Medicine and Health Sciences Commons^™

Advancing De Novo Lipogenesis: Genetic And Metabolic Insights, Sean M Hartig, Mark A Herman

Faculty, Staff and Students Publications

De novo lipogenesis (DNL) is the process whereby cells synthesize fatty acids from acetyl-CoA, contributing to steatosis in fatty liver disease. Two new studies, using genetic mouse models, metabolomics, and pharmacology, identified alternative pathways in DNL and unexpected physiological effects when targeting key enzymes in this pathway.

Modern Digital Query Analytics Of Patient Education Materials On Acanthosis Nigricans: Systematic Search And Content Analysis, Kevin Johny Varghese, Som Singh, Emily Kamali, Fahad Qureshi, Aleena Jamal, Fawad Qureshi

SKMC Student Presentations and Publications

BACKGROUND: Online digital materials are integral to patient education and health care outcomes in dermatology. Acanthosis nigricans (AN) is a common condition, often associated with underlying diseases such as insulin resistance. Patients frequently search the internet for information related to this cutaneous finding. To our knowledge, the quality of online educational materials for AN has not been systematically examined.

OBJECTIVE: The primary objective of this study was to profile the readability and quality of the content of publicly available digital educational materials on AN and identify questions frequently asked by patients.

METHODS: This study analyzed publicly available internet sources to …

Buprenorphine And Postpartum Contraception Utilization Among People With Opioid Use Disorder: A Multi-State Analysis, Kevin Y Xu, Jennifer K Bello, Joanna Buss, Hendrée E Jones, Laura J Bierut, Dustin Stwalley, Hannah S Szlyk, Caitlin E Martin, Jeannie C Kelly, Ebony B Carter, Elizabeth E Krans, Richard A Grucza

2020-Current year OA Pubs

BACKGROUND: The postpartum period provides an opportunity for birthing people with opioid use disorder (OUD) to consider their future reproductive health goals. However, the relationship between the use of medication for opioid use disorder (MOUD) and contraception utilization is not well understood. We used multistate administrative claims data to compare contraception utilization rates among postpartum people with OUD initiating buprenorphine (BUP) versus no medication (psychosocial services receipt without MOUD (PSY)) in the United States (US).

METHODS: In this retrospective cohort study, we analyzed data from the Merative™ MarketScan

RESULTS: Our sample consisted of 11,118 postpartum people with OUD. Among those, …

The Impact Of Covid-19 On Hiv Care: A Comprehensive Analysis Of Patient And Healthcare Providers Experiences At The Largest Hiv Treatment Center In Ghana, Peter Puplampu, Justice K Baah, Karl Osei Afoduo, Bright A Adjei, Araba Abaidoo-Myles, Victor G Davila-Roman, George B Kyei, Collins S Ahorlu

2020-Current year OA Pubs

BACKGROUND: We sought to determine how the COVID-19 pandemic affected care delivery for HIV patients in Ghana.

METHODS: Guided by the Consolidated Framework for Implementation Research (CFIR), we performed a cross-sectional study between May and July 2021 among 40 people living with HIV and 19 healthcare providers caring for HIV patients. In-depth interviews and focus group discussions were done with HIV patients, doctors, nurses, pharmacists, laboratory scientists, data scientists, administrators, and counselors to ascertain barriers and facilitators to HIV care during the pandemic. We asked for their input on removing barriers to care during this and future pandemics. Data was …

Null Method To Estimate The Maximal Pa At Subsaturating Concentrations Of Agonist, Allison L Germann, Spencer R Pierce, Joe Henry Steinbach, Gustav Akk

2020-Current year OA Pubs

The maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations. In this approach, the amplitude of the response to a high-efficacy control agonist applied alone is compared with the amplitude of the response to a control …

Distinct Properties And Activation Of Hexameric And Heptameric Pannexin 1 Channel Concatemers, Smriti Gupta, Yu-Hsin Chiu, Mohan C Manjegowda, Bimal N Desai, Kodi S Ravichandran, Douglas A Bayliss

2020-Current year OA Pubs

Pannexin 1 (PANX1) is a member of a topologically related and stoichiometrically diverse family of large pore membrane ion channels that support the flux of signaling metabolites (e.g., ATP) and fluorescent dyes. High-resolution structural analyses have identified PANX1 as a heptamer despite early evidence suggesting that it might be a hexamer. To determine if PANX1 channel activity is supported in both hexameric and heptameric conformations, we examined properties of concatenated PANX1 constructs comprising either six or seven subunits with intact or truncated C-termini (the latter to mimic caspase-cleavage activation). In whole-cell recordings from PANX1-deleted cells, the C-tail-truncated hexameric and heptameric …

