Digital Commons Network^™

No Evidence Of Pitavastatin Effect On Muscle Area Or Density Among People With Hiv, Kristine M Erlandson, Triin Umbleja, Heather J Ribaudo, Michael T Lu, Jana Taron, Marissa R Diggs, Pamela S Douglas, Kathleen V Fitch, Carl J Fichtenbaum, Markella V Zanni, Judith A Aberg, Maria C Rodriguez-Barradas, Katharine Breaux, Rosalba Gomez Morones, Craig A Sponseller, Judith S Currier, Gerald S Bloomfield, Sarah M Chu, Alex B Lu, Carlos D Malvestutto, Steven K Grinspoon, Todd T Brown

Faculty, Staff and Students Publications

Background: Skeletal muscle area (MA) and muscle density (MD) are key determinants of physical function and typically decline with increasing age. Statins have well-known musculoskeletal effects but whether statins impact MA or MD is not well established, especially in the setting of randomized treatment.

Methods: REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in people with HIV (PWH). Thoracic paraspinal, pectoralis, and infraspinatus MA and MD were assessed among Mechanistic Substudy participants with CT at baseline and month 24.

Results: Of 804 substudy participants, 510 remained on study treatment …

Potential Biological And Genetic Links Between Dementia And Osteoporosis: A Scoping Review, Abayomi N Ogunwale, Paul E Schulz, Jude K Des Bordes, Florent Elefteriou, Nahid J Rianon

Faculty, Staff and Students Publications

Background: The biological mediators for the epidemiologic overlap between osteoporosis and dementia are unclear. We undertook a scoping review of clinical studies to identify genetic and biological factors linked with these degenerative conditions, exploring the mechanisms and pathways connecting both conditions.

Methods: Studies selected (1) involved clinical research investigating genetic factors or biomarkers associated with dementia or osteoporosis, and (2) were published in English in a peer-reviewed journal between July 1993 and March 2025. We searched Medline Ovid, Embase, PsycINFO, the Cochrane Library, the Web of Science databases, Google Scholar, and the reference lists of studies following the guidelines for …

Genes Encoding Multiple Modulators Of The Immune Response Are Methylated In The Prostate Tumor Microenvironment Of African Americans, Vinay Kumar, Tara Sinta Kartika Jennings, Lucas Ueta, James Nguyen, Liankun Song, Michael Mcclelland, Weiping Chu, Michael Lilly, Michael Ittmann, Patricia Castro, Arash Rezazadeh Kalebasty, Dan Mercola, Omid Yazdanpanah, Xiaolin Zi, Farah Rahmatpanah

Faculty, Staff and Students Publications

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA).

Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and …

Mouse Metastable Epialleles Are Extremely Rare, Chathura J Gunasekara, Uditha Maduranga, Taylor Zhang, Jonathan N Wells, Maria S Baker, Eleonora Laritsky, Yumei Li, Cristian Coarfa, Yi Zhu, Robert A Waterland

Faculty, Staff and Students Publications

Metastable epialleles (MEs) are genomic loci at which epigenetic marks are established stochastically during early embryonic development and maintained during subsequent differentiation and throughout life, leading to stable epigenetic and phenotypic variation among genetically identical individuals. Although MEs were first described in mice over 20 years ago, the extent of epigenetic metastability in the mouse genome remains unknown. We present the first unbiased genome-wide screen for MEs in mice. Using deep whole-genome bisulfite sequencing across tissues derived from the three embryonic germ layers in isogenic C57BL/6J mice, we identified only 29 MEs, precisely localizing them and documenting their rarity. Consistent …

