compared with patients without lymphopenia after chemoradiotherapy. Additional analysis including flow cytometry and single-cell RNA sequencing further confirmed increased numbers of circulating MDSC in patients with lymphopenia when compared with patients without lymphopenia after chemoradiotherapy. Preclinical murine models were also established and demonstrated a causal relationship between radiation-induced MDSC and systemic lymphopenia using transfusion and depletion experiments. Pharmacological inhibition of MDSC using an arginase-1 inhibitor (CB1158) or phosphodiesterase-5 inhibitor (tadalafil) during radiation therapy (RT) successfully abrogated radiation-induced lymphopenia and improved survival in the preclinical models. CB1158 and tadalafil are promising drugs in reducing radiation-induced lymphopenia in patients with glioblastoma. These results demonstrate the promise of using these classes of drugs to reduce treatment-related lymphopenia and immunosuppression.
Document Type: Article
Publication Stage: Final
Source: Scopus
Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination with Extension of Survival among Patients with Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial
(2023) JAMA Oncology, 9 (1), pp. 112-121. Cited 4 times.
Liau, L.M.a , Ashkan, K.b , Brem, S.c , Campian, J.L.d , Trusheim, J.E.e , Iwamoto, F.M.f g , Tran, D.D.h , Ansstas, G.i , Cobbs, C.S.j , Heth, J.A.k , Salacz, M.E.l , D’Andre, S.m , Aiken, R.D.n , Moshel, Y.A.n , Nam, J.Y.o , Pillainayagam, C.P.p , Wagner, S.A.q , Walter, K.A.r , Chaudhary, R.s , Goldlust, S.A.t , Lee, I.Y.u , Bota, D.A.v , Elinzano, H.w , Grewal, J.x , Lillehei, K.y , Mikkelsen, T.u , Walbert, T.u , Abram, S.z , Brenner, A.J.aa , Ewend, M.G.ab , Khagi, S.ac , Lovick, D.S.ad , Portnow, J.ae , Kim, L.af , Loudon, W.G.ag , Martinez, N.L.ah , Thompson, R.C.ai , Avigan, D.E.aj , Fink, K.L.ak , Geoffroy, F.J.al , Giglio, P.am , Gligich, O.an , Krex, D.ao , Lindhorst, S.M.ap , Lutzky, J.aq , Meisel, H.-J.ar , Nadji-Ohl, M.as , Sanchin, L.ar , Sloan, A.at , Taylor, L.P.au , Wu, J.K.au , Dunbar, E.M.av , Etame, A.B.aw , Kesari, S.ax , Mathieu, D.ay , Piccioni, D.E.az , Baskin, D.S.ba , Lacroix, M.bb , May, S.-A.bc , New, P.Z.bd , Pluard, T.J.be , Toms, S.A.bf , Tse, V.bg , Peak, S.bg , Villano, J.L.bh , Battiste, J.D.bi , Mulholland, P.J.bj , Pearlman, M.L.bk , Petrecca, K.bl , Schulder, M.bm , Prins, R.M.bn , Boynton, A.L.bo , Bosch, M.L.bo
a Department of Neurosurgery, University of California, Los Angeles, United States
b King’s College Hospital, London, United Kingdom
c Department of Neurosurgery, Penn Brain Tumor Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
d Division of Neurology, Washington University, School of Medicine in St Louis, St Louis, MO, United States
e Givens Brain Tumor Center, Abbott Northwestern Hospital, Minneapolis, MN, United States
f Columbia University, Irving Medical Center, New York, NY, United States
g New York-Presbyterian Hospital, New York, NY, United States
h Preston A. Wells, Jr. Center for Brain Tumor Therapy, Division of Neuro-Oncology, Lillian S. Wells Department of Neurosurgery, University of Florida, College of Medicine, Gainesville, United States
i Department of Neurological Surgery, Washington University, School of Medicine in St Louis, St Louis, MO, United States
j Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Medical Center, Seattle, WA, United States
k Taubman Medical Center, University of Michigan, Ann Arbor, United States
l Neuro-Oncology Program, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
m Sutter Health, Sacramento, CA, United States
n Glasser Brain Tumor Center, Atlantic Healthcare, Summit, NJ, United States
o Department of Neurological Sciences, Rush Medical College, Chicago, IL, United States
p Department of Neurology, The Ohio State University, Columbus, United States
q The Cancer Center, Columbus Regional Health, Columbus, IN, United States
r University of Rochester, Rochester, NY, United States
s University of Cincinnati, Cincinnati, OH, United States
t John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, United States
