Digital Commons Network^™

High-Speed Voltage Imaging Of Action Potentials In Molecular Layer Interneurons Reveals Sensory-Driven Synchrony That Augments Movement, Spencer T Brown, Meghana R Holla, Michelle A Land, Shuyuan Yang, Alex J Mcdonald, François St-Pierre, Indira M Raman

Faculty, Staff and Students Publications

Testing whether the synchrony of action potential firing is a cerebellar coding mechanism requires simultaneous recording, with high temporal fidelity, from populations of identified neurons. Here, we used targeted one-photon voltage imaging at 2–4 kHz to record action potentials from groups of ~10–300 molecular layer interneurons (MLIs) expressing a positively tuned, genetically encoded voltage indicator, FORCE1f or pAce. In awake resting mice, crus I MLIs fired brief (~1-ms) spikes at 20–60 spikes/s. Sensory stimuli of air puffs to the whiskers evoked short-latency (< 10 ms) increases in spiking probability. In most trials, >50% of MLIs fired synchronously with 4-ms temporal precision. The magnitude of puff-evoked whisks correlated tightly with …

An Ehealth Delivery Alternative For Cancer Genetic Testing For Hereditary Predisposition In Patients With Metastatic Cancers: Protocol For A Randomized Trial, Kimberley T. Lee, Briana Mcleod, Brian Egleston, Sarah Brown, Sarah Howe, Dominique Fetzer, Lauren Gutstein, Cara Cacioppo, Dana Clark, Susan M. Domchek, Jessica Ebrahimzadeh, Dana Falcone, Demetrios Ofidis, Hannah Griffin, Rajia Mim, Santina Hernandez, Linda Fleisher, Kelsey Karpink, Enida Selmani, Aysha Tahsin, Lynne Wagner, Michelle Weinberg, Kuang-Yi Wen, Elisabeth Wood, Angela R. Bradbury

Department of Medical Oncology Faculty Papers

Background: Germline BRCA1 and BRCA2 testing is a standard evidence-based practice, with established risk reduction and cancer screening guidelines for genetic carriers. With Food and Drug Administration approval for poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors in patients with metastatic breast, ovarian, pancreatic, and prostate cancer, there is an additional therapeutic rationale for testing all patients with these cancers for germline BRCA1 and BRCA2 mutations. However, many at-risk patients do not have access to genetic services, leaving many genetic carriers unidentified.

Objective: The eREACH (A Randomized Study of an eHealth Delivery Alternative for Cancer Genetic Testing for Hereditary Predisposition in …

Prefrontal Cortex Astrocytes Modulate Distinct Neuronal Populations To Control Anxiety-Like Behavior, Eunyoung Kim, Hairuo Du, Yanqi Tan, Brandon L Brown, Yaowen Chang, Blanca Díaz-Castro, Jonathan V Sweedler, Xinzhu Yu

Faculty, Staff and Student Publications

Accumulating evidence has supported diverse regulatory functions of astrocytes in different neural circuits as well as various aspects of complex behaviors. However, little is known about how astrocytes regulate different neuronal subpopulations that are linked to specific behavioral aspects within a single brain region. Here, we show that astrocytes in the medial prefrontal cortex (mPFC) encode anxiogenic environmental cues in freely behaving mice. Silencing mPFC astrocyte Ca

Organizational Climate And Decision Aid Sustainability In Lupus Care: Mixed Methods Study, Aizhan Karabukayeva, Larry R Hearld, Nathan W Carroll, Reena Kelly, Jasvinder A Singh

Faculty, Staff and Students Publications

Background: Digital decision aids (DAs) are increasingly used in health care to support shared decision-making and promote patient engagement. In the context of systemic lupus erythematosus (SLE), a complex autoimmune disease characterized by diverse symptoms and uncertain prognoses, DAs offer guidance to patients in navigating treatment risks and benefits. Although numerous studies have examined the initial implementation of evidence-based tools, there is limited evidence on the organizational factors that influence their long-term sustainability in clinical practice. This gap is particularly salient for digital interventions, where integration into routine workflows and ongoing use require alignment with clinic readiness and culture. This …

Modeling The Importance Of Life Exposure Factors On Memory Performance In Diverse Older Adults: A Machine Learning Approach, Evan Fletcher, Marianne Chanti-Ketterl, Emily Hokett, Yi Lor, Umesh Venkatesan, Ruijia Chen, Omonigho M. Bubu, Rachel Whitmer, Paola Gilsanz, Zvinka Z. Zlatar

Moss-Magee Rehabilitation Papers

INTRODUCTION: Many health life exposure factors (LEFs) influence cognitive decline and dementia incidence, but their relative importance to episodic memory (an early indicator of cognitive decline) among diverse older adults is unclear. We used machine learning to rank LEFs for memory performance in a large and diverse US cohort.