Multi-Ancestry Genome-Wide Meta-Analysis Of 56,241 Individuals Identifies Known And Novel Cross-Population And Ancestry-Specific Associations As Novel Risk Loci For Alzheimer’S Disease, Farid Rajabli, Penelope Benchek, Giuseppe Tosto, Nicholas Kushch, Jin Sha, Katrina Bazemore, Congcong Zhu, Wan-Ping Lee, Jacob Haut, Kara L Hamilton-Nelson, Nicholas R Wheeler, Yi Zhao, John J Farrell, Michelle A Grunin, Yuk Yee Leung, Pavel P Kuksa, Donghe Li, Eder Lucio Da Fonseca, Jesse B Mez, Ellen L Palmer, Jagan Pillai, Richard M Sherva, Yeunjoo E Song, Xiaoling Zhang, Takeshi Ikeuchi, Taha Iqbal, Omkar Pathak, Otto Valladares, Dolly Reyes-Dumeyer, Amanda B Kuzma, Erin Abner, Larry D Adams, Perrie M Adams, Alyssa Aguirre, Marilyn S Albert, Roger L Albin, Mariet Allen, Lisa Alvarez, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S Atwood, Sanford Auerbach, Gayle Ayres, Clinton T Baldwin, Robert C Barber, Lisa L Barnes, Sandra Barral, Thomas G Beach, James T Becker, Gary W Beecham, Duane Beekly, Bruno A Benitez, David Bennett, John Bertelson, Thomas D Bird, Deborah Blacker, Bradley F Boeve, James D Bowen, Adam Boxer, James Brewer, James R Burke, Jeffrey M Burns, Joseph D Buxbaum, Nigel J Cairns, Laura B Cantwell, Chuanhai Cao, Christopher S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Scott Chasse, Marie-Francoise Chesselet, Nathaniel A Chin, Helena C Chui, Jaeyoon Chung, Suzanne Craft, Paul K Crane, David H Cribbs, Elizabeth A Crocco, Carlos Cruchaga, Michael L Cuccaro, Munro Cullum, Eveleen Darby, Barbara Davis, Philip L De Jager, Charles Decarli, John Detoledo, Malcolm Dick, Dennis W Dickson, Beth A Dombroski, Rachelle S Doody, Ranjan Duara, Nilüfer Ertekin-Taner, Denis A Evans, Kelley M Faber, Thomas J Fairchild, Kenneth B Fallon, David W Fardo, Martin R Farlow, Victoria Fernandez-Hernandez, Steven Ferris, Robert P Friedland, Tatiana M Foroud, Matthew P Frosch, Brian Fulton-Howard, Douglas R Galasko, Adriana Gamboa, Marla Gearing, Daniel H Geschwind, Bernardino Ghetti, John R Gilbert, Rodney C P Go, Alison M Goate, Thomas J Grabowski, Neill R Graff-Radford, Robert C Green, John H Growdon, Hakon Hakonarson, James Hall, Ronald L Hamilton, Oscar Harari, John Hardy, Lindy E Harrell, Elizabeth Head, Victor W Henderson, Michelle Hernandez, Timothy Hohman, Lawrence S Honig, Ryan M Huebinger, Matthew J Huentelman, Christine M Hulette, Bradley T Hyman, Linda S Hynan, Laura Ibanez, Gail P Jarvik, Suman Jayadev, Lee-Way Jin, Kim Johnson, Leigh Johnson, M Ilyas Kamboh, Anna M Karydas, Mindy J Katz, John S Kauwe, Jeffrey A Kaye, C Dirk Keene, Aisha Khaleeq, Masataka Kikuchi, Ronald Kim, Janice Knebl, Neil W Kowall, Joel H Kramer, Walter A Kukull, Frank M Laferla, James J Lah, Eric B Larson, Alan Lerner, James B Leverenz, Allan I Levey, Andrew P Lieberman, Richard B Lipton, Mark Logue, Oscar L Lopez, Kathryn L Lunetta, Constantine G Lyketsos, Douglas Mains, Flanagan E Margaret, Daniel C Marson, Eden Rr Martin, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Paul Massman, Arjun Masurkar, Wayne C Mccormick, Susan M Mccurry, Andrew N Mcdavid, Stefan Mcdonough, Ann C Mckee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, Thomas J Montine, Edwin S Monuki, John C Morris, Shubhabrata Mukherjee, Amanda J Myers, Trung Nguyen, Thomas Obisesan, Sid O'Bryant, John M Olichney, Marcia Ory, Raymond Palmer, Joseph E Parisi, Henry L Paulson, Valory Pavlik, David Paydarfar, Victoria Perez, Elaine Peskind, Ronald C Petersen, Helen Petrovitch, Aimee Pierce, Marsha Polk, Wayne W Poon, Huntington Potter, Liming Qu, Mary Quiceno, Joseph F Quinn, Ashok Raj, Murray Raskind, Eric M Reiman, Barry Reisberg, Joan S Reisch, John M Ringman, Erik D Roberson, Monica Rodriguear, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Donald R Royall, Marwan Sabbagh, A Dessa Sadovnick, Mark A Sager, Mary Sano, Andrew J Saykin, Julie A Schneider, Lon S Schneider, William W Seeley, Susan H Slifer, Scott Small, Amanda G Smith, Janet P Smith, Joshua A Sonnen, Salvatore Spina, Peter St George-Hyslop, Takiyah D Starks, Robert A Stern, Alan B Stevens, Stephen M Strittmatter, David Sultzer, Russell H Swerdlow, Rudolph E Tanzi, Jeffrey L Tilson, John Q Trojanowski, Juan C Troncoso, Magda Tsolaki, Debby W Tsuang, Vivianna M Van Deerlin, Linda J Van Eldik, Jeffery M Vance, Badri N Vardarajan, Robert Vassar, Harry V Vinters, Jean-Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Patrice L Whitehead, Ellen M Wijsman, Kirk C Wilhelmsen, Benjamin Williams, Jennifer Williamson, Henrik Wilms, Thomas S Wingo, Thomas Wisniewski, Randall L Woltjer, Martin Woon, Clinton B Wright, Chuang-Kuo Wu, Steven G Younkin, Chang-En Yu, Lei Yu, Xiongwei Zhu, Brian W Kunkle, William S Bush, Akinori Miyashita, Goldie S Byrd, Li-San Wang, Lindsay A Farrer, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Gerard D Schellenberg, Gyungah R Jun, Christiane Reitz, Adam C Naj, Alzheimer’S Disease Genetics Consortium (Adgc)