Opaque Ontology: Neuroimaging Classification Of Icd-10 Diagnostic Groups In The Uk Biobank, Ty Easley, Xiaoke Luo, Kayla Hannon, Petra Lenzini, Janine Bijsterbosch

2020-Current year OA Pubs

BACKGROUND: The use of machine learning to classify diagnostic cases versus controls defined based on diagnostic ontologies such as the International Classification of Diseases, Tenth Revision (ICD-10) from neuroimaging features is now commonplace across a wide range of diagnostic fields. However, transdiagnostic comparisons of such classifications are lacking. Such transdiagnostic comparisons are important to establish the specificity of classification models, set benchmarks, and assess the value of diagnostic ontologies.

RESULTS: We investigated case-control classification accuracy in 17 different ICD-10 diagnostic groups from Chapter V (mental and behavioral disorders) and Chapter VI (diseases of the nervous system) using data from the …

Scproatlas: An Atlas Of Multiplexed Single-Cell Spatial Proteomics Imaging In Human Tissues, Tiangang Wang, Xuanmin Chen, Yujuan Han, Jiahao Yi, Xi Liu, Pora Kim, Liyu Huang, Kexin Huang, Xiaobo Zhou

Faculty, Staff and Student Publications

Spatial proteomics can visualize and quantify protein expression profiles within tissues at single-cell resolution. Although spatial proteomics can only detect a limited number of proteins compared to spatial transcriptomics, it provides comprehensive spatial information with single-cell resolution. By studying the spatial distribution of cells, we can clearly obtain the spatial context within tissues at multiple scales. Spatial context includes the spatial composition of cell types, the distribution of functional structures, and the spatial communication between functional regions, all of which are crucial for the patterns of cellular distribution. Here, we constructed a comprehensive spatial proteomics functional annotation knowledgebase, scProAtlas (https://relab.xidian.edu.cn/scProAtlas/#/), …

Aspdb: An Integrative Knowledgebase Of Human Protein Isoforms From Experimental And Ai-Predicted Structures, Yuntao Yang, Himansu Kumar, Yuhan Xie, Zhao Li, Rongbin Li, Wenbo Chen, Chiamaka S Diala, Meer A Ali, Yi Xu, Albon Wu, Sayed-Rzgar Hosseini, Erfei Bi, Hongyu Zhao, Pora Kim, W Jim Zheng

Faculty, Staff and Student Publications

Alternative splicing is a crucial cellular process in eukaryotes, enabling the generation of multiple protein isoforms with diverse functions from a single gene. To better understand the impact of alternative splicing on protein structures, protein-protein interaction and human diseases, we developed ASpdb (https://biodataai.uth.edu/ASpdb/), a comprehensive database integrating experimentally determined structures and AlphaFold 2-predicted models for human protein isoforms. ASpdb includes over 3400 canonical isoforms, each represented by both experimentally resolved and predicted structures, and >7200 alternative isoforms with AlphaFold 2 predictions. In addition to detailed splicing events, 3D structures, sequence variations and functional annotations, ASpdb uniquely offers comparative analyses and …

Metsdb: A Knowledgebase Of Cancer Metastasis At Bulk, Single-Cell And Spatial Levels, Sijia Wu, Jiajin Zhang, Yanfei Wang, Xinyu Qin, Zhaocan Zhang, Zhennan Lu, Pora Kim, Xiaobo Zhou, Liyu Huang

Faculty, Staff and Student Publications

Cancer metastasis, the process by which tumour cells migrate and colonize distant organs from a primary site, is responsible for the majority of cancer-related deaths. Understanding the cellular and molecular mechanisms underlying this complex process is essential for developing effective metastasis prevention and therapy strategies. To this end, we systematically analysed 1786 bulk tissue samples from 13 cancer types, 988 463 single cells from 17 cancer types, and 40 252 spots from 45 spatial slides across 10 cancer types. The results of these analyses are compiled in the metsDB database, accessible at https://relab.xidian.edu.cn/metsDB/. This database provides insights into alterations in …

Crisprofft: Comprehensive Database Of Crispr/Cas Off-Targets, Grant Wang, Xiaona Liu, Aoqi Wang, Jianguo Wen, Pora Kim, Qianqian Song, Xiaona Liu, Xiaobo Zhou

