Medicine and Health Sciences Commons^™

Prospects For Finding The Mechanisms Of Sex Differences In Addiction With Human And Model Organism Genetic Analysis., Udita Datta, Sarah E Schoenrock, Jason A. Bubier, Molly A. Bogue, James D Jentsch, Ryan W Logan, Lisa M Tarantino, Elissa J Chesler

Faculty Research 2020

Despite substantial evidence for sex differences in addiction epidemiology, addiction-relevant behaviors and associated neurobiological phenomena, the mechanisms and implications of these differences remain unknown. Genetic analysis in model organism is a potentially powerful and effective means of discovering the mechanisms that underlie sex differences in addiction. Human genetic studies are beginning to show precise risk variants that influence the mechanisms of addiction but typically lack sufficient power or neurobiological mechanistic access, particularly for the discovery of the mechanisms that underlie sex differences. Our thesis in this review is that genetic variation in model organisms are a promising approach that can …

Molecular And Clonal Evolution In Recurrent Metastatic Gliosarcoma., Kevin J Anderson, Aaron C Tan, Jonathon Parkinson, Michael Back, Marina Kastelan, Allison Newey, Janice Brewer, Helen Wheeler, Amanda L Hudson, Samirkumar B Amin, Kevin C Johnson, Floris P Barthel, Roel G W Verhaak, Mustafa Khasraw

Faculty Research 2020

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence …

Circrnas Expressed In Human Peripheral Blood Are Associated With Human Aging Phenotypes, Cellular Senescence And Mouse Lifespan., Shahnaz Haque, Ryan M Ames, Karen Moore, Luke C Pilling, Luanne L. Peters, Stefania Bandinelli, Luigi Ferrucci, Lorna W Harries

Faculty Research 2020

Circular RNAs (circRNAs) are an emerging class of non-coding RNA molecules that are thought to regulate gene expression and human disease. Despite the observation that circRNAs are known to accumulate in older organisms and have been reported in cellular senescence, their role in aging remains relatively unexplored. Here, we have assessed circRNA expression in aging human blood and followed up age-associated circRNA in relation to human aging phenotypes, mammalian longevity as measured by mouse median strain lifespan and cellular senescence in four different primary human cell types. We found that circRNAs circDEF6, circEP300, circFOXO3 and circFNDC3B demonstrate associations with parental …

A Comprehensive And Comparative Phenotypic Analysis Of The Collaborative Founder Strains Identifies New And Known Phenotypes., Heike Kollmus, Helmut Fuchs, Christoph Lengger, Hamed Haselimashhadi, Molly A. Bogue, Manuela A Östereicher, Marion Horsch, Thure Adler, Juan Antonio Aguilar-Pimentel, Oana Veronica Amarie, Lore Becker, Johannes Beckers, Julia Calzada-Wack, Lillian Garrett, Wolfgang Hans, Sabine M Hölter, Tanja Klein-Rodewald, Holger Maier, Philipp Mayer-Kuckuk, Gregor Miller, Kristin Moreth, Frauke Neff, Birgit Rathkolb, Ildikó Rácz, Jan Rozman, Nadine Spielmann, Irina Treise, Dirk Busch, Jochen Graw, Thomas Klopstock, Eckhard Wolf, Wolfgang Wurst, Ali Önder Yildirim, Jeremy Mason, Arturo Torres, Mouse Phenome Database Team, Rudi Balling, Terry Mehaan, Valerie Gailus-Durner, Klaus Schughart, Martin Hrabě De Angelis

