Digital Commons Network^™

Comprehensive Resolution And Classification Of The Epstein Barr Virus Transcriptome, Truong D. Nguyen, Jia Wang, Meggie T. Lam, Harris Mcferrin, Tina M. O’Grady, Claire Roberts, Nicholas Van Otterloo, Trang T. Nguyen, Melody Baddoo, Dorota Wyczechowska, Maria Morales, Yan Dong, Erik K. Flemington

School of Graduate Studies Faculty Publications

Virus genomes harbor compacted repertoires of genes and regulatory elements. Through long-read sequencing, we provide a comprehensive Epstein Barr virus (EBV) transcriptome analysis, identifying 1453 transcript isoforms and resolving the major isoform of all but one lytic reading frame. Further, we categorize each transcript according to their dependence on viral DNA replication. We show that the late gene viral preinitiation complex, vPIC also activates early promoters/genes, we identify active alternate promoters with distinct dependencies on viral DNA replication, we discover biphasic promoters with embedded features of both early and late promoters. Genetic and chromatin interaction studies identify an enhancer function …

Blunted Cd40-Responsive Enhancer Activation In Crebbp-Mutant Lymphomas Can Be Restored By Enforced Cd4 T-Cell Engagement, Haopeng Yang, Wenchao Zhang, Vida Ravanmehr, Guiling Cui, Kevin Bowman, Ruidong Chen, Jared M Henderson, Shyanne Lockman, Estela Rojas, Ashley Wilson, Sydney Parsons, Ariel Mechaly, Leslie Regad, Ahmed Haouz, Christopher R Flowers, Sattva Neelapu, Loretta Nastoupil, R Eric Davis, Qing Deng, Fernando Rodrigues-Lima, Michael R Green

Faculty, Staff and Student Publications

The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in …

The Impact Of Genetic Ancestry On Survival Outcomes In Pediatric Rhabdomyosarcoma: A Report From The Children’S Oncology Group, Ekene A Onwuka, Christina L Magyar, Bailey A Martin-Giacalone, Michael E Scheurer, Deborah A Marquez-Do, Mark Zobeck, Elizabeth G Atkinson, Erin R Rudzinski, Michael A Arnold, Donald A Barkauskas, David Hall, Javed Khan, Jack F Shern, Paul Scheet, Brian Crompton, Corinne M Linardic, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Chad D Huff, Melissa A Richard, Philip J Lupo

Faculty, Staff and Student Publications

Emerging evidence suggests genetic ancestry may influence childhood cancer outcomes, but its impact on pediatric rhabdomyosarcoma (RMS) is unknown. We explored genetic ancestry's impact on survival among children with RMS. This multi-center observational cohort study is a secondary analysis of previously collected biobanking, genomic, and clinical data. The study included 920 individuals with newly diagnosed RMS under 40 years of age enrolled from 2005 to 2017 under the COG soft tissue sarcoma biobanking protocol D9902. The primary endpoints were (1) event-free survival (EFS), defined as the time from study enrollment to tumor recurrence/progression, secondary malignancy, or death from any cause; …

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 …

First-In-Human Phase I Open-Label Study Of The Anti-Tim-3 Monoclonal Antibody Incagn02390 In Patients With Select Advanced Or Metastatic Solid Tumors, Martin E. Gutierrez, Shou Ching Tang, John D. Powderly, Ani S. Balmanoukian, Paul E. Hoyle, Zhiwan Dong, Lulu Cheng, Xiaohua Gong, John E. Janik, Nawel Bourayou, Omid Hamid

School of Medicine Faculty Publications

Background T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is an immune checkpoint receptor upregulated during anti-programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy for cancer. TIM-3 blockade may improve the antitumor activity of PD-1/PD-L1inhibition. This phase 1 study evaluated INCAGN02390, a novel, fully human Fc-engineered antibody against TIM-3. Methods INCAGN02390 was evaluated by dose escalation at 10-1600 mg infused in 14-day cycles (every 2 weeks [Q2W]) in pretreated patients with select advanced/metastatic immunogenic solid tumors. Objectives included evaluation of safety/tolerability and maximum tolerated dose (MTD) (primary), pharmacokinetics, preliminary antitumor activity, pharmacodynamics, and immunogenicity (secondary). Results Forty patients were enrolled and …

