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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 …

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 …

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

Faculty, Staff and Students Publications

No abstract provided.

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 …

Adar And Hnrnpc Deficiency Synergize In Activating Endogenous Dsrna-Induced Type I Ifn Responses, Anna-Maria Herzner, Zia Khan, Eric L Van Nostrand, Sara Chan, Trinna Cuellar, Ronald Chen, Ximo Pechuan-Jorge, Laszlo Komuves, Margaret Solon, Zora Modrusan, Benjamin Haley, Gene W Yeo, Timothy W Behrens, Matthew L Albert

Faculty, Staff and Students Publications

Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA checkpoints, we conducted a candidate screen in THP-1 monocytes and found that hnRNPC and ADAR deficiency resulted in synergistic induction of MDA5-dependent IFN responses. RNA-seq analysis demonstrated dysregulation of Alu-containing introns in hnRNPC-deficient cells via utilization of unmasked cryptic splice sites, including introns containing ADAR-dependent A-to-I editing clusters. These putative MDA5 ligands showed reduced editing in the absence of ADAR, …

Endothelium-Specific Depletion Of Lrp1 Improves Glucose Homeostasis Through Inducing Osteocalcin, Hua Mao, Luge Li, Qiying Fan, Aude Angelini, Pradip K Saha, Cristian Coarfa, Kimal Rajapakshe, Dimuthu Perera, Jizhong Cheng, Huaizhu Wu, Christie M Ballantyne, Zheng Sun, Liang Xie, Xinchun Pi

Faculty, Staff and Students Publications

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density …

Devastating Effect Of Untreated Facial Squamous Cell Carcinoma, Nasim Khalfe, Ya Xu, Elizabeth May Schuele, Doris Lin

Faculty, Staff and Students Publications

Skin cancer develops primarily on areas of sun-exposed skin and can typically be treated if caught early. Here, we present a case of a 57-year-old man who presented with an extremely large facial squamous cell carcinoma with resulting perineural invasion and metastasis to parotid lymph nodes because he was unable to obtain timely treatment.

Predicting Lymph Node Metastasis In Non-Small Cell Lung Cancer: Prospective External And Temporal Validation Of The Hal And Homer Models, Gabriela Martinez-Zayas, Francisco A Almeida, Lonny Yarmus, Daniel Steinfort, Donald R Lazarus, Michael J Simoff, Timothy Saettele, Septimiu Murgu, Tarek Dammad, D Kevin Duong, Lakshmi Mudambi, Joshua J Filner, Sofia Molina, Carlos Aravena, Jeffrey Thiboutot, Asha Bonney, Adriana M Rueda, Labib G Debiane, D Kyle Hogarth, Harmeet Bedi, Mark Deffebach, Ala-Eddin S Sagar, Joseph Cicenia, Diana H Yu, Avi Cohen, Laura Frye, Horiana B Grosu, Thomas Gildea, David Feller-Kopman, Roberto F Casal, Michael Machuzak, Muhammad H Arain, Sonali Sethi, George A Eapen, Louis Lam, Carlos A Jimenez, Manuel Ribeiro, Laila Z Noor, Atul Mehta, Juhee Song, Humberto Choi, Junsheng Ma, Liang Li, David E Ost

Faculty, Staff and Students Publications

BACKGROUND: Two models, the Help with the Assessment of Adenopathy in Lung cancer (HAL) and Help with Oncologic Mediastinal Evaluation for Radiation (HOMER), were recently developed to estimate the probability of nodal disease in patients with non-small cell lung cancer (NSCLC) as determined by endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). The objective of this study was to prospectively externally validate both models at multiple centers.

RESEARCH QUESTION: Are the HAL and HOMER models valid across multiple centers?

