Digital Commons Network^™

Lifespan Benefits For The Combination Of Rapamycin Plus Acarbose And For Captopril In Genetically Heterogeneous Mice., Randy Strong, Richard A Miller, Catherine J Cheng, James F Nelson, Jonathan Gelfond, Shailaja Kesaraju Allani, Vivian Diaz, Angela Olsen Dorigatti, Jonathan Dorigatti, Elizabeth Fernandez, Andrzej Galecki, Brett Ginsburg, Karyn L Hamilton, Martin A Javors, Kerry Kornfeld, Matt Kaeberlein, Suja Kumar, David B Lombard, Marisa Lopez-Cruzan, Benjamin F Miller, Peter Rabinovitch, Peter C. Reifsnyder, Nadia Rosenthal, Molly A. Bogue, Adam B Salmon, Yousin Suh, Eric Verdin, Herbert Weissbach, John Newman, Francesca Maccchiarini, David E. Harrison

Faculty Research 2022

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice …

Advancing Clinical And Translational Research In Germ Cell Tumours (Gct): Recommendations From The Malignant Germ Cell International Consortium., Adriana Fonseca, João Lobo, Florette K Hazard, Joanna J Gell, Peter K Nicholls, Robert S Weiss, Lindsay Klosterkemper, Samuel L Volchenboum, James C Nicholson, A Lindsay Frazier, James F Amatruda, Aditya Bagrodia, Michelle Lockley, Matthew J Murray

Faculty Research 2022

Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, …

Single-Cell Rna Sequencing Reveals Molecular Features Of Heterogeneity In The Murine Retinal Pigment Epithelium., Ravi S Pandey, Mark P. Krebs, Mohan Bolisetty, Jeremy R. Charette, Juergen K. Naggert, Paul Robson, Patsy M. Nishina, Gregory W. Carter

Faculty Research 2022

Transcriptomic analysis of the mammalian retinal pigment epithelium (RPE) aims to identify cellular networks that influence ocular development, maintenance, function, and disease. However, available evidence points to RPE cell heterogeneity within native tissue, which adds complexity to global transcriptomic analysis. Here, to assess cell heterogeneity, we performed single-cell RNA sequencing of RPE cells from two young adult male C57BL/6J mice. Following quality control to ensure robust transcript identification limited to cell singlets, we detected 13,858 transcripts among 2667 and 2846 RPE cells. Dimensional reduction by principal component analysis and uniform manifold approximation and projection revealed six distinct cell populations. All …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer's Disease., Jaclyn M Eissman, Logan Dumitrescu, Emily R Mahoney, Alexandra N Smith, Shubhabrata Mukherjee, Michael L Lee, Phoebe Scollard, Seo Eun Choi, William S Bush, Corinne D Engelman, Qiongshi Lu, David W Fardo, Emily H Trittschuh, Jesse Mez, Catherine C Kaczorowski, Hector Hernandez Saucedo, Keith F Widaman, Rachel F Buckley, Michael J Properzi, Elizabeth C Mormino, Hyun Sik Yang, Theresa M Harrison, Trey Hedden, Kwangsik Nho, Shea J Andrews, Douglas Tommet, Niran Hadad, R Elizabeth Sanders, Douglas M Ruderfer, Katherine A Gifford, Xiaoyuan Zhong, Neha S Raghavan, Badri N Vardarajan, Margaret A Pericak-Vance, Lindsay A Farrer, Li San Wang, Carlos Cruchaga, Gerard D Schellenberg, Nancy J Cox, Jonathan L Haines, C Dirk Keene, Andrew J Saykin, Eric B Larson, Reisa A Sperling, Richard Mayeux, Michael L Cuccaro, David A Bennett, Julie A Schneider, Paul K Crane, Angela L Jefferson, Timothy J Hohman

Faculty Research 2022

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Antibody Responses To Sars-Cov-2 After Infection Or Vaccination In Children And Young Adults With Inflammatory Bowel Disease., Joelynn Dailey, Lina Kozhaya, Mikail Dogan, Dena Hopkins, Blaine Lapin, Katherine Herbst, Michael Brimacombe, Kristen Grandonico, Fatih Karabacak, John Schreiber, Bruce Tsan-Liang Liang, Juan C Salazar, Derya Unutmaz, Jeffrey S Hyams

Faculty Research 2022

BACKGROUND: Characterization of neutralization antibodies to SARS-CoV-2 infection or vaccination in children and young adults with inflammatory bowel disease (IBD) receiving biologic therapies is crucial.

METHODS: We performed a prospective longitudinal cohort study evaluating SARS-CoV-2 spike protein receptor binding domain (S-RBD) IgG positivity along with consistent clinical symptoms in patients with IBD receiving infliximab or vedolizumab. Serum was also obtained following immunization with approved vaccines. The IgG antibody to the spike protein binding domain of SARS-CoV-2 was assayed with a fluorescent bead-based immunoassay that takes advantage of the high dynamic range of fluorescent molecules using flow cytometry. A sensitive and …

Effects Of Paternal High-Fat Diet And Maternal Rearing Environment On The Gut Microbiota And Behavior., Austin C Korgan, Christine L Foxx, Heraa Hashmi, Saydie A Sago, Christopher E Stamper, Jared D Heinze, Elizabeth O'Leary, Jillian L King, Tara S Perrot, Christopher A Lowry, Ian C G Weaver

Faculty Research 2022

Exposing a male rat to an obesogenic high-fat diet (HFD) influences attractiveness to potential female mates, the subsequent interaction of female mates with infant offspring, and the development of stress-related behavioral and neural responses in offspring. To examine the stomach and fecal microbiome's potential roles, fecal samples from 44 offspring and stomach samples from offspring and their fathers were collected and bacterial community composition was studied by 16 small subunit ribosomal RNA (16S rRNA) gene sequencing. Paternal diet (control, high-fat), maternal housing conditions (standard or semi-naturalistic housing), and maternal care (quality of nursing and other maternal behaviors) affected the within-subjects …

Genome-Wide Transcript And Protein Analysis Highlights The Role Of Protein Homeostasis In The Aging Mouse Heart., Isabela Gerdes Gyuricza, Joel M Chick, Gregory R Keele, Andrew Deighan, Steven C. Munger, Ron Korstanje, Steven P Gygi, Gary Churchill

Faculty Research 2022

Investigation of the molecular mechanisms of aging in the human heart is challenging because of confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyze transcriptome and proteome data from 185 genetically diverse male and female mice at ages 6, 12, and 18 mo to characterize molecular changes that occur in the …

Functional Replacement Of Myostatin With Gdf-11 In The Germline Of Mice., Se-Jin Lee, Adam Lehar, Renata Rydzik, Daniel W Youngstrom, Shalender Bhasin, Yewei Liu, Emily L Germain-Lee

Faculty Research 2022

BACKGROUND: Myostatin (MSTN) is a transforming growth factor-ß superfamily member that acts as a major regulator of skeletal muscle mass. GDF-11, which is highly related to MSTN, plays multiple roles during embryonic development, including regulating development of the axial skeleton, kidneys, nervous system, and pancreas. As MSTN and GDF-11 share a high degree of amino acid sequence identity, behave virtually identically in cell culture assays, and utilize similar regulatory and signaling components, a critical question is whether their distinct biological functions result from inherent differences in their abilities to interact with specific regulatory and signaling components or whether their distinct …

Comprehensive Analysis Of Alternative Splicing In Gastric Cancer Identifies Epithelial-Mesenchymal Transition Subtypes Associated With Survival., Yukyung Jun, Yun-Suhk Suh, Sunghee Park, Jieun Lee, Jong-Il Kim, Sanghyuk Lee, Wan-Ping Lee, Olga Anczuków, Han-Kwang Yang, Charles Lee

Faculty Research 2022

Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer have not been comprehensively characterized. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa, identifying and experimentally validating eight splicing events that can classify all gastric cancers into three subtypes: epithelial-splicing (EpiS), mesenchymal-splicing (MesS), and hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial-mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in MesS and EpiS tumors, respectively. A simple classifier based only on …

Single-Cell Multi-Omics Reveals Dyssynchrony Of The Innate And Adaptive Immune System In Progressive Covid-19., Avraham Unterman, Tomokazu S Sumida, Nima Nouri, Xiting Yan, Amy Y Zhao, Victor Gasque, Jonas C Schupp, Hiromitsu Asashima, Yunqing Liu, Carlos Cosme, Wenxuan Deng, Ming Chen, Micha Sam Brickman Raredon, Kenneth B Hoehn, Guilin Wang, Zuoheng Wang, Giuseppe Deiuliis, Neal G Ravindra, Ningshan Li, Christopher Castaldi, Patrick Wong, John Fournier, Santos Bermejo, Lokesh Sharma, Arnau Casanovas-Massana, Chantal B F Vogels, Anne L Wyllie, Nathan D Grubaugh, Anthony Melillo, Hailong Meng, Yan Stein, Maksym Minasyan, Subhasis Mohanty, William E Ruff, Inessa Cohen, Khadir Raddassi, Laura E Niklason, Albert I Ko, Ruth R Montgomery, Shelli F Farhadian, Akiko Iwasaki, Albert C Shaw, David Van Dijk, Hongyu Zhao, Steven H Kleinstein, David A Hafler, Naftali Kaminski, Charles S Dela Cruz

Faculty Research 2022

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100A

Causes Of Death And Conditional Survival Estimates Of Long-Term Lung Cancer Survivors., Qun Zhang, Yuan Dai, Hongda Liu, Wenkui Sun, Yuming Huang, Zheng Gong, Shanlin Dai, Hui Kong, Weiping Xie

Faculty Research 2022

INTRODUCTION: Lung cancer ranks the leading cause of cancer-related death worldwide. This retrospective cohort study was designed to determine time-dependent death hazards of diverse causes and conditional survival of lung cancer.

METHODS: We collected 816,436 lung cancer cases during 2000-2015 in the SEER database, after exclusion, 612,100 cases were enrolled for data analyses. Cancer-specific survival, overall survival and dynamic death hazard were assessed in this study. Additionally, based on the FDA approval time of Nivolumab in 2015, we evaluated the effect of immunotherapy on metastatic patients' survival by comparing cases in 2016-2018 (immunotherapy era, n=7135) and those in 2013-2016 (non-immunotherapy …