Biochemistry, Biophysics, and Structural Biology Commons^™

Modeling Functional Connectivity With Learning And Memory In A Mouse Model Of Alzheimer’S Disease, Lindsay Fadel, Elizabeth Hipskind, Steen E Pedersen, Jonathan Romero, Caitlyn Ortiz, Eric Shin, Md Abul Hassan Samee, Robia G Pautler

Faculty, Staff and Students Publications

Introduction: Functional connectivity (FC) is a metric of how different brain regions interact with each other. Although there have been some studies correlating learning and memory with FC, there have not yet been, to date, studies that use machine learning (ML) to explain how FC changes can be used to explain behavior not only in healthy mice, but also in mouse models of Alzheimer's Disease (AD). Here, we investigated changes in FC and their relationship to learning and memory in a mouse model of AD across disease progression.

Methods: We assessed the APP/PS1 mouse model of AD and wild-type controls …

Addressing Unprofessional Behaviors In The Clinical Learning Environment: Lessons From A Multi-Year Virtual, Intergenerational, Interdisciplinary Workshop, Stacey Rose, Anita Kusnoor, Phuong Huynh, Jocelyn Greely, Yesenia Rojas-Khalil, Doris Kung, Anne Gill, Nadia Ismail, Nital Appelbaum

Faculty, Staff and Students Publications

INTRODUCTION: Optimizing the clinical learning environment (CLE) is a medical education priority nationwide.

MATERIALS AND METHODS: We developed a virtual, one-hour workshop engaging students, housestaff and faculty in small-group discussions of five case scenarios adapted from reported unprofessional behaviors in the CLE, plus didactics regarding mistreatment, microaggressions and bystander interventions.

RESULTS: Over two sessions (2021-2022), we engaged 340 students and 73 faculty/housestaff facilitators. Post-session surveys showed significant improvement in participants' ability to recognize and respond to challenges in the CLE.

DISCUSSION: Our innovative workshop, including scenarios derived from institutional reports of unprofessional behaviors, advanced participants' knowledge and commitment to improve …

Simple Improvements In Vector Design Afford Substantial Gains In Aav Delivery Of Aggregation-Slowing Aβ Variants, Ella Borgenheimer, Cameron Trueblood, Bryan L Nguyen, William R Lagor, Joanna L Jankowsky

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that …

Hemodynamic And Clinical Outcomes With Balloon-Expandable Valves Versus Self-Expanding Valves In Patients With Small Aortic Annulus Undergoing Transcatheter Aortic Valve Replacement: A Meta-Analysis Of Randomized Controlled Trials And Propensity Score Matched Studies, Mushood Ahmed, Areeba Ahsan, Shehroze Tabassum, Irra Tariq, Eeshal Zulfiqar, Mahnoor Farooq Raja, Asma Mahmood, Raheel Ahmed, Farhan Shahid, Syed Khurram M Gardezi, Mahboob Alam, Rodrigo Bagur, Mamas A Mamas

Faculty, Staff and Students Publications

Transcatheter aortic valve replacement (TAVR) is considered more effective than surgical aortic valve implantation for patients with a small aortic annulus (SAA), however, the comparative efficacy of different transcatheter heart valves (THVs) remains uncertain. A literature search was performed across databases from their inception until June 2024 to identify eligible randomized controlled trials (RCTs) and propensity-score matched (PSM) studies. Clinical outcomes were evaluated using a random-effects model to pool risk ratios (RRs) with 95 % confidence intervals (CIs). The analysis included 10 studies with 2,960 patients. BEVs were associated with a significantly smaller indexed effective orifice area (MD: -0.18, 95 …

Going Against The Family: Perturbation Of A Greenbeard Pathway Leads To Falsebeard Cheating, Peter Lehmann, Mariko Katoh-Kurasawa, Peter Kundert, Gad Shaulsky

