Digital Commons Network^™

The Association Between Apoe Genotype, Race, And Dementia: An Analysis Of 7 Population-Based Cohort Studies, Natalia Lakomski, Katherine Giorgio, John Stephen, Maxwell Mansolf, Aïcha Soumaré, Alden L Gross, Allison E Aiello, Archana Singh-Manoux, M Arfan Ikram, Catherine Helmer, Claudia L Satizabal, Deborah A Levine, Donald M Lloyd-Jones, Emily M Briceño, Farzaneh A Sorond, Frank J Wolters, Jayandra J Himali, Lenore J Launer, Djass Mbangdadji, David Li, Lihui Zhao, Oscar L Lopez, Stéphanie Debette, Sudha Seshadri, Suzanne E Judd, Timothy M Hughes, Vilmundur Guðnason, Michael Griswold, Paul S De Vries, Alison Fohner, Pamela L Lutsey, Rachel Zmora, Elizabeth A Peterson, Denise Scholtens, Norrina B Allen, Sanaz Sedaghat

Faculty, Staff and Student Publications

Background and objectives: The apolipoprotein E (APOE) haplotypes are known to be associated with dementia, with the ε4 haplotype associated with higher risk. It has been suggested that the APOE ε2 allele serves as a protective factor for dementia. However, data on the effects of the homozygous APOE ε2/ε2 genotype are limited, likely due to the rarity of the APOE ε2/ε2 genotype. Furthermore, the association between APOE genotypes and dementia may differ across self-reported race. We aim to investigate the association between APOE genotypes and dementia overall and across self-reported race, with a focus on the potential protective …

Extending Genome-Wide Association Studies To Admixed Cohorts With High Degrees Of Relatedness, Taotao Tan, Alejandra Vergara-Lope, José Jaime Martínez-Magaña, Nirav N Shah, Yi-Sian Lin, Kai Yuan, Jaime Berumen, Jesus Alegre-Díaz, Pablo Kuri-Morales, Roberto Tapia-Conyer, Joel Gelenter, Janitza L Montalvo-Ortiz, Wei Zhou, Jason M Torres, Elizabeth G Atkinson

Duncan NRI Faculty and Staff Publications

Admixed populations comprise a large portion of the human population worldwide, but are often excluded from genome-wide association studies (GWASs) due to analytic challenges. Our group developed Tractor, a local-ancestry-informed GWAS tool designed for admixed samples that produces accurate ancestry-specific effect sizes and boosts the discovery power to identify ancestry-enriched loci. However, Tractor operates under an assumption of unrelated samples. Here, to address this gap, we propose Tractor-Mix, which allows for well-calibrated association studies in datasets containing admixed samples with relatedness. Extensive simulations show that this method is competitive with other state-of-the-art approaches that do not produce ancestry-specific results. Empirical …

Navigating Undone Science: The Search For Adequate Endometriosis Care, Heather Welty, Melanie Jeske

Center for Medical Ethics and Health Policy Staff Publications

Endometriosis is an estrogen-dependent disease in which tissue similar to the lining of the uterus grows elsewhere in the body leading to a variety of symptoms including heavy and prolonged menstruation, chronic pain, cysts, infertility, and gastrointestinal issues. Despite being one of the most common gynecologic conditions, much remains unknown about potential risk factors for endometriosis, its etiology, and treatment options. First and second-line biomedical treatment options, complementary and alternative medicine, and lifestyle changes are all treatment options that people living with endometriosis (PLE) leverage to manage their symptoms. This article draws on in-depth interviews with 52 people living with …

Decision-Making Criteria In Polygenic Embryo Screening: A Survey Of Reproductive Medicine Physicians, Rémy A Furrer, Aayushi Gandhi, Dorit Barlevy, Shai Carmi, Todd Lencz, Stacey Pereira, Gabriel Lázaro-Muñoz

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Polygenic embryo screening (PES) examines embryos for their genetic likelihood of developing complex conditions and traits. The commercialization of PES places reproductive endocrinologists and infertility specialists (REIs) as the primary decision-makers in its use, despite professional guidelines cautioning that PES is not ready for clinical use.

