Digital Commons Network^™

Pancreatic Differentiation Of Stem Cells Reveals Pathogenesis Of A Syndrome Of Ketosis-Prone Diabetes, Diane Yang, Sanjeet Patel, Wojciech J Szlachcic, Jolanta Chmielowiec, Diane Scaduto, Nagireddy Putluri, Arun Sreekumar, James Suliburk, Michael Metzker, Ashok Balasubramanyam, Malgorzata Borowiak

Faculty, Staff and Students Publications

Genetic analysis of an adult patient with an unusual course of ketosis-prone diabetes (KPD) and lacking islet autoantibodies demonstrated a nucleotide variant in the 5′-untranslated region (UTR) of PDX1, a β-cell development gene. When differentiated to the pancreatic lineage, his induced pluripotent stem cells stalled at the definitive endoderm (DE) stage. Metabolomics analysis of the cells revealed that this was associated with leucine hypersensitivity during transition from the DE to the pancreatic progenitor (PP) stage, and RNA sequencing showed that defects in leucine-sensitive mTOR pathways contribute to the differentiation deficiency. CRISPR/Cas9 manipulation of the PDX1 variant demonstrated that it …

A Systematic Review Of The Use Of St John's Wort For Smoking Cessation In Adults, Namrata Walia, Sandra Gonzalez, Roger Zoorob

Faculty, Staff and Students Publications

St. John's wort (SJW) has been researched and clinically used for treating various psychiatric disorders, including depression. Few clinical trials have studied its use in smoking cessation. This systematic review provides comprehensive evidence of the studies conducted to date. Five databases were searched for randomized controlled trials (RCTs) that evaluated the effectiveness of SJW for smoking cessation in adults. The trials included the use of SJW alone, or along with nicotine replacement therapy, chromium, or behavioral therapies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to report this systematic review. Overall, four RCTs met the eligibility …

Hyperkalemia Management In The Emergency Department: An Expert Panel Consensus, Zubaid Rafique, Frank Peacock, Terra Armstead, Jason J Bischof, Joanna Hudson, Matthew R Weir, James Neuenschwander

Faculty, Staff and Students Publications

Hyperkalemia is a common electrolyte abnormality identified in the emergency department (ED) and potentially fatal. However, there is no consensus over the potassium threshold that warrants intervention or its treatment algorithm. Commonly used medications are at best temporizing measures, and the roles of binders are unclear in the emergent setting. As the prevalence of comorbid conditions altering potassium homeostasis rises, hyperkalemia becomes more common, and hence there is a need to standardize management. A panel was assembled to synthesize the available evidence and identify gaps in knowledge in hyperkalemia treatment in the ED. The panel was composed of 7 medical …

Cellular Regeneration As A Potential Strategy To Treat Cardiac Conduction Disorders, Satadru K Lahiri, Mohit M Hulsurkar, Xander Ht Wehrens

Faculty, Staff and Students Publications

Loss of atrioventricular conduction system (AVCS) cells due to either inherited or acquired deficits leads to conduction diseases, which can deteriorate into fatal cardiac arrhythmias and sudden death. In this issue of the JCI, Wang et al. constructed a mouse model of atrioventricular block (AVB) by inducing AVCS cell-specific injury using the Cx30.2 enhancer to drive expression of diphtheria toxin fragment A. AVCS cell ablation in adult mice led to irreversible AVB. jkjkIn contrast, AVCS cell injury in neonatal mice was followed by spontaneous recovery in a subset of mice, revealing a limited postnatal time window during which the regeneration …

The Ephb2 Receptor Uses Homotypic, Head-To-Tail Interactions Within Its Ectodomain As An Autoinhibitory Control Mechanism, Yan Xu, Dorothea Robev, Nayanendu Saha, Bingcheng Wang, Matthew B. Dalva, Kai Xu, Juha P. Himanen, Dimitar B. Nikolov

Department of Neuroscience Faculty Papers

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding …

Clinically Relevant Dosage Of Vancomycin Does Not Negatively Impact Periosteum Derived Osteoblast Precursor Cellular Functions, Alexis Hernandez