Faculty Research 2020

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the …

Human And Mouse Essentiality Screens As A Resource For Disease Gene Discovery., Pilar Cacheiro, Violeta Muñoz-Fuentes, Stephen A. Murray, Mary E Dickinson, Maja Bucan, Lauryl M J Nutter, Kevin A Peterson, Hamed Haselimashhadi, Ann M Flenniken, Hugh Morgan, Henrik Westerberg, Tomasz Konopka, Chih-Wei Hsu, Audrey Christiansen, Denise G Lanza, Arthur L Beaudet, Jason D Heaney, Helmut Fuchs, Valerie Gailus-Durner, Tania Sorg, Jan Prochazka, Vendula Novosadova, Christopher J Lelliott, Hannah Wardle-Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedlacek, David J Adams, John R Seavitt, Glauco Tocchini-Valentini, Fabio Mammano, Robert E Braun, Colin Mckerlie, Yann Herault, Martin Hrabě De Angelis, Ann-Marie Mallon, K C Kent Lloyd, Steve D M Brown, Helen Parkinson, Terrence F Meehan, Damian Smedley, Genomics England Research Consortium, International Mouse Phenotyping Consortium

Faculty Research 2020

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, …

Transplanting Cells From Old But Not Young Donors Causes Physical Dysfunction In Older Recipients., Binsheng Wang, Zukai Liu, Vicky P Chen, Lichao Wang, Christina L Inman, Yueying Zhou, Chun Guo, Tamar Tchkonia, David W Rowe, George A Kuchel, Paul Robson, James L Kirkland, Ming Xu

Faculty Research 2020

Adipose-derived mesenchymal stem cell (ADSC)-based regenerative therapies have shown potential for use in many chronic diseases. Aging diminishes stem cell regenerative potential, yet it is unknown whether stem cells from aged donors cause adverse effects in recipients. ADSCs can be obtained using minimally invasive approaches and possess low immunogenicity. Nevertheless, we found that transplanting ADSCs from old donors, but not those from young donors, induces physical dysfunction in older recipient mice. Using single-cell transcriptomic analysis, we identified a naturally occurring senescent cell-like population in ADSCs primarily from old donors that resembles in vitro-generated senescent cells with regard to a number …

Astrocyte Support For Oligodendrocyte Differentiation Can Be Conveyed Via Extracellular Vesicles But Diminishes With Age., Cory M Willis, Alexandra M Nicaise, Ernesto R Bongarzone, Maria Givogri, Cory R Reiter, Olivia Heintz, Evan R Jellison, Pearl A Sutter, Gregg Tehennepe, Guruprasad Ananda, Anthony T Vella, Stephen J Crocker

Faculty Research 2020

The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte …

Discovery Of A New Predominant Cytosine Dna Modification That Is Linked To Gene Expression In Malaria Parasites., Elie Hammam, Guruprasad Ananda, Ameya Sinha, Christine Scheidig-Benatar, Mylene Bohec, Peter R Preiser, Peter C Dedon, Artur Scherf, Shruthi S Vembar

Faculty Research 2020

DNA cytosine modifications are key epigenetic regulators of cellular processes in mammalian cells, with their misregulation leading to varied disease states. In the human malaria parasite Plasmodium falciparum, a unicellular eukaryotic pathogen, little is known about the predominant cytosine modifications, cytosine methylation (5mC) and hydroxymethylation (5hmC). Here, we report the first identification of a hydroxymethylcytosine-like (5hmC-like) modification in P. falciparum asexual blood stages using a suite of biochemical methods. In contrast to mammalian cells, we report 5hmC-like levels in the P. falciparum genome of 0.2-0.4%, which are significantly higher than the methylated cytosine (mC) levels of 0.01-0.05%. Immunoprecipitation of hydroxymethylated …

Stimulus Complexity And Mouse Strain Drive Escalation Of Operant Sensation Seeking Within And Across Sessions In C57bl/6j And Dba/2j Mice., Price E. Dickson, Guy Mittleman

Faculty Research 2020

Sensation seeking is a heritable trait that is genetically correlated with substance use; the shared genetic mechanisms underlying these traits are largely unknown. The relationship of sensation seeking and substance use has practical importance because discovering genes that drive sensation seeking can reveal genes driving substance use, and quantification of sensation seeking in mice is higher throughput and less technically challenging than quantification of volitional drug use. In order to fully understand the genetic mechanisms driving sensation seeking, it is critical to first understand the nongenetic factors driving sensation seeking. In the present study, we used the operant sensation seeking …

