Digital Commons Network^™

Structure Of A Eukaryotic Cholinephosphotransferase-1 Reveals Mechanisms Of Substrate Recognition And Catalysis, Lie Wang, Ming Zhou

Faculty, Staff and Students Publications

Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic cell membranes. In eukaryotes, two highly homologous enzymes, cholinephosphotransferase-1 (CHPT1) and choline/ethanolamine phosphotransferase-1 (CEPT1) catalyze the final step of de novo PC synthesis. CHPT1/CEPT1 joins two substrates, cytidine diphosphate-choline (CDP-choline) and diacylglycerol (DAG), to produce PC, and Mg2+ is required for the reaction. However, mechanisms of substrate recognition and catalysis remain unresolved. Here we report structures of a CHPT1 from Xenopus laevis (xlCHPT1) determined by cryo-electron microscopy to an overall resolution of ~3.2 Å. xlCHPT1 forms a homodimer, and each protomer has 10 transmembrane helices (TMs). The first 6 TMs carve …

Videolaryngoscopy Versus Direct Laryngoscopy For Tracheal Intubation In Neonates, Krithika Lingappan, Nicole Neveln, Jennifer L Arnold, Caraciolo J Fernandes, Mohan Pammi

Faculty, Staff and Students Publications

BACKGROUND: Establishment of a secure airway is a critical part of neonatal resuscitation in the delivery room and the neonatal intensive care unit. Videolaryngoscopy has the potential to facilitate successful endotracheal intubation, and decrease adverse consequences of a delay in airway stabilization. Videolaryngoscopy may enhance visualization of the glottis and intubation success in neonates. This is an update of a review first published in 2015, and updated in 2018.

OBJECTIVES: To determine the effectiveness and safety of videolaryngoscopy compared to direct laryngoscopy in decreasing the time and attempts required for endotracheal intubation and increasing the success rate on first intubation …

Topical Administration Of An Apoptosis Inducer Mitigates Bleomycin-Induced Skin Fibrosis, Md Nurul Huda, Edgar A Borrego, Cristina D Guerena, Armando Varela-Ramirez, Renato J Aguilera, Christine M Hamadani, Eden E L Tanner, Abu Zayed Md Badruddoza, Sandeep K Agarwal, Md Nurunnabi

Faculty, Staff and Students Publications

Pathological fibrosis is distinguished from physiological wound healing by persistent myofibroblast activation, suggesting that therapies that induce myofibroblast apoptosis selectively could prevent progression and potentially reverse the established fibrosis, such as for scleroderma (a heterogeneous autoimmune disease characterized by multiorgan fibrosis). Navitoclax (NAVI) is a BCL-2/BCL-xL inhibitor with antifibrotic properties and has been investigated as a potential therapeutic for fibrosis. NAVI makes myofibroblasts particularly vulnerable to apoptosis. However, despite NAVI's significant potency, clinical translation of BCL-2 inhibitors, NAVI in this case, is hindered due to the risk of thrombocytopenia. Therefore, in this work, we utilized a newly developed ionic liquid …

3-Phosphoinositide-Dependent Kinase 1 Drives Acquired Resistance To Osimertinib, Ismail M Meraz, Mourad Majidi, Bingliang Fang, Feng Meng, Lihui Gao, Ruping Shao, Renduo Song, Feng Li, Yonathan Lissanu, Huiqin Chen, Min Jin Ha, Qi Wang, Jing Wang, Elizabeth Shpall, Sung Yun Jung, Franziska Haderk, Philippe Gui, Jonathan Wesley Riess, Victor Olivas, Trever G Bivona, Jack A Roth