Seton Hall University Dissertations and Theses (ETDs)

Surgical site infections (SSI) can develop post-operatively and carry significant clinical and financial implications. SSI can carry a cost of up to $30,000 per case, as well as an estimated 6 day longer hospitalization. Patients with Type II Diabetes (DM) have an increased susceptibility to infection and suffer from poor bone healing overall. Therefore, diabetic patients who have undergone orthopedic surgery risk both an increased chance of developing an SSI as well as suboptimal bone healing. Vancomycin and other antibiotics have traditionally been used prophylactically to prevent infection, however the effect of vancomycin on bone healing in a diabetic population …

Supercoiling And Looping Promote Dna Base Accessibility And Coordination Among Distant Sites, Jonathan M Fogg, Allison K Judge, Erik Stricker, Hilda L Chan, Lynn Zechiedrich

Faculty, Staff and Students Publications

DNA in cells is supercoiled and constrained into loops and this supercoiling and looping influence every aspect of DNA activity. We show here that negative supercoiling transmits mechanical stress along the DNA backbone to disrupt base pairing at specific distant sites. Cooperativity among distant sites localizes certain sequences to superhelical apices. Base pair disruption allows sharp bending at superhelical apices, which facilitates DNA writhing to relieve torsional strain. The coupling of these processes may help prevent extensive denaturation associated with genomic instability. Our results provide a model for how DNA can form short loops, which are required for many essential …

Usability Of Abattoir-Acquired Pig Eyes For Refractive Excimer Laser Research, Marius Topka, Yao Zhang, Antonia Bock, Peter Riedel, Johannes Lörner, Alexander Hammer, Eva Maier, Friedrich Paulsen, Christian M Hammer

Faculty, Staff and Student Publications

The purpose of this study was to elucidate, under which conditions abattoir-acquired pig eyes are suitable for refractive excimer laser experiments. Porcine eyes from tunnel-scalded (n = 5) and tank-scalded (n = 10) pigs were compared to unscalded eyes (n = 5) and to eyes scalded in the laboratory (n = 5). The corneal epithelium was removed before an excimer laser was used to perform a - 8.0 D photoablation. Corneal thickness was measured by optical coherence topography before and after photoablation. The ablation depth was determined with a contour measuring station, the morphology of the ablated areas was characterized …

Leveraging High-Resolution 7-Tesla Mri To Derive Quantitative Metrics For The Trigeminal Nerve And Subnuclei Of Limbic Structures In Trigeminal Neuralgia, Judy Alper, Alan C. Seifert, Gaurav Verma, Kuang-Han Huang, Yael Jacob, Ameen Al Qadi, John W. Rutland, Sheetal Patel, Joshua Bederson, Raj K. Shrivastava, Bradley N. Delman, Priti Balchandani

Publications and Research

Background: Trigeminal Neuralgia (TN) is a chronic neurological disease that is strongly associated with neurovascular compression (NVC) of the trigeminal nerve near its root entry zone. The trigeminal nerve at the site of NVC has been extensively studied but limbic structures that are potentially involved in TN have not been adequately characterized. Specifically, the hippocampus is a stress-sensitive region which may be structurally impacted by chronic TN pain. As the center of the emotion-related network, the amygdala is closely related to stress regulation and may be associated with TN pain as well. The thalamus, which is involved in the trigeminal …

Discovery Of Potent Bet Bromodomain 1 Stereoselective Inhibitors Using Dna-Encoded Chemical Library Selections, Rajesh Sharma, Kyoung-Jae Choi, My Diem Quan, Sonum Sharma, Banumathi Sankaran, Hyekyung Park, Anel Lagrone, Jean J Kim, Kevin R Mackenzie, Allan Chris M Ferreon, Choel Kim, Josephine C Ferreon

