Medicine and Health Sciences Commons^™

New Statistical Method Identifies Cytokines That Distinguish Stool Microbiomes., Dake Yang, Jethro Johnson, Xin Zhou, Elena Deych, Berkley Shands, Blake Hanson, Erica Sodergren, George M. Weinstock, William D Shannon

Faculty Research 2019

Regressing an outcome or dependent variable onto a set of input or independent variables allows the analyst to measure associations between the two so that changes in the outcome can be described by and predicted by changes in the inputs. While there are many ways of doing this in classical statistics, where the dependent variable has certain properties (e.g., a scalar, survival time, count), little progress on regression where the dependent variable are microbiome taxa counts has been made that do not impose extremely strict conditions on the data. In this paper, we propose and apply a new regression model …

Genetic Perturbations Of Disease Risk Genes In Mice Capture Transcriptomic Signatures Of Late-Onset Alzheimer's Disease., Ravi S Pandey, Leah C. Graham, Asli Uyar, Christoph Preuss, Gareth R Howell, Gregory W. Carter

Faculty Research 2019

BACKGROUND: New genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer's disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease.

METHODS: We performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; …

Urolithiasis Is A Risk Factor For Uroseptic Shock And Acute Kidney Injury In Patients With Urinary Tract Infection., Chih-Yen Hsiao, Tsung-Hsien Chen, Yi-Chien Lee, Meng-Chang Hsiao, Peir-Haur Hung, Yih-Yuan Chen, Ming-Cheng Wang

Faculty Research 2019

Urinary tract infection (UTI) is a common complication in patients with urolithiasis. This study aimed to compare clinical manifestations and treatment outcomes among UTI patients with or without urolithiasis. It also focused on identifying relationships among urolithiasis, uroseptic shock, and acute kidney injury (AKI). This retrospective study enrolled hospitalized UTI patients who underwent imaging in an acute care setting from January 2006 to March 2015. Of 662 participants enrolled, 113 (17.1%) had urolithiasis, 107 (16.2%) developed uroseptic shock, and 184 (27.8%) developed AKI. A multivariate logistic regression analysis showed that in UTI patients, urolithiasis is associated with an increased risk …

Estimating Heritability And Genetic Correlations From Large Health Datasets In The Absence Of Genetic Data., Gengjie Jia, Yu Li, Hanxin Zhang, Ishanu Chattopadhyay, Anders Boeck Jensen, David R Blair, Lea Davis, Peter N Robinson, Torsten Dahlén, Søren Brunak, Mikael Benson, Gustaf Edgren, Nancy J Cox, Xin Gao, Andrey Rzhetsky

Faculty Research 2019

Typically, estimating genetic parameters, such as disease heritability and between-disease genetic correlations, demands large datasets containing all relevant phenotypic measures and detailed knowledge of family relationships or, alternatively, genotypic and phenotypic data for numerous unrelated individuals. Here, we suggest an alternative, efficient estimation approach through the construction of two disease metrics from large health datasets: temporal disease prevalence curves and low-dimensional disease embeddings. We present eleven thousand heritability estimates corresponding to five study types: twins, traditional family studies, health records-based family studies, single nucleotide polymorphisms, and polygenic risk scores. We also compute over six hundred thousand estimates of genetic, environmental …

Interleukin-27 Is Essential For Type 1 Diabetes Development And Sjögren Syndrome-Like Inflammation., Ashley E Ciecko, Bardees Foda, Jennifer Y Barr, Sheela Ramanathan, Mark A Atkinson, David V. Serreze, Aron M Geurts, Scott M Lieberman, Yi-Guang Chen

Faculty Research 2019

Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27^-/- and NOD.Il27ra^-/- strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity …

Growth Differentiation Factor 11 Locally Controls Anterior-Posterior Patterning Of The Axial Skeleton., Joonho Suh, Je-Hyun Eom, Na-Kyung Kim, Kyung Mi Woo, Jeong-Hwa Baek, Hyun-Mo Ryoo, Se-Jin Lee, Yun-Sil Lee

