Medical Specialties Commons^™

Direct Reprogramming Of Cardiomyocytes Into Cardiac Purkinje-Like Cells, Nicole Prodan, Faheem Ershad, Arfaxad Reyes-Alcaraz, Luge Li, Brandon Mistretta, Lei Gonzalez, Zhoulyu Rao, Cunjiang Yu, Preethi H Gunaratne, Na Li, Robert J Schwartz, Bradley K Mcconnell

Faculty, Staff and Students Publications

Currently, there are no treatments that ameliorate cardiac cell death, the underlying basis of cardiovascular disease. An unexplored cell type in cardiac regeneration is cardiac Purkinje cells; specialized cells from the cardiac conduction system (CCS) responsible for propagating electrical signals. Purkinje cells have tremendous potential as a regenerative treatment because they may intrinsically integrate with the CCS of a recipient myocardium, resulting in more efficient electrical conduction in diseased hearts. This study is the first to demonstrate an effective protocol for the direct reprogramming of human cardiomyocytes into cardiac Purkinje-like cells using small molecules. The cells generated were genetically and …

Intervening On Impostor Phenomenon: Prospective Evaluation Of A Workshop For Health Science Students Using A Mixed-Method Design, Shine Chang, Hwa Young Lee, Cheryl Anderson, Kava Lewis, Devasmita Chakraverty, Melinda Yates

Faculty, Staff and Student Publications

BACKGROUND: Unaddressed impostor feelings that impede developing interest in science and self-efficacy in conducting research have a dispiriting effect that perpetuates unsatisfactory diversity in the health science workforce when such feelings are experienced more by those historically underrepresented in the workforce. This warrants effective interventions to reduce the impact of impostor feelings and related factors that diminish career resilience. We examined the effects of a 90-minute workshop on impostor perceptions and growth mindset to raise awareness of impostor phenomenon (IP) and develop skills to manage IP successfully for students attending a 10-week summer research experience program.

METHODS: Using a convergent …

Left Atrial Veno-Arterial Extracorporeal Membrane Oxygenation (Lava-Ecmo): Percutaneous Bi-Atrial Drainage To Avoid Pulmonary Edema In A Patient With Left Ventricular Systolic Dysfunction, Kenneth R. Dulnuan, Joseph B. Zwischenberger, John G. Gurley, Maya Guglin

The VAD Journal

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is used in patients with severe cardiogenic shock refractory to medical therapy. During V-A ECMO, retrograde flow in the aorta towards the left ventricle (LV) causes increased left-sided filling pressures, which may lead to pulmonary edema. Different strategies have been proposed to decompress the left heart, including placement of an intraaortic balloon pump (IABP), Impella® (Abiomed), or TandemHeart® (Cardiac Assist). Percutaneous decompression of the left atrium via placement of a transseptal cannula incorporated into the existing venous limb had also been previously done. We describe the novel use of the VFEM venous femoral cannula …

Environmental Drivers Of The First Major Animal Extinction Across The Ediacaran White Sea-Nama Transition, Scott D Evans, Chenyi Tu, Adriana Rizzo, Rachel L Surprenant, Phillip C Boan, Heather Mccandless, Nathan Marshall, Shuhai Xiao, Mary L Droser

Faculty, Staff and Student Publications

The Ediacara Biota-the oldest communities of complex, macroscopic fossils-consists of three temporally distinct assemblages: the Avalon (ca. 575-560 Ma), White Sea (ca. 560-550 Ma), and Nama (ca. 550-539 Ma). Generic diversity varies among assemblages, with a notable decline at the transition from White Sea to Nama. Preservation and sampling biases, biotic replacement, and environmental perturbation have been proposed as potential mechanisms for this drop in diversity. Here, we compile a global database of the Ediacara Biota, specifically targeting taphonomic and paleoecological characters, to test these hypotheses. Major ecological shifts in feeding mode, life habit, and tiering level accompany an increase …

Severe Aortic Stenosis With Coronary Disease: Do Not Get Distracted!, Nils P Johnson, Rob Eerdekens, Pim A L Tonino

Faculty, Staff and Student Publications

No abstract provided.

Ventricular Septal Defect Doppler Peak Gradient Underestimates Right Ventricular Systolic Pressure In The Presence Of Right Bundle Branch Block, Santosh C Uppu, Shubhika Srivastava, Barry A Love

Faculty, Staff and Student Publications

Estimation of the right ventricular systolic pressure (RVSP) using echocardiographically derived maximal instantaneous gradient across the ventricular septal defect is a well-utilized tool, which can potentially underestimate the RVSP in patients with conduction abnormalities as such its utility in these patients is questionable.

Diet-Derived Metabolites And Mucus Link The Gut Microbiome To Fever After Cytotoxic Cancer Treatment, Zaker I Schwabkey, Diana H Wiesnoski, Chia-Chi Chang, Wen-Bin Tsai, Dung Pham, Saira S Ahmed, Tomo Hayase, Miriam R Ortega Turrubiates, Rawan K El-Himri, Christopher A Sanchez, Eiko Hayase, Annette C Frenk Oquendo, Takahiko Miyama, Taylor M Halsey, Brooke E Heckel, Alexandria N Brown, Yimei Jin, Mathilde Raybaud, Rishika Prasad, Ivonne Flores, Lauren Mcdaniel, Valerie Chapa, Philip L Lorenzi, Marc O Warmoes, Lin Tan, Alton G Swennes, Stephanie Fowler, Margaret Conner, Kevin Mchugh, Tyler Graf, Vanessa B Jensen, Christine B Peterson, Kim-Anh Do, Liangliang Zhang, Yushu Shi, Yinghong Wang, Jessica R Galloway-Pena, Pablo C Okhuysen, Carrie R Daniel-Macdougall, Yusuke Shono, Marina Burgos Da Silva, Jonathan U Peled, Marcel R M Van Den Brink, Nadim Ajami, Jennifer A Wargo, Pavan Reddy, Raphael H Valdivia, Lauren Davey, Gabriela Rondon, Samer A Srour, Rohtesh S Mehta, Amin M Alousi, Elizabeth J Shpall, Richard E Champlin, Samuel A Shelburne, Jeffrey J Molldrem, Mohamed A Jamal, Jennifer L Karmouch, Robert R Jenq

Faculty, Staff and Student Publications

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction …

Nurse-Initiated Treatment Reduces Costs For Acute Asthma In A Pediatric Emergency Department, Michael D. Johnson Md, Ms, Minkyoung Yoo Phd, Richard E. Nelson Phd, Amanda K. Nielson Md, Lauren Allen Mas, Nanette Dudley Md, Brandon Andersen Rrt, Amanda Orme Dnp, Cpnp-Ac, Cameron Mcfarland Np-C, Michael Mundorff Mba, Mhsa

Journal of Nursing & Interprofessional Leadership in Quality & Safety

Standardized emergency department (ED) pathways can improve care delivery to children with acute asthma, though their impact on hospitalization and costs is unclear. An Acute Asthma Care Pathway (AACP) that facilitates nurse initiation of treatment was implemented at a tertiary care pediatric ED using standard quality improvement methodology. The impact of implementation was assessed using process control methodology and multivariable time series analyses between pre- and post-implementation periods. Provision of a steroid within 30 minutes and 60 minutes of arrival increased by 21 and 22 percentage points respectively, IV magnesium sulfate administration increased by 30 percentage points, the proportion hospitalized …

Outcomes Of Asthma Quality Improvement In Pediatric Patients, Kathryn M. Murray Md, Faap

Journal of Nursing & Interprofessional Leadership in Quality & Safety

Introduction. The Utah Pediatric Partnership to Improve Healthcare Quality (UPIQ) and Utah Department of Health (UDOH) Asthma Program Learning Collaborative is a quality improvement initiative designed to standardize asthma care in pediatric patients and improve the overall assessment and patient education process for both healthcare providers and patients. The aim of the Asthma QI Project was to improve the diagnosis and management of asthma for patients in the state of Utah by implementing a standardized approach to the identification and treatment of patients with asthma.

Methods. Patients scheduled to see a healthcare provider at our pediatric clinic were screened for …

Transposon Mutagenesis Reveals Rbms3 Silencing As A Promoter Of Malignant Progression Of Brafv600e-Driven Lung Tumorigenesis, Aria Vaishnavi, Joseph Juan, Maebh Jacob, Christopher Stehn, Eric E Gardner, Michael T Scherzer, Sophia Schuman, J Edward Van Veen, Brandon Murphy, Christopher S Hackett, Adam J Dupuy, Steven A Chmura, Louise Van Der Weyden, Justin Y Newberg, Annie Liu, Karen Mann, Alistair G Rust, William A Weiss, Conan G Kinsey, David J Adams, Allie Grossmann, Michael B Mann, Martin Mcmahon

Faculty, Staff and Student Publications

Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a …

Preclinical Evaluation Of Combination Nemtabrutinib And Venetoclax In Chronic Lymphocytic Leukemia, Elizabeth M Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A Rogers, John C Byrd, Jennifer A Woyach

Faculty, Staff and Student Publications

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and …

A Polyamine-Centric, Blood-Based Metabolite Panel Predictive Of Poor Response To Car-T Cell Therapy In Large B Cell Lymphoma, Johannes F Fahrmann, Neeraj Y Saini, Chang Chia-Chi, Ehsan Irajizad, Paolo Strati, Ranjit Nair, Luis E Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan Iyer, Raphael Steiner, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Loretta Nastoupil, Preetesh Jain, Michael Wang, Michael Green, Jason Westin, Viktoria Blumenberg, Marco Davila, Richard Champlin, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Michael Jain, Robert Jenq, Christoph K Stein-Thoeringer, Marion Subklewe, Sattva S Neelapu, Sam Hanash

Faculty, Staff and Student Publications

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified …

Cerebral Blood Flow And Cardiovascular Risk Effects On Resting Brain Regional Homogeneity, Bhim M Adhikari, L Elliot Hong, Zhiwei Zhao, Danny J J Wang, Paul M Thompson, Neda Jahanshad, Alyssa H Zhu, Stefan Holiga, Jessica A Turner, Theo G M Van Erp, Vince D Calhoun, Kathryn S Hatch, Heather Bruce, Stephanie M Hare, Joshua Chiappelli, Eric L Goldwaser, Mark D Kvarta, Yizhou Ma, Xiaoming Du, Thomas E Nichols, Alan R Shuldiner, Braxton D Mitchell, Juergen Dukart, Shuo Chen, Peter Kochunov

Faculty, Staff and Student Publications

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy …

Anti-Diabetic Effects Of Glp1 Analogs Are Mediated By Thermogenic Interleukin-6 Signaling In Adipocytes, Absalon D Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G Kolonin

Faculty, Staff and Student Publications

Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced …

Effect Of Selective Decontamination Of The Digestive Tract On Hospital Mortality In Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial, The Suddicu Investigators For The Australian And New Zealand Intensive Care Society Clinical Trials Group, John A Myburgh, Ian M Seppelt, Fiona Goodman, Laurent Billot, Maryam Correa, Joshua S Davis, Anthony C Gordon, Naomi E Hammond, Jon Iredell, Qiang Li, Sharon Micallef, Jennene Miller, Jayanthi Mysore, Colman Taylor, Paul J Young, Brian H Cuthbertson, Simon R Finfer

Faculty, Staff and Student Publications

IMPORTANCE: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.

OBJECTIVE: To determine whether SDD reduces in-hospital mortality in critically ill adults.

DESIGN, SETTING, AND PARTICIPANTS: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.

INTERVENTIONS: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a …

Policy Considerations That Support Equitable Access To Responsible, Accountable, Safe, And Ethical Uses Of Psychedelic Medicines, Sean J Belouin, Lynnette A Averill, Jack E Henningfield, Stephen N Xenakis, Ingrid Donato, Charles S Grob, Ann Berger, Veronica Magar, Alicia L Danforth, Brian T Anderson

Faculty, Staff and Students Publications

There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine [MDMA]), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted Breakthrough Therapy designations by the US Food and Drug Administration and may potentially receive full FDA approval with similar regulatory considerations occurring in multiple countries. At the same time, regulatory changes are poised to increase access to legal or decriminalized psychedelic use in various non-medical settings. This review provides a brief discussion on the historical …

A, B, C'S Of Trk Receptors And Their Ligands In Ocular Repair, Akash Gupta, Jeremias G Galletti, Zhiyuan Yu, Kevin Burgess, Cintia S De Paiva

Faculty, Staff and Students Publications

Neurotrophins are a family of closely related secreted proteins that promote differentiation, development, and survival of neurons, which include nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. All neurotrophins signal through tropomyosin receptor kinases (TrkA, TrkB, and TrkC) which are more selective to NGF, brain-derived neurotrophic factor, and neurotrophin-3, respectively. NGF is the most studied neurotrophin in the ocular surface and a human recombinant NGF has reached clinics, having been approved to treat neurotrophic keratitis. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are less studied neurotrophins in the ocular surface, even though brain-derived neurotrophic factor is well characterized in …

Gene Therapy Knockdown Of Hippo Signaling Resolves Arrhythmic Events In Pigs After Myocardial Infarction, Sui Zhang, Shijie Liu, John P Leach, Ke Li, Emerson C Perin, James F Martin

Faculty, Staff and Students Publications

No abstract provided.

Targeted Genome Sequencing Identifies Multiple Rare Variants In Caveolin-1 Associated With Obstructive Sleep Apnea, Jingjing Liang, Heming Wang, Brian E Cade, Nuzulul Kurniansyah, Karen Y He, Jiwon Lee, Scott A Sands, Jennifer A Brody, Han Chen, Daniel J Gottlieb, Daniel S Evans, Xiuqing Guo, Sina A Gharib, Lauren Hale, David R Hillman, Pamela L Lutsey, Sutapa Mukherjee, Heather M Ochs-Balcom, Lyle J Palmer, Shaun Purcell, Richa Saxena, Sanjay R Patel, Katie L Stone, Gregory J Tranah, Eric Boerwinkle, Xihong Lin, Yongmei Liu, Bruce M Psaty, Ramachandran S Vasan, Ani Manichaikul, Stephen S Rich, Jerome I Rotter, Tamar Sofer, Susan Redline, Xiaofeng Zhu

Faculty, Staff and Students Publications

Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes.

Objectives: To search for rare variants contributing to OSA severity.

Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea-hypopnea index (AHI) in a total …

Tumor-Intrinsic Sirpa Promotes Sensitivity To Checkpoint Inhibition Immunotherapy In Melanoma, Zhicheng Zhou, Mei-Ju May Chen, Yikai Luo, Kamalika Mojumdar, Xin Peng, Hu Chen, Shweta V Kumar, Rehan Akbani, Yiling Lu, Han Liang

Faculty, Staff and Student Publications

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture …

Increased Circulating Cortisol After Vaginal Birth Is Associated With Increased Fgf19 Secretion In Neonatal Pigs, Caitlin Vonderohe, Gregory Guthrie, Barbara Stoll, Valeria Melendez Hebib, Harry Dawson, Douglas Burrin

Children’s Nutrition Research Center Staff Publications

The influence of birth modality (scheduled cesarean or spontaneous vaginal) on the development of the newborn has been a source of controversy in neonatology. The impact of cesarean vs vaginal birth on the development of bile acid and fibroblast growth factor 19 (FGF19) signaling is unknown. Our aim was to determine the effect of birth modality and gestational age (preterm vs term) on plasma hormone levels, bile acid pool distribution, expression of genes in the bile acid-FXR-FGF19 pathway, and plasma levels of FGF19 at birth and on day 3 of life in neonatal pigs. Four sows underwent cesarean delivery on …

