Medicine and Health Sciences Commons^™

Prefoldin Complex Promotes Interferon-Stimulated Gene Expression And Is Inhibited By Rotavirus Vp3, Yinxing Zhu, Yanhua Song, Dilip Kumar, Peter K Jackson, B V Venkataram Prasad, Siyuan Ding

2020-Current year OA Pubs

Timely induction of interferons and interferon-stimulated genes (ISGs) is critical for successful host defense against viral infections. VP3 encoded by rotavirus is implicated in interferon antagonism. However, the precise mechanisms remain incompletely understood. By conducting tandem-affinity purification coupled with high-resolution mass spectrometry, we identify the prefoldin complex as the top cellular binding partner of VP3. Rotavirus infection is significantly enhanced in prefoldin subunit knockout cells. Using proteome-wide label-free quantification, we find that prefoldin assists in folding ubiquitin-like-modifier-activating-enzyme-3 (UBA3), both of which positively regulate ISG expression. Through direct and competitive binding, VP3 interferes with the chaperone activity of prefoldin, leading to …

Excitotoxic Neuronal Death Requires Superoxide Entry Into Neurons Through Volume-Regulated Anion Channels, Kate Harris, Seok Joon Won, Gokhan Uruk, Nguyen Mai, Devran Ogut, Yonghui Zhao, Litao Xie, Paul Baxter, Katharina Everaerts, Rajan Sah, Raymond A Swanson

2020-Current year OA Pubs

Neuronal death in stroke and other conditions stems in part from stimulation of

Conventional Versus Advanced Imaging Selection For Endovascular Treatment Of Basilar Artery Occlusion Strokes, Huanwen Chen, Joshua Osbun, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Endovascular thrombectomy (EVT) is an effective treatment for basilar artery occlusion (BAO) stroke in select patients. While there is a growing body of literature suggesting that advanced imaging modalities such as computed tomography perfusion (CTP) and magnetic resonance (MR) may not be necessary for selecting anterior circulation large vessel occlusion stroke patients for EVT, whether advanced imaging may be superior to conventional imaging (non-contrast CT and CT angiography) in identifying good treatment candidates among BAO patients is less clear.

PATIENTS AND METHODS: This was a multicenter retrospective cohort study of BAO EVT patients treated from 2013 to 2022 in …

Loss Of Dihydroceramide Desaturase Drives Neurodegeneration By Disrupting Endoplasmic Reticulum And Lipid Droplet Homeostasis In Glial Cells, Yuqing Zhu, Kevin Cho, Haluk Lacin, Yi Zhu, Jose T Dipaola, Beth A Wilson, Gary Patti, James B Skeath

2020-Current year OA Pubs

Dihydroceramide desaturases convert dihydroceramides to ceramides, the precursors of all complex sphingolipids. Reduction of DEGS1 dihydroceramide desaturase function causes pediatric neurodegenerative disorder hypomyelinating leukodystrophy-18 (HLD-18). We discovered that

Danicamtiv Reduces Myosin's Working Stroke But Activates The Thin Filament By Accelerating Actomyosin Attachment, Brent Scott, Lina Greenberg, Caterina Squarci, Kenneth S Campbell, Michael J Greenberg

2020-Current year OA Pubs

Heart failure is a leading cause of death worldwide, and even with current treatments, the 5-y transplant-free survival rate is only ~50 to 70%. As such, there is a need to develop new treatments for patients that improve survival and quality of life. Recently, there have been efforts to develop small molecules for heart failure that directly target components of the sarcomere, including cardiac myosin. Danicamtiv is one of these molecules; however, its direct effects on myosin's single molecule mechanics and kinetics are not well understood. Using optical trapping techniques, stopped flow transient kinetics, and in vitro reconstitution assays, we …