Faculty, Staff and Students Publications

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of …

Co-Clinical Imaging Metadata Information (Cimi) For Cancer Research To Promote Open Science, Standardization, And Reproducibility In Preclinical Imaging, Stephen M Moore, James D Quirk, Andrew W Lassiter, Richard Laforest, Gregory D Ayers, Cristian T Badea, Andriy Y Fedorov, Paul E Kinahan, Matthew Holbrook, Peder E Z Larson, Renuka Sriram, Thomas L Chenevert, Dariya Malyarenko, John Kurhanewicz, A Mcgarry Houghton, Brian D Ross, Stephen Pickup, James C Gee, Rong Zhou, Seth T Gammon, Henry Charles Manning, Raheleh Roudi, Heike E Daldrup-Link, Michael T Lewis, Daniel L Rubin, Thomas E Yankeelov, Kooresh I Shoghi

Faculty, Staff and Students Publications

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an …

Rational Design Of Highly Potent And Selective Covalent Map2k7 Inhibitors, Dalton R Kim, Meghan J Orr, Ada J Kwong, Kristine K Deibler, Hasan H Munshi, Cory Seth Bridges, Taylor Jie Chen, Xiaoyu Zhang, H Daniel Lacorazza, Karl A Scheidt

Faculty, Staff and Students Publications

The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes, where it plays a critical role in the regulation of activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, which allows external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads immediately upstream to significant signal divergence and cross-talk. One such kinase, MAP2K7, also known as MEK7 and MKK7, is a protein of great interest in the molecular pathophysiology underlying pediatric T cell acute lymphoblastic leukemia (T-ALL). Herein, we describe the rational …

Sensor-Controlled Digital Game For Heart Failure Self-Management: Protocol For A Randomized Controlled Trial, Kavita Radhakrishnan, Christine Julien, Matthew O'Hair, Rachel Tunis, Grace Lee, Angelica Rangel, James Custer, Tom Baranowski, Paul J Rathouz, Miyong T Kim

Faculty, Staff and Students Publications

BACKGROUND: Heart failure (HF) is the leading cause of hospitalization among older adults in the United States. There are substantial racial and geographic disparities in HF outcomes, with patients living in southern US states having a mortality rate 69% higher than the national average. Self-management behaviors, particularly daily weight monitoring and physical activity, are extremely important in improving HF outcomes; however, patients typically have particularly low adherence to these behaviors. With the rise of digital technologies to improve health outcomes and motivate health behaviors, sensor-controlled digital games (SCDGs) have become a promising approach. SCDGs, which leverage sensor-connected technologies, offer the …

Exrna-Eclip Intersection Analysis Reveals A Map Of Extracellular Rna Binding Proteins And Associated Rnas Across Major Human Biofluids And Carriers, Emily L Laplante, Alessandra Stürchler, Robert Fullem, David Chen, Anne C Starner, Emmanuel Esquivel, Eric Alsop, Andrew R Jackson, Ionita Ghiran, Getulio Pereira, Joel Rozowsky, Justin Chang, Mark B Gerstein, Roger P Alexander, Matthew E Roth, Jeffrey L Franklin, Robert J Coffey, Robert L Raffai, Isabelle M Mansuy, Stavros Stavrakis, Andrew J Demello, Louise C Laurent, Yi-Ting Wang, Chia-Feng Tsai, Tao Liu, Jennifer Jones, Kendall Van Keuren-Jensen, Eric Van Nostrand, Bogdan Mateescu, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

Although the role of RNA binding proteins (RBPs) in extracellular RNA (exRNA) biology is well established, their exRNA cargo and distribution across biofluids are largely unknown. To address this gap, we extend the exRNA Atlas resource by mapping exRNAs carried by extracellular RBPs (exRBPs). This map was developed through an integrative analysis of ENCODE enhanced crosslinking and immunoprecipitation (eCLIP) data (150 RBPs) and human exRNA profiles (6,930 samples). Computational analysis and experimental validation identified exRBPs in plasma, serum, saliva, urine, cerebrospinal fluid, and cell-culture-conditioned medium. exRBPs carry exRNA transcripts from small non-coding RNA biotypes, including microRNA (miRNA), piRNA, tRNA, small …

Cord Blood Transplantation For Nonmalignant Disorders: Early Functional Immunity And High Survival, Caridad Martinez, Paibel Aguayo-Hiraldo, Natalia Chaimowitz, Lisa Forbes, Nicholas Rider, Sarah Nicholas, Filiz Seeborg, Javier Chinen, Ivan Chinn, Carla Davis, Howard Roseblatt, Lenora Noroski, Bilal Omer, Tami John, Khaled Yassine, Swati Naik, John Craddock, Saleh Bhar, Carl Allen, Nabil Ahmed, Ghadir Sasa, David Steffin, Erin Doherty, Anil George, Baheyeldin Salem, Brian Friend, Meenakshi Hegde, Malcolm K Brenner, Helen E Heslop, Ann Leen, Amanda Peña, Mengfen Wu, I Celine Hanson, Robert A Krance

Faculty, Staff and Students Publications

There is no consensus on the best donor for children with nonmalignant disorders and immune deficiencies in the absence of a matched related donor (MRD). We evaluated the 2-year overall survival (OS) after umbilical cord blood transplantation (UCBT) in patients with nonmalignant disorders from 2009 to 2020 enrolled in a prospective clinical trial using either 5/6 or 6/6 UCB as the cell source. Patients receive a fully ablative busulfan, cyclophosphamide, and fludarabine without serotherapy. Fifty-five children were enrolled, median age 5 months (range, 1-111 months); primary immune deficiency (45), metabolic (5), hemophagocytic lymphohistiocytosis (1), and hematologic disorders (4). Twenty-six patients …

Single-Cell Transcriptome Analysis Of Xenotransplanted Human Retinal Organoids Defines Two Migratory Cell Populations Of Nonretinal Origin, Ying V Liu, Clayton P Santiago, Akin Sogunro, Gregory J Konar, Ming-Wen Hu, Minda M Mcnally, Yu-Chen Lu, Miguel Flores-Bellver, Silvia Aparicio-Domingo, Kang V Li, Zhuo-Lin Li, Dzhalal Agakishiev, Sarah E Hadyniak, Katarzyna A Hussey, Tyler J Creamer, Linda D Orzolek, Derek Teng, M Valeria Canto-Soler, Jiang Qian, Zheng Jiang, Robert J Johnston, Seth Blackshaw, Mandeep S Singh

Faculty, Staff and Students Publications

Human retinal organoid transplantation could potentially be a treatment for degenerative retinal diseases. How the recipient retina regulates the survival, maturation, and proliferation of transplanted organoid cells is unknown. We transplanted human retinal organoid-derived cells into photoreceptor-deficient mice and conducted histology and single-cell RNA sequencing alongside time-matched cultured retinal organoids. Unexpectedly, we observed human cells that migrated into all recipient retinal layers and traveled long distances. Using an unbiased approach, we identified these cells as astrocytes and brain/spinal cord-like neural precursors that were absent or rare in stage-matched cultured organoids. In contrast, retinal progenitor-derived rods and cones remained in the …

Perspectives On Non-Prescription Antibiotic Use Among Hispanic Patients In The Houston Metroplex, Lindsey Laytner, Patricia Chen, Susan Nash, Michael K Paasche-Orlow, Richard Street, Roger Zoorob, Barbara Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

BACKGROUND: Non-prescription antibiotic use includes taking an antibiotic without medical guidance (e.g., leftovers, from friends/relatives, or purchased without a prescription). Non-prescription use contributes to antimicrobial resistance, adverse drug reactions, interactions, superinfection, and microbiome imbalance. Qualitative studies exploring perspectives regarding non-prescription use among Hispanic patients are lacking. We used the Kilbourne Framework for Advancing Health Disparities Research to identify factors influencing patients' non-prescription use and organize our findings.