Faculty Research 2019

Growth and differentiation factor 11 (GDF11) is a transforming growth factor β family member that has been identified as the central player of anterior-posterior (A-P) axial skeletal patterning. Mice homozygous for Gdf11 deletion exhibit severe anterior homeotic transformations of the vertebrae and craniofacial defects. During early embryogenesis, Gdf11 is expressed predominantly in the primitive streak and tail bud regions, where new mesodermal cells arise. On the basis of this expression pattern of Gdf11 and the phenotype of Gdf11 mutant mice, it has been suggested that GDF11 acts to specify positional identity along the A-P axis either by local changes in …

Comparative Analysis Of Metabolome Of Rice Seeds At Three Developmental Stages Using A Recombinant Inbred Line Population., Kang Li, Dehong Wang, Liang Gong, Yuanyuan Lyu, Hao Guo, Wei Chen, Cheng Jin, Xianqing Liu, Chuanying Fang, Jie Luo

Faculty Research 2019

Plants are considered an important food and nutrition source for humans. Despite advances in plant seed metabolomics, knowledge about the genetic and molecular bases of rice seed metabolomes at different developmental stages is still limited. Here, using Zhenshan 97 (ZS97) and Minghui 63 (MH63), we performed a widely targeted metabolic profiling in seeds during grain filling, mature seeds and germinating seeds. The diversity between MH63 and ZS97 was characterized in terms of the content of metabolites and the metabolic shifting across developmental stages. Taking advantage of the ultra-high-density genetic map of a population of 210 recombinant inbred lines (RILs) derived …

Assessment Of Bones Deficient In Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences., Lukas Altinbas, Nicole Bormann, Daniel Lehmann, Sarah Jeuthe, Dag Wulsten, Uwe Kornak, Peter N Robinson, Britt Wildemann, Georgios Kararigas

Faculty Research 2019

Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGFβ) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1^mgR/mgR mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae …

Pedia: Prioritization Of Exome Data By Image Analysis., Tzung-Chien Hsieh, Martin A Mensah, Jean T Pantel, Dione Aguilar, Omri Bar, Allan Bayat, Luis Becerra-Solano, Heidi B Bentzen, Saskia Biskup, Oleg Borisov, Oivind Braaten, Claudia Ciaccio, Marie Coutelier, Kirsten Cremer, Magdalena Danyel, Svenja Daschkey, Hilda David Eden, Koenraad Devriendt, Sandra Wilson, Sofia Douzgou, Dejan Đukić, Nadja Ehmke, Christine Fauth, Björn Fischer-Zirnsak, Nicole Fleischer, Heinz Gabriel, Luitgard Graul-Neumann, Karen W Gripp, Yaron Gurovich, Asya Gusina, Nechama Haddad, Nurulhuda Hajjir, Yair Hanani, Jakob Hertzberg, Konstanze Hoertnagel, Janelle Howell, Ivan Ivanovski, Angela Kaindl, Tom Kamphans, Susanne Kamphausen, Catherine Karimov, Hadil Kathom, Anna Keryan, Alexej Knaus, Sebastian Köhler, Uwe Kornak, Alexander Lavrov, Maximilian Leitheiser, Gholson J Lyon, Elisabeth Mangold, Purificación Marín Reina, Antonio Martinez Carrascal, Diana Mitter, Laura Morlan Herrador, Guy Nadav, Markus Nöthen, Alfredo Orrico, Claus-Eric Ott, Kristen Park, Borut Peterlin, Laura Pölsler, Annick Raas-Rothschild, Linda Randolph, Nicole Revencu, Christina Ringmann Fagerberg, Peter N Robinson, Stanislav Rosnev, Sabine Rudnik, Gorazd Rudolf, Ulrich Schatz, Anna Schossig, Max Schubach, Or Shanoon, Eamonn Sheridan, Pola Smirin-Yosef, Malte Spielmann, Eun-Kyung Suk, Yves Sznajer, Christian T Thiel, Gundula Thiel, Alain Verloes, Irena Vrecar, Dagmar Wahl, Ingrid Weber, Korina Winter, Marzena Wiśniewska, Bernd Wollnik, Ming W Yeung, Max Zhao, Na Zhu, Johannes Zschocke, Stefan Mundlos, Denise Horn, Peter M Krawitz

Faculty Research 2019

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists.

METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds.

RESULTS: …

The Alliance Of Genome Resources: Building A Modern Data Ecosystem For Model Organism Databases., Alliance Of Genome Resources Consortium, Carol J Bult, Judith A. Blake, Brian R Calvi, J. Michael Cherry, Valentina Difrancesco, Robert Fullem, Kevin L Howe, Thom Kaufman, Chris Mungall, Norbert Perrimon, Mary Shimoyama, Paul W Sternberg, Paul Thomas, Monte Westerfield

Faculty Research 2019

Model organisms are essential experimental platforms for discovering gene functions, defining protein and genetic networks, uncovering functional consequences of human genome variation, and for modeling human disease. For decades, researchers who use model organisms have relied on Model Organism Databases (MODs) and the Gene Ontology Consortium (GOC) for expertly curated annotations, and for access to integrated genomic and biological information obtained from the scientific literature and public data archives. Through the development and enforcement of data and semantic standards, these genome resources provide rapid access to the collected knowledge of model organisms in human readable and computation-ready formats that would …

The Jax Synteny Browser For Mouse-Human Comparative Genomics., Georgi Kolishovski, Anna Lamoureux, Paul Hale, Joel E Richardson, Jill M. Recla, Omoluyi Adesanya, Allen K. Simons, Govindarajan Kunde-Ramamoorthy, Carol J Bult

Faculty Research 2019

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the …

Differential Functions Of Splicing Factors In Mammary Transformation And Breast Cancer Metastasis., Sunghee Park, Mattia Brugiolo, Martin Akerman, Shipra Das, Laura M Urbanski, Adam Geier, Anil K Kesarwani, Martin Fan, Nathan Leclair, Kuan-Ting Lin, Leo Hu, Ian Hua, Joshy George, Senthil K Muthuswamy, Adrian R Krainer, Olga Anczuków

Faculty Research 2019

Misregulation of alternative splicing is a hallmark of human tumors, yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer and uncover differences and redundancies in their targets and biological functions. We identify splicing factors frequently altered in human breast tumors and assay their oncogenic functions using breast organoid models. We demonstrate that not all splicing factors affect mammary tumorigenesis in MCF-10A cells. Specifically, the upregulation of SRSF4, SRSF6, or TRA2β disrupts acinar morphogenesis and promotes cell …

Mia-Sig: Multiplex Chromatin Interaction Analysis By Signal Processing And Statistical Algorithms., Minji Kim, Meizhen Zheng, Simon Zhongyuan Tian, Byoungkoo Lee, Jeffrey Chuang, Yijun Ruan

Faculty Research 2019

The single-molecule multiplex chromatin interaction data are generated by emerging 3D genome mapping technologies such as GAM, SPRITE, and ChIA-Drop. These datasets provide insights into high-dimensional chromatin organization, yet introduce new computational challenges. Thus, we developed MIA-Sig, an algorithmic solution based on signal processing and information theory. We demonstrate its ability to de-noise the multiplex data, assess the statistical significance of chromatin complexes, and identify topological domains and frequent inter-domain contacts. On chromatin immunoprecipitation (ChIP)-enriched data, MIA-Sig can clearly distinguish the protein-associated interactions from the non-specific topological domains. Together, MIA-Sig represents a novel algorithmic framework for multiplex chromatin interaction analysis.

The Genetics Of Neuropathic Pain From Model Organisms To Clinical Application., Margarita Calvo, Alexander J Davies, Harry L Hébert, Greg A Weir, Elissa J Chesler, Nanna B Finnerup, Roy C Levitt, Blair H Smith, G Gregory Neely, Michael Costigan, David L Bennett

Faculty Research 2019

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and …

A Bayesian Mixture Model For The Analysis Of Allelic Expression In Single Cells., Kwangbom Choi, Narayanan Raghupathy, Gary Churchill

Faculty Research 2019

Allele-specific expression (ASE) at single-cell resolution is a critical tool for understanding the stochastic and dynamic features of gene expression. However, low read coverage and high biological variability present challenges for analyzing ASE. We demonstrate that discarding multi-mapping reads leads to higher variability in estimates of allelic proportions, an increased frequency of sampling zeros, and can lead to spurious findings of dynamic and monoallelic gene expression. Here, we report a method for ASE analysis from single-cell RNA-Seq data that accurately classifies allelic expression states and improves estimation of allelic proportions by pooling information across cells. We further demonstrate that combining …

Characterization Of Mucosal Dysbiosis Of Early Colonic Neoplasia., Bo-Young Hong, Takayasu Ideta, Bruno S Lemos, Yuichi Igarashi, Yuliana Tan, Michael Disiena, Allen Mo, John W Birk, Faripour Forouhar, Thomas J Devers, George M. Weinstock, Daniel W Rosenberg

Faculty Research 2019

Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesions in the colon that can be detected by high-definition chromoendoscopy with contrast dye spray. Although frequently associated with synchronous adenomas, their role in colorectal tumor development, particularly in the proximal colon, is still not clear. The goal of this study was to evaluate the profile of colon-adherent bacteria associated with proximal ACF and to investigate their relationship to the presence and subtype of synchronous polyps present throughout the colon. Forty-five subjects undergoing a screening or surveillance colonoscopy were included in this retrospective study. Bacterial cells adherent to the epithelia of …

Transcriptional Profiling Predicts Running Promotes Cerebrovascular Remodeling In Young But Not Midlife Mice., Kate E Foley, Hongtian Stanley Yang, Leah C. Graham, Gareth R Howell

Faculty Research 2019

BACKGROUND: The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer's disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood.

RESULTS: To better understand the effects of …

The Firre Locus Produces A Trans-Acting Rna Molecule That Functions In Hematopoiesis., Jordan P Lewandowski, James C Lee, Taeyoung Hwang, Hongjae Sunwoo, Jill M Goldstein, Abigail F Groff, Nydia P Chang, William Mallard, Adam Williams, Jorge Henao-Meija, Richard A Flavell, Jeannie T Lee, Chiara Gerhardinger, Amy J Wagers, John L Rinn

Faculty Research 2019

RNA has been classically known to play central roles in biology, including maintaining telomeres, protein synthesis, and in sex chromosome compensation. While thousands of long noncoding RNAs (lncRNAs) have been identified, attributing RNA-based roles to lncRNA loci requires assessing whether phenotype(s) could be due to DNA regulatory elements, transcription, or the lncRNA. Here, we use the conserved X chromosome lncRNA locus Firre, as a model to discriminate between DNA- and RNA-mediated effects in vivo. We demonstrate that (i) Firre mutant mice have cell-specific hematopoietic phenotypes, and (ii) upon exposure to lipopolysaccharide, mice overexpressing Firre exhibit increased levels of pro-inflammatory cytokines …

Evaluation Of 16s Rrna Gene Sequencing For Species And Strain-Level Microbiome Analysis., Jethro Johnson, Daniel Spakowicz, Bo-Young Hong, Lauren M Petersen, Patrick Demkowicz, Lei Chen, Shana Leopold, Blake M Hanson, Hanako O Agresta, Mark Gerstein, Erica Sodergren, George M. Weinstock