Mouse Phenome Database: A Data Repository And Analysis Suite For Curated Primary Mouse Phenotype Data., Molly A. Bogue, Vivek M. Philip, David O Walton, Stephen C. Grubb, Matthew H Dunn, Georgi Kolishovski, Jake Emerson, Gaurab Mukherjee, Timothy M Stearns, Hao He, Vinita Sinha, Beena Kadakkuzha, Govindarajan Kunde-Ramamoorthy, Elissa J Chesler

Faculty Research 2020

The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely accessed and highly functional data repository housing primary phenotype data for the laboratory mouse accessible via APIs and providing tools to analyze and visualize those data. Data come from investigators around the world and represent a broad scope of phenotyping endpoints and disease-related traits in naïve mice and those exposed to drugs, environmental agents or other treatments. MPD houses rigorously curated per-animal data with detailed protocols. Public ontologies and controlled vocabularies are used for annotation. In addition to phenotype tools, genetic analysis tools enable users to integrate and interpret genome-phenome relations …

The Monarch Initiative In 2019: An Integrative Data And Analytic Platform Connecting Phenotypes To Genotypes Across Species., Kent A Shefchek, Nomi L Harris, Michael Gargano, Nicolas Matentzoglu, Deepak Unni, Matthew Brush, Daniel Keith, Tom Conlin, Nicole Vasilevsky, Xingmin Aaron Zhang, James P Balhoff, Larry Babb, Susan M. Bello, Hannah Blau, Yvonne Bradford, Seth Carbon, Leigh Carmody, Lauren E Chan, Valentina Cipriani, Alayne Cuzick, Maria D Rocca, Nathan Dunn, Shahim Essaid, Petra Fey, Chris Grove, Jean-Phillipe Gourdine, Ada Hamosh, Midori Harris, Ingo Helbig, Maureen Hoatlin, Marcin Joachimiak, Simon Jupp, Kenneth B Lett, Suzanna E Lewis, Craig Mcnamara, Zoë M Pendlington, Clare Pilgrim, Tim Putman, Vida Ravanmehr, Justin Reese, Erin Riggs, Sofia Robb, Paola Roncaglia, James Seager, Erik Segerdell, Morgan Similuk, Andrea L Storm, Courtney Thaxon, Anne Thessen, Julius O B Jacobsen, Julie A Mcmurry, Tudor Groza, Sebastian Köhler, Damian Smedley, Peter N Robinson, Christopher J Mungall, Melissa A Haendel, Monica C Munoz-Torres, David Osumi-Sutherland

Faculty Research 2020

In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven't been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search. We develop many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery …

Genetic Interactions Affect Lung Function In Patients With Systemic Sclerosis., Anna L. Tyler, J Matthew Mahoney, Gregory W. Carter

Faculty Research 2020

Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. The most common cause of death in people with SSc is lung disease, but the pathogenesis of lung disease in SSc is insufficiently understood to devise specific treatment strategies. Developing targeted treatments requires not only the identification of molecular processes involved in SSc-associated lung disease, but also understanding of how these processes interact to drive pathology. One potentially powerful approach is to identify alleles that interact genetically to influence lung outcomes in patients with SSc. Analysis of interactions, rather than individual …

Methods For Comparative Chia-Pet And Hi-C Data Analysis., Dan Capurso, Zhonghui Tang, Yijun Ruan

Faculty Research 2020

The three-dimensional architecture of chromatin in the nucleus is important for genome regulation and function. Advanced high-throughput sequencing-based methods have been developed for capturing chromatin interactions (Hi-C, genome-wide chromosome conformation capture) or enriching for those involving a specific protein (ChIA-PET, chromatin interaction analysis with paired-end tag sequencing). There is widespread interest in utilizing and interpreting ChIA-PET and Hi-C. We review methods for comparative ChIA-PET and Hi-C data analysis and visualization. The topics reviewed include: downloading ChIA-PET and Hi-C data from the ENCODE and 4DN portals; processing ChIA-PET data using ChIA-PIPE; processing Hi-C data using Juicer or distiller and cooler; viewing …