STUDY DESIGN AND METHODS: This multicenter prospective observational cohort study enrolled consecutive patients with PET-CT clinical-radiographic stages T1-3, N0-3, M0 NSCLC undergoing EBUS-TBNA staging. …

A Narrative Review Of Interstitial Lung Disease In Anti-Synthetase Syndrome: A Clinical Approach, Naina Sawal, Sanjay Mukhopadhyay, Sheetal Rayancha, Alastair Moore, Puneet Garcha, Anupam Kumar, Viren Kaul

Faculty, Staff and Students Publications

Anti-synthetase syndrome (AS) is a rare autoimmune disorder characterized by the presence of aminoacyl-transfer RNA synthetase antibodies in conjunction with clinical features such as interstitial lung disease (ILD), Raynaud's phenomenon, nonerosive arthritis, and myopathy. AS distinguishes itself from other inflammatory myopathies by its significant lung involvement and rapidly progressive interstitial lung disease (AS-ILD), therefore the management of AS-ILD requires careful clinical, serologic and radiologic assessment. Glucocorticoids are considered the mainstay of therapy; however, additional immunosuppressive agents are often required to achieve disease control. Patient prognosis is highly dependent on early diagnosis and symptom recognition as the antibody profile is thought …

Treatment Options For Managing Obesity In Chronic Kidney Disease, Vishnu P Parvathareddy, Krishiv M Ella, Maulin Shah, Sankar D Navaneethan

Faculty, Staff and Students Publications

PURPOSE OF REVIEW: Obesity is a risk factor for the development and progression of chronic kidney disease (CKD). In this review, we provide a comprehensive overview of various management options (lifestyle intervention, medications, and bariatric surgery) to address obesity in those with CKD.

RECENT FINDINGS: Few clinical trials have examined the benefits of lifestyle modifications in those with preexisting CKD and suggest potential renal and cardiovascular benefits in this population. Yet, superiority of different dietary regimen to facilitate weight loss in CKD is unclear. Although medications could offer short-term benefits and assist weight loss, their safety and long-term benefits warrant …

Exogenous Inter-Α Inhibitor Proteins Prevent Cell Death And Improve Ischemic Stroke Outcomes In Mice, Louise D Mccullough, Meaghan Roy-O'Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C Kraushaar, Anjali Chauhan, Lauren H Sansing, Barbara S Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna

Faculty, Staff and Students Publications

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when …

Structure And Dynamics Of Photoreceptor Sensory Cilia, Theodore G Wensel, Valencia L Potter, Abigail Moye, Zhixian Zhang, Michael A Robichaux

Faculty, Staff and Students Publications

The rod and cone photoreceptor cells of the vertebrate retina have highly specialized structures that enable them to carry out their function of light detection over a broad range of illumination intensities with optimized spatial and temporal resolution. Most prominent are their unusually large sensory cilia, consisting of outer segments packed with photosensitive disc membranes, a connecting cilium with many features reminiscent of the primary cilium transition zone, and a pair of centrioles forming a basal body which serves as the platform upon which the ciliary axoneme is assembled. These structures form a highway through which an enormous flux of …

Zfta-Rela Dictates Oncogenic Transcriptional Programs To Drive Aggressive Supratentorial Ependymoma, Amir Arabzade, Yanhua Zhao, Srinidhi Varadharajan, Hsiao-Chi Chen, Selin Jessa, Bryan Rivas, Austin J Stuckert, Minerva Solis, Alisha Kardian, Dana Tlais, Brian J Golbourn, Ann-Catherine J Stanton, Yuen San Chan, Calla Olson, Kristen L Karlin, Kathleen Kong, Robert Kupp, Baoli Hu, Sarah G Injac, Madeline Ngo, Peter R Wang, Luz A De León, Felix Sahm, Daisuke Kawauchi, Stefan M Pfister, Charles Y Lin, H Courtney Hodges, Irtisha Singh, Thomas F Westbrook, Murali M Chintagumpala, Susan M Blaney, Donald W Parsons, Kristian W Pajtler, Sameer Agnihotri, Richard J Gilbertson, Joanna Yi, Nada Jabado, Claudia L Kleinman, Kelsey C Bertrand, Benjamin Deneen, Stephen C Mack

Faculty, Staff and Students Publications

Over 60% of supratentorial (ST) ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE driven ZRfus tumors by CUT&RUN, ChIP, ATAC, and RNA sequencing and compared to human ZRfus driven ependymoma. In addition to direct canonical NF-κB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates …

Renal Involvement And Its Treatment In Pediatric Patients With Proteinase-3 Anti-Neutrophil Cytoplasmic Antibody Positive Granulomatosis With Polyangiitis: A Case Series, Xiaoyan Wu, Elizabeth Mancuso, Isabel Armendi, David Krasinski, Lin Liu, Shauna Tarsi, Wayne R Waz, Rabheh Abdul-Aziz, Ewa Elenberg

Faculty, Staff and Students Publications

We describe three pediatric patients between the ages of 10 and 14 years old who were diagnosed with granulomatosis with polyangiitis (GPA) between 2014 and 2019. Each case involves variations in presentation, symptomatology, diagnostics, and induction and maintenance therapy regimens. Patient 1 presented with significant renal involvement, hypertensive emergency, and focal alveolar hemorrhage, a rare presentation of GPA that causes up to 60% mortality.Patient 2 presented with minimal renal involvement and a diffuse petechial rash, which is the most common cutaneous presentation of GPA. Finally, patient 3 presented with significant renal involvement and later on with symptoms of idiopathic intracranial …

Use Of Human Tissue Stem Cell-Derived Organoid Cultures To Model Enterohepatic Circulation, Sarah E Blutt, Sue E Crawford, Carolyn Bomidi, Xi-Lei Zeng, James R Broughman, Matthew Robertson, Cristian Coarfa, Mary Elizabeth M Tessier, Tor Savidge, F Blaine Hollinger, Steven A Curley, Mark Donowitz, Mary K Estes

Faculty, Staff and Students Publications

The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiological and pathophysiological processes that are unable to be studied using other model systems. Increased understanding of human epithelial tissues including intestine, stomach, liver, pancreas, lung, and brain have been achieved using organoids. However, it is not yet clear whether these cultures recapitulate in vivo organ-to-organ signaling or communication. In this work, we demonstrate that mature stem cell-derived intestinal and liver organoid cultures each express functional molecules that modulate bile acid uptake and recycling. These organoid cultures can be physically coupled in a Transwell system and …

Hemodynamic Outcomes After Valve-In-Valve Transcatheter Aortic Valve Replacement: A Single-Center Experience, R Yazan Kherallah, Srikanth Koneru, Zvonimir Krajcer, Ourania Preventza, Kathryn G Dougherty, Melissa L Mccormack, Briana T Costello, Stephanie Coulter, Neil E Strickman, Juan Carlos Plana Gomez, Ali Mortazavi, Jose G Díez, James J Livesay, Joseph S Coselli, Guilherme V Silva

Faculty, Staff and Students Publications

BACKGROUND: Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) has emerged as a safe, effective alternative to redo aortic valve surgery in high-risk patients with degenerated surgical bioprosthetic valves. However, ViV-TAVR has been associated high postprocedural valvular gradients, compared with TAVR for native-valve aortic stenosis.

METHODS: We performed a retrospective study of all patients who underwent ViV-TAVR for a degenerated aortic valve bioprosthesis between January 1, 2013 and March 31, 2019 at our center. The primary outcome was postprocedural mean aortic valve gradient. Outcomes were compared across surgical valve type (stented versus stentless), surgical valve internal diameter (≤19 versus >19 mm), and …

Continuous-Flow Left Ventricular Assist Device Support In Patients With Ischemic Versus Nonischemic Cardiomyopathy, Brendan P Chou, Andre Critsinelis, Harveen K Lamba, Gregory Long, Andrew B Civitello, Reynolds M Delgado, Subhasis Chatterjee

Faculty, Staff and Students Publications

To determine whether the cause of cardiomyopathy affects outcomes in patients who undergo continuous-flow left ventricular assist device support, we compared postimplant adverse events and survival between patients with ischemic and nonischemic cardiomyopathy. The inclusion criteria for the ischemic group were a history of myocardial infarction or revascularization (coronary artery bypass grafting or percutaneous coronary intervention), ≥75% stenosis of the left main or proximal left anterior descending coronary artery, or ≥75% stenosis of ≥2 epicardial vessels. From November 2003 through March 2016, 526 patients underwent device support: 256 (48.7%) in the ischemic group and 270 (51.3%) in the nonischemic group. …

Transcatheter Pulmonic Valve Implantation In Adult Patients With Prior Congenital Heart Surgery, Zachary A Spigel, Iki Adachi, Ziyad M Binsalamah, Dhaval Parekh, Athar M Qureshi

Faculty, Staff and Students Publications

BACKGROUND: Transcatheter pulmonary valve replacement (TPVR) is now an established modality for pulmonary valve replacement in suitable candidates. We aim to describe our experience with TPVR in adults.