Faculty, Staff and Students Publications

Background: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.

Results: We identify 13 loci with cross-population associations including known loci at/near CR1, …

Prognostic Gene Expression And Microrna Profiling Signatures And Genetic Alterations In Primary Testicular Diffuse Large B-Cell Lymphoma, Wenyu Shi, Zijun Y Xu-Monette, Youchao Jia, Alexandar Tzankov, Heounjeong Go, Ling Li, Maurilio Ponzoni, Yafei Wang, Qiongli Zhai, Anamarija M Perry, Shi Wang, Xiaoxiao Wang, April Chiu, Mina L Xu, Carlo Visco, Karen Dybkaer, Henry Withers, Mark Long, Alyssa F Yuan, Yi Miao, Everardo Macias, Dehong Wu, Wen Shuai, Bangchen Wang, Jianyong Li, Govind Bhagat, Youli Zu, Zenggang Pan, William Choi, Santiago Montes-Moreno, Weina Chen, J Han Van Krieken, Michael B Møller, Xinfang Yu, Benjamin M Parsons, Shanxiang Zhang, Eric D Hsi, Aliyah R Sohani, Jeremy S Abramson, Andrés J M Ferreri, Bing Xu, Yong Li, Ken H Young

Faculty, Staff and Students Publications

Primary testicular (PT) diffuse large B-cell lymphoma (DLBCL) is a rare and aggressive lymphoma with distinct clinical and molecular characteristics. To identify prognostic biomarkers in PT-DLBCL, in this study we analyzed DNA and RNA samples of PT-DLBCL tumors from 206 patients using next-generation sequencing platforms and assays. Genetic alteration analysis found that multiple chromosomal copy number variations (CNVs), TP53 transcript mutations with high variant allele frequency, and MCD subtype had significantly adverse prognostic effects, whereas elevated microsatellite instability had a significantly favorable prognostic effect in PT-DLBCL. Targeted RNA-seq analysis identified a PTL gene expression signature by comparing PT-DLBCL with systemic …

Publisher Correction: Comprehensive Evaluation Of Phosphoproteomic-Based Kinase Activity Inference, Sophia Müller-Dott, Eric J Jaehnig, Khoi Pham Munchic, Wen Jiang, Tomer M Yaron-Barir, Sara R Savage, Martin Garrido-Rodriguez, Jared L Johnson, Alessandro Lussana, Evangelia Petsalaki, Jonathan T Lei, Aurelien Dugourd, Karsten Krug, Lewis C Cantley, D R Mani, Bing Zhang, Julio Saez-Rodriguez

Faculty, Staff and Students Publications

No abstract provided.

Sensing The Stiffness: Cellular Mechano-Sensing At The Implant Interface, Patricia S Pardo, Delia Danila, Raja Devesh Kumar Misra, Aladin M Boriek

Faculty, Staff and Students Publications

In this perspective, we highlight the relevance of the FA-Hippo signaling pathway and its regulation of the Yes-associated protein (YAP) and the transcriptional coactivator with a PDZ-binding domain (TAZ) as main players in the process of implants integration. The modulation and responses of YAP/TAZ triggered by substrate and ECM stiffness are of particular interest in the construction of materials used for medical implants. YAP/TAZ nuclear localization and activity respond to the substrate stiffness by several mechanisms that involve the canonical and non-canonical Hippo signaling and independently of the Hippo cascade. YAP/TAZ regulate the expression of genes involved in several mechanisms …

Development And Validation Of Risk Models For Hospital-Acquired Bleeding In Medical Inpatients: The Medical Inpatients Thrombosis And Hemostasis (Mith) Study, Neil A Zakai, Katherine Wilkinson, Andrew D Sparks, Ryan T Packer, Nicholas S Roetker, Allen B Repp, Mansour Gergi, Chris Holmes, Mary Cushman, Timothy B Plante, Hanny Al-Samkari, Allyson M Pishko, William A Wood, Camila Masias, Radhika Gangaraju, Ang Li, David Garcia, Kerri L Wiggins, Jordan K Schaefer, Nicholas L Smith, Augusto Ferraris, Karlyn A Martin, Deirdra R Terrell, Leslie A Mcclure

Faculty, Staff and Students Publications

Background: Hospital-acquired (HA) bleeding in medical inpatients is a serious complication with limited tools to predict risk.