From Novice To Expert: Preparing Your Peer Review, Diana M Proctor, Rachy Abraham, Shannon Esher Righi

Faculty, Staff and Student Publications

Peer review is the process by which the quality of scholarly work is assessed prior to being published, presented, or funded. The consequences of flawed research entering the public domain in the "post-truth" era highlight the need to improve peer review quality, which we believe can be achieved by standardizing training. Here, we aim to enhance the quality of published literature by presenting a systematic guide to train new reviewers (and aid experienced ones) in the art of peer reviewing the rigor of scientific manuscripts.

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. …

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 …

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 …

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 …

The Effect Of Temperature For Producing Thayer-Martin Agar Media Using Sheep Blood On Neisseria Gonorrhoeae Growth With Various Inoculums, Ika Ningsih, Kayla Adyapratista Sumadiyo

Indonesian Journal of Medical Chemistry and Bioinformatics

Neisseria gonorrhoeae is a Gram-negative bacterium in the form of diplococci that infects mucous membranes through direct inoculation, is fastidious, and requires special media for growth because it is susceptible to heating and dryness, so it cannot survive long outside its host. Thayer-Martin agar media is a selective culture medium for the diagnosis of Neisseria gonorrhoeae bacterial infections enriched with sheep blood. The purpose of this study was to determine the optimum temperature for various temperature variations of making Thayer-Martin agar when mixing with sheep blood, compared to the temperature according to the manufacturer's procedure. Determining this ideal temperature may …

Pi(4)P Recruits Cide Proteins To Promote The Formation Of Unilocular Lipid Droplets During Adipogenesis And Hepatic Steatosis, Jin Wu, Mingming Gao, Xiaoqin Wu, Yang Liu, Taiping Zhang, Yan Liang, Haixia Yang, Chengxin Ma, Youpi Ye, Chunmei Chang, Peng Li, Feng-Jung Chen, Hongyuan Yang

Faculty, Staff and Student Publications

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be defined. Phosphoinositides mark cellular organelles and regulate organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on the LD surface …

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. …

Polymorphic Α-Glucans As Structural Scaffolds In Cryptococcus Cell Walls For Chitin, Capsule, And Melanin: Insights From 13c And 1h Solid-State Nmr, Ankur Ankur, Jayasubba Reddy Yarava, Isha Gautam, Faith J. Scott, Frederic Mentink-Vigier, Christine Chrissian, Li Xie, Dibakar Roy, Ruth E. Stark, Tamara L. Doering, Ping Wang, Tuo Wang

School of Graduate Studies Faculty Publications

Cryptococcus species are major fungal pathogens responsible for life-threatening infections in approximately a million individuals globally each year, with alarmingly high mortality rates. These fungi are distinguished by a distinctive cell wall architecture further reinforced by two virulence-associated layers, melanin and capsule, rendering them insensitive to antifungal agents targeting the cell wall, such as echinocandins. The molecular interplay between these three biomolecular layers remains poorly understood. Here we employ solid-state NMR spectroscopy to examine intact cells of both wild-type and capsule-deficient strains of C. neoformans, along with melanized cells. High-resolution 13C and 1H data revealed five distinct structural forms of …

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 …

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 …

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. …

Sex-Specific Effects Of Early-Life Unpredictability On Hippocampal And Amygdala Responses To Novelty In Adolescents, Elysia Poggi Davis, Bianca T. Leonard, Robert J. Jirsaraie, David B. Keator, Steven L. Small, Curt A. Sandman, Victoria B. Risbrough, Hal S. Stern, Laura M. Glynn, Michael A. Yassa, Tallie Z. Baram, Jerod M. Rasmussen

Psychology Faculty Articles and Research

Background

Unpredictable childhood experiences are an understudied form of early-life adversity that impact neurodevelopment. The neurobiological processes by which exposure to early-life unpredictability impact development and vulnerability to psychopathology remain poorly understood. In the current study, we investigated the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala.

