Medicine and Health Sciences Commons^™

In Silico Analysis Of Dnd1 And Its Co-Expressed Genes In Human Cancers, Yun Zhang, Yafang Li, Dhruv Chachad, Bin Liu, Jyotsna D Godavarthi, Abie Williams-Villalobo, Latifat Lasisi, Shunbin Xiong, Angabin Matin

Faculty, Staff and Students Publications

Dead-End (DND1) is an RNA-binding protein involved in translational regulation. Defects in DND1 gene causes germ cell tumors and sterility in rodents. Experimental studies with human somatic cancer cells indicate that DND1 has anti-proliferative and pro-apoptotic function in some while oncogenic function in other cells. We examined The Cancer Genome Atlas data for gene alterations and gene expression changes in DND1 in a variety of human cancers. We found that DND1 is amplified, deleted or mutated in multiple human cancers. In different cancers, DND1 alteration correlates with increased diagnosis age of patients, shift in tumor spectrum or change of tumor …

Randomised Trial: Peppermint Oil (Menthol) Pharmacokinetics In Children And Effects On Gut Motility In Children With Functional Abdominal Pain, Robert J Shulman, Bruno P Chumpitazi, Susan M Abdel-Rahman, Uttam Garg, Salma Musaad, Gregory L Kearns

Faculty, Staff and Students Publications

AIMS: Little is known regarding the pharmacokinetics and pharmacodynamics of menthol, the active ingredient in peppermint oil (PMO). Our aim was to investigate the pharmacokinetics of menthol at 3 dose levels in children and determine their effects on gut motility and transit.

METHODS: Thirty children ages 7-12 years with functional abdominal pain underwent wireless motility capsule (WMC) testing. Approximately 1 week later they were randomized to 180, 360 or 540 mg of enteric coated PMO (10 participants per dose). Menthol pharmacokinetics were determined via blood sampling over 24 hours. They then took their respective dose of PMO (180 mg once, …

Effect Of Domperidone Therapy On Gastroparesis Symptoms: Results Of A Dynamic Cohort Study By Niddk Gastroparesis Consortium, Irene Sarosiek, Mark Van Natta, Henry P Parkman, Thomas Abell, Kenneth L Koch, Braden Kuo, Robert J Shulman, Gianrico Farrugia, Madhusudan Grover, Frank A Hamilton, Pankaj J Pasricha, Katherine P Yates, Laura Miriel, Laura Wilson, Goro Yamada, James Tonascia, Richard W Mccallum

Faculty, Staff and Students Publications

BACKGROUND & AIMS: The use of domperidone (DOM) for gastroparesis (GP) remains controversial and limited. We aimed to present outcomes of DOM therapy for treatment of patients participating in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) Registries (GpR).

METHODS: The GpCRC cohort consisted of patients with GP (75%) and with GP-like symptoms but with normal gastric emptying (25%). The DOM group initiated therapy during the 96 weeks of enrollment in GpR1 and GpR2. Patients who had previously taken or who were on DOM therapy at enrollment were excluded from this analysis. …

The Impact Of Response To Iron Therapy On Maternal And Neonatal Outcomes Among Pregnant Women With Anemia, Sarah E Detlefs, Michael D Jochum, Bahram Salmanian, Jennifer R Mckinney, Kjersti M Aagaard

Faculty, Staff and Students Publications

BACKGROUND: Anemia during pregnancy is associated with increased risks of preterm birth, preeclampsia, cesarean delivery, and maternal morbidity. The most prevalent modifiable cause of pregnancy-associated anemia is iron deficiency. However, it is still unclear whether iron therapy can reduce the risks of adverse outcomes in women with anemia.

OBJECTIVE: This study aimed to determine whether response to iron therapy among women with anemia is associated with a change in odds of adverse maternal and neonatal outcomes.

STUDY DESIGN: This was a population-based cohort study (2011-2019) using an institutional database composed of obstetrical patients from 2 delivery hospitals. Patients with adequate …

The Acute Influence Of Vasopressin On Hemodynamic Status And Tissue Oxygenation Following The Norwood Procedure, Ronald A Bronicki, Sebastian Acosta, Fabio Savorgnan, Saul Flores, Barbara-Jo Achuff, Rohit Loomba, Mubbasheer Ahmed, Nancy Ghanayem, Jeffrey S Heinle, Vicken Asadourian, Javier J Lasa

Faculty, Staff and Students Publications

OBJECTIVES: Arginine vasopressin (AVP) is used to treat hypotension. Because AVP increases blood pressure by increasing systemic vascular resistance, it may have an adverse effect on tissue oxygenation following the Norwood procedure.