Faculty, Staff and Students Publications

Expression of a few master transcription factors can reprogram the epigenetic landscape and three-dimensional chromatin topology of differentiated cells and achieve pluripotency. During reprogramming, thousands of long-range chromatin contacts are altered, and changes in promoter association with enhancers dramatically influence transcription. Molecular participants at these sites have been identified, but how this re-organization might be orchestrated is not known. Biomolecular condensation is implicated in subcellular organization, including the recruitment of RNA polymerase in transcriptional activation. Here, we show that reprogramming factor KLF4 undergoes biomolecular condensation even in the absence of its intrinsically disordered region. Liquid-liquid condensation of the isolated KLF4 …

Associations Between Air Pollution Exposure And Empirically Derived Profiles Of Cognitive Performance In Older Women, Andrew J. Petkus, Diana Younan, Xinhui Wang, Daniel P. Beavers, Mark A. Espeland, Margaret Gatz, Tara Gruenewald, Joel D. Kaufman, Helena C. Chui, Joshua Millstein, Stephen R. Rapp, Joann E. Manson, Susan M. Resnick, Gregory A. Wellenius, Eric A. Whitsel, Keith Widaman, Jiu-Chiuan Chen

Psychology Faculty Articles and Research

Background:Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. Objective:We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women. Method:Women (N = 2,142) from the Women’s Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant’s addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. Result:Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10–1.52) or superior attention (OR = 1.30; 95% CI = 1.10–1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17–1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67–0.97). Conclusion:Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains.

The Immunotherapy Candidate Tnfsf4 May Help The Induction Of A Promising Immunological Response In Breast Carcinomas, Kai Li, Lei Ma, Ye Sun, Xiang Li, Hong Ren, Shou-Ching Tang, Xin Sun

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Immune checkpoint blockade, an immunotherapy, has been applied in multiple systemic malignancies and has improved overall survival to a relatively great extent; whether it can be applied in breast cancer remains unknown. We endeavored to explore possible factors that may influence immunotherapy outcomes in breast cancer using several public databases. The possible treatment target TNF superfamily member 4 (TNFSF4) was selected from many candidates based on its abnormal expression profile, survival-associated status, and ability to predict immune system reactions. For the first time, we identified the oncogenic features of TNFSF4 in breast carcinoma. TNFSF4 was revealed to be closely related …

Protein Cofactors And Substrate Influence Mg2+-Dependent Structural Changes In The Catalytic Rna Of Archaeal Rnase P, Ila A Marathe, Stella M Lai, Walter J Zahurancik, Michael G Poirier, Vicki H Wysocki, Venkat Gopalan

Faculty, Staff and Student Publications

The ribonucleoprotein (RNP) form of archaeal RNase P comprises one catalytic RNA and five protein cofactors. To catalyze Mg2+-dependent cleavage of the 5' leader from pre-tRNAs, the catalytic (C) and specificity (S) domains of the RNase P RNA (RPR) cooperate to recognize different parts of the pre-tRNA. While ∼250-500 mM Mg2+ renders the archaeal RPR active without RNase P proteins (RPPs), addition of all RPPs lowers the Mg2+ requirement to ∼10-20 mM and improves the rate and fidelity of cleavage. To understand the Mg2+- and RPP-dependent structural changes that increase activity, we used pre-tRNA cleavage and ensemble FRET assays to …

Validation Of An Electronic Trigger To Measure Missed Diagnosis Of Stroke In Emergency Departments, Viralkumar Vaghani, Li Wei, Umair Mushtaq, Dean F Sittig, Andrea Bradford, Hardeep Singh

Faculty, Staff and Students Publications

OBJECTIVE: Diagnostic errors are major contributors to preventable patient harm. We validated the use of an electronic health record (EHR)-based trigger (e-trigger) to measure missed opportunities in stroke diagnosis in emergency departments (EDs).