METHODS: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) and Study of Healthy Aging in African Americans (STAR), participants underwent neuropsychological testing and answered questionnaires about multiple LEFs. XGBoost and Shapley Additive exPlanation values ranked the importance of factors influencing cross-sectional episodic memory in the full sample and by sex and …

Deep Phenotyping Of Obesity: Electronic Health Record-Based Temporal Modeling Study, Xiaoyang Ruan, Shuyu Lu, Liwei Wang, Andrew Wen, Sameer Murali, Hongfang Liu

Faculty, Staff and Student Publications

Background: Obesity affects approximately 40% of adults and 15%-20% of children and adolescents in the United States, and poses significant economic and psychosocial burdens. Currently, patient responses to any single antiobesity medication (AOM) vary significantly, making obesity deep phenotyping and associated precision medicine important targets of investigation.

Objective: This study aimed to evaluate the potential of electronic health records (EHR) as a primary data source for obesity deep phenotyping. We conducted an in-depth analysis of the data elements and quality available from obesity patients prior to pharmacotherapy and applied a multimodal longitudinal deep autoencoder to investigate the feasibility, data requirements, …

Multi-Ancestral Genome-Wide Association Study Of Clinically Defined Nicotine Dependence Reveals Strong Genetic Correlations With Other Substance Use Disorders And Health-Related Traits, Emma C Johnson, Jared V Balbona, Alexander S Hatoum, David A A Baranger, Louis Fox, Paul W Jeffries, Laura J Bierut, Andrew C Heath, Pamela A Madden, Elliot C Nelson, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement.

METHODS: We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes.

RESULTS: We replicated the well-known association at the

CONCLUSIONS: Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics …

Trpc4 Regulates Limbic Behavior And Neuronal Development By Stabilizing Dendrite Branches Through Actomyosin-Driven Integrin Activation, Jaepyo Jeon, Travis I Moore, Insuk So, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer, Michael X Zhu

Faculty, Staff and Student Publications

Transient Receptor Potential Canonical 4 (TRPC4) channels have been implicated in multiple neurological functions, including anxiety and sociability. TRPC4 variants were also found in patients with autism. However, the contributions of TRPC4 to neurodevelopment remain undefined. Here, we show that neurobehavioral deficits appear early in young TRPC4 knockout (Trpc4^−/−) mice immediately after weaning, manifesting as alterations in multiple, limbic-related behaviors, such as nesting, marble burying, burrowing, self-grooming, and social interactions. Hippocampal neurons of Trpc4−/− mice exhibit reduced dendritic arborization both in vivo and in vitro. Mechanistically, we found that TRPC4 expression in dendrites surged at the …

Experience-Dependent Intrinsic Plasticity In Layer Iv Of Barrel Cortex At Whisking Onset, Molly C Shallow, Lucy Tian, Bryan T Higashikubo, Hudson Lin, Katheryn B Lefton, Siyu Chen, Joseph D Dougherty, Joe P Culver, Mary E Lambo, Keith B Hengen

2020-Current year OA Pubs

The development of motor control over sensory organs is a critical milestone, enabling active exploration and shaping of the sensory environment. Whether the onset of sensory organ motor control directly influences the development of corresponding sensory cortices remains unknown. Here, we confirm and exploit the late onset of whisking behavior in mice to address this question in the somatosensory system. Using ex vivo electrophysiology, we describe a transient increase in the intrinsic excitability of excitatory neurons in layer IV of the barrel cortex, which processes whisker input, immediately following the onset of active whisking on postnatal days 13 and 14. …

