Medical Specialties Commons^™

Characterizing The Metabolites Of The Tyrosine-Kinase Inhibitor Pexidartinib In Mouse Feces, Urine, Plasma, And Liver, Xuan Qin, Si Chen, John M Hakenjos, Jian Wang, Lei Guo, Ashish Dogra, Zhaoyong Hu, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Pexidartinib (PEX, TURALIO®), a tyrosine kinase inhibitor, is approved for treating tenosynovial giant cell tumor in adults. However, its potential to cause fatal liver injury has prompted the U.S. FDA to issue a black box warning, and the mechanisms underlying its hepatotoxicity remain largely unknown. As biotransformation may contribute to PEX-induced hepatotoxicity, understanding its metabolism is essential. Our previous research indicated that PEX forms reactive metabolites in human and mouse liver microsomes and in human hepatocytes. We investigated PEX metabolism and liver distribution in mice with a focus on metabolite characterization. Our data shows that PEX is mainly excreted into …

Multisite Assembly Of Gateway Induced Clones (Magic): A Flexible Cloning Toolbox For Use In Vertebrate Model Systems, William B Gillespie, Yuwen Zhang, Oscar E Ruiz, Juan Cerda, Joshua Ortiz-Guzman, Michelle Sherman, Williamson D Turner, Gabrielle Largoza, Lili E Mosser, Esther Fujimoto, Chi-Bin Chien, Kristen M Kwan, Benjamin R Arenkiel, W Patrick Devine, Joshua D Wythe

Duncan NRI Faculty and Staff Publications

Here, we present MultiSite Assembly of Gateway Induced Clones (MAGIC), which leverages Gateway-based recombinatorial cloning technology for rapid, modular assembly of plasmids to facilitate transgenesis in cells and vertebrate animal models. The MAGIC collection of plasmids spans a range of in vitro and in vivo uses, from tools for optically and chemically tunable gene expression, to simultaneous expression of microRNAs and fluorescent reporters, to a suite of distinct subcellular compartmental fluorescent reporters, to Cre and Dre recombinase-dependent gene expression. MAGIC system components are compatible with existing MultiSite Gateway Tol2 systems currently used in zebrafish and mammalian lentiviral and adenoviral Destination …

Short- And Mid-Term Outcomes Of The Extravascular Implantable Cardioverter-Defibrillator In Pediatric And Adolescent Patients: A Single-Center Experience., Nikola Dragisic, Emily R. Backes, Lindsey Malloy-Walton, Edo Bedzra, William Gibson, Philip M. Chang

Manuscripts, Articles, Book Chapters and Other Papers

Experience with the Aurora extravascular (EV) implantable cardioverter-defibrillator (ICD) (Medtronic, Minneapolis, MN, USA) remains limited among pediatric centers in contrast to its broader implantation in adults. We evaluated our single-center experience with the EV ICD as part of our standard ICD options for treatment of malignant ventricular arrhythmias in pediatric subjects. Following approval for EV ICD implantation at our center, five consecutive adolescent patients underwent implantation over a 7-month period. Patient characteristics, qualification for EV ICD placement, nuances in EV ICD implantation in each patient, and post-implant follow-up were reviewed. A total of six out of eight consecutive ICD candidates …

Imaging Features Of High-Grade Astrocytoma With Piloid Features: A Single Center Case Series, Heba Al Qudah, Jackson D Hamilton, Maria A Gubbiotti, Ahmed Msherghi, Hamza A Salim, Sahar Alizada, Ho-Ling Liu, Vinodh A Kumar, Max Wintermark, Rami W Eldaya

Faculty, Staff and Student Publications

High-grade astrocytoma with piloid features (HGAP) is a recently described IDH-wildtype tumor with limited literature describing its imaging features. We present our institution's experience and the largest imaging-focused cohort of HGAP reported to date, offering a comprehensive analysis of MRI features of seventeen intracranial and one spinal HGAP, while introducing novel imaging features that have not been previously described. These include focal areas of diffusion restriction, surrounding spiculated, finger-like enhancement and increased perfusion metrics. Additionally, we highlight imaging features of HGAP arising in patients with Neurofibromatosis Type 1, such as intraventricular tumor spread, unusual temporal lobe location and multifocal presentation.