u Department of Neurosurgery, Henry Ford Health System, Detroit, MI, United States
v Department of Neurology, Chao Family Comprehensive Cancer Center, University of California, Irvine, United States
w Rhode Island Hospital, Providence, United States
x Long Island Brain Tumor Center, NSPC, Lake Success, NY, United States
y Department of Neurosurgery, University of Colorado, Health Sciences Center, Boulder, United States
z Ascension St Thomas Brain and Spine Tumor Center, Howell Allen Clinic, Nashville, TN, United States
aa Mays Cancer Center, UT Health San Antonio, San Antonio, TX, United States
ab Department of Neurosurgery, UNC School of Medicine, UNC Health, Chapel Hill, NC, United States
ac The Geisel School of Medicine, Dartmouth, Hanover, NH, United States
ad Advent Health, Kansas City, KS, United States
ae Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA, United States
af Division of Neuro-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ag Saint Joseph’s Hospital, Orange, CA, United States
ah Jefferson Hospital for Neurosciences, Jefferson University, Philadelphia, PA, United States
ai Department of Neurological Surgery, Vanderbilt University, Medical Center, Nashville, TN, United States
aj Beth Israel Deaconess Medical Center, Harvard Medical School, Cambridge, MA, United States
ak Baylor Scott & White Neuro-Oncology Associates, Dallas, TX, United States
al Illinois Cancer Care, Galesburg, Peoria, United States
am Medical University of South Carolina Neurosciences, Charleston, United States
an Mount Sinai Medical Center, Miami Beach, FL, United States
ao Uniklinikum Dresden, Dresden, Germany
ap Hollings Cancer Center, Medical University of South Carolina, Charleston, United States
aq Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
ar BG Klinikum Bergmannstrost, Halle, Germany
as Neurochirurgie Katharinenhospital, Klinikum der Landeshauptstadt Stuttgart, Stuttgart, Germany
at Seidman Cancer Center, University Hospitals-Cleveland Medical Center, Cleveland, OH, United States
au Department of Neurosurgery, Tufts Medical Center, Boston, MA, United States
av Piedmont Physicians Neuro-Oncology, Piedmont Brain Tumor Center, Atlanta, GA, United States
aw Department of Neuro-Oncology, Moffitt Cancer Center, United States
ax Pacific Neurosciences Institute, Saint John’s Cancer Institute, Santa Monica, CA, United States
ay Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC, Canada
az UC San Diego Moore’s Cancer Center, San Diego, CA, United States
ba Department of Neurosurgery, Houston Methodist Hospital, Houston, TX, United States
bb Geisinger Neuroscience Institute, Danville, PA, United States
bc Klinik für Neurochirurgie, Chemnitz, Germany
bd Baptist Health System, San Antonio, Texas, United States
be Saint Luke’s Cancer Institute, Kansas City, MO, United States
bf Departments of Neurosurgery and Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, United States
bg Kaiser Permanente, Redwood City, CA, United States
bh University of Kentucky Markey Cancer Center, Department of Medicine, Neurosurgery, and Neurology, University of Kentucky, Lexington, United States
bi Oklahoma University, Health Science Center, Oklahoma City, United States
bj University College London Hospitals, London, United Kingdom
bk Blue Sky Neurology/Neuro-Oncology, Inglewood, CA, United States
bl Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada
bm Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Uniondale, NY, United States
bn University of California, Los Angeles, United States
bo Northwest Biotherapeutics Inc, Bethesda, MD, United States
Abstract
Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P =.002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P <.001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P =.03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968. © 2023 American Medical Association. All rights reserved.
Funding details
Northwest Biotherapeutics
Document Type: Article
Publication Stage: Final
Source: Scopus
On-device synaptic memory consolidation using Fowler-Nordheim quantum-tunneling
(2023) Frontiers in Neuroscience, 16, art. no. 1050585, .
Rahman, M., Bose, S., Chakrabartty, S.
Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Introduction: For artificial synapses whose strengths are assumed to be bounded and can only be updated with finite precision, achieving optimal memory consolidation using primitives from classical physics leads to synaptic models that are too complex to be scaled in-silico. Here we report that a relatively simple differential device that operates using the physics of Fowler-Nordheim (FN) quantum-mechanical tunneling can achieve tunable memory consolidation characteristics with different plasticity-stability trade-offs. Methods: A prototype FN-synapse array was fabricated in a standard silicon process and was used to verify the optimal memory consolidation characteristics and used for estimating the parameters of an FN-synapse analytical model. The analytical model was then used for large-scale memory consolidation and continual learning experiments. Results: We show that compared to other physical implementations of synapses for memory consolidation, the operation of the FN-synapse is near-optimal in terms of the synaptic lifetime and the consolidation properties. We also demonstrate that a network comprising FN-synapses outperforms a comparable elastic weight consolidation (EWC) network for some benchmark continual learning tasks. Discussions: With an energy footprint of femtojoules per synaptic update, we believe that the proposed FN-synapse provides an ultra-energy-efficient approach for implementing both synaptic memory consolidation and continual learning on a physical device. Copyright © 2023 Rahman, Bose and Chakrabartty.
Author Keywords
continual learning; hardware synapse; memory consolidation; neuromorphic; quantum-tunneling
Funding details
National Science Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
Resting state network mapping in individuals using deep learning
(2023) Frontiers in Neurology, 13, art. no. 1055437, .
Luckett, P.H.a , Lee, J.J.b , Park, K.Y.a , Raut, R.V.c d , Meeker, K.L.e , Gordon, E.M.e , Snyder, A.Z.b e , Ances, B.M.e , Leuthardt, E.C.a f g h i j k , Shimony, J.S.b
a Division of Neurotechnology, Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Physiology and Biophysics, University of Washington, Seattle, WA, United States
d MindScope Program, Allen Institute, Seattle, WA, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
h Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States
i Center for Innovation in Neuroscience and Technology, Division of Neurotechnology, Washington University School of Medicine, St. Louis, MO, United States
j Brain Laser Center, Washington University School of Medicine, St. Louis, MO, United States
k National Center for Adaptive Neurotechnologies, Albany, NY, United States
Abstract
Introduction: Resting state functional MRI (RS-fMRI) is currently used in numerous clinical and research settings. The localization of resting state networks (RSNs) has been utilized in applications ranging from group analysis of neurodegenerative diseases to individual network mapping for pre-surgical planning of tumor resections. Reproducibility of these results has been shown to require a substantial amount of high-quality data, which is not often available in clinical or research settings. Methods: In this work, we report voxelwise mapping of a standard set of RSNs using a novel deep 3D convolutional neural network (3DCNN). The 3DCNN was trained on publicly available functional MRI data acquired in n = 2010 healthy participants. After training, maps that represent the probability of a voxel belonging to a particular RSN were generated for each participant, and then used to calculate mean and standard deviation (STD) probability maps, which are made publicly available. Further, we compared our results to previously published resting state and task-based functional mappings. Results: Our results indicate this method can be applied in individual subjects and is highly resistant to both noisy data and fewer RS-fMRI time points than are typically acquired. Further, our results show core regions within each network that exhibit high average probability and low STD. Discussion: The 3DCNN algorithm can generate individual RSN localization maps, which are necessary for clinical applications. The similarity between 3DCNN mapping results and task-based fMRI responses supports the association of specific functional tasks with RSNs. Copyright © 2023 Luckett, Lee, Park, Raut, Meeker, Gordon, Snyder, Ances, Leuthardt and Shimony.
Author Keywords
brain mapping; deep learning; machine learning; representation of function; resting state functional MRI
Funding details
National Institutes of Health
Document Type: Article
Publication Stage: Final
Source: Scopus
SIK3 and Wnk converge on Fray to regulate glial K+ buffering and seizure susceptibility
(2023) PLoS Genetics, 19 (1), art. no. e1010581, .
