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Pharmacophore Modeling For Biological Targets With High Flexibility: Lxrβ Case Study, Sophia Kchouk, Lamees Hegazy

2020-Current year OA Pubs

No abstract provided.

Perspectives Of Participation In Daily Life From Cancer Survivors: A Qualitative Analysis, Allison J L'Hotta, Nirmala Shivakumar, Kathleen D Lyons, Audrey Trebelhorn, Annamayil Manohar, Allison A King

2020-Current year OA Pubs

OBJECTIVE: To characterize how survivors of cancer define participation.

DESIGN: Cross-sectional qualitative study.

SETTING: Participants were enrolled from a large academic medical center in the Midwestern United States. Interviews were conducted over Zoom or phone.

PARTICIPANTS: Survivors of cancer (N=40) with brain, breast, colorectal, or lung cancer (n=10 per group). Participants were purposively sampled to maximize variation in the study sample. Participant ages ranged from 26-83 years, with a mean age of 55 years. Seventy percent of participants were receiving active cancer treatment at the time of the interview.

INTERVENTIONS: Not applicable.

MAIN OUTCOME MEASURES: Participant perspectives gathered from 1-on-1 …

Living With Cervical Spinal Cord Injury During The Covid-19 Pandemic: A Qualitative Study, Elspeth J R Hill, Allison J L'Hotta, Carie R Kennedy, Aimee S James, Ida K Fox

2020-Current year OA Pubs

OBJECTIVE: To understand how COVID-19 has affected the daily lives of people living with cervical spinal cord injury (SCI).

DESIGN: Cross sectional qualitative study.

SETTING: Academic medical center in the Midwestern United States.

PARTICIPANTS: Ten community-dwelling individuals (8 men, 2 women), average 11.6 years post-mid-cervical level SCI (N=10).

INTERVENTIONS: Not applicable.

MAIN OUTCOME MEASURES: Semistructured interviews were completed by phone. The research team used thematic analysis and inductive strategies to analyze the data in this exploratory investigation.

RESULTS: People with cervical SCI living in the United States during the spring of 2020 experienced changes to their daily lives. Participants described …

Implications Of Conformational Flexibility, Lipid Binding, And Regulatory Domains In Cell-Traversal Protein Celtos For Apicomplexan Migration, Hirdesh Kumar, John R Jimah, Santosh A Misal, Nichole D Salinas, Michal Fried, Paul H Schlesinger, Niraj H Tolia

2020-Current year OA Pubs

Malaria and other apicomplexan-caused diseases affect millions of humans, agricultural animals, and pets. Cell traversal is a common feature used by multiple apicomplexan parasites to migrate through host cells and can be exploited to develop therapeutics against these deadly parasites. Here, we provide insights into the mechanism of the Cell-traversal protein for ookinetes and sporozoites (CelTOS), a conserved cell-traversal protein in apicomplexan parasites and malaria vaccine candidate. CelTOS has previously been shown to form pores in cell membranes to enable traversal of parasites through cells. We establish roles for the distinct protein regions of Plasmodium vivax CelTOS and examine the …

A Narrative Review Of Irritable Bowel Syndrome With Diarrhea: A Primer For Primary Care Providers, Baha Moshiree, Joel J Heidelbaugh, Gregory S Sayuk

2020-Current year OA Pubs

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic disorder of gut-brain interaction, characterized by recurrent abdominal pain in association with more frequent, loose stools. The pathophysiology of irritable bowel syndrome (IBS) includes disordered gut motility, alterations in gut microbiota, neural-hormonal system abnormalities, immune reactivity, and visceral hypersensitivity. Timely diagnosis of IBS-D can be achieved easily using clinical criteria. Formal IBS diagnosis is important for optimizing treatment and patient outcomes and facilitating patient access to appropriate educational resources. Yet, given the symptom overlap with other gastrointestinal conditions, diagnosis of IBS-D often is perceived to be challenging. Treatment of IBS includes …

Empirical Transmit Field Bias Correction Of T1w/T2w Myelin Maps, Matthew F. Glasser, Timothy S. Coalson, Michael P. Harms, Junqian Xu, Graham L. Baum, Joonas A. Autio, Edward J. Auerbach, Douglas N. Greve, Essa Yacoub, David C. Van Essen, Nicholas A. Bock, Takuya Hayashi

2020-Current year OA Pubs

T1-weighted divided by T2-weighted (T1w/T2w) myelin maps were initially developed for neuroanatomical analyses such as identifying cortical areas, but they are increasingly used in statistical comparisons across individuals and groups with other variables of interest. Existing T1w/T2w myelin maps contain radiofrequency transmit field (B1+) biases, which may be correlated with these variables of interest, leading to potentially spurious results. Here we propose two empirical methods for correcting these transmit field biases using either explicit measures of the transmit field or alternatively a 'pseudo-transmit' approach that is highly correlated with the transmit field at 3T. We find that the resulting corrected …