Dna Methylation Signatures Of Cardiovascular Health Provide Insights Into Diseases, Madeleine Carbonneau, Yi Li, Yishu Qu, Yinan Zheng, Alexis C Wood, Mengyao Wang, Chunyu Liu, Tianxiao Huan, Roby Joehanes, Xiuqing Guo, Jie Yao, Kent D Taylor, Russell P Tracy, Peter Durda, Yongmei Liu, W Craig Johnson, Wendy S Post, Tom Blackwell, Jerome I Rotter, Stephen S Rich, Susan Redline, Myriam Fornage, Jun Wang, Hongyan Ning, Lifang Hou, Donald Lloyd-Jones, Kendra Ferrier, Yuan-I Min, April P Carson, Laura M Raffield, Alexander Teumer, Hans J Grabe, Henry Völzke, Matthias Nauck, Marcus Dörr, Arce Domingo-Relloso, Amanda Fretts, Maria Tellez-Plaza, Shelley A Cole, Ana Navas-Acien, Meng Wang, Joanne M Murabito, Nancy L Heard-Costa, Brenton Prescott, Vanessa Xanthakis, Dariush Mozaffarian, Daniel Levy, Jiantao Ma

Faculty, Staff and Students Publications

Background: The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.

Methods: We calculated the American Heart Association's Life's Essential 8 score to reflect CVH in 5 cohorts with diverse backgrounds (mean age 54 years, 55% women, and enrollment year ranging from 1989 to 2012). Epigenome-wide association studies (EWAS) for Life's Essential 8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with Life's Essential 8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident cardiovascular disease (CVD), cardiovascular …

Kdm2b Variants In The Cxxc Domain Impair Its Dna-Binding Ability And Cause A Distinct Neurodevelopmental Syndrome, Amber S E Van Oirsouw, Michael A Hadders, Martijn Koetsier, Edith D J Peters, Nurit Assia Batzir, Tahsin Stefan Barakat, Diana Baralle, Adelyn Beil, Marie-Noëlle Bonnet-Dupeyron, Philip M Boone, Arjan Bouman, Deanna Alexis Carere, Benjamin Cogne, Leslie Dunnington, Laura S Farach, Casie A Genetti, Bertrand Isidor, Louis Januel, Aakash Joshi, Nayana Lahiri, Kristen N Lee, Idit Maya, Meriel Mcentagart, Hope Northrup, Mathilde Pujalte, Kate Richardson, Susan Walker, Bobby P C Koeleman, Mariëlle Alders, Richard H Van Jaarsveld, Renske Oegema

Faculty, Staff and Student Publications

Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants' effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the …

Exploring Young Adults' Experiences And Beliefs In Asthma Medication Management: Pilot Qualitative Study Comparing Human And Multiple Ai Thematic Analysis, Ruth Ndarake Jeminiwa, Caroline Popielaski, Amber King

College of Pharmacy Faculty Papers

BACKGROUND: Young adults take their asthma maintenance medication 67% of the time or less. Understanding the specific needs and behaviors of young adults with asthma is essential for developing targeted interventions to improve disease self-management. Artificial intelligence (AI) has demonstrated its utility in summarizing and identifying patterns in qualitative research and may support or augment human coding efforts. However, there is pause literature to support this assertion.

OBJECTIVE: The objective of this study is to begin to explore the medication management-related needs of young adults with asthma via a pilot feasibility study. We aim to understand how to best assist …

Lipidomic And Proteomic Insights From Extracellular Vesicles In The Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes, Chioma M Okeoma, Wasifa Naushad, Bryson C Okeoma, Carlos Gartner, Yulica Santos-Ortega, Calvin Vary, Savio Lima-Bastos, Victor Corasolla Carregari, Martin R Larsen, Alessio Noghero, Consuelo Walss-Bass, Rodrigo Grassi-Oliveira

Faculty, Staff and Student Publications

Substance use disorder (SUD) significantly increases the risk of neurotoxicity, inflammation, oxidative stress, and impaired neuroplasticity. The activation of inflammatory pathways by substances may lead to reactive astrogliosis and chronic neuroinflammation, potentially mediated by the release of extracellular particles (EPs), such as extracellular condensates (ECs) and extracellular vesicles (EVs). These particles, which reflect the physiological, pathophysiological, and metabolic states of their cells of origin, might carry molecular signatures indicative of SUD. In particular, our study investigated neuroinflammatory signatures in SUD patients by isolating EVs from the dorsolateral prefrontal cortex (dlPFC) Brodmann's area 9 (BA9) from postmortem subjects. We isolated BA9-derived …

