Digital Commons Network^™

Genetic Regulation Of Uterine Organogenesis, Diana A. Machado

Dissertations and Theses (Open Access)

In eutherian and marsupial mammals, the site of embryo implantation and gestation is the uterus. The precursor tissue of the uterus, oviducts, cervix, and upper vagina is the Müllerian duct epithelium and its adjacent mesenchyme. Morphological uterine variation between species is established during embryogenesis by species-specific differences in Müllerian duct fusion at the midline, growth, and differentiation. For example, laboratory mice have a bipartite uterus with two uterine horns and a single cervix, whereas humans have a simplex uterus with a single chamber and single cervix. In humans, variations in the fusion process can alter typical uterine morphology, correlating with …

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 …

Function And Regulation Of Long Polar Fimbriae During Enterohemorrhagic Escherichia Coli Infection, Walter J. Galdamez

Dissertations and Theses (Open Access)

Enterohemorrhagic Escherichia coli (EHEC) is a foodborne pathogen that causes severe gastrointestinal disease and hemolytic uremic syndrome. EHEC employs multiple virulence factors to colonize the host intestine, including the locus of enterocyte effacement (LEE) encoded type III secretion system, intimin, and flagella, yet the role of long polar fimbriae (Lpf) in adhesions and infection remains less well understood. Long polar fimbriae can mediate bacterial attachment to host cells in vitro, yet the regulation and function of its two fimbrial operons, lpf1 and lpf2 in vivo remain poorly understood. Preliminary RNA-seq data from zebrafish infected with EHEC reveal that expression of …

Hyperadhesive Von Willebrand Factor Contributes To Pathogenesis Of Preeclampsia, Yajuan Wang, Chenyu Wang, Katie L Houck, Xiaoli Gao, Yuanyuan Chen, Xin Xu, Xue Zhao, Miguel A Cruz, Shu Zhang, Chester Q Li, Fengxia Xue, Min Li, Swati Shree, Jing-Fei Dong, Cha Han

Children’s Nutrition Research Center Staff Publications

Background: Preeclampsia is the most common complication of pregnancy, significantly affecting maternal and fetal health, and is characterized by placental and systemic endotheliopathy. Patients with preeclampsia have elevated levels of VWF (von Willebrand Factor), which is associated with poor clinical outcomes. However, whether VWF serves as a marker for endotheliopathy or contributes to the pathogenesis of preeclampsia remains poorly understood.

Methods: We investigated the role of hyperadhesive VWF in the development of preeclampsia by studying patients, evaluating mouse models, and performing in vitro experiments.

Results: We show that patients develop VWF- and fibrin-rich thrombosis in the placenta and have significantly …

All-Cause And Cause-Specific Mortality In Gambling Disorder: Evidence From A Nation-Wide Matched And Sibling Cohort Study In Taiwan, Yang-Chieh Brian Chen, Chih-Wei Hsu, Liang-Jen Wang, Mu-Hong Chen, Yao-Hsu Yang, Chih-Sung Liang, Edward Chia-Cheng Lai

Children’s Nutrition Research Center Staff Publications

Background and aims: Gambling disorder (GD) has been linked to suicidal ideation and suicide deaths; however, evidence on all-cause and cause-specific mortality-particularly in Asian populations-remains limited. Using a retrospective cohort study based on nationwide matched and sibling cohort, we investigated all-cause and cause-specific mortality risk in patients with GD.

Design, setting and participants: A retrospective cohort study was conducted using 2000-2022 data from Taiwan's National Health Insurance Research Database. A cohort of 961 individuals diagnosed with GD was identified. An age- and sex-matched control cohort (n = 3,844) and an unaffected sibling cohort (n = 675) were constructed. Cumulative survival …

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, …

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 …

Agent-Based Modeling Of Cellular Dynamics In Adoptive Cell Therapies, Yujia Wang

Dissertations and Theses (Open Access)

Adoptive cell therapies (ACT) have shown promising progress in combating cancer, but clinical responses remain heterogeneous. Key determinants, including the functional states of infused cells, tumor–immune interactions, and dosing strategies, are difficult to resolve experimentally in the dynamic and heterogeneous tumor microenvironment, limiting optimization of ACT products and treatment regimens. To address the gap, we developed ABMACT (Agent-Based Model for Adoptive Cell Therapies), a computational framework that reconstruct key cellular functions, interactions, and molecular signatures to recapitulate cell population dynamics associated with differential treatment responses. ABMACT encodes autonomous “virtual cells” using literature-informed rules calibrated with experimental data, enabling simulation of …

Transcriptional Regulation In The Uterine Luminal Epithelium, Evelyn A. Carrion

Dissertations and Theses (Open Access)