METHODS: Our study includes Hispanic primary care clinic patients with different types of health insurance coverage in the Houston metroplex who endorsed non-prescription use in a previous survey. Semistructured interviews explored the factors …

Advantages Of Whole Genome Sequencing In Mitigating The Helicobacter Pylori Antimicrobial Resistance Problem, Kartika Afrida Fauzia, Ricky Indra Alfaray, Yoshio Yamaoka

Faculty, Staff and Students Publications

Helicobacter pylori antimicrobial resistance is a critical public health issue. Typically, antimicrobial resistance epidemiology reports include only the antimicrobial susceptibility test results for H. pylori. However, this phenotypic approach is less capable of answering queries related to resistance mechanisms and specific mutations found in particular global regions. Whole genome sequencing can help address these two questions while still offering quality control and is routinely validated against AST standards. A comprehensive understanding of the mechanisms of resistance should improve H. pylori eradication efforts and prevent gastric cancer.

Dna Supercoiling-Induced Shapes Alter Minicircle Hydrodynamic Properties, Radost Waszkiewicz, Maduni Ranasinghe, Jonathan M Fogg, Daniel J Catanese, Maria L Ekiel-Jeżewska, Maciej Lisicki, Borries Demeler, Lynn Zechiedrich, Piotr Szymczak

Faculty, Staff and Students Publications

DNA in cells is organized in negatively supercoiled loops. The resulting torsional and bending strain allows DNA to adopt a surprisingly wide variety of 3-D shapes. This interplay between negative supercoiling, looping, and shape influences how DNA is stored, replicated, transcribed, repaired, and likely every other aspect of DNA activity. To understand the consequences of negative supercoiling and curvature on the hydrodynamic properties of DNA, we submitted 336 bp and 672 bp DNA minicircles to analytical ultracentrifugation (AUC). We found that the diffusion coefficient, sedimentation coefficient, and the DNA hydrodynamic radius strongly depended on circularity, loop length, and degree of …

Tmem106b Regulates Microglial Proliferation And Survival In Response To Demyelination, Tingting Zhang, Weilun Pang, Tuancheng Feng, Jennifer Guo, Kenton Wu, Mariela Nunez Santos, Akshayakeerthi Arthanarisami, Alissa L Nana, Quynh Nguyen, Peter J Kim, Joanna L Jankowsky, William W Seeley, Fenghua Hu

Faculty, Staff and Students Publications

TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B …

Exercise Reprograms The Inflammatory Landscape Of Multiple Stem Cell Compartments During Mammalian Aging, Ling Liu, Soochi Kim, Matthew T Buckley, Jaime M Reyes, Jengmin Kang, Lei Tian, Mingqiang Wang, Alexander Lieu, Michelle Mao, Cristina Rodriguez-Mateo, Heather D Ishak, Mira Jeong, Joseph C Wu, Margaret A Goodell, Anne Brunet, Thomas A Rando

Faculty, Staff and Students Publications

Exercise has the ability to rejuvenate stem cells and improve tissue regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. We subjected young and old mice to aerobic exercise and generated a single-cell transcriptomic atlas of muscle, neural, and hematopoietic stem cells with their niche cells and progeny, complemented by whole transcriptome analysis of single myofibers. We found that exercise ameliorated the upregulation of a number of inflammatory pathways associated with old age and restored aspects of intercellular communication mediated …