Faculty Research 2019

The 16S rRNA gene has been a mainstay of sequence-based bacterial analysis for decades. However, high-throughput sequencing of the full gene has only recently become a realistic prospect. Here, we use in silico and sequence-based experiments to critically re-evaluate the potential of the 16S gene to provide taxonomic resolution at species and strain level. We demonstrate that targeting of 16S variable regions with short-read sequencing platforms cannot achieve the taxonomic resolution afforded by sequencing the entire (~1500 bp) gene. We further demonstrate that full-length sequencing platforms are sufficiently accurate to resolve subtle nucleotide substitutions (but not insertions/deletions) that exist between …

Therapeutic Administration Of Tregitope-Human Albumin Fusion With Insulin Peptides To Promote Antigen-Specific Adaptive Tolerance Induction., Anne S De Groot, Gail Skowron, James Robert White, Christine Boyle, Guilhem Richard, David V. Serreze, William D Martin

Faculty Research 2019

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells. Among the therapies being evaluated for T1D is the restoration of regulatory T cell (Treg) activity, specifically directed toward down-modulation of beta-islet antigen-specific T effector cells. This is also known as antigen-specific adaptive tolerance induction for T1D (T1D ASATI). Tregitopes (T regulatory cell epitopes) are natural T cell epitopes derived from immunoglobulin G (IgG) that were identified in 2008 and have been evaluated in several autoimmune disease models. In the T1D ASATI studies presented here, Tregitope peptides were …

Cisplatin-Resistant Triple-Negative Breast Cancer Subtypes: Multiple Mechanisms Of Resistance., David P. Hill, Akeena Harper, Joan Malcolm, Monica Mcandrews, Susan Mockus, Sara E. Patterson, Timothy Reynolds, Erich J Baker, Carol J Bult, Elissa J Chesler, Judith A. Blake

Faculty Research 2019

BACKGROUND: Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies.

METHODS: In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated …

Genetic Background Modifies Cns-Mediated Sensorimotor Decline In The Ad-Bxd Mouse Model Of Genetic Diversity In Alzheimer's Disease., Kristen M S O'Connell, Andrew R Ouellette, Sarah M Neuner, Amy R Dunn, Catherine Kaczorowski

Faculty Research 2019

Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD-BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD-BXDs and the relationship to cognitive decline in these mice. …

Split Selectable Markers., Nathaniel L. Jillette, Menghan Du, Jacqueline Jufen Zhu, Peter Cardoz, Albert W Cheng

Faculty Research 2019

Selectable markers are widely used in transgenesis and genome editing for selecting engineered cells with a desired genotype but the variety of markers is limited. Here we present split selectable markers that each allow for selection of multiple "unlinked" transgenes in the context of lentivirus-mediated transgenesis as well as CRISPR-Cas-mediated knock-ins. Split marker gene segments fused to protein splicing elements called "inteins" can be separately co-segregated with different transgenic vectors, and rejoin via protein trans-splicing to reconstitute a full-length marker protein in host cells receiving all intended vectors. Using a lentiviral system, we create and validate 2-split Hygromycin, Puromycin, Neomycin …

Plantsimlab - A Modeling And Simulation Web Tool For Plant Biologists., S Ha, E Dimitrova, S Hoops, D Altarawy, M Ansariola, D Deb, J Glazebrook, R Hillmer, H Shahin, F Katagiri, J Mcdowell, M Megraw, J Setubal, B M Tyler, Reinhard Laubenbacher

Faculty Research 2019

BACKGROUND: At the molecular level, nonlinear networks of heterogeneous molecules control many biological processes, so that systems biology provides a valuable approach in this field, building on the integration of experimental biology with mathematical modeling. One of the biggest challenges to making this integration a reality is that many life scientists do not possess the mathematical expertise needed to build and manipulate mathematical models well enough to use them as tools for hypothesis generation. Available modeling software packages often assume some modeling expertise. There is a need for software tools that are easy to use and intuitive for experimentalists.

