Force and energy transmission at the brain-skull interface of the minipig in vivo and post-mortem
(2025) Journal of the Mechanical Behavior of Biomedical Materials, 161, art. no. 106775, .
Wang, S.a , Eckstein, K.N.a , Okamoto, R.J.a , McGarry, M.D.J.b , Johnson, C.L.c , Bayly, P.V.a d
a Washington University in St. Louis, Mechanical Engineering and Material Science, United States
b Dartmouth College, Thayer School of Engineering, United States
c University of Delaware, Biomedical Engineering, United States
d Washington University in St. Louis, Biomedical Engineering, United States
Abstract
The brain-skull interface plays an important role in the mechano-pathology of traumatic brain injury (TBI). A comprehensive understanding of the mechanical behavior of the brain-skull interface in vivo is significant for understanding the mechanisms of TBI and creating accurate computational models. Here we investigate the force and energy transmission at the minipig brain-skull interface by non-invasive methods in the live (in vivo) and dead animal (in situ). Displacement fields in the brain and skull were measured in four female minipigs by magnetic resonance elastography (MRE), and the relative displacements between the brain and skull were estimated. Surface maps of deviatoric stress, the apparent mechanical properties of the brain-skull interface, and the net energy flux were generated for each animal when alive and at specific times post-mortem. After death, these maps reveal increases in relative motion between brain and skull, brain surface stress, stiffness of brain-skull interface, and net energy flux from skull to brain. These results illustrate the ability to study both skull and brain mechanics by MRE; the observed post-mortem decrease in the protective capability of the brain-skull interface emphasizes the importance of measuring its behavior in vivo. © 2024 Elsevier Ltd
Author Keywords
Brain-skull interface; Magnetic resonance elastography; Post-mortem changes; Traumatic brain injury
Funding details
National Institutes of HealthNIHR01 EB027577
Office of Naval ResearchONRN00014-22-1-2198
Document Type: Article
Publication Stage: Final
Source: Scopus
Adverse Childhood Experiences and Socioemotional Outcomes of Children Born Very Preterm
(2025) Journal of Pediatrics, 276, art. no. 114377, .
Bishop, C.L.a , Lean, R.E.a , Smyser, T.A.a , Smyser, C.D.b c d , Rogers, C.E.a b
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: To examine whether adverse childhood experiences (ACEs) confer risk for socioemotional problems in children born very preterm (VPT). Study design: As part of a longitudinal study, 96 infants born VPT at 23-30 weeks of gestation were recruited from a level III neonatal intensive care unit and underwent follow-up at ages 2 and 5 years. Eighty-three full-term (FT) (37-41 weeks gestation) children were recruited from an adjoining obstetric service and the local community. ACEs were assessed with the Child Life Events Scale at age 2 and Preschool Age Psychiatric Assessment at age 5. At age 5, internalizing, externalizing, and attention deficit hyperactivity disorder (ADHD) symptoms were assessed with the Child Behavior Checklist and Conner’s Rating Scale-Revised, respectively. Covariates including socioeconomic disadvantage, maternal distress, and parent ADHD symptoms were assessed at the 2- and/or 5-year follow-up. Mediation and moderation analysis, accounting for family clustering, examined associations between birth group, ACEs, and socioemotional outcomes. Results: After covariate adjustment, children born VPT experienced more ACEs (P < .001), particularly medical ACEs (P < .01), and had worse ADHD and internalizing outcomes (P < .05) than full-term children. ACEs mediated the association between birth group and ADHD outcomes (95% CI, 0.11-4.08). There was no evidence of mediation for internalizing outcomes. Higher parent ADHD symptoms (P < .001) and maternal distress (P < .05) were associated with poorer internalizing outcomes. Conclusions: Screening for childhood ACEs should be embedded in the follow-up care of children born VPT and their families. Strategies to screen for and address parent psychosocial functioning may be important to support children’s socioemotional development. © 2024 Elsevier Inc.
Author Keywords
prematurity; psychopathology; stress; trauma
Funding details
Doris Duke Charitable FoundationDDCF
Cerebral Palsy International Research FoundationCPIRF
Child Neurology FoundationCNF
National Institutes of HealthNIHK01-MH122735, K02-NS089852, K23-MH105179, R37-MH113570, UL1-TR000448, R01-HD057098
Intellectual and Developmental Disabilities Research Center, School of Medicine, Washington University in St. LouisIDDRCP50-HD103525
Document Type: Article
Publication Stage: Final
Source: Scopus
Targeting TREM2 signaling shows limited impact on cerebrovascular calcification
(2025) Life Science Alliance, 8 (1), .
Sridhar, S.a b , Zhou, Y.c , Ibrahim, A.d , Bertazzo, S.e , Wyss, T.f , Swain, A.c , Maheshwari, U.a , Huang, S.-F.a , Colonna, M.c , Keller, A.a b
a https://ror.org/02crff812 Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of ZurichZurich, Switzerland
b https://ror.org/02crff812 Neuroscience Centre Zurich, University of Zurich and ETH ZurichZurich, Switzerland
c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
d South San Francisco, CA, United States
e https://ror.org/02jx3x895 Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
f AGORA Cancer Research Center, Swiss Institute of Bioinformatics, Lausanne, Switzerland
Abstract
Brain calcification, the ectopic mineral deposits of calcium phosphate, is a frequent radiological finding and a diagnostic criterion for primary familial brain calcification. We previously showed that microglia curtail the growth of small vessel calcification via the triggering receptor expressed in myeloid 2 (TREM2) in the Pdgfbret/ret mouse model of primary familial brain calcification. Because boosting TREM2 function using activating antibodies has been shown to be beneficial in other disease conditions by aiding in microglial clearance of diverse pathologies, we investigated whether administration of a TREM2-activating antibody could mitigate vascular calcification in Pdgfbret/ret mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGFβ signaling. Administration of a TREM2-activating antibody increased TREM2-dependent microglial deposition of cathepsin K, a collagen-degrading protease, onto calcifications. However, this did not ameliorate the calcification load or alter the mineral composition and the microglial phenotype around calcification. We therefore conclude that targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications. © 2024 Sridhar et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Protocol for a non-surgical model of perineural invasion for assessing neural drivers of cancer aggressiveness in mice
(2024) STAR Protocols, 5 (4), art. no. 103345, .
Zaninelli, T.H., Saraiva-Santos, T., Patlin, B.H., Stratton, M.S., Chen, D.Y., Pinho-Ribeiro, F.A.
Division of Dermatology, Department of Medicine, Washington University School of Medicine in St. Louis, Saint Louis, MO, United States
Abstract
Perineural invasion (PNI) is a significant risk factor for cancer recurrence and metastasis; however, its mechanisms relating to cancer aggressiveness remain poorly understood. Here, we present a protocol for a non-surgical model of PNI in mice using a neurotropic melanoma cell line that migrates from the skin to the sciatic nerve. We describe the steps for cell culture and injection, tumor burden measurements, mouse euthanasia, and tissue dissection. We then detail procedures for sample cross-section and confocal imaging. © 2024 The Author(s)
Author Keywords
Cancer; Model Organisms; Neuroscience
Funding details
Institute of Clinical and Translational SciencesICTS
School of Medicine, Washington University in St. LouisWUSM
Elsa U. Pardee FoundationEUPF
Chan Zuckerberg InitiativeCZI
Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. LouisMIR
National Institutes of HealthNIHS10OD027042, S10OD025264
National Institutes of HealthNIH
National Cancer InstituteNCIP30CA091842
National Cancer InstituteNCI
Silicon Valley Community FoundationSVCF2024-338502
Silicon Valley Community FoundationSVCF
Document Type: Article
Publication Stage: Final
Source: Scopus
Genotype‒phenotype correlation in recessive DNAJB4 myopathy
(2024) Acta Neuropathologica Communications, 12 (1), art. no. 171, .
Inoue, M.a , Jayaraman, D.b c , Bengoechea, R.a , Bhadra, A.d , Genetti, C.A.b , Aldeeri, A.A.b e , Turan, B.f , Pacheco-Orozco, R.A.g h , Al-Maawali, A.i , Al Hashmi, N.j , Zamani, A.G.f , Göktaş, E.f , Pekcan, S.k , Çağlar, H.T.k , True, H.d , Beggs, A.H.b , Weihl, C.C.a
a Department of Neurology, Washington University School of Medicine, Box 8111, 4523 Clayton Avenue, Saint Louis, MO 63110, United States
b Division of Genetics and Genomics, Boston Children’s Hospital, The Manton Center for Orphan Disease Research, Harvard Medical School, Boston, United States
c Department of Neurology, Division of Neuromuscular Medicine, Massachusetts General Hospital and Brigham and Women’s Hospital, Boston, United States
d Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, United States
e Department of Internal Medicine, King Saud University, Riyadh, Saudi Arabia
f Department of Medical Genetics, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
g Organización Clinica General del Norte, Barranquilla, Colombia
h Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
i Department of Genetics, Sultan Qaboos University Hospital, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
j Royal Hospital, National Genetic Center, Ministry of Health, Muscat, Oman
k Department of Pediatric Pulmonology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
Abstract
Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype. © The Author(s) 2024.