Faculty, Staff and Students Publications

Greenbeards facilitate cooperation by encoding a perceptible signal, the ability to detect it, and a tendency to help others that display it. Falsebeards are hypothetical cheaters that display the signal without being altruistic. Despite many examples of greenbeards, evidence for falsebeards is scarce. The Dictyostelium discoideum tgrB1-tgrC1 allorecognition pathway encodes a greenbeard. It allows development, which yields fruiting bodies with altruistic stalks that increase spore dispersal. Here we show that cells lacking rapgapB, a tgrB1-tgrC1 signaling element, cheat by avoiding the stalk fate and generating more spores in chimeras than in pure populations. rapgapB– cells cheat only on …

National Liver Cancer Screening Trial (Tracer) Study Protocol, Amit G Singal, Neehar D Parikh, Fasiha Kanwal, Jorge A Marrero, Sneha Deodhar, Stephanie Page-Lester, Camden Lopez, Ziding Feng, Nabihah Tayob

Faculty, Staff and Students Publications

BACKGROUND: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice. …

Telemedicine For Patients With Systemic Lupus Erythematosus In A Publicly Funded Hospital System: Retrospective Study, Sebastian Bruera, Kristen Andrews Staggers, Maria Eugenia Suarez-Almazor, Sandeep Krishna Agarwal

Faculty, Staff and Students Publications

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that requires frequent clinic and laboratory visits. However, patients with SLE, particularly those who are underresourced, have unacceptably high rates of no-shows.

OBJECTIVE: This study aims to determine no-show rates associated with telemedicine visits during the COVID-19 pandemic in comparison to no-show rates associated with contemporaneous and historic in-person visits.

METHODS: We performed a retrospective cohort study in a publicly funded county hospital system in Houston, Texas. We identified a cohort of established patients with SLE by the International Classification of Diseases codes that were independently confirmed as SLE by …

Economic And Humanistic Burden Of Rheumatoid Arthritis: Results From The Us National Survey Data 2018-2020, Yinan Huang, Jieni Li, Sandeep Krishna Agarwal

Faculty, Staff and Students Publications

OBJECTIVE: Our objective was to estimate the economic and humanistic burden among US adults with rheumatoid arthritis (RA).

METHODS: This study analyzed results from the Medical Expenditure Panel Survey from 2018 to 2020. Adults (aged ≥18 years) self-reporting with RA or with the presence of the International Classification of Disease, 10th Revision clinical modification codes were identified. Healthcare expenditures (inpatient care, outpatient care, emergency department, office visits, prescription medications, home health, and others) were measured. The Short Form 12 Health Survey physical component summary (PCS), mental component summary (MCS), activities of daily living (ADL), and instrumental ADL (IADL) were measured. …

Vital Exhaustion And Biomarkers Associated With Cardiovascular Risk: The Aric Study, Matthew R Deshotels, Mahmoud Al Rifai, Caroline Sun, Ali Agha, Elizabeth Selvin, B Gwen Windham, Viola Vaccarino, Erin D Michos, Hani Jneid, Glenn N Levine, Christopher Fagundes, Salim S Virani, Christie M Ballantyne, Vijay Nambi

Faculty, Staff and Students Publications

BACKGROUND: Vital exhaustion, defined as excessive fatigue, demoralization, and irritability due to chronic stress, is independently associated with cardiovascular disease (CVD).

OBJECTIVES: The purpose of this study was to examine the association of vital exhaustion with biomarkers associated with CVD risk in the ARIC (Atherosclerosis Risk In Communities) study.

METHODS: We examined the cross-sectional association of vital exhaustion (assessed using the Maastricht Vital Exhaustion Questionnaire [MVEQ]) with cardiac biomarker (high-sensitivity troponin T [hs-TnT], N-terminal pro-B-type natriuretic peptide [NT-proBNP]) and high-sensitivity C-reactive protein (hs-CRP) levels in 11,542 ARIC study participants without CVD at ARIC visit 2 using multivariable logistic and linear …

Conservative Approach Versus Percutaneous Coronary Intervention In Patients With Spontaneous Coronary Artery Dissection From A National Population-Based Cohort Study, Chayakrit Krittanawong, Beatriz Castillo Rodriguez, Song Peng Ang, Yusuf Kamran Qadeer, Zhen Wang, Mahboob Alam, Samin Sharma, Hani Jneid

Faculty, Staff and Students Publications

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a rare and often underdiagnosed cause of acute coronary syndrome (ACS), predominantly affecting younger women without traditional cardiovascular risk factors. The management of SCAD remains a subject of debate, likely secondary to inconclusive evidence. This study aims to compare the clinical outcomes of SCAD patients treated with optimal medical therapy (OMT) versus those who underwent percutaneous coronary intervention (PCI) using a national population-based cohort.

