Biochemistry, Biophysics, and Structural Biology Commons^™

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 …

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Physiology Faculty Publications

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

RESULTS: Single-cell …

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, …

Targeting The Cdk6 Dependence Of Ph+ Acute Lymphoblastic Leukemia, Patrizia Porazzi, Marco De Dominici, Joseph Salvino, Bruno Calabretta

Department of Cancer Biology Faculty Papers

Ph+ ALL is a poor-prognosis leukemia subtype driven by the BCR-ABL1 oncogene, either the p190-or the p210-BCR/ABL isoform in a 70:30 ratio. Tyrosine Kinase inhibitors (TKIs) are the drugs of choice in the therapy of Ph+ ALL. In combination with standard chemotherapy, TKIs have markedly improved the outcome of Ph+ ALL, in particular if this treatment is followed by bone marrow transplantation. However, resistance to TKIs develops with high frequency, causing leukemia relapse that results in

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 …

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 …

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 …

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 …

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 …

Pgc1Α Is Required For The Renoprotective Effect Of Lncrna Tug1 In Vivo And Links Tug1 With Urea Cycle Metabolites, Li Li, Jianyin Long, Koki Mise, Daniel L Galvan, Paul A Overbeek, Lin Tan, Shwetha V Kumar, Wai Kin Chan, Phillip L Lorenzi, Benny H Chang, Farhad R Danesh

Faculty, Staff and Students Publications

lncRNA taurine-upregulated gene 1 (Tug1) is a promising therapeutic target in the progression of diabetic nephropathy (DN), but the molecular basis of its protection remains poorly understood. Here, we generate a triple-mutant diabetic mouse model coupled with metabolomic profiling data to interrogate whether Tug1 interaction with peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) is required for mitochondrial remodeling and progression of DN in vivo. We find that, compared with diabetic conditional deletion of Pgc1α in podocytes alone (db/db; Pgc1αPod-f/f), diabetic Pgc1α knockout combined with podocyte-specific Tug1 overexpression (db/db; TugPodTg; Pgc1αPod-f/f) reverses the protective phenotype of …

A Noncoding Rna Modulator Potentiates Phenylalanine Metabolism In Mice, Yajuan Li, Zhi Tan, Yaohua Zhang, Zhao Zhang, Qingsong Hu, Ke Liang, Yao Jun, Youqiong Ye, Yi-Chuan Li, Chunlai Li, Lan Liao, Jianming Xu, Zhen Xing, Yinghong Pan, Sujash S Chatterjee, Tina K Nguyen, Heidi Hsiao, Sergey D Egranov, Nagireddy Putluri, Cristian Coarfa, David H Hawke, Preethi H Gunaratne, Kuang-Lei Tsai, Leng Han, Mien-Chie Hung, George A Calin, Fares Namour, Jean-Louis Guéant, Ania C Muntau, Nenad Blau, V Reid Sutton, Manuel Schiff, François Feillet, Shuxing Zhang, Chunru Lin, Liuqing Yang

Faculty, Staff and Students Publications

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. We demonstrated that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine, musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell (hiPSC)-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that …

Investigations In The Cellular And Molecular Biology Of Human Airway Mucociliary Tissue, Vincent Manna

Graduate School of Biomedical Sciences Theses and Dissertations

Our laboratory has integrated the use of a human-derived, in vitro model of airway mucociliary tissue. We isolate human nasal epithelial cells (HNECs) from the nasal mucociliary tissue of donors with a small brush and expand the airway progenitor cells in culture. The HNECs are then seeded onto semi-permeable transwell inserts. The inserts are in contact with the media in the lower chamber but don’t contain media in the upper chamber therefore the cells are exposed to the air while drawing nutrients from the media below, this is called the Air-Liquid Interface (ALI). HNECs cultured at the ALI initiate a …

Cd148 Deficiency In Fibroblasts Promotes The Development Of Pulmonary Fibrosis, Konstantin Tsoyi, Xiaoliang Liang, Giulia De Rossi, Stefan W Ryter, Kevin Xiong, Sarah G Chu, Xiaoli Liu, Bonna Ith, Lindsay J Celada, Freddy Romero, Matthew J Robertson, Anthony J Esposito, Sergio Poli, Souheil El-Chemaly, Mark A Perrella, Yuanyuan Shi, James Whiteford, Ivan O Rosas

Faculty, Staff and Students Publications

Rationale: CD148/PTRJ (receptor-like protein tyrosine phosphatase η) exerts antifibrotic effects in experimental pulmonary fibrosis via interactions with its ligand syndecan-2; however, the role of CD148 in human pulmonary fibrosis remains incompletely characterized.