Gxd's Rna-Seq And Microarray Experiment Search: Using Curated Metadata To Reliably Find Mouse Expression Studies Of Interest., Constance M. Smith, James W Godwin, Richard M. Baldarelli, Jonathan S Beal, Olin Blodgett, Sharon C Giannatto, Joel E Richardson, Martin Ringwald

Faculty Research 2020

The Gene Expression Database (GXD), an extensive community resource of curated expression information for the mouse, has developed an RNA-Seq and Microarray Experiment Search (http://www.informatics.jax.org/gxd/htexp_index). This tool allows users to quickly and reliably find specific experiments in ArrayExpress and the Gene Expression Omnibus (GEO) that study endogenous gene expression in wild-type and mutant mice. Standardized metadata annotations, curated by GXD, allow users to specify the anatomical structure, developmental stage, mutated gene, strain and sex of samples of interest, as well as the study type and key parameters of the experiment. These searches, powered by controlled vocabularies and ontologies, can be …

Integrating Image Caption Information Into Biomedical Document Classification In Support Of Biocuration., Xiangying Jiang, Pengyuan Li, James A. Kadin, Judith A. Blake, Martin Ringwald, Hagit Shatkay

Faculty Research 2020

Gathering information from the scientific literature is essential for biomedical research, as much knowledge is conveyed through publications. However, the large and rapidly increasing publication rate makes it impractical for researchers to quickly identify all and only those documents related to their interest. As such, automated biomedical document classification attracts much interest. Such classification is critical in the curation of biological databases, because biocurators must scan through a vast number of articles to identify pertinent information within documents most relevant to the database. This is a slow, labor-intensive process that can benefit from effective automation.

We present a document classification …

Improving Preclinical To Clinical Translation In Alzheimer's Disease Research., Stacey J Sukoff Rizzo, Andi Masters, Kristen D. Onos, Sara Quinney, Michael Sasner, Adrian Oblak, Bruce T Lamb, Paul R Territo, Model-Ad Consortium

Faculty Research 2020

Introduction: Preclinical testing in animal models is a critical component of the drug discovery and development process. While hundreds of interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments in animal models, none have confirmed efficacy in Alzheimer's disease (AD) clinical trials. Critically this lack of translation to the clinic points in part to issues with the animal models, the preclinical assays used, and lack of scientific rigor and reproducibility during execution. In an effort to improve this translation, the Preclinical Testing Core (PTC) of the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium has established a rigorous …

Automated Generation Of Gene Summaries At The Alliance Of Genome Resources., Ranjana Kishore, Valerio Arnaboldi, Ceri E Van Slyke, Juancarlos Chan, Robert S Nash, Jose M Urbano, Mary E. Dolan, Stacia R Engel, Mary Shimoyama, Paul W Sternberg, The Alliance Of Genome Resources

Faculty Research 2020

Short paragraphs that describe gene function, referred to as gene summaries, are valued by users of biological knowledgebases for the ease with which they convey key aspects of gene function. Manual curation of gene summaries, while desirable, is difficult for knowledgebases to sustain. We developed an algorithm that uses curated, structured gene data at the Alliance of Genome Resources (Alliance; www.alliancegenome.org) to automatically generate gene summaries that simulate natural language. The gene data used for this purpose include curated associations (annotations) to ontology terms from the Gene Ontology, Disease Ontology, model organism knowledgebase (MOK)-specific anatomy ontologies and Alliance orthology data. …

Deep Functional And Molecular Characterization Of A High-Risk Undifferentiated Pleomorphic Sarcoma., Noah E Berlow, Catherine S Grasso, Michael J Quist, Mingshan Cheng, Regina Gandour-Edwards, Brian S Hernandez, Joel E Michalek, Christopher Ryan, Paul Spellman, Ranadip Pal, Lynn S Million, Mark Renneker, Charles Keller