METHODS: We conducted a retrospective analysis using the National Inpatient Sample (NIS) database from 2016 to 2020. The study included patients identified with SCAD using the ICD-10-CM (the International …

Trends And Disparities In Coronary Artery Disease And Obesity-Related Mortality In The United States From 1999-2022, Mushood Ahmed, Hira Javaid, Aimen Shafiq, Zain Ali Nadeem, Areeba Ahsan, Abdullah Nofal, Raheel Ahmed, Mahboob Alam, Marat Fudim, Gregg C Fonarow, Mamas A Mamas

Faculty, Staff and Students Publications

BACKGROUND: Almost half of the US adult population has obesity, which predisposes to atherosclerosis and can lead to poor prognosis in coronary artery disease (CAD). We aim to identify CAD and obesity-related mortality trends among adults in the United States stratified by age, sex, race and geographical location.

METHODS: The CDC-WONDER database was used to extract death certificate data for adults aged ≥ 25 years. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and temporal trends were described by calculating annual percent change (APC) and the average APC (AAPC) in the rates using Joinpoint …

Pkc-Mediated Phosphorylation Governs The Stability And Function Of Celf1 As A Driver Of Emt In Breast Epithelial Cells, Shebna Massey, Natee Kongchan, Yang Gao, Arindam Chaudhury, Emuejevoke Olokpa, Jason Karch, Anna Malovannaya, Chonghui Cheng, Xiang Zhang, Joel R Neilson

Faculty, Staff and Students Publications

Epithelial to mesenchymal transition (EMT) is believed to be a principal factor contributing to cancer metastasis. The post-transcriptional and post-translational mechanisms underlying EMT are comparatively underexplored. We previously demonstrated that the CELF1 RNA binding protein is necessary and sufficient to drive the EMT of breast epithelial cells, and that the relative protein expression of CELF1 in this context was dictated at the post-translational level. Here, we elucidate the mechanism of this regulation. Mass spectrometric analysis of CELF1 isolated from mesenchymal MCF-10A cells identified multiple sites of serine and threonine phosphorylation on the protein, correlating with the increased stability of this …

Takotsubo Syndrome: An International Expert Consensus Report On Practical Challenges And Specific Conditions (Part-1: Diagnostic And Therapeutic Challenges), Kenan Yalta, John E Madias, Nicholas G Kounis, Shams Y-Hassan, Marija Polovina, Servet Altay, Alexandre Mebazaa, Mehmet Birhan Yilmaz, Yuri Lopatin, Mamas A Mamas, Robert J Gil, Ritu Thamman, Abdallah Almaghraby, Biykem Bozkurt, Gani Bajraktari, Thomas Fink, Vassil Traykov, Stephane Manzo-Silberman, Ulvi Mirzoyev, Sekib Sokolovic, Zviad V Kipiani, Cecilia Linde, Petar M Seferovic

Faculty, Staff and Students Publications

In the recent years, there has been a burgeoning interest in Takotsubo syndrome (TTS), which is renowned as a specific form of reversible myocardial dysfunction. Despite the extensive literature available on TTS, clinicians still face several practical challenges associated with the diagnosis and management of this phenomenon. This potentially results in the underdiagnosis and improper management of TTS in clinical practice. The present paper, the first part (part-1) of the consensus report, aims to cover diagnostic and therapeutic challenges associated with TTS along with certain recommendations to combat these challenges.

