Digital Commons Network^™

Methylation-Mediated Silencing Of Ptprd Induces Pulmonary Hypertension By Promoting Pulmonary Arterial Smooth Muscle Cell Migration Via The Pdgfrb/Plcγ1 Axis, Junhua Xu, Yanfeng Zhong, Haoyang Yin, John Linneman, Yixuan Luo, Sijian Xia, Qinyi Xia, Lei Yang, Xingtao Huang, Kang Kang, Jun Wang, Yanqin Niu, Li Li, Deming Gou

2020-Current year OA Pubs

OBJECTIVE: Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension.

METHODS: We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia.

RESULTS: We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary …

Multimodal Magnetic Resonance Neuroimaging Measures Characteristic Of Early Cart-Treated Pediatric Hiv: A Feature Selection Approach, Isaac L Khobo, Marcin Jankiewicz, Martha J Holmes, Francesca Little, Mark F Cotton, Barbara Laughton, Andre J W Van Der Kouwe, Allison Moreau, Emmanuel Nwosu, Ernesta M Meintjes, Frances C Robertson

2020-Current year OA Pubs

Children with perinatally acquired HIV (CPHIV) have poor cognitive outcomes despite early combination antiretroviral therapy (cART). While CPHIV-related brain alterations can be investigated separately using proton magnetic resonance spectroscopy (

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

2020-Current year OA Pubs

No abstract provided.

The Nepenthesin Insert In The Plasmodium Falciparum Aspartic Protease Plasmepsin V Is Necessary For Enzyme Function, Alexander J Polino, Justin J Miller, Soumendranath Bhakat, Sumit Mukherjee, Suhas Bobba, Gregory R Bowman, Daniel E Goldberg

2020-Current year OA Pubs

Plasmepsin V (PM V) is a pepsin-like aspartic protease essential for growth of the malarial parasite Plasmodium falciparum. Previous work has shown PM V to be an endoplasmic reticulum-resident protease that processes parasite proteins destined for export into the host cell. Depletion or inhibition of the enzyme is lethal during asexual replication within red blood cells as well as during the formation of sexual stage gametocytes. The structure of the Plasmodium vivax PM V has been characterized by X-ray crystallography, revealing a canonical pepsin fold punctuated by structural features uncommon to secretory aspartic proteases; however, the function of this unique …

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 …

Sleep-Promoting Neurons Remodel Their Response Properties To Calibrate Sleep Drive With Environmental Demands, Stephane Dissel, Markus K. Klose, Bruno Van Swinderen, Lijuan Cao, Melanie Ford, Erica M. Periandri, Joseph D. Jones, Zhaoyi Li, Paul J. Shaw

2020-Current year OA Pubs

Falling asleep at the wrong time can place an individual at risk of immediate physical harm. However, not sleeping degrades cognition and adaptive behavior. To understand how animals match sleep need with environmental demands, we used live-brain imaging to examine the physiological response properties of the dorsal fan-shaped body (dFB) following interventions that modify sleep (sleep deprivation, starvation, time-restricted feeding, memory consolidation) in Drosophila. We report that dFB neurons change their physiological response-properties to dopamine (DA) and allatostatin-A (AstA) in response to different types of waking. That is, dFB neurons are not simply passive components of a hard-wired circuit. Rather, …

Association Of Male Hypogonadism With Risk Of Hospitalization For Covid-19, Sandeep Dhindsa, Cosette Champion, Ekamjit Deol, Matthew Lui, Robert Campbell, Jennifer Newman, Aparna Yeggalam, Srikanth Nadella, Vaishaliben Ahir, Ekta Shrestha, Thomas Kannampallil, Abhinav Diwan

2020-Current year OA Pubs

Importance: Male sex is associated with severe COVID-19. It is not known whether the risk of hospitalization differs between men with hypogonadism, men with eugonadism, and those receiving testosterone therapy (TTh).

Objective: To compare COVID-19 hospitalization rates for men with hypogonadism who were not receiving TTh, men with eugonadism, and men receiving TTh.

Design, Setting, and Participants: This cohort study was conducted in 2 large academic health systems in St Louis, Missouri, among 723 men with a history of COVID-19 who had testosterone concentrations measured between January 1, 2017, and December 31, 2021.

Exposures: The primary exposure was gonadal status …

Measuring Transcription Factor Binding And Gene Expression Using Barcoded Self-Reporting Transposon Calling Cards And Transcriptomes, Matthew Lalli, Allen Yen, Urvashi Thopte, Fengping Dong, Arnav Moudgil, Xuhua Chen, Jeffrey Milbrandt, Joseph D Dougherty, Robi D Mitra

2020-Current year OA Pubs

Calling cards technology using self-reporting transposons enables the identification of DNA-protein interactions through RNA sequencing. Although immensely powerful, current implementations of calling cards in bulk experiments on populations of cells are technically cumbersome and require many replicates to identify independent insertions into the same genomic locus. Here, we have drastically reduced the cost and labor requirements of calling card experiments in bulk populations of cells by introducing a DNA barcode into the calling card itself. An additional barcode incorporated during reverse transcription enables simultaneous transcriptome measurement in a facile and affordable protocol. We demonstrate that barcoded self-reporting transposons recover

Pregnancy Outcomes Related To The Treatment Of Sarcomas With Anthracyclines And/Or Ifosfamide During Pregnancy, Devon Miller, John A Livingston, Yeonhee Park, Kristi Posey, Sonia Godbole, Keith Skubitz, Steven I Robinson, Mark Agulnik, Lara E Davis, Brian A Van Tine, Angela C Hirbe, Amanda Parkes

2020-Current year OA Pubs

BACKGROUND: Sarcomas are rare diagnoses but are seen with relative frequency in adolescents and young adults and thus can present in pregnancy. We sought to study the administration of anthracyclines and/or ifosfamide in pregnancy-associated sarcomas.