METHODS: Retrospective analysis of continuously captured hemodynamic data of neonates receiving AVP following the Norwood procedure.

RESULTS: We studied 64 neonates exposed to AVP within 7 days after the Norwood procedure. For the entire group, AVP significantly increased mean blood pressure (2.5 ± 6.3) and cerebral and renal oxygen extraction ratios (4.1% ± 9.6% and 2.0% ± 4.7%, respectively;

CONCLUSIONS: The right ventricle to pulmonary artery shunt cohort …

Virtual Deliberate Practice Module For Tracheostomy Change Training: An Application Of Educational Design Research, Jennifer Christina Benjamin, Saul Flores, Parag Jain, Shelley Kumar, Satid Thammasitboon

Faculty, Staff and Students Publications

BACKGROUND: The pandemic poses challenges for in-person procedural skills training. We developed a virtual module for teaching hands-on tracheostomy skills.

OBJECTIVE: To develop and evaluate a virtual module prototype grounded in deliberate practice using tracheostomy change as an example.

METHODS: After identifying desirable features of a virtual module by surveying stakeholders, we designed a prototype using VoiceThread, a multimedia-based collaborative learning platform. We created an asynchronous module accessible to learners for repeated skill practice and for video upload of individual performance on a tracheostomy task trainer using personal devices. This virtual module provided a four-step coaching (demonstration, deconstruction, formulation, and …

Prognostic And Predictive Biomarkers In Patients With Coronavirus Disease 2019 Treated With Tocilizumab In A Randomized Controlled Trial, Jennifer Tom, Min Bao, Larry Tsai, Aditi Qamra, David Summers, Montserrat Carrasco-Triguero, Jacqueline Mcbride, Carrie M Rosenberger, Celia J F Lin, William Stubbings, Kevin G Blyth, Jordi Carratalà, Bruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H Van Der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Farrah Kheradmand, Ivan O Rosas, Fang Cai

Faculty, Staff and Students Publications

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.

DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.

SETTING: Hospitals in North America and Europe.

PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care.

INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo.

MEASUREMENTS AND MAIN …

Isoform-Specific Functions Of Pparγ In Gene Regulation And Metabolism, Wenxiang Hu, Chunjie Jiang, Mindy Kim, Yang Xiao, Hannah J Richter, Dongyin Guan, Kun Zhu, Brianna M Krusen, Arielle N Roberts, Jessica Miller, David J Steger, Mitchell A Lazar

Faculty, Staff and Students Publications

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, …

P16 Represses Dna Damage Repair Via A /Novel Ubiquitin-Dependent Signaling Cascade, David P Molkentine, Jessica M Molkentine, Kathleen A Bridges, David R Valdecanas, Annika Dhawan, Reshub Bahri, Andrew J Hefner, Manish Kumar, Liangpeng Yang, Mohamed Abdelhakiem, Phillip M Pifer, Vlad Sandulache, Aakash Sheth, Beth M Beadle, Howard D Thames, Kathryn A Mason, Curtis R Pickering, Raymond E Meyn, Heath D Skinner

Faculty, Staff and Students Publications

Squamous cell carcinoma driven by human papillomavirus (HPV) is more sensitive to DNA-damaging therapies than its HPV-negative counterpart. Here, we show that p16, the clinically used surrogate for HPV positivity, renders cells more sensitive to radiotherapy via a ubiquitin-dependent signaling pathway, linking high levels of this protein to increased activity of the transcription factor SP1, increased HUWE1 transcription, and degradation of ubiquitin-specific protease 7 (USP7) and TRIP12. Activation of this pathway in HPV-positive disease led to decreased homologous recombination and improved response to radiotherapy, a phenomenon that can be recapitulated in HPV-negative disease using USP7 inhibitors in clinical development. This …

Constipation In Patients With Symptoms Of Gastroparesis: Analysis Of Symptoms And Gastrointestinal Transit, Henry P Parkman, Emily Sharkey, Richard W Mccallum, William L Hasler, Kenneth L Koch, Irene Sarosiek, Thomas L Abell, Braden Kuo, Robert J Shulman, Madhusudan Grover, Gianrico Farrugia, Ron Schey, James Tonascia, Frank Hamilton, Pankaj J Pasricha, Nih/Niddk Gastroparesis Consortium

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Constipation can be an important symptom in some patients with gastroparesis. The aims were to: 1) Determine prevalence of constipation and delayed colonic transit in patients with symptoms of gastroparesis; 2) Correlate severity of constipation to severity of symptoms of gastroparesis; and 3) Relate severity of constipation to GI transit delays assessed by gastric emptying scintigraphy (GES) and wireless motility capsule (WMC).