Author Keywords
Chaperonopathy; DNAJB4; Heat shock proteins; Protein aggregate myopathy; Respiratory failure; Rigid spine syndrome
Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSMDA961862
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
Muscular Dystrophy AssociationMDAR25NS070682
Muscular Dystrophy AssociationMDA
National Institute of Neurological Disorders and StrokeNINDSP50HD105351
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
Minority stress mediates associations of sexual minority state policies and tobacco use among US sexual minority young adults
(2024) Drug and Alcohol Dependence, 265, art. no. 112477, .
Romm, K.F.a b , Vogel, E.A.a b , Dyar, C.c , Drabble, L.A.d e , Cavazos-Rehg, P.A.f , Berg, C.J.g h
a TSET Health Promotion Research Center, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
b Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
c College of Nursing, The Ohio State University, Columbus, OH 43210, United States
d School of Social Work, San José State University, San José, CA 95192, United States
e Center for Applied Research in Human Services, College of Health and Human Sciences, San José State University, San José, CA 95192, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Prevention and Community Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, United States
h George Washington Cancer Center, George Washington University, Washington, DC 20052, United States
Abstract
Introduction: State policies surrounding sexual minority (SM) rights are associated with tobacco use among SM individuals. Research is scant regarding the role of distinct SM policy categories on SM young adults’ (SMYAs) tobacco use and mechanisms explaining these associations. Methods: We analyzed 2023 survey data from 1100 SMYAs (ages 18–34; 14.2 % gender minority; 66.1 % bisexual+, 29.1 % monosexual; 53.2 % racial/ethnic minority) with representation across 45 US states and DC. Regression-based models examined: 1) direct associations of residing in states with negative and limited (vs. comprehensive) SM state policies with respect to 7 policy categories (relationship/parent recognition, nondiscrimination, religious exemptions, LGBTQ youth, healthcare, criminal justice, gender identity documents) with minority stress (mental health, internalized stigma, community connectedness); 2) direct associations of policy categories and minority stress with tobacco use (past-month cigarette, e-cigarette, any tobacco use, number of products used); and 3) indirect associations of policy categories with tobacco use through minority stress. Results: Relative to residing in states with comprehensive policies, residing in states with limited relationship/parent recognition policies indirectly predicted higher odds of e-cigarette use through mental health; weaker nondiscrimination policies indirectly predicted using more tobacco products through internalized stigma; and negative healthcare policies indirectly predicted higher odds of cigarette and any tobacco use through community connectedness. Conclusions: These novel findings regarding associations among distinct SM policy categories, minority stress mediators, and tobacco use outcomes warrant further examination to better understand these distinct mechanisms, ultimately to inform SM-related policy and advocacy efforts, as well as tobacco prevention and cessation efforts. © 2024 The Author(s)
Author Keywords
Minority stress; Policy; Sexual minority; Tobacco use; Young adults
Funding details
Oklahoma Tobacco Settlement Endowment TrustTSET
National Cancer InstituteNCI
National Institute of Environmental Health SciencesNIEHS
Stephenson Cancer CenterSCCP30CA225520, K01DA055073
Stephenson Cancer CenterSCC
National Institute on Drug AbuseNIDAR01DA054751, K01DA055073, R01DA059480
National Institute on Drug AbuseNIDA
Tobacco Settlement Endowment TrustTSET#R22-03
Tobacco Settlement Endowment TrustTSET
National Institutes of HealthNIHR21CA261884, R01CA278229, R01CA275066
National Institutes of HealthNIH
Fogarty International CenterFICR01TW012456, D43ES030927
Fogarty International CenterFIC
National Institute on Minority Health and Health DisparitiesNIMHDR21MD019345
National Institute on Minority Health and Health DisparitiesNIMHD
American Cancer SocietyACS134128-IRG-19-142
American Cancer SocietyACS
Document Type: Article
Publication Stage: Final
Source: Scopus
The effects of mosaicism on biological and clinical markers of Alzheimer’s disease in adults with Down syndrome
(2024) eBioMedicine, 110, art. no. 105433, .
a Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
b Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
e Institute of Translational Research, University of North Texas Health Sciences Center, Fort Worth, TX, United States
f Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
g Departments of Radiology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
h Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
i Department of Neurology, UC Irvine, Irvine, CA, United States
j Waisman Center and Department of Human Development and Family Studies, University of Wisconsin–Madison, Madison, WI, United States
k Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
l Department of Pathology & Laboratory Medicine and Department of Neurology, UC Irvine, Irvine, CA, United States
m Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States
Abstract
Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer’s disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. Findings: For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. Interpretation: Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. Funding: National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873). © 2024 The Author(s)
Author Keywords
Alzheimer’s disease; CSF; Down syndrome; Mosaicism; PET; Plasma biomarkers
Document Type: Article
Publication Stage: Final
Source: Scopus
Neighborhood demographics in relation to marketing and regulation-related factors among cannabis retailers in 5 US cities
(2024) Drug and Alcohol Dependence, 265, art. no. 112471, .
Berg, C.J.a b , Schleicher, N.C.c , Cavazos-Rehg, P.A.d , Romm, K.F.e f , LoParco, C.R.a , Cui, Y.a , Wang, Y.a b , McCready, D.M.a , Chakraborty, R.g , Henriksen, L.c
a Department of Prevention and Community Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States
b George Washington Cancer Center, George Washington University, Washington, DC, United States
c Stanford Prevention Research Center, Stanford University School of Medicine, Palo Alto, CA, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e TSET Health Promotion Research Center, Stephenson Cancer Center, College of Medicine, University of Oklahoma Health Sciences, Oklahoma City, OK, United States
f Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences, Oklahoma City, OK, United States
g School of Nursing, George Washington University, Washington, DC, United States
Abstract
Objectives: This study assessed differences in cannabis retailer practices by neighborhood sociodemographics, which can inform disparity-relevant interventions. Methods: Multilevel multivariable logistic regressions examined retailers’ census tract demographics (percent <21 years-old; non-Hispanic White, Black, or other race, Hispanic; median household income [MHHI]) in relation to 2022 audit data regarding marketing (youth-oriented signs, health-claims, exterior ads, price specials, membership programs, delivery/pick-up) and regulatory compliance (pregnancy and health-risk warning signage, exterior minimum-age signage) among 150 randomly-selected retailers in 5 US cities/states (Denver, Colorado; Seattle, Washington; Portland, Oregon; Las Vegas, Nevada; Los Angeles, California). Results: 20.7 % had youth-oriented signage, 28.7 % health-claim signage, 27.3 % exterior ads, 75.3 % price specials, 39.3 % membership programs, 28.0 % delivery/pick-up, 72.0 % pregnancy warnings, 38.0 % health-risk warnings, and 64.0 % minimum-age signage. Retailers in tracts with higher percent <21 and non-Hispanic White had lower odds of youth-oriented signage. Higher MHHI had higher odds of health-claims; higher percent Hispanic had lower odds of health-claims. Higher MHHI had lower odds of exterior ads. Higher percent <21 had lower odds of price specials. Higher percent non-Hispanic White had higher odds of membership programs. Higher percent non-Hispanic White, other race, and Hispanic had higher odds of delivery/pick-up; higher MHHI had lower odds of delivery/pick-up. Higher percent non-Hispanic White had higher odds of pregnancy warnings. Higher percent <21 had lowers odds of health-risk warnings. Demographics were unrelated to minimum-age signage. Conclusions: Given key findings (e.g., less regulation-related signage in racial/ethnic minority communities), cannabis retail could exacerbate disparities, underscoring the need for related regulatory and prevention efforts. © 2024 Elsevier B.V.
Author Keywords
Cannabis; Health communication; Health disparities; Health policy; Marketing; Public health
Funding details
Oklahoma Tobacco Settlement Endowment TrustTSET
National Institutes of HealthNIH
National Institute of Environmental Health SciencesNIEHS
Fogarty International CenterFICR21MD019345, D43TW012456, R01TW010664, R01DA059480, D43ES030927
Fogarty International CenterFIC
National Cancer InstituteNCIR21CA261884, R01CA275066, R01CA215155, R01CA239178, R01CA278229
National Cancer InstituteNCI
National Science FoundationNSF2415890
National Science FoundationNSF
American Cancer SocietyACS134128-IRG-19-142
American Cancer SocietyACS
Tobacco Settlement Endowment TrustTSET#R22-03
Tobacco Settlement Endowment TrustTSET
National Institute on Drug AbuseNIDAR01DA054751
National Institute on Drug AbuseNIDA
Stephenson Cancer CenterSCCF32DA060612, P30CA225520
Stephenson Cancer CenterSCC
Document Type: Article
Publication Stage: Final
Source: Scopus
Endolymphatic hydrops and cochlear synaptopathy after noise exposure are distinct sequelae of hair cell stereociliary bundle trauma
(2024) Scientific Reports, 14 (1), art. no. 25660, .