Objectives: This study aimed to develop and validate risk assessment models (RAMs) for anatomic location-specific HA bleeding in medical inpatients using objective and routinely available risk factors.

Methods: Patients aged ≥18 years admitted to medical hospital services from 6 health systems and 15 hospitals in the United States between 2016 and 2020 for at least 1 midnight and without bleeding at admission were eligible for inclusion. Two health systems (10 hospitals) formed the development cohort, and 4 systems (5 hospitals) constituted the validation …

Elimination Of Hiv Reservoirs Harboring Intact Proviruses, Min Li, Khanghy Truong, Suman Sharma, Baichao Sun, Min Chen, Jason T Kimata, Jin Wang

Faculty, Staff and Students Publications

Background: Human immunodeficiency virus (HIV) establishes persistent infection by integrating its proviral DNA into the host genome. While most integrated proviruses are defective, a small portion of proviruses are intact that represent a major obstacle to achieving an HIV cure. We have designed an approach for selective elimination of host cells harboring replication-competent HIV (SECH), through inhibition of autophagy and anti-apoptotic molecules during viral reactivation. However, the effects of SECH on the dynamics of intact and defective HIV provirus remain unclear.

Methods: We isolated DNA from HIV-infected samples after SECH treatments. We analyzed HIV-1 proviruses in these samples by intact …

Spase: Spatially Resolved Pathology Scores Using Optimal Transport On Spatial Transcriptomics Data, Mohammad Nuwaisir Rahman, Mohammed Abid Abrar, Vikram Rakesh Shaw, James F Martin, M Saifur Rahman, Md Abul Hassan Samee

Faculty, Staff and Students Publications

Pathological events often impact tissue regions in a spatial variable manner, making it challenging to identify therapeutic targets. Spatial transcriptomics (ST) is a powerful technology to map spatially variable molecular mechanisms, yet suitable analytical methods have been lacking. We introduce SPaSE (Spatially-resolved Pathology ScorE), an optimal transport-based algorithm to compare ST data from diseased and control tissues. SPaSE computes a “pathology score” for each spot in the diseased sample, quantifying the pathological impact at that spot. In post-MI (myocardial infarction) mouse hearts, these scores delineated zones that matched independent expert annotations. Modeling pathology scores from gene expression revealed signatures predictive …

Development And Extensive Sequencing Of A Broadly-Consented Genome In A Bottle Matched Tumor-Normal Pair, Jennifer H Mcdaniel, Vaidehi Patel, Nathan D Olson, Hua-Jun He, Zhiyong He, Kenneth D Cole, Alexander A Gooden, Anthony Schmitt, Kristin Sikkink, Fritz J Sedlazeck, Harsha Doddapaneni, Shalini N Jhangiani, Donna M Muzny, Marie-Claude Gingras, Heer Mehta, Sairam Behera, Luis F Paulin, Alex R Hastie, Hung-Chun Yu, Victor Weigman, Alison Rojas, Katie Kennedy, Jamie Remington, Isai Salas-González, Mitch Sudkamp, Kelly Wiseman, Bryan R Lajoie, Shawn Levy, Miten Jain, Stuart Akeson, Giuseppe Narzisi, Zoe Steinsnyder, Catherine Reeves, Jennifer Shelton, Sarah B Kingan, Christine Lambert, Primo Baybayan, Aaron M Wenger, Ian J Mclaughlin, Aaron Adamson, Christopher Kingsley, Melanie Wescott, Young Kim, Benedict Paten, Jimin Park, Ivo Violich, Karen H Miga, Joshua Gardner, Brandy Mcnulty, Gail L Rosen, Rajiv Mccoy, Francesco Brundu, Erfan Sayyari, Konrad Scheffler, Sean Truong, Severine Catreux, Lesley Chapman Hannah, Doron Lipson, Hila Benjamin, Nika Iremadze, Ilya Soifer, Gat Krieger, Stephen Eacker, Mary Wood, Erin Cross, Greg Husar, Stephen Gross, Michael Vernich, Mikhail Kolmogorov, Tanveer Ahmad, Ayse G Keskus, Asher Bryant, Francoise Thibaud-Nissen, Jonathan Trow, Jacqueline Proszynski, Jeremy Wain Hirschberg, Krista Ryon, Christopher E Mason, Mital S Bhakta, J Zachary Sanborn, Elizabeth M Munding, Justin Wagner, Chunlin Xiao, Andrew S Liss, Justin M Zook