Lones, L.a , DiAntonio, A.a b
a Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
b Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
Glial cells play a critical role in maintaining homeostatic ion concentration gradients. Salt-inducible kinase 3 (SIK3) regulates a gene expression program that controls K+ buffering in glia, and upregulation of this pathway suppresses seizure behavior in the eag, Shaker hyperexcitability mutant. Here we show that boosting the glial SIK3 K+ buffering pathway suppresses seizures in three additional molecularly diverse hyperexcitable mutants, highlighting the therapeutic potential of upregulating glial K+ buffering. We then explore additional mechanisms regulating glial K+ buffering. Fray, a transcriptional target of the SIK3 K+ buffering program, is a kinase that promotes K+ uptake by activating the Na+/K+/Cl- co-transporter, Ncc69. We show that the Wnk kinase phosphorylates Fray in Drosophila glia and that this activity is required to promote K+ buffering. This identifies Fray as a convergence point between the SIK3-dependent transcriptional program and Wnk-dependent post-translational regulation. Bypassing both regulatory mechanisms via overexpression of a constitutively active Fray in glia is sufficient to robustly suppress seizure behavior in multiple Drosophila models of hyperexcitability. Finally, we identify cortex glia as a critical cell type for regulation of seizure susceptibility, as boosting K+ buffering via expression of activated Fray exclusively in these cells is sufficient to suppress seizure behavior. These findings highlight Fray as a key convergence point for distinct K+ buffering regulatory mechanisms and cortex glia as an important locus for control of neuronal excitability. Copyright: © 2023 Lones, DiAntonio. 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 details
National Institutes of Health
Document Type: Article
Publication Stage: Final
Source: Scopus
Polygenic Risk for Schizophrenia, Major Depression, and Post-traumatic Stress Disorder and Hippocampal Subregion Volumes in Middle Childhood
(2023) Behavior Genetics, .
Pine, J.G.a , Paul, S.E.a , Johnson, E.b , Bogdan, R.a , Kandala, S.b , Barch, D.M.a b c
a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Studies demonstrate that individuals with diagnoses for Major Depressive Disorder (MDD), Post-traumatic Stress Disorder (PTSD), and Schizophrenia (SCZ) may exhibit smaller hippocampal gray matter relative to otherwise healthy controls, although the effect sizes vary in each disorder. Existing work suggests that hippocampal abnormalities in each disorder may be attributable to genetic liability and/or environmental variables. The following study uses baseline data from the Adolescent Brain and Cognitive DevelopmentSM Study (ABCD Study®) to address three open questions regarding the relationship between genetic risk for each disorder and hippocampal volume reductions: (a) whether polygenic risk scores (PGRS) for MDD, PTSD, and SCZ are related to hippocampal volume; (b) whether PGRS for MDD, PTSD, and SCZ are differentially related to specific hippocampal subregions along the longitudinal axis; and (c) whether the association between PGRS for MDD, PTSD, and SCZ and hippocampal volume is moderated by sex and/or environmental adversity. In short, we did not find associations between PGRS for MDD, PTSD, and SCZ to be significantly related to any hippocampal subregion volumes. Furthermore, neither sex nor environmental adversity significantly moderated these associations. Our study provides an important null finding on the relationship genetic risk for MDD, PTSD, and SCZ to measures of hippocampal volume. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Depression; Hippocampus; Postraumatic-stress disorder; Schizophrenia
Funding details
National Institutes of Health
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Evaluation of rAAVrh74 gene therapy vector seroprevalence by measurement of total binding antibodies in patients with Duchenne muscular dystrophy
(2023) Therapeutic Advances in Neurological Disorders, 16, .