Methods: This survey examines how 152 US REIs perceive and approach potential clinical decision-making scenarios regarding the use of PES.

Results: REIs were more likely to offer PES for medical conditions (up to 62% for cancer) than for traits (eg, 0% for skin color, 10% for body mass index). When evaluating 11 potential …

Diabetter Together: Outcomes Of A Randomized Controlled Trial Evaluating A Peer Mentor Behavioral Intervention For Young Adults With Type 1 Diabetes During The Transfer From Pediatric To Adult Care, Marisa E Hilliard, Charles G Minard, Samantha A Carreon, Wendy L Levy, Sarah K Lyons, Randi Streisand, Tricia S Tang, Siripoom V Mckay, Sridevi Devaraj, Barbara J Anderson

Faculty, Staff and Students Publications

Objective: Transition between pediatric and adult health care is complex, with high risk for loss to follow-up and suboptimal health outcomes for young adults with type 1 diabetes. This trial evaluated the efficacy of DiaBetter Together, a 12-month strengths-based behavioral intervention delivered by trained peer mentors. The intervention aimed to help young adults navigate the transfer process to promote optimal glycemic outcomes, shorten time to adult care follow-up, and improve psychosocial outcomes.

Research design and methods: Using a single-site randomized clinical trial design, we compared the 12-month intervention to usual care among n = 100 young adults aged 17-25 years …

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. …

Dupilumab Versus Placebo In Adults And Adolescents With Eosinophilic Gastritis (Degas): A Double-Blind, Placebo-Controlled, Phase 2, Multicentre, Randomised Controlled Trial, Nirmala P Gonsalves, Evan S Dellon, Kara L Kliewer, Tetsuo Shoda, Regina Yearout, Seema S Aceves, Nicoleta C Arva, John A Besse, Julie M Caldwell, Mirna Chehade, Amaziah Coleman, Margaret H Collins, Sara Anvari, Gary W Falk, Sandeep K Gupta, Girish Hiremath, David A Katzka, Paneez Khoury, John Leung, Calies Menard-Katcher, Paul Menard-Katcher, Kathryn A Peterson, Maria A Pletneva, Amanda K Rudman Spergel, Jonathan M Spergel, Tatyana Vaysman, Joshua B Wechsler, Benjamin L Wright, Guang-Yu Yang, Xue Zhang, Meijian Zhou, Ashish Bansal, Bram P Raphael, Amr Radwan, Jennifer Maloney, Antonio Martin, Yamo Deniz, Glenn T Furuta, Lisa J Martin, Marc E Rothenberg

Faculty, Staff and Students Publications

Background: Eosinophilic gastritis currently has no approved treatments and is postulated to be driven by type 2 inflammation. Dupilumab blocks type 2 cytokines IL-4 and IL-13 and has efficacy in multiple diseases characterised by type 2 inflammation, including eosinophilic oesophagitis. We aimed to assess the efficacy and safety of dupilumab in patients with eosinophilic gastritis.

Methods: DEGAS was a proof-of-concept, phase 2, multicentre, randomised controlled trial consisting of a 12-week, double-blind, placebo-controlled period, followed by a 24-week open-label extension period. Patients aged 12-70 years from 11 hospitals in the USA with histologically active eosinophilic gastritis (≥30 eosinophils per high-power field …

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, …

Rates Of, Reasons For, And Reactions To Discontinuation Of Glp-1 Receptor Agonists: A Narrative Review, Henry D Heisey, L Parker Gregg, Christopher D Verrico, Dennis T Villareal, Terri L Fletcher