Medicc2: Whole-Genome Doubling Aware Copy-Number Phylogenies For Cancer Evolution, Tom L Kaufmann, Marina Petkovic, Thomas B K Watkins, Emma C Colliver, Sofya Laskina, Nisha Thapa, Darlan C Minussi, Nicholas Navin, Charles Swanton, Peter Van Loo, Kerstin Haase, Maxime Tarabichi, Roland F Schwarz

Faculty, Staff and Student Publications

Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states.

Tumor Suppressor Dear1 Regulates Mammary Epithelial Cell Fate And Predicts Early Onset And Metastasis In Triple Negative Breast Cancer, Uyen Q Le, Nanyue Chen, Seetharaman Balasenthil, Eugene Lurie, Fei Yang, Suyu Liu, Laura Rubin, Luisa Maren Solis Soto, Maria Gabriela Raso, Harsh Batra, Aysegul A Sahin, Ignacio I Wistuba, Ann Mcneill Killary

Faculty, Staff and Student Publications

Triple negative breast cancer (TNBC) is a disease of poor prognosis, with the majority classified as the basal-like subtype associated with epithelial-mesenchymal transition and metastasis. Because basal breast cancers originate from proliferative luminal progenitor-like cells upon dysregulation of proper luminal differentiation, genes regulating luminal-basal transition are critical to elucidate novel therapeutic targets to improve TNBC outcomes. Herein we demonstrate that the tumor suppressor DEAR1/TRIM62 is a critical regulator of luminal cell fate. DEAR1 loss in human mammary epithelial cells results in significantly enhanced mammosphere formation that is accelerated in the presence of TGF-β/SMAD3 signaling. Mammospheres formed following DEAR1 loss are …

Gating Intermediates Reveal Inhibitory Role Of The Voltage Sensor In A Cyclic Nucleotide-Modulated Ion Channel, Xiaolong Gao, Philipp A M Schmidpeter, Vladimir Berka, Ryan J Durham, Chen Fan, Vasanthi Jayaraman, Crina M Nimigean

Faculty, Staff and Student Publications

Understanding how ion channels gate is important for elucidating their physiological roles and targeting them in pathophysiological states. Here, we used SthK, a cyclic nucleotide-modulated channel from Spirochaeta thermophila, to define a ligand-gating trajectory that includes multiple on-pathway intermediates. cAMP is a poor partial agonist for SthK and depolarization increases SthK activity. Tuning the energy landscape by gain-of-function mutations in the voltage sensor domain (VSD) allowed us to capture multiple intermediates along the ligand-activation pathway, highlighting the allosteric linkage between VSD, cyclic nucleotide-binding (CNBD) and pore domains. Small, lateral displacements of the VSD S4 segment were necessary to open the …

Region-Specific Denoising Identifies Spatial Co-Expression Patterns And Intra-Tissue Heterogeneity In Spatially Resolved Transcriptomics Data, Linhua Wang, Mirjana Maletic-Savatic, Zhandong Liu

Duncan NRI Faculty and Staff Publications

Spatially resolved transcriptomics is a relatively new technique that maps transcriptional information within a tissue. Analysis of these datasets is challenging because gene expression values are highly sparse due to dropout events, and there is a lack of tools to facilitate in silico detection and annotation of regions based on their molecular content. Therefore, we develop a computational tool for detecting molecular regions and region-based Missing value Imputation for Spatially Transcriptomics (MIST). We validate MIST-identified regions across multiple datasets produced by 10x Visium Spatial Transcriptomics, using manually annotated histological images as references. We benchmark MIST against a spatial k-nearest neighboring …

Conformational Motions And Ligand-Binding Underlying Gating And Regulation In Ip3r Channel, Guizhen Fan, Mariah R Baker, Lara E Terry, Vikas Arige, Muyuan Chen, Alexander B Seryshev, Matthew L Baker, Steven J Ludtke, David I Yule, Irina I Serysheva