Methods

Participants included 150 youths (54% female). Early-life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in 1 or more task–functional magnetic resonance imaging scans between the ages of 8 and 17 (223 total observations) measuring blood oxygen level–dependent (BOLD) …

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 …

Conserved Missense Variant Pathogenicity And Correlated Phenotypes Across Paralogous Genes, Tobias Brünger, Alina Ivaniuk, Eduardo Pérez-Palma, Ludovica Montanucci, Stacey Cohen, Lacey Smith, Shridhar Parthasarathy, Ingo Helbig, Michael Nothnagel, Patrick May, Dennis Lal

Faculty, Staff and Student Publications

Background: The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research shows that the deleterious effects and the subsequent molecular consequences of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantify on an exome-wide scale whether the existence of pathogenic variants in paralogous genes at a conserved position can serve as evidence for the pathogenicity of a new variant. For the gene family of voltage-gated sodium channels, where variants and expert-curated clinical phenotypes are available, we also assess whether phenotype patterns of multiple disorders for …

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 …

Convergent Reduction Of Olfactory Genes And Olfactory Bulb Size In Mammalian Species At Altitude, Allie M Graham, Elysia Saputra, Bogdan Kirilenko, Jason S Presnell, Arianna Harrington, Chad Huff, Michael Hiller, Nathan Clark

Faculty, Staff and Student Publications

The invasion of specialized ecological niches can cause drastic changes to selection regimes, resulting in genomic and phenotypic transformation.

An Integrative Genomics Approach For The Discovery Of Potential Clinically Actionable Diagnostic And Prognostic Biomarkers In Colorectal Cancer, Mark Fertel, Duaa Mohammad Alawad, Chindo Hicks

School of Graduate Studies Faculty Publications

Background: Despite remarkable progress in clinical management of patients and intensified screening, colorectal cancer remains the second most common cause of cancer-related death in the United States. The recent surge of next generation sequencing has enabled genomic analysis of colorectal cancer genomes. However, to date, there is little information about leveraging gene expression data and integrating it with somatic mutation information to discover potential biomarkers and therapeutic targets. Here, we integrated gene expression data with somatic mutation information to discover potential diagnostic and prognostic biomarkers and molecular drivers of colorectal cancer. Methods: We used publicly available gene expression and somatic …

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 …

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. …

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 …

Preliminary Investigation Of The Association Between Epigenetic Aging Acceleration And Amyloid Biomarkers In Bipolar Disorder, Gabriel R Fries, Steven De La Garza, Ning O Zhao, Andres W Bass, Camila N C Lima, Nobuhide Kobori, Tatiana Barichello, Gustavo Turecki, Paul E Schulz, Breno S Diniz, Jair C Soares

Faculty, Staff and Student Publications

Objectives: Bipolar disorder (BD) has been associated with an elevated risk of Alzheimer's Disease (AD). We assessed AD biomarkers in BD and tested whether epigenetic aging (EA) acceleration is associated with changes in these markers.

Design, setting, participants: Cross-sectional study of n = 58 living individuals with BD and n = 20 age- and sex-matched control participants, as well as analyses of postmortem brain samples (Brodmann area 9/46) from n = 46 individuals with BD.

Measurements: Amyloid beta (Aβ)40, Aβ42, and total Tau levels were measured in plasma from individuals with BD and controls, and Aβ42 levels were measured in …

Pan-Cancer, Multi-Omic Correlates Of Survival Transcending Tumor Lineage Across 11,019 Patients Reveal Targets And Pathways, Yiqun Zhang, Fengju Chen, Chad J Creighton

Faculty, Staff and Students Publications

Molecular correlates of cancer patient overall survival (OS) can provide new insights. Here, we systematically cataloged pan-cancer, multi-omic correlates of OS transcending tumor lineage across 11,019 patients, involving multiple cancer types while correcting for cancer-type-intrinsic OS differences. Significant fractions of genes with mRNA associated with OS in pan-cancer analyses showed concordant associations at the levels of DNA copy number alteration or methylation. Pan-cancer gene signatures of T-cell and macrophage tumor infiltrates were associated with better and worse OS, respectively. Pathways implicated by molecular OS associations included metabolism, PI3K/Akt, Wnt, and TGF-beta receptor. Significant fractions of worse OS-associated genes were essential …