METHODS: This is a descriptive study of all TPVR performed in adults with congenital heart disease at a single institution from 2010-2020. All adult patients (defined as 18 years old or older at TPVR) were included. Time-to-event outcomes were described using Kaplan-Meier estimates with 95% confidence intervals (CIs).

RESULTS: Out of a total of 200 patients that had undergone TPVR, 81 patients (57% male) met the inclusion criteria, with a median age …

Cd11c Participates In Triggering Acute Graft-Versus-Host Disease During Bone Marrow Transplantation, Qianqian Wang, Xiuhua Su, Yi He, Mei Wang, Donglin Yang, Rongli Zhang, Jialin Wei, Qiaoling Ma, Weihua Zhai, Aiming Pang, Yong Huang, Sizhou Feng, Christie M Ballantyne, Huaizhu Wu, Xiaolei Pei, Xiaoming Feng, Mingzhe Han, Erlie Jiang

Faculty, Staff and Students Publications

CD11c is a canonical dendritic cell (DC) marker with poorly defined functions in the immune system. Here, we found that blocking CD11c on human peripheral blood mononuclear cell‐derived DCs (MoDCs) inhibited the proliferation of CD4+ T cells and the differentiation into IFN‐γ‐producing T helper 1 (Th1) cells, which were critical in acute graft‐versus‐host disease (aGVHD) pathogenesis. Using allogeneic bone marrow transplantation (allo‐BMT) murine models, we consistently found that CD11c‐deficient recipient mice had alleviated aGVHD symptoms for the decreased IFN‐γ‐expressing CD4+ Th1 cells and CD8+ T cells. Transcriptional analysis showed that CD11c participated in several immune regulation functions including maintaining antigen …

Hiv-1 Viral Protein R Couples Metabolic Inflexibility With White Adipose Tissue Thermogenesis, Neeti Agarwal, Dinakar Iyer, Pradip Saha, Aaron R Cox, Yan Xia, Netanya S Utay, Anoma Somasundaram, Ulrich Schubert, Jordan E Lake, Sean M Hartig, Ashok Balasubramanyam

Faculty, Staff and Students Publications

Persons living with HIV (PLWH) manifest chronic disorders of brown and white adipose tissues that lead to diabetes and metabolic syndrome. The mechanisms that link viral factors to defective adipose tissue function and abnormal energy balance in PLWH remain incompletely understood. Here, we explored how the HIV accessory protein viral protein R (Vpr) contributes to adaptive thermogenesis in two mouse models and human adipose tissues. Uncoupling protein 1 (UCP1) gene expression was strongly increased in subcutaneous white adipose tissue (WAT) biopsy specimens from PLWH and in subcutaneous WAT of the Vpr mice, with nearly equivalent mRNA copy number. Histology and …

A Simplified Approach To Identification Of Risk Status In Patients With Atherosclerotic Cardiovascular Disease, Aparna Sajja, Hsin-Fang Li, Kateri J Spinelli, Amir Ali, Salim S Virani, Seth S Martin, Ty J Gluckman

Faculty, Staff and Students Publications

OBJECTIVE: The 2018 American Heart Association/American College of Cardiology (AHA/ACC) Blood Cholesterol Guideline recommendation to classify patients with atherosclerotic cardiovascular disease (ASCVD) as very high-risk (VHR) vs not-VHR (NVHR) has important implications for escalation of medical therapy. We aimed to define the prevalence and clinical characteristics of these two groups within a large multi-state healthcare system and develop a simpler means to assist clinicians in identifying VHR patients using classification and regression tree (CART) analysis.