Faculty, Staff and Students Publications

Inositol-1,4,5-trisphosphate receptors (IP3Rs) are activated by IP3 and Ca2+ and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP3R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP3, Ca2+ and ATP, revealing conformational changes that couple ligand-binding to channel opening. Using a deep-learning approach and 3D variability analysis we extracted molecular motions of the key protein domains from cryo-EM density data. We find that IP3 binding relies upon intrinsic flexibility of the ARM2 domain in the …

Applications Of Covalent Chemistry In Targeted Protein Degradation, Dong Lu, Xin Yu, Hanfeng Lin, Ran Cheng, Erika Y Monroy, Xiaoli Qi, Meng C Wang, Jin Wang

Faculty, Staff and Students Publications

Proteolysis-targeting chimeras (PROTACs) and targeted covalent inhibitors (TCIs) are currently two exciting strategies in the fields of chemical biology and drug discovery. Extensive research in these two fields has been conducted, and significant progress in these fields has resulted in many clinical candidates, some of which have been approved by FDA. Recently, a novel concept termed covalent PROTACs that combine these two strategies has emerged and gained an increasing interest in the past several years. Herein, we briefly review and highlight the mechanism and advantages of TCIs and PROTACs, respectively, and the recent development of covalent PROTACs using irreversible and …

High Throughput Sequencing For Clinical Tuberculosis: An Overview, Tara E Ness, Andrew Dinardo, Maha R Farhat

Faculty, Staff and Students Publications

High throughput sequencing (HTS) can identify the presence of Mycobacterium tuberculosis DNA in a clinical sample while also providing information on drug susceptibility. Multiple studies have provided a context for exploring the clinical application of HTS for TB diagnosis. The workflow challenges, strengths and limitations of the various sequencing platforms, and tools used for analysis are presented to provide a framework for further innovations in the field.

Ontology-Based Feature Engineering In Machine Learning Workflows For Heterogeneous Epilepsy Patient Records, Satya S Sahoo, Katja Kobow, Jianzhe Zhang, Jeffrey Buchhalter, Mojtaba Dayyani, Dipak P Upadhyaya, Katrina Prantzalos, Meenakshi Bhattacharjee, Ingmar Blumcke, Samuel Wiebe, Samden D Lhatoo

Faculty, Staff and Student Publications

Biomedical ontologies are widely used to harmonize heterogeneous data and integrate large volumes of clinical data from multiple sources. This study analyzed the utility of ontologies beyond their traditional roles, that is, in addressing a challenging and currently underserved field of feature engineering in machine learning workflows. Machine learning workflows are being increasingly used to analyze medical records with heterogeneous phenotypic, genotypic, and related medical terms to improve patient care. We performed a retrospective study using neuropathology reports from the German Neuropathology Reference Center for Epilepsy Surgery at Erlangen, Germany. This cohort included 312 patients who underwent epilepsy surgery and …

Challenges Associated With The Integration Of Immuno-Oncology Agents In Clinical Practice, Patrice Lazure, Aparna R Parikh, Neal E Ready, Marianne J Davies, Sophie Péloquin, Jeffrey M Caterino, Robert Lewandowski, Alexander J Lazar, Suzanne Murray

Faculty, Staff and Student Publications

Background: The availability of new immuno-oncology therapeutics markedly impacts oncology clinicians' treatment decision-making. To effectively support healthcare professionals (HCPs) in their practice, it is important to better understand the challenges and barriers that can accompany the introduction of these agents. This study aimed to establish the types and causes of clinical challenges posed by the introduction of new immuno-oncology agents.

Methods: The mixed-methods design included qualitative in-depth interviews and group discussions with HCPs, in which participants discussed clinical challenges and potential underlying reasons for these challenges. Qualitative findings informed a quantitative survey. This survey investigated the extent and distribution of …