Digital Commons Network^™

Quantitative Imaging Of Pyruvate Metabolism In A Patient With Anaplastic Thyroid Cancer, James A Bankson, Joshua S Niedzielski, Collin J Harlan, Yunyun Chen, Christopher M Walker, Philip L Lorenzi, Lin Tan, Vikas Kundra, Matthew E Merritt, Mukundan Ragavan, Dawid Schellingerhout, Renjie He, Yao Ding, Sahana Datar, Qing Wang, Christine B Peterson, Clifton D Fuller, Vlad C Sandulache, Stephen Y Lai

Faculty, Staff and Students Publications

Purpose: Magnetic resonance imaging using hyperpolarized (HP) [1-13C]-pyruvate enables assessment of pyruvate metabolism in vivo and offers new insight into metabolic changes in response to cancer therapy. Widely used semi-quantitative metrics of pyruvate metabolism can be affected by physiological factors that are extrinsic to intracellular metabolism. A validated pharmacokinetic (PK) model for analysis of intracellular pyruvate metabolism is needed to enhance the accuracy of quantitative metrics and clinical translation of metabolic MRI using HP pyruvate.

Methods: A PK model with two physical compartments and two chemical pools was developed to analyze the conversion of labeled pyruvate into lactate in vitro. …

Colocalization Of Eqtls With Type 2 Diabetes And Glycemic Traits Using Whole-Genome Sequences In Diverse Populations From The Nhlbi Trans-Omics In Precision Medicine (Topmed) Program, Ningyuan Wang, Daniel A Dicorpo, Yixin Zhang, Erica Kleinbrink, Donna K Arnett, John Barnard, John Blangero, Donald W Bowden, April P Carson, Yii-Der Ida Chen, Mina K Chung, Joanne E Curran, Dawood Darbar, Ravindranath Duggirala, Patrick T Ellinor, Diane Fatkin, Myriam Fornage, Nancy Heard-Costa, Jiang He, Lifang Hou, Sharon L R Kardia, Charles Kooperberg, Ruth J F Loos, David D Mcmanus, Braxton D Mitchell, Ryan L Minster, Kari E North, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Dan Roden, Jerome I Rotter, Moore B Shoemaker, Jonathan D Smith, David R Van Wagoner, Francois Aguet, Kristin Ardlie, Joshua C Bis, Jennifer A Brody, Brian E Cade, Clary B Clish, Paul S De Vries, James S Floyd, Barry I Freedman, Stacey Gabriel, Robert E Gerzsten, Mark O Goodarzi, Charles Gu, Xiuqing Guo, Namrata Gupta, Susan R Heckbert, Sarah Hsu, Yi-Jen Hung, Rita R Kalyani, Tanika N Kelly, Gregory L Kinney, Changwei Li, Simin Liu, Yongmei Liu, Donald M Lloyd-Jones, Joann E Manson, Rasika A Mathias, Josep M Mercader, Alanna C Morrison, Take Naseri, Suna Onengut, Nicholette D Palmer, Patricia A Peyser, Qibin Qi, Sridharan Raghavan, Alex P Reiner, Mary R Rooney, Magdalena Sevilla-Gonzalez, Chloe Sarnowski, Joshua D Smith, Jennifer A Smith, Nicole L Spartano, Usman Tahir, Kent D Taylor, Deirdre K Tobias, Russel P Tracy, Satupa'itea Viali, Heming Wang, Alexis C Wood, Lisa R Yanek, Wei Zhao, Yinan Zheng, Josée Dupuis, Ching-Ti Liu, Robert Sladek, Jennifer Wessel, James B Meigs, Alisa K Manning, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium

Faculty, Staff and Students Publications

Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to …

Proteomic Signatures Of 3-Year Progression From Impaired Fasting Glucose To Diabetes: The Atherosclerosis Risk In Communities (Aric) Study, Mary R Rooney, Justin B Echouffo Tcheugui, Jingsha Chen, Keenan A Walker, Christie M Ballantyne, Eric Boerwinkle, Tanika N Kelly, Chiadi E Ndumele, James S Pankow, Morgan E Grams, Wendy S Post, Peter J Ganz, Alexis C Wood, Jerome I Rotter, Elizabeth Selvin, Josef Coresh

Faculty, Staff and Students Publications

Objective: To identify proteomic signatures underlying 3-year progression from impaired fasting glucose (IFG) to diabetes.