METHODS: We performed a retrospective analysis of all patients in a 28-hospital US healthcare system in 2018. ICD-10 codes were used to define the ASCVD …

Critical Care Service Delivery Across Healthcare Systems In Low-Income And Low-Middle-Income Countries: Protocol For A Systematic Review, Andrew George Lim, Sean Kivlehan, Lia Ilona Losonczy, Srinivas Murthy, Enrico Dippenaar, Richard Lowsby, Marc Li Chuan L C Yang, Michael S Jaung, P Andrew Stephens, Nicole Benzoni, Nana Sefa, Emily Suzanne Bartlett, Brandon Alexander Chaffay, Naeha Haridasa, Bernadett Pua Velasco, Sojung Yi, Caitlin A Contag, Amir Lotfy Rashed, Patrick Mccarville, Paul D Sonenthal, Nebiyu Shukur, Abdelouahab Bellou, Carl Mickman, Adhiti Ghatak-Roy, Allison Ferreira, Neill Kj Adhikari, Teri Reynolds

Faculty, Staff and Students Publications

INTRODUCTION: Critical care in low-income and low-middle income countries (LLMICs) is an underdeveloped component of the healthcare system. Given the increasing growth in demand for critical care services in LLMICs, understanding the current capacity to provide critical care is imperative to inform policy on service expansion. Thus, our aim is to describe the provision of critical care in LLMICs with respect to patients, providers, location of care and services and interventions delivered.

METHODS AND ANALYSIS: We will search PubMed/MEDLINE, Web of Science and EMBASE for full-text original research articles available in English describing critical care services that specify the location …

Applying The Plan-Do-Study-Act Cycle In Medical Education To Refine An Antibiotics Therapy Active Learning Session, Stacey Rose, Richard Hamill, Andrew Caruso, Nital P Appelbaum

Faculty, Staff and Students Publications

BACKGROUND: Active learning improves learner engagement and knowledge retention. The application of continuous quality improvement methodologies, such as the Plan-Do-Study-Act (PDSA) framework, may be useful for optimizing medical education, including active learning sessions. We aimed to enhance student satisfaction and achievement of learning outcomes by applying the PDSA framework to an antibiotic utilization curriculum for medical students.

METHODS: Guided by the Plan-Do-Study-Act framework, between February 2017 and July 2019, we developed, implemented, and revised an active learning session for medical students, focused on appropriate utilization of antibiotics during their Internal Medicine clerkship.

RESULTS: Across twelve sessions, 367 students (83.4%) completed …

Dermatitis Herpetiformis: An Update On Diagnosis, Disease Monitoring, And Management, Christopher N Nguyen, Soo-Jung Kim

Faculty, Staff and Students Publications

Dermatitis herpetiformis (DH), Duhring disease, is caused by gluten sensitivity and affects 11.2 to 75.3 per 100,000 people in the United States and Europe with an incidence of 0.4 to 3.5 per 100,000 people per year. DH is characterized by a symmetrical blistering rash on the extensor surfaces with severe pruritus. The diagnosis continues to be made primarily by pathognomonic findings on histopathology, especially direct immunofluorescence (DIF). Recently, anti-epidermal transglutaminase (TG3) antibodies have shown to be a primary diagnostic serology, while anti-tissue transglutaminase (TG2) and other autoantibodies may be used to support the diagnosis and for disease monitoring. Newly diagnosed …

Macrocyclic Immunoproteasome Inhibitors As A Potential Therapy For Alzheimer's Disease, Min Jae Lee, Deepak Bhattarai, Hyeryung Jang, Ahreum Baek, In Jun Yeo, Seongsoo Lee, Zachary Miller, Sukyeong Lee, Jin Tae Hong, Dong-Eun Kim, Wooin Lee, Kyung Bo Kim

Faculty, Staff and Students Publications

Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (

Adipose Tissue Hyaluronan Production Improves Systemic Glucose Homeostasis And Primes Adipocytes For Cl 316,243-Stimulated Lipolysis, Yi Zhu, Na Li, Mingyang Huang, Mason Bartels, Sophie Dogné, Shangang Zhao, Xi Chen, Clair Crewe, Leon Straub, Lavanya Vishvanath, Zhuzhen Zhang, Mengle Shao, Yongjie Yang, Christy M Gliniak, Ruth Gordillo, Gordon I Smith, William L Holland, Rana K Gupta, Bingning Dong, Nathalie Caron, Yong Xu, Yucel Akgul, Samuel Klein, Philipp E Scherer

Faculty, Staff and Students Publications

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma …