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Environmental Light Controls The Daily Organization Of Breathing By Activating Brn3b-Expressing Intrinsically Photosensitive Retinal Ganglion Cells In Mice, Aaron A. Jones, Allison R. Spears, Deanna M. Arble

Biological Sciences Faculty Research and Publications

Rhythmic, daily fluctuations in minute ventilation are controlled by the endogenous circadian clock located in the suprachiasmatic nucleus (SCN). While light serves as a potent synchronizer for the SCN, it also influences physiology and behavior by activating Brn3b-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). It is currently unclear the extent to which the external light environment shapes daily ventilatory patterns independent of the SCN. To determine the relative influence of environmental light versus circadian timing on the organization of daily rhythms in minute ventilation, we used whole-body plethysmography to measure the breathing of mice housed on a non-entraining T28 cycle …

Ai Regulation Has Its Own Alignment Problem: The Technical And Institutional Feasibility Of Disclosure, Registration, Licensing, And Auditing, Neel Guha, Christie M. Lawrence, Lindsey A. Gailmard, Kit T. Rodolfa, Faiz Surani, Rishi Bommasani, Inioluwa Deborah Raji, Mariano-Florentino Cuéllar, Colleen Honigsberg, Percy Liang, Daniel E. Ho

Faculty Scholarship

Calls for regulating artificial intelligence (“AI”) are widespread, but there remains little consensus on both the specific harms that regulation can and should address and the appropriate regulatory actions to take. Computer scientists propose technical solutions that may be infeasible or illegal; lawyers propose regulation that may be technically impossible; and commentators propose policies that may backfire. AI regulation, in that sense, has its own alignment problem, in which proposed interventions are often misaligned with societal values.This Article assesses the alignment and technical and institutional feasibility of four dominant proposals for AI regulation in the United States: disclosure, registration, licensing, …

Chronic Β3-Ar Stimulation Activates Distinct Thermogenic Mechanisms In Brown And White Adipose Tissue And Improves Systemic Metabolism In Aged Mice, Duraipandy Natarajan, Bhuvana Plakkot, Kritika Tiwari, Shoba Ekambaram, Weidong Wang, Michael Rudolph, Mahmoud A Mohammad, Shaji K Chacko, Madhan Subramanian, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar, Priya Balasubramanian

Faculty, Staff and Students Publications

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a …

Template-Assisted Covalent Modification Underlies Activity Of Covalent Molecular Glues, Yen-Der Li, Michelle W Ma, Muhammad Murtaza Hassan, Moritz Hunkeler, Mingxing Teng, Kedar Puvar, Justine C Rutter, Ryan J Lumpkin, Brittany Sandoval, Cyrus Y Jin, Anna M Schmoker, Scott B Ficarro, Hakyung Cheong, Rebecca J Metivier, Michelle Y Wang, Shawn Xu, Woong Sub Byun, Brian J Groendyke, Inchul You, Logan H Sigua, Isidoro Tavares, Charles Zou, Jonathan M Tsai, Paul M C Park, Hojong Yoon, Felix C Majewski, Haniya T Sperling, Jarrod A Marto, Jun Qi, Radosław P Nowak, Katherine A Donovan, Mikołaj Słabicki, Nathanael S Gray, Eric S Fischer, Benjamin L Ebert

Faculty, Staff and Students Publications

Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans-labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4BD2 serves as a template to optimally orient the degrader for covalent modification of DCAF16Cys58. This process stabilizes …

Immunopeptidomic Mhc-I Profiling And Immunogenicity Testing Identifies Tcj2 As A New Chagas Disease Mrna Vaccine Candidate, Leroy Versteeg, Rakesh Adhikari, Gonteria Robinson, Jungsoon Lee, Junfei Wei, Nelufa Islam, Brian Keegan, William K Russell, Cristina Poveda, Maria Jose Villar, Kathryn Jones, Maria Elena Bottazzi, Peter Hotez, Edwin Tijhaar, Jeroen Pollet

Faculty, Staff and Students Publications

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease. Globally 6 to 7 million people are infected by this parasite of which 20-30% will progress to develop Chronic Chagasic Cardiomyopathy (CCC). Despite its high disease burden, no clinically approved vaccine exists for the prevention or treatment of CCC. Developing vaccines that can stimulate T. cruzi-specific CD8+ cytotoxic T cells and eliminate infected cells requires targeting parasitic antigens presented on major histocompatibility complex-I (MHC-I) molecules. We utilized mass spectrometry-based immunopeptidomics to investigate which parasitic peptides are displayed on MHC-I of T. cruzi infected cells. Through duplicate experiments, we identified an …