METHODS: Patients with symptoms of gastroparesis underwent gastric emptying scintigraphy (GES), wireless motility capsule (WMC) assessing gastric emptying, small bowel transit, and colonic transit, and questionnaires assessing symptoms using a modified Patient Assessment of Upper …

Genetic Subtyping And Phenotypic Characterization Of The Immune Microenvironment And Myc/Bcl2 Double Expression Reveal Heterogeneity In Diffuse Large B-Cell Lymphoma, Zijun Y Xu-Monette, Li Wei, Xiaosheng Fang, Qingyan Au, Harry Nunns, Máté Nagy, Alexandar Tzankov, Feng Zhu, Carlo Visco, Govind Bhagat, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D Hsi, Fredrick B Hagemeister, Xiaoping Sun, Xin Han, Heounjeong Go, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Benjamin M Parsons, J Han Van Krieken, Miguel A Piris, Jane N Winter, Yong Li, Bing Xu, Maher Albitar, Hua You, Ken H Young

Faculty, Staff and Students Publications

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is molecularly and clinically heterogeneous, and can be subtyped according to genetic alterations, cell-of-origin, or microenvironmental signatures using high-throughput genomic data at the DNA or RNA level. Although high-throughput proteomic profiling has not been available for DLBCL subtyping, MYC/BCL2 protein double expression (DE) is an established prognostic biomarker in DLBCL. The purpose of this study is to reveal the relative prognostic roles of DLBCL genetic, phenotypic, and microenvironmental biomarkers.

EXPERIMENTAL DESIGN: We performed targeted next-generation sequencing; IHC for MYC, BCL2, and FN1; and fluorescent multiplex IHC for microenvironmental markers in a large cohort of …

Visual Pigment-Deficient Cones Survive And Mediate Visual Signaling Despite The Lack Of Outer Segments, Hui Xu, Nange Jin, Jen-Zen Chuang, Zhao Zhang, Xiaoyue Zhong, Zhijing Zhang, Ching-Hwa Sung, Christophe P Ribelayga, Yingbin Fu

Faculty, Staff and Students Publications

Rhodopsin and cone opsins are essential for light detection in vertebrate rods and cones, respectively. It is well established that rhodopsin is required for rod phototransduction, outer segment disk morphogenesis, and rod viability. However, the roles of cone opsins are less well understood. In this study, we adopted a loss-of-function approach to investigate the physiological roles of cone opsins in mice. We showed that cones lacking cone opsins do not form normal outer segments due to the lack of disk morphogenesis. Surprisingly, cone opsin-deficient cones survive for at least 12 mo, which is in stark contrast to the rapid rod …

A Call For An Integrated Approach To Improve Efficiency, Equity And Sustainability In Rare Disease Research In The United States, Meghan C Halley, Hadley Stevens Smith, Euan A Ashley, Aaron J Goldenberg, Holly K Tabor

Faculty, Staff and Students Publications

To build a more efficient, equitable, and sustainable approach to rare disease research in the United States, we must prioritize integrated research infrastructure and approaches that focus on understanding connections across rare diseases.

Otosyphilis: A Rare Cause Of Reversible Hearing Loss In A Teenage Male, Shan He, Anna H Messner, Gayatri Mirani

Faculty, Staff and Students Publications

A high index of suspicion and a thorough neurotologic examination at the onset of presentation are imperative to generate the diagnosis of otosyphilis. Complete audiologic recovery is rare but possible in approximately 20%-25% of patients after appropriate treatment. We present a case of reversible hearing loss secondary to otosyphilis in a teenage male patient with a new diagnosis of human immunodeficiency virus (HIV). Audiology findings were consistent with mixed hearing loss. Lumbar puncture results were consistent with neurosyphilis. Prompt treatment with a 14-day course of intravenous penicillin led to the complete recovery of hearing. In this case report, the pathophysiology, …

Cross-Roads For Meta-Analysis And Network Meta-Analysis Of H Pylori Therapy, David Y Graham, Ruben Hernaez, Theodore Rokkas

