Medicine and Health Sciences Commons^™

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 …