Research design and methods: We examined IFG progression in the Atherosclerosis Risk in Communities (ARIC) study from visit 2 (1990-1992) to visit 3 (1993-1995). We tested associations of 4,955 plasma proteins (SomaScan version 4.0) with ∼3-year progression from IFG (FG 100-125 mg/dL without diabetes) to diabetes (diagnosis, medication, or FG ≥126 mg/dL) using logistic regression models adjusted for demographics, cardiometabolic risk factors, and baseline glucose with Bonferroni correction (P < 10-5). We explored biological pathways enriched among the top proteins and calculated improvements in prediction (ΔAUC and net reclassification using 3-year risk thresholds of 6% and 15% in 80% training and 20% internal validation subsamples). We validated results in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.

Results: There were 3,786 ARIC participants with IFG (mean [SD] age 57 [6] years, 52% female, …

De Novo Complex Genomic Rearrangement Spanning 2q31.1 In A Proband With Congenital Malformations: Genotype-Phenotype Correlation And Development Of A Cgr Detection Pipeline, Katherine Helle, Jesse D Bengtsson, Mira Gandhi, Christopher M Grochowski, Ming Yin Lun, Neha Sudhir, Shalini N Jhangiani, Fritz J Sedlazeck, Seema R Lalani, Neil A Hanchard, Claudia M B Carvalho

Faculty, Staff and Students Publications

The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in-house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read-depth data revealed a de novo complex genomic rearrangement (CGR) spanning 2.7 Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short-read and long-read GS, and optical genome mapping (OGM). This in-house …

Impact Of Prematurity On Nutrient Signaling And Protein Synthesis In Skeletal Muscle, Antonio C Ramos Dos Santos, Ki Beom Jang, Marta L Fiorotto, Teresa A Davis

Faculty, Staff and Students Publications

Preterm birth disrupts nutrient-responsive signaling pathways critical for skeletal muscle growth and long-term metabolic health. Despite improvements in neonatal care, preterm infants often experience postnatal growth failure marked by impaired lean mass accretion. This review examines how prematurity intrinsically alters insulin and amino acid signaling to mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of translation initiation and protein synthesis. Evidence from translational models reveals blunted activation of mTORC1 and its downstream effectors, independent of birth weight or comorbidities. Defects in insulin-PDK1/mTORC2-Akt signaling and amino acid sensing, particularly leucine sensing, contribute to impaired mTORC1-dependent translation initiation and reduced …

Sez6-Targeting Antibody-Drug Conjugate Abbv-706 In Advanced Small Cell Lung Cancer And Solid Tumors: A Phase 1 Trial, Lauren Averett Byers, Daniel Morgensztern, Et Al.

2020-Current year OA Pubs

Seizure-related homolog 6 (SEZ6) is expressed in small cell lung cancer (SCLC) and neuroendocrine neoplasms. In an open label, phase 1 trial, ABBV-706, an antibody-drug conjugate with a SEZ6-directed antibody linked to topoisomerase-1 inhibitor (Top1i), was administered intravenously every 3 weeks (Q3W) to 288 patients with advanced solid tumors; 240 received monotherapy, including 124 with relapsed/refractory (R/R) SCLC. Primary objectives of dose escalation (part 1, advanced solid tumors), dose optimization and expansion (part 2, R/R SCLC only) and dose expansion (part 4, central nervous system tumors and high-grade neuroendocrine neoplasms only) were to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity …

Ophthoevidence Report: Comparative Effects Of Prophylactic Strategies For Post-Intravitreal Injection Endophthalmitis: Protocol For A Systematic Review And Network Meta-Analysis, Maryam Ghadimi, Dena Zeraatkar, João Pedro Lima, Jinhui Ma, Sunir J. Garg, Peter Kaiser, David Steel, Tien Yin Wong, Sobha Sivaprasad, Charles Wykoff, Varun Chaudhary

Wills Eye Hospital Papers

BACKGROUND: Endophthalmitis is a rare but serious complication of intravitreal injections (IVI). To mitigate the risk of post-injection endophthalmitis (PIE), retinal specialists use different strategies, combining various prophylactic measures. However, existing systematic reviews have evaluated the effects of these measures in isolation, which does not consider their concurrent use in practice. A trustworthy systematic review with network meta-analysis (NMA) by providing a framework for simultaneous comparisons of different prophylactic combinations is essential to guide decision-making.