Phosphorylation Toggles The Sars-Cov-2 Nucleocapsid Protein Between Two Membrane-Associated Condensate States, Bruna Favetta, Huan Wang, Jasmine Cubuk, Arjun Singh, Mayur Barai, Cesar Ramirez, Haiyan Zheng, Adam J Gormley, N Sanjeeva Murthy, Gregory Dignon, Andrea Soranno, Zheng Shi, Benjamin S Schuster

2020-Current year OA Pubs

The Nucleocapsid protein (N) of SARS-CoV-2 plays a critical role in the viral lifecycle by regulating RNA replication and by packaging the viral genome. N and RNA phase separate to form condensates that may be important for these functions. Both functions occur at membrane surfaces, but how N toggles between these two membrane-associated functional states is unclear. Here, we reveal that phosphorylation switches how N condensates interact with membranes, in part by modulating condensate material properties. Our studies also show that phosphorylation alters N's interaction with viral membrane proteins. We gain mechanistic insight through structural analysis and molecular simulations, which …

Single-Neuron Datasets For Linguistic And Semantic Processing In The Human Amygdala And Hippocampus, Yue Wang, Runnan Cao, Jon T Willie, Peter Brunner, Shuo Wang

2020-Current year OA Pubs

Understanding linguistic and semantic processing in the human brain involves exploring intricate neural networks. However, it remains unclear whether and how the amygdala and hippocampus are involved in these processes. Here, we recorded single-neuron activity from the human amygdala and hippocampus while neurosurgical patients with intractable epilepsy performed various language tasks. Specifically, we recorded from 68 neurons in 7 patients for the visual language localizer task, 115 neurons in 12 patients for the auditory language localizer task, 88 neurons in 9 patients for the TIMIT task, and 51 neurons in 4 patients for the natural story task. Together, our comprehensive …

Multivariate Protein Landscape Of Host Response In Hospitalised Patients With Suspected Infection In The Emergency Department, Pratik Sinha, Et Al.

2020-Current year OA Pubs

Suspected infection requiring hospitalisation has highly heterogenous presentation. Yet, variances in host response and its implications are largely unknown. In this multicentre cohort of 3802 individual patients presenting to the Emergency Department (ED) with suspected infection requiring hospitalisation, we apply uniform manifold approximation and projections and K-means clustering to 29 plasma proteins to identify biologically discrete host response clusters. In this work, we first describe two large clusters, called "Dysregulated" and "Undifferentiated", with abnormal protein concentrations and adverse outcomes in the former. Through further clustering, we identify 4 sub-clusters in the Dysregulated cluster, each with discrete biological signatures, clinical correlates, …

The 10-Year Anniversary Of The Dissemination And Implementation Models In Health Interactive Webtool: History, Refinement, Use, And Guidance, Borsika A Rabin, Bryan Ford, Rachel G Tabak, Rebekah Gomes, Kera N Swanson, Sara Malone, Maggie Padek Kalman, Ross C Brownson, Russell E Glasgow

2020-Current year OA Pubs

Theories, models, and frameworks (TMFs) are essential tools in dissemination and implementation (D&I) research, yet selecting and applying the most appropriate TMF is routinely a challenge, particularly for those new to the field. To address this need, we developed the

Evaluating Snapshotnir For Tissue Oxygenation Measurement Across Skin Types After Mastectomy, Saif Badran, Sara Saffari, William R Moritz, Gary B Skolnick, Amanda M Westman, Mitchell A Pet, Justin M Sacks

2020-Current year OA Pubs

Accurate monitoring of mastectomy skin flap (MSF) perfusion is critical, especially in patients with darker skin pigmentation at higher risk of misdiagnosed tissue ischemia. Near-infrared spectroscopy (NIRS) devices, such as SnapshotNIR, offer real-time tissue oxygen saturation measurements (StO

Leveraging Sequences Missing From The Human Genome To Diagnose Cancer, Ilias Georgakopoulos-Soares, Christopher A Maher, Et Al.