Faculty, Staff and Students Publications

GLP-1RAs are increasingly used for their glucose-lowering and weight-management effects, but many patients discontinue them. In this narrative review we aim to review real-world, quantitative and qualitative GLP-1RA discontinuation, adherence, and persistence evidence as it aligns with an established conceptual framework for understanding medication adherence in noncommunicable chronic disease. Many inconsistencies exist in how discontinuation, adherence, and persistence are studied in this literature. Few qualitative studies have focused on discontinuation of GLP-1RAs. Quantitative approaches often focus on medication-related factors and more superficial aspects of socioeconomic and condition-related factors. Very few studies encompass all 5 dimensions of the medication adherence conceptual …

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 …

Cost-Effectiveness Of Hes V2.0 And Galad For Hepatocellular Carcinoma Surveillance In Patients With Cirrhosis, Mert Sahinkoc, Gizem S Nemutlu, Hashem B El-Serag, Mary Linton B Peters, Ali Hajjar, Anthony E Samir, Leigh Anne Dageforde, Fasiha Kanwal, Jagpreet Chhatwal

Faculty, Staff and Students Publications

Background: Ultrasound-based surveillance for HCC is limited by suboptimal sensitivity and low adherence. Blood-based biomarkers are potential alternatives for routine HCC surveillance. We aimed to define optimal sensitivity, specificity, and cost parameters under which blood-based biomarkers could serve as cost-effective alternatives in patients with cirrhosis.

Methods: We developed a microsimulation model of the natural history of HCC in individuals with compensated cirrhosis. We compared the cost-effectiveness of biannual surveillance using 2 blood-based biomarkers-HES V2.0 and GALAD-versus ultrasound-based surveillance across a range of sensitivity, specificity, test costs, and adherence levels. Outcomes included quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios …

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 …

Finding And Using Validated Surveys In Health Science Research, Tracy Ashby

Library Class: Lunch & Learn

Join us as we introduce techniques for identifying and using validated surveys in health sciences research. Learn strategies for finding reliable, evidence-based measurement tools in the databases and gain tips on how to evaluate their quality and relevance.

Extracorporeal Rescue In Massive Pulmonary Embolism: A Case Of Chronic Thromboembolic Pulmonary Hypertension Unveiled, Kenzo Ramos, Kari Gorder

Journal of Shock and Hemodynamics

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare yet curable cause of pulmonary hypertension from unresolved pulmonary emboli. We present the case of a 48-year-old man with progressive dyspnea and leg swelling, who was found to have bilateral pulmonary emboli with right heart strain. He developed cardiac arrest during thrombectomy, requiring emergent veno-arterial extracorporeal membrane oxygenation (V-A ECMO). Further evaluation revealed acute emboli superimposed on CTEPH. After incomplete thrombectomy and persistent instability, he underwent successful pulmonary endarterectomy with ECMO decannulation, leading to recovery of right ventricular function and discharge in stable condition. This case illustrates that previously unrecognized CTEPH may …

Spae: Deciphering Cell Cycle Dynamics And Cell States In Single-Cell Rna-Seq Data, Jiahao Yi, Jiajia Liu, Peng Guo, Yuan-Nong Ye, Xiaobo Zhou

Faculty, Staff and Student Publications

Rapid advances in single-cell RNA sequencing (scRNA-seq) technology have enabled the investigation of gene expression changes at the single-cell level, particularly for elucidating the heterogeneity among cells and complex biological processes. This technique reveals subtle molecular differences within individual cells, thereby offering a unique viewpoint for the investigation of cell cycle progression, cellular differentiation, and disease pathogenesis. However, accurately identifying and analyzing cell cycle dynamics in scRNA-seq data remains challenging due to the complexity of the data and the subtle differences between cell states. To address this challenge, we developed the integrated Sinusoidal and Piecewise AutoEncoder (SPAE), an autoencoder-based piecewise …