Randomised, Placebo-Controlled Trial Of Oral Hymecromone In Adults With Pulmonary Hypertension, Kathryn Czepiel, Nadine Nagy, Tamera Panjalingam, Anissa Kalinowski, Adam R Frymoyer, Harry Karmouty-Quintana, Bo Gu, Haley Hedlin, Gernot Kaber, Sylvie Dobrota Lai, Joelle I Rosser, Paul L Bollyky, Vinicio De Jesus Perez, Roham T Zamanian

Faculty, Staff and Student Publications

Background: Pulmonary hypertension (PH) is a progressive cardiopulmonary condition associated with increased morbidity and mortality. The extracellular matrix component hyaluronan (HA) is linked to vascular remodelling and interstitial fibrosis in PH. We hypothesised that inhibition of HA synthesis with hymecromone could serve as a reverse-remodelling therapy in PH.

Methods: We performed a proof-of-concept phase IIa randomised, double-blind, placebo-controlled study in adults with pulmonary arterial hypertension and PH associated with interstitial lung disease (PH-ILD). Patients were randomised to a 5:3 ratio and stratified by PH group to receive oral hymecromone or placebo two times per day over 24 weeks. The primary …

Artificial Intelligence Algorithm Predicts Response To Immune Checkpoint Inhibitors, Faisal Fa'ak, Nicolas Coudray, George Jour, Milad Ibrahim, Irineu Illa-Bochaca, Shi Qiu, Adalberto Claudio Quiros, Ke Yuan, Douglas B Johnson, David L Rimm, Jeffrey S Weber, Aristotelis Tsirigos, Iman Osman

2020-Current year OA Pubs

PURPOSE: Cancer treatment has been revolutionized by immune checkpoint inhibitors (ICI). However, a subset of patients do not respond and/or they experience significant adverse events. Attempts to integrate reliable biomarkers of ICI response as part of standard care have been hampered by limited generalizability. We previously reported our supervised machine learning (ML) model in a retrospective cohort of metastatic melanoma.

EXPERIMENTAL DESIGN: In this study, we expanded our testing to include larger cohorts of patients with melanoma accrued at several sites, including patients enrolled in clinical trials in both adjuvant and metastatic settings. We examined pretreatment hematoxylin and eosin slides …

Male Caregiving Experience Alters Hippocampal Neuroplasticity And Transcription Independent Of Reproduction In A Biparental Species., Maria E Colt, Priyanka Agarwal, Erica R Glasper, Heidi Fisher

Faculty Research 2025

In mammals, measurable changes in brain and behavior accompany the transition to parenthood. In the biparental California mouse, Peromyscus californicus, fathers experience enhanced neuroplasticity, including increased hippocampal dendritic spine density, reduced anxiety, and improved memory. Here, we first investigate whether siring offspring or pup interaction drives structural neuroplasticity in fathers and find that hippocampal spine density is positively associated with caregiving experience, even in the absence of reproduction. Next, we evaluate the transcriptional response to caregiving in the hippocampus of these males and identify 158 differentially expressed genes between fathers and non-fathers, many of which are associated with neurogenesis, neuronal …

Variability In Long Covid Definitions And Validation Of Published Prevalence Rates, Lauren E. Wisk, Michelle L'Hommedieu, Kate Diaz Roldan, Imtiaz Ebna Mannan, Erica S. Spatz, Robert A. Weinstein, Arjun K. Venkatesh, Michael Gottlieb, Ryan Huebinger, Kristin L. Rising, Juan Carlos C. Montoy, Kari A. Stephens, Robert M. Rodriguez, Mandy J. Hill, Kelli N. O'Laughlin, Nicole L. Gentile, Ahamed H. Idris, Shu-Xia Li, Michelle Santangelo, Efrat R. Kean, Samuel A. Mcdonald, Kristyn Gatling, Joann G Elmore

Jefferson Center for Connected Care Faculty Papers

IMPORTANCE: Long COVID definitions vary widely, and no consensus exists on how to accurately measure its prevalence, complicating both clinical care and research.

