Digital Commons Network^™

Astrovirus Replication In Human Intestinal Enteroids Reveals Multi-Cellular Tropism And An Intricate Host Innate Immune Landscape, Abimbola O. Kolawole, Andrew B Janowski, David Wang, Christiane E. Wobus, Et Al.

Open Access Publications

Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLB-type and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE …

Sequence Specificity Despite Intrinsic Disorder: How A Disease-Associated Val/Met Polymorphism Rearranges Tertiary Interactions In A Long Disordered Protein, Ruchi Lohia, Reza Salari, Grace Brannigan

Open Access Publications

The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica-exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and …

Phase I, Open-Label, Dose-Escalation Study Of The Safety, Pharmacokinetics, Pharmacodynamics, And Efficacy Of Gsk2879552 In Relapsed/Refractory Sclc, Todd M Bauer, Benjamin Besse, Alex Martinez-Marti, Jose Manuel Trigo, Victor Moreno, Pilar Garrido, Geraldine Ferron-Brady, Yuehui Wu, Jennifer Park, Therese Collingwood, Ryan G Kruger, Helai P Mohammad, Marc S Ballas, Arindam Dhar, Ramaswamy Govindan

Open Access Publications

INTRODUCTION: This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC.

METHODS: This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters …

Inhibition Of 4-Aminobutyrate Aminotransferase Protects Against Injury-Induced Osteoarthritis In Mice, Jie Shen, Cuicui Wang, Jun Ying, Taotao Xu, Audrey Mcalinden, Regis J. O'Keefe

Open Access Publications

Recently we demonstrated that ablation of the DNA methyltransferase enzyme, Dnmt3b, resulted in catabolism and progression of osteoarthritis (OA) in murine articular cartilage through a mechanism involving increased mitochondrial respiration. In this study, we identify 4-aminobutyrate aminotransferase (Abat) as a downstream target of Dnmt3b. Abat is an enzyme that metabolizes γ-aminobutyric acid to succinate, a key intermediate in the tricarboxylic acid cycle. We show that Dnmt3b binds to the Abat promoter, increases methylation of a conserved CpG sequence just upstream of the transcriptional start site, and inhibits Abat expression. Dnmt3b deletion in articular chondrocytes results in reduced methylation of the …

Race And Risk Of Subsequent Aggressive Breast Cancer Following Ductal Carcinoma In Situ, Ying Liu, Robert West, Jason D Weber, Graham A Colditz

Open Access Publications

BACKGROUND: General populations of black women have a higher risk of developing breast cancer negative for both estrogen receptor (ER) and progesterone receptor (PR) in comparison with white counterparts. Racial differences remain unknown in the risk of developing aggressive invasive breast cancer (IBC) that is characterized by negativity for both ER and PR (ER-PR-) or higher 21-gene recurrence scores after ductal carcinoma in situ (DCIS).

METHODS: This study identified 163,892 women (10.5% black, 9.8% Asian, and 8.6% Hispanic) with incident DCIS between 1990 and 2015 from the Surveillance, Epidemiology, and End Results data sets. Cox proportional hazards regression was used …

Vincristine And Bortezomib Use Distinct Upstream Mechanisms To Activate A Common Sarm1-Dependent Axon Degeneration Program, Stefanie Geisler, Ryan A Doan, Galen C Cheng, Aysel Cetinkaya-Fisgin, Shay X Huang, Ahmet Höke, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge …

Mechanisms Of Pathogen Invasion Into The Central Nervous System, Matthew D. Cain, Hamid Salimi, Michael S. Diamond, Robyn S. Klein

Pathology Research and Scholarship

CNS infections continue to rise in incidence in conjunction with increases in immunocompromised populations or conditions that contribute to the emergence of pathogens, such as global travel, climate change, and human encroachment on animal territories. The severity and complexity of these diseases is impacted by the diversity of etiologic agents and their routes of neuroinvasion. In this review, we present historical, clinical, and molecular concepts regarding the mechanisms of pathogen invasion of the CNS. We also discuss the structural components of CNS compartments that influence pathogen entry and recent discoveries of the pathways exploited by pathogens to facilitate CNS infections. …

Unraveling The Functional Role Of The Orphan Solute Carrier, Slc22a24 In The Transport Of Steroid Conjugates Through Metabolomic And Genome-Wide Association Studies, Sook Wah Yee, Adrian Stecula, Huan-Chieh Chien, Ling Zou, Elena V Feofanova, Marjolein Van Borselen, Kit Wun Kathy Cheung, Noha A Yousri, Karsten Suhre, Jason M Kinchen, Eric Boerwinkle, Roshanak Irannejad, Bing Yu, Kathleen M Giacomini