Faculty Research 2020

Nonrhabdomyosarcoma soft-tissue sarcomas (STSs) are a class of 50+ cancers arising in muscle and soft tissues of children, adolescents, and adults. Rarity of each subtype often precludes subtype-specific preclinical research, leaving many STS patients with limited treatment options should frontline therapy be insufficient. When clinical options are exhausted, personalized therapy assignment approaches may help direct patient care. Here, we report the results of an adult female STS patient with relapsed undifferentiated pleomorphic sarcoma (UPS) who self-drove exploration of a wide array of personalized Clinical Laboratory Improvement Amendments (CLIAs) level and research-level diagnostics, including state of the art genomic, proteomic,

Machine Learning-Based Automated Phenotyping Of Inflammatory Nocifensive Behavior In Mice., Janine M Wotton, Emma Peterson, Laura C. Anderson, Stephen A. Murray, Robert E Braun, Elissa J Chesler, Jacqueline K White, Vivek Kumar

Faculty Research 2020

The discovery and development of new and potentially nonaddictive pain therapeutics requires rapid, yet clinically relevant assays of nociception in preclinical models. A reliable and scalable automated scoring system for nocifensive behavior of mice in the formalin assay would dramatically lower the time and labor costs associated with experiments and reduce experimental variability. Here, we present a method that exploits machine learning techniques for video recordings that consists of three components: key point detection, per frame feature extraction using these key points, and classification of behavior using the GentleBoost algorithm. This approach to automation is flexible as different model classifiers …

Proceedings Of The Comprehensive Oncology Network Evaluating Rare Cns Tumors (Nci-Connect) Oligodendroglioma Workshop., Marta Penas-Prado, Jing Wu, Daniel P Cahill, Daniel J Brat, Joseph F Costello, Paul G Kluetz, J Gregory Cairncross, Martin Van Den Bent, Roel G W Verhaak, Orwa Aboud, Peter Burger, Susan M Chang, Christine Cordova, Raymond Y Huang, Lindsay S Rowe, Martin J B Taphoorn, Mark R Gilbert, Terri S Armstrong, Nci-Connect Oligodendr0glioma Worhshop

Faculty Research 2020

Background: Oligodendroglioma is a rare primary central nervous system (CNS) tumor with highly variable outcome and for which therapy is usually not curative. At present, little is known regarding the pathways involved with progression of oligodendrogliomas or optimal biomarkers for stratifying risk. Developing new therapies for this rare cancer is especially challenging. To overcome these challenges, the neuro-oncology community must be particularly innovative, seeking multi-institutional and international collaborations, and establishing partnerships with patients and advocacy groups thereby ensuring that each patient enrolled in a study is as informative as possible.

Methods: The mission of the National Cancer Institute's NCI-CONNECT program …

Loss Of Trp53 (P53) Accelerates Tumorigenesis And Changes The Tumor Spectrum Of Sjl/J Mice., Jane Branca, Benjamin E. Low, Ruth L. Saxl, Jennifer K Sargent, Rosalinda A. Doty, Michael V. Wiles, Beth L Dumont, Muneer G. Hasham

Faculty Research 2020

Known as the guardian of the genome, transformation-related protein 53 (TRP53) is a well -known tumor suppressor. Here, we describe a novel TRP53 deficient mouse model on a tumor prone background-SJL/J mice. The absence of TRP53 (TRP53 nullizygosity) leads to a shift in the tumor spectrum from a non-Hodgkin's-like disease to thymic lymphomas and testicular teratomas at a very rapid tumor onset averaging ~12 weeks of age. In haplotype studies, comparing tumor prone versus tumor resistant Trp53 null mouse strains, we found that other tumor suppressor, DNA repair and/or immune system genes modulate tumor incidence in TRP53 null strains, suggesting …