Transcriptional Regulation in the Uterine Luminal Epithelium

Evelyn A. Carrion

Advisor: Richard R. Behringer, PhD

Abstract

The uterus is an organ comprised of multiple tissues that are essential for women’s health and reproduction. The uterus is composed of multiple tissue layers, including the perimetrium, myometrium, and the endometrium. The endometrium is the inner lining of the uterus, and contains the luminal epithelium, glandular epithelium, and stroma. The luminal epithelium is a simple columnar layer of cells that is necessary for embryo implantation. The uterus is derived in part from the embryonic precursor tissue called the Müllerian duct. There are no …

Ai-Driven Segmentation And Volumetric Response Modeling Of Liver Regions To Radiotherapy, Aashish Chandra Gupta

Dissertations and Theses (Open Access)

In liver-directed radiotherapy (RT), liver regions receiving higher doses typically undergo atrophy while contralateral/adjacent lower-dose regions may exhibit compensatory hypertrophy through regeneration of healthy tissue. Optimizing the RT plan to promote regional hypertrophy while minimizing the risk of developing atrophy has the potential to enhance post-RT liver function and long-term survivorship. However, current clinical practice largely relies on global liver dose-volume metrics during RT-planning, which may obscure favorable dose-response correlation and limit actionable guidance for clinicians. Therefore, we hypothesized that post-RT regional liver response is governed by a combination of region-specific dose-volume and patient clinical features, and that these responses …

Regulation Of Müllerian Duct Mesenchyme Transcription During Mammalian Sex Differentiation, Haowen Li, Richard R Behringer, Rachel D Mullen

Dissertations and Theses (Open Access)

Sp7/Osterix (Osx) encodes a zinc-finger transcription factor of the Specificity-protein family discovered by Nakashima et al. at the MD Anderson Cancer Center. While primarily recognized for its role in osteogenesis, Osx has also been implicated in mammalian reproductive development, particularly in male sex differentiation, where Müllerian Duct (MD) regression occurs, mediated by anti-Müllerian hormone (AMH) signaling. AMH-induced regression signals are transduced by the mesenchymal tissue surrounding the ductal structure, known as the Müllerian Duct mesenchyme (MDM). It was discovered that AMH signaling is necessary and sufficient for driving Osx expression in MDM. A previous transgenic mouse reporter …

Oxidative Stress Mediated Glutamate Release And Nmda Receptor-Dependent Synaptic Remodeling In Radiation-Induced Cognitive Dysfunction, Thanh Lam

Dissertations and Theses (Open Access)

In children younger than 14 years old, the brain and other parts of the central nervous system are the most common sites for solid tumors. Radiotherapy is an effective treatment for central nervous system (CNS) tumors. However, it often causes a progressive decline in cognitive functions, which is especially devastating for pediatric patients. Although post-mitotic neurons are generally considered resistant to radiation-induced immediate cell death, ionizing radiation causes complex neurochemical and structural changes that damage synaptic integrity. In this study, we examined the molecular cascades following a 10 Gy radiation dose applied to mouse cortical neurons. We found that radiation-induced …

From Geometry To Recognition: A Quantitative Framework For Tcr-Pmhc Structural Analysis In The Age Of Predicted Structures, Kun Hee Kim

Dissertations and Theses (Open Access)

Recognition of antigen by a T cell begins with a single physical event, the engagement of the T cell receptor (TCR) with a peptide-major histocompatibility complex (pMHC), and this interaction is encoded in the geometry with which the receptor docks onto the composite pMHC surface. Whether that docking geometry is biologically organized, and whether the structures now produced at scale by prediction preserve recognition or only reproduce that organization, are the two questions this thesis addresses. Two gaps stand in the way. The first is a gap of measurement, because docking geometry has never been made quantitatively comparable across many …

Antigen Discovery In Multiple Myeloma Using Integrated Long-Read Transcriptomics And Immunopeptidomics, Aya Albittar

Dissertations and Theses (Open Access)

Multiple myeloma (MM) remains an incurable plasma cell malignancy, with relapse driven by persistent chemotherapy-resistant cells and residual disease following treatment. Although immunotherapies have transformed MM care, their success depends on identifying tumor-specific antigens that can be safely targeted. While aberrant genomic structural variation and transcriptional dysregulation are increasingly recognized as sources of novel antigens in MM, the HLA-presented antigenic landscape of MM remains incompletely characterized, particularly for non-canonical, structurally-derived peptides, and long-read transcriptome-informed immunopeptidomic data specific to MM remain scarce.