Bi-Allelic Variants In Ints11 Are Associated With A Complex Neurological Disorder, Burak Tepe, Erica L Macke, Marcello Niceta, Monika Weisz Hubshman, Oguz Kanca, Laura Schultz-Rogers, Yuri A Zarate, G Bradley Schaefer, Jorge Luis Granadillo De Luque, Daniel J Wegner, Benjamin Cogne, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Eric J Wagner, Lynn S Pais, Jennifer E Neil, Ganeshwaran H Mochida, Christopher A Walsh, Nurit Magal, Valerie Drasinover, Mordechai Shohat, Tanya Schwab, Chris Schmitz, Karl Clark, Anthony Fine, Brendan Lanpher, Ralitza Gavrilova, Pierre Blanc, Lydie Burglen, Alexandra Afenjar, Dora Steel, Manju A Kurian, Prab Prabhakar, Sophie Gößwein, Nataliya Di Donato, Enrico S Bertini, Undiagnosed Diseases Network, Michael F Wangler, Shinya Yamamoto, Marco Tartaglia, Eric W Klee, Hugo J Bellen

Faculty, Staff and Students Publications

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Glynac (Glycine And N-Acetylcysteine) Supplementation In Old Mice Improves Brain Glutathione Deficiency, Oxidative Stress, Glucose Uptake, Mitochondrial Dysfunction, Genomic Damage, Inflammation And Neurotrophic Factors To Reverse Age-Associated Cognitive Decline: Implications For Improving Brain Health In Aging, Premranjan Kumar, Ob W Osahon, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Cognitive decline frequently occurs with increasing age, but mechanisms contributing to age-associated cognitive decline (ACD) are not well understood and solutions are lacking. Understanding and reversing mechanisms contributing to ACD are important because increased age is identified as the single most important risk factor for dementia. We reported earlier that ACD in older humans is associated with glutathione (GSH) deficiency, oxidative stress (OxS), mitochondrial dysfunction, glucose dysmetabolism and inflammation, and that supplementing GlyNAC (glycine and N-acetylcysteine) improved these defects. To test whether these defects occur in the brain in association with ACD, and could be improved/reversed with GlyNAC supplementation, we …

Osteoprogenitor-Gmp Crosstalk Underpins Solid Tumor-Induced Systemic Immunosuppression And Persists After Tumor Removal, Xiaoxin Hao, Yichao Shen, Nan Chen, Weijie Zhang, Elizabeth Valverde, Ling Wu, Hilda L Chan, Zhan Xu, Liqun Yu, Yang Gao, Igor Bado, Laura Natalee Michie, Charlotte Helena Rivas, Luis Becerra Dominguez, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Fengshuo Liu, Yunfeng Ding, David G Edwards, Jun Liu, Angela Alexander, Naoto T Ueno, Po-Ren Hsueh, Chih-Yen Tu, Liang-Chih Liu, Shu-Hsia Chen, Mien-Chie Hung, Bora Lim, Xiang H-F Zhang

Faculty, Staff and Students Publications

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitors (OPs) expansion, hematopoietic stem cell dislocation and CD41− granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41− GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in hematopoietic program. Importantly, these effects persist …

Srsf1 Haploinsufficiency Is Responsible For A Syndromic Developmental Disorder Associated With Intellectual Disability, Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus Leblanc, Emma Van Reempts, Frederic Tran Mau-Them, Ingrid M Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J Louie, Michael J Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley Mcconkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R Roeder, Tadahiro Mitani, Jennifer E Posey, Daniel Calame, Hagith Yonath, Jill A Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello

Faculty, Staff and Students Publications

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals …

Very-Long-Chain Fatty Acids Induce Glial-Derived Sphingosine-1-Phosphate Synthesis, Secretion, And Neuroinflammation, Hyung-Lok Chung, Qi Ye, Ye-Jin Park, Zhongyuan Zuo, Jung-Wan Mok, Oguz Kanca, Sudhir Gopal Tattikota, Shenzhao Lu, Nobert Perrimon, Hyun Kyoung Lee, Hugo J Bellen

Faculty, Staff and Students Publications

VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-κB activation, and macrophage infiltration into the CNS. Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also …

Adiposity-Associated Atrial Fibrillation: Molecular Determinants, Mechanisms, And Clinical Significance, Monika Gawałko, Arnela Saljic, Na Li, Issam Abu-Taha, Thomas Jespersen, Dominik Linz, Stanley Nattel, Jordi Heijman, Anke Fender, Dobromir Dobrev