Notch Signaling Regulates The Secretion Of Pro-Metastatic Factors In Extracellular Vesicles In Liposarcoma, Menchus Quan, Yi-Kai Liu, Ying Zhao, Madeline Kay, Kai Sun, Timothy P Gavin, Raphael E Pollock, W Andy Tao, Shihuan Kuang

The Brown Foundation: Institute of Molecular Medicine

Notch signaling is an emerging regulator of liposarcoma (LPS), but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alters the proteomes of LPS-derived extracellular vesicles (EVs). We used quantitative mass spectrometry to profile the EV proteome in multiple contexts: cultured LPS cells, LPS tumor, circulating EVs of LPS-bearing mice, and human LPS samples. We found that Notch signaling increases the secretion of EV proteins that favor tumor progression and metastasis but suppresses immune responses in murine LPS cells. Overlapping murine and human LPS data identifies 18 proteins that …

Myeloid Mmp14 Couples Extracellular Proteolysis To Inflammatory And Metabolic Remodeling During Obesity, Long J Shao, Fathima Elizondo, Feng Gao, Elizabeth L Lieu, Bharati Reddi, Maryam Elizondo, Iqbal Mahmud, Kristin Eckel-Mahan, Philipp E Scherer, Xin Ge, Huaizhu Wu, Sean Hartig, Kai Sun

The Brown Foundation: Institute of Molecular Medicine

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring …

Tic-Related Functional Impairment Drives The Relationship Between Tics And Depression In Youth With Tourette Syndrome, Benjamin J Mitchell, Emily I Braley, Erika S Trent, Steve Barash, Mark F Gordon, Jordan Stiede, Eric A Storch

Faculty, Staff and Students Publications

Although many youth with Tourette syndrome (TS) have at least 1 comorbid psychiatric condition (eg, obsessive-compulsive disorder), the extent to which TS is associated with depression remains unclear. This cross-sectional study examined relationships among tic severity, tic-related functional impairment, and depressive symptoms in 277 youth with TS. Tic-related impairment, but not tic severity, was associated with both self- and parent-reported depressive symptoms. An age × sex interaction emerged, such that among younger participants, females reported higher depressive symptoms than males; however, this effect was observed only for self-report, not parent report. Additionally, both depressive symptoms and tic severity were associated …

Genetic Associations With Pulmonary Embolism Among Those With A Deep Vein Thrombosis: The International Network Against Venous Thrombosis Consortium, Susana Lozano-Esparza, Gabrielle E Shakt, Jennifer A Brody, Angel Martinez-Perez, Matthew P Conomos, Marine Germain, Katharine R Clapham, Maris Teder-Laving, Astrid Van Hylckama Vlieg, Anni Kauko, Florian Thibord, Ohanna C L Bezerra, Girish N Nadkarni, Gaëlle Munsch, Therese Haugdahl Nøst, Ellen L Goode, Yuekai Ji, Daniel I Chasman, Alexander P Reiner, Constance Turman, Kerri L Wiggins, Colleen M Sitlani, Juan Carlos Souto, Pamela L Lutsey, Tiffany Bellomo, Estonian Biobank, Million Veteran Program, Ruifang Li-Gao, Aleksi Kristian Winstén, Ming-Huei Chen, Ron Do, Lénaick Gourhant, Kristian Hveem, Sebastian M Armasu, Noémie Saut, Nathan Pankratz, Franco Giulianini, Jeffrey Haessler, Mingyang Song, Robert Olaso, Eric Boerwinkle, Daniel Dochtermann, Jose Manuel Soria, Stephen S Rich, David Smadja, Satoshi Koyama, Frits R Rosendaal, Teemu Niiranen, France Gagnon, Ha My T Vy, Neil Zakai, Catherine Lemarie, Anne Heidi Skogholt, Jean-François Deleuze, James S Pankow, Paul M Ridker, Yuxi Liu, Kenneth M Rice, Saiju Pyarajan, Mary Cushman, Jospeh Emmerich, Bruce M Psaty, Pradeep Natarajan, Andrew D Johnson, Marc A Rodger, Pierre Suchon, Francis Couturaud, Pierre-Emmanuel Morange, Weihong Tang, Charles Kooperberg, Christopher Kabrhel, Maria Sabater-Lleal, David-Alexandre Trégouët, Alisa S Wolberg, Scott M Damrauer, Nicholas L Smith

Children’s Nutrition Research Center Staff Publications

Background: Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE), the latter of which often originates from DVT and can be fatal.