Fong, M.L.a , Paik, C.B.a , Quiñones, P.M.a , Walker, C.B.a b , Serafino, M.J.a , Pan, D.W.a , Martinez, E.a , Wang, J.a , Phillips, G.W.c , Applegate, B.E.a d , Gratton, M.A.e , Oghalai, J.S.a d
a Caruso Department of Otolaryngology – Head and Neck Surgery, University of Southern California, Los Angeles, CA 90033, United States
b Department of Biomedical Engineering, Texas A & amp;M University, College Station, TX 77843, United States
c Department of Otolaryngology – Head and Neck Surgery, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, United States
e Center for Sensory Neuroscience, Boys Town National Research Hospital, Omaha, NE 68010, United States
Abstract
Endolymphatic hydrops, increased endolymphatic fluid within the cochlea, is the key pathologic finding in patients with Meniere’s disease, a disease of episodic vertigo, fluctuating hearing loss, tinnitus, and aural fullness. Endolymphatic hydrops also can occur after noise trauma and its presence correlates with cochlear synaptopathy, a form of hearing loss caused by reduced numbers of synapses between hair cells and auditory nerve fibers. Here we tested whether there is a mechanistic link between these two phenomena by using multimodal imaging techniques to analyze the cochleae of transgenic mice exposed to blast and osmotic challenge. In vivo cochlear imaging after blast exposure revealed dynamic increases in endolymph that involved hair cell mechanoelectrical transduction channel block but not the synaptic release of glutamate at the hair cell–auditory nerve synapse. In contrast, ex vivo and in vivo auditory nerve imaging revealed that synaptopathy requires glutamate release from hair cells but not endolymphatic hydrops. Thus, although endolymphatic hydrops and cochlear synaptopathy are both observed after noise exposure, one does not cause the other. They are simply co-existent sequelae that derive from the traumatic stimulation of hair cell stereociliary bundles. Importantly, these data argue that Meniere’s disease derives from hair cell transduction channel blockade. © The Author(s) 2024.
Author Keywords
Auditory nerve; Cochlea; Hair cell; Hearing; Optical coherence tomography; Osmosis
Funding details
University of Southern CaliforniaUSC
School of Medicine, Washington University in St. LouisWUSM
National Institutes of HealthNIH
National Institute of Biomedical Imaging and BioengineeringNIBIBR01DC015385, R01EB027113
National Institute of Biomedical Imaging and BioengineeringNIBIB
National Institute on Deafness and Other Communication DisordersNIDCDR25DC019700, R01DC017741, R01DC013774, R01DC014450
National Institute on Deafness and Other Communication DisordersNIDCD
Document Type: Article
Publication Stage: Final
Source: Scopus
Complex emotion processing and early life adversity in the Healthy Brain Network sample
(2024) Developmental Cognitive Neuroscience, 70, art. no. 101469, .
Furtado, E.J.a , Camacho, M.C.b , Chin, J.H.d , Barch, D.M.c
a the Institute of Child Development at University of Minnesota Twin Cities, Minneapolis, MN 55455, United States
b Department of Psychiatry at Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Psychological and Brain Sciences at Washington University in St. Louis, St. Louis, MO 63110, United States
d Department of Psychology, University of Denver, Denver, CO 80208, United States
Abstract
Objective: Early life adversity (ELA) has shown to have negative impacts on mental health. One possible mechanism is through alterations in neural emotion processing. We sought to characterize how multiple indices of ELA were related to naturalistic neural socio-emotional processing. Method: In 521 5–15-year-old participants from the Healthy Brain Network Biobank, we identified scenes that elicited activation of the Default Mode Network (DMN), Ventral Attention Network (VAN), Cingulo-Opercular Network (CON) and amygdala, all of which are networks shown to be associated with ELA. We used linear regression to examine associations between activation and ELA: negative parenting, social status, financial insecurity, neighborhood disadvantage, negative experiences, and parent psychopathology. Results: We found DMN, VAN, CON and amygdala activation during sad/emotional, bonding, action, conflict, sad, or fearful scenes. Greater inconsistent discipline was associated with greater VAN activation during sad or emotional scenes. Conclusion: Findings suggest that the DMN, VAN, CON networks and the amygdala support socio-emotional processing consistent with prior literature. Individuals who experienced inconsistent discipline may have greater sensitivity to parent–child separation signals. Since no other ELA–activation associations were found, it is possible that unpredictability may be more strongly associated with complex neural emotion processing than socio-economic status or negative life events. © 2024 The Authors
Author Keywords
Adolescence; Adversity; Emotion processing; Naturalistic fMRI
Document Type: Article
Publication Stage: Final
Source: Scopus
A place-based spatial analysis of racial inequities in overdose in St. Louis County Missouri, United States
(2024) International Journal of Drug Policy, 134, art. no. 104611, .
Marotta, P.L.a b c , Leach, B.C.a b m , Hutson, W.D.a b d e , Caplan, J.M.f g , Lohmann, B.h , Hughes, C.h , Banks, D.a d e , Roll, S.a b c , Chun, Y.a b c , Jabbari, J.a b c , Ancona, R.a d i , Mueller, K.a d e j , Cooper, B.a d i n , Anasti, T.a b c , Dell, N.a d e , Winograd, R.k , Heimer, R.l
a Washington University in St. LouisMO, United States
b Brown School, Washington University in St. Louis, St. Louis, MO, United States
c Social Policy Institute, Washington University in St. LouisMO, United States
d School of Medicine, Washington University in St. LouisMO, United States
e Department of Psychiatry, Washington University in St. LouisMO, United States
f Simsi, Inc.NJ, United States
g Rutgers University School of Criminal Justice Center on Public Security NewarkNJ, United States
h St Louis County – Circuit Attorney’s Office Law Enforcement Assisted Diversion Program (LEAD), St. Louis, MO, United States
i Institute for Informatics, Washington University in St. LouisMO, United States
j Department of Emergency Medicine, Washington University in St. Louis, United States
k Department of Psychological Sciences, University of Missouri, St. Louis, United States
l Department of the Epidemiology of Microbial Diseases and the Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, CT, United States
m University of California San Francisco, Department of Medicine, Division of Health Equity and Society, San Francisco, CA, United States
n Public Health Data & Training Center, Institute for Public Health Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objective: The objective of this study was to identify place features associated with increased risk of drug-involved fatalities and generate a composite score measuring risk based on the combined effects of features of the built environment. Methods: We conducted a geospatial analysis of overdose data from 2022 to 2023 provided by the St. Louis County Medical Examiner’s Office to test whether drug-involved deaths were more likely to occur near 54 different place features using Risk Terrain Modeling (RTM). RTM was used to identify features of the built environment that create settings of heightened overdose risk. Risk was estimated using Relative Risk Values (RRVs) and a composite score measuring Relative Risk Scores (RRS) across the county was produced for drugs, opioids, and stimulants, as well as by Black and White decedents. Results: In the model including all drugs, deaths were more likely to occur in close proximity to hotels/motels (RRV=39.65, SE=0.34, t-value=10.81 p<.001), foreclosures (RRV=4.42, SE=0.12, t-value = 12.80, p<.001), police departments (RRV=3.13, SE=0.24, t-score=4.86, p<.001), and restaurants (RRV=2.33, SE=0.12, t-value=7.16, p<.001). For Black decedents, deaths were more likely to occur near foreclosures (RRV=9.01, SE=0.18, t-value =11.92, p<.001), and places of worship (RRV= 2.51, SE=0.18, t-value = 11.92, p<.001). For White decedents, deaths were more likely to occur in close proximity to hotels/motels (RRV=38.97, SE=0.39, t-value=9.30, p<.001) foreclosures (RRV=2.57, SE=0.16, t-value =5.84, p<.001), restaurants (RRV=2.52, SE=0.17, t-value=5.33, p<.001) and, auto painting/repair shops (RRV=0.04, SE=0.18, t-value =3.39, p<.001). Conclusion: These findings suggest that places of worship, the hospitality industry, and housing authorities may be physical features of the environment that reflect social conditions that are conducive to overdose. The scaling up of harm reduction strategies could be enhanced by targeting places where features are co-located. © 2024
Author Keywords
Opioid use disorders; Overdose prevention; Racial equity; Spatial modeling; Stimulant use disorders
Document Type: Article
Publication Stage: Final
Source: Scopus
Spatial, transcriptomic, and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition
(2024) Cell Reports, 43 (11), art. no. 114876, .