Genome-Derived Ampullary Adenocarcinoma Classifier And Postresection Prognostication, Brett L Ecker, Kenneth Seier, Austin M Eckhoff, Gabriella N Tortorello, Peter J Allen, Vinod P Balachandran, Nicola Blackburn, Michael I D'Angelica, Ronald P Dematteo, Daniel G Blazer, Jeffrey A Drebin, William E Fisher, Danielle Fortuna, Anthony J Gill, Marie-Claude Gingras, T Peter Kingham, Major K Lee, Michael E Lidsky, Daniel P Nussbaum, Michael J Overman, Jaswinder S Samra, Ronglai Shen, Carlie S Sigel, Kevin C Soares, Charles M Vollmer, Alice C Wei, Sabino Zani, Robert E Roses, Mithat Gonen, William R Jarnagin

Faculty, Staff and Students Publications

Importance: Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use.

Objective: To test external validity of the prognostic value of the hidden genome classifier of AA.

Design, setting, and participants: This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020.

Exposures: The multilevel meta-feature regression model previously trained on …

Retinal Ganglion Cell Circuits And Glial Interactions In Humans And Mice, Kang-Chieh Huang, Mohamed Tawfik, Melanie A Samuel

Faculty, Staff and Students Publications

Retinal ganglion cells (RGCs) are the brain's gateway for vision, and their degeneration underlies several blinding diseases. RGCs interact with other neuronal cell types, microglia, and astrocytes in the retina and in the brain. Much knowledge has been gained about RGCs and glia from mice and other model organisms, often with the assumption that certain aspects of their biology may be conserved in humans. However, RGCs vary considerably between species, which could affect how they interact with their neuronal and glial partners. This review details which RGC and glial features are conserved between mice, humans, and primates, and which differ. …

A New Ex Vivo Model System To Analyze Factors Affecting The Integrity Of Fetal Membranes In Fetoscopic Surgery, Serjosha Robmann, Raoul Hopf, Costanza Giampietro, Lukas Moser, Alexandra Dolder, Magdalena Sanz Cortes, Martin Ehrbar, Nicole Ochsenbein, Jan Deprest, Edoardo Mazza

Faculty, Staff and Students Publications

We developed an ex vivo model system to analyze the influence of relevant environmental and mechanical factors potentially affecting the integrity of fetal membranes during fetoscopic surgery. The set-up exposes amniochorion membranes to insufflation at predefined levels of gas pressure, flow, humidity, and temperature. Change in fetal membranes stiffness is quantified during the phase mimicking surgery through measurement of membranes' strain in response to cyclic overpressure. The trocar induced perforation creates a mechanical weakness whose stability is assessed by increasing the insufflation pressure until membrane rupture. Damage of the epithelial cells lining the amnion is assessed through live-dead staining. Initial …

Differentiating Mycosis Fungoides Lesions From Their Mimickers Clinically And Histologically: A Single Tertiary Center Retrospective Analysis In Saudi Arabia, Fatimah M. Budair, Ahmed A. Alsayyah, Omar M. Alakloby

Saudi Medical Journal

Objectives: To identify the clinical and histological features of MF that can assist in distinguishing MF from MF-mimicking cases. Although mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma, clinicopathological correlations are required to establish an accurate diagnosis, which are currently lacking. Methods: This retrospective observational study evaluated the clinical presentations, characteristics, and histological features of 56 patients with suspected MF who presented to our clinic between January 2018 and August 2022. Immunohistochemistry was performed, and the loss of CD5 and CD7 T-cells and T-cell receptor rearrangement was evaluated. Results: Overall, 34 patients were diagnosed with MF, …

Pathogenicity And Virulence Of Human Respiratory Syncytial Virus: Multifunctional Nonstructural Proteins Ns1 And Ns2, Trudy N Merritt, Jingjing Pei, Daisy W Leung

2020-Current year OA Pubs

Human respiratory syncytial virus (hRSV) is a major cause of lower respiratory tract infections in young children, the elderly, and immunocompromised. Despite its discovery over 60 years ago and the global impact on human health, limited effective prophylactic or therapeutic options have been available for hRSV infections. This has largely been attributed to the legacy of vaccine failure in the 1960s using a formalin-inactivated RSV , which led to enhancement of disease post exposure to hRSV infection and hampered subsequent development of vaccine candidates. Recent FDA approval of vaccines for older adults and pregnant individuals are major advancements but leaves …

