Digital Commons Network^™

Argonaut: A Web Platform For Collaborative Multi-Omic Data Visualization And Exploration, Dain R Brademan, Ian J Miller, Nicholas W Kwiecien, David J Pagliarini, Michael S Westphall, Joshua J Coon, Evgenia Shishkova

Open Access Publications

Researchers now generate large multi-omic datasets using increasingly mature mass spectrometry techniques at an astounding pace, facing new challenges of "Big Data" dissemination, visualization, and exploration. Conveniently, web-based data portals accommodate the complexity of multi-omic experiments and the many experts involved. However, developing these tailored companion resources requires programming expertise and knowledge of web server architecture-a substantial burden for most. Here, we describe Argonaut, a simple, code-free, and user-friendly platform for creating customizable, interactive data-hosting websites. Argonaut carries out real-time statistical analyses of the data, which it organizes into easily sharable projects. Collaborating researchers worldwide can explore the results, visualized …

Proceedings From The Fourth International Symposium On Sigma-2 Receptors: Role In Health And Disease, Nicholas J Izzo, Martí Colom-Cadena, Aladdin A Riad, Jinbin Xu, Meharvan Singh, Carmen Abate, Michael A Cahill, Tara L Spires-Jones, Wayne D Bowen, Robert H Mach, Susan M Catalano

Open Access Publications

The sigma-2 receptor (S2R) complex has been implicated in central nervous system disorders ranging from anxiety and depression to neurodegenerative disorders such as Alzheimer's disease (AD). The proteins comprising the S2R complex impact processes including autophagy, cholesterol synthesis, progesterone signaling, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. While there has been much progress in understanding the role of S2R in cellular processes and its potential therapeutic value, a great deal remains unknown. The

The Glycoprotease Cpaa Secreted By Medically Relevant Acinetobacter Species Targets Multiple O-Linked Host Glycoproteins, M Florencia Haurat, Nichollas E Scott, Gisela Di Venanzio, Juvenal Lopez, Benjamin Pluvinage, Alisdair B Boraston, Michael J Ferracane, Mario F Feldman

Open Access Publications

Glycans decorate proteins and affect their biological function, including protection against proteolytic degradation. However, pathogenic, and commensal bacteria have evolved specific glycoproteases that overcome the steric impediment posed by carbohydrates, cleaving glycoproteins precisely at their glycosylation site(s). Medically relevant

Isg15 Connects Autophagy And Ifn-Γ-Dependent Control Of Toxoplasma Gondii Infection In Human Cells, Jaya Bhushan, Joshua B Radke, Yi-Chieh Perng, Michael Mcallaster, Deborah J Lenschow, Herbert W Virgin, L David Sibley

Open Access Publications

The intracellular protozoan parasite

Alternative Splicing During The Chlamydomonas Reinhardtii Cell Cycle, Manishi Pandey, Gary D Stormo, Susan K Dutcher

Open Access Publications

Genome-wide analysis of transcriptome data in

Identifying And Validating Subtypes Within Major Psychiatric Disorders Based On Frontal-Posterior Functional Imbalance Via Deep Learning, Miao Chang, Fay Y Womer, Xiaohong Gong, Weixiong Zhang, Et Al

Open Access Publications

Converging evidence increasingly implicates shared etiologic and pathophysiological characteristics among major psychiatric disorders (MPDs), such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Examining the neurobiology of the psychotic-affective spectrum may greatly advance biological determination of psychiatric diagnosis, which is critical for the development of more effective treatments. In this study, ensemble clustering was developed to identify subtypes within a trans-diagnostic sample of MPDs. Whole brain amplitude of low-frequency fluctuations (ALFF) was used to extract the low-dimensional features for clustering in a total of 944 participants: 581 psychiatric patients (193 with SZ, 171 with BD, and 217 …

Phase 1 Study Of The Mdm2 Antagonist Ro6839921 In Patients With Acute Myeloid Leukemia, Geoffrey L Uy, Sarit Assouline, Anne-Marie Young, Steven Blotner, Brian Higgins, Lin-Chi Chen, Karen Yee