Arokiaraj, C.M.a b , Leone, M.J.c d , Kleyman, M.c , Chamessian, A.e f , Noh, M.-C.a b , Phan, B.N.c d , Lopes, B.C.a b , Corrigan, K.A.a b , Cherupally, V.K.c , Yeramosu, D.c , Franusich, M.E.c , Podder, R.c , Lele, S.c , Shiers, S.i , Kang, B.c , Kennedy, M.M.c , Chen, V.c , Chen, Z.c h , Mathys, H.a , Dum, R.P.a , Lewis, D.A.k , Qadri, Y.g , Price, T.J.i , Pfenning, A.R.c l , Seal, R.P.a b j
a Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
b Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
c Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, United States
d Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
e Department of Anesthesiology, Duke University Medical Center, Durham, NC 27708, United States
f Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Anesthesiology, Emory University, Atlanta, GA 30038, United States
h Department of Biological Sciences, Mellon College of Science, Carnegie Mellon University, Pittsburgh, PA 15213, United States
i Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, United States
j Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
k Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States
l Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA 15213, United States
Abstract
Key mechanisms underlying chronic pain occur within the dorsal horn. Genome-wide association studies (GWASs) have identified genetic variants predisposed to chronic pain. However, most of these variants lie within regulatory non-coding regions that have not been linked to spinal cord biology. Here, we take a multi-species approach to determine whether chronic pain variants impact the regulatory genomics of dorsal horn neurons. First, we generate a large rhesus macaque single-nucleus RNA sequencing (snRNA-seq) atlas and integrate it with available human and mouse datasets to produce a single unified, species-conserved atlas of neuron subtypes. Cellular-resolution spatial transcriptomics in mouse shows the precise laminar location of these neuron subtypes, consistent with our analysis of neuron-subtype-selective markers in macaque. Using this cross-species framework, we generate a mouse single-nucleus open chromatin atlas of regulatory elements that shows strong and selective relationships between the neuron-subtype-specific chromatin regions and variants from major chronic pain GWASs. © 2024 The Author(s)
Author Keywords
cell types; chronic pain; CP: Neuroscience; GWAS; human; mouse; multiplexed in situ hybridization; rhesus macaque; single-nucleus ATAC-seq; single-nucleus RNA sequencing; spatial transcriptomics; spinal cord; variants
Funding details
University of Pittsburgh
Medical Center, University of PittsburghUPMC
National Institutes of HealthNIHNS111791, NS133364, NS104964, MH051234, NS111929, NS109792
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Failure in a population: Tauopathy disrupts homeostatic set-points in emergent dynamics despite stability in the constituent neurons
(2024) Neuron, 112 (21), pp. 3567-3584.e5.
McGregor, J.N.a , Farris, C.A.a , Ensley, S.a , Schneider, A.a , Fosque, L.J.a , Wang, C.b c , Tilden, E.I.d , Liu, Y.a , Tu, J.a , Elmore, H.a , Ronayne, K.D.a , Wessel, R.e , Dyer, E.L.f , Bhaskaran-Nair, K.a , Holtzman, D.M.b , Hengen, K.B.a
a Department of Biology, Washington University in Saint Louis, St. Louis, MO, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in Saint Louis, St. Louis, MO, United States
c Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China
d Department of Neuroscience, Washington University in Saint Louis, St. Louis, MO, United States
e Department of Physics, Washington University in Saint Louis, St. Louis, MO, United States
f Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
Abstract
Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity. We continuously tracked hippocampal neuronal activity across the lifetime of a mouse model of tauopathy. We were unable to detect effects of disease in measures of single-neuron firing activity. By contrast, as tauopathy progressed, there was disruption of network-level neuronal activity, quantified by measuring neuronal pairwise interactions and criticality, a homeostatically controlled, ideal computational regime. Deviations in criticality correlated with symptoms, predicted underlying anatomical pathology, occurred in a sleep-wake-dependent manner, and could be used to reliably classify an animal’s genotype. This work illustrates how neurodegeneration may disrupt the computational capacity of neurobiological systems. © 2024 The Author(s)
Author Keywords
behavior; criticality; hippocampus; homeostasis; neurodegeneration; neurophysiology; sleep; tau
Funding details
National Institutes of HealthNIH29225, 1R01NS118442-01, RF1AG047644, RF1NS090934
National Institutes of HealthNIH
National Science FoundationNSFIIS-2146072
National Science FoundationNSF
JPB FoundationJPBF1R01EB029852
JPB FoundationJPBF
Document Type: Article
Publication Stage: Final
Source: Scopus
Concurrent optogenetic motor mapping of multiple limbs in awake mice reveals cortical organization of coordinated movements
(2024) Brain Stimulation, 17 (6), pp. 1229-1240.
Khanal, N.a b , Padawer-Curry, J.A.a b , Voss, T.d , Schulte, K.A.e , Bice, A.R.b , Bauer, A.Q.a b c
a Imaging Science Program, Washington University in St. Louis, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Biophotonics Center, School of Engineering, Vanderbilt University, Keck FEL Center, Suite 200, 410 24th Ave. South, Nashville, TN 37232, United States
e University of Missouri School of Medicine, 1 Hospital Dr, Columbia, MO 65212, United States
Abstract
Background: Motor mapping allows for determining the macroscopic organization of motor circuits and corresponding motor movement representations on the cortex. Techniques such as intracortical microstimulation (ICMS) are robust, but can be time consuming and invasive, making them non-ideal for cortex-wide mapping or longitudinal studies. In contrast, optogenetic motor mapping offers a rapid and minimally invasive technique, enabling mapping with high spatiotemporal resolution. However, motor mapping has seen limited use in tracking 3-dimensonal, multi-limb movements in awake animals. This gap has left open questions regarding the underlying organizational principles of motor control of coordinated, ethologically-relevant movements involving multiple limbs. Objective: Our first objective was to develop Multi-limb Optogenetic Motor Mapping (MOMM) to concurrently map motor movement representations of multiple limbs with high fidelity in awake mice. Having established MOMM, our next objective was determine whether maps of coordinated and ethologically-relevant motor output were topographically organized on the cortex. Methods: We combine optogenetic stimulation with a deep learning driven pose-estimation toolbox, DeepLabCut (DLC), and 3-dimensional triangulation to concurrently map motor movements of multiple limbs in awake mice. Results: MOMM consistently revealed cortical topographies for all mapped features within and across mice. Many motor maps overlapped and were topographically similar. Several motor movement representations extended beyond cytoarchitecturally defined somatomotor cortex. Finer articulations of the forepaw resided within gross motor movement representations of the forelimb. Moreover, many cortical sites exhibited concurrent limb coactivation when photostimulated, prompting the identification of several cortical regions harboring coordinated and ethologically-relevant movements. Conclusions: The cortex appears to be topographically organized by motor programs, which are responsible for coordinated, multi-limbed, and behavior-like movements. © 2024
Author Keywords
Cortical organization; Motor circuitry; Motor mapping; Optogenetics
Document Type: Article
Publication Stage: Final
Source: Scopus
Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains
(2024) Science Translational Medicine, 16 (771), p. eabo1997.
Zhu, B.a b , Park, J.-M.c d , Coffey, S.R.c e , Russo, A.c , Hsu, I.-U.d f , Wang, J.a b , Su, C.a g , Chang, R.d f h , Lam, T.T.i , Gopal, P.P.j , Ginsberg, S.D.k l , Zhao, H.a , Hafler, D.A.c h m n , Chandra, S.S.c d h , Zhang, L.c d h
a Department of Biostatistics, Yale School of Public Health, CT 06510, New Haven, United States
b Program of Computational Biology and Bioinformatics, Yale University, CT 06510, New Haven, United States
c Department of Neurology, Yale University School of Medicine, CT 06510, New Haven, United States
d Department of Neuroscience, Yale University School of Medicine, CT 06510, New Haven, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Cellular and Molecular Physiology, Yale University School of Medicine, CT 06510, New Haven, United States
g Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA 30322, United States
h Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, United States
i Department of Molecular Biophysics and Biochemistry and Keck MS & Proteomics Resource, Yale University, CT 06510, New Haven, United States
j Department of Pathology, Yale University School of Medicine, CT 06510, New Haven, United States
k Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA
l Departments of Psychiatry, Neuroscience & Physiology, NYU Neuroscience Institute, New York University Grossman School of Medicine, NY, NY 10016, United States
m Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
n Department of Immunobiology, Yale University School of Medicine, CT 06510, New Haven, United States
Abstract
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.
Document Type: Article
Publication Stage: Final
Source: Scopus
Multiomic and clinical analysis of multiply recurrent meningiomas reveals risk factors, underlying biology, and insights into evolution
(2024) Science Advances, 10 (43), art. no. eadn4419, .
Pugazenthi, S.a , Patel, B.a b , English, C.W.c , Leidig, W.A.a , McGeehan, K.P.a d , McCornack, C.R.a d , Mok, S.a , Anzaldua-Campos, M.a , Nouri, S.H.c , Roberts, K.e , Chatrath, A.a , Khan, A.B.c , Gadot, R.c , Yano, H.a b f g , Klisch, T.J.h i , Harmanci, A.S.b j , Patel, A.J.b i j k , Kim, A.H.a b f g l
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
d Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neuropathology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
h Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
i Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
j Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, United States
k Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, United States
l Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
An important subset of meningiomas behaves aggressively and is characterized by multiple recurrences. We identify clinical, genetic, and epigenetic predictors of multiply recurrent meningiomas (MRMs) and evaluate the evolution of these meningiomas in patient-matched samples. On multivariable binomial logistic regression, MRMs were significantly associated with male sex (P = 0.012), subtotal resection (P = 0.001), higher number of meningiomas on presentation (P = 0.017), and histopathological sheeting (P = 0.002). Multiomic analysis of primary meningiomas revealed that MRMs have greater copy number losses (P = 0.0313) and increased DNA methylation (P = 0.0155). In meningioma cells with knockdown of EDNRB, a locus with greater promoter methylation and decreased gene expression in MRMs had increased proliferation (P < 0.0001). MRM recurrences were found to be similar to primaries but have a greater burden of copy number gains (P < 0.0001) and increased methylation (P = 0.0045). This clinical and multiomic investigation of MRMs harbors implications for the future development of biomarkers and therapeutic agents for these challenging tumors. Copyright © 2024 The Authors, some rights reserved;
Document Type: Article
Publication Stage: Final
Source: Scopus
An autonomous implantable device for the prevention of death from opioid overdose
(2024) Science Advances, 10 (43), art. no. eadr3567, .
