Digital Commons Network^™

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. …

Opposing Roles For Myeloid And Smooth Muscle Cell Sting In Pulmonary Hypertension, Ann T Pham, Shiza Virk, Aline C Oliveira, Matthew D Alves, Chunhua Fu, Yutao Zhang, Jimena Alvarez-Castanon, Brian B Lee, Keira L Lee, Radwan Mashina, Katherine E Ray, Patrick Donabedian, Elnaz Ebrahimi, Harsh Patel, Reeha Patel, Duncan Lewis, Zhiguang Huo, Harry Karmouty-Quintana, Li Chen, Lei Jin, Andrew J Bryant

Faculty, Staff and Student Publications

There is an emerging role for stimulator of interferon genes (STING) signaling in pulmonary hypertension (PH) development. Related to this, prior research has demonstrated the relevance of immune checkpoint protein programmed death ligand 1 (PD-L1) expression by immunoregulatory myeloid cells in PH. However, there remains a need to elucidate the cell-specific role of STING expression, and the STING/PD-L1 signaling axis in PH, before readily available disease-modifying therapies can be applied for patients with the disease. Here, through generation of bone marrow chimeric mice, we show that STING-/- mice receiving WT bone marrow were protected against PH secondary to chronic hypoxia. …

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 …

Food Noise: Definition, Measurement, And Future Research Directions, Emily J Dhurandhar, Kevin C Maki, Nikhil V Dhurandhar, Theodore K Kyle, Sydney Yurkow, Misty A W Hawkins, Jon Agley, Emily H Ho, Lawrence J Cheskin, Thorkild I A Sørensen, Xi Rita Wang, David B Allison

Children’s Nutrition Research Center Staff Publications

The term food noise has been recently popularized by individuals managing their weight or adhering to specific diets for health reasons. Anecdotal evidence from patients and clinical observations suggests that food noise involves constant preoccupation with food-related decisions-such as which foods to eat, caloric intake, macronutrient balance, and meal timing-which can become intrusive and unpleasant. Food noise also appears to affect cognitive burden and quality of life, and is being cited as one reason weight-loss attempts fail. The increase in public discourse about food noise has highlighted its potential significance, yet a formal clinical definition and method of measurement of …

Dr Kinase: Predicting The Drug-Resistance Hotspots Of Protein Kinases, Shaofeng Lin, Chao Tu, Ruifeng Hu, Haiji Wang, Zongcheng Dong, Hui Luo, Lan Kuang, Tao Wang, Liming Wang, Zhongming Zhao, Zhihong Li, Haodong Xu

Faculty, Staff and Student Publications

Protein kinases (PKs) regulate various cellular functions, and are targeted by small-molecule kinase inhibitors (KIs) in cancers and other diseases. However, drug resistance (DR) of KIs occurs through critical mutations in four types of representative hotspots, including gatekeeper, G-loop, αC-helix, and A-loop. KI DR has become a common clinical complication affecting multiple cancers, targeted kinases, and drugs. To tackle this challenge, we report an upgraded web server, namely Dr. Kinase, for predicting the loci of four DR hotspots and assessing effects of mutations on DR hotspots for PKs in our previous studies, by utilizing multimodal features and deep hybrid learning. …

Development And Validation Of A Novel Clinical Risk Score To Predict Hypoxaemia In Children With Pneumonia Using The Who Prepare Dataset, Rainer Tan, Arjun Chandna, Tim Colbourn, Shubhada Hooli, Carina King, Norman Lufesi, Eric D Mccollum, Charles Mwansambo, Joseph L Mathew, Clare L Cutland, Shabir A Madhi, Marta Nunes, Sudha Basnet, Tor A Strand, Kerry-Ann F O'Grady, Brad Gessner, Emmanuel Addo-Yobo, Noel Chisaka, Patricia Hibberd, Prakash M Jeena, Juan M Lozano, William B Maleod, Archana Patel, Donald M Thea, Ngoc Tuong Vy Nguyen, Marilla Lucero, Syed Mohammad Akram Uz Zaman, Shinjini Bhatnagar, Nitya Wadhwa, Rakesh Lodha, Satinder Aneja, Mathuram Santosham, Shally Awasthi, Ashish Bavdekar, Monidarin Chou, Pagbajabyn Nymadawa, Jean William Pape, Glaucia Paranhos-Baccala, Valentina S Picot, Mala Rakoto-Andrianarivelo, Vanessa Rouzier, Graciela Russomando, Mariam Sylla, Philippe Vanhems, Jianwei Wang, Romina Libster, Alexey W Clara, Fenella Beynon, Gillian Levine, Chris A Rees, Mark I Neuman, Shamim Qazi, Yasir Bin Nisar, World Health Organization Prepare Study Group