Late Morbidity And Mortality In Survivors Of Childhood Ependymoma: A Report From The Childhood Cancer Survivor Study (Ccss), Katharine R Lange, Peter De Blank, Mengqi Xing, Sedigheh Mirzaei, Deo Kumar Srivastava, Kevin Oeffinger, Joseph Neglia, Kevin Krull, Paul C Nathan, Rebecca Howell, Kirsten K Ness, Lucie M Turcotte, Wendy Leisenring, Gregory T Armstrong, Tara Brinkman, Daniel C Bowers, Mehmet Fatih Okcu

Faculty, Staff and Student Publications

Background/objectives: Treatment of childhood ependymoma evolved from 1970 to 1999 by reducing radiation volumes and incorporating chemotherapy. The impact of these changes on long-term health outcomes remains unknown. In this report, we evaluated temporal changes in all-cause and cause-specific late mortality, chronic health conditions (CHCs), and subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort of adult survivors of pediatric ependymoma, diagnosed between 1970 and 1999.

Methods: A total of 404 five-year survivors of ependymoma (47.5% female, 80.7% non-Hispanic White, median 6 (range 0-20) years at diagnosis, 22 (5-49) years from diagnosis) diagnosed between 1970 and 1999 and …

Management Of Stenotrophomonas Mediastinitis After Heart Transplantation For Persistent Driveline Infection: A Case Report, James Lee West, Charles W. Hoopes, Jeremey Walker, Anoma Nellore, Erik J. Orozco-Hernandez

Department of Surgery Faculty Papers

We report a 62-year-old male who had a Heartware left ventricular assist device (LVAD) implantation and subsequently developed a persistent driveline infection, culminating in an abscess along the driveline site despite 18 months of antibiotic treatment. His situation was further complicated post-transplant by the onset of mediastinitis, linked to a previously undervalued Stenotrophomonas maltophilia infection. This report highlights the potential risks of heart transplantation in patients with unresolved LVAD driveline infections, particularly mediastinitis. The presence of existing driveline infections, combined with the immunosuppressed status of patients, necessitates aggressive surgical measures. Our treatment approach, involving multiple mediastinal washouts, omental flap use, …

In-Silico Assessment Of Aortic Valve Function And Mechanics Under Hypertension, Jason A. Shar, Philippe Sucosky

Faculty Articles

Introduction: Calcific aortic valve disease (CAVD) is the most common heart valve disorder. While hypertension is a major risk factor, the mechanisms by which elevated blood pressure contributes to calcification are largely unknown. Given the established sensitivity of aortic valve (AV) tissue to mechanical cues, hypertension may subject AV leaflets to a stress state conducive to CAVD. To address this hypothesis, the objective of this study was to compare AV function and mechanics under normotensive (NTN, 120/ 80 mmHg), pre-hypertensive (preHTN, 125/80 mmHg) and hypertensive (HTN, 130/90 mmHg) conditions using fluid-structure interaction modeling.

Methods: AV flow and leaflet dynamics were …

Sulindac Sulfide Suppresses Oncogenic Transformation Through Let-7b-Mediated Repression Of K-Ras Signaling, Zhipin Liang, Ruixia Ma, Bin Yi, Adam I. Riker, Yaguang Xi

School of Graduate Studies Faculty Publications

No abstract provided.

A Role For Gut Mycobiome And Altered Fungal-Bacterial Interactions In Women With Endometriosis†, Chandni Talwar, Ashirbad Guria, Kristi Hoffman, Scott Biest, Patricia Jimenez, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Endometriosis is a gynecological pathology prevalent in reproductive age women in which the inner uterine wall (endometrium) grows outside as ectopic lesions. The inflammation resulting from these growing implants closely associates with disease severity, causing chronic pain and infertility. Emerging studies have found altered bacterial communities in endometriosis and a causal role for gut bacteria in endometriosis. However, the role of the gut mycobiome, i.e., the fungal component of the microbiome in endometriosis is a current knowledge gap that needs to be addressed. In this study, utilizing the stool samples from women with endometriosis, we found that the gut fungal …

Vitamin D Is Glucoprotective In Aging Males But Not Females, Olivia Z B Ginnard, Maria Morales, Ji Youn Youn, Yong Xu, Stephanie R Sisley

Faculty, Staff and Students Publications

Vitamin D supplementation is linked to many beneficial health outcomes in the geriatric population, such as decreased mortality, epigenetic aging, and fracture risk. Conversely, type 2 diabetes is strongly linked to vitamin D deficiency in older adults. However, there is a discrepancy between clinical trials in adults on the efficacy of vitamin D treatment in prediabetes and diabetes. In addition, human data indicates there may be sexual dimorphism in the effect of vitamin D deficiency on dysglycemia that is more pronounced in men. These incongruities may be due to our limited understanding of the underlying mechanisms of vitamin D in …

Severe Myocarditis In The Pediatric Patient: A Simulation For Emergency Department Management, Prayerna Uppal, Anita Thomas, Robyn Wing, Lauren Kinneman, Cassandra Koid Jia Shin, Daisy Ciener, Jean I. Pearce, Claire Smith, Jennifer Reid, Kimberly Stone, Katina Summerford, Katherine Wolpert

School of Medicine Faculty Publications

Myocarditis in a pediatric patient can present with a variety of signs and symptoms, leading to a broad differential diagnosis. Delays in the correct identification of myocarditis and the initiation of appropriate interventions can have a detrimental impact on patient outcomes. In this case, a simulated five-year-old patient with myocarditis and secondary cardiogenic shock presents to the emergency department (ED). The goals of this simulation curriculum were to familiarize trainees and ED providers with the often nonspecific presentation of pediatric myocarditis, educate the care team about crucial interventions that positively or negatively impact the patient's stabilization course, and reinforce the …

Oligomeric Cystatin C Supports The Immunosuppressive Activity Of Myeloid Cells Through Interaction With Inhibitory Receptors, Chengcheng Zhang, Yubo He, Xiaoye Liu, Jingjing Xie, Meng Fang, Xing Yang, Ryan Huang, Qi Lou, Bufan Li, Ankit Gupta, Cheryl Lewis, Marc I Diamond, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C-a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein-within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes …

From Chest Pain To Recovery: A Rare Case Of Anomalous Origin Of The Circumflex Artery From The Pulmonary Artery In A Child And The Role Of Timely Surgical Intervention, A.V. Kauk, Serezha Manukian, A.N. Arkhipov, A.V. Voitov, I.A. Soynov

Journal of the Saudi Heart Association

This report highlights the diagnostic challenges and successful surgical management in a symptomatic pediatric case with anomalous origin of the circumflex artery from the pulmonary artery. A 4-year-old boy presented emergently with dyspnea and substernal pain. Coronary angiography identified the circumflex artery originating anomalously from the right pulmonary artery. Emergency surgical reimplantation to the aorta was performed, with subsequent normalization of cardiac function (EF 67% at 3-month follow-up). Although exceptionally rare, anomalous origin of the circumflex artery from the pulmonary artery requires high clinical suspicion in pediatric patients with ischemic symptoms. Early anatomical correction yields excellent outcomes, as demonstrated in …

Corrigendum To “The Usefulness Of 3d Heart Models As A Tool Of Congenital Heart Disease Education: A Narrative Review” [J Saudi Heart Assoc. 37 (2025) Article 1]

Journal of the Saudi Heart Association

No abstract provided.

Design, Optimization, And Development Of Ripk1 Degraders With Improved Pharmacokinetic And Pharmacodynamic Properties, Dong Lu, Xin Yu, Hanfeng Lin, Ran Cheng, Bin Yang, Min Zhang, Jingjing Chen, Feng Li, Xiaoli Qi, Jin Wang

Faculty, Staff and Students Publications

Pharmacological degradation of receptor-interacting protein kinase 1 (RIPK1) offers a compelling therapeutic strategy to overcome its scaffolding role in tumor resistance and to enhance the efficacy of immune checkpoint blockade (ICB) therapies. In this study, we report the discovery of a novel RIPK1 degrader, LD5097(24b), developed through systematic optimization of its precursor compound, LD4172—specifically refining the linker, RIPK1 warhead exit vector, and VHL ligand components. LD5097(24b) exhibits potent and selective RIPK1 degradation, triggering rapid and efficient downregulation of RIPK1 and significantly enhancing TNFα-mediated apoptosis in Jurkat cells. Compared to LD4172, LD5097(24b) demonstrates markedly improved metabolic stability and pharmacokinetic properties. In …

Culture-Independent Meta-Pangenomics Enabled By Long-Read Metagenomics Reveals Associations With Pediatric Undernutrition, Jeremiah J Minich, Nicholas Allsing, M Omar Din, Michael J Tisza, Kenneth Maleta, Daniel Mcdonald, Nolan Hartwick, Allen Mamerto, Caitriona Brennan, Lauren Hansen, Justin Shaffer, Emily R Murray, Tiffany Duong, Rob Knight, Kevin Stephenson, Mark J Manary, Todd P Michael

Faculty, Staff and Students Publications

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44-64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species …

Genetic And Embryonic Transcriptome Analyses Reveal The Molecular And Developmental Basis Of Mayer-Rokitansky-Küster-Hauser Syndrome, Na Chen, Xi Cheng, Sen Zhao, Hengqiang Zhao, Chenglu Qin, Yaru Zhang, Xijuan Lin, Qing Li, Yuan Wang, Jia Kang, Jing Yu, Jianbin Guo, Qianqian Gao, Jiali Duan, Yuchen Niu, Jianzhong Su, Zhihong Wu, Terry Jianguo Zhang, Wanlu Liu, Pengfei Liu, Shan Deng, Nan Wu, Lan Zhu

Faculty, Staff and Students Publications

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterised by aplasia of the uterus, cervix and upper part of the vagina. The genetic aetiology remains incompletely understood.

Methods: We performed gene-level and gene set-level burden analyses based on exome sequencing/genome sequencing data from 727 probands with MRKHS and 2504 female control individuals. Single-cell RNA sequencing (scRNA-seq) was performed on human and mouse embryonic metanephros at different developmental stages. Genetic and transcriptomic data were integrated to prioritise suboptimal genetic signals, identify relevant cell types and determine key developmental stages. Potential digenic inheritance was assessed and prioritised using coexpression patterns from scRNA-seq data.

Results: We …

Prevalence Of Potentially Inappropriate Medications In People Living With Hiv: A Systematic Review And Meta-Analysis, Mustapha Muhammed Abubakar, Abdulmuminu Isah, Ruth Jeminiwa, Ibraheem Abioye, Ismaeel Yunusa, Mohammed Abba-Aji, Osagie Kenneth Cole, Jamila Sani, Mukhtar Ijaiya, Chukwuemeka Nwachuya, Yusuf Ibrahim, Mustapha Usman, Duke Daniels, Oluwaseun Samuel Ilugbuhi, Blessing Onyinye Ukoha-Kalu

College of Pharmacy Faculty Papers

BACKGROUND: Potentially inappropriate medications (PIM) are associated with adverse health outcomes. The use of PIM among persons living with HIV (PLHIV) could be more problematic due to peculiarities such as antiretroviral toxicity and drug-disease interactions. However, PIM among PLHIV continues to receive little attention. Therefore, we aimed to systematically review and estimate the prevalence of PIM among PLHIV.

METHODS: We searched the PubMed, Scopus, and Web of Science databases to identify relevant studies from 1 January 2014 to 30 June 2024. Studies included were peer-reviewed articles that determined PIM prevalence using validated explicit or implicit tools and provided statistical information …

The American Dermatological Association And The Story Of American Dermatology, Thomas N. Helm, Lawrence C. Parish, Amy S. Paller, David M. Pariser

Department of Dermatology and Cutaneous Biology Faculty Papers

No abstract provided.

Developing A General Ai Model For Integrating Diverse Genomic Modalities And Comprehensive Genomic Knowledge, Zhenhao Zhang, Xinyu Bao, Linghua Jiang, Xin Luo, Zheyu Zhang, Jing Yin, Meiqi Zhao, Yichun Wang, Annelise Comai, Joerg Waldhaus, Anders S Hansen, Wenbo Li, Jie Liu

Faculty, Staff and Student Publications

Advances in next-generation sequencing technologies have vastly expanded the availability of diverse genomic, epigenomic, and transcriptomic data, presenting the opportunity to develop a general AI model that integrates comprehensive genomic knowledge into a unified model. Unlike previous predictive models, which are typically specialized to certain tasks, our general AI model unifies a wide range of genomic modalities, such as nascent RNA and ultra-high-resolution chromatin organization, within a multi-task architecture. Using ATAC-seq and DNA sequences as inputs, we incorporated diverse genomic modalities as output, and the model exhibits strong generalizability across different cell types and tissues in all tasks we trained. …