Ciatti, J.L.a b , Vázquez-Guardado, A.b c , Brings, V.E.d e , Park, J.b , Ruyle, B.d e f , Ober, R.A.g h , McLuckie, A.J.g , Talcott, M.R.i , Carter, E.A.g , Burrell, A.R.g , Sponenburg, R.A.j , Trueb, J.b , Gupta, P.d e , Kim, J.b , Avila, R.k , Seong, M.b , Slivicki, R.A.d e , Kaplan, M.A.b k , Villalpando-Hernandez, B.a b , Massaly, N.d e , Montana, M.C.d , Pet, M.l , Huang, Y.a k m , Morón, J.A.d e f , Gereau, R.W., IVd e f n , Rogers, J.A.a b o p
a Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, United States
b Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL 60208, United States
c Department of Electrical and Computer Engineering, North Carolina State University, Raleigh, NC 27606, United States
d Depart-ment of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neuroscience, Washington University, St. Louis, MO 63110, United States
g Center for Comparative Medicine, Northwestern University, Evanston, IL 60208, United States
h Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
i Division of Cardiology, Washington University School of Medicine, St. Louis, MO 63110, United States
j Chemistry of Life Processes Institute (Quantitative Bio-element Imaging Center), Northwestern University, Evanston, IL 60208, United States
k Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, United States
l Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
m Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, United States
n Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, United States
o Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, United States
p Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
Abstract
Opioid overdose accounts for nearly 75,000 deaths per year in the United States, now a leading cause of mortality among young people aged 18 to 45 years. At overdose levels, opioid-induced respiratory depression becomes fatal without the administration of naloxone within minutes. Currently, overdose survival relies on bystander intervention, requiring a nearby person to find the overdosed individual and have immediate access to naloxone to administer. To circumvent the bystander requirement, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose while simultaneously contacting first responders. We present three Naloximeter platforms, for fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that can broadly benefit a susceptible population recovering from opioid use disorder. Copyright © 2024 The Authors, some rights reserved;
Document Type: Article
Publication Stage: Final
Source: Scopus
Direct targeting of mitochondria by cisplatin leads to cytotoxicity in zebrafish lateral-line hair cells
(2024) iScience, 27 (10), art. no. 110975, .
Lee, D.S.a , Schrader, A.a , Zou, J.b , Ang, W.H.b c , Warchol, M.E.a d , Sheets, L.a e
a Department of Otolaryngology – Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Chemistry, National University of Singapore, Singapore, 117543, Singapore
c NUS Graduate School – Integrated Science and Engineering Programme (ISEP), National University of Singapore, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore
d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Cisplatin is a chemotherapy drug that causes permanent hearing loss by injuring cochlear hair cells. Hair cell mitochondria have emerged as potential mediators of hair cell cytotoxicity. Using in vivo live imaging of hair cells in the zebrafish lateral-line organ expressing a genetically encoded indicator of cumulative mitochondrial activity, we first demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conducted time-lapse imaging to understand dynamic changes in mitochondrial homeostasis and observe elevated mitochondrial and cytosolic calcium that surge prior to hair cell death. Furthermore, using a localized probe that fluoresces in the presence of cisplatin, we show that cisplatin directly accumulates in hair cell mitochondria, and this accumulation occurs before mitochondrial dysregulation and apoptosis. Our findings provide evidence that cisplatin directly targets hair cell mitochondria and support that the mitochondria are integral to cisplatin cytotoxicity in hair cells. © 2024 The Author(s)
Author Keywords
biological sciences; cancer systems biology; natural sciences; pharmacology; systems biology
Funding details
National Institute on Deafness and Other Communication DisordersNIDCD
MC-LI-2018-762
American Society of Pediatric OtolaryngologyASPO930395
American Society of Pediatric OtolaryngologyASPO
National Institutes of HealthNIHT32DC000022
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Mutational scanning of CRX classifies clinical variants and reveals biochemical properties of the transcriptional effector domain
(2024) Genome Research, 34 (10), pp. 1540-1552.
Shepherdson, J.L.a b , Granas, D.M.a b , Li, J.a b , Shariff, Z.a b , Plassmeyer, S.P.c d , Holehouse, A.S.c d , White, M.A.a b , Cohen, B.A.a b
a Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
b Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
c Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
d Center for Biomolecular Condensates, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
Abstract
The transcription factor (TF) cone-rod homeobox (CRX) is essential for the differentiation and maintenance of photoreceptor cell identity. Several human CRX variants cause degenerative retinopathies, but most are variants of uncertain significance. We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitutions in CRX using a cell-based transcriptional reporter assay, curating a high-confidence list of nearly 2000 variants with altered transcriptional activity. In the structured homeodomain, activity scores closely aligned to a predicted structure and demonstrated position-specific constraints on amino acid substitution. In contrast, the intrinsically disordered transcriptional effector domain displayed a qualitatively different pattern of substitution effects, following compositional constraints without specific residue position requirements in the peptide chain. These compositional constraints were consistent with the acidic exposure model of transcriptional activation. We evaluated the performance of the DMS assay as a clinical variant classification tool using gold-standard classified human variants from ClinVar, identifying pathogenic variants with high specificity and moderate sensitivity. That this performance could be achieved using a synthetic reporter assay in a foreign cell type, even for a highly cell type-specific TF like CRX, suggests that this approach shows promise for DMS of other TFs that function in cell types that are not easily accessible. Together, the results of the CRX DMS identify molecular features of the CRX effector domain and demonstrate utility for integration into the clinical variant classification pipeline. © 2024 Shepherdson et al.
Funding details
National Institutes of HealthNIH
National Human Genome Research InstituteNHGRIR21HG012146
National Human Genome Research InstituteNHGRI
National Cancer InstituteNCIF30EY033640, 1DP2CA290639, R01GM121755
National Cancer InstituteNCI
National Institute of General Medical SciencesNIGMSR01GM092910
National Institute of General Medical SciencesNIGMS
National Eye InstituteNEIR01EY027784
National Eye InstituteNEI
Document Type: Article
Publication Stage: Final
Source: Scopus
Self-regulated analgesia in males but not females is mediated by endogenous opioids
(2024) PNAS Nexus, 3 (10), art. no. pgae453, .
Dean, J.G.a , Reyes, M.a , Oliva, V.a , Khatib, L.a , Riegner, G.a , Gonzalez, N.a , Posey, G.b , Collier, J.b , Birenbaum, J.a , Chakravarthy, K.a , Wells, R.E.c d , Goodin, B.c d , Fillingim, R.e , Zeidan, F.a
a Department of Anesthesiology, University of California, La Jolla, San Diego, CA 92013, United States
b Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27109, United States
c Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC 27109, United States
d Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63130, United States
e Department of Community Dentistry and Behavioral Science, The University of Florida, Gainesville, FL 32611, United States
Abstract
Converging lines of preclinical and clinical research indicate that females, in stark contrast to males, display an increased prevalence of chronic pain. Females also demonstrate weaker analgesic efficacy in response to opioid therapies when compared with males. These sex-specific differences may be driven by dimorphic endogenous opioidergic responses. In rodent models, analgesia exhibited in males but not females was reversed by inhibiting endogenous opioidergic reception. In humans, the sex-specific endogenous system(s) supporting the direct attenuation of evoked pain has not been identified. To determine whether opioidergic blockade reverses self-regulated analgesia in males as compared to females, the present study combined two operationally analogous clinical trials (n = 98; 51 females and 47 males). In a double-blinded, counterbalanced study involving healthy (n = 39) and chronic low back pain (n = 59) populations, a high-dose naloxone (μ-, κ-, δ-opioid antagonist) vs. placebo-saline cross-over design (15 mg/kg bolus +0.1 mg/kg/h) tested the hypothesis that endogenous opioids mediate analgesia in males but not females. An 11-point visual analog scale (VAS) (0 = no pain; 10 = worst pain imaginable) evaluated pain ratings in response to noxious heat stimulation (49 °C; calf). After baseline pain testing, participants were randomized to a validated four-session mindfulness meditation or sham mindfulness meditation training intervention. Participants practiced their respective meditation during noxious heat, intravenous high-dose naloxone, and placebo saline, respectively. In males and females, meditation significantly lowered evoked pain during saline infusion. Intravenous naloxone inhibited analgesia in males, but pain relief was well preserved in females. The present findings indicate that endogenous opioids mediate self-regulated analgesia in males but not females and underscore the need to establish sex-specific pain therapeutics. © 2024 The Author(s).