2020-Current year OA Pubs

BACKGROUND: Cancer diagnosis using cell-free DNA (cfDNA) has the potential to improve treatment and survival but has several technical limitations.

METHODS: In this study, we developed a prediction model based on neomers, DNA sequences 13-17 nucleotides in length that are predominantly absent from the genomes of healthy individuals and are created by tumor-associated mutations.

RESULTS: We show that neomer-based classifiers can accurately detect cancer, including early stages, and distinguish subtypes and features. Analysis of 2577 cancer genomes from 21 cancer types shows that neomers can distinguish tumor types with higher accuracy than state-of-the-art methods. Generation and analysis of 465 cfDNA …

Dexamethasone-Eluting Cochlear Implants Reduce Inflammation And Foreign Body Response In Human And Murine Cochleae, Muhammad Taifur Rahman, Keiko Hirose, Et Al.

2020-Current year OA Pubs

The inflammatory foreign body response (FBR) following cochlear implantation (CI) can negatively impact CI outcomes, including increased electrode impedances. This study aims to investigate the long-term efficacy of dexamethasone-eluting cochlear implant and locally delivered dexamethasone, a potent anti-inflammatory glucocorticoid, on the intracochlear FBR and electrical impedance post-implantation in a murine model. Preliminary impedance data in humans are also provided as a complement to the murine data to illustrate generalizability and reinforce implications related to clinical application. The left ears of CX3CR1

The Promise And Peril Of Comparing Fluorescence Lifetime In Biology Revealed By Simulations, Pingchuan Ma, Peter Chen, Scott Sternson, Yao Chen

2020-Current year OA Pubs

Signaling dynamics are crucial in biological systems, and biosensor-based real-time imaging has revolutionized their analysis. Fluorescence lifetime imaging microscopy (FLIM) excels over the widely used fluorescence intensity imaging by allowing the measurement of absolute signal levels independent of sensor concentration. This capability enables the comparison of signaling dynamics across different animals, body regions, and timeframes. However, FLIM's advantage can be compromised by factors like autofluorescence in biological experiments. To address this, we introduce FLiSimBA, a flexible computational framework for realistic

Multi-Ancestral Genome-Wide Association Study Of Clinically Defined Nicotine Dependence Reveals Strong Genetic Correlations With Other Substance Use Disorders And Health-Related Traits, Emma C Johnson, Jared V Balbona, Alexander S Hatoum, David A A Baranger, Louis Fox, Paul W Jeffries, Laura J Bierut, Andrew C Heath, Pamela A Madden, Elliot C Nelson, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement.

METHODS: We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes.

RESULTS: We replicated the well-known association at the

CONCLUSIONS: Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics …

Experience-Dependent Intrinsic Plasticity In Layer Iv Of Barrel Cortex At Whisking Onset, Molly C Shallow, Lucy Tian, Bryan T Higashikubo, Hudson Lin, Katheryn B Lefton, Siyu Chen, Joseph D Dougherty, Joe P Culver, Mary E Lambo, Keith B Hengen

2020-Current year OA Pubs

The development of motor control over sensory organs is a critical milestone, enabling active exploration and shaping of the sensory environment. Whether the onset of sensory organ motor control directly influences the development of corresponding sensory cortices remains unknown. Here, we confirm and exploit the late onset of whisking behavior in mice to address this question in the somatosensory system. Using ex vivo electrophysiology, we describe a transient increase in the intrinsic excitability of excitatory neurons in layer IV of the barrel cortex, which processes whisker input, immediately following the onset of active whisking on postnatal days 13 and 14. …

O-Glcnac Transferase Plays Dual Antiviral Roles By Integrating Innate Immunity And Lipid Metabolism, Hong Dong, Yong Zhang, Michael J Holtzman, Et Al.