Takotsubo Syndrome: An International Expert Consensus Report On Practical Challenges And Specific Conditions (Part-2: Specific Entities, Risk Stratification And Challenges After Recovery), Kenan Yalta, John E Madias, Nicholas G Kounis, Shams Y-Hassan, Marija Polovina, Servet Altay, Alexandre Mebazaa, Mehmet Birhan Yilmaz, Yuri Lopatin, Mamas A Mamas, Robert J Gil, Ritu Thamman, Abdallah Almaghraby, Biykem Bozkurt, Gani Bajraktari, Thomas Fink, Vassil Traykov, Stephane Manzo-Silberman, Ulvi Mirzoyev, Sekib Sokolovic, Zviad V Kipiani, Cecilia Linde, Petar M Seferovic

Faculty, Staff and Students Publications

Takotsubo syndrome (TTS) still remains as an enigmatic phenomenon. In particular, long-term challenges (including clinical recurrence and persistent symptoms) and specific entities in the setting of TTS have been the evolving areas of interest. On the other hand, a significant gap still exists regarding the proper risk-stratification of this phenomenon in the short and long terms. The present paper, the second part (part-2) of the consensus report, aims to discuss less well-known aspects of TTS including specific entities, challenges after recovery and risk-stratification.

Electric Potential Energy Optimized 3d Radial Sampling Trajectories For Mri, Christopher Huynh, Datta Singh Goolaub, Christopher K Macgowan

Faculty, Staff and Students Publications

A novel method for creating “golden” 3D center-out radial MRI sampling trajectories was developed and analyzed. This method, called ELECTRO (ELECTRic potential energy Optimized), uses repulsive forces to minimize electric potential energy. An objective function , the electric potential energies of all subsets of consecutive readouts in a 3D radial trajectory, and its reduced form were minimized using a multi-stage optimization strategy. A metric called normalized mean nearest neighbor angular distance (NMNA) was proposed for describing distributions of points on a sphere. ELECTRO and other relevant golden trajectories were compared in silico using NMNA and point spread function analysis. Consecutive …

Porous Iron Electrodes Reduce Energy Consumption During Electrocoagulation Of A Virus Surrogate: Insights Into Performance Enhancements Using Three-Dimensional Neutron Computed Tomography, Kyungho Kim, Cesar Castillo, Gyoung G Jang, Yuxuan Zhang, Costas Tsouris, Shankararaman Chellam

Faculty, Staff and Students Publications

Electrocoagulation has attracted significant attention as an alternative to conventional chemical coagulation because it is capable of removing a wide range of contaminants and has several potential advantages. In contrast to most electrocoagulation research that has been performed with nonporous electrodes, in this study, we demonstrate energy-efficient iron electrocoagulation using porous electrodes. In batch operation, investigation of the external pore structures through optical microscopy suggested that a low porosity electrode with sparse connection between pores may lead to mechanical failure of the pore network during electrolysis, whereas a high porosity electrode is vulnerable to pore clogging. Electrodes with intermediate porosity, …

Churning The Tides Of Care: When Nurse Turnover Makes Waves In Patient Access To Primary Care, Kelley Arredondo, Ashley M Hughes, Houston F Lester, Trang N D Pham, Laura A Petersen, Lechauncy Woodard, Richard Sorelle, Cheng Rebecca Jiang, Frederick L Oswald, Daniel R Murphy, Hilary N Touchett, Joshua Hamer, Sylvia J Hysong

Faculty, Staff and Students Publications

BACKGROUND: Team-based primary care (PC) enhances the quality of and access to health care. The Veterans Health Administration (VHA) implements team-based care through Patient Aligned Care Teams (PACTs), consisting of four core members: a primary care provider, registered nurse (RN) care manager, licensed vocational nurse, and scheduling clerk. RNs play a central role: they coordinate patient care, manage operational needs, and serve as a patient point of contact. Currently, it is not known how varying levels of RN staffing on primary care teams impact patient outcomes.

