Digital Commons Network^™

Health And Disease Markers Correlate With Gut Microbiome Composition Across Thousands Of People., Ohad Manor, Chengzhen L Dai, Sergey A Kornilov, Brett Smith, Nathan D Price, Jennifer C Lovejoy, Sean M Gibbons, Andrew T Magis

Articles, Abstracts, and Reports

Variation in the human gut microbiome can reflect host lifestyle and behaviors and influence disease biomarker levels in the blood. Understanding the relationships between gut microbes and host phenotypes are critical for understanding wellness and disease. Here, we examine associations between the gut microbiota and ~150 host phenotypic features across ~3,400 individuals. We identify major axes of taxonomic variance in the gut and a putative diversity maximum along the Firmicutes-to-Bacteroidetes axis. Our analyses reveal both known and unknown associations between microbiome composition and host clinical markers and lifestyle factors, including host-microbe associations that are composition-specific. These results suggest potential opportunities …

Comparison Of Virus Concentration Methods For The Rt-Qpcr-Based Recovery Of Murine Hepatitis Virus, A Surrogate For Sars-Cov-2 From Untreated Wastewater, Warish Ahmed, Paul M. Bertsch, Aaron Bivins, Kyle Bibby, Kata Farkas, Amy Gathercole, Eiji Haramoto, Pradip Gyawali, Asja Korajkic, Brian R. Mcminn, Jochen F. Mueller, Stuart L. Simpson, Wendy J M Smith, Erin M. Symonds, Kevin V. Thomas, Rory Verhagen, Masaaki Kitajima

All publications

There is currently a clear benefit for many countries to utilize wastewater-based epidemiology (WBE) as part of ongoing measures to manage the coronavirus disease 2019 (COVID-19) global pandemic. Since most wastewater virus concentration methods were developed and validated for nonenveloped viruses, it is imperative to determine the efficiency of the most commonly used methods for the enveloped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Municipal wastewater seeded with a human coronavirus (CoV) surrogate, murine hepatitis virus (MHV), was used to test the efficiency of seven wastewater virus concentration methods: (A–C) adsorption-extraction with three different pre-treatment options, (D–E) centrifugal filter device …

Covid-19-Associated Acute Kidney Injury: Consensus Report Of The 25th Acute Disease Quality Initiative (Adqi) Workgroup, Mitra K Nadim, Anitha Vijayan, Et Al

Open Access Publications

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the …

Splicing Factor Sf3b1 Promotes Endometrial Cancer Progression Via Regulating Ksr2 Rna Maturation, Pooja Popli, Megan M Richters, Sangappa B Chadchan, Tae Hoon Kim, Eric Tycksen, Obi Griffith, Premal H Thaker, Malachi Griffith, Ramakrishna Kommagani

2020-Current year OA Pubs

Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer-alternative mRNA splicing-and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed …

Adaptive Thermogenesis Enhances The Life-Threatening Response To Heat In Mice With An Ryr1 Mutation, Hui J Wang, Chang Seok Lee, Rachel Sue Zhen Yee, Linda Groom, Inbar Friedman, Lyle Babcock, Dimitra K Georgiou, Jin Hong, Amy D Hanna, Joseph Recio, Jong Min Choi, Ting Chang, Nadia H Agha, Jonathan Romero, Poonam Sarkar, Nicol Voermans, M Waleed Gaber, Sung Yun Jung, Matthew L Baker, Robia G Pautler, Robert T Dirksen, Sheila Riazi, Susan L Hamilton

Faculty, Staff and Students Publications

Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to …

Covid-19 Pandemic-Related Practices And Policies Affecting The Continuity Of Behavioral Health Care Among Children With Diabetes., Lauren Clary, Christine Wang, Meghan E Byrne, Maureen Monaghan

COVID-19 Publications by GW Authors

COVID-19 has led to substantial challenges in continuing to deliver behavioral health care to all patients, including children with chronic diseases. In the case of diabetes, maintaining strong connections among children, their families, and their care team is essential to promote and sustain daily adherence to a complex medical regimen. The purpose of this paper is to describe COVID-19 pandemic-related practices and policies affecting the continuity of behavioral health care among children with diabetes. Challenges and opportunities were encountered at the provider, patient, and family levels throughout the rapid transition period from in-person to online care to ensure continuity of …