2020-Current year OA Pubs

Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of the antiviral immune responses. Here, by studying a mouse model with a catalytically impaired OGT, we discover a catalytic activity-independent function of OGT in restraining influenza A virus (IAV) infection in addition to its catalytic activity-dependent effect on MAVS-mediated antiviral immunity. Biochemical studies reveal a critical antiviral effect based on OGT interacting with IAV genomic RNA that requires its N-terminal …

Echocardiographic Assessment Of Pulmonary Hemodynamics And Right Ventricular Performance In Neonatal Murine Hypoxia, Kel Vin Woo, Philip T Levy, Carla J Weinheimer, Amanda L Hauck, Aaron Hamvas, David M Ornitz, Attila Kovacs, Gautam K Singh

2020-Current year OA Pubs

No abstract provided.

Revisiting The Effect Of Udenafil On Exercise Performance In Patients With Fontan Circulation: Results Of A Post Hoc Analysis Of The Fuel Trial, David J Goldberg, William B Orr, Et Al.

2020-Current year OA Pubs

BACKGROUND: In the FUEL (Fontan Udenafil Exercise Longitudinal) trial, a positive treatment effect was identified for outcomes at the ventilatory anaerobic threshold but not for the primary outcome, oxygen consumption (Vo

METHODS: Participants were divided into subgroups by baseline predicted peak Vo

RESULTS: Of the 379 participants with paired exercise data, 302 (80%) had a baseline peak Vo

CONCLUSIONS: In this post hoc subgroup analysis, after exclusion of patients with Fontan circulation with near-normal baseline peak Vo

REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT0274115.

Quantifying Collective Interactions In Biomolecular Phase Separation, Hannes Ausserwöger, Ella De Csilléry, Daoyuan Qian, Georg Krainer, Timothy J Welsh, Tomas Sneideris, Titus M Franzmann, Seema Qamar, Nadia A Erkamp, Jonathon Nixon-Abell, Mrityunjoy Kar, Peter St George-Hyslop, Anthony A Hyman, Simon Alberti, Rohit V Pappu, Tuomas P J Knowles

2020-Current year OA Pubs

Biomolecular phase separation is an emerging theme for protein assembly and cellular organisation. The collective forces driving such condensation, however, remain challenging to characterise. Here we show that tracking the dilute phase concentration of only one component suffices to quantify composition and energetics of multicomponent condensates. Applying this assay to several disease- and stress-related proteins, we find that monovalent ions can either deplete from or enrich within the dense phase in a context-dependent manner. By analysing the effect of the widely used modulator 1,6-hexanediol, we find that the compound inhibits phase separation by acting as a solvation agent that expands …

Factors That Influence Female Orthopaedic Surgeons' Decision To Pursue A Career In Sports Medicine: A Mixed-Methods Study, Nichelle M Enata, Katherine M Gerull, Ahmed Hanafy, Mary K Mulcahey, Derrick M Knapik, Matthew V Smith

2020-Current year OA Pubs

BACKGROUND: Despite the increased percentage of women in medical school and in orthopaedic residency programs, the percentage of women pursuing careers in sports medicine has only increased 3% over the past decade.

PURPOSE: To investigate the experiences and perceptions of female orthopaedic surgeons about sports medicine, identifying factors influencing career interest in this surgical subspecialty.

STUDY DESIGN: Cross-sectional study.

METHODS: A mixed-methods approach, combining an online survey and qualitative interviews, was utilized to compare the clinical experiences and personal perceptions of women in orthopaedic sports medicine with women in other orthopaedic subspecialties. Surveys were distributed to members of the Ruth …