Faculty, Staff and Student Publications

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value

Dhx33 Interacts With Ap-2Β To Regulate Bcl-2 Gene Expression And Promote Cancer Cell Survival, Jiuling Wang, Weimin Feng, Zhen Yuan, Jason D. Weber, Yandong Zhang

Open Access Publications

The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of

Omnipresence Of Inflammasome Activities In Inflammatory Bone Diseases, Yael Alippe, Gabriel Mbalaviele

Open Access Publications

The inflammasomes are intracellular protein complexes that are assembled in response to a variety of perturbations including infections and injuries. Failure of the inflammasomes to rapidly clear the insults or restore tissue homeostasis can result in chronic inflammation. Recurring inflammation is also provoked by mutations that cause the constitutive assembly of the components of these protein platforms. Evidence suggests that chronic inflammation is a shared mechanism in bone loss associated with aging, dysregulated metabolism, autoinflammatory, and autoimmune diseases. Mechanistically, inflammatory mediators promote bone resorption while suppressing bone formation, an imbalance which over time leads to bone loss and increased fracture …

Vitamin D Status And Risk Of Incident Tuberculosis Disease: A Nested Case-Control Study, Systematic Review, And Individual-Participant Data Meta-Analysis, Omowunmi Aibana, Chuan-Chin Huang, Said Aboud, Alberto Arnedo-Pena, Mercedes C Becerra, Juan Bautista Bellido-Blasco, Ramesh Bhosale, Roger Calderon, Silvia Chiang, Carmen Contreras, Ganmaa Davaasambuu, Wafaie W Fawzi, Molly F Franke, Jerome T Galea, Daniel Garcia-Ferrer, Maria Gil-Fortuño, Barbará Gomila-Sard, Amita Gupta, Nikhil Gupte, Rabia Hussain, Jesus Iborra-Millet, Najeeha T Iqbal, Jose Vicente Juan-Cerdán, Aarti Kinikar, Leonid Lecca, Vidya Mave, Noemi Meseguer-Ferrer, Grace Montepiedra, Ferdinand M Mugusi, Olumuyiwa A Owolabi, Julie Parsonnet, Freddy Roach-Poblete, Maria Angeles Romeu-García, Stephen A Spector, Christopher R Sudfeld, Mark W Tenforde, Toyin O Togun, Rosa Yataco, Zibiao Zhang, Megan B Murray

Faculty, Staff and Student Publications

BACKGROUND: Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk.

METHODS AND FINDINGS: We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. …

Best Practices For Bioinformatic Characterization Of Neoantigens For Clinical Utility, Megan M Richters, Huiming Xia, Katie M Campbell, William E Gillanders, Obi L Griffith, Malachi Griffith

Open Access Publications

Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequencing technologies to identify neoantigens and to create personalized immunotherapies for cancer treatment. To create a personalized cancer vaccine, neoantigens must be computationally predicted from matched tumor-normal sequencing data, and then ranked according to their predicted capability in stimulating a T cell response. This candidate neoantigen prediction process involves multiple steps, including somatic mutation identification, HLA typing, peptide processing, and peptide-MHC binding prediction. The general workflow has been utilized for many preclinical and clinical …

Blood Leukocyte Dna Methylation Predicts Risk Of Future Myocardial Infarction And Coronary Heart Disease, Golareh Agha, Michael M Mendelson, Cavin K Ward-Caviness, Roby Joehanes, Tianxiao Huan, Rahul Gondalia, Elias Salfati, Jennifer A Brody, Giovanni Fiorito, Jan Bressler, Brian H Chen, Symen Ligthart, Simonetta Guarrera, Elena Colicino, Allan C Just, Simone Wahl, Christian Gieger, Amy R Vandiver, Toshiko Tanaka, Dena G Hernandez, Luke C Pilling, Andrew B Singleton, Carlotta Sacerdote, Vittorio Krogh, Salvatore Panico, Rosario Tumino, Yun Li, Guosheng Zhang, James D Stewart, James S Floyd, Kerri L Wiggins, Jerome I Rotter, Michael Multhaup, Kelly Bakulski, Steven Horvath, Philip S Tsao, Devin M Absher, Pantel Vokonas, Joel Hirschhorn, M Daniele Fallin, Chunyu Liu, Stefania Bandinelli, Eric Boerwinkle, Abbas Dehghan, Joel D Schwartz, Bruce M Psaty, Andrew P Feinberg, Lifang Hou, Luigi Ferrucci, Nona Sotoodehnia, Giuseppe Matullo, Annette Peters, Myriam Fornage, Themistocles L Assimes, Eric A Whitsel, Daniel Levy, Andrea A Baccarelli