Goedeker, N.L.a , Dharia, S.D.b , Griffin, D.A.b , Coy, J.b , Truesdale, T.b , Parikh, R.b , Whitehouse, K.b , Santra, S.b , Asher, D.R.b , Zaidman, C.M.c
a Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8111, St. Louis, MO 63110, United States
b Sarepta Therapeutics, Inc, Cambridge, MA, United States
c Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Adeno-associated virus (AAV) vectors are a promising platform for in vivo transfer of transgenes designed to treat diseases. Pre-existing humoral immunity to these vectors can potentially impact the safety and efficacy of gene therapies. Consequently, individuals with pre-existing antibodies to the specific AAV serotypes used may be excluded from clinical trials and treatments. Recombinant AAV serotype rh74 (rAAVrh74), a vector originally isolated from rhesus monkeys and potentially less immunogenic than other serotypes isolated from humans (e.g. AAV2, AAV5, and AAV9), efficiently transduces muscle and is being investigated for use in gene therapy for Duchenne muscular dystrophy (DMD). Objective: To evaluate prevalence of total binding antibodies (neutralizing and non-neutralizing) against rAAVrh74 in patients with DMD. Methods: Eligible individuals (N = 107) were ⩾ 4 to < 18 years old with genetically confirmed DMD and were excluded from the study if they lived with a person who had known exposure to rAAVrh74 or other gene transfer therapy, or if they received prior treatment with gene transfer therapy. A single blood sample was obtained from each participant, and anti-rAAVrh74 total binding antibodies were measured by enzyme-linked immunosorbent assay. Total binding antibody level < 1:400 was defined as not elevated or seronegative. Primary endpoint was the percentage of subjects with elevated total antibody titers to rAAVrh74. Results: A large preponderance (86.1%) of patients with DMD in this data set was seronegative for anti-rAAVrh74 total binding antibodies. These patients would potentially meet the antibody status eligibility criterion for entry into rAAVrh74-based gene therapy clinical trials. Conclusion: Measuring total binding antibodies is a more comprehensive approach to assess pre-existing immune response versus measuring neutralizing antibodies alone. The low seroprevalence of total binding antibodies against rAAVrh74 shown here supports the broad applicability of rAAVrh74-based gene transfer therapy for patients with DMD and potentially other neuromuscular diseases. © The Author(s), 2023.
Author Keywords
AAVrh74; antibodies; Duchenne muscular dystrophy; gene transfer therapy; immunity; rAAVrh74
Funding details
Sarepta Therapeutics
Document Type: Article
Publication Stage: Final
Source: Scopus
Moderators and Mediators of a Digital Cognitive Behavior Therapy-Guided Self-Help Intervention for Eating Disorders: Informing Future Design Efforts
(2023) Journal of Consulting and Clinical Psychology, .
Graham, A.K.a , Fitzsimmons-Craft, E.E.b , Sadeh-Sharvit, S.c , Balantekin, K.N.d , Eichen, D.M.e , Firebaugh, M.-L.b , Goel, N.J.f , Monterubio, G.E.b , Karam, A.M.b , Flatt, R.E.g , Jo, B.h , Jacobi, C.i , Wilfley, D.E.b , Taylor, C.B.c i , Trockel, M.h
a Center for Behavioral Intervention Technologies, Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, United States
b Department of Psychiatry, Washington University School of Medicine, United States
c Center for m2Health, Palo Alto University, United States
d Department of Exercise and Nutrition Sciences, University at Buffalo, United States
e Department of Pediatrics, University of California, San Diego, United States
f Department of Psychology, Virginia Commonwealth University, United States
g Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, United States
h Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States
i Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Germany
Abstract
Objective: The Student Bodies-Eating Disorders intervention (SB-ED), a digital cognitive behavior therapy-guided self-help intervention for college women with an eating disorder, is effective for reducing eating disorder psychopathology. The purpose of this study was to evaluate moderators and mediators of the SB-ED intervention. To our knowledge, this is the first evaluation of clinical mediators of a digital intervention for women with eating disorders. Method: This is an exploratory secondary analysis of a cluster randomized trial comparing the SB-ED intervention to referral to usual care among 690 women at 27 United States colleges. Moderators included body mass index (BMI), race, ethnicity, weight/shape concerns, eating disorder impairment, thin ideal internalization, depression, anxiety, and motivation for treatment, assessed at baseline. Thin ideal internalization and depressive symptoms were tested as predictors at postintervention and mediators at 2-year follow-up. Outcome was change in global eating disorder psychopathology. Results: BMI moderated the effect of the intervention at follow-up (but not posttreatment), with individuals with a lower BMI experiencing more continued improvements in eating disorder psychopathology following the intervention than individuals with a higher BMI. Thin ideal internalization mediated the effect of the intervention at follow-up, and depression partially mediated the effect of the intervention at follow-up. Conclusions: Results of the mediator analyses suggest that helping college women reduce inflated internalization of the thin ideal and improve depressive symptoms leads to improvements in eating disorder psychopathology. Results also suggest opportunities to optimize the intervention so individuals across the BMI spectrum experience ongoing improvements over time © 2023 American Psychological Association
Author Keywords
Digital mental health intervention; Eating disorders; Guided self-help; Mediators; Moderators
Funding details
National Science Foundation
National Institute of Mental Health
National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases
National Center on Minority Health and Health Disparities
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Ageing among Black and non-Hispanic White older adults: A community-based system dynamics approach to examining quality of life
(2023) Systems Research and Behavioral Science, .