Objectives: The aim of this study was to identify causal genetic factors that alter risk of PE among those with a presumed DVT.

Methods: Using a case-only design of VTE, we conducted meta-analyses of genome-wide association studies (GWASs) in the International Network Against Venous Thrombosis Consortium. Among participants diagnosed with VTE, each study identified those who had a clinically reported PE, with or without a clinically reported DVT; those remaining had isolated DVT. Logistic regression …

Simbinder-If: Structure-Aware Antibody Affinity Optimization Via Efficient Preference Learning, Xinyan Zhao, Yi-Ching Tang, Rivaaj Monsia, Victor J Cantu, Ashwin Kumar Ramesh, Siyu Yang, Xiaozhong Liu, Zhiqiang An, Xiaoqian Jiang, Yejin Kim

The Brown Foundation: Institute of Molecular Medicine

Motivation: Antibody therapeutic efficacy depends on high-affinity target engagement, yet laboratory affinity maturation is slow and costly. Most protein language models (PLMs) lack explicit training for high affinity, and current preference optimization methods introduce computational overhead without clear affinity improvements. Therefore, structure-aware and parameter-efficient approaches for antibody affinity optimization are urgently needed.

Results: We propose SimBinder-IF, a structure-aware antibody optimization model trained by freezing the Evolutionary Scale Modeling inverse folding (ESM-IF) structure encoder and fine-tuning only its decoder via Simple Preference Optimization (SimPO) to prefer stronger binders. In generalization tests across seven held-out complexes (93 477 mutants), SimBinder-IF shows a …

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 …

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 …

Using Polygenic Risk Scores To Evaluate Definitions Of Self-Reported Sleep Phenotypes Across Cohorts, Annah B Wyss, Michael Brown, Xiang Li, Brian W Spitzer, Zhijie Huang, Heming Wang, Richa Saxena, Linda Gallo, Qibin Qi, Wassim Tarraf, Robert Kaplan, Melissa Lamar, Hector M González, Charles Decarli, Myriam Fornage, Jerome I Rotter, Stephen S Rich, Kent D Taylor, Xiuqing Guo, Alexis C Wood, Peter Y Liu, Susan R Heckbert, Chloé Sarnowski, Jan Bressler, Alanna C Morrison, Bing Yu, Pamela L Lutsey, Carmen R Isasi, Susan Redline, Tamar Sofer

Faculty, Staff and Students Publications

Study objectives: Since genome-wide association studies (GWAS) of sleep phenotypes have been conducted in differing populations and definitions of sleep phenotypes vary across studies, we investigated associations between several polygenic risk scores (PRSs) and potential sleep definitions among multiethnic cohorts.

Methods: Using data from four cohorts (HCHS/SOL, ARIC, MESA, BHS, N = 16 895), we considered multiple definitions of short and long sleep, insomnia, and excessive daytime sleepiness (EDS). PRSs were developed based on summary statistics from GWAS in European ancestry individuals from the UK Biobank (UKB) and from GWAS conducted in a multiethnic population from the Million Veteran Program …

Functional Divergence Of Capicua Isoforms Explains Differential Tissue Vulnerability In Neurological Disease, Hamin Lee, Esmeralda Villavicencio Gonzalez, Elias M Rivera, Mark A Durham, Ronald Richman, Elizabeth H-Y Chu, Kailey Xia, Hu Chen, Zhandong Liu, Surabi Veeraragavan, Binoy Shivanna, Huda Y Zoghbi

Faculty, Staff and Students Publications

Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid β production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or …

Overcoming Igf1r-Mediated Resistance To Oncolytic Hsv1 And Radiotherapy Via Triple Combination Therapy, Alexandra A Miller, Min-Hye Noh, Jin Muk Kang, Jiyeon Kim, Lily Nguyen, Amanda S Kouaho, Grace Nguyen, Minxin Huang, Stephanie M Bean, Joshua Davis, Matthew P Mullarkey, Sunil Krishnan, Zhongming Zhao, E Antonio Chiocca, Tae Jin Lee, Ji Young Yoo

The Brown Foundation: Institute of Molecular Medicine

FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as a promising viro-immunotherapy for solid tumors. However, tumor- and tumor microenvironment (TME)-associated adaptations following viral treatment, such as feedback immune suppression, neoangiogenesis, and enhanced tumor aggressiveness, often hinder complete tumor eradication. A deeper understanding of the molecular mechanisms underlying resistance to oHSV is crucial to enhancing its clinical impact. We recently discovered that oHSV induces Insulin-like growth factor 2 (IGF2) secretion, shaping an immunosuppressive TME. Similarly, radiotherapy (RTx) activates the IGF1/IGF1R and YAP1 signaling pathways, further promoting therapeutic resistance. In this study, we investigated how oHSV-induced Insulin-like growth factor 1 …

Quality Of Life And Depressive Symptoms In Older Adults: Findings From An Integrated Epilepsy Self-Management Data Set, Elaine T Kiriakopoulos, Farren Briggs, Nicole Fiorelli, Robin E Mcgee, Erica K Johnson, Barbara C Jobst, Ross Shegog, Refugio Sepulveda, Tanya Sprulli, Cam Escoffery, Rakale C Quarells, Molly Mcvoy, Sakshi Priy, Clara Adeniyi, Martha Sajatovic

Faculty, Staff and Student Publications

Background: In the U.S., about one million people with active epilepsy are adults aged 55+. Older adults with epilepsy (OAWE) experience complex health conditions that compromise quality of life (QOL). The contribution of depressive symptom dimensions to health-related QOL remains underexplored in OAWE.

Methods: We analyzed baseline data from 13 epilepsy self-management studies in the CDC-sponsored MEW-DB (Managing Epilepsy Well Database), including adults ages 55 and older (N = 198). The primary outcome was health-related QOL, assessed via the 10-item Quality of Life in Epilepsy scale (QOLIE-10), which was inverse rank normalized (mean = 0, SD = 1). Primary predictors …

Epilepsy-Associated Digenic Variants Affecting An Actin-Mitochondria-Glutamate Pathway Promote Seizure Susceptibility, Shenzhao Lu, Mengqi Ma, Shabab B Hannan, Mingxi Deng, Hu Chen, Zhijian Yu, Lindsey D Goodman, Haein Kim, Yun Zhao, Sandeep Kumar Dubey, Wen-Wen Lin, Xueyang Pan, Debdeep Dutta, Vishnu Anand Cuddapah, Jill A Rosenfeld, Xi Luo, Zhandong Liu, Joshua M Shulman, Hugo J Bellen

Faculty, Staff and Students Publications

Epilepsy affects approximately 50 million people worldwide, yet more than half of individuals with a presumed genetic cause still lack a molecular diagnosis despite the identification of over 1,000 monogenic epilepsy genes. This diagnostic gap is unlikely to be resolved by improved variant detection alone, suggesting that variants affecting the same biological pathway may combine to cause disease. By studying epilepsy-associated actin regulatory genes, we identified a conserved "actin-mitochondria-glutamate (AMG) pathway". We demonstrate that reduced actin polymerization promotes DRP1-mediated mitochondrial fission, increases reactive oxygen species (ROS) levels, and enhances glutamatergic transmission, leading to seizures. The glial innate immune pathway, a …

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 …