Faculty, Staff and Students Publications

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from seventeen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, Hi-C, …

Altered Patterning Of Neural Activity In A Neuropathology, Clarissa Hoffman, Jingheng Cheng, Rodrigo Morales, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

The dynamics of neural circuits and their role in mediating cellular and organismal phenomena remain poorly understood, despite numerous efforts to dissect these processes through precise instantaneous measurements or longer-time averages and approximations. We use an alternative approach: we investigate these dynamics at the system's mesoscale by analyzing spike trains and waveforms. These extended activity patterns carry robust, tractable information, are highly responsive to physiological specifics, and enable detailed tracking of circuit behavior. In particular, this methodology allows for characterizing the functionality of tau-pathology-afflicted hippocampal circuits and identifying circuit-level abnormalities that are missed by through traditional analyses. In healthy mice, …

Epha4 Signaling Dysregulation Links Abnormal Locomotion And The Development Of Idiopathic Scoliosis, Lianlei Wang, Xinyu Yang, Sen Zhao, Pengfei Zheng, Wen Wen, Kexin Xu, Xi Cheng, Qing Li, Anas M Khanshour, Yoshinao Koike, Junjun Liu, Xin Fan, Nao Otomo, Zefu Chen, Yaqi Li, Lulu Li, Haibo Xie, Panpan Zhu, Xiaoxin Li, Yuchen Niu, Shengru Wang, Sen Liu, Suomao Yuan, Chikashi Terao, Ziquan Li, Shaoke Chen, Xiuli Zhao, Pengfei Liu, Jennifer E Posey, Zhihong Wu, Guixing Qiu, Disco Study Group (Deciphering Disorders Involving Scoliosis & Comorbidities), Shiro Ikegawa, James R Lupski, Jonathan J Rios, Carol A Wise, Jianguo T Zhang, Chengtian Zhao, Nan Wu

Faculty, Staff and Students Publications

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited …

Gene Expression In Tumor And Adjacent Normal Tissues In Lung Adenocarcinoma Subtypes, Olga Y Gorlova, Ivan P Gorlov, R Taylor Ripley, Chao Cheng, Yafang Li, Bo Peng, Yanhong Liu, Hee-Jin Jang, Sung Wook Kang, Claire Lee, Priyanka Ranchod, Bryan M Burt, Hyun-Sung Lee, Christopher I Amos

Faculty, Staff and Students Publications

Background: Lung adenocarcinoma (LUAD) has several histologically distinct subtypes that differ by a number of clinical features including patient survival. Molecular mechanisms underlying histological and clinical differences between subtypes remain poorly understood.

Methods: We conducted a comparative analyses of gene expression in acinar, lepidic, papillary and solid subtypes, as well as mucinous adenocarcinoma. We used a novel, more efficient approach to identify subtype-specific genes. We compared the mean gene expression level separately for tumors and adjacent normal tissue with pure or a highly represented (≥ 75%) subtype of interest to the mean expression in tumors where the subtype of interest …

Exogenous Arginine Differentially Regulates Inflammatory Cytokine And Inducible Nitric Oxide Synthase Expression In Macrophages, Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther

Faculty, Staff and Students Publications

Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is …

Spatial Proximity Of Immune Cell Pairs To Cancer Cells In The Tumor Microenvironment As Biomarkers For Patient Stratification, Jian-Rong Li, Xingxin Pan, Yupei Lin, Yanding Zhao, Yanhong Liu, Yong Li, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Background/objectives: The tumor microenvironment (TME) plays a critical role in cancer progression by shaping immune responses and influencing patient outcomes. We hypothesized that the relative proximity of specific immune cell pairs to cancer cells within the TME could help predict their pro- or anti-tumor functions and reflect clinically relevant immune dynamics.

Methods: We analyzed imaging mass cytometry (IMC) data from lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) cohorts. For each immune cell pair, we calculated a relative distance (RD) score, which quantifies the spatial difference in proximity to cancer cells. We assessed the prognostic and predictive significance of these …

Ovochymase 2 Is A Key Regulatory Factor Modulating Proteolytic Pathways And Sperm Maturation In The Mammalian Epididymis, Katarzyna Kent, Kaori Nozawa, Antrix Jain, Anna Malovannaya, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