OBJECTIVE: This study aims to empirically assess how the stability of RN staffing within …

Identification Of An Ionic Mechanism For Erα-Mediated Rapid Excitation In Neurons, Meng Yu, Na Yin, Bing Feng, Peiyu Gao, Kaifan Yu, Hesong Liu, Hailan Liu, Yongxiang Li, Olivia Z Ginnard, Kristine M Conde, Mengjie Wang, Xing Fang, Longlong Tu, Jonathan C Bean, Qingzhuo Liu, Yue Deng, Yuxue Yang, Junying Han, Sanika V Jossy, Megan L Burt, Huey Zhong Wong, Yongjie Yang, Benjamin R Arenkiel, Yang He, Shaodong Guo, Pierre Gourdy, Jean-Francois Arnal, Francoise Lenfant, Zhao Wang, Chunmei Wang, Yanlin He, Yong Xu

Faculty, Staff and Students Publications

The major female ovarian hormone, 17β-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-α (ERα), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERα with a preference to the membrane-bound ERα. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion. In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERα …

Design And Cohort Characteristics Of Track, A Prospective Study Of Hyperkalaemia Management Decision-Making, Judith Hsia, Nitin Shivappa, Ameet Bakhai, Jordi Bover, Javed Butler, Pietro Manuel Ferraro, Linda Fried, Markus P Schneider, Navdeep Tangri, Wolfgang C Winkelmayer, Meredith Bishop, Hungta Chen, Anna-Karin Sundin, Marc P Bonaca

Faculty, Staff and Students Publications

BACKGROUND: Guideline-recommended hyperkalaemia management includes dietary potassium (K

METHODS: This study enrolled participants within 21 days of an episode of hyperkalaemia in four European countries (UK, Spain, Germany, Italy) and the USA. During the 12-month follow up, data collected will include participant and healthcare provider characteristics (specialty and practice setting), hyperkalaemia treatment objectives and strategies, rationale for management decisions and indicators of response and patient-reported perceptions of their hyperkalaemia treatment.

RESULTS: The enrolled cohort includes 1330 participants, mean age 68 years, of whom 31% were women. At baseline, 6% reported heart failure, 55% chronic kidney disease, 29% both and 9% …

A Method For Rapid And Reliable Quantification Of Vegf-Cell Binding Activity, Prabuddha Waduge, Avinash Kaur, Wei Li

Faculty, Staff and Students Publications

Vascular endothelial growth factor (VEGF) is a pleiotropic growth factor that binds a broad spectrum of cell types and regulates diverse cellular processes, including angiogenesis, growth and survival. However, it is technically difficult to quantify VEGF-cell binding activity because of reversible nature of ligand-receptor interactions. Here we used T7 bacteriophage display to quantify and compare binding activity of three human VEGF-A (hVEGF) isoforms, including hVEGF111, 165 and 206. All three isoforms bound equally well to immobilized aflibercept, a decoy VEGF receptor. hVEGF111-Phage exhibited minimal binding to immobilized heparan sulfate, whereas hVEGF206-Phage and hVEGF165-Phage had the highest and intermediate binding to …

Multivalent Protein-Nucleic Acid Interactions Probed By Composition-Gradient Multiangle Light Scattering, Josephine C Ferreon, Natee Kongchan, Phoebe S Tsoi, Kyoung-Jae Choi, Sophia Kenrick, Joel Neilson, Allan Chris M Ferreon

Faculty, Staff and Students Publications

Many RNA-binding proteins, such as TDP-43 or CELF1, interact multivalently with nucleic acid repetitive elements. The molecular stoichiometry of protein to nucleic acid is often difficult to assess, particularly by standard electrophoretic mobility shift assays (EMSAs). Here, we investigate the use of composition-gradient multiangle light scattering (CG-MALS) for quantifying binding affinity and stoichiometry for two RNA-binding proteins with their nucleic acid partners of varied sequence and length: TDP43's N-terminal RNA recognition motifs with both TG/GU-repeat ssDNA and ssRNA, respectively, and CELF1's two N-terminal RNA recognition motifs with (TG/UGUU/GU) repeats and an experimentally defined cognate GU-rich element (GRE). Our CG-MALS data …

Meta-Analysis Comparing Oral Anticoagulant Monotherapy Versus Dual Antithrombotic Therapy In Patients With Atrial Fibrillation And Stable Coronary Artery Disease, Mushood Ahmed, Areeba Ahsan, Aimen Shafiq, Raheel Ahmed, Mahboob Alam, Pierre Sabouret, Jamal S Rana, Gregg C Fonarow

Faculty, Staff and Students Publications

BACKGROUND: Oral anticoagulants (OACs) are routinely used for the management of atrial fibrillation (AF) while antiplatelet agents are used in coronary artery disease (CAD). However, data regarding the comparative clinical outcomes of OAC monotherapy versus dual antithrombotic therapy (anticoagulant plus antiplatelet agent) in patients with AF and stable CAD are limited.