Pyrazole-Based Lactate Dehydrogenase Inhibitors With Optimized Cell Activity And Pharmacokinetic Properties, Ganesha Rai, Daniel J. Urban, Bryan T. Mott, Xin Hu, Shyh-Ming Yang, Gloria A. Benavides, Michelle S. Johnson, Giuseppe L. Squadrito, Kyle R. Brimacombe, Tobie D. Lee, Dorian M. Cheff, Hu Zhu, Mark J. Henderson, Katherine Pohida, Gary A. Sulikowski, David M. Dranow, Md Kabir, Pranav Shah, Elias Padilha, Dingyin Tao, Yuhong Fang, Plamen P. Christov, Kwangho Kim, Somnath Jana, Pavan Muttil, Tamara Anderson, Nitesh K Kunda, Helen J. Hathaway, Donna F. Kusewitt, Nobu Oshima, Murali Cherukuri, Douglas R. Davies, Jeffrey P. Norenberg, Larry A. Sklar, William J. Moore, Chi V Dang, Gordon M. Stott, Leonard Neckers, Andrew J. Flint, Victor M. Darley-Usmar, Anton Simeonov, Alex G. Waterson, Ajit Jadhav, Matthew D. Hall, David J. Maloney

Pathology Research and Scholarship

Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, …

Feasibility And Potential Efficacy Of Commercial Mhealth/Ehealth Tools For Weight Loss In African American Breast Cancer Survivors: Pilot Randomized Controlled Trial, Jeanne M Ferrante, Katie A Devine, Alicja Bator, Ashley Rodgers, Pamela A Ohman-Strickland, Elisa V Bandera, Kevin O Hwang

Faculty, Staff and Student Publications

Weight management after breast cancer (BC) treatment in African American (AA) women is crucial to reduce comorbid conditions and health disparities. We examined feasibility and potential efficacy of commercial eHealth/mHealth tools for weight management in AA BC survivors in New Jersey. Participants (N = 35) were randomized to an intervention (SparkPeople) plus activity tracker, Fitbit Charge (n = 18), or wait-list active control group (Fitbit only, n = 17). Anthropometric, behavioral, and quality of life (QOL) outcomes were collected at baseline, 3, 6, and 12 months. Differences in outcomes were assessed using intent-to-treat analysis. Retention was 97.1%. Both groups lost …

Giant Gastric Ulcers: An Unusual Culprit, Aamer Abbass, Sameen Khalid, Vaishnavi Boppana, Joshua Hanson, Henry Lin, Denis Mccarthy

Pathology Research and Scholarship

Mycophenolate Mofetil (MMF) is routinely used immunosuppressant in solid organ transplantation is commonly associated with several gastrointestinal (GI) side effects. Here we present a case of giant gastric ulcer of 5 cm from MMF use post cardiac transplant. CASE DESCRIPTION: A 56-year-old male with history of severe ischemic cardiomyopathy post heart transplant was on immunosuppression with MMF, tacrolimus and prednisone for 5 months. He presented with severe epigastric pain and intermittent episodes of melena for 1 month. His pain radiated to back that is worsened with eating. Associated with loss of appetite, vomiting and 16-pound weight loss in 3 months. …

National Nutrition Strategies That Focus On Maternal, Infant, And Young Child Nutrition In Southeast Asia Do Not Consistently Align With Regional And International Recommendations, Tuan T. Nguyen, Ashley Darnell, Amy Weissman, Jennifer Cashin, Mellissa Withers, Roger Mathisen, Karin Lapping, Timothy D. Mastro, Edward A. Frongillo Jr.

Faculty Publications

We examined the consistency of national nutrition strategies and action plans (NNS) focusing on maternal, infant, and young child nutrition in Southeast Asia with regional and international recommendations. Between July and December 2017, we identified and extracted information on context, objectives, interventions, indicators, strategies, and coordination mechanisms from the most recent NNS in nine Southeast Asian countries. All NNS described context, objectives, and the following interventions: antenatal care, micronutrient supplementation during pregnancy, breastfeeding promotion, improved complementary feeding, nutrition in emergencies, and food fortification or dietary diversity. Micronutrient supplementation for young children was included in eight NNS; breastfeeding promotion during pregnancy …