Solid-State Nmr Compositional Analysis Of Sputum From People With Cystic Fibrosis, Kathy Duong, Evan Moss, Courtney Reichhardt

2020-Current year OA Pubs

People with the genetic disease cystic fibrosis (CF) often have chronic airway infections and produce airway secretions called sputum. A better understanding of sputum composition is desired in order to track changes in response to CF therapeutics and to improve laboratory models for the study of CF airway infections. The glycosylated protein mucin is a primary component. Along with extracellular DNA, mucin gives rise to the high viscoelasticity of sputum, which inhibits airway clearance and is thought to promote chronic airway infections in people with CF. Past studies of sputum composition identified additional biomolecular components of sputum including other proteins, …

Experiences In Providing A Community Educational Resource For The All Of Us Researcher Workbench, Deborah I Ritter, Jinyoung Byun, Jun Wang, Stephen Richards, Pamela N Luna, Laterrica Williams, Julie R Coleman, Jasmine N Baker, Shamika Ketkar, Ashley M Butler, Latanya Hammonds-Odie, Elizabeth G Atkinson, Kim C Worley, Debra D Murray, Brendan Lee, Steven E Scherer

Faculty, Staff and Students Publications

OBJECTIVE: Educational offerings to fill the bioinformatics knowledge gap are a key component to enhancing access and use of health data from the All of Us Research Program. We developed a Train the Trainer-based, innovative training series including project-based learning, modular on-demand demonstrations, and unstructured tutorial time as a model for educational engagement in the All of Us community.

MATERIALS AND METHODS: We highlight our training modules and content, with training survey data informing cycles of development in the creation of a 6-module training series with modular demonstrations.

RESULTS: We have conducted 2 public iterations of the Train the Trainer …

Rfc2 May Contribute To The Pathogenicity Of Williams Syndrome Revealed In A Zebrafish Model, Ji-Won Park, Tae-Ik Choi, Tae-Yoon Kim, Yu-Ri Lee, Dilan Wellalage Don, Jaya K George-Abraham, Laurie A Robak, Cristina C Trandafir, Pengfei Liu, Jill A Rosenfeld, Tae Hyeong Kim, Florence Petit, Yoo-Mi Kim, Chong Kun Cheon, Yoonsung Lee, Cheol-Hee Kim

Faculty, Staff and Students Publications

Williams syndrome (WS) is a rare multisystemic disorder caused by recurrent microdeletions on 7q11.23, characterized by intellectual disability, distinctive craniofacial and dental features, and cardiovascular problems. Previous studies have explored the roles of individual genes within these microdeletions in contributing to WS phenotypes. Here, we report five patients with WS with 1.4 Mb-1.5 Mb microdeletions that include RFC2, as well as one patient with a 167-kb microdeletion involving RFC2 and six patients with intragenic variants within RFC2. To investigate the potential involvement of RFC2 in WS pathogenicity, we generate a rfc2 knockout (KO) zebrafish using CRISPR-Cas9 technology. Additionally, we generate …

Hands-On Training About Data Clustering With Orange Data Mining Toolbox, Janez Demšar, Blaž Zupan

Faculty, Staff and Students Publications

Data clustering is a core data science approach widely used and referenced in the scientific literature. Its algorithms are often intuitive and can lead to exciting, insightful results that are easy to interpret. For these reasons, data clustering techniques could be the first method encountered in data science training. This paper proposes a hands-on approach to data clustering training suitable for introductory courses. The education approach features problem-based training that starts with the data and gradually introduces various data processing and analysis methods, illustrating them through visual representations of data and models. The proposed training is suitable for a general …