Circulating Genomic Landscape Following Cyclin-Dependent Kinase 4/6 Inhibitors Exposure In Hr + /Her2- Metastatic Breast Cancer: A Retrospective Multi-Institutional Consortium Analysis, Letizia Pontolillo, Andrew A Davis, Katherine Clifton, Emily Podany, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are the mainstay of treatment for hormone receptor positive, HER2 negative (HR + /HER2-) metastatic breast cancer (MBC). However, disease progression is inevitable and unveiling resistance mechanisms is crucial to guide post-CDK4/6i therapeutic strategies. In this study, we retrospectively analyzed a real-world, multi-institutional cohort of patients with HR + /HER2- MBC characterized by circulating tumor DNA (ctDNA) through next-generation sequencing (NGS) before starting second-line treatment. Among 93 patients previously treated with CDK4/6i, PIK3CA (37.6%), ESR1 (46.2%) and TP53 (31.2%) were the most altered genes. Comparing with a CDK4/6i plus ET naïve …

A Chronic Acinetobacter Baumannii Pneumonia Model To Study Long-Term Virulence Factors, Antibiotic Treatments, And Polymicrobial Infections, Clay D Jackson-Litteken, Gisela Di Venanzio, Manon Janet-Maitre, Ítalo A Castro, Joseph J Mackel, Leslie D Wilson, David A Rosen, Carolina B López, Mario F Feldman

2020-Current year OA Pubs

Acinetobacter baumannii causes prolonged infections that disproportionately affect immunocompromised populations. Our understanding of A. baumannii respiratory pathogenesis relies on an acute murine infection model with limited clinical relevance that employs an unnaturally high number of bacteria and requires assessment of bacterial load at 24-36 h post-infection. Here, we demonstrate that low intranasal inoculums in tlr4 mutant mice allows for infections lasting at least 3 weeks. Using this "chronic infection model" we determine the adhesin InvL is a virulence factor required during later stages of infection, despite being dispensable in the early phase. We also demonstrate that the chronic model enables …

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett's Esophagus Development, Ramon U. Jin, Yuanwei Xu, T. Mamie Lih, Yang-Zhe Huang, Toni M. Nittolo, Blake E. Sells, Olivia M. Dres, Jean S. Wang, Qing K. Li, Hui Zhang, Jason C. Mills

2020-Current year OA Pubs

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

Informatics At The Frontier Of Cancer Research, Kathleen Noller, Malachi Griffith, Daniel Marcus, Et Al.

2020-Current year OA Pubs

Digitized healthcare data, high-throughput profiling technologies, and data repositories have facilitated the emergence of a new era of cancer research. Each data stream requires specialized analysis methods for interpretation. The data-driven era of cancer research requires the development, enhancement, and sustainment of informatics technology software infrastructure, including fundamental methodology development in artificial intelligence and data science. We review current and emerging informatics technology developments for cancer research and discovery, spanning molecular and cellular characterizations, image analysis, informatics, and therapeutics. Summarizing the diverse methods and applications of informatics throughout cancer research identifies themes and emerging areas for the next generation of …

Integration Of Spatial Protein Imaging And Transcriptomics In The Human Kidney Tracks The Regenerative Potential Of Proximal Tubules, Mahla Asghari, Sanjay Jain, Et Al.

2020-Current year OA Pubs

The organizational principles of nephronal segments are based on anatomical and physiological attributes that are linked to the homeostatic functions of the kidney. Recent molecular approaches have uncovered layers of deeper signatures and states in tubular cells that arise at various time points on the disease trajectory. Here, we introduce an analytical pipeline of multiplexed spatial protein imaging integrated with RNA expression to characterize proximal tubular subpopulations and neighborhoods in human kidney tissue. We demonstrate that, in reference tissue, a large proportion of S1 proximal tubular epithelial cells expresses thymus antigen 1 (THY1), a mesenchymal stromal and stem cell marker …

Cortical Spectral Dynamics Of Vibrotactile Frequency Processing, Nabi Rustamov, Phillip Demarest, Zhuangyu Han, Safia Mohamud, Simon Haroutounian, Eric C Leuthardt