Redefining Cardiac Biomarkers In Predicting Mortality Of Inpatients With Covid-19, Juan-Juan Qin, Xu Cheng, Feng Zhou, Fang Lei, Gauri Akolkar, Jingjing Cai, Xiao-Jing Zhang, Alice Blet, Jing Xie, Peng Zhang, Ye-Mao Liu, Zizhen Huang, Ling-Ping Zhao, Lijin Lin, Meng Xia, Ming-Ming Chen, Xiaohui Song, Liangjie Bai, Ze Chen, Xingyuan Zhang, Da Xiang, Jing Chen, Qingbo Xu, Xin-Liang Ma, Rhian M Touyz, Chen Gao, Haitao Wang, Liming Liu, Weiming Mao, Pengcheng Luo, Youqin Yan, Ping Ye, Manhua Chen, Guohua Chen, Lihua Zhu, Zhi-Gang She, Xiaodong Huang, Yufeng Yuan, Bing-Hong Zhang, Yibin Wang, Peter P Liu, Hongliang Li

Department of Emergency Medicine Faculty Papers

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.

The Central Melanocortin System And Human Obesity, Yongjie Yang, Yong Xu

Children’s Nutrition Research Center Staff Publications

The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that …

Evidence For Craniofacial Enhancer Variation Underlying Nonsyndromic Cleft Lip And Palate, Vershanna E Morris, S Shahrukh Hashmi, Lisha Zhu, Lorena Maili, Christian Urbina, Steven Blackwell, Matthew R Greives, Edward P Buchanan, John B Mulliken, Susan H Blanton, W Jim Zheng, Jacqueline T Hecht, Ariadne Letra

Faculty, Staff and Student Publications

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified using VISTA Enhancer Browser and previous publications. Prioritization was based on patterning defects in knockout mice, deletion/duplication of craniofacial genes in animal models and results of whole exome/whole genome sequencing studies. This resulted in 20 craniofacial enhancers to be investigated. Custom amplicon-based …

Policies And Practices Of Shea Research Network Hospitals During The Covid-19 Pandemic., Michael S. Calderwood, Valerie M. Deloney, Deverick J. Anderson, Vincent Chi-Chung Cheng, Shruti Gohil, Jennie H. Kwon, Lona Mody, Elizabeth Monsees, Valerie M. Vaughn, Timothy L. Wiemken, Matthew J. Ziegler, Eric Lofgren

Manuscripts, Articles, Book Chapters and Other Papers

To understand hospital policies and practices as the COVID-19 pandemic accelerated, the Society for Healthcare Epidemiology of America (SHEA) conducted a survey through the SHEA Research Network (SRN). The survey assessed policies and practices around the optimization of personal protection equipment (PPE), testing, healthcare personnel policies, visitors of COVID-19 patients in relation to procedures, and types of patients. Overall, 69 individual healthcare facilities responded in the United States and internationally, for a 73% response rate.

Mir-30a Targets Gene Networks That Promote Browning Of Human And Mouse Adipocytes, Pradip K Saha, Mark P Hamilton, Kimal Rajapakshe, Vasanta Putluri, Jessica B Felix, Peter Masschelin, Aaron R Cox, Mandeep Bajaj, Nagireddy Putluri, Cristian Coarfa, Sean M Hartig

Faculty, Staff and Students Publications

MicroRNA-30a (miR-30a) impacts adipocyte function, and its expression in white adipose tissue (WAT) correlates with insulin sensitivity in obesity. Bioinformatic analysis demonstrates that miR-30a expression contributes to 2% of all miRNA expression in human tissues. However, molecular mechanisms of miR-30a function in fat cells remain unclear. Here, we expanded our understanding of how miR-30a expression contributes to antidiabetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity and metabolic functions in adipocytes. We found that WAT isolated from diabetic patients shows reduced miR-30a levels and diminished expression of the canonical PPARγ target genes ADIPOQ and FABP4 relative to lean counterparts. In human adipocytes, …

An Autism-Linked Missense Mutation In Shank3 Reveals The Modularity Of Shank3 Function, Li Wang, Kaifang Pang, Kihoon Han, Carolyn J Adamski, Wei Wang, Lingjie He, Jason K Lai, Vitaliy V Bondar, Joseph G Duman, Ronald Richman, Kimberley F Tolias, Patrick Barth, Timothy Palzkill, Zhandong Liu, J Lloyd Holder, Huda Y Zoghbi

Faculty, Staff and Students Publications

Genome sequencing has revealed an increasing number of genetic variations that are associated with neuropsychiatric disorders. Frequently, studies limit their focus to likely gene-disrupting mutations because they are relatively easy to interpret. Missense variants, instead, have often been undervalued. However, some missense variants can be informative for developing a more profound understanding of disease pathogenesis and ultimately targeted therapies. Here we present an example of this by studying a missense variant in a well-known autism spectrum disorder (ASD) causing gene SHANK3. We analyzed Shank3's in vivo phosphorylation profile and identified S685 as one phosphorylation site where one ASD-linked variant has …

Safety And Immunogenicity Of Fc-Eda, A Recombinant Ectodysplasin A1 Replacement Protein, In Human Subjects, Iris Körber, Ophir D Klein, Patrick Morhart, Florian Faschingbauer, Dorothy K Grange, Angus Clarke, Christine Bodemer, Silvia Maitz, Kenneth Huttner, Neil Kirby, Caroline Durand, Holm Schneider

2020-Current year OA Pubs

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if …

Application Of Human Factors Methods To Understand Missed Follow-Up Of Abnormal Test Results, Deevakar Rogith, Tyler Satterly, Hardeep Singh, Dean F Sittig, Elise Russo, Michael W Smith, Don Roosan, Viraj Bhise, Daniel R Murphy

Faculty, Staff and Students Publications

OBJECTIVE: This study demonstrates application of human factors methods for understanding causes for lack of timely follow-up of abnormal test results ("missed results") in outpatient settings.

METHODS: We identified 30 cases of missed test results by querying electronic health record data, developed a critical decision method (CDM)-based interview guide to understand decision-making processes, and interviewed physicians who ordered these tests. We analyzed transcribed responses using a contextual inquiry (CI)-based methodology to identify contextual factors contributing to missed results. We then developed a CI-based flow model and conducted a fault tree analysis (FTA) to identify hierarchical relationships between factors that delayed …

Usability Testing Of A Sensor-Controlled Digital Game To Engage Older Adults With Heart Failure In Physical Activity And Weight Monitoring, Kavita Radhakrishnan, Christine Julien, Matthew O'Hair, Thomas Baranowski, Grace Lee, Catherine Allen, Atami Sagna, Edison Thomaz, Miyong Kim

Faculty, Staff and Students Publications

BACKGROUND: Poor self-management of heart failure (HF) has contributed to poor health outcomes. Sensor-controlled digital games (SCDGs) integrates data from behavior-tracking sensors to trigger progress, rewards, content, and positive feedback in a digital game to motivate real-time behaviors.

OBJECTIVES: To assess the usability of an SCDG prototype over a week of game-playing among 10 older adults with HF in their homes.

METHODS: During initial play, participants' SCDG experiences were observed in their homes using a checklist based on the seven-item Serious Game User Evaluator (SeGUE) instrument. After a week of game-playing, participants completed a survey guided by the Intrinsic Motivation …

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 …

Trem2 Activation On Microglia Promotes Myelin Debris Clearance And Remyelination In A Model Of Multiple Sclerosis, Francesca Cignarella, Fabia Filipello, Bryan Bollman, Claudia Cantoni, Alberto Locca, Robert Mikesell, Melissa Manis, Adiljan Ibrahim, Li Deng, Bruno A Benitez, Carlos Cruchaga, Danilo Licastro, Kathie Mihindukulasuriya, Oscar Harari, Michael Buckland, David M Holtzman, Arnon Rosenthal, Tina Schwabe, Ilaria Tassi, Laura Piccio

2020-Current year OA Pubs

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the …

Anesthetic Drugs And Cancer Progression, Juan P Cata, Anil K Sood, Holger K Eltzschig

Faculty, Staff and Student Publications

No abstract provided.

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 …

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 …

Atrial Myocyte Nlrp3/Camkii Nexus Forms A Substrate For Postoperative Atrial Fibrillation, Jordi Heijman, Azinwi Phina Muna, Tina Veleva, Cristina E Molina, Henry Sutanto, Marcel Tekook, Qiongling Wang, Issam H Abu-Taha, Marcel Gorka, Stephan Künzel, Ali El-Armouche, Hermann Reichenspurner, Markus Kamler, Viacheslav Nikolaev, Ursula Ravens, Na Li, Stanley Nattel, Xander H T Wehrens, Dobromir Dobrev

Faculty, Staff and Students Publications

RATIONALE: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.