Faculty, Staff and Students Publications

Helicobacter pylori infections are responsible for tremendous morbidity and mortality worldwide, leading to efforts to eradicate the organism. However, the effectiveness of antimicrobial therapy has been undermined by the progressive development of antimicrobial resistance. Treatments and treatment guidelines have been based on traditional pairwise meta-analyses of randomized controlled trials. More recently, network meta-analyses have also been utilized in an attempt to provide useful information to the clinician regarding which therapies appear best and which to avoid as the least efficacious. However, both forms of meta-analysis have been undermined by the same problems including the poor quality of the clinical trials …

Symptom Clusters, Physical Activity, And Quality Of Life: A Latent Class Analysis Of Children During Maintenance Therapy For Leukemia, Mary C Hooke, Michelle A Mathiason, Audrey Blommer, Jessica Hutter, Pauline Mitby, Olga Taylor, Michael E Scheurer, Alicia S Kunin-Batson, Wei Pan, Marilyn J Hockenberry

Faculty, Staff and Students Publications

BACKGROUND: Children undergoing treatment for acute lymphocytic leukemia (ALL) report co-occurring symptoms of fatigue, sleep disturbances, and depression as a symptom cluster. Physical activity (PA) may influence symptom severity and quality of life (QOL).

OBJECTIVES: This study examined changes in symptoms and QOL during ALL maintenance in children categorized by symptom cluster and explored the influence of PA and symptoms on QOL.

METHODS: Self-report of fatigue, sleep disturbance, and depression; QOL; and PA were measured at the beginning and end of maintenance in 42 children aged 3 to 18 years with ALL. Children were categorized into symptom cluster groups based …

'Analogy-Based Comprehensive Diabetes Education' (Abcde) Improves Glycemic Control Of Diabetic Patients In An Underserved Population: Results Of A Retrospective Chart Analysis, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Diabetes is the leading global cause for blindness, kidney failure and amputations. Preventing these complications requires optimal glycemic control, and it is imperative that diabetic patients understand the fundamental concepts of diabetes care. Although patients attend formal diabetes education classes, many do not comprehend basic concepts of diabetes, and are often noncompliant with diet, exercise and medications. A novel approach termed 'analogy-based comprehensive diabetes education' (ABCDE) was developed to educate HIV-patients with diabetes about basic concepts of diabetes care. The object of this manuscript is to report the results of a retrospective chart review on the impact of ABCDE on …

The Influence Of Preoperative Dialysis On Survival After Continuous-Flow Left Ventricular Assist Device Implantation, Harveen K Lamba, Fadi I Musfee, Subhasis Chatterjee, Ajith P Nair, Andrew B Civitello, Leo Simpson, O H Frazier, George V Letsou

Faculty, Staff and Students Publications

OBJECTIVES: Dialysis is considered a contraindication to continuous-flow left ventricular assist device (CF-LVAD) implantation. We evaluated clinical outcomes and survival in carefully selected, low-risk patients with renal failure who required dialysis before CF-LVAD implantation.

METHODS: We extracted medical record data of patients who underwent CF-LVAD placement at our centre between 1 January 2006 and 31 August 2017, with 2 clinical scenarios: those who required long-term (>14 days) dialysis and those who required short-term (≤14 days) dialysis immediately before implantation. Demographic, clinical and intraoperative characteristics and survival outcomes were assessed.

RESULTS: Of 621 patients who underwent CF-LVAD implantation during the …

Syndecan-2 Regulates Pad2 To Exert Antifibrotic Effects On Ra-Ild Fibroblasts, Konstantin Tsoyi, Anthony J Esposito, Bo Sun, Ryan G Bowen, Kevin Xiong, Fernando Poli, Rafael Cardenas, Sarah G Chu, Xiaoliang Liang, Stefan W Ryter, Christine Beeton, Tracy J Doyle, Matthew J Robertson, Lindsay J Celada, Freddy Romero, Souheil Y El-Chemaly, Mark A Perrella, I-Cheng Ho, Ivan O Rosas

Faculty, Staff and Students Publications

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix …

Repair-Assisted Damage Detection Reveals Biological Disparities In Prostate Cancer Between African Americans And European Americans, Kimiko L Krieger, Jie H Gohlke, Kevin J Lee, Danthasinghe Waduge Badrajee Piyarathna, Patricia D Castro, Jeffrey A Jones, Michael M Ittmann, Natalie R Gassman, Arun Sreekumar

Faculty, Staff and Students Publications

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues. Tissue microarrays with matched tumor-benign adjacent pairs from 77 AA and EA PCa patients were analyzed for abasic sites, oxidative lesions, crosslinks, and uracil content using the Repair Assisted Damage Detection (RADD) assay. Our analysis revealed that AA PCa, overall, have more DNA damage than …