Faculty, Staff and Students Publications

Background: Hypoxaemia predicts mortality at all levels of care, and appropriate management can reduce preventable deaths. However, pulse oximetry and oxygen therapy remain inaccessible in many primary care health facilities. We aimed to develop and validate a simple risk score comprising commonly evaluated clinical features to predict hypoxaemia in 2-59-month-old children with pneumonia.

Methods: Data from seven studies conducted in five countries from the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) dataset were included. Readily available clinical features and demographic variables were used to develop a multivariable logistic regression model to predict hypoxemia (oxygen saturation < 90%) at presentation to care. The adjusted log coefficients were transformed to derive the PREPARE hypoxemia risk score and its diagnostic value was assessed in a held-out, temporal validation dataset. The model and risk score were analysed by evaluating the area under the receiver operating characteristic curve (AUC), sensitivity and specificity.

Results: We included 14 …

Mtmr Regulates Kras Function By Controlling Plasma Membrane Levels Of Phospholipids, Taylor E Lange, Ali Naji, Ransome Van Der Hoeven, Hong Liang, Yong Zhou, Gerald R V Hammond, John F Hancock, Kwang-Jin Cho

Faculty, Staff and Student Publications

KRAS, a small GTPase involved in cell proliferation and differentiation, frequently gains activating mutations in human cancers. For KRAS to function, it must bind the plasma membrane (PM) via interactions between its membrane anchor and phosphatidylserine (PtdSer). Therefore, depleting PM PtdSer abrogates KRAS PM binding and activity. From a genome-wide siRNA screen to identify genes regulating KRAS PM localization, we identified a set of phosphatidylinositol (PI) 3-phosphatases: myotubularin-related proteins (MTMR) 2, 3, 4, and 7. Here, we show that silencing MTMR 2/3/4/7 disrupts KRAS PM interactions by reducing PM PI 4-phosphate (PI4P) levels, thereby disrupting the localization and operation of …

N-Methyl-D-Aspartate Receptor Antibody And Sensory Gating Deficits In Non-Smoking, Minimal Antipsychotic Medication Exposure, And First-Episode Patients With Schizophrenia, Jinghui Tong, Kebing Yang, Wei Li, Leilei Wang, Yi Yin, Yanfang Zhou, Junchao Huang, Ping Zhang, Yanli Zhao, Song Chen, Hongzhen Fan, Yimin Cui, Xingguang Luo, Shuping Tan, Zhiren Wang, Wei Feng, Baopeng Tian, Chiang-Shan R Li, L Elliot Hong, Yunlong Tan

Faculty, Staff and Student Publications

Background and hypothesis: Sensory gating deficit is considered a pathophysiological feature of schizophrenia, which has been linked to N-methyl-d-aspartate receptor (NMDAR) hypofunction as one of the potential underlying mechanisms. Here, we hypothesize that higher levels of NMDAR antibody (Ab) may contribute to the sensory gating deficits in schizophrenia.

Study design: We enrolled 72 non-smoking inpatients with first-episode schizophrenia (FES), most of them with only a relatively short duration of exposure to antipsychotic medications, and 51 non-smoking healthy controls (HC). Sensory gating was measured by P50 evoked potentials ratio and the difference between the two stimuli in an auditory paired-stimuli paradigm …

Consideration Of Patient Phenotypes In Geographic Atrophy Due To Age-Related Macular Degeneration, Rishi P Singh, Christina Y Weng, John W Kitchens, Jaclyn Quilantan, Roy Schwartz, Caroline R Baumal, Roger A Goldberg

Faculty, Staff and Students Publications

Geographic atrophy (GA) is a form of advanced age-related macular degeneration (AMD) affecting approximately 1 million people in the USA and 5 million globally. In this review, retinal imaging techniques used for diagnosis and monitoring progression of GA in AMD, and the risk factors associated with the development and progression of GA are summarised. To familiarise clinicians with common phenotypes of patients with GA, the clinical and imaging features that may lead to rapid progression of GA in various phenotypes are highlighted. With the recent US Food and Drug Administration approval of new GA treatments that reduce lesion growth, understanding …

Overexpression Of Tsg101 Causes The Development Of Adenosquamous Mammary Carcinoma, Rayane Dennaoui, Patrick D. Rädler, Madison N. Wicker, Kerry Vistisen, Rosa-Maria Ferraiuolo, Aleata A. Triplett, Hridaya Shrestha, Tessa A. Liner, Karoline C. Manthey, Hallgeir Rui, Robert D. Cardiff, Teresa M. Gunn, Charles M. Perou, Kay-Uwe Wagner

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

BACKGROUND: The mammalian Tumor Susceptibility Gene 101 (TSG101) encodes a protein with diverse functions that control the proliferation and survival of cells, but its role in malignant transformation and cancer development has remained enigmatic.

METHODS: To study the pro-tumorigenic functions of TSG101, we developed a bi-transgenic mouse model that expresses exogenous TSG101 along with a luciferase reporter in a ligand-controlled manner in the mammary gland epithelium. We performed a comprehensive histopathologic, biochemical, and molecular characterization of ductal hyperplasia and mammary tumors. Unsupervised hierarchical clustering based on 1,723 intrinsic genes of ten TSG101-overexpressing cancers alongside 251 tissue samples representing 31 reference …

Psychopharmacological Therapy Positively Modulates Disease Activity In Inflammatory Bowel Disease: A Systematic Review, Federica Di Vincenzo, Antonio Maria D'Onofrio, Angelo Del Gaudio, Elena Chiera, Gaspare Filippo Ferrajoli, Francesco Pesaresi, Alessio Simonetti, Marianna Mazza, Georgios Demetrios Kotzalidis, Mauro Pettorruso, Giovanni Martinotti, Loris Riccardo Lopetuso, Antonio Gasbarrini, Gabriele Sani, Gionata Fiorino, Franco Scaldaferri, Giovanni Camardese

Faculty, Staff and Students Publications

Depression, anxiety, and perceived stress are common comorbidities in patients with inflammatory bowel disease (IBD) and may negatively influence the disease course. Likewise, severe IBD may contribute to the development or worsening of psychiatric symptoms. Despite the established relevance of the gut-brain axis and frequent use of psychotropic medications in IBD patients, limited evidence exists regarding the effects of psychiatric treatments on gastrointestinal disease activity. Therefore, the aim of this systematic review is to evaluate the effectiveness of psychiatric therapies on gastrointestinal symptoms and disease activity in patients with IBD. The work was conducted in accordance with PRISMA guidelines. Searches …

Prediction Of Generalized Anxiety Disorder Treatment Outcomes With Neurobehavioral Responses To Approach-Avoidance Conflict: A Randomized Clinical Trial., Hannah Berg, Timothy J. Mcdermott, Rayus Kuplicki, Hung-Wen Yeh, Wesley K. Thompson, Ryan Smith, Elisabeth Akeman, Namik Kirlic, Ashley Clausen, Mallory Cannon, Evan White, Christopher R. Martell, Kate B. Wolitzky-Taylor, Michelle G. Craske, James L. Abelson, Martin P. Paulus, Robin L. Aupperle

Manuscripts, Articles, Book Chapters and Other Papers

Treatments for generalized anxiety disorder (GAD) often aim to address maladaptive approach-avoidance behavior patterns. Approach-avoidance conflict (AAC) offers a potential framework for identifying treatment outcome predictors and informing optimization of GAD treatment. The current study examined whether pre-treatment neurobehavioral AAC indices predict symptom improvement in behavioral activation (BA) and exposure therapy (EXP) for GAD. Treatment-seeking adults meeting criteria for GAD completed a randomized clinical trial with pre-treatment blinding, conducted from 2016-2021. Participants were randomized to complete 10 manualized sessions of BA or EXP. Participants completed an AAC task during functional magnetic resonance imaging pre-treatment. Computational parameters of task behavior were …