Clinical Trial Data Of Anti-Pd-1/Pd-L1 Therapy For Recurrent Or Metastatic Nasopharyngeal Carcinoma: A Review, Douglas R Adkins, Robert I. Haddad

2020-Current year OA Pubs

IMPORTANCE: Anti-programmed cell death receptor-1 (PD-1) therapy is standard of care for incurable recurrent or metastatic non-nasopharyngeal head and neck cancer. In contrast, there are no regulatory agency-approved anti-PD-1 agents indicated for the treatment of recurrent or metastatic nasopharyngeal carcinomas (RM-NPC) in the Western hemisphere, and no standard treatment option exists beyond first-line chemotherapy for RM-NPC. The pace of development of novel systemic therapy regimens for RM-NPC has been slow compared to many other advanced tumor types, leaving an unmet clinical need for these patients with a poor prognosis.

OBSERVATIONS: Recent clinical trials have documented the clinical activity of anti-PD-1 …

High-Coverage Whole-Genome Sequencing Of The Expanded 1000 Genomes Project Cohort Including 602 Trios, Marta Byrska-Bishop, Haley J Abel, Allison A Regier, Ira M Hall, Et Al.

2020-Current year OA Pubs

The 1000 Genomes Project (1kGP) is the largest fully open resource of whole-genome sequencing (WGS) data consented for public distribution without access or use restrictions. The final, phase 3 release of the 1kGP included 2,504 unrelated samples from 26 populations and was based primarily on low-coverage WGS. Here, we present a high-coverage 3,202-sample WGS 1kGP resource, which now includes 602 complete trios, sequenced to a depth of 30X using Illumina. We performed single-nucleotide variant (SNV) and short insertion and deletion (INDEL) discovery and generated a comprehensive set of structural variants (SVs) by integrating multiple analytic methods through a machine learning …

Proteomic Identification Of Potential Target Proteins Of Cathepsin W For Its Development As A Drug Target For Influenza, Sira C Günther, Carles Martínez-Romero, Milagros Sempere Borau, Christine T N Pham, Adolfo García-Sastre, Silke Stertz

2020-Current year OA Pubs

Influenza A virus (IAV) coopts numerous host factors for efficient replication. The cysteine protease cathepsin W (CTSW) has been identified as one host factor required for IAV entry, specifically for the escape of IAVs from late endosomes. However, the substrate specificity of CTSW and the proviral mechanism are thus far unknown. Here, we show that intracellular but not secreted CTSW promotes viral entry. We reveal 79 potential direct and 31 potential indirect cellular target proteins of CTSW using the high-throughput proteomic approach terminal amine isotopic labeling of substrates (TAILS) and determine the cleavage motif shared by the substrates of CTSW. …

Evolution Of Multiple Domains Of The Hiv-1 Envelope Glycoprotein During Coreceptor Switch With Ccr5 Antagonist Therapy, Yueqi Du, Ellen Wu, Xiang Gao, Jie Zhang, John C Martin, Bruce A Rosa, Makedonka Mitreva, Lee Ratner

2020-Current year OA Pubs

HIV-1 uses CD4 as a receptor and chemokine receptors CCR5 and/or CXCR4 as coreceptors. CCR5 antagonists are a class of antiretrovirals used to inhibit viral entry. Phenotypic prediction algorithms such as Geno2Pheno are used to assess CCR5 antagonist eligibility, for which the V3 region is screened. However, there exist scenarios where the algorithm cannot give an accurate prediction of tropism. The current study examined coreceptor shift of HIV-1 from CCR5-tropic strains to CXCR4-tropic or dual-tropic strains among five subjects in a clinical trial of the CCR5 antagonist vicriviroc. Envelope gene amplicon libraries were constructed and subjected to next-generation sequencing, as …

Membrane Integrity Contributes To Resistance Of Cryptococcus Neoformans To The Cell Wall Inhibitor Caspofungin, Brenda Moreira-Walsh, Abigail Ragsdale, Woei Lam, Rajendra Upadhya, Evan Xu, Jennifer K Lodge, Maureen J Donlin

2020-Current year OA Pubs

The fungal pathogen Cryptococcus neoformans causes up to 278 000 infections each year globally, resulting in up to 180,000 deaths annually, mostly impacting immunocompromised people. Therapeutic options for C. neoformans infections are very limited. Caspofungin, a member of the echinocandin class of antifungals, is generally well tolerated but clinically ineffective against C. neoformans. We sought to identify biological processes that can be targeted to render the cell more susceptible to echinocandins by screening the available libraries of gene deletion mutants made in the KN99α background for caspofungin sensitivity. We adapted a Candida albicans fungal biofilm assay for the growth characteristics …

Optimal Urine Culture Diagnostic Stewardship Practice- Results From An Expert Modified-Delphi Procedure, Kimberly C Claeys, Stephen Y Liang, Et Al.