OBJECTIVE: To assess long COVID prevalence using various definitions from published literature.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter cohort study used data from the longitudinal Innovative Support for Patients With SARS-CoV-2 Infections Registry (INSPIRE). Participants aged 18 years or older with symptoms suggestive of COVID-19 illness at the time of their index SARS-CoV-2 test enrolled at 8 sites across the US from December 11, 2020, through August 29, 2022, with follow-up surveys collected through February 28, …

Assessing The Muc5b Promoter Variant In A Large Cohort Of Systemic Sclerosis-Associated Interstitial Lung Disease, Carlos Rosa-Baez, Carlos Rangel-Pelaez, Inmaculada Rodriguez-Martin, Martin Kerick, Alfredo Guillen-Del-Castillo, Carmen P Simeon-Aznar, José Luis Callejas, Alexandre E Voskuyl, Alexander Kreuter, Oliver Distler, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Jeska K De Vries-Bouwstra, Ariane L Herrick, Yannick Allanore, Lorenzo Beretta, Maureen D Mayes, Christopher P Denton, Shervin Assassi, Javier Martin, Marialbert Acosta-Herrera

Faculty, Staff and Student Publications

Objective: The common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.

Methods: Samples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their …

Regional Heterogeneity Of The Blood-Brain Barrier, Marie Blanchette, Kaja Bajc, Benjamin D Gastfriend, Caterina P Profaci, Nadine Ruderisch, Cayce E Dorrier, Guo Zhong, Raquel Cuevas-Diaz Duran, Sean S Harvey, Iris H Garcia-Pak, Lucija Pintarić, Manon Leclerc, Louise Reveret, Vincent Émond, Annette Wang, Deepti Pant, Linus T Tsai, Frédéric Calon, Nina Isoherranen, Sean P Palecek, Eric V Shusta, Jiaqian Wu, Richard Daneman

The Brown Foundation: Institute of Molecular Medicine

The blood-brain barrier (BBB), formed by specialized endothelial cells (ECs), regulates the extracellular composition of the central nervous system (CNS). Little is known about whether there are regional specializations of the BBB that may control the function of specific neural circuits. We use single cell RNA-seq to characterize ECs from nine CNS regions in male mice: cortex, hippocampus, cerebellum, spinal cord, striatum, thalamus, hypothalamus, midbrain, and medulla/pons. Although there is a core BBB transcriptional profile, there are significant regional specializations. Stra6, a retinoid transporter, is highly enriched in the BBB of the nucleus accumbens shell (ShNAc) and ventral cochlear nucleus, …

Micbg406a Polymorphism Reduces Risk Of Mechanical Ventilation And Death During Viral Acute Lung Injury, Harry Pickering, Narges Alipanah-Lechner, Ernie Chen, Dylan Duchen, Holden T Maecker, Seunghee Kim-Schulze, Ruth R Montgomery, Chris Cotsapas, Hanno Steen, Florian Krammer, Charles R Langelier, Ofer Levy, Lindsey R Baden, Esther Melamed, Lauren Ir Ehrlich, Grace A Mccomsey, Rafick P Sekaly, Charles B Cairns, Elias K Haddad, Albert C Shaw, David A Hafler, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez Sesma, Viviana Simon, Monica Kraft, Chris Bime, David J Erle, Joanna Schaenmann, Al Ozonoff, Bjoern Peters, Steven H Kleinstein, Alison D Augustine, Joann Diray-Arce, Patrice M Becker, Nadine Rouphael, Matthew C Altman, Steve Bosinger, Walter Eckalbar, Carolyn S Calfee, Oscar A Aguilar, Elaine F Reed, John R Greenland, Daniel R Calabrese

Faculty, Staff and Students Publications

MHC class I polypeptide-related sequence B (MICB) is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from IMPACC. Associations between MICBG406A and outcomes were determined by linear regression or Cox proportional hazards models. We also measured immune profiles of peripheral blood and the upper and lower …

In Vivo Prime Editing Rescues Alternating Hemiplegia Of Childhood In Mice., Alexander A Sousa, Markus Terrey, Holt A Sakai, Christine Q Simmons, Elena Arystarkhova, Natalia S Morsci, Laura C. Anderson, Jun Xie, Fabian Suri-Payer, Linda C Laux, Emmanuel Roze, Sylvie Forlani, Guangping Gao, Simon Frost, Nina Frost, Kathleen J Sweadner, Alfred L George, Cathleen Lutz, David R Liu

Faculty Research 2025

Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na⁺/K⁺ ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models. We used PE and BE to correct five prevalent ATP1A3 mutations with 43%–90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the CNS of two AHC mouse models, yielding up to 48% DNA correction and 73% mRNA correction in bulk brain …