Exploring Sex-Specific Clinical Features In Chinese Patients With Takotsubo Syndrome, Hong-Yi Duan, Ling-Lin Wang, Ling-Chun Lyu, Zhen-Hua Shi, Xiao-Ping Lin, Zheng-Yang Yu, Guo-Hua Fan, Jing Chen, Xin-Hong Yang, Wei Deng, Chang-Wu Xu, Yan Huang, Qing Zhou, Jin-Ling Chen, Hong-Ning Song, Dong Hu, Jin-Qiu Liu, Hector Barajas-Martinez, Charles Antzelevitch, Kan Liu, Hong Jiang, Dan Hu

Department of Medicine Faculty Papers

BACKGROUND: Takotsubo syndrome (TTS) is considered as a transient acute heart failure syndrome predominant in females. However, data on Chinese TTS patients are limited. Therefore, this study aimed to investigate the clinical characteristics of Chinese TTS patients, identify prognostic markers.

METHODS: A total of 258 TTS patients were enrolled. Data on clinical characteristics and in-hospital major adverse cardiovascular events (MACE) were collected and analyzed. The latter included severe heart failure, shock, malignant arrhythmia, and death.

RESULTS: The average age of TTS patients was 59.3 ± 19.2 years. Female patients accounted for 68.9%. MACE occurred in 41.4% of patients during hospitalization. …

Hikikomori Risk In The Uk, Gregory Gorman, Alison Bacon, Jon May, Stephen Minton

School of Psychology

Background: Hikikomori syndrome involves voluntary withdrawal from social life, school and work, with onset typically in young adulthood. Hikikomori risk has not been examined in the UK, and these studies aimed to validate and refine the Hikikomori Risk Inventory-24 (HRI-24) screening tool in UK young adults. Methods/Results: In Study 1, participants (n = 341) completed the HRI-24. Item analysis and confirmatory factor analysis resulted in a shorter 13-item HRI (HRI-13), which demonstrated a perfect correlation with the full HRI-24. Both the HRI-13 and HRI-24 showed strong convergent and divergent validity, correlating with depression, anxiety, avoidant coping and negative early life …

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking Into Cell-Free Therapies For Bone-Affected Lysosomal Storage Disorders, Andrés Felipe Leal, Harry Pachajoa, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Lysosomal storage disorders (LSDs) constitute a group of monogenic systemic diseases resulting from deficiencies in specific lysosomal enzymes that cause the intralysosomal accumulation of non- or partially degraded substrates, leading to lysosomal dysfunction. In some cases of LSDs, the bone is more severely affected, thus producing skeletal manifestations in patients. Current therapies, such as enzyme replacement therapy (ERT) and gene therapy (GT), show limited efficacy in correcting skeletal abnormalities. Increasing evidence suggests that microenvironmental disturbances also contribute significantly to disease pathogenesis. Therefore, therapeutic strategies targeting lysosomal dysfunction and microenvironmental dysregulation are needed. Mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) are emerging as …

Human Extravillous Trophoblasts Require Src-2 For Sustained Viability, Migration, And Invasion, Vineet K Maurya, Pooja Popli, Bryan C Nikolai, David M Lonard, Ramakrishna Kommagani, Bert W O'Malley, John P Lydon

Faculty, Staff and Students Publications

Defective placentation is a recognized etiology for several gestational complications that include early pregnancy loss, preeclampsia, and intrauterine growth restriction. Sustained viability, migration, and invasion are essential cellular properties for embryonic extravillous trophoblasts to execute their roles in placental development and function, while derailment of these cellular processes is linked to placental disorders. Although the cellular functions of extravillous trophoblasts are well recognized, our understanding of the pivotal molecular determinants of these functions is incomplete. Using the HTR-8/SVneo immortalized human extravillous trophoblast cell line, we report that steroid receptor coactivator-2 (SRC-2), a coregulator of transcription factor-mediated gene expression, is essential …

Supporting Patients With Advanced Cancer And Their Spouses In Parenting Minor Children: Results Of A Randomized Controlled Trial, Kathrin Milbury, Sujin Ann-Yi, Meagan S Whisenant, Morgan Jones, Yisheng Li, Victoria Necroto, Sania D Yousuf, Mariana Chavez-Macgregor, Larrisa Meyers, Eduardo Bruera

Faculty, Staff and Student Publications

Introduction: Patients with advanced cancer and their spousal caregivers who parent minor children report unmet parenting concerns and increased psychological distress. Seeking to address these important supportive care needs, this RCT examined the feasibility, acceptability, and initial evidence for the efficacy of a novel psychosocial intervention.