Faculty, Staff and Student Publications

The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated protein) programmable nuclease system continues to evolve, with in vivo therapeutic gene editing increasingly applied in clinical settings. However, off-target effects remain a significant challenge, hindering its broader clinical application. To enhance the development of gene-editing therapies and the accuracy of prediction algorithms, we developed CRISPRoffT (https://ccsm.uth.edu/CRISPRoffT/). Users can access a comprehensive repository of off-target regions predicted and validated by a diverse range of technologies across various cell lines, Cas enzyme variants, engineered sgRNAs (single guide RNAs) and CRISPR editing systems. CRISPRoffT integrates results of off-target analysis from 74 studies, encompassing …

Cansar 2024-An Update To The Public Drug Discovery Knowledgebase, Phillip W Gingrich, Rezvan Chitsazi, Ansuman Biswas, Chunjie Jiang, Li Zhao, Joseph E Tym, Kevin M Brammer, Jun Li, Zhigang Shu, David S Maxwell, Jeffrey A Tacy, Ioan L Mica, Michael Darkoh, Patrizio Di Micco, Kaitlyn P Russell, Paul Workman, Bissan Al-Lazikani

Faculty, Staff and Student Publications

canSAR (https://cansar.ai) continues to serve as the largest publicly available platform for cancer-focused drug discovery and translational research. It integrates multidisciplinary data from disparate and otherwise siloed public data sources as well as data curated uniquely for canSAR. In addition, canSAR deploys a suite of curation and standardization tools together with AI algorithms to generate new knowledge from these integrated data to inform hypothesis generation. Here we report the latest updates to canSAR. As well as increasing available data, we provide enhancements to our algorithms to improve the offering to the user. Notably, our enhancements include a revised ligandability classifier …

Dimensionality Reduction For Visualizing Spatially Resolved Profiling Data Using Spasne, Yuansheng Zhou, Chen Tang, Xue Xiao, Xiaowei Zhan, Tao Wang, Guanghua Xiao, Lin Xu

Faculty, Staff and Student Publications

Background: Spatially resolved profiling technologies to quantify transcriptomes, epigenomes, and proteomes have been emerging as groundbreaking methods for comprehensive molecular characterizations. Dimensionality reduction and visualization is an essential step to analyze and interpret spatially resolved profiling data. However, state-of-the-art dimensionality reduction methods for single-cell sequencing data, such as the t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP), were not tailored for spatially resolved profiling data.

Results: Here we developed a spatially resolved t-SNE (SpaSNE) method to integrate both spatial and molecular information. We applied it to a variety of public spatially resolved profiling datasets that were …

Intrinsic Adaptive Plasticity In Mouse And Human Sensory Neurons, Lisa A Mcilvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau

Faculty, Staff and Student Publications

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory …

Circakb: A Comprehensive Knowledgebase Of Circadian Genes Across Multiple Species, Xingchen Zhu, Xiao Han, Zhijin Li, Xiaobo Zhou, Seung-Hee Yoo, Zheng Chen, Zhiwei Ji

Faculty, Staff and Student Publications

Circadian rhythms, which are the natural cycles that dictate various physiological processes over a 24-h period, have been increasingly recognized as important in the management and treatment of various human diseases. However, the lack of sufficient data and reliable analysis methods have been a major obstacle to understanding the bidirectional interaction between circadian variation and human health. We have developed CircaKB, a comprehensive knowledgebase of circadian genes across multiple species. CircaKB is the first knowledgebase that provides systematic annotations of the oscillatory patterns of gene expression at a genome-wide level for 15 representative species. Currently, CircaKB contains 226 time-course transcriptome …

Intrinsic Adaptive Plasticity In Mouse And Human Sensory Neurons, Lisa A Mcilvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau

2020-Current year OA Pubs

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory …

Automated Breast Density Assessment For Full-Field Digital Mammography And Digital Breast Tomosynthesis, Shu Jiang, Debbie L Bennett, Simin Chen, Adetunji T Toriola, Graham A Colditz

2020-Current year OA Pubs

Mammographic density is a strong risk factor for breast cancer and is reported clinically as part of Breast Imaging Reporting and Data System (BI-RADS) results issued by radiologists. Automated assessment of density is needed that can be used for both full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) as both types of exams are acquired in standard clinical practice. We trained a deep learning model to automate the estimation of BI-RADS density from a prospective Washington University clinic-based cohort of 9,714 women, entering into the cohort in 2013 with follow-up through October 31, 2020. The cohort included 27% non-Hispanic …

Plural Molecular And Cellular Mechanisms Of Pore Domain, Timothy J Abreo, Emma C Thompson, Anuraag Madabushi, Kristen L Park, Heun Soh, Nissi Varghese, Carlos G Vanoye, Kristen Springer, Jim Johnson, Scotty Sims, Zhigang Ji, Ana G Chavez, Miranda J Jankovic, Bereket Habte, Aamir R Zuberi, Cathleen M Lutz, Zhao Wang, Vaishnav Krishnan, Lisa Dudler, Stephanie Einsele-Scholz, Jeffrey L Noebels, Alfred L George, Atul Maheshwari, Anastasios Tzingounis, Edward C Cooper

Faculty, Staff and Students Publications

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. Kcnq2G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal …

Fluorescence Lifetime Sorting Reveals Tunable Enzyme Interactions Within Cytoplasmic Condensates, Leyla E Fahim, Joshua M Marcus, Noah D Powell, Zachary A Ralston, Katherine Walgamotte, Eleonora Perego, Giuseppe Vicidomini, Alessandro Rossetta, Jason E Lee

Faculty, Staff and Students Publications

Ribonucleoprotein (RNP) condensates partition RNA and protein into multiple liquid phases. The multiphasic feature of condensate-enriched components creates experimental challenges for distinguishing membraneless condensate functions from the surrounding dilute phase. We combined fluorescence lifetime imaging microscopy (FLIM) with phasor plot filtering and segmentation to resolve condensates from the dilute phase. Condensate-specific lifetimes were used to track protein-protein interactions by measuring FLIM-Förster resonance energy transfer (FRET). We used condensate FLIM-FRET to evaluate whether mRNA decapping complex subunits can form decapping-competent interactions within P-bodies. Condensate FLIM-FRET revealed the presence of core subunit interactions within P-bodies under basal conditions and the disruption of …

Myo5b And The Polygenic Landscape Of Very Early-Onset Inflammatory Bowel Disease In An Ethnically Diverse Population, Ashleigh Watson, R Alan Harris, Amy C Engevik, Numan Oezguen, Maribeth R Nicholson, Sarah Dooley, Rachel Stubler, Lisa Forbes Satter, Lina B Karam, Richard Kellermayer

Faculty, Staff and Students Publications

Background: Genetic discovery in very early-onset inflammatory bowel disease (VEO-IBD) can elucidate not only the origins of VEO-IBD, but also later-onset inflammatory bowel disease. We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients.

Methods: Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD "susceptibility" single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored …

Integrative Multiomics Reveals Common Endotypes Across Psen1, Psen2, And App Mutations In Familial Alzheimer's Disease, Phoebe Valdes, Andrew B Caldwell, Qing Liu, Michael Q Fitzgerald, Srinivasan Ramachandran, Celeste M Karch, Dominantly Inherited Alzheimer Network (Dian), Douglas R Galasko, Shauna H Yuan, Steven L Wagner, Shankar Subramaniam

2020-Current year OA Pubs

BACKGROUND: PSEN1, PSEN2, and APP mutations cause Alzheimer's disease (AD) with an early age at onset (AAO) and progressive cognitive decline. PSEN1 mutations are more common and generally have an earlier AAO; however, certain PSEN1 mutations cause a later AAO, similar to those observed in PSEN2 and APP.

METHODS: We examined whether common disease endotypes exist across these mutations with a later AAO (~ 55 years) using hiPSC-derived neurons from familial Alzheimer's disease (FAD) patients harboring mutations in PSEN1

RESULTS: We identified common disease endotypes, such as dedifferentiation, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. …

Couple-Based Lifestyle Intervention For Minority Prostate Cancer Survivors: A Randomized Feasibility Trial, Dalnim Cho, Yisheng Li, Karen Basen-Engquist, Chiara Acquati, Nga T T Nguyen, Hilary Ma, Curtis A Pettaway, Lorna H Mcneill

Faculty, Staff and Student Publications

Background: Black and Hispanic prostate cancer (PCa) survivors, who face a high burden of comorbid conditions and often engage in low levels of physical activity and healthy eating, remain significantly underrepresented in lifestyle intervention studies.

Purpose: Given the significance of spousal influence, we developed a culturally tailored lifestyle intervention for these survivors and their spouses and assessed its feasibility, acceptability, and impact on behavioral change.

