Medicine and Health Sciences Commons^™

The National Covid Cohort Collaborative (N3c): Rationale, Design, Infrastructure, And Deployment., Melissa A Haendel, Christopher G Chute, Tellen D Bennett, David A Eichmann, Justin Guinney, Warren A Kibbe, Philip R O Payne, Emily R Pfaff, Peter N Robinson, Joel H Saltz, Heidi Spratt, Christine Suver, John Wilbanks, Adam B Wilcox, Andrew E Williams, Chunlei Wu, Clair Blacketer, Robert L Bradford, James J Cimino, Marshall Clark, Evan W Colmenares, Patricia A Francis, Davera Gabriel, Alexis Graves, Raju Hemadri, Stephanie S Hong, George Hripscak, Dazhi Jiao, Jeffrey G Klann, Kristin Kostka, Adam M Lee, Harold P Lehmann, Lora Lingrey, Robert T Miller, Michele Morris, Shawn N Murphy, Karthik Natarajan, Matvey B Palchuk, Usman Sheikh, Harold Solbrig, Shyam Visweswaran, Anita Walden, Kellie M Walters, Griffin M Weber, Xiaohan Tanner Zhang, Richard L Zhu, Benjamin Amor, Andrew T Girvin, Amin Manna, Nabeel Qureshi, Michael G Kurilla, Sam G Michael, Lili M Portilla, Joni L Rutter, Christopher P Austin, Ken R Gersing

Faculty Research 2021

OBJECTIVE: Coronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers.

MATERIALS AND METHODS: The Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We …

Multiwalled Carbon Nanotubes Co-Delivering Sorafenib And Epidermal Growth Factor Receptor Sirna Enhanced Tumor-Suppressing Effect On Liver Cancer., Zhili Wen, Yuliang Feng, Youwen Hu, Lingyan Lian, Hongyan Huang, Li Guo, Shanwen Chen, Qian Yang, Moran Zhang, Lijun Wan, Kedong Xu, Degejirifu, Xiaohua Yan

Faculty Research 2021

OBJECTIVE: This study aimed to investigate the effects of multiwalled carbon nanotubes (MWNTs) co-delivering sorafenib (Sor) and epidermal growth factor receptor (EGFR) siRNA (MWNT/Sor/siRNA) on tumor growth in liver cancer (LC).

RESULTS: MWNT/Sor/siRNA was proved to possess increased Sor release, high siRNA stability, and enhanced cellular uptake. In addition, MWNT treatment has few effects on cell proliferation and apoptosis in HepG2 cells; however, MWNT/Sor/siRNA treatment significantly inhibited clone number and induced cell apoptosis, which shows a more favorable antitumor effect than MWNT/Sor and free Sor and free siRNA in HepG2 cells. Moreover MWNT/Sor/siRNA treatment has the most significant antitumor effect …

The Gene Ontology Resource: Enriching A Gold Mine., Gene Ontology Consortium, Judith A. Blake, Mary E. Dolan, Harold J. Drabkin, David P. Hill

Faculty Research 2021

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles …

Mouse Genome Database (Mgd): Knowledgebase For Mouse-Human Comparative Biology., Judith A. Blake, Richard M. Baldarelli, James A. Kadin, Joel E Richardson, Cynthia Smith, Carol J Bult, Mouse Genome Database Group

Faculty Research 2021

The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the community model organism knowledgebase for the laboratory mouse, a widely used animal model for comparative studies of the genetic and genomic basis for human health and disease. MGD is the authoritative source for biological reference data related to mouse genes, gene functions, phenotypes and mouse models of human disease. MGD is the primary source for official gene, allele, and mouse strain nomenclature based on the guidelines set by the International Committee on Standardized Nomenclature for Mice. MGD's biocuration scientists curate information from the biomedical literature and from large and small datasets contributed …

Regen Med Therapeutic Opportunities For Fighting Covid-19., Anthony Atala, Alicia Henn, Martha Lundberg, Taby Ahsan, Jordan Greenberg, Jeff Krukin, Steven Lynum, Cathleen Lutz, Kyle Cetrulo, Mohammad Albanna, Taciana Pereira, Shannon Eaker, Joshua Hunsberger

Faculty Research 2021

This perspective from a Regenerative Medicine Manufacturing Society working group highlights regenerative medicine therapeutic opportunities for fighting COVID-19. This article addresses why SARS-CoV-2 is so different from other viruses and how regenerative medicine is poised to deliver new therapeutic opportunities to battle COVID-19. We describe animal models that depict the mechanism of action for COVID-19 and that may help identify new treatments. Additionally, organoid platforms that can recapitulate some of the physiological properties of human organ systems, such as the lungs and the heart, are discussed as potential platforms that may prove useful in rapidly screening new drugs and identifying …

Molecular Estimation Of Neurodegeneration Pseudotime In Older Brains., Sumit Mukherjee, Laura Heath, Christoph Preuss, Suman Jayadev, Gwenn A Garden, Anna K Greenwood, Solveig K Sieberts, Philip L De Jager, Nilüfer Ertekin-Taner, Gregory W. Carter, Lara M Mangravite, Benjamin A Logsdon

Faculty Research 2020

The temporal molecular changes that lead to disease onset and progression in Alzheimer's disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage-or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10-5), Aβ (CERAD score, …