10 Practical Priorities To Prevent And Manage Serious Allergic Reactions: Ga2len Anacare And Efa Anaphylaxis Manifesto, Antonella Muraro, Debra De Silva, Marcia Podesta, Aikaterini Anagnostou, Victoria Cardona, Susanne Halken, Pete Smith, Luciana Kase Tanno, Paul Turner, Margitta Worm, Montserrat Alvaro-Lozano, Stefania Arasi, Anna Asarnoj, Simona Barni, Kirsten Beyer, Lucy A Bilaver, Andrew Bird, Roberta Bonaguro, Helen A Brough, R Sharon Chinthrajah, Emma E Cook, Céline Demoulin, Antoine Deschildre, Timothy E Dribin, Motohiro Ebisawa, Montserrat Fernandez-Rivas, Alessandro Fiocchi, David M Fleischer, Eleanor Garrow, Jennifer Gerdts, Mattia Giovannini, Kirsi M Järvinen, Mary Kelly, Edward F Knol, Gideon Lack, Francesca Lazzarotto, Thuy-My Le, Stephanie Leonard, Jay Lieberman, Michael Makris, Lianne Mandelbaum, Mary Jane Marchisotto, Gustavo Andres Marino, Francesca Mori, Caroline Nilsson, Anna Nowak-Wegrzyn, Mikaela Odemyr, H N G Oude Elberink, Kati Palosuo, Nandinee Patel, Jennifer Pier, Sung Poblete, Rima Rachid, Pablo Rodríguez Del Río, Maria Said, Hugh A Sampson, Angel Sánchez Sanz, Sabine Schnadt, Fallon Schultz, Alice Toniolo, Julia E M Upton, Carina Venter, Brian P Vickery, Berber Vlieg-Boerstra, Julie Wang, Graham Roberts, Torsten Zuberbier, Ga2len Anacare Centres And Efa

Faculty, Staff and Students Publications

This Anaphylaxis Manifesto calls on communities to prioritise 10 practical actions to improve the lives of people at risk of serious allergic reactions. The Global Allergy and Asthma European Network and the European Federation of Allergy and Airways Diseases Patients' Associations (EFA) compiled patient-centric priorities. We used qualitative consensus methods, research evidence and feedback from over 200 patient groups, stakeholder organisations and healthcare professionals. We encourage healthcare, education and food organisations to collaborate with people at risk of serious allergic reactions to tackle safety, anxiety and financial burdens for individuals and societies. Key priorities for prevention include awareness-raising campaigns for …

A Proteome-Wide Association Study Identifies Putative Causal Proteins For Breast Cancer Risk, Tianying Zhao, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Jill E Henry, Bing Zhang, Xingyi Guo, Michele L Cote, Qiuyin Cai, Xiao-Ou Shu, Wei Zheng, Jirong Long

Faculty, Staff and Students Publications

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 breast cancer risk-associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue related to breast cancer risk.

METHODS: We profiled the proteome in fresh frozen breast tissue samples from 120 cancer-free European-ancestry women from the Susan G. Komen Tissue Bank (KTB). Protein expression levels were log2-transformed then normalized via quantile and inverse-rank transformations. GWAS data were also generated for …

Tyk2 Regulates Tau Levels, Phosphorylation And Aggregation In A Tauopathy Mouse Model, Jiyoen Kim, Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-Eun Chloe Chung, Bradley Hyman, David M Holtzman, Huda Yahya Zoghbi

Faculty, Staff and Students Publications

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau …

Cadasil: A Notch3-Associated Cerebral Small Vessel Disease, Lamei Yuan, Xiangyu Chen, Joseph Jankovic, Hao Deng

Faculty, Staff and Students Publications

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of …

Π-Hub: The Proteomic Navigator Of The Human Body, Fuchu He, Ruedi Aebersold, Mark S Baker, Xiuwu Bian, Xiaochen Bo, Daniel W Chan, Cheng Chang, Luonan Chen, Xiangmei Chen, Yu-Ju Chen, Heping Cheng, Ben C Collins, Fernando Corrales, Jürgen Cox, Weinan E, Jennifer E Van Eyk, Jia Fan, Pouya Faridi, Daniel Figeys, George Fu Gao, Wen Gao, Zu-Hua Gao, Keisuke Goda, Wilson Wen Bin Goh, Dongfeng Gu, Changjiang Guo, Tiannan Guo, Yuezhong He, Albert J R Heck, Henning Hermjakob, Tony Hunter, Narayanan Gopalakrishna Iyer, Ying Jiang, Connie R Jimenez, Lokesh Joshi, Neil L Kelleher, Ming Li, Yang Li, Qingsong Lin, Cui Hua Liu, Fan Liu, Guang-Hui Liu, Yansheng Liu, Zhihua Liu, Teck Yew Low, Ben Lu, Matthias Mann, Anming Meng, Robert L Moritz, Edouard Nice, Guang Ning, Gilbert S Omenn, Christopher M Overall, Giuseppe Palmisano, Yaojin Peng, Charles Pineau, Terence Chuen Wai Poon, Anthony W Purcell, Jie Qiao, Roger R Reddel, Phillip J Robinson, Paola Roncada, Chris Sander, Jiahao Sha, Erwei Song, Sanjeeva Srivastava, Aihua Sun, Siu Kwan Sze, Chao Tang, Liujun Tang, Ruijun Tian, Juan Antonio Vizcaíno, Chanjuan Wang, Chen Wang, Xiaowen Wang, Xinxing Wang, Yan Wang, Tobias Weiss, Mathias Wilhelm, Robert Winkler, Bernd Wollscheid, Limsoon Wong, Linhai Xie, Wei Xie, Tao Xu, Tianhao Xu, Liying Yan, Jing Yang, Xiao Yang, John Yates, Tao Yun, Qiwei Zhai, Bing Zhang, Hui Zhang, Lihua Zhang, Lingqiang Zhang, Pingwen Zhang, Yukui Zhang, Yu Zi Zheng, Qing Zhong, Yunping Zhu, Π-Hub Consortium

Faculty, Staff and Students Publications

The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies. Recent advances in proteomic technology and computational sciences now provide opportunities to investigate the intricate biology of the human body …

The Internist's Post V.1 N.10, The University Of Texas Rio Grande Valley. School Of Medicine, Eunbee Cho, Osiris Fernandez, Hector D. Preciado, Sobia Memon, Diana Acosta Pozo, Corey Haines, Roque Mifuji Lira, Martha Solis, Cesar Gutierrez

School of Medicine Publications

No abstract provided.

Accelerating Heritability, Genetic Correlation, And Genome-Wide Association Imaging Genetic Analyses In Complex Pedigrees, Brian Donohue, Si Gao, Thomas E. Nichols, Bhim M. Adhikari, Yizhou Ma, Neda Jahanshad, Francis J. Mcmahon, Elizabeth M. Humphries, William Burroughs, John Blangero

School of Medicine Publications

National and international biobanking efforts led to the collection of large and inclusive imaging genetics datasets that enable examination of the contribution of genetic and environmental factors to human brains in illness and health. High-resolution neuroimaging (~104–6 voxels) and genetic (106–8 single nucleotide polymorphic [SNP] variants) data are available in statistically powerful (N = 103–5) epidemiological and disorder-focused samples. Performing imaging genetics analyses at full resolution afforded in these datasets is a formidable computational task even under the assumption of unrelatedness among the subjects. The computational complexity rises as ~N2–3 (where N is the sample size), when …

Modification Of A Parent-Report Sleep Scale For Individuals With Cdkl5 Deficiency Disorder: A Psychometric Study, Jacinta M Saldaris, Scott Demarest, Peter Jacoby, Heather E Olson, Kiran Maski, Elia Pestana-Knight, Dana Price, Rajsekar Rajaraman, Bernhard Suter, Judith Weisenberg, Helen Leonard, Eric D Marsh, Tim A Benke, Jenny Downs

Faculty, Staff and Students Publications

Study objectives: Sleep difficulties are common in CDKL5 deficiency disorder, a developmental and epileptic encephalopathy. This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Somnolence (DOES), and Sleep Breathing Disorders domains of the Sleep Disturbance Scale for Children for CDKL5 deficiency disorder.

Methods: A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a United States Centers of Excellence clinic or registered with the International CDKL5 Disorder Database.

Results: The median age was 10.3 years (range 3.2-40.7 years) and 105 (84%) …

Pathophysiology And Treatment Of Prediabetes And Type 2 Diabetes In Youth, Fida Bacha, Tamara S Hannon, Mustafa Tosur, Julie M Pike, Ashley Butler, Kalie L Tommerdahl, Philip S Zeitler

Faculty, Staff and Students Publications

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, …

Shared Genetic Architecture Of Non-Viral Cirrhosis With Several Pleiotropic Traits: A Nested Case-Control Study In The Uk Biobank, Jinyoung Byun, Hyun-Seok Kim, Younghun Han, Aaron P Thrift, Sabrina M Lin, Xiangjun Xiao, Hyeyeun Lim, Goo Jun, Stacia M Desantis, Hashem B El-Serag, Fasiha Kanwal, Christopher I Amos

Faculty, Staff and Students Publications

Background & aims: Cirrhosis is a leading cause of liver-related mortality and a multifactorial disease. To date, the complex genetic architecture of non-viral cirrhosis has not been fully explored. Cross-trait genetic correlations can elucidate the common genetic etiology of genetically correlated phenotypes. This study aims to identify polygenic and pleiotropic traits associated with cirrhosis using the linkage disequilibrium score regression analysis.