OBJECTIVES: To present a protocol for addressing the comparative effects of different strategies for the prevention of PIE.

METHODS: We will search Medline, EMBASE, Cochrane …

Under Pressure: Negative Urgency And Disordered Eating In The Context Of Parental Differential Support, Hamide Gozu, Jenna K. Rieder

College of Humanities and Sciences Faculty Papers

Disordered eating behaviors are prevalent in emerging adulthood and may be shaped by family dynamics. This study examined associations among maternal and paternal differential support, weight-shape concerns, and binge eating and compensatory behaviors in emerging adulthood, while testing the moderating role of negative urgency. Participants were 517 emerging adults from across the United States (ages 18-29; M = 22.60, SD = 3.81; 76% female). Participants reported on parental differential support, weight-shape concerns, eating behaviors, and negative urgency. Using moderated-mediation analyses, we found that weight-shape concerns mediated associations between differential support and eating behaviors. Unequal maternal support and paternal favoritism showed …

Effects Of Non-Surgical Periodontal Therapy On Dental Plaque Microbiome, Qingguo Wang, Bing-Yan Wang, Derek Wilus, Hua Xie

Faculty, Staff and Student Publications

Periodontitis, a chronic inflammatory disease affecting approximately 40% of U.S. adults aged 30 years and older, is characterized by dysbiosis of the dental plaque microbiome. However, although scaling and root planing (SRP) is the cornerstone of periodontal treatment, its effects on the taxonomic composition and functional potential of the dental plaque microbiome remain incompletely understood. In this study, we used whole-metagenome shotgun sequencing to characterize taxonomic composition and functional potential in dental plaque microbiomes collected from 39 patients with Stage II or III generalized periodontitis before and 3–4 months after SRP. Consistent with clinical improvement, periodontal therapy significantly reduced probing …

Neural-Immune-Cardiovascular Axis: From Mechanistic Crosstalk To Therapeutic Targets In Cardiovascular Disease, Junkang Cheng, Shuang Gao, Haowei Zhang, Wei Gao, Zeyuan Mei, Xiaoling Liu, Jocelyn Gao, Chenghu Guo, Guipeng An

Student Papers, Posters & Projects

The neural-immune-cardiovascular axis represents an emerging and highly integrated physiological and pathophysiological concept, describing a complex bidirectional communication network between the nervous, immune, and vascular systems. This review systematically examines the pivotal role of this axis in maintaining cardiovascular homeostasis and in the pathogenesis of cardiovascular diseases. We first provide an overview of the fundamental signaling pathways between the components of this axis. Subsequently, we delve into the specific crosstalk mechanisms within the axis in the context of major cardiovascular conditions, including atherosclerosis, hypertension, and heart failure. A central focus is placed on critically evaluating the potential therapeutic targets and …

Loss Of Atp-Dependent Citrate Lyase Drives Left Ventricular Dysfunction By Metabolic Remodeling, Shijie Liu, Seth T Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Mahmoud H Elbatreek, Adrian Arrieta, Ian K Williamson, Rebecca L Salazar, Janet Pham, Angela Davidian, Radhika Khanna Neicheril, Benjamin D Gould, Heidi Vitrac, Alia Sadiq, An Q Dinh, Evan C Lien, Francisca N De Luna Vitorino, Joanna M Gongora, Sara A Martinez, Melanie T Odenkirk, Anna K Boatman, Jessie R Chappel, Lawrence S C Czer, Evan P Kransdorf, David J Lefer, Blake M Hanson, Benjamin A Garcia, Erin M Baker, Matthew G Vander Heiden, Philip L Lorenzi, Heinrich Taegtmeyer, David Piwnica-Worms, James F Martin, Anja Karlstaedt

Faculty, Staff and Student Publications

Background: Metabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase, Acly), which produces acetyl-coenzyme A (CoA) from citrate and CoA and supports de novo lipid synthesis. However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated.

Methods: We used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced …

Molecular Mechanism Leading To Human Coronary Atherosclerosis Assessed By Proteomic Analysis And Rna Sequences, Sarah J Parker, Chunhong Mao, David L Caudell, Austin Lyle Seals, Yizhi Wang, Thomas D Green, Joseph M Mcclung, Joshua T Maxwell, Jacolby T Roddey, Kiarash Shakeriastani, Chiung-Ting Wu, Yingzhou Lu, Do-Kyun Kim, Justyna Fert-Bober, Dongping Du, Archana Bhat, Niveda Sundararaman, Matthew Ayres, Rakhi Pandey, Saurabh Bhardwaj, Genesio M Karere, Dana Troxclair, Fannie Jackson, Gordon L Love, Richard Vander Heide, James Hixson, Jennifer E Van Eyk, Yue Wang, David Herrington

Faculty, Staff and Student Publications

Background and aims: Atherosclerosis results from cellular and extracellular changes in the arterial wall, preceded by molecular shifts that initiate disease and drive tissue conversion, yet these changes are not yet fully described. More data are needed concerning these early changes in the coronary artery molecular landscape that signify the initiation of atherosclerosis and the subsequent tissue pheno-conversion to atherosclerotic plaque. This report summarizes results from a large biorepository of human coronary artery tissue, applying state-of-the-art omics technology, advanced data analytic methods, and an arterial organoid model system to predict molecular dynamics and identify potential regulatory mechanisms that could interrupt …

Rsv Can Infect The Human Nasal Epithelium Via The Basolateral Route And Shows Distinct Subgroup Infectivity And Basal Cell Tropism, Ashley Murray, Divya Nagaraj, Emily M Schultz, Gina Aloisio, Erin Nicholson, Sarah E Blutt, Vasanthi Avadhanula, Pedro A Piedra

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) causes millions of lower respiratory tract infections (LRTIs) in young children, older adults, and immunocompromised populations every year. RSV infection initiates in the upper respiratory tract and can progress to the lower airways, resulting in bronchiolitis, pneumonia, and even death. RSV primarily infects epithelial cells apically, but we hypothesized that basolateral exposure of the respiratory epithelium could provide an alternative mechanism of infection that contributes to LRTI development. Using a human nose organoid-air-liquid interface (HNO-ALI) model, we performed apical and basolateral inoculations with contemporaneous RSV strains (RSV/A/Ontario [RSV/A/ON] and RSV/B/Buenos Aires [RSV/B/BA]) representing the two RSV …

Interstitial Fluid N-Glycans Serve As A Proxy For Serum Biomarker Discovery In A Pilot Study, Radka Saldova, Talus K. Gaymore, Caitriona Walsh, Eder Zavala, Paula M. Mendes

Student Papers, Posters & Projects

Protein glycosylation is the most prevalent post-translational modification and is known to undergo profound alterations in disease. While serum N-glycosylation has been extensively studied, interstitial fluid is gaining prominence as a minimally invasive biomarker source, underscored by the widespread clinical adoption of wearable glucose monitors in diabetic patients. However, the glycomic landscape of interstitial fluid remains largely unexplored. Here, we have performed a comparative analysis of the N-glycome from interstitial fluid and matched plasma from five healthy volunteers using liquid chromatography, mass spectrometry and exoglycosidase digestions. Strikingly, the interstitial fluid N-glycome closely shows overlapping profiles with the plasma of each …

Neurofilament Light Chain (Nfl) As A Surrogate Outcome Measure For Gm2 Gangliosidoses., Kyriakos Martakis, Nicolas J. Abreu, Joshua J. Baker, Peter R. Baker Ii, Ian Billington, T Andrew Burrow, Mallory Factor, Taylor Fields, Cassandra Fields, Jennifer L. Gannon, Megan Grosso, Jorgji Kerthi, Marc C. Patterson, Brian J. Shayota, Michael Strupp, Lennard Strupp, Tatiana Bremova-Ert

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The GM2 gangliosidoses (GM2) are ultra-rare neurodegenerative disorders caused by deficient hexosaminidase A and/or B activity, leading to lysosomal GM2 ganglioside accumulation. Disease onset ranges from infancy to adulthood, with earlier onset associated with more rapid progression. Neurofilament light chain (NfL), a sensitive marker of axonal injury, has been extensively investigated as a biomarker for neurodegenerative disorders, including GM2.

METHODS: To evaluate its clinical utility as a biomarker for GM2, NfL was measured in patients with GM2 enrolled in a Phase 2b, multinational, rater-blinded study of levacetylleucine [NCT03759665], and in its open-label Extension Phase (EP).

RESULTS: Nineteen participants had …

Tau Seeds Induce Neurofibrillary Tangle Formation Across Brain Regions Via Individual-Specific Connectivity, Audrey J Weber, Bernard Ng, Kelsey M Greathouse, David A Bennett, Shinya Tasaki, Chris Gaiteri, Jeremy H Herskowitz

Faculty, Staff and Student Publications

The spread of tau pathology across the cerebral cortex is closely tied to cognitive decline in Alzheimer's disease (AD). To investigate mechanisms underlying tau spread, we measured bioactivity of tau seeds from inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) synaptosomes in 128 individuals and demonstrated that tau seed bioactivity associates with tau phosphorylation, neurofibrillary tangles (NFTs), and cognitive impairment. Incorporating genotype data from the same individuals within a Mendelian randomization framework showed that tau seeds in ITG induce NFTs locally as well as drive tau seeds and NFTs in SFG. Integrating antemortem functional magnetic resonance imaging data from …

Exploring Factors Associated With High Frequency Emergency Department Use By Children And Young People: A Retrospective Cohort Study, Akshay Kumar, Rebecca M Simpson, Kerryn Husk, Graham D Johnson, Chris Burton

Peninsula Medical School

Objective To explore drivers of high frequency emergency department (ED) use by children and young people, particularly among those attending EDs most often.Design A population-based retrospective cohort study using routinely collected linked healthcare data.Setting EDs in the Yorkshire and Humber region of the UK.Patients 288 545 children and young people aged 17 and under making at least one ED attendance in the year period 1 April 2016 to 31 March 2017.Main outcome measures ED attendances made by individuals in the year period.Results Of the 288 545 distinct children and young people making at least one attendance to an ED, 27 …

Llm-As-A-Judge For Infection Prevention And Control And Antimicrobial Resistance Impact: Comparing Three Main Llms Vs. Human Experts' Assessment, Marcello Di Pumpo, Leonardo Villani, Maria Rosaria Gualano, Danilo Buonsenso, Francesca Raffaelli, Daniele Donà, Patrizia Laurenti, Vittorio Maio, Stefania Boccia, Walter Ricciardi

College of Population Health Faculty Papers

BACKGROUND: Large language models (LLMs) are increasingly used to generate health information, yet their reliability as evaluators remains unclear. This study investigated the feasibility of an LLM-as-a-judge methodology in the context of infection prevention and antimicrobial resistance (AMR), comparing automated ratings with human expert benchmarks.

METHODS: We performed a secondary analysis of an expert-annotated dataset of health messages. Three leading LLMs (ChatGPT, Claude, Gemini) independently evaluated the same messages using an adapted DISCERN tool across five domains: information reliability, quality, AMR impact, persuasiveness, and overall score. We utilized descriptive statistics, intra-rater reliability tests, and mixed-effects ordinal regression to analyze divergence …

Food As Medicine: Effects Of A Culinary Medicine Food-Demonstration On Medical Students' Nutrition Knowledge, Confidence, And Satisfaction: An Exploratory Pilot Non-Randomized Pre-Post Intervention Study., Niayesh Mardmomen, Cyrus Fatemi, Olivia K Smith, Michael B. Roberts, Farzaneh Daghigh