Discontinuation Rates And Predictors Of Medical Cannabis Cessation For Chronic Musculoskeletal Pain, Mohammad Khak, Sina Ramtin, Juliet Chung, Asif M. Ilyas, Ari Greis

Rothman Institute Papers

Medical cannabis (MC) is increasingly used as a treatment for chronic musculoskeletal pain, but there is limited data on factors influencing its discontinuation. This study aims to investigate the rates of MC discontinuation and explore factors influencing it in patients with chronic musculoskeletal pain. A retrospective analysis was conducted on 78 patients certified for medical cannabis over a 2 year period. Patient demographics, pain origin, and Global Physical Health (GPH) and Global Mental Health (GMH) scores were collected before intervention. Discontinuation rates were measured at three-month and one-year follow-up. Statistical analyses, including Fisher's Exact Test and two-sample t-tests, were performed …

Adipokines And Transitions In Metabolic Health Over Time: The Atherosclerosis Risk In Communities (Aric) Study, Bige Ozkan, Sui Zhang, Justin B Echouffo-Tcheugui, Roberta Florido, Vijay Nambi, Erin D Michos, Layla A Abushamat, Kunihiro Matsushita, Gary Gerstenblith, Roger S Blumenthal, Ron Hoogeveen, Christie M Ballantyne, Josef Coresh, Elizabeth Selvin, Chiadi E Ndumele

Faculty, Staff and Students Publications

Context: Transitions in metabolic health status over time are strongly linked to risk for cardiovascular events, particularly among individuals with obesity. Adipokines are proteins with metabolic effects, but their role in transitions in metabolic health status over time is unknown.

Objective: To evaluate the associations of adiponectin and leptin with metabolic risk transitions over time.

Methods: Among 8423 individuals who attended ARIC Visits 2 (1990-1992) and 4 (1996-1998), we evaluated prospective associations of Visit 2 levels of the adipokines adiponectin and leptin (per 1-SD higher) with 6-year transitions in metabolic health. Metabolic health was categorized as metabolically "healthy" [no metabolic …

Tet2-Mutant Myeloid Cells Mitigate Alzheimer’S Disease Progression Via Cns Infiltration And Enhanced Phagocytosis In Mice, Katie A Matatall, Trisha K Wathan, Minh Nguyen, Hu Chen, Alexandra Mcdonald, Guantong Qi, Julia A Belk, Marcus A Florez, Duy T Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M Buttigieg, Chih-Wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E Kennedy, Arushana A Maknojia, Apoorva Thatavarty, Josaura V Fernandez Sanchez, Hind Bouzid, Surabi Veeraragavan, Susan Crocker, Margaret A Goodell, Antony Rodriguez, Siddhartha Jaiswal, Michael J Rauh, Eirini P Papapetrou, Samuele G Marro, Katherine Y King

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than …

Artificial Transneurons Emulate Neuronal Activity In Different Areas Of Brain Cortex, Rivu Midya, Ambarish S Pawar, Debi P Pattnaik, Eric Mooshagian, Pavel Borisov, Thomas D Albright, Lawrence H Snyder, R Stanley Williams, J Joshua Yang, Alexander G Balanov, Sergei Gepshtein, Sergey E Savel'ev

2020-Current year OA Pubs

Rapid development of memristive elements emulating biological neurons creates new opportunities for brain-like computation at low energy consumption. A first step toward mimicking complex neural computations is the analysis of single neurons and their characteristics. Here we measure and model spiking activity in artificial neurons built using diffusive memristors. We compare activity of these artificial neurons with the spiking activity of biological neurons measured in sensory, pre-motor, and motor cortical areas of the monkey (male) brain. We find that artificial neurons can operate in diverse self-sustained and noise-induced spiking regimes that correspond to the activity of different types of cortical …

Feasibility And Preliminary Efficacy Of A Lymphedema And Fibrosis Self-Management Program For Head And Neck Cancer Survivors: A Pilot Randomized Controlled Trial, Jie Deng, Barbara Murphy, Lucy Andersen, Erin Mcmenamin, John Lukens, Joy Cohn, Karthik Rajasekaran, Ryan Quinn, Bryan Spinelli, Alexander Lin

Department of Physical Therapy Faculty Papers

OBJECTIVES: Survivors of head and neck cancer (HNC) are at high risk for developing lymphedema and fibrosis (LEF). Once diagnosed with LEF, survivors must engage in a lifelong program of self-care to minimize long-term adverse effects. However, evidence-based LEF self-management (SM) programs are lacking. To fill this void, we developed and pilot-tested a LEF-SM program for HNC survivors.

MATERIALS AND METHODS: The LEF-SM Program was developed using the Information-Motivation-Behavioral Skills model of health behavior change as a framework. The program was pilot tested in a three-group randomized controlled trial evaluating feasibility and preliminary efficacy. Fifty-nine participants were randomized to: Usual …

Analysis Of Lifespan Across Diversity Outbred Mouse Studies Identifies Multiple Longevity-Associated Loci., Martin N Mullis, Kevin M Wright, Anil Raj, Daniel M Gatti, Peter C. Reifsnyder, Kevin Flurkey, Jonathan R Archer, Laura Robinson, Andrea Di Francesco, Karen L. Svenson, Ron Korstanje, David E Harrison, J Graham Ruby, Gary Churchill

Faculty Research 2025

Lifespan is an integrative phenotype whose genetic architecture is likely to highlight multiple processes with high impact on health and aging. Here, we conducted a genetic mega-analysis of longevity in Diversity Outbred (DO) mice that included 2,444 animals from 3 independently conducted lifespan studies. We identified 8 loci that contributed significantly to lifespan independently of diet and drug treatment in at least one study. One of these loci also influenced lifespan in a sex-dependent manner, and we detected an additional locus with a diet-specific effect on lifespan. Collectively, these loci explained over half of the estimated heritable variation in lifespan …

Rare Variants In Bmal1 Are Associated With A Neurodevelopmental Syndrome, Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U. Rehman, Carol J. Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W. Scherer, Ingo Helbig, Amita Sehgal

Manuscripts, Articles, Book Chapters and Other Papers

Through international gene-matching efforts, we identified 10 individuals with ultrarare heterozygous variants, including 5 de novo variants, in BMAL1, a core component of the molecular clock. Instead of an isolated circadian phenotype seen with disease-causing variants in other molecular clock genes, all individuals carrying BMAL1 variants surprisingly share a clinical syndrome manifest as developmental delay and autism spectrum disorder, with variably penetrant sleep disturbances, seizures, and marfanoid habitus. Variants were functionally tested in cultured cells using a Per2-promoter driven luciferase reporter and revealed both loss-of-function and gain-of-function changes in circadian rhythms. The tested BMAL1 variants disrupted PER2 mRNA …

Genetic Overlap Between Functional Impairment And Depression And Anxiety Symptom Severity: Evidence From The Glad Study, Megan Skelton, Jessica Mundy, Abigail Ter Kuile, Brett Adey, Cherie Armour, Joshua Buckman, Jonathan Coleman, Molly Davies, Colette R. Hirsch, Matthew Hotopf, Ian Jones, Gursharan Kalsi, Georgina Krebs, Sang Hyuck Lee, Yuhao Lin, Andrew M. Mcintosh, Alicia J. Peel, Christopher Rayner, Katharine Rimes, Daniel J. Smith, Katherine N. Thompson, David Veale, James T.R. Walters, Christopher Hübel, Gerome Breen, Thalia C. Eley

School of Psychology

BACKGROUND: Functional impairment in daily activities, such as work and socializing, is part of the diagnostic criteria for major depressive disorder and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms, and functional impairment.

METHODS: In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analyzed total scores …

Association Between Allostatic Load And Accelerated White Matter Brain Aging: Findings From The Uk Biobank, Li Feng, Zhenyao Ye, Zewen Du, Yezhi Pan, Travis Canida, Hongjie Ke, Song Liu, Shuo Chen, L Elliot Hong, Peter Kochunov, Jie Chen, David K Y Lei, Edmond Shenassa, Tianzhou Ma

Faculty, Staff and Student Publications

White matter (WM) brain age, a neuroimaging-derived biomarker indicating WM microstructural changes, helps predict dementia and neurodegenerative disorder risks. The cumulative effect of chronic stress on WM brain aging remains unknown. In this study, we assessed cumulative stress using a multi-system composite allostatic load (AL) index based on inflammatory, anthropometric, respiratory, lipidemia, and glucose metabolism measures, and investigated its association with WM brain age gap (BAG), computed from diffusion tensor imaging data using a machine learning model, among 22 951 European ancestries aged 40 to 69 (51.40% women) from UK Biobank. Linear regression, Mendelian randomization, along with inverse probability weighting, …