2020-Current year OA Pubs

BACKGROUND: Urine cultures are nonspecific and often lead to misdiagnosis of urinary tract infection and unnecessary antibiotics. Diagnostic stewardship is a set of procedures that modifies test ordering, processing, and reporting in order to optimize diagnosis and downstream treatment. In this study, we aimed to develop expert guidance on best practices for urine culture diagnostic stewardship.

METHODS: A RAND-modified Delphi approach with a multidisciplinary expert panel was used to ascertain diagnostic stewardship best practices. Clinical questions to guide recommendations were grouped into three thematic areas (ordering, processing, reporting) in practice settings of emergency department, inpatient, ambulatory, and long-term care. Fifteen …

Blocking Chop-Dependent Txnip Shuttling To Mitochondria Attenuates Albuminuria And Mitigates Kidney Injury In Nephrotic Syndrome, Sun-Ji Park, Yeawon Kim, Chuang Li, Junwoo Suh, Jothilingam Sivapackiam, Tassia M Goncalves, George Jarad, Guoyan Zhao, Fumihiko Urano, Vijay Sharma, Ying Maggie Chen

2020-Current year OA Pubs

Albuminuria is a hallmark of glomerular disease of various etiologies. It is not only a symptom of glomerular disease but also a cause leading to glomerulosclerosis, interstitial fibrosis, and eventually, a decline in kidney function. The molecular mechanism underlying albuminuria-induced kidney injury remains poorly defined. In our genetic model of nephrotic syndrome (NS), we have identified CHOP (C/EBP homologous protein)-TXNIP (thioredoxin-interacting protein) as critical molecular linkers between albuminuria-induced ER dysfunction and mitochondria dyshomeostasis. TXNIP is a ubiquitously expressed redox protein that binds to and inhibits antioxidant enzyme, cytosolic thioredoxin 1 (Trx1), and mitochondrial Trx2. However, very little is known about …

Distinct Sensitivities To Sars-Cov-2 Variants In Vaccinated Humans And Mice, Alexandra C Walls, Laura A Vanblargan, Michael S Diamond, Et Al.

2020-Current year OA Pubs

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited …

Spatiotemporal Correlation Analysis Of Hydraulic Fracturing And Stroke In The United States, Chuanbo Hu, Bin Liu, Shuo Wang, Zhenduo Zhu, Amelia Adcock, James Simpkins, Xin Li

2020-Current year OA Pubs

Hydraulic fracturing or fracking has led to a rapid growth of oil and gas production in the United States, but the impact of fracking on public health is an important but underresearched topic. We designed a methodology to study spatiotemporal correlations between the risk of fracking and stroke mortality. An annualized loss expectancy (ALE) model is applied to quantify the risk of fracking. The geographically and temporally weighted regression (GTWR) model is used to analyze spatiotemporal correlations of stroke mortality, fracking ALE, and nine other socioeconomic- and health-related factors. The analysis shows that fracking ALE is moderately correlated with stroke …

A Multitrait Locus Regulates Sarbecovirus Pathogenesis, Alexandra Schäfer, Emma S Winkler, Michael S Diamond, Et Al

2020-Current year OA Pubs

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential …

Re-Examining Rotavirus Innate Immune Evasion: Potential Applications Of The Reverse Genetics System, Avan Antia, Amanda N Pinski, Siyuan Ding

2020-Current year OA Pubs

Rotaviruses represent one of the most successful pathogens in the world, with high infectivity and efficient transmission between the young of many animal species, including humans. To overcome host defenses, rotaviruses have evolved a plethora of strategies to effectively evade the innate immune response, establish initial infection in the small intestine, produce progeny, and shed into the environment. Previously, studying the roles and relative contributions of specific rotaviral factors in innate immune evasion had been challenging without a plasmid-only reverse genetics system. Although still in its infancy, current reverse genetics technology will help address important research questions regarding rotavirus innate …

A Pilot Randomized Trial To Examine Effects Of A Hybrid Closed-Loop Insulin Delivery System On Neurodevelopmental And Cognitive Outcomes In Adolescents With Type 1 Diabetes, Allan L Reiss, Ana Maria Arbelaez, Et Al