Trani, J.-F.a b , Giesecke, M.a , Hovmand, P.c , Miller, N.d , Cartmill, M.K.a , Mandujano Acevedo, N.a , Lee, S.a , Liem, W.e , Gillani, B.f , Babulal, G.g
a Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States
b National Center of Arts and Crafts, Paris, France
c Center for Community Health Integration, School of Medicine Case Western Reserve University, Cleveland, OH, United States
d Anthropology Department, Washington University in St. Louis, St. Louis, MO, United States
e Feinberg School of Medicine, Northwestern University, Evanston, IL, United States
f Jack, Joseph and Morton Mandel School of Applied Social Sciences within Case Western Reserve University, Cleveland, OH, United States
g Department of Neurology and Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Older adults are living longer in the United States and the proportion of those belonging to minoritized groups is growing. The value and characteristics of quality of life (QoL) at an older age have becoming of central concern to policy makers. To investigate the wicked problem of ageing and QoL, we conducted and compared two group model building workshops in St. Louis City, one with 16 White and another with 10 Black American older adults, age 65 and older. Group model building workshops involve communities in the identification and testing of shared solutions to pressing and complex problems. Findings demonstrated that racial disparities in terms of material and environmental resources represent significant barriers to QoL for both Black and White participants. Results underscore the need to address social determinants of health that impede healthy ageing and damage well-being and QoL of older adults. © 2023 John Wiley & Sons Ltd.
Author Keywords
ageing; community-based system dynamics; group model building; quality of life; racial disparities
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations of parent–adolescent closeness with P3 amplitude, frontal theta, and binge drinking among offspring with high risk for alcohol use disorder
(2023) Alcoholism: Clinical and Experimental Research, .
Pandey, G.a , Kuo, S.I.-C.b , Horne-Osipenko, K.A.a , Pandey, A.K.a , Kamarajan, C.a , de Viteri, S.S.a , Kinreich, S.a , Chorlian, D.B.a , Kuang, W.a , Stephenson, M.b , Kramer, J.c , Anokhin, A.d , Zang, Y.e , Kuperman, S.f , Hesselbrock, V.g , Schuckit, M.h , Dick, D.b , Chan, G.g , McCutcheon, V.V.d , Edenberg, H.i , Bucholz, K.K.d , Meyers, J.L.a , Porjesz, B.a
a Department of Psychiatry and Behavioral Sciences, State University of New York, Downstate Health Sciences University, Brooklyn, NY, United States
b Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
c Department of Psychiatry, University of Iowa, Iowa City, IA, United States
d Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Department of Biostatistics, School of Medicine, Indiana University, Indianapolis, IN, United States
f Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
g Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
h Department of Psychiatry, University of California San Diego, La JollaCA, United States
i Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
Abstract
Background: Parents impact their offspring’s brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring. Methods: Self-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task. Results: Multivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father’s and mothers’ AUD symptoms, socioeconomic status, and offspring impulsivity in the model. Conclusions: Among high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences. © 2023 Research Society on Alcohol.
Author Keywords
alcohol use disorder; frontal theta; P3 amplitude; parent–adolescent closeness
Funding details
National Institute on Alcohol Abuse and Alcoholism
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Efficient Training on Alzheimer’s Disease Diagnosis with Learnable Weighted Pooling for 3D PET Brain Image Classification
(2023) Electronics (Switzerland), 12 (2), art. no. 467, .
Xing, X.a b , Rafique, M.U.c , Liang, G.d , Blanton, H.a , Zhang, Y.a , Wang, C.e , Jacobs, N.f , Lin, A.-L.b g h
a Department of Computer Science, University of Kentucky, Lexington, KY 40506, United States
b Department of Radiology, University of Missouri, Columbia, MO 65212, United States
c Kitware Inc, Clifton Park, NY 12065, United States
d Department of Computing and Cyber Security, Texas A & M University-San Antonio, San Antonio, TX 78224, United States
e Department of Computer Science, University of Missouri, Columbia, MO 65211, United States
f Department of Computer Science & Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
g Department of Biological Sciences, University of Missouri, Columbia, MO 65211, United States
h Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65211, United States
Abstract
Three-dimensional convolutional neural networks (3D CNNs) have been widely applied to analyze Alzheimer’s disease (AD) brain images for a better understanding of the disease progress or predicting the conversion from cognitively impaired (CU) or mild cognitive impairment status. It is well-known that training 3D-CNN is computationally expensive and with the potential of overfitting due to the small sample size available in the medical imaging field. Here we proposed a novel 3D-2D approach by converting a 3D brain image to a 2D fused image using a Learnable Weighted Pooling (LWP) method to improve efficient training and maintain comparable model performance. By the 3D-to-2D conversion, the proposed model can easily forward the fused 2D image through a pre-trained 2D model while achieving better performance over different 3D and 2D baselines. In the implementation, we chose to use ResNet34 for feature extraction as it outperformed other 2D CNN backbones. We further showed that the weights of the slices are location-dependent and the model performance relies on the 3D-to-2D fusion view, with the best outcomes from the coronal view. With the new approach, we were able to reduce 75% of the training time and increase the accuracy to 0.88, compared with conventional 3D CNNs, for classifying amyloid-beta PET imaging from the AD patients from the CU participants using the publicly available Alzheimer’s Disease Neuroimaging Initiative dataset. The novel 3D-2D model may have profound implications for timely AD diagnosis in clinical settings in the future. © 2023 by the authors.
Author Keywords
3D-to-2D module; Alzheimer’s disease; deep learning; efficient training
Funding details
National Institutes of Health
U.S. Department of Defense
National Institute on Aging
National Institute of Biomedical Imaging and Bioengineering
Alzheimer’s Disease Neuroimaging Initiative
Document Type: Article
Publication Stage: Final
Source: Scopus
Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age
(2023) Biology, 12 (1), art. no. 33, . Cited 1 time.
Jiménez-Balado, J.a , Giralt-Steinhauer, E.a , Fernández-Pérez, I.a , Rey, L.a , Cuadrado-Godia, E.a b , Ois, Á.a b , Rodríguez-Campello, A.a b , Soriano-Tárraga, C.c , Lazcano, U.d , Macias-Gómez, A.a , Suárez-Pérez, A.a , Revert, A.a , Estragués, I.a , Beltrán-Mármol, B.e , Medrano-Martorell, S.e , Capellades, J.e , Roquer, J.a b , Jiménez-Conde, J.a b
a Neurovascular Research Group, Department of Neurology, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, 08003, Spain
b Medicine Department, DCEXS-Universitat Pompeu Fabra (UPF), Barcelona, 08002, Spain
c Department of Psychiatry, NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Unidad de Investigación AP-OSIs, Donostia, 20014, Spain
e Radiology Department, Neuroradiology Unit, Hospital del Mar, Barcelona, 08003, Spain
Abstract
In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively high median WMH volume (median = 8.8 cm3, Q1–Q3 = 4.05–18.8). After adjusting for potential confounders, we observed a significant effect of B-ageHannum on WMH volume (βHannum = 0.023, p-value = 0.029) independently of C-age, which remained significant (βC-age = 0.021, p-value = 0.036). Finally, we performed a mediation analysis, which allowed us to discover that 42.7% of the effect of C-age on WMH is mediated by B-ageHannum. On the other hand, B-ageHoarvath showed no significant associations with WMH after being adjusted for C-age. In conclusion, we show for the first time that biological age, measured through DNA methylation, contributes substantially to explain WMH volumetric burden irrespective of chronological age. © 2022 by the authors.
Author Keywords
biological age; cerebral small vessel disease; DNA methylation; epigenetic clock; epigenetics; white matter hyperintensities
Funding details
Instituto de Salud Carlos III
Ministerio de Ciencia e Innovación
Document Type: Article
Publication Stage: Final
Source: Scopus
Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia
(2023) Nature Immunology, .
Zhou, Y.a , Tada, M.b , Cai, Z.a , Andhey, P.S.a , Swain, A.a , Miller, K.R.c f , Gilfillan, S.a , Artyomov, M.N.a , Takao, M.d e , Kakita, A.b , Colonna, M.a
a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
c 10x Genomics, Pleasanton, CA, United States
d Department of Clinical Laboratory and Internal Medicine, National Center of Neurology and Psychiatry (NCNP), National Center Hospital, Tokyo, Japan
e Department of Brain Bank, Mihara Memorial Hospital, Isesaki, Japan
f Deepcell, Menlo Park, CA, United States
Abstract
The TREM2–DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer’s disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu–Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways. © 2023, Springer Nature America, Inc.