Funding details
University of California, San DiegoUCSD
National Center for Complementary and Integrative HealthNCCIHR21-AT010352, R01-AT009693, R01AT011502
National Center for Complementary and Integrative HealthNCCIH
National Center for Advancing Translational SciencesNCATSUL1TR001442
National Center for Advancing Translational SciencesNCATS
Document Type: Article
Publication Stage: Final
Source: Scopus
Social Determinants of Health Affect Psychological Distress among People with Disabilities
(2024) International Journal of Environmental Research and Public Health, 21 (10), art. no. 1359, .
Kersey, J.a , Devlin, A.b , Shyres, S.a , Kringle, E.A.c , Housten, A.J.d
a Program in Occupational Therapy, School of Medicine, Washington University, St. Louis, MO 63110, United States
b Independent Researcher, St. Louis, MO 63118, United States
c School of Kinesiology, College of Education and Human Development, University of Minnesota, Minneapolis, MN 55455, United States
d Department of Surgery, School of Medicine, Washington University, St. Louis, MO 63110, United States
Abstract
People with disabilities experience inequitable exposure to social determinants of health (SDOH) that contribute to disparate health outcomes, including psychological distress. There is little research examining which SDOH have the strongest effect on psychological distress among people with disabilities. This leaves healthcare providers and policy makers with insufficient information to make well-informed treatment decisions or allocate resources effectively. We explored the association between SDOH and disability and which factors may moderate the association between disability and psychological distress. Using data from the US Census Bureau’s Household Pulse Survey (Phase 3.5), we examined SDOH among people with and without disability (n = 26,354). Among people with disability, the odds of severe psychological distress were highest among those who had low incomes (OR = 4.41, 95% CI: 3.51–5.60), were food insecure (OR = 3.75, 95% CI: 3.43–4.10), housing insecure (OR = 3.17, 95% CI: 2.82–3.58), or were unable to work (OR = 1.98, 95% CI: 1.80–2.18). Only difficulty paying for household expenses moderated the association between disability and severe psychological distress (OR = 9.81, 95% CI: 7.11–13.64). These findings suggest that supporting employment and economic opportunities and improving access to safe and affordable housing and food may improve psychological well-being among people with disabilities. © 2024 by the authors.
Author Keywords
community resources; neighborhood characteristics; persons with disabilities; social determinants of health
Document Type: Article
Publication Stage: Final
Source: Scopus
Understanding Onset, Dynamic Transitions, and Associated Inequality Risk Factors for Adverse Posttraumatic Neuropsychiatric Sequelae After Trauma Exposure
(2024) Psychiatric Research and Clinical Practice, .
Lee, C.a , House, S.L.b , Beaudoin, F.L.c d , Neylan, T.C.e , Clifford, G.D.f g , Linnstaedt, S.D.h , Germine, L.T.i j k , Rauch, S.L.i k l , Haran, J.P.m , Storrow, A.B.n , Lewandowski, C.o , Musey, P.I., Jr.p , Hendry, P.L.q , Sheikh, S.q , Punches, B.E.r s , Swor, R.A.t , Hudak, L.A.u , Pascual, J.L.v w , Seamon, M.J.w x , Harris, E.y , Pearson, C.z , Peak, D.A.aa ab , Domeier, R.M.ac , Rathlev, N.K.ad , O’Neil, B.J.ae , Sergot, P.af , Sanchez, L.D.ab ag , Bruce, S.E.ah , Sheridan, J.F.ai aj , Harte, S.E.ak al , Koenen, K.C.am , Kessler, R.C.an , McLean, S.A.ao ap , Yang, Q.aq , An, X.h
a University of Arizona College of Nursing, Tucson, AZ, United States
b Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Epidemiology, Brown University, Providence, Rhode, United States
d Department of Emergency Medicine, Brown University, Providence, Rhode, United States
e Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, United States
f Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
g Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
h Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
i Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
j The Many Brains Project, Belmont, MA, United States
k Department of Psychiatry, Harvard Medical School, Boston, MA, United States
l Department of Psychiatry, McLean Hospital, Belmont, MA, United States
m Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States
n Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
o Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
p Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
q Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, United States
r Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, United States
s Ohio State University College of Nursing, Columbus, OH, United States
t Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, United States
u Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
v Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
w Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
x Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, United States
y Department of Emergency Medicine, Einstein Medical Center, Philadelphia, PA, United States
z Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
aa Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
ab Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
ac Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, United States
ad Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
ae Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
af Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, TX, United States
ag Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
ah Department of Psychological Sciences, University of Missouri – St. Louis, St. Louis, MO, United States
ai Division of Biosciences, Ohio State University College of Dentistry, Columbus, OH, United States
aj Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, United States
ak Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
al Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
am Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
an Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
ao Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
ap Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
aq Duke University, School of Nursing, Durham, NC, United States
Abstract
Objective: Several gaps remain in the understanding of the onset, dynamic transitions, and associated risk factors of adverse posttraumatic neuropsychiatric sequelae (APNS) in the acute post-trauma window. Based on serial assessments of symptoms from a large cohort study, we identified homogeneous statuses across multiple APNS symptom domains and investigated the dynamic transitions among these statuses during the first 2 months after trauma exposure. Furthermore, we studied how symptom onset and transitions are affected by equity-relevant characteristics. Methods: The analysis was based on 2557 participants enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA). APNS symptoms comprised pain, depression, sleep discontinuity, nightmares, avoidance, re-experience, anxiety, hyperarousal, somatic symptoms, and mental fatigue. We identified the homogeneous status of APNS symptoms at baseline, 1 month, and 2 months, and explored transition probabilities among these statuses using latent transition analysis. Equity-relevant characteristics included gender, race, education, family income, childhood trauma, and area deprivation. Results: Three homogeneous statuses–low-, moderate-, and severe-symptom–were identified. While the majority of trauma survivors with severe- or moderate-symptom status maintained the same status over time, some transitioned to a less severe symptom status, particularly within the first month. Specifically, females, non-whites, and those with higher childhood trauma were associated with a decreased likelihood of transitioning to a less severe symptom status. From one to 2 months, lower income was associated with a decreased likelihood of transitioning from moderate-to low-symptom status. Conclusions: The findings can inform early intervention strategies for APNS, potentially reducing health disparities among trauma survivors. © 2024 The Author(s). Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development
(2024) Nature Immunology, .
Okuyama, K.a , Yamashita, M.a b , Koumoundourou, A.c , Wiegreffe, C.c , Ohno-Oishi, M.a i , Murphy, S.J.H.a j , Zhao, X.d , Yoshida, H.e , Ebihara, T.a k , Satoh-Takayama, N.f , Kojo, S.a l , Ohno, H.f , Morio, T.b , Wu, Y.g m , Puck, J.h , Xue, H.-H.d , Britsch, S.c , Taniuchi, I.a
a Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
b Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
c Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany
d Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, United States
e YCI Laboratory for Immunological Transcriptomics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
f Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
g YCI Laboratory for Next-Generation Proteomics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
h Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
i Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan
j Medical Scientist Training Program, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
k Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan
l Department of Immunology and Stem Cell Biology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
m Chemical Biology Mass Spectrometry Platform, Faculty of Science, University of Geneva, Geneva, Switzerland
Abstract
Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11BN441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11bN440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46+ cells in the thymus and reduction in TBR1+ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11bN440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Funding details
Japan Society for the Promotion of ScienceJSPS
Deutsche ForschungsgemeinschaftDFGBR 2215/1-2
Deutsche ForschungsgemeinschaftDFG
ocument Type: Article
Publication Stage: Article in Press
Source: Scopus
Fundamental effects of array density and modulation frequency on image quality of diffuse optical tomography
(2024) Medical Physics, .
Fan, W.a , Trobaugh, J.W.b , Zhang, C.b , Yang, D.e , Culver, J.P.a b c d e , Eggebrecht, A.T.a b c d e
a Department of Physics, Washington University, St. Louis, MO, United States
b Department of Electrical and Systems Engineering, Washington University, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
d Department of Neuroscience, Washington University, St. Louis, MO, United States
e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Diffuse optical tomography (DOT) provides three-dimensional image reconstruction of chromophore perturbations within a turbid volume. Two leading strategies to optimize DOT image quality include, (i) arrays of regular, interlacing, high-density (HD) grids of sources and detectors with closest spacing less than 15 mm, or (ii) source modulated light of order ∼100 MHz. Purpose: However, the general principles for how these crucial design parameters of array density and modulation frequency may interact to provide an optimal system design have yet to be elucidated. Methods: Herein, we systematically evaluated how these design parameters effect image quality via multiple key metrics. Specifically, we simulated 32 system designs with realistic measurement noise and quantified localization error, spatial resolution, signal-to-noise, and localization depth of field for each of ∼85 000 point spread functions in each model. Results: We found that array density had a far stronger effect on image quality metrics than modulation frequency. Additionally, model fits for image quality metrics revealed that potential improvements diminish with regular arrays denser than 9 mm closest spacing. Further, for a given array density, 300 MHz source modulation provided the deepest reliable imaging compared to other frequencies. Conclusions: Our results indicate that both array density and modulation frequency affect the spatial sampling of tissue, which asymptotically saturates due to photon diffusivity within a turbid volume. In summary, our results provide comprehensive perspectives for optimizing future DOT system designs in applications from wearable functional brain imaging to breast tumor detection. © 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.