2020-Current year OA Pubs

While scientific research has extensively explored how the brain integrates touch and pain signals, the cerebral processing of specific vibrotactile frequencies remains poorly understood. This gap is particularly significant given clinical evidence that vibrotactile stimulation can reduce pain in both chronic pain patients and experimental settings. Our study investigated the cortical electrophysiological correlates of peripheral vibrotactile stimulation across different frequencies in healthy volunteers, with a focus on frequency-dependent patterns of neuronal activation. While electroencephalogram (EEG) was recorded, healthy participants received vibrotactile stimulation (high-frequency burst stimulation with different inter-burst intervals) to the left index fingertip at frequencies corresponding to established neural …

Multimodal Spatial Transcriptomic Characterization Of Mouse Kidney Injury And Repair, Qiao Xuanyuan, Haojia Wu, Hemalatha Sundaramoorthi, Pierre Isnard, Changfeng Chen, Waleed Rahmani, Benjamin D Humphreys

2020-Current year OA Pubs

The transition from acute kidney injury to chronic kidney disease is characterized by significant changes in the cellular composition and molecular interactions within the kidney. Utilizing high-resolution Xenium and whole transcriptome Visium spatial transcriptomics platforms, we analyze over a million cells on 12 male mouse kidneys across six stages of renal injury and repair. We define and validate 20 major kidney cell populations and delineate distinct cellular neighborhoods through this multimodal spatial analysis. We further reveal a specific fibro-inflammatory niche enriched in failed-repair proximal tubule cells, fibroblasts, and immune cells, with conserved neighborhood gene signatures across mouse and human. Within …

Hybrid Reference Genome Assembly For The Archetypal Leishmania (Viannia) Guyanensis Bearing The Dsrna Totivirus Lrv1, Peter J Myler, Gowthaman Ramasamy, Wesley C Warren, Deborah E Dobson, Stephen M Beverley

2020-Current year OA Pubs

We report a high-quality hybrid genome assembly and annotation for a

The Genetic Architecture Of Cervical Length Is Shared With Spontaneous Preterm Birth Risk, Hope M Wolf, Bradley T Webb, Jerome F Strauss 3rd, Adi L Tarca, Roberto Romero, Sonia S Hassan, Shawn J Latendresse, Tinnakorn Chaiworapongsa, Stanley Berry, Nardhy Gomez-Lopez, Piya Chaemsaithong, Timothy P York

2020-Current year OA Pubs

BACKGROUND: Sonographic cervical length is a powerful predictor of maternal risk for spontaneous preterm birth (sPTB). Twin and family studies have established a maternal genetic heritability for sPTB ranging from 13 to 20%, however, there is no corresponding estimate for the heritability of mid-trimester cervical length, or an understanding of how genetic factors contribute to cervical changes across pregnancy.

METHODS: This study was based on a prospective longitudinal cohort of (N = 5,160) Black/African American women who underwent serial sonographic examination of the uterine cervix during pregnancy and were genotyped via next-generation low-pass whole genome sequencing.

RESULTS: Bivariate genetic correlations …

Genetic Deletion Of The Sodium Phosphate Cotransporter Napi2a Ameliorates Heart Failure In Mice, Hiroko Yamauchi-Sawada, Benjamin D Humphreys, Et Al.

2020-Current year OA Pubs

Apical membrane sodium transporters in renal proximal tubules, such as sodium-glucose co-transporter 2, are attractive therapeutic targets for the treatment of heart failure (HF). Sodium-phosphate co-transporter 2a (NaPi2a) is predominantly expressed in the apical membrane of proximal tubular epithelia and functions to reabsorb filtered phosphate and sodium. It currently remains unclear whether the inhibition of NaPi2a attenuates HF. We found that NaPi2a deficiency improved the cardiac phenotypes of the HF models of transverse aortic constriction (TAC) and doxorubicin (Dox) cardiotoxicity. Natriuretic and phosphaturetic effects were observed in NaPi2a-KO mice under normal conditions, resulting in low serum phosphate and fibroblast growth …