Spermatozoa acquire fertilizing competence during epididymal transit through proteolytic, chaperone-mediated, and post-translational modifications. Ovochymase 2, an epididymis-specific trypsin-like serine protease, has emerged as a central regulator of this maturation process. Here, we integrate targeted gene disruption, comprehensive proteomic profiling, and affinity-based proteome enrichment to delineate how Ovochymase 2 influences sperm functionality. Deletion of Ovochymase 2 disrupts the proteome of epididymal sperm, resulting in diminished levels of core fertility-related factors-including a disintegrin and metalloprotease domain 3, β-defensins, and protease-inhibitor complexes-while inducing compensatory upregulation of alternate proteases and chaperones. Interaction assays confirm direct or indirect associations between Ovochymase 2 and sperm surface …

A Mouse Model Engineered To Spatiotemporally Control Cre Expression In Progesterone Receptor Positive Cells†, Elvis Quiroz, Ryan M Marquardt, Shu-Yun Li, Artiom Gruzdev, David Cunefare, Charan Ganta, San-Pin Wu, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

The Cre/loxP system is widely used for site-specific genetic manipulation in mice. The PgrCre mouse model, where Cre recombinase is driven by the progesterone receptor promoter, is commonly used for gene ablation in Pgr-positive uterine cells. However, the PgrCre is active in the neonatal uterus and does not allow temporal control. To enhance the functionality of the PgrCre mouse, we generated and characterized an inducible PgriCreERT2 mouse, in which iCreERT2 is inserted downstream of the endogenous Pgr promoter. PgriCreERT2 mice crossed with Rosa26-CAG-LSL-Sun1-sfGFP-myc reporter mice demonstrated tamoxifen-dependent recombination in uterine stromal fibroblasts and a subset of epithelial cells. Tamoxifen-induced ablation …

Oral Dosing Of The Nucleoside Analog Obeldesivir Is Efficacious Against Rsv Infection In African Green Monkeys, Jared Pitts, J Lizbeth Reyes Zamora, Savrina Manhas, Thomas Aeschbacher, Josolyn Chan, Vincent Cutillas, Varsha Nair, Nicholas C Riola, Arya Vijjapurapu, Meghan S Vermillion, Stacey Eng, Christopher Richards, Dong Han, Jason K Perry, Subhra Chaudhuri, Szu-Wen Liu, Clarissa Martinez, Nadine Peinovich, Kai-Hui Sun, Arthur Cai, Ross Martin, Jasmine Moshiri, Charlotte Hedskog, Darius Babusis, Dustin S Siegel, Rao Kalla, Vasanthi Avadhanula, Pedro A Piedra, Kim Stobbelaar, Peter L Delputte, Caleb Marceau, Roberto Mateo, Evguenia Maiorova, Hongmei Mo, Raju Subramanian, Richard L Mackman, Tomas Cihlar, Simon P Fletcher, John P Bilello

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20–0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identify a single amino acid substitution, I777L, in the L polymerase with …

Global Diversity Of Soil-Transmitted Helminths Reveals Population-Biased Genetic Variation That Impacts Diagnostic Targets, Marina Papaiakovou, Andrea Waeschenbach, Olumide Ajibola, Sitara Sr Ajjampur, Roy M Anderson, Robin Bailey, Jade Benjamin-Chung, Maria Cambra-Pellejà, Nicolas R Caro, David Chaima, Rubén O Cimino, Piet Cools, Anélsio Cossa, Julia Dunn, Sean Galagan, Javier Gandasegui, Berta Grau-Pujol, Emma L Houlder, Moudachirou Ibikounlé, Timothy P Jenkins, Khumbo Kalua, Eyrun F Kjetland, Alejandro J Krolewiecki, Bruno Levecke, Adrian Jf Luty, Andrew S Macdonald, Inácio Mandomando, Malathi Manuel, Maria Martínez-Valladares, Rojelio Mejia, Zeleke Mekonnen, Augusto Messa, Harriet Mpairwe, Osvaldo Muchisse, Jose Muñoz, Pauline Mwinzi, Valdemiro Novela, Maurice R Odiere, Charfudin Sacoor, Judd L Walson, Steven A Williams, Stefan Witek-Mcmanus, D Timothy J Littlewood, Cinzia Cantacessi, Stephen R Doyle

Faculty, Staff and Students Publications

Soil-transmitted helminths (STHs) are intestinal parasites that affect over a billion people worldwide. STH control relies on microscopy-based diagnostics to monitor parasite prevalence and enable post-treatment surveillance; however, molecular diagnostics are rapidly being developed due to increased sensitivity, particularly in low-STH-prevalence settings. The genetic diversity of helminths and its potential impact on molecular diagnostics remain unclear. Using low-coverage genome sequencing, we assess the genetics of STHs within worm, faecal, and purified egg samples from 27 countries, identifying differences in the genetic connectivity and diversity of STH-positive samples across regions and cryptic diversity between closely related human- and pig-infective species. We …