Funding details
National Institutes of Health
Japan Agency for Medical Research and Development
Niigata University
Japan Society for the Promotion of Science
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Characterizing Alcohol Expectancies in the ABCD Study: Associations with Sociodemographic Factors, the Immediate Social Environment, and Genetic Propensities
(2023) Behavior Genetics, .
Johnson, E.C.a , Paul, S.E.b , Baranger, D.A.A.b , Hatoum, A.S.a b b , Colbert, S.M.C.a , Lin, S.b , Wolff, R.b , Gorelik, A.J.b , Hansen, I.b , Karcher, N.R.a , Bogdan, R.b , Agrawal, A.a
a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, CB 8134, St. Louis, MO 63110, United States
b Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, United States
Abstract
Alcohol expectancies (AEs) are associated with likelihood of alcohol initiation and subsequent alcohol use disorders. It is unclear whether genetic predisposition to alcohol use and/or related traits contributes to shaping how one expects to feel when drinking alcohol. We used the Adolescent Brain Cognitive Development study to examine associations between genetic propensities (i.e., polygenic risk for problematic alcohol use, depression, risk-taking), sociodemographic factors (i.e., parent income), and the immediate social environment (i.e., peer use and disapproval toward alcohol) and positive and negative AEs in alcohol-naïve children (max analytic N = 5,352). Mixed-effect regression models showed that age, parental education, importance of the child’s religious beliefs, adverse childhood experiences, and peer disapproval of alcohol use were associated with positive and/or negative AEs, to varying degrees. Overall, our results suggest several familial and psychosocial predictors of AEs but little evidence of contributions from polygenic liability to problematic alcohol use or related phenotypes. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Adverse childhood experiences; Alcohol expectancies; Educational attainment; Peer deviance; Polygenic risk scores; Religiosity
Funding details
National Institutes of Health
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Multiple sessions of therapeutic electrical stimulation using implantable thin-film wireless nerve stimulators improve functional recovery after sciatic nerve isograft repair
(2022) Muscle and Nerve, .
Birenbaum, N.K.a , Yan, Y.b , Odabas, A.b , Chandra, N.S.a , Ray, W.Z.b , MacEwan, M.R.b
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Introduction/Aims: Although therapeutic electrical stimulation (TES) of injured peripheral nerve promotes axon regeneration and functional recovery, clinical applications of this therapy are limited to the intraoperative timeframe. Implantable, thin-film wireless nerve stimulators offer a potential solution to this problem by enabling delivery of electrical stimuli to an injured nerve over a period of several days post-surgery. The aim of this study was to determine the optimal time course of stimulation for maximizing functional recovery in a rat sciatic nerve isograft repair model. Methods: Adult male Lewis rats underwent thin-film wireless nerve stimulator implantation following sciatic nerve transection and 40 mm nerve isograft repair. Immediately after surgery, animals began a daily regimen of TES for up to 12 consecutive days. Functional recovery was assessed by compound muscle action potential (CMAP), evoked muscle force, wet muscle mass, and axon counting. Results: Serial CMAP measurements increased in amplitude over the course of the study, yet no significant difference between cohorts for serial or terminal CMAPs was observed. Axon counts and wet muscle mass measurements were greatest in the 6-day stimulation group, which correlated with a significant increase in evoked muscle force for the 6-day stimulation group at the terminal time point. Discussion: Six daily sessions of TES were found to be most effective for augmenting functional recovery compared to other time courses of stimulation. Future studies should incorporate additional subjects and track axonal sprouting or measure neurotrophin levels during the therapeutic window to further elucidate the mechanisms behind, and ideal amount of, TES. © 2022 Wiley Periodicals LLC.
Author Keywords
nerve graft; nerve regeneration; peripheral nerve injury; repetitive nerve stimulation; therapeutic electrical stimulation; wireless nerve stimulator
Funding details
U.S. Department of Defense
Document Type: Article
Publication Stage: Article in Press
Source: Scopus