Novel Role Of Ghrelin Receptor In Gut Dysbiosis And Experimental Colitis In Aging, Ji Yeon Noh, Chia-Shan Wu, Jennifer A A Deluca, Sridevi Devaraj, Arul Jayaraman, Robert C Alaniz, Xiao-Di Tan, Clinton D Allred, Yuxiang Sun

Faculty, Staff and Students Publications

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout …

Fully Resolved Assembly Of Cryptosporidium Parvum, Vipin K Menon, Pablo C Okhuysen, Cynthia L Chappell, Medhat Mahmoud, Medhat Mahmoud, Qingchang Meng, Harsha Doddapaneni, Vanesa Vee, Yi Han, Sejal Salvi, Sravya Bhamidipati, Kavya Kottapalli, George Weissenberger, Hua Shen, Matthew C Ross, Kristi L Hoffman, Sara Javornik Cregeen, Donna M Muzny, Ginger A Metcalf, Richard A Gibbs, Joseph F Petrosino, Fritz J Sedlazeck

Faculty, Staff and Students Publications

BACKGROUND: Cryptosporidium parvum is an apicomplexan parasite commonly found across many host species with a global infection prevalence in human populations of 7.6%. Understanding its diversity and genomic makeup can help in fighting established infections and prohibiting further transmission. The basis of every genomic study is a high-quality reference genome that has continuity and completeness, thus enabling comprehensive comparative studies.

FINDINGS: Here, we provide a highly accurate and complete reference genome of Cryptosporidium parvum. The assembly is based on Oxford Nanopore reads and was improved using Illumina reads for error correction. We also outline how to evaluate and choose from …

Sars-Cov-2 Infection Increases Risk Of Acute Kidney Injury In A Bimodal Age Distribution, Erica C Bjornstad, Gary Cutter, Pramod Guru, Shina Menon, Isabella Aldana, Scott House, Nancy M Tofil, Catherine A St Hill, Yasir Tarabichi, Valerie M Banner-Goodspeed, Amy B Christie, Surapaneni Krishna Mohan, Devang Sanghavi, Jarrod M Mosier, Girish Vadgaonkar, Allan J Walkey, Rahul Kashyap, Vishakha K Kumar, Vikas Bansal, Karen Boman, Mayank Sharma, Marija Bogojevic, Neha Deo, Lynn Retford, Ognjen Gajic, Katja M Gist, Sccm Discovery Virus Investigators Group

Faculty, Staff and Students Publications

BACKGROUND: Hospitalized patients with SARS-CoV2 develop acute kidney injury (AKI) frequently, yet gaps remain in understanding why adults seem to have higher rates compared to children. Our objectives were to evaluate the epidemiology of SARS-CoV2-related AKI across the age spectrum and determine if known risk factors such as illness severity contribute to its pattern.

METHODS: Secondary analysis of ongoing prospective international cohort registry. AKI was defined by KDIGO-creatinine only criteria. Log-linear, logistic and generalized estimating equations assessed odds ratios (OR), risk differences (RD), and 95% confidence intervals (CIs) for AKI and mortality adjusting for sex, pre-existing comorbidities, race/ethnicity, illness severity, …

Reducing Influenza Virus Transmission: The Potential Value Of Antiviral Treatment, Frederick G Hayden, Jason Asher, Benjamin J Cowling, Aeron C Hurt, Hideyuki Ikematsu, Klaus Kuhlbusch, Annabelle Lemenuel-Diot, Zhanwei Du, Lauren Ancel Meyers, Pedro A Piedra, Takahiro Takazono, Hui-Ling Yen, Arnold S Monto

Faculty, Staff and Students Publications

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication after antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients seems to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of …

Depletion Of The Apical Endosome In Response To Viruses And Bacterial Toxins Provides Cell-Autonomous Host Defense At Mucosal Surfaces, Keiko Maeda, Nicholas C Zachos, Megan H Orzalli, Stefanie S Schmieder, Denis Chang, Katlynn Bugda Gwilt, Michele Doucet, Nicholas W Baetz, Sun Lee, Sue E Crawford, Mary K Estes, Jonathan C Kagan, Jerrold R Turner, Wayne I Lencer