METHODS: Using two frameworks, the Safer Dx Trigger Tools Framework and the Symptom-disease Pair Analysis of Diagnostic Error Framework, we applied a symptom-disease pair-based e-trigger to identify patients hospitalized for stroke who, in the preceding 30 days, were discharged from the ED with benign headache or dizziness diagnoses. The algorithm was applied to Veteran Affairs National Corporate Data Warehouse on patients seen between 1/1/2016 and 12/31/2017. Trained …

Development Of A Recombinant Vaccine Against Human Onchocerciasis., David Abraham, John Graham-Brown, Darrick Carter, Sean A. Gray, Jessica A. Hess, Benjamin L. Makepeace, Sara Lustigman

Department of Microbiology and Immunology Faculty Papers

Introduction: Human onchocerciasis caused by the filarial nematode parasite Onchocerca volvulus remains a major cause of debilitating disease infecting millions primarily in Sub-Saharan Africa. The development of a prophylactic vaccine, along with mass drug administration, would facilitate meeting the goal of onchocerciasis elimination by 2030.

Areas covered: Models used to study immunity to Onchocerca include natural infection of cattle with Onchocerca ochengi and O. volvulus infective third-stage larvae implanted within diffusion chambers in mice. A vaccine, comprised of two adjuvanted recombinant antigens, induced protective immunity in genetically diverse mice suggesting that it will function similarly in diverse human populations. These …

A Structural Study Of The Cytoplasmic Chaperone Effect Of 14-3-3 Proteins On Ataxin-1, Seppe Leysen, Rebecca Jane Burnley, Elizabeth Rodriguez, Lech-Gustav Milroy, Lorenzo Soini, Carolyn J Adamski, Larissa Nitschke, Rachel Davis, Tomas Obsil, Lucas Brunsveld, Tom Crabbe, Huda Yahya Zoghbi, Christian Ottmann, Jeremy Martin Davis

Faculty, Staff and Students Publications

Expansion of the polyglutamine tract in the N terminus of Ataxin-1 is the main cause of the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1). However, the C-terminal part of the protein - including its AXH domain and a phosphorylation on residue serine 776 - also plays a crucial role in disease development. This phosphorylation event is known to be crucial for the interaction of Ataxin-1 with the 14-3-3 adaptor proteins and has been shown to indirectly contribute to Ataxin-1 stability. Here we show that 14-3-3 also has a direct anti-aggregation or "chaperone" effect on Ataxin-1. Furthermore, we provide structural and …

Determining Effective Drug Concentrations For Selection And Counterselection Genetics In Drosophila Melanogaster, Nick Matinyan, Yezabel Gonzalez, Herman A Dierick, Koen J T Venken

Faculty, Staff and Students Publications

We recently integrated into fly genetics a set of four selection and two counterselection markers and their corresponding drugs that can be used individually or in combination. These markers eliminate the need to visually screen progeny. Before using these markers in new genetic backgrounds, effective selection/counterselection concentrations should be established for each marker/drug combination. This protocol describes how to set up, perform, and analyze a drug titration curve to determine the effective selection/counterselection drug concentrations for their corresponding markers. For complete details on the use and execution of this protocol, please refer to Matinyan et al., 2021.

Identification Of Micrornas And Gene Regulatory Networks In Cleft Lip Common In Humans And Mice, Hiroki Yoshioka, Aimin Li, Akiko Suzuki, Sai Shankar Ramakrishnan, Zhongming Zhao, Junichi Iwata

Faculty, Staff and Student Publications

The etiology of cleft lip with/without cleft palate (CL/P), one of the most frequent craniofacial birth defects worldwide, is complicated by contributions of both genetic and environmental factors. Understanding the etiology of these conditions is essential for developing preventive strategies. This study thus aims to identify regulatory networks of microRNAs (miRNAs), transcriptional factors (TFs) and non-TF genes associated with cleft lip (CL) that are conserved in humans and mice. Notably, we found that miR-27b, miR-133b, miR-205, miR-376b and miR-376c were involved in the regulation of CL-associated gene expression in both humans and mice. Among the candidate miRNAs, the overexpression of …

Front-Loading Of Anatomy Content Has No Effect On Long-Term Anatomy Knowledge Retention Among Physical Therapy Students: A Prospective Cohort Study., Amy H. Amabile, Kim Nixon-Cave, Larry J. Georgetti, Ashley C. Sims