Objectives: We investigated the role of CD148 in the profibrotic phenotype of fibroblasts in idiopathic pulmonary fibrosis (IPF).

Methods: Conditional CD148 fibroblast-specific knockout mice were generated and exposed to bleomycin and then assessed for pulmonary fibrosis. Lung fibroblasts (mouse lung and human IPF lung), and precision-cut lung slices from human patients with IPF were isolated and subjected to experimental treatments. A CD148-activating 18-aa mimetic peptide (SDC2-pep) derived from …

Neurovascular Regulation In Diabetic Retinopathy And Emerging Therapies, Liyang Ji, Hong Tian, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Diabetic retinopathy (DR) is the leading cause of vision loss in working adults in developed countries. The disease traditionally classified as a microvascular complication of diabetes is now widely recognized as a neurovascular disorder resulting from disruption of the retinal neurovascular unit (NVU). The NVU comprising retinal neurons, glia and vascular cells coordinately regulates blood flow, vascular density and permeability to maintain homeostasis. Disturbance of the NVU during DR can lead to vision-threatening clinical manifestations. A limited number of signaling pathways have been identified for intercellular communication within the NVU, including vascular endothelial growth factor (VEGF), the master switch for …

Sugar-Sweetened Beverage Consumption May Modify Associations Between Genetic Variants In The Chrebp (Carbohydrate Responsive Element Binding Protein) Locus And Hdl-C (High-Density Lipoprotein Cholesterol) And Triglyceride Concentrations, Danielle E Haslam, Gina M Peloso, Melanie Guirette, Fumiaki Imamura, Traci M Bartz, Achilleas N Pitsillides, Carol A Wang, Ruifang Li-Gao, Jason M Westra, Niina Pitkänen, Kristin L Young, Mariaelisa Graff, Alexis C Wood, Kim V E Braun, Jian'an Luan, Mika Kähönen, Jessica C Kiefte-De Jong, Mohsen Ghanbari, Nathan Tintle, Rozenn N Lemaitre, Dennis O Mook-Kanamori, Kari North, Mika Helminen, Yasmin Mossavar-Rahmani, Linda Snetselaar, Lisa W Martin, Jorma S Viikari, Wendy H Oddy, Craig E Pennell, Frits R Rosendall, M Arfan Ikram, Andre G Uitterlinden, Bruce M Psaty, Dariush Mozaffarian, Jerome I Rotter, Kent D Taylor, Terho Lehtimäki, Olli T Raitakari, Kara A Livingston, Trudy Voortman, Nita G Forouhi, Nick J Wareham, Renée De Mutsert, Steven S Rich, Joann E Manson, Samia Mora, Paul M Ridker, Jordi Merino, James B Meigs, Hassan S Dashti, Daniel I Chasman, Alice H Lichtenstein, Caren E Smith, Josée Dupuis, Mark A Herman, Nicola M Mckeown

Faculty, Staff and Students Publications

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the

METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near

RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers …

Modulation Of Glucose Homeostasis By Nucleotide P2y2 Receptor And Biological Sex, Hailee Anne Marino

Graduate Theses/Dissertations

Recent insights into the pathological role of Nucleotide P2Y₂ receptor suggest P2Y₂R involvement in high fat diet-induced obesity and potentiates insulin resistance. However, these recent insights do not demonstrate how P2Y₂R modulates glucose homeostasis under physiological conditions. Further, it remains unknown how sex biological factors influence P2Y₂R receptor signaling in the regulation of glucose homeostasis. The research objective for the present study is to elucidate the novel roles of P2Y₂ in fasting blood glucose and glucose tolerance (basal insulin sensitivity) under resting conditions in males and females. We expected that under physiological …

Nucleotide P2y₂ Receptor-Dependent Leukocyte-Endothelial Interaction, Spencer E. Thomas

Graduate Theses/Dissertations

Extracellular nucleotides (ATP, UTP) released from cells act on nucleotide receptors to promote vascular inflammation. Increased leukocyte-endothelial interaction is a hallmark of vascular inflammation. The nucleotide P2Y₂ receptor (P2Y₂R), activated by extracellular ATP≈UTP, plays a role in cardiovascular homeostasis and immune regulation. Moreover, accumulating evidence from studies in vitro and in vivo models have implicated the P2Y₂R in the inflammatory response significantly contributing to the progression and pathogenesis of asthma, atherosclerosis, sepsis, and ischemia. I hypothesized that P2Y₂R activation by UTP, an agonist of the receptor, increased leukocyte rolling and adhesion in the microvasculature from baseline. To test the hypothesis, …

Metabolomics Profiling Of Patients With A-Β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis, Farook Jahoor, Jean W Hsu, Paras B Mehta, Kelly R Keene, Ruchi Gaba, Surya Narayan Mulukutla, Eunice Caducoy, W Frank Peacock, Sanjeet G Patel, Rasmus Bennet, Ake Lernmark, Ashok Balasubramanyam

Faculty, Staff and Students Publications

When stable and near-normoglycemic, patients with “A−β+” ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A−β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as …

African Swine Fever Virus Cd2v Protein Induces Β-Interferon Expression And Apoptosis In Swine Peripheral Blood Mononuclear Cells, Sabal Chaulangain, Gustavo A. Delhon, Sushil Khatiwada, Daniel L. Rock

School of Veterinary and Biomedical Sciences: Faculty Publications

African swine fever (ASF) is a hemorrhagic disease of swine characterized by massive lymphocyte depletion in lymphoid tissues due to the apoptosis of B and T cells, a process likely triggered by factors released or secreted by infected macrophages. ASFV CD2v (EP402R) has been implicated in viral virulence and immunomodulation in vitro; however, its actual function(s) remains unknown. We found that CD2v expression in swine PK15 cells induces NF-κB-dependent IFN-β and ISGs transcription and an antiviral state. Similar results were observed for CD2v protein treated swine PBMCs and macrophages, the major ASFV target cell. Notably, treatment of swine PBMCs and …

Structure And Function Of An Arabidopsis Thaliana Sulfate Transporter, Lie Wang, Kehan Chen, Ming Zhou

Faculty, Staff and Students Publications

Plant sulfate transporters (SULTR) mediate absorption and distribution of sulfate (SO42−) and are essential for plant growth; however, our understanding of their structures and functions remains inadequate. Here we present the structure of a SULTR from Arabidopsis thaliana, AtSULTR4;1, in complex with SO42− at an overall resolution of 2.8 Å. AtSULTR4;1 forms a homodimer and has a structural fold typical of the SLC26 family of anion transporters. The bound SO42− is coordinated by side-chain hydroxyls and backbone amides, and further stabilized electrostatically by the conserved Arg393 and two helix dipoles. Proton and SO42− are co-transported by AtSULTR4;1 and a …

Medical Schools Ignore The Nature Of Consciousness At Great Cost, Anoop Kumar

Journal of Wellness

The essential question of the relationship between consciousness and matter is ignored in medical school curricula, leading to a machine-like view of the human being that contributes to physician burnout and intellectual dissatisfaction. The evidence suggesting that the brain may not be the seat of consciousness is generally ignored to preserve the worldview of the primacy of matter. By investigating new frameworks detailing the nature of consciousness at different levels of hierarchy, we can bring intellectual rigor to a once opaque subject that supports a fundamental reality about our experience: We are human beings, not only human bodies.

A Synthetic Circuit For Buffering Gene Dosage Variation Between Individual Mammalian Cell, Jin Yang, Jihwan Lee, Michelle A Land, Shujuan Lai, Oleg A Igoshin, François St-Pierre

Faculty, Staff and Students Publications

Precise control of gene expression is critical for biological research and biotechnology. However, transient plasmid transfections in mammalian cells produce a wide distribution of copy numbers per cell, and consequently, high expression heterogeneity. Here, we report plasmid-based synthetic circuits - Equalizers - that buffer copy-number variation at the single-cell level. Equalizers couple a transcriptional negative feedback loop with post-transcriptional incoherent feedforward control. Computational modeling suggests that the combination of these two topologies enables Equalizers to operate over a wide range of plasmid copy numbers. We demonstrate experimentally that Equalizers outperform other gene dosage compensation topologies and produce as low cell-to-cell …

Administrative Coding In Electronic Health Care Record-Based Research Of Nafld: An Expert Panel Consensus Statement, Hannes Hagström, Leon A Adams, Alina M Allen, Christopher D Byrne, Yoosoo Chang, Henning Grønbaek, Mona Ismail, Peter Jepsen, Fasiha Kanwal, Jennifer Kramer, Jeffrey V Lazarus, Michelle T Long, Rohit Loomba, Philip N Newsome, Ian A Rowe, Seungho Ryu, Jörn M Schattenberg, Marina Serper, Nick Sheron, Tracey G Simon, Elliot B Tapper, Sarah Wild, Vincent Wai-Sun Wong, Yusuf Yilmaz, Shira Zelber-Sagi, Fredrik Åberg

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Electronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

APPROACH AND RESULTS: Researchers with an interest in EHR-based NAFLD research were invited to collectively define …

Factors Associated With Access To And Receipt Of Liver Transplantation In Veterans With End-Stage Liver Disease, Fasiha Kanwal, Ruben Hernaez, Yan Liu, Thomas J Taylor, Abbas Rana, Jennifer R Kramer, Aanand D Naik, Donna Smith, Tamar Taddei, Steven M Asch

Faculty, Staff and Students Publications

IMPORTANCE: Organ scarcity means few patients with advanced liver disease undergo a transplant, making equitable distribution all the more crucial. Disparities may arise at any stage in the complex process leading up to this curative therapy.