2020-Current year OA Pubs

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) …

Clonal Hematopoiesis: Mechanisms Driving Dominance Of Stem Cell Clones, Grant A Challen, Margaret A Goodell

2020-Current year OA Pubs

The discovery of clonal hematopoiesis (CH) in older individuals has changed the way hematologists and stem cell biologists view aging. Somatic mutations accumulate in stem cells over time. While most mutations have no impact, some result in subtle functional differences that ultimately manifest in distinct stem cell behaviors. With a large pool of stem cells and many decades to compete, some of these differences confer advantages under specific contexts. Approximately 20 genes are recurrently found as mutated in CH, indicating they confer some advantage. The impact of these mutations has begun to be analyzed at a molecular level by modeling …

A Molecular Understanding Of Alphavirus Entry, Autumn C. Holmes, Katherine Basore, Daved H. Fremont, Michael S. Diamond

Open Access Publications

Alphaviruses cause severe human illnesses including persistent arthritis and fatal encephalitis. As alphavirus entry into target cells is the first step in infection, intensive research efforts have focused on elucidating aspects of this pathway, including attachment, internalization, and fusion. Herein, we review recent developments in the molecular understanding of alphavirus entry both in vitro and in vivo and how these advances might enable the design of therapeutics targeting this critical step in the alphavirus life cycle.

Spontaneous Restoration Of Functional Β-Cell Mass In Obese Sm/J Mice, Mario A Miranda, Caryn Carson, Celine L St Pierre, Juan F Macias-Velasco, Jing W Hughes, Marcus Kunzmann, Heather Schmidt, Jessica P Wayhart, Heather A Lawson

Open Access Publications

Maintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J's diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J …

Neurofibromatosis 1 - Mutant Microglia Exhibit Sexually-Dimorphic Cyclic Amp-Dependent Purinergic Defects, Nirmeen Elmadany, Francesca Logiacco, Alice Buonfiglioli, Verena C Haage, Elizabeth C Wright-Jin, Alexander Schattenberg, Roxane M Papawassiliou, Helmut Kettenmann, Marcus Semtner, David H Gutmann

Open Access Publications

As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/-) mice, purinergic control of phagocytosis was only affected in male Nf1+/- mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-induced accumulation of microglial processes were also only impaired in male, but not female Nf1+/-, microglia. These defects resulted …

Rugged Landscapes: Complexity And Implementation Science, Joseph T Ornstein, Ross A Hammond, Margaret Padek, Stephanie Mazzucca, Ross C Brownson

2020-Current year OA Pubs

BACKGROUND: Mis-implementation-defined as failure to successfully implement and continue evidence-based programs-is widespread in public health practice. Yet the causes of this phenomenon are poorly understood.

METHODS: We develop an agent-based computational model to explore how complexity hinders effective implementation. The model is adapted from the evolutionary biology literature and incorporates three distinct complexities faced in public health practice: dimensionality, ruggedness, and context-specificity. Agents in the model attempt to solve problems using one of three approaches-Plan-Do-Study-Act (PDSA), evidence-based interventions (EBIs), and evidence-based decision-making (EBDM).

RESULTS: The model demonstrates that the most effective approach to implementation and quality improvement depends on the …

Adaptation Of Arginine Synthesis Among Uropathogenic Branches Of The Escherichia Coli Phylogeny Reveals Adjustment To The Urinary Tract Habitat, Michael E Hibbing, Karen W Dodson, Vasilios Kalas, Swaine L Chen, Scott J Hultgren

Open Access Publications

Urinary tract infections (UTIs) are predominantly caused by uropathogenic

Tissue-Specific Usage Of Transposable Element-Derived Promoters In Mouse Development, Benpeng Miao, Shuhua Fu, Cheng Lyu, Paul Gontarz, Ting Wang, Bo Zhang

2020-Current year OA Pubs

BACKGROUND: Transposable elements (TEs) are a significant component of eukaryotic genomes and play essential roles in genome evolution. Mounting evidence indicates that TEs are highly transcribed in early embryo development and contribute to distinct biological functions and tissue morphology.

RESULTS: We examine the epigenetic dynamics of mouse TEs during the development of five tissues: intestine, liver, lung, stomach, and kidney. We found that TEs are associated with over 20% of open chromatin regions during development. Close to half of these accessible TEs are only activated in a single tissue and a specific developmental stage. Most accessible TEs are rodent-specific. Across …

Understanding The Impact Of Antibiotic Perturbation On The Human Microbiome, Drew J Schwartz, Amy E Langdon, Gautam Dantas

2020-Current year OA Pubs

The human gut microbiome is a dynamic collection of bacteria, archaea, fungi, and viruses that performs essential functions for immune development, pathogen colonization resistance, and food metabolism. Perturbation of the gut microbiome's ecological balance, commonly by antibiotics, can cause and exacerbate diseases. To predict and successfully rescue such perturbations, first, we must understand the underlying taxonomic and functional dynamics of the microbiome as it changes throughout infancy, childhood, and adulthood. We offer an overview of the healthy gut bacterial architecture over these life stages and comment on vulnerability to short and long courses of antibiotics. Second, the resilience of the …

Digenic Variants In The Fgf21 Signaling Pathway Associated With Severe Insulin Resistance And Pseudoacromegaly, Stephen I Stone, Daniel J Wegner, Jennifer A Wambach, F Sessions Cole, Fumihiko Urano, David M Ornitz

Open Access Publications

Insulin-mediated pseudoacromegaly (IMPA) is a rare disease of unknown etiology. Here we report a 12-year-old female with acanthosis nigricans, hirsutism, and acromegalic features characteristic of IMPA. The subject was noted to have normal growth hormone secretion, with extremely elevated insulin levels. Studies were undertaken to determine a potential genetic etiology for IMPA. The proband and her family members underwent whole exome sequencing. Functional studies were undertaken to validate the pathogenicity of candidate variant alleles. Whole exome sequencing identified monoallelic, predicted deleterious variants in genes that mediate fibroblast growth factor 21 (FGF21) signaling,

Integrase-Rna Interactions Underscore The Critical Role Of Integrase In Hiv-1 Virion Morphogenesis, Jennifer L. Elliott, Jenna E. Eschbach, Pratibha C. Koneru, Wen Li, Maritza Puray-Chavez, Dana Townsend, Dana Q. Lawson, Alan N. Engelman, Mamuka Kvaratskhelia, Sebla B. Kutluay

Open Access Publications

A large number of human immunodeficiency virus 1 (HIV-1) integrase (IN) alterations, referred to as class II substitutions, exhibit pleiotropic effects during virus replication. However, the underlying mechanism for the class II phenotype is not known. Here we demonstrate that all tested class II IN substitutions compromised IN-RNA binding in virions by one of the three distinct mechanisms: (i) markedly reducing IN levels thus precluding the formation of IN complexes with viral RNA; (ii) adversely affecting functional IN multimerization and consequently impairing IN binding to viral RNA; and (iii) directly compromising IN-RNA interactions without substantially affecting IN levels or functional …

Interplay Of Rfx Transcription Factors 1, 2 And 3 In Motile Ciliogenesis, Sylvain Lemeille, Marie Paschaki, Dominique Baas, Laurette Morlé, Jean-Luc Duteyrat, Aouatef Ait-Lounis, Emmanuèle Barras, Fabien Soulavie, Julie Jerber, Joëlle Thomas, Yong Zhang, Michael J. Holtzman, W Stephen Kistler, Walter Reith, Bénédicte Durand

Open Access Publications

Cilia assembly is under strict transcriptional control during animal development. In vertebrates, a hierarchy of transcription factors (TFs) are involved in controlling the specification, differentiation and function of multiciliated epithelia. RFX TFs play key functions in the control of ciliogenesis in animals. Whereas only one RFX factor regulates ciliogenesis in C. elegans, several distinct RFX factors have been implicated in this process in vertebrates. However, a clear understanding of the specific and redundant functions of different RFX factors in ciliated cells remains lacking. Using RNA-seq and ChIP-seq approaches we identified genes regulated directly and indirectly by RFX1, RFX2 and RFX3 …

Chamber-Specific Transcriptional Responses In Atrial Fibrillation, Catherine E Lipovsky, Jesus Jimenez, Qiusha Guo, Gang Li, Tiankai Yin, Stephanie C Hicks, Somya Bhatnagar, Kentaro Takahashi, David M Zhang, Brittany D Brumback, Uri Goldsztejn, Rangarajan D Nadadur, Carlos Perez-Cervantez, Ivan P Moskowitz, Shaopeng Liu, Bo Zhang, Stacey L Rentschler

Open Access Publications

Atrial fibrillation (AF) is the most common cardiac arrhythmia, yet the molecular signature of the vulnerable atrial substrate is not well understood. Here, we delineated a distinct transcriptional signature in right versus left atrial cardiomyocytes (CMs) at baseline and identified chamber-specific gene expression changes in patients with a history of AF in the setting of end-stage heart failure (AF+HF) that are not present in heart failure alone (HF). We observed that human left atrial (LA) CMs exhibited Notch pathway activation and increased ploidy in AF+HF but not in HF alone. Transient activation of Notch signaling within adult CMs in a …

Etv6 Germline Mutations Cause Hdac3/Ncor2 Mislocalization And Upregulation Of Interferon Response Genes, Marlie H Fisher, Gregory D Kirkpatrick, Brett Stevens, Courtney Jones, Michael Callaghan, Madhvi Rajpurkar, Joy Fulbright, Megan A Cooper, Jesse Rowley, Christopher C Porter, Arthur Gutierrez-Hartmann, Kenneth Jones, Craig Jordan, Eric M Pietras, Jorge Di Paola

Open Access Publications

ETV6 is an ETS family transcription factor that plays a key role in hematopoiesis and megakaryocyte development. Our group and others have identified germline mutations in ETV6 resulting in autosomal dominant thrombocytopenia and predisposition to malignancy; however, molecular mechanisms defining the role of ETV6 in megakaryocyte development have not been well established. Using a combination of molecular, biochemical, and sequencing approaches in patient-derived PBMCs, we demonstrate abnormal cytoplasmic localization of ETV6 and the HDAC3/NCOR2 repressor complex that led to overexpression of HDAC3-regulated interferon response genes. This transcriptional dysregulation was also reflected in patient-derived platelet transcripts and drove aberrant proplatelet formation …

Inherited Risk For Autism Through Maternal And Paternal Lineage, Dan Bai, Natasha Marrus, Benjamin Hon Kei Yip, Abraham Reichenberg, John N Constantino, Sven Sandin

2020-Current year OA Pubs

BACKGROUND: Autism spectrum disorder (ASD) is highly familial, with a positively skewed male-to-female ratio that is purported to arise from the so-called female protective effect. A serious implication of a female protective effect is that familial ASD liability would be expected to aggregate asymptomatically in sisters of affected probands, who would incur elevated rates of ASD among their offspring. Currently, there exist no data on second-generation recurrence rates among families affected by ASD.

METHODS: We analyzed data from the Swedish National Patient Register and the Multi-Generation Register for a cohort of children born between 2003 and 2012. ASD was ascertained …

Swell1 Regulates Skeletal Muscle Cell Size, Intracellular Signaling, Adiposity And Glucose Metabolism, Ashutosh Kumar, Litao Xie, Chau My Ta, Antentor O Hinton, Susheel K Gunasekar, Rachel A Minerath, Karen Shen, Joshua M Maurer, Chad E Grueter, E Dale Abel, Gretchen Meyer, Rajan Sah

2020-Current year OA Pubs

Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 (

Anti-Human Trem2 Induces Microglia Proliferation And Reduces Pathology In An Alzheimer's Disease Model, Shoutang Wang, Carla M. Yuede, Susan Gilfillan, Marco Colonna, Et Al

Open Access Publications

TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid β (Aβ) accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in …

Higher Csf Strem2 And Microglia Activation Are Associated With Slower Rates Of Beta-Amyloid Accumulation, Michael Ewers, Laura Piccio, Carlos Cruchaga, Et Al

Open Access Publications

Microglia activation is the brain's major immune response to amyloid plaques in Alzheimer's disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid-beta (Aβ) accumulation remains unclear. To address this question, we pursued a two-pronged translational approach. Firstly, in non-demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross-sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated …

Amygdalin Promotes Fracture Healing Through Tgf- Β/Smad Signaling In Mesenchymal Stem Cells, Jun Ying, Jie Shen, Et Al

Open Access Publications

No abstract provided.

Bypass Of Dna Interstrand Crosslinks By A Rev1-Dna Polymerase Ζ Complex, Rachel Bezalel-Buch, Young K. Cheun, Upasana Roy, Orlando D. Schärer, Peter M. Burgers

Open Access Publications

DNA polymerase ζ (Pol ζ) and Rev1 are essential for the repair of DNA interstrand crosslink (ICL) damage. We have used yeast DNA polymerases η, ζ and Rev1 to study translesion synthesis (TLS) past a nitrogen mustard-based interstrand crosslink (ICL) with an 8-atom linker between the crosslinked bases. The Rev1-Pol ζ complex was most efficient in complete bypass synthesis, by 2-3 fold, compared to Pol ζ alone or Pol η. Rev1 protein, but not its catalytic activity, was required for efficient TLS. A dCMP residue was faithfully inserted across the ICL-G by Pol η, Pol ζ, and Rev1-Pol ζ. Rev1-Pol …

Severe Immunosuppression And Not A Cytokine Storm Characterizes Covid-19 Infections, Kenneth E Remy, Monty Mazer, David A Striker, Ali H Ellebedy, Andrew H Walton, Jacqueline Unsinger, Teresa M Blood, Philip A Mudd, Daehan J Yi, Daniel A Mannion, Dale F Osborne, R Scott Martin, Nitin J Anand, James P Bosanquet, Jane Blood, Anne M Drewry, Charles C Caldwell, Isaiah R Turnbull, Scott C Brakenridge, Lyle L Moldwawer, Richard S Hotchkiss

Open Access Publications

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-ɣ …

A Simplified Quantitative Real-Time Pcr Assay For Monitoring Sars-Cov-2 Growth In Cell Culture, Christian Shema Mugisha, Hung R Vuong, Maritza Puray-Chavez, Adam L Bailey, Julie M Fox, Rita E Chen, Alex W Wessel, Jason M Scott, Houda H Harastani, Adrianus C M Boon, Haina Shin, Sebla B Kutluay

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions within just a few months, causing severe respiratory disease and mortality. Assays to monitor SARS-CoV-2 growth

Malignant Cell-Specific Cxcl14 Promotes Tumor Lymphocyte Infiltration In Oral Cavity Squamous Cell Carcinoma, Anuraag Parikh, Juneho Shin, William Faquin, Derrick T Lin, Itay Tirosh, John B Sunwoo, Sidharth V Puram

Open Access Publications

OBJECTIVES: To explore lymphocyte infiltration as a potential mechanism behind CXCL14-mediated tumor growth suppression in oral cavity squamous cell carcinoma (OSCC).

METHODS: We analyzed single cell RNA-sequencing (scRNA-seq) data from OSCC to identify expression changes among malignant cells in lymph nodes (LN) versus primary tumors. CXCL14 expression in murine OSCC cell lines was quantified using qRT-PCR. Short hairpin RNA knockdown of CXCL14 was performed in mouse oral cavity (MOC)1 cells, and CXCL14 overexpression was performed in MOC2 cells. Cells in each condition were injected into C57BL/6 mice with and without T cell depletion, and tumor volume was measured. At 30 …

Co-Clinical Imaging Resource Program (Cirp): Bridging The Translational Divide To Advance Precision Medicine, Kooresh I. Shoghi, Richard Laforest, Daniel S. Marcus, Et Al

Open Access Publications

The National Institutes of Health's (National Cancer Institute) precision medicine initiative emphasizes the biological and molecular bases for cancer prevention and treatment. Importantly, it addresses the need for consistency in preclinical and clinical research. To overcome the translational gap in cancer treatment and prevention, the cancer research community has been transitioning toward using animal models that more fatefully recapitulate human tumor biology. There is a growing need to develop best practices in translational research, including imaging research, to better inform therapeutic choices and decision-making. Therefore, the National Cancer Institute has recently launched the Co-Clinical Imaging Research Resource Program (CIRP). Its …