Methods: Survivor-spouse couples were randomly assigned to an intervention group (n = 22), which received 12 health-coaching calls over 6 months, or a usual-care control group (n = 9). Assessments were conducted at baseline (T1), …

Early Treatment Discontinuation In Patients With Deficient Mismatch Repair Or Microsatellite Instability High Metastatic Colorectal Cancer Receiving Immune Checkpoint Inhibitors, Julien Taieb, Margherita Ambrosini, Emily Alouani, Sara Lonardi, Frank A Sinicrope, Marie Decraecker, Alice Boileve, Emilie Hafliger, Thibault Mazard, Simon Pernot, Pauline Parent, Javier Ros, Michael J Overman, Priya Jayachandran, Vincenzo Nasca, Lisa Salvatore, Rosine Guimbaud, Chiara Cremolini, David Tougeron, Filippo Pietrantonio

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD).

Methods: To assess whether ETD is associated with similar outcomes compared …

Us Military Veterans’ Perceived Concordance With Their Providers Regarding Persistent Physical Symptoms Prospectively Predicts Satisfaction With Care And Adherence To Care Plans, L Alison Phillips, Laura M Lesnewich, Katharine Bloeser, Yong Lin, Rachel L Boska, Justeen K Hyde, Peter J Bayley, Helena K Chandler, Matthew J Reinhard, Susan L Santos, Rachel Stewart, Drew A Helmer, Lisa M Mcandrew

Center for Medical Ethics and Health Policy Staff Publications

Background: Medically unexplained, persistent physical symptoms and syndromes are commonly seen in primary care. These are debilitating for patients and difficult to treat, causing frustration for patients and providers.

Purpose: This study investigates how well US military veterans with multiple persistent physical symptoms (PPS), called Gulf War illness (GWI), agree with their healthcare providers about their illness. This agreement, called perceived concordance, is hypothesized to influence veterans' satisfaction with care, adherence to care plans, and disability levels.

Methods: Participants were 230 veterans with GWI deployed to the 1990-1991 Gulf War who were recruited from Veteran Affairs primary care and War …

A Prospective, Multicenter Analysis Of The Integrated 31-Gene Expression Profile Test For Sentinel Lymph Node Biopsy (I31-Gep For Slnb) Test Demonstrates Reduced Number Of Unnecessary Slnbs In Patients With Cutaneous Melanoma., J Michael Guenther, Andrew Ward, Brian J Martin, Mark Cripe, Rohit Sharma, Stanley P Leong, Joseph I Clark, John Hamner, Timothy Beard

Oncology Articles

BACKGROUND: National Comprehensive Cancer Network guidelines recommend sentinel lymph node biopsy (SLNB) for patients with > 10% risk of positivity, consider SLNB with 5-10% risk, and foregoing with <  5% risk. The integrated 31-gene expression profile (i31-GEP) algorithm combines the 31-GEP with clinicopathologic variables, estimating SLN positivity risk.

METHODS: The i31-GEP SLNB risk prediction accuracy was assessed in patients with T1-T2 tumors enrolled in the prospective, multicenter DECIDE study (n = 322). To determine if incorporating the i31-GEP into decision-making resulted in fewer SLNBs performed, propensity score-matching was performed to a non-overlapping cohort for whom the 31-GEP was not used for SLNB decision-making.

RESULTS: No patients with <  5% i31-GEP predicted risk had a positive SLNB (0/35). Propensity matching demonstrated an 18.5% reduction in SLNBs performed (43.7% vs. 62.2%. p <  0.001). The i31-GEP could have reduced the number of unnecessary biopsies by 25.0% (35/140).

CONCLUSIONS: This prospective study confirmed the performance and clinical utility of the i31-GEP for …

A Propofol Binding Site In The Voltage Sensor Domain Mediates Inhibition Of Hcn1 Channel Activity, Verena Burtscher, Lei Wang, John Cowgill, Zi-Wei Chen, Christopher Edge, Edward Smith, Yongchang Chang, Lucie Delemotte, Alex S Evers, Baron Chanda

2020-Current year OA Pubs

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) ion channels are members of the cyclic nucleotide-binding family and are crucial for regulating cellular automaticity in many excitable cells. HCN channel activation contributes to pain perception, and propofol, a widely used anesthetic, acts as an analgesic by inhibiting the voltage-dependent activity of HCN channels. However, the molecular determinants of propofol action on HCN channels remain unknown. Here, we use a propofol-analog photoaffinity labeling reagent to identify propofol binding sites in the human HCN1 isoform. Mass spectrometry analyses combined with molecular dynamics simulations show that a binding pocket is formed by extracellularly facing residues in …

Rapid Viral Suppression Using Integrase Inhibitors During Acute Hiv-1 Infection, Mehri S Mckellar, Jessica R Keys, Lindsey M Filiatreau, Kara S Mcgee, Joann D Kuruc, Guido Ferrari, David M Margolis, Joseph J Eron, Charles B Hicks, Cynthia L Gay

2020-Current year OA Pubs

BACKGROUND: Antiretroviral therapy (ART) is recommended for all individuals with HIV infection, including those with acute HIV-1 infection (AHI). While recommendations are similar to those for chronic infection, efficacy data regarding treatment of acute HIV is limited.

METHODS: This was a single arm, 96-week study of a once-daily integrase inhibitor (INSTI)-based regimen using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) in AHI. Primary endpoint was proportion of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL by treatment weeks 24 and 48, respectively. We also examined time to viral suppression and weight gain after treatment initiation. Outcomes and characteristics were compared with a historical AHI cohort using a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF).

RESULTS: Thirty-three participants with AHI were enrolled with 31 available for analyses. Most were African American (61%) and men who have sex with men (73%). Median age was 26 (IQR 22-42). Demographics …

Rethinking The Rise Of Early-Onset Gastrointestinal Cancers: A Call To Action, Benjamin A Weinberg, Caitlin C Murphy, David R Freyer, K Leigh Greathouse, Jan K Blancato, Elena M Stoffel, Julia L Drewes, Anne Blaes, John M Salsman, Y Nancy You, Hannah Arem, Reetu Mukherji, Priyanka Kanth, Xin Hu, Anne Fabrizio, Marion L Hartley, Marios Giannakis, John L Marshall

Faculty, Staff and Student Publications

Since the early 1990s, there has been a dramatic rise in gastrointestinal cancers diagnosed in patients under age 50 for reasons that remain poorly understood. The most significant change has been the increase in incidence rates of early-onset colorectal cancer, especially rates of left-sided colon and rectal cancers. Increases in gastric, pancreatic, and other gastrointestinal cancer diagnoses have further contributed to this trend. We formed a multidisciplinary Think Tank to develop a strategic, coordinated approach to studying early-onset gastrointestinal cancers. This area of research is challenging given multifactorial etiologies. We focused on epidemiology and the environment, the microbiome, and survivorship …

Comprehensive Characterization Of The Transcriptional Landscape In Alzheimer’S Disease (Ad) Brains, Chengxuan Chen, Zhao Zhang, Yuan Liu, Wei Hong, Hande Karahan, Jun Wang, Wenbo Li, Lixia Diao, Meichen Yu, Andrew J Saykin, Kwangsik Nho, Jungsu Kim, Leng Han

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the leading dementia among the elderly with complex origins. Despite extensive investigation into the AD-associated protein-coding genes, the involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized the landscape of ncRNAs and PTM events in 1460 samples across six brain regions sourced from the Mount Sinai/JJ Peters VA Medical Center Brain Bank Study and Mayo cohorts, encompassing 33,321 long ncRNAs, 92,897 enhancer RNAs, 53,763 alternative polyadenylation events, and 900,221 A-to-I RNA editing events. We additionally identified 25,351 aberrantly expressed ncRNAs and altered PTM events associated with AD …

Detection Of Clinically Relevant Monogenic Copy-Number Variants By A Comprehensive Genome-Wide Microarray With Exonic Coverage, Matthew Hoi Kin Chau, Stephanie A Anderson, Rodger Song, Lance Cooper, Patricia A Ward, Bo Yuan, Chad Shaw, Paweł Stankiewicz, Sau Wai Cheung, Liesbeth Vossaert, Yue Wang, Nichole M Owen, Janice Smith, Carlos A Bacino, Katharina V Schulze, Weimin Bi

Faculty, Staff and Students Publications

Background: Disease-causing copy-number variants (CNVs) often encompass contiguous genes and can be detected using chromosomal microarray analysis (CMA). Conversely, CNVs affecting single disease-causing genes have historically been challenging to detect due to their small sizes.

Methods: A custom comprehensive CMA (Baylor College of Medicine - BCM v11.2) containing 400k probes and featuring exonic coverage for >4200 known or candidate disease-causing genes was utilized for the detection of CNVs at single-exon resolution. CMA results across a consecutive clinical cohort of more than 13 000 patients referred for genetic investigation at Baylor Genetics were examined. The genomic characteristics of CNVs impacting single …