2020-Current year OA Pubs

Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed …

N1-Methylpseudouridine Found Within Covid-19 Mrna Vaccines Produces Faithful Protein Products, Kyusik Q Kim, Bhagyashri D Burgute, Shin-Cheng Tzeng, Crystal Jing, Courtney Jungers, Junya Zhang, Liewei L Yan, Richard D Vierstra, Sergej Djuranovic, Bradley S Evans, Hani S Zaher

2020-Current year OA Pubs

Synthetic mRNA technology is a promising avenue for treating and preventing disease. Key to the technology is the incorporation of modified nucleotides such as N1-methylpseudouridine (m1Ψ) to decrease immunogenicity of the RNA. However, relatively few studies have addressed the effects of modified nucleotides on the decoding process. Here, we investigate the effect of m1Ψ and the related modification pseudouridine (Ψ) on translation. In a reconstituted system, we find that m1Ψ does not significantly alter decoding accuracy. More importantly, we do not detect an increase in miscoded peptides when mRNA containing m1Ψ is translated in cell culture, compared with unmodified mRNA. …

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S. Regalado, Alan C. Braverman, Et Al.

2020-Current year OA Pubs

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

Subcortical-Cortical Dynamical States Of The Human Brain And Their Breakdown In Stroke, Chiara Favaretto, Michele Allegra, Gustavo Deco, Nicholas V Metcalf, Joseph C Griffis, Gordon L Shulman, Andrea Brovelli, Maurizio Corbetta

2020-Current year OA Pubs

The mechanisms controlling dynamical patterns in spontaneous brain activity are poorly understood. Here, we provide evidence that cortical dynamics in the ultra-slow frequency range (<0.01-0.1 Hz) requires intact cortical-subcortical communication. Using functional magnetic resonance imaging (fMRI) at rest, we identify Dynamic Functional States (DFSs), transient but recurrent clusters of cortical and subcortical regions synchronizing at ultra-slow frequencies. We observe that shifts in cortical clusters are temporally coincident with shifts in subcortical clusters, with cortical regions flexibly synchronizing with either limbic regions (hippocampus/amygdala), or subcortical nuclei (thalamus/basal ganglia). Focal lesions induced by stroke, especially those damaging white matter connections between basal ganglia/thalamus and cortex, provoke anomalies in the fraction times, dwell times, and transitions between DFSs, causing a bias toward abnormal network integration. Dynamical anomalies observed 2 weeks after stroke recover in time and contribute to explaining neurological impairment and long-term outcome.

Capg Is Required For Ebola Virus Infection By Controlling Virus Egress From Infected Cells, Hiroyuki Mori, James P Connell, Callie J Donahue, Ruthmabel Boytz, Yen Thi Kim Nguyen, Daisy W Leung, Douglas J Lacount, Robert A Davey

2020-Current year OA Pubs

The replication of Ebola virus (EBOV) is dependent upon actin functionality, especially at cell entry through macropinocytosis and at release of virus from cells. Previously, major actin-regulatory factors involved in actin nucleation, such as Rac1 and Arp2/3, were shown important in both steps. However, downstream of nucleation, many other cell factors are needed to control actin dynamics. How these regulate EBOV infection remains largely unclear. Here, we identified the actin-regulating protein, CAPG, as important for EBOV replication. Notably, knockdown of CAPG specifically inhibited viral infectivity and yield of infectious particles. Cell-based mechanistic analysis revealed a requirement of CAPG for virus …

Apoptosis Detection In Retinal Ganglion Cells Using Quantitative Changes In Multichannel Fluorescence Colocalization, Xudong Qiu, Seth T Gammon, James R Johnson, Federica Pisaneschi, Steven W Millward, Edward M Barnett, David Piwnica-Worms

2020-Current year OA Pubs

KcapTR488 is a dual-fluorophore peptide sensor for the real-time reporting of programmed cell death by fluorescence imaging. KcapTR488 contains a nuclear localization sequence (NLS) conjugated with Texas Red, a caspase-cleavable sequence (DEVD), and a C-terminus conjugated to Alexa Fluor 488 (AF488). The synthesis and preliminary evaluation in cellulo of KcapTR488 for monitoring cell death by fluorescence imaging has been previously reported, but its utility in vivo has yet to be tested or validated. Herein, in vitro solution experiments verified the intramolecular fluorescence resonance energy transfer (FRET) between the two fluorophores and enabled a quantitative analysis of enzyme rates and selectivity. …

Organization Of The Gravity-Sensing System In Zebrafish, Zhikai Liu, David G C Hildebrand, Joshua L Morgan, Yizhen Jia, Nicholas Slimmon, Martha W Bagnall