PCOM Scholarly Works

Background: Diet plays a central role in the development of chronic diseases, making nutrition-focused interventions a powerful tool for improving population health. However, substantial gaps in nutrition education persist in the U.S. medical education, and medical students frequently report receiving limited nutrition training despite its importance in patient care. Methods: A non-randomized pre-post intervention study with a one-month follow-up was conducted among osteopathic medical students. Participants attended a culinary medicine food-demonstration featuring five case-based topics and three chef-prepared recipes. Nutrition knowledge, satisfaction with nutrition education, confidence in nutrition counseling, and personal nutrition-related behaviors were assessed at baseline, immediately …

Longitudinal Genomic Surveillance Of Sars-Cov-2 In A University Microcosm Reflects Global Evolutionary Trends, Sankar Prasad Chaki, Melissa M Kahl-Mcdonagh, Benjamin W Neuman, Loni A Taylor, Rebecca S B Fischer, Blake M Hanson, Marlisa S Hardy, Jo Ann Culpepper, Eric Boerwinkle, Kurt A Zuelke

Faculty, Staff and Student Publications

SARS-CoV-2 transmission has declined, yet ongoing viral evolution continues to pose public health challenges. This study conducted long-term (2020-2024) genomic surveillance within a large and globally diverse university community. Viral genomes obtained from clinical (n = 1,786) and surveillance (n = 888) testing samples were classified under clade, lineage, and variant systems, and compared with global genomic data sets. Local patterns broadly paralleled global evolutionary trends, including the phased emergence of major variants, episodic introductions of new lineages, and shifts in dominant clades. Lineage diversity peaked during fall semesters and was highest among undergraduate-aged individuals, with similar distributions …

Prenatal Predictors Of Fetal And Neonatal Death In Truncus Arteriosus: A Fetal Heart Society Research Collaborative Study., Kelly Cox, Nazia Husain, Deidra Ansah, Tiffany Knight, Alexandra Channing, Bettina Cuneo, Preeta Dhanantwari, Mary Donofrio, Miwa Geiger, Lisa Howley, Lisa K. Hornberger, Simone Javeri, Edward G. Jones, Michelle Kaplinski, Ann Kavanaugh-Mchugh, Maria Kiaffas, Katherine Kosiv, Christina Laternser, Olivia Low, Anita J. Moon-Grady, Shabnam Peyvandi, Nelangi Pinto, Avaliese Porlier, Aaron Prosnitz, Rashmi Rao, David Schidlow, Elena Sinkovskaya, Ranjini Srinivasan, Corey Stiver, Emilio Quezada, Bhawna Arya, Sheetal Patel

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Fetal and neonatal outcomes and factors increasing mortality risk in fetal truncus arteriosus are not well characterized. We aimed to examine the prenatally encountered cardiac spectrum, define extracardiac and genetic associations, explore clinical outcomes and identify prenatal factors associated with worse outcomes in a contemporary large cohort.

METHODS: A multicenter retrospective cohort study was conducted via the Fetal Heart Society Research Collaborative including fetal truncus arteriosus cases encountered between January 1, 2010, and September 1, 2021, within 22 North American cardiac centers. Demographic, clinical, anatomic, and functional fetal echocardiographic variables were analyzed for associations with presurgical death (fetal death/neonatal …

Multiple Event Segmentation Mechanisms In The Human Brain, Tan T Nguyen, Joset A Etzel, Matthew A Bezdek, Jeffrey M Zacks

2020-Current year OA Pubs

The human brain segments continuous experience into discrete events, with theoretical accounts proposing two distinct mechanisms: creating boundaries at points of high

Feasibility Evaluation Of Tumor Treating Fields For Brainstem Gliomas, Anthony Chen, Ryan Shah, William Shi, Noa Urman, Nadav Shapira, Nicholas Avgeropoulos, Patrick Conlon, Neil Mookerjee, Wenyin Shi

Department of Radiation Oncology Faculty Papers

PURPOSE: Tumor treating fields (TTFields) are FDA-approved for supratentorial glioblastoma, but feasibility in infratentorial tumors remains poorly defined. This simulation study evaluated TTFields dose in brainstem gliomas using patient-specific modeling with scalp-only transducer arrays.

METHODS: MRI and CT imaging from seven patients with brainstem gliomas were used for TTFields planning with MAXPOINT® (Novocure, Switzerland). Clinical target volume (CTV) was defined as enhancing tumor on T1 post-contrast MRI (Gross tumor volume, GTV) plus a 3 mm peritumoral expansion. The platform optimized scalp-only array layouts, and finite element calculations generated maps of local minimum field intensity (LMiFI, V/cm) and local minimum power …

Long-Term Inactivation Mediated By Different Fgf-A Homologues On Heterologously Expressed Nav1.2 Currents, Yenisleidy Lorenzo-Ceballos, Pedro L Martinez-Espinosa, Xiao-Ming Xia, Christopher J Lingle

2020-Current year OA Pubs

A-isoforms of cytosolic growth factor homologous factors (FGF11-14) mediate long-term inactivation (LTI) of voltage-dependent sodium (NaV) channels. LTI is a rapid onset process that is competitive with the fast inactivation (IF) intrinsic to NaV channels, with little or no interconversion between inactivated states. Since recovery from LTI is orders of magnitude slower than recovery from IF, repetitive depolarizations lead to use-dependent accumulation of NaV channels in slow recovery states, thereby limiting NaV availability during trains of action potentials. Of the two or more N-terminal splice variants of the various FGF homologues, LTI specifically arises only from the A-isoform of each …

High-Order Brain Interactions During Ketamine-Induced State Changes: A Functional Marker Of Response In Late-Life Treatment-Resistant Depression?, Krisha Shah, Rubén Herzog, Alan C Swann, Brittany O'Brien, Rahul Balakrishnan, Sanjay J Mathew, Nicholas Murphy

Faculty, Staff and Students Publications

Ketamine is a fast-acting intervention for treatment-resistant depression (TRD), yet only a subset of patients show robust clinical response, and the underlying neural mechanisms remain unclear. High-order interactions (HOI) derived from multivariate information theory provide a framework for examining nonlinear dependencies among brain regions beyond pairwise connectivity. One such metric, the O-information, captures the balance between synergistic and redundant interactions across three or more variables. In this secondary analysis of a randomized, double-blind, midazolam-controlled trial (NCT02556606), we examined EEG-derived HOI in 30 late-life veterans with TRD following a single 40-minute intravenous infusion of ketamine (0.1, 0.25, 0.5 mg/kg; n = …

Advancing Bioinformatics With Language Models: Components, Applications, And Perspectives, Jiajia Liu, Mengyuan Yang, Yankai Yu, Haixia Xu, Tiangang Wang, Kang Li, Xiaobo Zhou

Faculty, Staff and Student Publications

Large language models (LLMs) are deep learning-based artificial intelligence models that have achieved remarkable success in natural language processing. Typically composed of neural networks with billions of parameters, they are trained on massive unlabeled datasets using self-supervised or semi-supervised learning. Beyond language, LLMs hold immense potential for addressing complex bioinformatics challenges. This review provides a comprehensive overview of transformer-based model applications in genomics, transcriptomics, proteomics, drug discovery, and single-cell analysis. We discuss critical components, including tokenization strategies for diverse biological data, transformer architectures, attention mechanisms, and pretraining approaches. We also survey currently available foundation models and their downstream applications across …

Bi-Allelic Loss-Of-Function Variants In Tmem63b Cause Syndromic Surfactant Dysfunction Disorder, Sock Hoai Chan, Audra N Iness, Jill A Rosenfeld, Mir Reza Bekheirnia, Lindsay C Burrage, Matthew Hoi Kin Chau, Chaerish Eint Myet Chae Htoo, Eric C Kao, Shamika Ketkar, Wan Wan Lim, Xi Luo, Rifhan Mazlan, Elizabeth Mizerik, Kein Seong Mun, Kalyani R Patel, Lorraine Potocki, Christina K Rapp, Xavier Roca, Ana Saianda, Ignacio Iglesias-Serrano, Everlyn C Siew, Donald Yuhui Sim, David R Spielberg, Sok-Kun Tae, Jing Xian Teo, Julian Warfsmann, Fan Xia, Child-Eu Registry, Saumya S Jamuar, Ee Shien Tan, Matthias Griese, Weng Khong Lim, Meow-Keong Thong, Keren Machol

Faculty, Staff and Students Publications

Transmembrane protein 63B gene (TMEM63B) encodes a mechanosensitive ion channel expressed in alveolar type II epithelial cells, where it mediates stretch-induced surfactant secretion. While heterozygous gain-of-function variants in TMEM63B have been associated with developmental and epileptic encephalopathy, no human disorder has previously been linked to bi-allelic loss-of-function variants. Here, we report five individuals from four unrelated families with childhood interstitial lung disease and bi-allelic predicted loss-of-function variants in TMEM63B. Affected individuals presented with early-onset respiratory distress, chronic hypoxemia, and diffuse parenchymal lung abnormalities on chest imaging. One individual died in infancy, two underwent bilateral lung transplantation, and two require oxygen …

The Critical Pediatric Obesity Window: Pre-Pubertal Metabolic Disease And The Fallacy Of Delayed Intervention., Matthew Lindquist, Brooke Sweeney

Manuscripts, Articles, Book Chapters and Other Papers

Despite increasing recognition of pediatric obesity as a chronic disease, many clinicians continue to rely on "watchful waiting," assuming pubertal growth will mitigate excess weight and metabolic risk. Current evidence contradicts this approach. Children under 12 years of age with obesity frequently demonstrate clinically significant metabolic disease, including insulin resistance, dyslipidemia, dysglycemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), often before symptoms emerge. Puberty does not reverse these processes; rather, physiologic pubertal insulin resistance amplifies preexisting metabolic dysfunction and accelerates disease progression. Delayed intervention allows potentially irreversible injury during a critical period of metabolic plasticity. This article reviews contemporary biologic …

Functional Assessment Of A Convergent Gene Network Underlying Allergic Diseases And Ige., Pradeep Eranti, Raphaël Vernet, Christophe Linhard, Bing Ge, Laura Beaumier, Anne-Marie Madore, Sébastien Chanoine, Bénédicte L. Tremblay, Xiaojian Shao, Isabelle Pin, Mark Lathrop, Elin Grundberg, Valérie Siroux, Tomi Pastinen, Catherine Laprise, Emmanuelle Bouzigon, Florence Demenais

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The relationships between allergic diseases (AD) and IgE levels are complex.

OBJECTIVE: We sought to identify genes associated with AD and IgE having close proximity in the interactome and to elucidate the associated biological mechanisms.

METHODS: We integrated a comprehensive interactome with data from genome-wide (GWAS) and epigenome-wide (EWAS) association studies of AD and IgE levels, respectively. We used the SigMod algorithm to identify gene modules enriched in AD- and IgE-associated signals. We performed a connectivity analysis of these two modules to characterize direct cross-trait connections. Finally, we conducted an in-depth functional analysis of the directly-connected AD and IgE …

Acute Intermittent Hypoxia And Acute Intermittent Hypercapnic Hypoxia Elicit Cortico-Diaphragmatic Plasticity In People With Chronic Spinal Cord Injury, Alysha Bogard, Michela Mir, Tommy Sutor, Jessica Dunn, Kathryn Cavka, Arian Vistamehr, Hannah Snyder, Joseph Welch, Jayakrishnan Nair, Gina Brunetti, Gordon Mitchell, Emily Fox

Department of Physical Therapy Faculty Papers

Respiratory impairment is a leading cause of morbidity and mortality after spinal cord injury (SCI), highlighting the need for interventions that improve breathing function. In people with SCI, acute intermittent hypoxia (AIH) elicits respiratory motor plasticity and improves inspiratory function. However, in uninjured people facilitation of corticospinal diaphragm motor evoked potential (MEP) amplitude occurs only when AIH is combined with mild hypercapnia (acute intermittent hypercapnic hypoxia; AIHH). It remains unclear whether AIHH similarly enhances diaphragm corticospinal excitability after SCI. We tested the hypothesis that AIHH increases diaphragm MEP amplitude and reduces MEP onset latency in individuals with chronic SCI, whereas …