Department of Physical Therapy Faculty Papers

BACKGROUND: Information learned over a longer period of time has been shown to result in better long-term knowledge retention than information learned over a shorter period of time. In order to address multiple curricular goals, the timing and spacing of anatomy content within the Doctor of Physical Therapy (DPT) program at our institution recently changed from a very spaced to a very compressed format. The purpose of the present study was to assess differences in anatomy knowledge retention that might have been impacted by this change. The research hypothesis was that students receiving spaced instruction would have significantly better anatomy …

Multiplexed Drug-Based Selection And Counterselection Genetic Manipulations In Drosophila, Nick Matinyan, Mansi S Karkhanis, Yezabel Gonzalez, Antrix Jain, Alexander Saltzman, Anna Malovannaya, Alejandro Sarrion-Perdigones, Herman A Dierick, Koen J T Venken

Faculty, Staff and Students Publications

The power of Drosophila melanogaster as a model system relies on tractable germline genetic manipulations. Despite Drosophila's expansive genetics toolbox, such manipulations are still accomplished one change at a time and depend predominantly on phenotypic screening. We describe a drug-based genetic platform consisting of four selection and two counterselection markers, eliminating the need to screen for modified progeny. These markers work reliably individually or in combination to produce specific genetic outcomes. We demonstrate three example applications of multiplexed drug-based genetics by generating (1) transgenic animals, expressing both components of binary overexpression systems in a single transgenesis step; (2) dual selectable …

Exercise Intolerance In Older Adults With Heart Failure With Preserved Ejection Fraction: Jacc State-Of-The-Art Review, Ambarish Pandey, Sanjiv J Shah, Javed Butler, Dean L Kellogg, Gregory D Lewis, Daniel E Forman, Robert J Mentz, Barry A Borlaug, Marc A Simon, Julio A Chirinos, Roger A Fielding, Elena Volpi, Anthony J A Molina, Mark J Haykowsky, Flora Sam, Bret H Goodpaster, Alain G Bertoni, Jamie N Justice, James P White, Jingzhone Ding, Scott L Hummel, Nathan K Lebrasseur, George E Taffet, Iraklis I Pipinos, Dalane Kitzman

Faculty, Staff and Students Publications

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the …

Intouch September 13, 2021, New York Medical College

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Ankyrin-Dependent Na+ Channel Clustering Prevents Neuromuscular Synapse Fatigue, Chuansheng Zhang, Abhijeet Joshi, Yanhong Liu, Ozlem Sert, Seth G Haddix, Lindsay H Teliska, Anne Rasband, George G Rodney, Matthew N Rasband

Faculty, Staff and Students Publications

Skeletal muscle contraction depends on activation of clustered acetylcholine receptors (AchRs) and muscle-specific Na+ channels (Nav1.4). Some Nav1.4 channels are highly enriched at the neuromuscular junction (NMJ) and their clustering is thought to be essential for effective muscle excitation. However, this has not been experimentally tested, and how NMJ Na+ channels are clustered is unknown. Here, using muscle-specific AnkyrinR, AnkyrinB, and AnkyrinG single, double, and triple-conditional knockout mice we show that Nav1.4 channels fail to cluster only after deletion of all three ankyrins. Remarkably, ankyrin-deficient muscles have normal NMJ morphology, AchR clustering, sarcolemmal levels of Nav1.4, and muscle force, and …

Understanding Pediatric Surgery Cancellation: Geospatial Analysis, Lei Liu, Yizhao Ni, Andrew F Beck, Cole Brokamp, Ryan C Ramphul, Linda D Highfield, Megha Karkera Kanjia, J Nick Pratap

Faculty, Staff and Students Publications

BACKGROUND: Day-of-surgery cancellation (DoSC) represents a substantial wastage of hospital resources and can cause significant inconvenience to patients and families. Cancellation is reported to impact between 2% and 20% of the 50 million procedures performed annually in American hospitals. Up to 85% of cancellations may be amenable to the modification of patients' and families' behaviors. However, the factors underlying DoSC and the barriers experienced by families are not well understood.