OBJECTIVE: To examine the rate of and factors associated with referral, wait-listing, and receipt of liver allografts.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used linked data from comprehensive electronic medical records and the United Network of Organ Sharing. Adult patients with cirrhosis and a Model for End-Stage Liver Disease with addition of sodium score of at least 15 points between October 1, …

Central And Peripheral Arterial Diseases In Chronic Kidney Disease: Conclusions From A Kidney Disease: Improving Global Outcomes (Kdigo) Controversies Conference, Kirsten L Johansen, Pranav S Garimella, Caitlin W Hicks, Philip A Kalra, Dearbhla M Kelly, Sven Martens, Kunihiro Matsushita, Pantelis Sarafidis, Manish M Sood, Charles A Herzog, Michael Cheung, Michel Jadoul, Wolfgang C Winkelmayer, Holger Reinecke, Conference Participants

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, …

Sex-Related Disparities In Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease, Michelle T Lee, Dhruv Mahtta, David J Ramsey, Jing Liu, Arunima Misra, Khurram Nasir, Zainab Samad, Dipti Itchhaporia, Safi U Khan, Richard S Schofield, Christie M Ballantyne, Laura A Petersen, Salim S Virani

Faculty, Staff and Students Publications

IMPORTANCE: There is a paucity of data regarding secondary prevention care disparities in women with premature and extremely premature atherosclerotic cardiovascular disease (ASCVD), defined as an ASCVD event at 55 years or younger and 40 years or younger, respectively.

OBJECTIVE: To evaluate sex-based differences in antiplatelet agents, any statin, high-intensity statin (HIS) therapy, and statin adherence in patients with premature and extremely premature ASCVD.

DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional, multicenter, nationwide VA health care system-based study with patients enrolled in the Veterans With Premature Atherosclerosis (VITAL) registry. The study assessed patients who had at least 1 primary …

High Burden Of Subclinical And Cardiovascular Disease Risk In Adults With Metabolically Healthy Obesity: The Atherosclerosis Risk In Communities (Aric) Study, Yvonne Commodore-Mensah, Mariana Lazo, Olive Tang, Justin B Echouffo-Tcheugui, Chiadi E Ndumele, Vijay Nambi, Dan Wang, Christie Ballantyne, Elizabeth Selvin

Faculty, Staff and Students Publications

OBJECTIVE: It is controversial whether adults who are obese but "metabolically healthy" have cardiovascular disease (CVD) risk comparable with that of normal-weight adults. High-sensitivity cardiac troponin T (hs-cTnT), a biomarker of myocardial damage, is useful in characterizing subclinical CVD. We categorized obesity phenotypes and studied their associations with subclinical and clinical CVD and CVD subtypes, including heart failure (HF).

RESEARCH DESIGN AND METHODS: We conducted cross-sectional and prospective analyses of 9,477 adults in the Atherosclerosis Risk in Communities (ARIC) study. We used the Adult Treatment Panel III criteria and BMI to define obesity phenotypes as follows: metabolically healthy normal weight, …

Gene Therapy Knockdown Of Hippo Signaling Induces Cardiomyocyte Renewal In Pigs After Myocardial Infarction, Shijie Liu, Ke Li, Leonardo Wagner Florencio, Li Tang, Todd R Heallen, John P Leach, Yidan Wang, Francisco Grisanti, James T Willerson, Emerson C Perin, Sui Zhang, James F Martin

Faculty, Staff and Students Publications

Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav …

Left Ventricular Recovery With Explantation Of Continuous-Flow Left Ventricular Assist Device After 5 Years Of Support, Andre Critsinelis, Chitaru Kurihara, Masashi Kawabori, Tadahisa Sugiura, Andrew B Civitello, Jeffrey A Morgan

Faculty, Staff and Students Publications

Mechanical circulatory support may result in sufficient myocardial recovery to allow for explantation of the left ventricular assist device (LVAD). The duration of support associated with left ventricular recovery has generally been 6-12 months. In this report, we present a patient in whom the left ventricle recovered after 5 years of support with a LVAD. Our report demonstrates that long-term monitoring for left ventricular recovery is prudent and may allow for late device explantation.