Patients and methods: Patients with a metastatic solid malignancy and their spouses completed self-reported validated assessments of psychological symptoms and cancer-related parenting outcomes and were then randomized to the parent support intervention or a usual care (UC) group. Both groups were reassessed 6 and 12 weeks later. Dyads randomized to the counselor-led intervention attended …

Improving Genetics Equity: Identifying Women Eligible For Genetic Care Services Using Mammography Clinics In Underserved Areas As Screening Hubs, Darya Kizub, Rachel Bluebond, Sierra Green, Jessica Duckworth, Sreejesh Shanker, Autumn Vara, Banu Arun

Faculty, Staff and Student Publications

PURPOSE: Fewer than 20% of underserved individuals undergo guideline-concordant hereditary breast and ovarian cancer (HBOC) genetic testing (GT). Our study aimed to determine the proportion of women eligible for HBOC GT using a cancer genetics risk assessment (CGRA) tool at breast cancer (BC) screening clinics in underserved communities and to describe the program's impact.

METHODS: Participants were women who presented for BC screening at The Rose clinics, serving low-income underserved communities in southeast Texas, and completed the CGRA. High-risk individuals received bilingual educational materials and a saliva-based GT kit. Those with a pathogenic variant (PV) or a variant of uncertain …

Genomic Rare Variant Mechanisms For Congenital Cardiac Laterality Defect: A Digenic Model Approach, Archana Rai, Jonathan Klonowski, Bo Yuan, Karen J Coveler, Zain Dardas, Iman Egab, Jiaoyang Xu, Philip J Lupo, A J Agopian, Dennis Kostka, Cecilia W Lo, S Stephen Yi, Bruce D Gelb, Christine E Seidman, Eric Boerwinkle, Jennifer E Posey, Richard A Gibbs, James R Lupski, Shaine A Morris, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

Laterality defects are defined by perturbations in the usual left-right asymmetry of organs. The genetic etiology that underlies congenital heart disease (CHD) is often unknown (less than 40%), so we used a digenic model approach for the identification of contributing variants in known laterality-defect-associated genes (n = 115) in the exome/genome sequencing (ES/GS) data from individuals with clinically diagnosed laterality defects. The unsolved ES/GS data were analyzed from three CHD cohorts: Baylor College of Medicine-Genomics Research to Elucidate the Genetics of Rare Diseases (BCM-GREGoR; n= 251 proband ES), Gabriella Miller Kids First Pediatric Research Program (Kids First; n = 158 …

Amino Acid Transporter Lat1 (Slc7a5) Promotes Metabolic Rewiring In Tnbc Progression Through The L-Trp/Qprt/Nad+ Pathway, Margot Y. Fedoroff, Lei Zhao, Shaomin Wang, Alok Bhushan, Haifeng Yang, Karen M. Bussard, Stephen C. Peiper, Jun He

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Cancer cells uptake excessive nutrients by expressing higher levels of glucose and/or amino acid transporters to meet their increased energy demands. L-type amino acid transporter 1 (LAT1), is regarded as a cancer-specific transporter for the uptake of large neutral amino acids such as L-tryptophan. However, the mechanism by which LAT1 rewires cellular metabolism to promote cancer progression and chemoresistance have not yet been investigated.

METHODS: The protein levels of LAT1, p-PKM2, and p-LDHA were determined in breast cancer tissue arrays by immunohistochemistry staining followed by survival analysis. The orthotopic breast cancer models in mice, syngeneic breast cancer models, and …

Recurrent De Novo Variants In The Spliceosomal Factor Crnkl1 Are Associated With Severe Microcephaly And Pontocerebellar Hypoplasia With Seizures, Sankalita Ray Das, Rosie Sullivan, Mischa S G Ruegg, Julia Horsfield, Jordan Doran, Gemma Poke, Nathalie De Vries, Sarah Duerinckx, Damien Lederer, Muzhirah Haniffa, Wee-Teik Keng, Gaik-Siew Ch'ng, David A Parry, Andrew P Jackson, Masamune Sakamoto, Naomichi Matsumoto, Noriko Miyake, Shin Nabatame, Hidetoshi Taniguchi, Emma Wakeling, Katrin Õunap, Pilvi Ilves, Ghayda Mirzaa, Andrew Timms, Emily Pao, Kimberly A Aldinger, William Dobyns, Axel Bohring, Beate Behre, Daniel G Calame, James R Lupski, Juan M Pascual, Marc Abramowicz, Gregory Gimenez, Louise S Bicknell

Faculty, Staff and Students Publications

Splicing is a complex process that is required to create the transcriptomic diversity needed for specialized functions in higher eukaryotes. The spliceosome contains more than 100 proteins and RNA molecules, which coordinate this dynamic process. Despite the ubiquity of splicing, pathogenic variants in spliceosomal components often cause a tissue-specific phenotype, hinting at further complexities that are not yet fully understood. We have identified a cohort of ten families with de novo missense variants in a spliceosomal component, CRNKL1, where nine individuals harbor one of two missense variants that both affect the same amino acid, Arg267. All affected individuals share a …

Hallmarks Of Stem Cell Aging, Thomas A Rando, Anne Brunet, Margaret A Goodell

Faculty, Staff and Students Publications

As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.

Testosterone Deficiency And Treatments: Common Misconceptions And Practical Guidance For Patient Care, Mohit Khera, James M Hotaling, Martin Miner

Faculty, Staff and Students Publications

Introduction: Misconceptions about testosterone therapy are prevalent and there is an unmet need for a review of current literature that can be leveraged by physicians to deliver safe and effective care for men with hypogonadism.

Objectives: This review aims to address common misconceptions about testosterone therapy using current literature and synthesize practical guidance for clinicians with patients who are starting testosterone therapy.

Methods: A literature search of PubMed, Embase, CINAHL was carried out to identify associations between testosterone therapy and prostate cancer, cardiovascular risk, and hepatic toxicity; definitions of hypogonadism; and practical guidance for clinician with patients starting testosterone therapy. …

Parkinson Disease Signaling Pathways, Molecular Mechanisms, And Potential Therapeutic Strategies: A Comprehensive Review, Muhammad S Khan, Somayyeh Nasiripour, Jean C Bopassa

Faculty, Staff and Student Publications

Parkinson's disease (PD) is considered the second most common neurodegenerative disease worldwide; treating this disease remains quite challenging. Environmental and genetic factors may play a role in the pathophysiology of PD. α-synuclein aggregation, oxidative stress, ferroptosis, mitochondrial failure, neuroinflammation, and gut dysbiosis are among the known risk factors of PD. The pathophysiology of Parkinson's disease is complicated by the interconnections between these molecular pathways, which also present significant obstacles to treatment development. However, due to its complex mechanism and long latency, PD is difficult to diagnose and detect, which presents a barrier to treatment. In addition, the need to develop …

Transcriptomic And Histological Characteristics Of Innate Immune Activation In Brain Parenchyma In A Rat Model Of Neonatal Intraventricular Hemorrhage, Miriam Zamorano, Sanjna Udtha, Aidan M Collier, Erica Underwood, Razan El Sayed, Ankit Agarwal, Devin S Hatchell, Chunfeng Tan, Paul J Nietert, Scott D Olson, Brandon A Miller

Faculty, Staff and Student Publications

Background: Intraventricular hemorrhage (IVH) remains a major complication in preterm infants with lifelong sequelae. There is no effective treatment for IVH other than supportive care and surgery for post-hemorrhagic hydrocephalus. We previously reported that the innate neuroimmune response in an animal model of IVH was dependent on developmental stage, only occurring in older animals.