OBJECTIVE: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.

METHODS AND RESULTS: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca

CONCLUSIONS: Preexisting Ca

Antibodies To Variable Domain 4 Linear Epitopes Of The Chlamydia Trachomatis Major Outer Membrane Protein Are Not Associated With Chlamydia Resolution Or Reinfection In Women, Amanda L. Collar, Alexandria C. Linville, Susan B. Core, Cosette M. Wheeler, William M. Geisler, David S. Peabody, Bryce Chackerian, Kathryn M. Frietze

Pathology Research and Scholarship

Chlamydia trachomatis is an obligate intracellular bacterium. C. trachomatis infection is the most prevalent bacterial sexually transmitted infection and can lead to pelvic inflammatory disease and infertility in women. There is no licensed vaccine for C. trachomatis prevention, in part due to gaps in our knowledge of C. trachomatis-specific immune responses elicited during human infections. Previous investigations of the antibody response to C. trachomatis have identified immunodominant antigens and antibodies that can neutralize infection in cell culture. However, epitope-specific responses to C. trachomatis are not well characterized, and the impact of these antibodies on infection outcome is unknown. We …

Loss Of Speg Inhibitory Phosphorylation Of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation, Hannah M Campbell, Ann P Quick, Issam Abu-Taha, David Y Chiang, Carlos F Kramm, Tarah A Word, Sören Brandenburg, Mohit Hulsurkar, Katherina M Alsina, Hui-Bin Liu, Brian Martin, Dennis Uhlenkamp, Oliver M Moore, Satadru K Lahiri, Eleonora Corradini, Markus Kamler, Albert J R Heck, Stephan E Lehnart, Dobromir Dobrev, Xander H T Wehrens

Faculty, Staff and Students Publications

BACKGROUND: Enhanced diastolic calcium (Ca

METHODS: Western blotting was performed with right atrial biopsies from patients with paroxysmal AF. SPEG atrial knockout mice were generated using adeno-associated virus 9. In mice, AF inducibility was determined using intracardiac programmed electric stimulation, and diastolic Ca

RESULTS: Western blotting revealed decreased SPEG protein levels in atrial biopsies from patients with paroxysmal AF in comparison with patients in sinus rhythm. SPEG atrial-specific knockout mice exhibited increased susceptibility to pacing-induced AF by programmed electric stimulation and enhanced Ca

CONCLUSIONS: Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2-mediated sarcoplasmic reticulum Ca

Structural Characterization Of A Clinically Described Heparin-Like Substance In Plasma Causing Bleeding, Yanlei Yu, Karen Bruzdoski, Vadim Kostousov, Lisa Hensch, Shiu-Ki Hui, Fakiha Siddiqui, Amber Farooqui, Ahmed Kouta, Fuming Zhang, Jawed Fareed, Jun Teruya, Robert J Linhardt

Faculty, Staff and Students Publications

Heparin-like substances (HLS) have been described in various clinical situations, including in settings of liver disease associated with infection, transplant, and metastasis. HLS are generally attributed to circulating glycosaminoglycans. Initial results for this patient showed coagulopathy due to liver disease without HLS. Two weeks after liver transplantation, a 10 year-old female with liver failure patient began to bleed from catheter insertion sites, mouth, and nares and HLS was suspected. The patient subsequently died and these clinical samples resulted in the isolation of a single heparan sulfate (HS) present at high concentrations in the plasma. Analysis of this HS showed it …

A Novel Bioaugmentation Technique Effectively Increases The Skin-Associated Microbial Diversity Of Captive Eastern Hellbenders, Erin K. Kenison, Obed Hernandez-Gomez, Rod N. Williams

Natural Sciences and Mathematics | Faculty Scholarship

Captive environments are maintained in hygienic ways that lack free-flowing microbes found in animals’ natural environments. As a result, captive animals often have depauperate host-associated microbial communities compared to conspecifics in the wild and may have increased disease susceptibility and reduced immune function. Eastern hellbenders (Cryptobranchus alleganiensis alleganiensis) have suffered precipitous population declines over the past few decades. To bolster populations, eastern hellbenders are reared in captivity before being translocated to the wild. However, the absence of natural microbial reservoirs within the captive environment diminishes the diversity of skin-associated bacteria on hellbender skin and may negatively influence their ability to …

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 …