A Practical Primer On How To Detect And Treat Depression In Ckd, L Parker Gregg, Lynnel Goodman, Ella Q Carroll, S Susan Hedayati

Faculty, Staff and Students Publications

Detection and management of depression have special considerations in people with kidney disease. Screening should be done every 6-12 months using a self-reported questionnaire. Clinicians should rule out symptoms from medical conditions such as dialysis inadequacy or hypothyroidism and confirm the presence of sadness or anhedonia. Sertraline has shown limited efficacy and an increased risk for adverse effects such as gastrointestinal symptoms, so cautious, gradual dose titration is warranted. Cognitive behavioral therapy has potential benefit for depressive symptoms in people with kidney disease. Current trials are evaluating behavioral activation therapy. Physical activity has many benefits and likely improves depression.

The Unfolded Protein Response-Novel Mechanisms, Challenges, And Key Considerations For Therapeutic Intervention, P M Quan Mai, Tam-Anh Truong, Sai Kumar Samala, Bhoomika Muruvekere Lakshmisha, Prapannajeet Biswal, Khadijeh Koushki, Prudhvi Chand Mallepaddi, Geraldine Vijay, Sunil Krishnan

Faculty, Staff and Student Publications

Background: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER's capacity to handle large protein loads within it, and still fold and process these proteins accurately. Many recent studies have documented the non-canonical roles of the UPR, outside of protein quality control, in the context of lipid metabolism and the immune system in cancer. Cancer cells have been known to hijack the UPR to promote survival and evade immune surveillance. However, the underlying mechanisms remain poorly understood.

Objectives: Here, we critically …

Primary Intramedullary Spinal Melanocytomas: Case Report And Review Of Clinical Features, Diagnosis, And Management, Gil Kimchi, Samantha Varela, Juan Pablo Zuluaga-Garcia, Francisco Call-Orellana, Esteban Ramirez Ferrer, Romulo Augusto Andrade De Almeida, Maria A Gubbiotti, Isabella C Glitza, Andrew J Bishop, Jonathan D Grant, Robert Y North, Christopher A Alvarez-Breckenridge, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Objective: Intramedullary melanocytomas are extremely rare spinal cord tumors with distinct histopathological and imaging characteristics. This report reviews the literature on this pathology and presents a representative case study, highlighting aspects of diagnosis and management.

Methods: A scoping review of PubMed, Web of Science, and Embase databases was conducted to identify reports on intramedullary melanocytomas, focusing on clinical presentation, imaging features, histopathology, treatment, and outcomes. Case reports and case series were included due to the rarity of these tumors.

Results: Twelve manuscripts met the inclusion criteria, including 15 patients. In the majority of patients, intramedullary melanocytomas present with progressive myelopathy …

Early Dapagliflozin In Non-Diabetic Acute Myocardial Infarction Patients Post-Pci: Effects On Cardiovascular Outcomes And Left Ventricular Remodeling, Hazem Salama Emad Salem, Ramzy Mohamed El-Mawardy, Mohamed Elsayed Zahran, Islam Mohamed Bastawy, Mina Fahim Aziz, Abdelrahman Elsayed Attia

Journal of the Saudi Heart Association

Background: Early initiation of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, may improve cardiovascular outcomes in acute myocardial infarction (AMI) by mitigating adverse remodeling and enhancing cardiac function. Objectives: To assess dapagliflozin’s impact on major adverse cardiovascular events (MACE) and left ventricular (LV) recovery in non-diabetic AMI patients using speckle-tracking echocardiography (STE). Methods: This prospective, single-blinded randomized controlled trial (RCT) enrolled 200 non-diabetic patients with a first episode of AMI, including both ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), following successful percutaneous coronary intervention (PCI). Participants received guideline-directed therapy and were randomized to dapagliflozin + standard …

Acute Gastropericardial Fistula With Cardiac Tamponade And Septic Pericarditis Due To Helicobacter Pylori–Induced Gastric Ulcer Perforation, Stephen J. Bordes, Christopher D. Oubre, Preethi H. Kanumuri, Nicholas Leblanc, Richard Lewis, Thomas Marsden, Terry Stelly

School of Medicine Faculty Publications

No abstract provided.

Stereotactic Body Radiation Therapy Utilization Trends For Stage I Non-Small Cell Lung Cancer, Sara Sakowitz, Haley I Tupper, Lawrence N Benjamin, Scott Oh, Tao He, Reza Ronaghi, Colleen L Channick, Brian J Rosenberg, Ramin Salehi-Rad, Malcolm I Smith, Joanne M Bando, Timothy J Young, Igor Barjaktarvic, Maria A Velez Velez, Arjan Gower, Amy L Cummings, Jonathan Goldman, Aaron E Lisberg, Edward B Garon, Jane Yanagawa, Emily A Cameron, Bryan M Burt, Sha'shonda L Revels, Paul Toste, Jay M Lee, Alan Lee, Jie Deng, Hanjoo Lee, Peyman Benharash, Drew Moghanaki

Faculty, Staff and Students Publications

No abstract provided.

Discovery Of A Novel Small Molecule Degrader Of Wild Type And Mutant Estrogen Receptors Using Dna Encoded Libraries, Anil Kumar Devakrishnan, Chandrashekhar Madasu, Yong Wang, Ramkumar Modukuri, Kurt M Bohren, Kevin R Mackenzie, Damian W Young, Suzanne A W Fuqua, Martin M Matzuk, Murugesan Palaniappan

Faculty, Staff and Students Publications

Estrogen receptor α (ERα) variants with mutations in the ligand binding domain (LBD) are less sensitive than wild type to standard-of-care drugs that bind ERα directly. To identify novel small-molecule drugs that target ERα mutants, we screened our multibillion-compound DNA-encoded libraries against ERα LBD variants. CDD-1274, which was highly enriched with all three variants, blocked spontaneous coactivator peptide recruitment to mutant ERα LBDs and inhibited estradiol-driven proliferative markers in several ER-positive breast cancer cell lines, but not in ER-negative breast cancer cells. We demonstrated that CDD-1274 induced proteasomal degradation of ERα variants in breast cancer cell lines and caused Y537S …

Low Mutation Rate But High Male-Bias In The Germline Of A Short-Lived Opossum, Yadira Peña-García, Richard J Wang, Muthuswamy Raveendran, R Alan Harris, Paul B Samollow, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

Age and sex have been found to be important determinants of the mutation rate per generation in mammals, but the mechanisms underlying these factors are still unclear. One approach to distinguishing between alternative mechanisms is to study species that reproduce at very young ages, as competing hypotheses make different predictions about patterns of mutation in these organisms. Here, we study the germline mutation rate in the gray short-tailed opossum, Monodelphis domestica, a laboratory model species that becomes reproductively mature at less than 6 mo of age. Whole-genome sequencing of 22 trios reveals one of the lowest mutation rates per generation …

Slc35g3 Is A Udp-N-Acetylglucosamine Transporter For Sperm Glycoprotein Formation And Underpins Male Fertility In Mice, Daisuke Mashiko, Shingo Tonai, Haruhiko Miyata, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Despite the recognized importance of glycans in biological phenomena, their complex roles in spermatogenesis and sperm function remain unclear. SLC35G3, a 10-transmembrane protein specifically found in early round spermatids, belongs to the sugar-nucleotide transporter family, indicating its involvement in glycan formation. In this study, we found that Slc35g3 knockout male mice were sterile due to impaired sperm functions in uterotubal junction passage, zona pellucida binding, and oocyte fusion. Mouse SLC35G3 has UDP-GlcNAc transporter activity, and its ablation caused abnormal processing of the sperm plasma membrane and acrosome membrane proteins. Reported human SLC35G3 mutations (F267L and T179HfsTer27) diminished the UDP-GlcNAc transporter …

Genome-Wide Discovery Of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity, Marissa Granitto, Lois Parks, Molly S Shook, Carmy Forney, Xiaoting Chen, Lee E Edsall, Omer A Donmez, Sreeja Parameswaran, Kristen S Fisher, Aram Zabeti, Lucinda P Lawson, Matthew T Weirauch, Leah C Kottyan

Faculty, Staff and Students Publications

Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system with a complex etiology involving environmental and genetic factors. Numerous genetic risk loci for multiple sclerosis have been nominated through genome-wide association studies, with most associated variants residing in noncoding regions. However, further work is needed to understand how genetic variation contributes to disease-related alterations to gene expression. Here, we use Massively Parallel Reporter Assays to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,275 variants distributed among multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our …