Methods: We conducted genome-wide association analysis of 9,622,842 imputed SNPs on 3,368 non-viral cirrhosis cases and 258,258 controls, and cross-trait analysis between non-viral cirrhosis and various polygenic and pleiotropic traits using the UK Biobank cohort study. We further performed …

Association Of Left Atrial Function With Frailty: The Atherosclerosis Risk In Communities (Aric) Study, Daokun Sun, Romil R Parikh, Wendy Wang, Anne Eaton, Pamela L Lutsey, B Gwen Windham, Riccardo M Inciardi, Scott D Solomon, Christie M Ballantyne, Amil M Shah, Lin Yee Chen

Faculty, Staff and Students Publications

Background: Frailty is common in people with cardiovascular disease. Worse left atrial (LA) function is an independent risk factor for cardiovascular disease. However, whether worse LA function is associated with frailty is unclear.

Methods: We included 3292 older adults from the Atherosclerosis Risk in Communities study who were non-frail at baseline (visit 5, 2011-2013) and had LA function (reservoir, conduit, and contractile strain) measured from two-dimensional speckle-tracking echocardiography. LA stiffness index was calculated as a ratio of E/e' to LA reservoir strain. Frailty was defined using the validated Fried frailty phenotype. Incident frailty was assessed between 2016 and 2019 during …

A Transgenic Mouse Model Of Down Syndrome Acute Lymphoblastic Leukemia Identifies Targetable Vulnerabilities, Jacob J Junco, Max Rochette, Michelle Alozie, Raushan Rashid, Maci Terrell, Barry Zorman, Pavel Sumazin, Lauren Rowland, Gino Dettorre, Reid T Powell, Clifford C Stephan, Peter J Davies, Margarita Martinez-Moczygemba, Jun J Yang, Karen R Rabin

Faculty, Staff and Students Publications

No abstract provided.

Validation Of Human Telomere Length Multi-Ancestry Meta-Analysis Association Signals Identifies Pop5 And Kbtbd6 As Human Telomere Length Regulation Genes, Rebecca Keener, Surya B. Chhetri, Carla J. Connelly, Margaret A. Taub, Matthew P. Conomos, Joshua Weinstock, Bohan Ni, Benjamin Strober, Stella Aslibekyan, John Blangero

School of Medicine Publications

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of …

The Effects Of Mosaicism On Biological And Clinical Markers Of Alzheimer's Disease In Adults With Down Syndrome, Laura Xicota, Rachel L Henson, Beau Ances, Et Al.

2020-Current year OA Pubs

BACKGROUND: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.

METHODS: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma …

Subcutaneous Ocrelizumab In Multiple Sclerosis: Results Of The Phase 1b Ocarina I Study, Scott D Newsome, Robert T Naismith, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open-label, multicenter, Phase 1b, dose-finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825).

METHODS: Patients with relapsing or primary progressive multiple sclerosis (aged 18-65 years; Expanded Disability Status Scale score 0.0-6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 …

Dysfunctional Alpha Modulation As A Mechanism Of Working Memory Impairment In Serious Mental Illness, Molly A Erickson, Megan A Boudewyn, Kurt Winsler, Charlotte Li, Deanna M Barch, Cameron S Carter, Michael J Frank, James M Gold, Angus W Macdonald 3rd, John D Ragland, Steven M Silverstein, Andrew Yonelinas, Steven J Luck

2020-Current year OA Pubs

BACKGROUND: People with psychosis and mood disorders experience disruptions in working memory; however, the underlying mechanism remains unknown. We focused on 2 potential mechanisms: poor attentional engagement should be associated with elevated levels of prestimulus alpha-band activity within the electroencephalogram (EEG), whereas impaired working memory encoding should be associated with reduced poststimulus alpha suppression.

METHODS: We collected EEG data from 68 people with schizophrenia, 43 people with bipolar disorder with a history of psychosis, 53 people with major depressive disorder, and 90 healthy comparison subjects while they completed a spatial working memory task. We quantified attention lapsing, memory precision, and …