Author Keywords
array density; diffuse optical tomography; frequency domain; functional near-infrared spectroscopy; image quality; inverse problem; localization depth of field; modulation frequency; point spread function; regularization parameters; spatial resolution
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Mediators That Matter: Psychological Distress, Developmental Assets, and Educational Outcomes Among Black Youth
(2024) Journal of Educational Psychology, 116 (8), pp. 1317-1332.
Rose, T.a , Joe, S.b , Hancock, G.R.c
a School of Social Work, University of Maryland, Baltimore, United States
b Brown School, Washington University, St. Louis, United States
c Department of Human Development and Quantitative Methodology, University of Maryland, United States
Abstract
Persistent inequities in the educational success of Black adolescents are a critical social justice concern. Though psychological distress has been associated with worse educational outcomes, less is known about the mechanisms that may influence this association. This study used nationally representative cross-sectional data from the National Survey of American Life-Adolescent (2001–2004) to explore how developmental assets (i.e., self-esteem, mastery, school bonding, educational aspirations, and educational expectations) mediate associations between psychological distress (i.e., perceived stress, depressive symptoms) and educational outcomes (i.e., grades, grade repetition, suspensions, and expulsions) among 1, 170 Black adolescents ages 13–17 (52% female; Mage = 15). The study found that educational expectations were a statistically significant mediator; lower psychological distress was associated with greater expectations which, in turn, was linked to better grades, lower grade repetition, and fewer expulsions. Additionally, school bonding was a statistically significant mediator such that lower perceived stress and depressive symptoms were associated with better school bonding. In turn, school bonding was associated with higher grades and fewer school expulsions. Self-esteem also significantly mediated the association between psychological distress and grade repetition. Study findings can contribute to precision in identifying culturally relevant targets of interventions among Black adolescents and help to address racial disparities in adolescent educational outcomes. © (2024), (American Psychological Association). All rights reserved.
Author Keywords
developmental assets; educational expectations; educational outcomes; school bonding; self-esteem
Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Institutes of HealthNIHR03HD099390
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Associations between polygenic scores for cognitive and non-cognitive factors of educational attainment and measures of behavior, psychopathology, and neuroimaging in the adolescent brain cognitive development study
(2024) Psychological Medicine, .
Gorelik, A.J.a , Paul, S.E.a , Miller, A.P.b , Baranger, D.A.A.a , Lin, S.a , Zhang, W.c , Elsayed, N.M.a , Modi, H.a , Addala, P.d , Bijsterbosch, J.c , Barch, D.M.a , Karcher, N.R.b , Hatoum, A.S.a , Agrawal, A.b , Bogdan, R.a , Johnson, E.C.b
a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychology, Emory University, Atlanta, GA, United States
Abstract
Background Educational attainment (EduA) is correlated with life outcomes, and EduA itself is influenced by both cognitive and non-cognitive factors. A recent study performed a ‘genome-wide association study (GWAS) by subtraction,’ subtracting genetic effects for cognitive performance from an educational attainment GWAS to create orthogonal ‘cognitive’ and ‘non-cognitive’ factors. These cognitive and non-cognitive factors showed associations with behavioral health outcomes in adults; however, whether these correlations are present during childhood is unclear. Methods Using data from up to 5517 youth (ages 9-11) of European ancestry from the ongoing Adolescent Brain Cognitive DevelopmentSM Study, we examined associations between polygenic scores (PGS) for cognitive and non-cognitive factors and cognition, risk tolerance, decision-making & personality, substance initiation, psychopathology, and brain structure (e.g. volume, fractional anisotropy [FA]). Within-sibling analyses estimated whether observed genetic associations may be consistent with direct genetic effects. Results Both PGSs were associated with greater cognition and lower impulsivity, drive, and severity of psychotic-like experiences. The cognitive PGS was also associated with greater risk tolerance, increased odds of choosing delayed reward, and decreased likelihood of ADHD and bipolar disorder; the non-cognitive PGS was associated with lack of perseverance and reward responsiveness. Cognitive PGS were more strongly associated with larger regional cortical volumes; non-cognitive PGS were more strongly associated with higher FA. All associations were characterized by small effects. Conclusions While the small sizes of these associations suggest that they are not effective for prediction within individuals, cognitive and non-cognitive PGS show unique associations with phenotypes in childhood at the population level. Copyright © The Author(s), 2024. Published by Cambridge University Press.
Author Keywords
academic achievement; cognitive performance; educational attainment; genetics; late childhood; middle childhood; neuroimaging; polygenic scores
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Individual-level metabolic connectivity from dynamic [18F]FDG PET reveals glioma-induced impairments in brain architecture and offers novel insights beyond the SUVR clinical standard
(2024) European Journal of Nuclear Medicine and Molecular Imaging, .
Vallini, G.a , Silvestri, E.a , Volpi, T.b c , Lee, J.J.d , Vlassenko, A.G.d , Goyal, M.S.d , Cecchin, D.b e , Corbetta, M.b f , Bertoldo, A.a b
a Department of Information Engineering, University of Padova, Padova, Italy
b Padova Neuroscience Center, University of Padova, Padova, Italy
c Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, United States
d Neuroimaging Laboratories, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
e Department of Medicine, Unit of Nuclear Medicine, University of Padova, Padova, Italy
f Department of Neuroscience, University of Padova, Padova, Italy
Abstract
Purpose: This study evaluates the potential of within-individual Metabolic Connectivity (wi-MC), from dynamic [18F]FDG PET data, based on the Euclidean Similarity method. This approach leverages the biological information of the tracer’s full temporal dynamics, enabling the direct extraction of individual metabolic connectomes. Specifically, the proposed framework, applied to glioma pathology, seeks to assess sensitivity to metabolic dysfunctions in the whole brain, while simultaneously providing further insights into the pathophysiological mechanisms regulating glioma progression. Methods: We designed an index (Distance from Healthy Group, DfHG) based on the alteration of wi-MC in each patient (n = 44) compared to a healthy reference (from 57 healthy controls), to individually quantify metabolic connectivity abnormalities, resulting in an Impairment Map highlighting significantly compromised areas. We then assessed whether our measure of metabolic network alteration is associated with well-established markers of disease severity (tumor grade and volume, with and without edema). Subsequently, we investigated disruptions in wi-MC homotopic connectivity, assessing both affected and seemingly healthy tissue to deepen the pathology’s impact on neural communication. Finally, we compared network impairments with local metabolic alterations determined from SUVR, a validated diagnostic tool in clinical practice. Results: Our framework revealed how gliomas cause extensive alterations in the topography of brain networks, even in structurally unaffected regions outside the lesion area, with a significant reduction in connectivity between contralateral homologous regions. High-grade gliomas have a stronger impact on brain networks, and edema plays a mediating role in global metabolic alterations. As compared to the conventional SUVR-based analysis, our approach offers a more holistic view of the disease burden in individual patients, providing interesting additional insights into glioma-related alterations. Conclusion: Considering our results, individual PET connectivity estimates could hold significant clinical value, potentially allowing the identification of new prognostic factors and personalized treatment in gliomas or other focal pathologies. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
Author Keywords
Brain network alterations; Cancer neuroscience; Glioma; Individual-level metabolic connectivity; SUVR; [18F]FDG dynamic PET
Funding details
National Institutes of HealthNIH
McDonnell Center for Systems Neuroscience
National Institute on AgingNIAR01AG053503, R01AG057536
National Institute on AgingNIA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Subcutaneous ocrelizumab in multiple sclerosis: Results of the Phase 1b OCARINA I study
(2024) Annals of Clinical and Translational Neurology, .
Newsome, S.D.a , Goldstick, L.b , Robertson, D.S.c , Bowen, J.D.d , Naismith, R.T.e , Townsend, B.f , Figueiredo, C.f , Kletzl, H.f , Giraudon, M.f , Bortolami, O.g , Zecevic, D.f , Giacobino, C.f , Clinch, S.h , Shen, Y.-A.i , Deol-Bhullar, G.j , Bermel, R.A.k
a Johns Hopkins University School of Medicine, Baltimore, MD, United States
b University of Cincinnati Waddell Center for Multiple Sclerosis, Cincinnati, OH, United States
c College of Medicine, University of South Florida, Tampa, FL, United States
d Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, WA, United States
e Department of Neurology, Neuroimmunology Section, Washington University, St. Louis, MO, United States
f F. Hoffmann-La Roche Ltd, Basel, Switzerland
g IQVIA RDS, Milan, Italy
h Roche Products Ltd, Welwyn Garden City, United Kingdom
i Genentech, Inc., South San Francisco, CA, United States
j Hoffmann-La Roche Limited, Mississauga, ON, Canada
k Department of Neurology, Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States
Abstract
Objective: Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open-label, multicenter, Phase 1b, dose-finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825). Methods: Patients with relapsing or primary progressive multiple sclerosis (aged 18–65 years; Expanded Disability Status Scale score 0.0–6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 mg. Following dose escalation, new patients in Group A were randomized (1:1) to receive a single 600 mg intravenous ocrelizumab dose or the candidate subcutaneous dose, which was predicted to result in similar exposure as the 600 mg intravenous dose while being safe and well tolerated. The area under the concentration–time curve for both formulations was used to select the subcutaneous ocrelizumab dose. Patients in all cohorts could enter a dose-continuation phase. Results: Eighty-eight and 47 patients were enrolled into Group A and B, respectively; most patients were female (72.7%/63.0%), and mean age at baseline was 45.7 and 39.7 years, respectively. Subcutaneous ocrelizumab was well tolerated across all doses tested. The 920 mg subcutaneous ocrelizumab dose was selected for the OCARINA II study based on pharmacokinetic and safety data. Interpretation: Subcutaneous ocrelizumab may provide patients with multiple sclerosis with an additional treatment option. © 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
F. Hoffmann-La Roche
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The effect of social retelling on event recall
(2024) Memory, .