We established an integrated antigen discovery platform combining long-read RNA sequencing (Iso-Seq) with mass spectrometry-based HLA immunoprecipitation and immunopeptidomics …

Systemic Corticosteroids In The Management Of Sinonasal Disease: An Evidence-Based Expert Review, Andrew Thamboo, Deanna Gigliotti, Eugenio De Corso, Stella Lee, Benjamin S Bleier, Christopher J Chin, Marie-Noelle Corriveau, Valerie Hox, Claire Hopkins, Peter H Hwang, Arif Janjua, Ludger Klimek, Daniel Lee, John Lee, Amber Luong, Geoffrey Mortuaire, Joaquim Mullol, Zara M Patel, John Scott, Doron Sommer, Leigh Sowerby, Marc Tewfik, Beatrice Voizard, Martin Wagenmannm, Sarah K Wise, Jonathan Yip, Quirina Thompson, Martin Desrosiers, Yvonne Chan

The Brown Foundation: Institute of Molecular Medicine

Background: Chronic rhinosinusitis (CRS) is a prevalent, heterogeneous inflammatory disease associated with significant morbidity. Systemic corticosteroids (SCS) are commonly prescribed for their anti-inflammatory effects, but cumulative exposure carries risks, including metabolic, cardiovascular, and skeletal complications. Despite widespread use, evidence-based guidance on optimal indications, timing, and duration of SCS in CRS remains inconsistent.

Methodology/principal: An evidence-based review was performed using MEDLINE, EMBASE, and Cochrane databases (2013-2023). Studies were screened and categorized into two primary groups: CRS with (CRSwNP) or without (CRSsNP) nasal polyps. Within CRSwNP, evidence was subcategorized by indication, including (1) polyp size reduction, (2) olfactory dysfunction, (3) comorbid disease, …

Understanding Hypertensive Renal Injury: A Well-Structured Approach, Peter A Doris

The Brown Foundation: Institute of Molecular Medicine

No abstract provided.

Computable Phenotypes For Research Using Real-World Data: Experiences From The Nih Pragmatic Trials Collaboratory, Marisa L Conte, Judith M Schlaeger, Guilherme Del Fiol, James R Campbell, Andrea L Cheville, Keith Marsolo, Kari A Stephens, Miriam O Ezenwa, Andrew D Boyd, Juanita E Darby, Nadine S Matthie, P Michael Ho, Alice Pressman, Morgan Justice, Carol Reynolds Geary, Keturah R Faurot, Alex Fist, Karen Staman, Hulin Wu, Rachel L Richesson

Faculty, Staff and Student Publications

Objectives: Embedded pragmatic clinical trials (ePCTs) are conducted as part of routine clinical care and therefore use data collected from real-world data sources, such as electronic health record systems and administrative claims. A common approach for using these types of data across all phases of trial conduct is to create a computable phenotype (an explicitly defined data query data, including specified data types, data codes, and logical parameters) to capture patients with a clinical condition, exposure, symptom, characteristic, treatment, or outcome of interest.

Materials and methods: The Electronic Health Record (EHR) Core Working Group of the NIH Pragmatic Trials Collaboratory …

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 …

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 …

"It Doesn't Matter Where Ocd Comes From," Or Does It?, Caitlin M Pinciotti, Ryan J Mccarty, Gabriella T Ponzini

Faculty, Staff and Students Publications

Purpose of review: This review critically evaluates the claim that etiology is not relevant to cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD). Research on the clinical presentation and treatment outcomes associated with traumatic/stressor and biological etiologies is presented.

Recent findings: The extant literature demonstrates varying clinical utility across the reviewed etiologies. Traumatic/stressor etiologies show the most consistent and robust evidence of clinical utility, demonstrating compelling associations with clinical presentation and treatment outcomes, while also being amenable to existing evidence-based approaches. Medical conditions (e.g., Pediatric Acute onset Neuropsychiatric Syndrome) and neurobiological factors also demonstrate considerable associations with OCD presentation, yet …

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 …

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 …

Dupilumab For Patients With Allergic Fungal Rhinosinusitis, Amber U Luong, Joshua M Levy, Sarah K Wise, Joseph K Han, Mamoru Yoshikawa, Luo Zhang, Rodney Schlosser, Prerna Ranganathan, Paula Dakin, Jennifer Maloney, George D Yancopoulos, Andrew P Fontenot, Neelam A Phadke, Lacey R Robinson

The Brown Foundation: Institute of Molecular Medicine

Background: Allergic fungal rhinosinusitis (AFRS) is a severe subtype of chronic rhinosinusitis characterized by fungal hypersensitivity and accentuated type 2 inflammation. Dupilumab-a fully human mAb blocking IL-4/13, approved for type 2 inflammatory diseases, including chronic rhinosinusitis with nasal polyps-may benefit patients with AFRS.

Objective: We sought to understand the effect of dupilumab in AFRS.

Methods: In this phase 3 trial, patients with AFRS age ≥6 years were randomized to dupilumab or matched placebo for 52 weeks. The primary end point was Lund-Mackay computed tomography score, quantifying sinus opacification, at 52 weeks. Secondary end points were multiplicity-controlled and hierarchically tested.

Results: …

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 …

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 …

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 …