RESULTS: …

Functional Profiling Of Single Crispr/Cas9-Edited Human Long-Term Hematopoietic Stem Cells., Elvin Wagenblast, Maria Azkanaz, Sabrina A Smith, Lorien Shakib, Jessica L Mcleod, Gabriela Krivdova, Joana Araújo, Leonard D. Shultz, Olga I Gan, John E Dick, Eric R Lechman

Faculty Research 2019

In the human hematopoietic system, rare self-renewing multipotent long-term hematopoietic stem cells (LT-HSCs) are responsible for the lifelong production of mature blood cells and are the rational target for clinical regenerative therapies. However, the heterogeneity in the hematopoietic stem cell compartment and variable outcomes of CRISPR/Cas9 editing make functional interrogation of rare LT-HSCs challenging. Here, we report high efficiency LT-HSC editing at single-cell resolution using electroporation of modified synthetic gRNAs and Cas9 protein. Targeted short isoform expression of the GATA1 transcription factor elicit distinct differentiation and proliferation effects in single highly purified LT-HSC when analyzed with functional in vitro differentiation …

Increased Interactions And Engulfment Of Dendrites By Microglia Precede Purkinje Cell Degeneration In A Mouse Model Of Niemann Pick Type-C., Larisa Kavetsky, Kayla K Green, Bridget R Boyle, Fawad A K Yousufzai, Zachary M Padron, Sierra E Melli, Victoria L Kuhnel, Harriet M. Jackson, Rosa E Blanco, Gareth R Howell, Ileana Soto

Faculty Research 2019

Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1^nmf164 mouse cerebellum, microglia …

Bmp Signaling Mediates Glioma Stem Cell Quiescence And Confers Treatment Resistance In Glioblastoma., Rohit Sachdeva, Megan Wu, Kevin C Johnson, Hyunsoo Kim, Angela Celebre, Uswa Shahzad, Maya Srikanth Graham, John A Kessler, Jeffrey Chuang, Jason Karamchandani, Markus Bredel, Roel G W Verhaak, Sunit Das

Faculty Research 2019

Despite advances in therapy, glioblastoma remains an incurable disease with a dismal prognosis. Recent studies have implicated cancer stem cells within glioblastoma (glioma stem cells, GSCs) as mediators of therapeutic resistance and tumor progression. In this study, we investigated the role of the transforming growth factor-β (TGF-β) superfamily, which has been found to play an integral role in the maintenance of stem cell homeostasis within multiple stem cell systems, as a mediator of stem-like cells in glioblastoma. We find that BMP and TGF-β signaling define divergent molecular and functional identities in glioblastoma, and mark relatively quiescent and proliferative GSCs, respectively. …

Editorial: Long Non-Coding Rnas And Immunity., Grace J Kwon, Jorge Henao-Mejia, Adam Williams

Faculty Research 2019

No abstract provided.

Early-Life Dna Methylation Profiles Are Indicative Of Age-Related Transcriptome Changes., Niran Hadad, Dustin R Masser, Laura Blanco-Berdugo, David R Stanford, Willard M Freeman

Faculty Research 2019

BACKGROUND: Alterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions are observed with brain aging and can be prevented by anti-aging interventions, but the relationship of altered methylation to gene expression is poorly understood.

RESULTS: Paired analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers. Altered promoter methylation with aging was found to be generally un-related to …

Debutant Ios App And Gene-Disease Complexities In Clinical Genomics And Precision Medicine., Zeeshan Ahmed, Saman Zeeshan, Ruoyun Xiong, Bruce T Liang

Faculty Research 2019

BACKGROUND: The last decade has seen a dramatic increase in the availability of scientific data, where human-related biological databases have grown not only in count but also in volume, posing unprecedented challenges in data storage, processing, analysis, exchange, and curation. Next generation sequencing (NGS) advancements have facilitated and accelerated the process of identifying genetic variations. Adopting NGS with Whole-Genome and RNA sequencing in a diagnostic context has the potential to improve disease-risk detection in support of precision medicine and drug discovery. Several bioinformatics pipelines have been developed to strengthen variant interpretation by efficiently processing and analyzing sequence data, whereas many …