Genome Report: Whole-Genome Assembly Of The Relapsing Fever Tick Ornithodoros Turicata Dugès (Acari: Argasidae), Mackenzie Tietjen, Amanda R Stahlke, David Luecke, Perot Saelao, Sheina B Sim, Scott M Geib, Brian E Scheffler, Anna K Childers, Alexander R Kneubehl, Pete D Teel, Job E Lopez

Faculty, Staff and Students Publications

The soft tick family Argasidae contains vectors of medical and veterinary importance, but few molecular resources are available compared to hard ticks (Ixodidae). One example is Ornithodoros turicata, a recognized vector of Borrelia turicatae, causal agent of human relapsing fever, and a putative vector of African swine fever virus. To address the current lack of molecular resources for the Argasidae, we generated a chromosome-level genome assembly for O. turicata using PacBio sequencing in conjunction with an Illumina Hi-C library. The resulting reference genome has a total of 1.1 Gb in length and was assembled into 10 chromosomes and 368 unplaced …

Inferring Chromosome Segregation Error Stage And Crossover In Trisomic Disorders With Application To Down Syndrome, Zhenhua Li, Wenjian Yang, Gang Wu, Ti-Cheng Chang, Zhongshan Cheng, Meenakshi Devidas, Mary Shago, Andrew J Carroll, Nyla A Heerema, Julie M Gastier-Foster, Brent L Wood, Lauren Sanclemente, Elizabeth A Raetz, Stephen P Hunger, Mignon L Loh, Eleanor Feingold, Tracie C Rosser, Emily G Allen, Stephanie L Sherman, Karen R Rabin, Philip J Lupo, Jun J Yang

Faculty, Staff and Students Publications

Errors in chromosome segregation during gametogenesis, such as nondisjunction (NDJ) errors, have severe consequences in human reproduction, and a better understanding of their etiology is of fundamental interest in genetics. Mapping NDJ errors to meiotic/mitotic stages typically requires proband-parent comparison, limiting its applicability. Herein, we develop Mis-segregation Error Identification through Hidden Markov Models (MeiHMM), a method for inferring NDJ error stage and crossover events based on only genomic data of trisomic probands. Guided by triallelic genotype/haplotype configurations, MeiHMM discerns the allelic origin at each locus, which informs NDJ error during gamete formation, without identifying the parental origin of the trisomy. …

Distinct Systemic Impacts Of Aβ42 And Tau Revealed By Whole-Organism Snrna-Seq, Ye-Jin Park, Tzu-Chiao Lu, Tyler Jackson, Lindsey D Goodman, Lindsey Ran, Jiaye Chen, Chung-Yi Liang, Erin Harrison, Christina Ko, Xi Chen, Baiping Wang, Ao-Lin Hsu, Elizabeth Ochoa, Kevin F Bieniek, Shinya Yamamoto, Yi Zhu, Hui Zheng, Yanyan Qi, Hugo J Bellen, Hongjie Li

Faculty, Staff and Students Publications

Both neuronal and peripheral tissues become disrupted in Alzheimer's disease (AD). However, a comprehensive understanding of how AD impacts different tissues across the whole organism is lacking. Using Drosophila, we generated an AD Fly Cell Atlas (AD-FCA) based on whole-organism single-nucleus transcriptomes of 219 cell types from flies expressing AD-associated proteins, either human amyloid-β 42 peptide (Aβ42) or Tau, in neurons. We found that Aβ42 primarily affects the nervous system, including sensory neurons, while Tau induces accelerated aging in peripheral tissues. We identified a neuronal cluster enriched in Aβ42 flies, which has high lactate dehydrogenase (LDH) expression. This LDH-high cluster …

Single-Cell Profiling Of Bone Metastasis Ecosystems From Multiple Cancer Types Reveals Convergent And Divergent Mechanisms Of Bone Colonization, Fengshuo Liu, Yunfeng Ding, Zhan Xu, Xiaoxin Hao, Tianhong Pan, George Miles, Siyue Wang, Yi-Hsuan Wu, Jun Liu, Igor L Bado, Weijie Zhang, Ling Wu, Yang Gao, Liqun Yu, David G Edwards, Hilda L Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang, Zbigniew Gugala, Robert L Satcher, Xiang H-F Zhang

Faculty, Staff and Students Publications

Bone is a common site for metastasis of solid cancers. The diversity of histological and molecular characteristics of bone metastases (BMs) remains poorly studied. Here, we performed single-cell RNA sequencing on 42 BMs from eight cancer types, identifying three distinct ecosystem archetypes, each characterized by an enrichment of specific immune cells: macrophages/osteoclasts, regulatory/exhausted T cells, or monocytes. We validated these archetypes by immunostaining on tissue sections and bioinformatic analysis of bulk RNA sequencing/microarray data from 158 BMs across more than 10 cancer types. Interestingly, we found only a modest correlation between the BM archetypes and the tissues of origin; BMs …