Faculty, Staff and Student Publications

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among …

Burden Of Disease In Pediatric Patients With Hypophosphatasia: Results From The Hpp Impact Patient Survey And The Hpp Outcomes Study Telephone Interview., Eric T. Rush, Scott Moseley, Anna Petryk

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Hypophosphatasia (HPP) is a rare, inherited, metabolic bone disease caused by deficient tissue-non-specific isoenzyme of alkaline phosphatase activity that manifests as a broad range of signs/symptoms, including bone mineralization defects and systemic complications. The burden of disease is poorly characterized, particularly in children. This study aimed to characterize the patient-reported burden of disease among children with HPP using two survey instruments: the HPP Impact Patient Survey (HIPS) and the HPP Outcomes Study Telephone interview (HOST).

METHODS: Between September 2009 and June 2011, pediatric patients (aged younger than 18 years) with HPP were recruited to participate in the study via …

Advances In Gene Ontology Utilization Improve Statistical Power Of Annotation Enrichment, Eugene Waverly Hinderer Iii, Robert M. Flight, Rashmi Dubey, James N. Macleod, Hunter N. B. Moseley

Maxwell H. Gluck Equine Research Center Faculty Publications

Gene-annotation enrichment is a common method for utilizing ontology-based annotations in gene and gene-product centric knowledgebases. Effective utilization of these annotations requires inferring semantic linkages by tracing paths through edges in the ontological graph, referred to as relations. However, some relations are semantically problematic with respect to scope, necessitating their omission or modification lest erroneous term mappings occur. To address these issues, we created the Gene Ontology Categorization Suite, or GOcats—a novel tool that organizes the Gene Ontology into subgraphs representing user-defined concepts, while ensuring that all appropriate relations are congruent with respect to scoping semantics. Here, we demonstrate the …

Measurement Repeatability Of 18 F-Fdg Pet/Ct Versus 18 F-Fdg Pet/Mri In Solid Tumors Of The Pelvis, Tyler J Fraum, Kathryn J Fowler, John P Crandall, Richard A Laforest, Amber Salter, Hongyu An, Michael A Jacobs, Perry W Grigsby, Farrokh Dehdashti, Richard L Wahl

Open Access Publications

Knowledge of the within-subject variability of

Cancer Cell Population Growth Kinetics At Low Densities Deviate From The Exponential Growth Model And Suggest An Allee Effect., Kaitlyn E Johnson, Grant Howard, William Mo, Michael K Strasser, Ernesto A B F Lima, Sui Huang, Amy Brock

Articles, Abstracts, and Reports

Most models of cancer cell population expansion assume exponential growth kinetics at low cell densities, with deviations to account for observed slowing of growth rate only at higher densities due to limited resources such as space and nutrients. However, recent preclinical and clinical observations of tumor initiation or recurrence indicate the presence of tumor growth kinetics in which growth rates scale positively with cell numbers. These observations are analogous to the cooperative behavior of species in an ecosystem described by the ecological principle of the Allee effect. In preclinical and clinical models, however, tumor growth data are limited by the …

The Case For Patient Navigation In Lung Cancer Screening In Vulnerable Populations: A Systematic Review., Christine S Shusted, Julie A Barta, Michael Lake, Rickie Brawer, Brooke Ruane, Teresa E Giamboy, Baskaran Sundaram, Nathaniel R Evans, Ronald E Myers, Gregory C Kane

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

Patient navigation has been proposed to combat cancer disparities in vulnerable populations. Vulnerable populations often have poorer cancer outcomes and lower levels of screening, adherence, and treatment. Navigation has been studied in various cancers, but few studies have assessed navigation in lung cancer. Additionally, there is a lack of consistency in metrics to assess the quality of navigation programs. The authors conducted a systematic review of published cancer screening studies to identify quality metrics used in navigation programs, as well as to recommend standardized metrics to define excellence in lung cancer navigation. The authors included 26 studies evaluating navigation metrics …