Faculty, Staff and Students Publications

Polarized epithelial cells form an essential barrier against infection at mucosal surfaces. Many pathogens breach this barrier to cause disease, often by co-opting cellular endocytosis mechanisms to enter the cell through the lumenal (apical) cell surface. We recently discovered that the loss of the cell polarity gene PARD6B selectively diminishes apical endosome function. Here, we find that in response to the entry of certain viruses and bacterial toxins into the epithelial cells via the apical membrane, PARD6B and aPKC, two components of the PARD6B-aPKC-Cdc42 apical polarity complex, undergo rapid proteasome-dependent degradation. The perturbation of apical membrane glycosphingolipids by toxin- or …

Regulation Of The Double-Stranded Rna Response Through Adar1 Licenses Metaplastic Reprogramming In Gastric Epithelium, José B Sáenz, Nancy Vargas, Charles J Cho, Jason C Mills

Faculty, Staff and Students Publications

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of …

Myocardial Rev-Erb-Mediated Diurnal Metabolic Rhythm And Obesity Paradox, Shiyang Song, Chih-Liang Tien, Hao Cui, Paul Basil, Ningxia Zhu, Yingyun Gong, Wenbo Li, Hui Li, Qiying Fan, Jong Min Choi, Weijia Luo, Yanfeng Xue, Rui Cao, Wenjun Zhou, Andrea R Ortiz, Brittany Stork, Vatsala Mundra, Nagireddy Putluri, Brian York, Maoping Chu, Jiang Chang, Sung Yun Jung, Liang Xie, Jiangping Song, Lilei Zhang, Zheng Sun

Faculty, Staff and Students Publications

BACKGROUND: The nuclear receptor Rev-erbα/β, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear.

METHODS: We generated mouse lines with cardiac-specific Rev-erbα/β knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) …

Cryo-Et Of Toxoplasma Parasites Gives Subnanometer Insight Into Tubulin-Based Structures, Stella Y Sun, Li-Av Segev-Zarko, Muyuan Chen, Grigore D Pintilie, Michael F Schmid, Steven J Ludtke, John C Boothroyd, Wah Chiu

Faculty, Staff and Students Publications

Tubulin is a conserved protein that polymerizes into different forms of filamentous structures in Toxoplasma gondii, an obligate intracellular parasite in the phylum Apicomplexa. Two key tubulin-containing cytoskeletal components are subpellicular microtubules (SPMTs) and conoid fibrils (CFs). The SPMTs help maintain shape and gliding motility, while the CFs are implicated in invasion. Here, we use cryogenic electron tomography to determine the molecular structures of the SPMTs and CFs in vitrified intact and detergent-extracted parasites. Subvolume densities from detergent-extracted parasites yielded averaged density maps at subnanometer resolutions, and these were related back to their architecture in situ. An intralumenal spiral …

Retinal Horizontal Cells Use Different Synaptic Sites For Global Feedforward And Local Feedback Signaling, Christian Behrens, Shubhash Chandra Yadav, Maria M Korympidou, Yue Zhang, Silke Haverkamp, Stephan Irsen, Anna Schaedler, Xiaoyu Lu, Zhuohe Liu, Jan Lause, François St-Pierre, Katrin Franke, Anna Vlasits, Karin Dedek, Robert G Smith, Thomas Euler, Philipp Berens, Timm Schubert

Faculty, Staff and Students Publications

In the outer plexiform layer (OPL) of the mammalian retina, cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). In the mouse, this transmission is modulated by a single horizontal cell (HC) type. HCs perform global signaling within their laterally coupled network but also provide local, cone-specific feedback. However, it is unknown how HCs provide local feedback to cones at the same time as global forward signaling to CBCs and where the underlying synapses are located. To assess how HCs simultaneously perform different modes of signaling, we reconstructed the dendritic trees of five …

Imaging-Based Screening Of Deubiquitinating Proteases Identifies Otubain-1 As A Stabilizer Of C-Myc, Shannon E Moree, Laure Maneix, Polina Iakova, Fabio Stossi, Ergun Sahin, Andre Catic

Faculty, Staff and Students Publications

The ubiquitin-proteasome pathway precisely controls the turnover of transcription factors in the nucleus, playing an important role in maintaining appropriate quantities of these regulatory proteins. The transcription factor c-MYC is essential for normal development and is a critical cancer driver. Despite being highly expressed in several tissues and malignancies, the c-MYC protein is also continuously targeted by the ubiquitin-proteasome pathway, which can either facilitate or inhibit c-MYC degradation. Deubiquitinating proteases can remove ubiquitin chains from target proteins and rescue them from proteasomal digestion. This study sought to determine novel elements of the ubiquitin-proteasome pathway that regulate c-MYC levels. We performed …