Genetic Variant Effects On Gene Expression In Human Pancreatic Islets And Their Implications For T2d., Ana Viñuela, Arushi Varshney, Martijn Van De Bunt, Rashmi B Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew A Brown, Michael R Erdos, João Fadista, Ola Hansson, Gad Hatem, Cédric Howald, Apoorva K Iyengar, Paul Johnson, Ulrika Krus, Patrick E Macdonald, Anubha Mahajan, Jocelyn E Manning Fox, Narisu Narisu, Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I Panousis, Anthony Payne, Michael L. Stitzel, Swarooparani Vadlamudi, Ryan Welch, Francis S Collins, Karen L Mohlke, Anna L Gloyn, Laura J Scott, Emmanouil T Dermitzakis, Leif Groop, Stephen C J Parker, Mark I Mccarthy

Faculty Research 2020

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in …

Prognostic Gene Expression Signature For High-Grade Serous Ovarian Cancer., J Millstein, T Budden, E L Goode, M S Anglesio, A Talhouk, M P Intermaggio, H S Leong, S Chen, W Elatre, B Gilks, T Nazeran, M Volchek, R C Bentley, C Wang, D S Chiu, S Kommoss, S C Y Leung, J Senz, A Lum, V Chow, H Sudderuddin, R Mackenzie, Joshy George, Aocs Group, S Fereday, J Hendley, N Traficante, H Steed, J M Koziak, M Köbel, I A Mcneish, T Goranova, D Ennis, G Macintyre, D Silva De Silva, T Ramón Y Cajal, J García-Donas, S Hernando Polo, G C Rodriguez, K L Cushing-Haugen, H R Harris, C S Greene, R A Zelaya, S Behrens, R T Fortner, P Sinn, E Herpel, J Lester, J Lubiński, O Oszurek, A Tołoczko, C Cybulski, J Menkiszak, C L Pearce, M C Pike, C Tseng, J Alsop, V Rhenius, H Song, M Jimenez-Linan, A M Piskorz, A Gentry-Maharaj, C Karpinskyj, M Widschwendter, N Singh, C J Kennedy, R Sharma, P R Harnett, B Gao, S E Johnatty, R Sayer, J Boros, S J Winham, G L Keeney, S H Kaufmann, M C Larson, H Luk, B Y Hernandez, P J Thompson, L R Wilkens, M E Carney, B Trabert, J Lissowska, L Brinton, M E Sherman, C Bodelon, S Hinsley, L A Lewsley, R Glasspool, S N Banerjee, E A Stronach, P Haluska, I Ray-Coquard, S Mahner, B Winterhoff, D Slamon, D A Levine, L E Kelemen, J Benitez, J Chang-Claude, J Gronwald, A H Wu, U Menon, M T Goodman, J M Schildkraut, N Wentzensen, R Brown, A Berchuck, G Chenevix-Trench, A Defazio, S A Gayther, M J García, M J Henderson, M A Rossing, A Beeghly-Fadiel, P A Fasching, S Orsulic, B Y Karlan, G E Konecny, D G Huntsman, D D Bowtell, J D Brenton, J A Doherty, P D P Pharoah, S J Ramus

Faculty Research 2020

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.

PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for …

Dual Roles Of Neutrophils In Metastatic Colonization Are Governed By The Host Nk Cell Status., Peishan Li, Mingyang Lu, Jiayuan Shi, Li Hua, Zheng Gong, Qing Li, Leonard D. Shultz, Guangwen Ren

Faculty Research 2020

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell …

Inter-Strain Epigenomic Profiling Reveals A Candidate Iap Master Copy In C3h Mice., Rita Rebollo, Mariana Galvão-Ferrarini, Liane Gagnier, Ying Zhang, Ardian Ferraj, Christine R Beck, Matthew C Lorincz, Dixie L Mager

Faculty Research 2020

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, …

Covid-19 Preclinical Models: Human Angiotensin-Converting Enzyme 2 Transgenic Mice., Cathleen Lutz, Leigh Maher, Charles Lee, Wonyoung Kang

Faculty Research 2020

Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and …

Ten Simple Rules For Providing Effective Bioinformatics Research Support., Judit Kumuthini, Michael Chimenti, Sven Nahnsen, Alexander Peltzer, Rebone Meraba, Ross Mcfadyen, Gordon Wells, Deanne Taylor, Mark Maienschein-Cline, Jian-Liang Li, Jyothi Thimmapuram, Radha Murthy-Karuturi, Lyndon Zass

Faculty Research 2020

Life scientists are increasingly turning to high-throughput sequencing technologies in their research programs, owing to the enormous potential of these methods. In a parallel manner, the number of core facilities that provide bioinformatics support are also increasing. Notably, the generation of complex large datasets has necessitated the development of bioinformatics support core facilities that aid laboratory scientists with cost-effective and efficient data management, analysis, and interpretation. In this article, we address the challenges-related to communication, good laboratory practice, and data handling-that may be encountered in core support facilities when providing bioinformatics support, drawing on our own experiences working as support …

Cellular Senescence In Progenitor Cells Contributes To Diminished Remyelination Potential In Progressive Multiple Sclerosis., Alexandra M Nicaise, Laura J Wagstaff, Cory M Willis, Carolyn Paisie, Harshpreet Chandok, Paul Robson, Valentina Fossati, Anna Williams, Stephen J Crocker

Faculty Research 2019

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2⁺ progenitor cells within white matter lesions …