OBJECTIVE: This study aims to conduct a geospatial analysis of patient-specific variables from electronic health records (EHRs) of Cincinnati Children's Hospital Medical Center (CCHMC) and of Texas Children's Hospital (TCH), …

Invariant Natural Killer T-Cell Subsets Have Diverse Graft-Versus-Host-Disease-Preventing And Antitumor Effects, Kristina Maas-Bauer, Juliane K Lohmeyer, Toshihito Hirai, Teresa Lopes Ramos, Furqan M Fazal, Ulrike M Litzenburger, Kathryn E Yost, Jessica V Ribado, Neeraja Kambham, Arielle S Wenokur, Po-Yu Lin, Maite Alvarez, Melissa Mavers, Jeanette Baker, Ami S Bhatt, Howard Y Chang, Federico Simonetta, Robert S Negrin

Faculty, Staff and Students Publications

Invariant natural killer T (iNKT) cells are a T-cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic graft-versus-host-disease (GVHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2, and iNKT17 sublineages, which differ transcriptomically and epigenomically and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GVHD is currently unknown. In this work, we generated highly purified murine iNKT sublineages, characterized their transcriptomic and epigenomic landscape, …

Dna-Encoded Chemistry Technology Yields Expedient Access To Sars-Cov-2m Pro Inhibitors, Srinivas Chamakuri, Shuo Lu, Melek Nihan Ucisik, Kurt M Bohren, Ying-Chu Chen, Huang-Chi Du, John C Faver, Ravikumar Jimmidi, Feng Li, Jian-Yuan Li, Pranavanand Nyshadham, Stephen S Palmer, Jeroen Pollet, Xuan Qin, Shannon E Ronca, Banumathi Sankaran, Kiran L Sharma, Zhi Tan, Leroy Versteeg, Zhifeng Yu, Martin M Matzuk, Timothy Palzkill, Damian W Young

Faculty, Staff and Students Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration–approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition …

Dna-Encoded Chemistry Technology Yields Expedient Access To Sars-Cov-2m Pro Inhibitors, Srinivas Chamakuri, Shuo Lu, Melek Nihan Ucisik, Kurt M Bohren, Ying-Chu Chen, Huang-Chi Du, John C Faver, Ravikumar Jimmidi, Feng Li, Jian-Yuan Li, Pranavanand Nyshadham, Stephen S Palmer, Jeroen Pollet, Xuan Qin, Shannon E Ronca, Banumathi Sankaran, Kiran L Sharma, Zhi Tan, Leroy Versteeg, Zhifeng Yu, Martin M Matzuk, Timothy Palzkill, Damian W Young

Faculty, Staff and Students Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration–approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition …

Beta-Blockers In The Critically Ill: Friend Or Foe?, Mourad H Senussi

Faculty, Staff and Students Publications

No abstract provided.

The Onset Of Exercise-Associated Hyponatremia And Individual Differences In Inappropriate Arginine Vasopressin Excretion: A Review Of Proposed Mechanisms, Michelle Stehman, Stephen A. Maris

Topics in Exercise Science and Kinesiology

Topics in Exercise Science and Kinesiology Volume 2: Issue 1, Article 10, 2021. Exercise-associated hyponatremia (EAH) has been reported to develop during endurance events such as triathlons and marathons. As these events become more popular, the incidence of developing EAH also increases. The development of EAH is commonly associated with the overconsumption of hypotonic fluids such as water and tends to be more prevalent in females. There is also evidence to suggest the inappropriate secretion of arginine vasopressin (AVP) leading to water retention may predispose an individual for developing EAH, especially when coupled with the overconsumption of fluids. Recent research …

The Concurrence Of Dna Methylation And Demethylation Is Associated With Transcription Regulation, Jiejun Shi, Jianfeng Xu, Yiling Elaine Chen, Jason Sheng Li, Ya Cui, Lanlan Shen, Jingyi Jessica Li, Wei Li

Children’s Nutrition Research Center Staff Publications

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. …