Customized Methylc-Capture Sequencing To Evaluate Variation In The Human Sperm Dna Methylome Representative Of Altered Folate Metabolism., Donovan Chan, Xiaojian Shao, Marie-Charlotte Dumargne, Mahmoud Aarabi, Marie-Michelle Simon, Tony Kwan, Janice L. Bailey, Bernard Robaire, Sarah Kimmins, Maria C. San Gabriel, Armand Zini, Clifford Librach, Sergey Moskovtsev, Elin Grundberg, Guillaume Bourque, T Pastinen, Jacquetta M. Trasler

Manuscripts, Articles, Book Chapters and Other Papers

Background: The sperm DNA methylation landscape is unique and critical for offspring health. If gamete-derived DNA methylation escapes reprograming in early embryos, epigenetic defects in sperm may be transmitted to the next generation. Current techniques to assess sperm DNA methylation show bias toward CpG-dense regions and do not target areas of dynamic methylation, those predicted to be environmentally sensitive and tunable regulatory elements.

Objectives: Our goal was to assess variation in human sperm DNA methylation and design a targeted capture panel to interrogate the human sperm methylome.

Methods: To characterize variation in sperm DNA methylation, we performed whole genome bisulfite …

Rheumatoid Arthritis-Relevant Dna Methylation Changes Identified In Acpa-Positive Asymptomatic Individuals Using Methylome Capture Sequencing., Xiaojian Shao, Marie Hudson, Ines Colmegna, Celia M T Greenwood, Marvin J. Fritzler, Philip Awadalla, T Pastinen, Sasha Bernatsky

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk.

METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. …

Fetal Fibronectin Testing For Reducing The Risk Of Preterm Birth., Vincenzo Berghella, Gabriele Saccone

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: Fetal fibronectin (FFN) is an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes, between chorion and decidua, where it is concentrated in this area between decidua and trophoblast. In normal conditions, FFN is found at very low levels in cervicovaginal secretions. Levels greater than or equal to 50 ng/mL at or after 22 weeks have been associated with an increased risk of spontaneous preterm birth. In fact, FFN is one of the best predictors of preterm birth in all populations studied so far, and can help in selecting which women are at significant risk for …

Comparison Of The Use Of Wireless Capsule Endoscopy With Magnetic Resonance Enterography In Children With Inflammatory Bowel Disease., Nadia Mazen Hijaz, Thomas M. Attard, Jennifer Colombo, Neil J. Mardis, Craig A. Friesen

Manuscripts, Articles, Book Chapters and Other Papers

Background: Magnetic resonance enterography (MRE) and wireless capsule endoscopy (WCE) are equally accepted modalities for noninvasive screening of small bowel involvement (SBI) in children with Crohn's disease (CD) and indeterminate colitis (IC) albeit there is a paucity of data comparing the two and thereby guiding the clinician in selecting the ideal diagnostic approach. Therefore, the goal of this study is to provide additional evidence for capsule endoscopy role in the evaluation of established Crohn's disease exacerbation compared to MRE in relation to Pediatric Crohn's Disease Activity Index (PCDAI), and histological indices.

Aim: To prospectively compare the findings of MRE and …

Physician Practices For Withdrawal Of Medications In Inactive Systemic Juvenile Arthritis, Childhood Arthritis And Rheumatology Research Alliance (Carra) Survey., Susan Shenoi, Kabita Nanda, Grant S. Schulert, John F. Bohnsack, Ashley M. Cooper, Bridget Edghill, Miriah C. Gillispie-Taylor, Baruch Goldberg, Olha Halyabar, Thomas G. Mason, Tova Ronis, Rayfel Schneider, Richard K. Vehe, Karen Onel, Childhood Arthritis And Rheumatology Research Alliance Systemic Juvenile Idiopathic Arthritis Workgroup

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: We describe a Childhood Arthritis and Rheumatology Research Alliance (CARRA) survey of North American pediatric rheumatologists that assesses physician attitudes on withdrawal of medications in systemic juvenile idiopathic arthritis (SJIA).

METHODS: A REDCap anonymous electronic survey was distributed to 100 random CARRA JIA workgroup physician-voting members. The survey had three broad sections including: A) demographic information; B) physicians' opinions on clinical inactive disease (CID) in SJIA and C) existing practices for withdrawing medications in SJIA.