2020-Current year OA Pubs

Motor circuits develop in sequence from those governing fast movements to those governing slow. Here we examine whether upstream sensory circuits are organized by similar principles. Using serial-section electron microscopy in larval zebrafish, we generated a complete map of the gravity-sensing (utricular) system spanning from the inner ear to the brainstem. We find that both sensory tuning and developmental sequence are organizing principles of vestibular topography. Patterned rostrocaudal innervation from hair cells to afferents creates an anatomically inferred directional tuning map in the utricular ganglion, forming segregated pathways for rostral and caudal tilt. Furthermore, the mediolateral axis of the ganglion …

Statistical Validation Of Risk Alleles In Genetic Addiction Risk Severity (Gars) Test: Early Identification Of Risk For Alcohol Use Disorder (Aud) In 74,566 Case-Control Subjects, Kenneth Blum, Mark S Gold, Et Al.

2020-Current year OA Pubs

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in

Neurogenetic And Epigenetic Aspects Of Cannabinoids, Catherine A Dennen, Kenneth Blum, Abdalla Bowirrat, Jag Khalsa, Panayotis K Thanos, David Baron, Rajendra D Badgaiyan, Ashim Gupta, Eric R Braverman, Mark S Gold

2020-Current year OA Pubs

Cannabis is one of the most commonly used and abused illicit drugs in the world today. The United States (US) currently has the highest annual prevalence rate of cannabis consumption in the world, 17.9% in individuals aged 12 or older, and it is on the rise. With increasing cannabis use comes the potential for an increase in abuse, and according to the Substance Abuse and Mental Health Services Administration (SAMHSA), approximately 5.1% of Americans had Cannabis Use Disorder (CUD) in 2020. Research has shown that genetics and epigenetics play a significant role in cannabis use and CUD. In fact, approximately …

Modelling Neurological Diseases In Large Animals: Criteria For Model Selection And Clinical Assessment, Samantha L Eaton, Jonathan D Cooper, Et Al.

2020-Current year OA Pubs

No abstract provided.

Impacts Of A Workplace-Based Weight-Control Intervention On Objective And Perceived Physical Activity Among A Subgroup Of Workers, Rachel Tabak, Ryan Colvin, Jaime R Strickland, Ann Marie Dale, Maura Kepper, Tara Ruggeri, Bradley Evanoff

2020-Current year OA Pubs

Physical activity (PA) has many benefits; however, groups facing barriers to health-promoting behaviors are less likely to be physically active. This may be addressed through workplace interventions. The current study employs objective (accelerometry) and perceived (International Physical Activity Questionnaire [IPAQ]) measures of PA among a subset of participants from the "Working for You" study, which tests a multi-level (work group and individual) workplace intervention targeted at workers with low-incomes. Linear mixed and hierarchical logistic regression models are used to determine the intervention's impact on moderate- to vigorous-PA (MVPA) and achieving the PA Guideline for Americans (≥150 minutes MVPA/week), respectively from …

Heavy Metals In Breast Implant Capsules And Breast Tissue: Findings From The Systemic Symptoms In Women-Biospecimen Analysis Study: Part 2, Roger Wixtrom, Caroline Glicksman, Marshall Kadin, Marisa Lawrence, Melinda Haws, Sarah Ferenz, James Sung, Patricia Mcguire

2020-Current year OA Pubs

BACKGROUND: Breast Implant Illness (BII), as described in recent medical literature and by social media, describes a range of symptoms in patients with breast implants for which there are no physical findings or laboratory results that explain their symptoms.

OBJECTIVES: Part 2 of this study aims to determine whether heavy metals are present in the capsules around saline and silicone implants and if there are statistical differences in the type or level of these metals between women with or without symptoms. Demographic data was collected to investigate potential alternate sources of metals: inhaled, absorbed, or ingested.

METHODS: A prospective, blinded …

Layer-Specific Developmentally Precise Axon Targeting Of Transient Suppressed-By-Contrast Retinal Ganglion Cells (Tsbc Rgcs), Nai-Wen Tien, Carmela Vitale, Tudor C Badea, Daniel Kerschensteiner

2020-Current year OA Pubs

The mouse retina encodes diverse visual features in the spike trains of >40 retinal ganglion cell (RGC) types. Each RGC type innervates a specific subset of the >50 retinorecipient brain areas. Our catalog of RGC types and feature representations is nearing completion. Yet, we know little about where specific RGC types send their information. Furthermore, the developmental strategies by which RGC axons choose their targets and pattern their terminal arbors remain obscure. Here, we identify a genetic intersection (