PATIENTS AND METHODS: We conducted a multi-institutional retrospective study, identifying sarcoma patients who received anthracyclines and/or ifosfamide during pregnancy. Chart review identified variables related to demographics, cancer diagnosis, therapies, and outcome of the patient and fetus. Wilcoxon rank-sum test compared two independent samples.

RESULTS: We identified 13 patients at seven institutions with sarcoma who received anthracyclines and/or ifosfamide during pregnancy, including four bone sarcomas and …

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 …

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 …

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. …

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 …

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 …

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 …

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 …

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 …

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

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.

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 (

C10pred: A First Machine Learning Based Tool To Predict C10 Family Cysteine Peptidases Using Sequence-Derived Features, Adeel Malik, Nitin Mahajan, Tanveer Ali Dar, Chang-Bae Kim

2020-Current year OA Pubs

No abstract provided.

Mutational Analyses Of The Cysteine-Rich Domain Of Yvh1, A Protein Required For Translational Competency In Yeast, Hannah Zang, Robert Shackelford, Alice Bewley, Alexander E Beeser

2020-Current year OA Pubs

Ribosome assembly is a complex biological process facilitated by >200

Association Between Antidepressant Use And Ed Or Hospital Visits In Outpatients With Sars-Cov-2, Bradley A Fritz, Nicolas Hoertel, Eric J Lenze, Farid Jalali, Angela M Reiersen

2020-Current year OA Pubs

Antidepressants have previously been associated with better outcomes in patients hospitalized with COVID-19, but their effect on clinical deterioration among ambulatory patients has not been fully explored. The objective of this study was to assess whether antidepressant exposure was associated with reduced emergency department (ED) or hospital visits among ambulatory patients with SARS-CoV-2 infection. This retrospective cohort study included adult patients (N = 25 034) with a positive SARS-CoV-2 test performed in a non-hospital setting. Logistic regression analyses tested associations between home use of antidepressant medications and a composite outcome of ED visitation or hospital admission within 30 days. Secondary …

The Feel Of Inclusivity, Kristen M Patti, Gary J Patti

2020-Current year OA Pubs

Collaboration between diverse groups with different perspectives promotes scientific discovery. To enhance these partnerships and facilitate communication, innovative advances in universal design are essential.

Cochlear Ribbon Synapse Maturation Requires Nlgn1 And Nlgn3, Miguel A Ramirez, Yuzuru Ninoyu, Cayla Miller, Leonardo R Andrade, Seby Edassery, Ewa Bomba-Warczak, Briana Ortega, Uri Manor, Mark A Rutherford, Rick A Friedman, Jeffrey N Savas

2020-Current year OA Pubs

Hearing depends on precise synaptic transmission between cochlear inner hair cells and spiral ganglion neurons through afferent ribbon synapses. Neuroligins (Nlgns) facilitate synapse maturation in the brain, but they have gone unstudied in the cochlea. We report

A User-Friendly Tool For Cloud-Based Whole Slide Image Segmentation With Examples From Renal Histopathology, Brendon Lutnick, Sanjay Jain, Et Al

2020-Current year OA Pubs

Background: Image-based machine learning tools hold great promise for clinical applications in pathology research. However, the ideal end-users of these computational tools (e.g., pathologists and biological scientists) often lack the programming experience required for the setup and use of these tools which often rely on the use of command line interfaces.

Methods: We have developed

Results: By segmenting glomeruli, interstitial fibrosis and tubular atrophy, and vascular structures from renal and non-renal WSIs, we demonstrate the scalability, best practices for transfer learning, and effects of dataset variability. Finally, we demonstrate an application for animal model research, analyzing glomerular features in three …

Localization Of Epigenetic Markers In Leishmania Chromatin, Jacquelyn R Mcdonald, Bryan C Jensen, Aakash Sur, Iris L K Wong, Stephen M Beverley, Peter J Myler

2020-Current year OA Pubs

Eukaryotes use histone variants and post-translation modifications (PTMs), as well as DNA base modifications, to regulate DNA replication/repair, chromosome condensation, and gene expression. Despite the unusual organization of their protein-coding genes into large polycistronic transcription units (PTUs), trypanosomatid parasites also employ a "histone code" to control these processes, but the details of this epigenetic code are poorly understood. Here, we present the results of experiments designed to elucidate the distribution of histone variants and PTMs over the chromatin landscape of