Harris, K., McDermott, K.
Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Retelling an event in a social setting often means talking about it less factually than we might if trying to recall it as accurately as possible. These distortions that arise from socially oriented retellings could affect the ability to later recall the same event accurately. Does retelling a story in a social situation impair memory compared to not retelling it at all? Or could retrieving the memory, even with a socially oriented mindset, still improve memory? We explored social retelling’s effect on memory in a two-session study. Participants heard two stories twice and, after a distractor task, retold the stories according to one of three randomly assigned conditions: social retelling (retell the stories as if talking to friends), accuracy retelling (retell the stories as accurately as possible), or no retelling. A day later, everyone retold the stories as accurately as possible. Participants in the accuracy retelling group included more specific details in their session two retellings than did the social retelling group, which included more specific details than the no retelling group. Elaborations in session two did not differ across groups. Findings suggest retelling a story in a social situation benefits memory, though not as much as retelling a story accurately does. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
Memory; recall; retellings; social cognition
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
(2024) Neuron, .
Carling, G.K.a b , Fan, L.a , Foxe, N.R.a b , Norman, K.a , Wong, M.Y.a , Zhu, D.a , Corona, C.c , Razzoli, A.d e , Yu, F.a , Yarahmady, A.f , Ye, P.a , Chen, H.a , Huang, Y.a g , Amin, S.a , Sereda, R.h , Lopez-Lee, C.a b , Zacharioudakis, E.i , Chen, X.j , Xu, J.k , Cheng, F.k , Gavathiotis, E.i , Cuervo, A.M.h , Holtzman, D.M.j , Mok, S.-A.f , Sinha, S.C.a , Sidoli, S.i , Ratan, R.R.c , Luo, W.a , Gong, S.a , Gan, L.a
a Helen and Robert Appel Alzheimer’s Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, United States
b Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, United States
c Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY 10605, United States
d Transfusion Medicine Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42122, Italy
e Clinical and Experimental PhD Program, University of Modena and Reggio Emilia, Modena, 41121, Italy
f Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
g Biochemistry, Structural Biology, Cell Biology, Developmental Biology, and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, United States
h Department of Developmental and Molecular Biology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, United States
i Department of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, United States
j Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
k Cleveland Clinic Genome Center and Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, United States
Abstract
The strongest risk factors for late-onset sporadic Alzheimer’s disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk. © 2024 The Author(s)
Author Keywords
Alzheimer’s disease; APOE; cGAS; inflammation; interferon; microglia; R47H; senescence; tau; TREM2
Funding details
Rainwater Charitable FoundationRCF
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
BrightFocus FoundationBFF
Tau Consortium
National Institutes of HealthNIH1R01AG079291-01A1, R01AG079557-01, R01AG064239, R01AG076448, F31AG079560, R01AG072758, R01AG074541, K99AG078493, R01AG054214
NIH Office of the DirectorODS10OD030286
A20201312F
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma
(2024) Cancer Cell, . Cited 1 time.
Hamilton, A.K.a , Radaoui, A.B.a , Tsang, M.a , Martinez, D.c , Conkrite, K.L.a , Patel, K.a , Sidoli, S.d , Delaidelli, A.e f , Modi, A.a , Rokita, J.L.g , Lane, M.V.a , Hartnett, N.a , Lopez, R.D.a , Zhang, B.g , Zhong, C.g , Ennis, B.g , Miller, D.P.g , Brown, M.A.g , Rathi, K.S.a g h , Raman, P.a g h , Pogoriler, J.c , Bhatti, T.c , Pawel, B.c n , Glisovic-Aplenc, T.a , Teicher, B.i , Erickson, S.W.j , Earley, E.J.j , Bosse, K.R.a b , Sorensen, P.H.e f , Krytska, K.a , Mosse, Y.P.a b , Havenith, K.E.k , Zammarchi, F.k , van Berkel, P.H.k , Smith, M.A.i , Garcia, B.A.l o , Maris, J.M.a b m , Diskin, S.J.a b m
a Center for Childhood Cancer Research and Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
b Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
c Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
d Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, United States
e Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
f Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
g Center for Data-Driven Discovery in Biomedicine and Division of Neurosurgery, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
h Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
i National Cancer Institute, Bethesda, MD 20892, United States
j RTI International, Research Triangle Park, Durham, NC 27709, United States
k ADC Therapeutics (UK) Ltd, London, W12 0BZ, United Kingdom
l Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
m Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
n Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
o Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate immunotherapeutic targets, and we prioritize delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlates with a super-enhancer. Immunofluorescence, flow cytometry, and immunohistochemistry show robust cell surface expression of DLK1. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells results in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target. © 2024 The Author(s)
Author Keywords
antibody-drug conjugate; cancer; DLK1; immunotherapy; mass spectrometry; neuroblastoma; surfaceome
Funding details
W. W. Smith Charitable Trust
Mark Foundation For Cancer Research
National Institutes of HealthNIHU01-CA199222, R35-CA220500, U54-CA232568, F31-CA225069, U01-CA199287, R03-CA230366, U01-CA263957, T32-CA009140, R01-CA237562, R01-CA204974
National Institutes of HealthNIH
Alex’s Lemonade Stand Foundation for Childhood CancerALSFSU2C-AACR-DT1113
Alex’s Lemonade Stand Foundation for Childhood CancerALSF
National Cancer InstituteNCICA278687-01
National Cancer InstituteNCI
Cancer Research UKCRUKCGCATF-2021/100002
Cancer Research UKCRUK
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Preoperative predictors of acute postoperative anxiety and depression using ecological momentary assessments: a secondary analysis of a single-centre prospective observational study
(2024) British Journal of Anaesthesia, .
Aminpour, E.a , Holzer, K.J.a , Frumkin, M.b c d , Rodebaugh, T.L.e , Jones, C.a , Haroutounian, S.a , Fritz, B.A.a
a Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
c Department of Psychiatry, Harvard Medical School, Boston, MA, United States
d Department of Psychological and Brain Sciences, Washington University School of Medicine, Saint Louis, MO, United States
e Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Abstract
Background: Postoperative anxiety and depression can negatively affect surgical outcomes and patient wellbeing. This study aimed to quantify the incidence of postoperative worsening anxiety and depression symptoms and to identify preoperative predictors of these conditions. Methods: This prospective, observational cohort study included 1168 patients undergoing surgery lasting >1 h with overnight admission at a university-affiliated quaternary referral centre. Postoperative anxiety and depression symptoms were measured using standardised, thrice-daily ecological momentary assessments (EMAs) for 30 days. Co-primary outcomes were worsening anxiety and depression symptoms, each defined as a slope >0 when EMA was modelled as a linear function of time. Multivariable logistic regression was performed to identify independent preoperative predictors of each outcome. Results: Postoperative worsening anxiety occurred in 60 patients (5%), and postoperative worsening depression occurred in 86 patients (7%). Predictors of postoperative worsening of anxiety symptoms included preoperative Patient-Reported Outcome Measurement Information System (PROMIS) anxiety symptoms (adjusted odds ratio [aOR] 2.48, 95% credible interval [CI] 1.29–4.79, for mild symptoms; aOR 2.22, 95% CI 1.10–4.51, for moderate to severe symptoms), and preoperative pain (aOR 3.46, 95% CI 1.32–9.12). Predictors of postoperative worsening depression symptoms included preoperative PROMIS depression symptoms (aOR 2.26, 95% CI 1.24–4.14, for mild symptoms; aOR 3.79, 95% CI 2.10–6.81, for moderate to severe symptoms). Self-reported history of anxiety or depression did not independently predict either outcome. Conclusions: Postoperative worsening anxiety and depression appear to be associated more closely with preoperative active mental health or pain symptoms rather than self-reported history of these conditions. Preoperative identification of at-risk patients will require screening for symptoms rather than simple history taking. © 2024 British Journal of Anaesthesia
Author Keywords
ecological momentary assessments; patient-reported outcomes measurement information system; perioperative mental health; postoperative anxiety; postoperative depression
Document Type: Article
Publication Stage: Article in Press
Source: Scopus