Psilocybin Treatment Extends Cellular Lifespan And Improves Survival Of Aged Mice, Kosuke Kato, Jennifer M Kleinhenz, Yoon-Joo Shin, Cristian Coarfa, Ali J Zarrabi, Louise Hecker

Faculty, Staff and Students Publications

Psilocybin, the naturally occurring psychedelic compound produced by hallucinogenic mushrooms, has received attention due to considerable clinical evidence for its therapeutic potential to treat various psychiatric and neurodegenerative indications. However, the underlying molecular mechanisms remain enigmatic, and few studies have explored its systemic impacts. We provide the first experimental evidence that psilocin (the active metabolite of psilocybin) treatment extends cellular lifespan and psilocybin treatment promotes increased longevity in aged mice, suggesting that psilocybin may be a potent geroprotective agent.

The Benefits Of Exercise Training In Combination With Weight Loss Therapies, Bryan C Jiang, Dennis T Villareal

Faculty, Staff and Students Publications

The primary treatment for obesity involves calorie restriction (CR) to promote dietary weight loss achieved through interventions including behavioral modification, bariatric surgery, and antiobesity medications. In adults with obesity, CR-induced weight loss enhances physical function and improves quality of life, while also reducing the burden of various obesity-related chronic conditions, including hypertension, diabetes, obstructive sleep apnea, and atherosclerotic heart disease. However, it is also associated with a decline in lean mass and bone mineral density, which increases the risk of sarcopenia and osteoporosis. When performed alongside CR, progressive resistance training (RT) attenuates this loss of lean mass and bone mass, …

Infantile Pyknocytosis Revisited: Possible Familial Trend In A Study Of 9 Patients, Aileen Y Hu, Amy M Coffey, Jyotinder N Punia, Andrea N Marcogliese, Choladda V Curry, M Tarek Elghetany

Faculty, Staff and Students Publications

Context.—: Infantile pyknocytosis (IP) is an uncommon cause of transient neonatal hemolytic anemia and hyperbilirubinemia occurring in approximately 10% of cases of unexplained neonatal hemolytic anemia.

Objective.—: To study cases of IP with focus on long-term follow-up, perinatal events, and family history.

Design.—: Cases were prospectively identified during review of peripheral blood smears for neonatal hyperbilirubinemia during an 11-year period. Clinical and laboratory parameters, follow-up data, and family history were recorded.

Results.—: Nine cases of IP were identified from the morphologic recognition of pyknocytes and clinical and laboratory evidence of hemolysis, and included 6 males and 3 females. Age at …

High-Affinity Cd16a Polymorphism Associated With Reduced Risk Ofsevere Covid-19, Anita E Qualls, Tasha Tsao, Irene Lui, Shion A Lim, Yapeng Su, Ernie Chen, Dylan Duchen, Holden T Maecker, Seunghee Kim-Schulze, Ruth R Montgomery, Florian Krammer, Charles R Langelier, Ofer Levy, Lindsey R Baden, Esther Melamed, Lauren Ir Ehrlich, Grace A Mccomsey, Rafick P Sekaly, Charles B Cairns, Elias K Haddad, Albert C Shaw, David A Hafler, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez-Sesma, Viviana Simon, Monica Kraft, Christian Bime, Carolyn S Calfee, David J Erle, Joanna Schaenmann, Al Ozonoff, Bjoern Peters, Steven H Kleinstein, Alison D Augustine, Joann Diray-Arce, Patrice M Becker, Nadine Rouphael, Impacc Network, Jason D Goldman, Daniel R Calabrese, James R Heath, James A Wells, Elaine F Reed, Lewis L Lanier, Harry Pickering, Oscar A Aguilar

Faculty, Staff and Students Publications

CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1,027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 …

Retinal Ganglion Cell Migration And Viability Requires The Kinase Lkb1, Robert D Mackin, Ritika V Bhalla, Viktor Akhanov, Qudrat T Abdulwahab, Courtney A Burger, Melanie A Samuel

Faculty, Staff and Students Publications

The arrangement of neurons into ordered layers underlies circuit function in many nervous system regions. This is particularly true in the mammalian retina. Here, fate-committed retinal ganglion cells (RGCs) migrate from the apical to the inner retina, where they form connections that enable vision. The mechanisms that permit ganglion cell migration and whether distinct ganglion cell types use different migration modes are unknown. We show that the serine/threonine kinase LKB1 regulates ganglion cell migration and nuclear positioning. In the absence of LKB1, many ganglion cells remain in the apical retina. Misplaced cells show modified morphologies and display altered cytoskeletal proteins. …