Methods: This study utilized a lysed-blood injection model of IVH in rats. This model specifically captures the effects of blood products released by IVH on brain parenchyma. We performed RNAseq and differential gene expression analysis on CD11b/c-positive cells in the brain (microglia/macrophages) to define gene expression …

Direct Inhibition Of Ras Reveals The Features Of Oncogenic Signaling Driven By Ras G12 And Q61 Mutations, Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa De Stanchina, Scott W Lowe, Richard A Burkhart, Jacquelyn W Zimmerman, Rona Yaeger, Scott E Kopetz, Neal Rosen, Sandra Misale

Faculty, Staff and Student Publications

RAS genes are frequently mutated in cancer, often at codons 12 and 61. With the recent introduction of RAS inhibitors, we can now directly investigate the effects of specific RAS mutations in cancer cells. In this study, we demonstrate that in tumors with RASG12X mutations, mutant RAS can be activated by receptor tyrosine kinases (RTK), and PI3K activation is dependent on mutant RAS. Conversely, RASQ61X mutations activate the MAPK cascade independently of RTKs, and inhibition of RASQ61X impairs MAPK pathway activation but leaves the PI3K pathway unaffected. Our characterization of these distinct features of G12X and Q61X mutations suggests that …

Ptpn11 Mutations Define A Rare But Highly Adverse Subset Of Myelodysplastic Syndromes, Alexandre Bazinet, Alex Bataller, Guillermo Montalban-Bravo, Kelly Chien, Koji Sasaki, Wei Ying Jen, Mahesh Swaminathan, Tapan Kadia, Courtney Dinardo, Farhad Ravandi, Guillermo Garcia-Manero, Hagop Kantarjian

Faculty, Staff and Student Publications

No abstract provided.

Assessment Of Functioning Using The Whodas 20 Among People With Myasthenia Gravis-Associated Disability: A Nationwide Follow-Up Study, Jia-Pei Hong, Chih-Hong Lee, Chien Tai Hong, Lung Chan, Chen-Chih Chung, Prangthip Charoenpong, Hou-Chang Chiu, Tsan-Hon Liou

Faculty, Staff and Students Publications

Background: Advancements in treatment have increased the life expectancy of patients with Myasthenia Gravis (MG), yet the understanding of functional changes in these individuals remains limited. In our study, we explored the functional abilities of individuals with MG using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0).

Methods: This observational study analyzed data from 286 patients with MG, acquired from the Data Bank of Persons with Disabilities (TDPD) in Taiwan between July 11, 2012, and December 31, 2021. Participants were diagnosed with MG after the acute phase. The functional disability outcome was assessed using the WHODAS 2.0. Due …

Pan-Cancer Copy Number Analysis Identifies Optimized Size Thresholds And Co-Occurrence Models For Individualized Risk Stratification, Minh P Nguyen, William C Chen, Kanish Mirchia, Abrar Choudhury, Naomi Zakimi, Vijay Nitturi, Tiemo J Klisch, Stephen T Magill, Calixto-Hope G Lucas, Akash J Patel, David R Raleigh

Faculty, Staff and Students Publications

Chromosome instability leading to aneuploidy and accumulation of copy number gains or losses is a hallmark of cancer. Copy number alteration (CNA) signatures are increasingly used for cancer risk stratification, but size thresholds for defining CNAs across cancers are variable and the biological and clinical implications of CNA size heterogeneity and co-occurrence are incompletely understood. Here we analyze CNA and clinical data from 691 meningiomas and 10,383 tumors from The Cancer Genome Atlas to develop cancer- and chromosome-specific size-dependent CNA and CNA co-occurrence models to predict tumor control and overall survival. Our results shed light on technical considerations for biomarker …

Serological Analysis Indicating The Exposure Of Two Volunteers To Relapsing Fever Borrelia Sp. In Nayarit, Mexico, Sofía L Luna-Rojas, Edwin Vázquez-Guerrero, Jose A Hernández-Martínez, Jeanet Serafín-López, Fernando Martínez-Hernández, José Alejandro Martinez-Ibarra, Rigoberto Hernández-Castro, Job E López, J Antonio Ibarra

Faculty, Staff and Students Publications

Relapsing fever caused by Borrelia sp. is a neglected disease in Mexico and more studies are needed to update its presence in multiple regions of the country. Here, recombinant proteins glycerophosphodiester phosphodiesterase (GlpQ) and three Borrelia immunogenic protein A (BipA) variants were used for serosurveillance in 142 human serum samples. Results showed that two persons were positive to Borrelia extracts and GlpQ but negative to all three BipA, suggesting they were infected by relapsing fever spirochetes of a yet to be determined species. This shows that testing for GlpQ and Borrelia extracts are a useful tool for potential infections and …