Faculty, Staff and Students Publications

Obesity is an important contributing factor to the pathophysiology of atrial fibrillation (AF) and its complications by causing systemic changes, such as altered haemodynamic, increased sympathetic tone, and low-grade chronic inflammatory state. In addition, adipose tissue is a metabolically active organ that comprises various types of fat deposits with discrete composition and localization that show distinct functions. Fatty tissue differentially affects the evolution of AF, with highly secretory active visceral fat surrounding the heart generally having a more potent influence than the rather inert subcutaneous fat. A variety of proinflammatory, profibrotic, and vasoconstrictive mediators are secreted by adipose tissue, particularly …

Systemic Sclerosis Associated Interstitial Lung Disease: A Conceptual Framework For Subclinical, Clinical And Progressive Disease, David Roofeh, Kevin K Brown, Ella A Kazerooni, Donald Tashkin, Shervin Assassi, Fernando Martinez, Athol U Wells, Ganesh Raghu, Christopher P Denton, Lorinda Chung, Anna-Maria Hoffmann-Vold, Oliver Distler, Kerri A Johannson, Yannick Allanore, Eric L Matteson, Leticia Kawano-Dourado, John D Pauling, James R Seibold, Elizabeth R Volkmann, Simon L F Walsh, Chester V Oddis, Eric S White, Shaney L Barratt, Elana J Bernstein, Robyn T Domsic, Paul F Dellaripa, Richard Conway, Ivan Rosas, Nitin Bhatt, Vivien Hsu, Francesca Ingegnoli, Bashar Kahaleh, Puneet Garcha, Nishant Gupta, Surabhi Khanna, Peter Korsten, Celia Lin, Stephen C Mathai, Vibeke Strand, Tracy J Doyle, Virginia Steen, Donald F Zoz, Juan Ovalles-Bonilla, Ignasi Rodriguez-Pinto, Padmanabha D Shenoy, Andrew Lewandoski, Elizabeth Belloli, Alain Lescoat, Vivek Nagaraja, Wen Ye, Suiyuan Huang, Toby Maher, Dinesh Khanna

Faculty, Staff and Students Publications

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD).

METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification.

RESULTS: Forty-four experts (53%) completed …

Genome-Wide Analysis Of Structural Variants In Parkinson Disease, Kimberley J Billingsley, Jinhui Ding, Pilar Alvarez Jerez, Anastasia Illarionova, Kristin Levine, Francis P Grenn, Mary B Makarious, Anni Moore, Daniel Vitale, Xylena Reed, Dena Hernandez, Ali Torkamani, Mina Ryten, John Hardy, Uk Brain Expression Consortium (Ukbec), Ruth Chia, Sonja W Scholz, Bryan J Traynor, Clifton L Dalgard, Debra J Ehrlich, Toshiko Tanaka, Luigi Ferrucci, Thomas G Beach, Geidy E Serrano, John P Quinn, Vivien J Bubb, Ryan L Collins, Xuefang Zhao, Mark Walker, Emma Pierce-Hoffman, Harrison Brand, Michael E Talkowski, Bradford Casey, Mark R Cookson, Androo Markham, Mike A Nalls, Medhat Mahmoud, Fritz J Sedlazeck, Cornelis Blauwendraat, J Raphael Gibbs, Andrew B Singleton

Faculty, Staff and Students Publications

OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.

METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 …

Managing Interruptions To Improve Diagnostic Decision-Making: Strategies And Recommended Research Agenda, Jennifer F Sloane, Chris Donkin, Ben R Newell, Hardeep Singh, Ashley N D Meyer

Faculty, Staff and Students Publications

Interruptions are an inevitable occurrence in health care. Interruptions in diagnostic decision-making are no exception and can have negative consequences on both the decision-making process and well-being of the decision-maker. This may result in inaccurate or delayed diagnoses. To date, research specific to interruptions on diagnostic decision-making has been limited, but strategies to help manage the negative impacts of interruptions need to be developed and implemented. In this perspective, we first present a modified model of interruptions to visualize the interruption process and illustrate where potential interventions can be implemented. We then consider several empirically tested strategies from the fields …

Obstructive Sleep Apnea Modulates Clinical Outcomes Post-Acute Myocardial Infarction: A Large Longitudinal Veterans’ Dataset Report, Ritwick Agrawal, Amir Sharafkhaneh, Vijay Nambi, Ahmed Bahammam, Javad Razjouyan

Faculty, Staff and Students Publications

BACKGROUND: While the longer-term Obstructive Sleep apnea (OSA)-related intermittent hypoxia (IH) leads to various comorbidities, it has become increasingly evident that OSA confers protective advantages during and after acute myocardial infarction (AMI). We hypothesized in patients who were admitted with acute MI, the presence of OSA is associated with lower in-hospital mortality compared to those without a prior diagnosis of OSA.

METHODS: In this nationwide retrospective study utilizing Veterans Health Administration records, we included patients hospitalized for MI with a history of sleep disorders from 1999 to 2020. We divided patients into two cohorts: those with OSA and those without …

Associations Between Avocado Intake And Lower Rates Of Incident Type 2 Diabetes In Us Adults With Hispanic/Latino Ancestry, Alexis C Wood, Mackenzie K Senn, Jerome I Rotter

Faculty, Staff and Students Publications

BACKGROUND/PURPOSE: Hispanic/Latinos in the US are at increased risk for type 2 diabetes (T2D). Data suggest that avocado intake is associated with better glycemic control, but whether this translates to protection from T2D has not been studied. The goal of the current analyses was to examine whether consuming avocados at baseline is associated with lower incident T2D over a six-year period, compared to not consuming avocados at baseline.

SUBJECTS/METHODS: Using data from a large population of US adults with Hispanic ancestry, without known or unknown T2D at baseline (N=6,159), participants were classified as avocado consumers (N=983) or non-consumers (N=5,176) based …

Dietary Effects On Monocyte Phenotypes In Subjects With Hypertriglyceridemia And Metabolic Syndrome, Zeqin Lian, Xiao-Yuan Dai Perrard, Antu Kalathookunnel Antony, Xueying Peng, Lu Xu, Jing Ni, Bingqian Zhang, Veronica O'Brien, Anum Saeed, Xiaoming Jia, Aliza Hussain, Bing Yu, Scott I Simon, Frank M Sacks, Ron C Hoogeveen, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

In patients with hypertriglyceridemia, a short-term low–saturated fat vs high–saturated fat diet induced lower plasma lipids and improved monocyte phenotypes. These findings highlight the role of diet fat content and composition for monocyte phenotypes and possibly cardiovascular disease risk in these patients. (Effects of Dietary Interventions on Monocytes in Metabolic Syndrome; NCT03591588)

Cervical Myelomalacia Diagnosed Via Magnetic Resonance Imaging In A Patient With A Spinal Cord Stimulator For Complex Regional Pain Syndrome: A Case Report, Mashfee Khan, Krishna Shah

Faculty, Staff and Students Publications

Background: Neuromodulation is used to treat chronic pain, especially failed back surgery syndrome (FBSS) and complex regional pain syndrome (CPRS) type 1 and type 2. Until recently, neuromodulation had significant restrictions on magnetic resonance imaging (MRI) usage (4). Our patient provided Health Insurance Portability and Accountability Act of 1996 (HIPAA) compliant consent for the inclusion of his clinical information in this report.

Case report: A 43-year-old man developed CPRS of his right upper extremity that was treated with an MRI-compatible high frequency spinal cord stimulator (SCS). Two years later, he presented with worsening neck and right upper extremity neuropathic pain. …