METHODS: A comprehensive search of major databases including PubMed/MEDLINE, Cochrane Library, and Embase was performed from inception to September 1, 2024 to identify randomized control trials (RCTs) that compared OAC monotherapy with dual antithrombotic therapy in patients with AF and stable CAD. The risk ratios (RRs) were estimated with …

Integrated Safety And Efficacy Analyses Of Phase 3 Trials Of A Microbiome Therapeutic For Recurrent Cdi, Colleen S Kraft, Matthew Sims, Michael Silverman, Thomas J Louie, Paul Feuerstadt, Edward S Huang, Sahil Khanna, Charles S Berenson, Elaine E L Wang, Stuart H Cohen, Louis Korman, Christine Lee, Colleen R Kelly, Alberto Odio, Paul P Cook, Bret Lashner, Mayur Ramesh, Princy Kumar, Ananya De, Asli Memisoglu, David A Lombardi, Brooke R Hasson, Barbara H Mcgovern, Lisa Von Moltke, Darrell S Pardi, Ecospor Iii And Ecospor Iv Investigators

Faculty, Staff and Students Publications

INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI.

OBJECTIVE, DESIGN, AND PATIENTS: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities.

METHODS: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest …

Vglut2-Based Glutamatergic Signaling In Central Noradrenergic Neurons Is Dispensable For Normal Breathing And Chemosensory Reflexes, Yuan Chang, Savannah Lusk, Andersen Chang, Christopher S Ward, Russell S Ray

Faculty, Staff and Students Publications

Central noradrenergic (NA) neurons are key constituents of the respiratory homeostatic network. NA dysfunction is implicated in several developmental respiratory disorders including Congenital Central Hyperventilation Syndrome (CCHS), Sudden Infant Death Syndrome (SIDS), and Rett Syndrome. The current unchallenged paradigm in the field, supported by multiple studies, is that glutamate co-transmission in subsets of central NA neurons plays a role in breathing control. If true, NA-glutamate co-transmission may also be mechanistically important in respiratory disorders. However, the requirement of NA-derived glutamate in breathing has not been directly tested and the extent of glutamate co-transmission in the central NA system remains uncharacterized. …

Myc Induces Oncogenic Stress Through Rna Decay And Ribonucleotide Catabolism In Breast Cancer, Jitendra K Meena, Jarey H Wang, Nicholas J Neill, Dianne Keough, Nagireddy Putluri, Panagiotis Katsonis, Amanda M Koire, Hyemin Lee, Elizabeth A Bowling, Siddhartha Tyagi, Mayra Orellana, Rocio Dominguez-Vidaña, Heyuan Li, Kenneth Eagle, Charles Danan, Hsiang-Ching Chung, Andrew D Yang, William Wu, Sarah J Kurley, Brian M Ho, Joseph R Zoeller, Calla M Olson, Kristen L Meerbrey, Olivier Lichtarge, Arun Sreekumar, Clifford C Dacso, Luke W Guddat, Dominik Rejman, Dana Hocková, Zlatko Janeba, Lukas M Simon, Charles Y Lin, Monica C Pillon, Thomas F Westbrook

Faculty, Staff and Students Publications

Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting …

Characteristics Of Patients With Spontaneous Coronary Artery Dissection Presenting With Sudden Cardiac Arrest In The United States And The Potential Role Of Implantable Cardioverter Defibrillator Therapy, Chayakrit Krittanawong, Yusuf Kamran Qadeer, Song Peng Ang, Zhen Wang, Mahboob Alam, Samin Sharma, Hani Jneid

Faculty, Staff and Students Publications

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a disease entity that often occurs in young, healthy women and can cause life-threatening ventricular arrhythmias and sudden cardiac arrest. However, the characteristics and outcomes of SCAD with cardiac arrest are not well characterized.

METHODS: This study investigated the baseline characteristics of SCAD patients with cardiac arrest using the National Inpatient Sample (NIS) database between 2016 and 2020. In addition, we also sought to determine the potential impact that implantable cardioverter defibrillator (ICD) therapy had on morbidity and mortality in SCAD patients presenting with cardiac arrest.

RESULTS: Our findings showed that the SCAD …

Death-Associated Protein Kinase 3 Modulates Migration And Invasion Of Triple-Negative Breast Cancer Cells, Junkai Wang, Anh M Tran-Huynh, Beom-Jun Kim, Doug W Chan, Matthew V Holt, Diana Fandino, Xin Yu, Xiaoli Qi, Jin Wang, Weijie Zhang, Yi-Hsuan Wu, Meenakshi Anurag, Xiang H F Zhang, Bing Zhang, Chonghui Cheng, Charles E Foulds, Matthew J Ellis

Faculty, Staff and Students Publications

Sixteen patient-derived xenografts (PDXs) were analyzed using a mass spectrometry (MS)-based kinase inhibitor pull-down assay (KIPA), leading to the observation that death-associated protein kinase 3 (DAPK3) is significantly and specifically overexpressed in the triple-negative breast cancer (TNBC) models. Validation studies confirmed enrichment of DAPK3 protein, in both TNBC cell lines and tumors, independent of mRNA levels. Genomic knockout of DAPK3 in TNBC cell lines inhibited in vitro migration and invasion, along with down-regulation of an epithelial–mesenchymal transition (EMT) signature, which was confirmed in vivo. The kinase and leucine-zipper domains within DAPK3 were shown by a mutational analysis to be essential …

A Curious Case Of Medium-Vessel Vasculitis, Nisa N Ilsin, Haleigh D Stafford, Anna Catinis, Theodore Rosen

Faculty, Staff and Students Publications

Vasculitis, or the inflammation of vessels due to primary or secondary causes, may arise from numerous etiologies, often leading to diagnostic uncertainty. Delayed treatment due to diagnostic or etiologic uncertainty presents a significant clinical risk, with consequences including organ failure and mortality. We describe a case of a 58-year-old male with a history including ankylosing spondylitis who presented with painful ulcers involving the bilateral lower extremities following a trip to the southern Texas border. Histopathology revealed medium-vessel vasculitis; however, the search for a likely etiology in the setting of a unique combination of potential vasculitis precipitants, including glochid inoculation, a …

Lysineless Hibit And Nanoluc Tagging Systems As Alternative Tools For Monitoring Targeted Protein Degradation, Hanfeng Lin, Kristin Riching, May Poh Lai, Dong Lu, Ran Cheng, Xiaoli Qi, Jin Wang

Faculty, Staff and Students Publications

Target protein degradation (TPD) has emerged as a revolutionary approach in drug discovery, leveraging the cell’s intrinsic machinery to selectively degrade disease-associated proteins. Nanoluciferase (nLuc) fusion proteins and the NanoBiT technology offer two robust and sensitive screening platforms to monitor the subtle changes in protein abundance induced by TPD molecules. Despite these advantages, concerns have arisen regarding potential degradation artifacts introduced by tagging systems due to the presence of lysine residues on them, prompting the development of alternative tools. In this study, we introduce HiBiT-RR and nLucK0, variants devoid of lysine residues, to mitigate such artifacts. Our findings demonstrate that …

Znf397 Deficiency Triggers Tet2-Driven Lineage Plasticity And Ar-Targeted Therapy Resistance In Prostate Cancer, Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjöström, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A Johnson, Xiang Li, Xiaoling Li, Lauren A Metang, Atreyi Mukherji, Quanhui Xu, Carla R Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B Hanker, Ganesh V Raj, Guanghui Zhu, Housheng H He, Zhao Wang, Carlos L Arteaga, Han Liang, Felix Y Feng, Yunguan Wang, Tao Wang, Ping Mu

Faculty, Staff and Students Publications

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our …