RESULTS: The survey had an 86% response rate. 88 and 93% of participants agreed with the current criteria for CID and clinical remission on …

A Novel Rapamycin Analog Is Highly Selective For Mtorc1 In Vivo., Katherine H. Schreiber, Sebastian I. Arriola Apelo, Deyang Yu, Jacqueline A Brinkman, Michael C Velarde, Faizan A Syed, Chen-Yu Liao, Emma L. Baar, Kathryn A. Carbajal, Dawn S. Sherman, Denise Ortiz, Regina Brunauer, Shany E. Yang, Stelios T Tzannis, Brian K Kennedy, Dudley W Lamming

Natural Sciences and Mathematics | Student Professional Publications

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In …

Computational Analysis Of Hla-Presentation Of Non-Synonymous Recipient Mismatches Indicates Effect On The Risk Of Chronic Graft-Vs.-Host Disease After Allogeneic Hsct., Jarmo Ritari, Kati Hyvärinen, Satu Koskela, Riitta Niittyvuopio, Anne Nihtinen, Urpu Salmenniemi, Mervi Putkonen, Liisa Volin, Tony Kwan, T Pastinen, Maija Itälä-Remes, Jukka Partanen

Manuscripts, Articles, Book Chapters and Other Papers

Genetic mismatches in protein coding genes between allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipient and donor can elicit an alloimmunity response via peptides presented by the recipient HLA receptors as minor histocompatibility antigens (mHAs). While the impact of individual mHAs on allo-HSCT outcome such as graft-vs.-host and graft-vs.-leukemia effects has been demonstrated, it is likely that established mHAs constitute only a small fraction of all immunogenic non-synonymous variants. In the present study, we have analyzed the genetic mismatching in 157 exome-sequenced sibling allo-HSCT pairs to evaluate the significance of polymorphic HLA class I associated peptides on clinical outcome. We applied …

A Sparse Covarying Unit That Describes Healthy And Impaired Human Gut Microbiota Development, Arjun S Raman, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Sathish Subramanian, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of …

Effects Of Microbiota-Directed Foods In Gnotobiotic Animals And Undernourished Children, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Vanderlene L Kung, Jiye Cheng, Robert Y Chen, Sathish Subramanian, Carrie A Cowardin, Martin F Meier, David O'Donnell, Michael Talcott, Larry D Spears, Clay F Semenkovich, Christopher Sawyer, Richard D Head, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF …

In Vivo Effectiveness And Safety Of Probiotics On Prophylaxis And Treatment Of Oral Candidiasis: A Systematic Review And Meta-Analysis, Lijun Hu, Mimi Zhou, Andrew L. Young, Weiwei Zhao, Zhimin Yan

All Dugoni School of Dentistry Faculty Articles

BACKGROUND: To systematically review and assess the in vivo effectiveness and safety of probiotics for prophylaxis and treating oral candidiasis.

METHODS: A literature search for studies published in English until August 1, 2018 was conducted in the following databases: PubMed, EMBASE, Cochrane Library, and Web of Science. Randomized controlled clinical trials and experimental mouse animal model studies comparing probiotics (at any dosage and in any form) with control groups (placebo, blank control or other agents) and reporting outcomes of the prophylactic and therapeutic effects were considered for inclusion. A descriptive study and, potentially, a meta-analysis were planned.

RESULTS: Six randomized …

New Insights Into Dna Methylation Signatures: Smarca2 Variants In Nicolaides-Baraitser Syndrome., Eric Chater-Diehl, Resham Ejaz, Cheryl Cytrynbaum, Michelle T. Siu, Andrei Turinsky, Sanaa Choufani, Sarah J. Goodman, Omar Abdul-Rahman, Melanie Bedford, Naghmeh Dorrani, Kendra Engleman, Josue Flores-Daboub, David Genevieve, Roberto Mendoza-Londono, Wendy Meschino, Laurence Perrin, Nicole Safina, Sharron Townshend, Stephen W. Scherer, Evdokia Anagnostou, Amelie Piton, Matthew Deardorff, Michael Brudno, David Chitayat, Rosanna Weksberg

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures.

METHODS: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification …

Integrative Analysis Of Vascular Endothelial Cell Genomic Features Identifies Aida As A Coronary Artery Disease Candidate Gene., Simon Lalonde, Valérie-Anne Codina-Fauteux, Sébastian Méric De Bellefon, Francis Leblanc, Mélissa Beaudoin, Marie-Michelle Simon, Rola Dali, Tony Kwan, Ken Sin Lo, T Pastinen, Guillaume Lettre

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene …