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The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder.

J Clin Invest 2021 Apr 13. Epub 2021 Apr 13.

Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, United States of America.

Opioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. Read More

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Predictors of Parental Barriers to Reduce Excessive Child Screen Time Among Parents of Under-Five Children in Selangor, Malaysia: Cross-sectional Study.

J Med Internet Res 2021 Apr 13;23(4):e25219. Epub 2021 Apr 13.

Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.

Background: Globally, there is an increasing prevalence of excessive screen time exposure among young children, including in Malaysia. Parents are advised to limit this exposure, but there are barriers for many of them to follow this recommendation. To date, there is a lack of research on the factors that cause these parental barriers. Read More

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Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition.

Nat Genet 2021 Apr 12. Epub 2021 Apr 12.

Human Oncology and Pathogenesis Program, Memorial Sloan KetterAbsolute numbers of live mature hematopoietic cellsing Cancer Center, New York, NY, USA.

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Read More

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CRISPR screens identify a novel combination treatment targeting BCL-X and WNT signaling for KRAS/BRAF-mutated colorectal cancers.

Oncogene 2021 Apr 12. Epub 2021 Apr 12.

Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Korea.

Metastatic or recurrent colorectal cancer (CRC) patients require systemic chemotherapy, but the therapeutic options of targeted agents remain limited. CRC patients with KRAS or BRAF gene mutations exhibit a worse prognosis and are resistant to anti-EGFR treatment. Previous studies have shown that the expression of anti-apoptotic protein BCL-X is increased in CRC patients with KRAS/BRAF mutations, suggesting BCL-X as a therapeutic target for this subgroup. Read More

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Structure-based phylogeny identifies Avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice.

J Clin Invest 2021 Apr 12. Epub 2021 Apr 12.

Department of Ophthalmology, Stanford University, Palo Alto, United States of America.

Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target. We hypothesized that drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. Read More

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Functional Movement Screen Detected Asymmetry & Normative Values Among College-Aged Students.

Int J Sports Phys Ther 2021 Apr 1;16(2):450-458. Epub 2021 Apr 1.

Texas A&M Central Texas.

Background: The Functional Movement Screen (FMS™) is a popular test used by sports medicine professionals to identify dysfunctional movement patterns by analyzing mobility and stability during prescribed movements. Although the FMS™ has been a popular topic of research in recent years, normative data and asymmetries in college-aged students have not been established through research.

Purpose: The objective was to determine normative FMS™ scores, report frequency counts for FMS™ asymmetries, and determine if the number of sports seasons and number of different sports an individual participated in during high school varied between university students that showed FMS™ identified asymmetries. Read More

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Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing.

Cell 2021 Apr 7. Epub 2021 Apr 7.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142, USA. Electronic address:

A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff-a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Read More

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A cell-based screening method using an intracellular antibody for discovering small molecules targeting the translocation protein LMO2.

Sci Adv 2021 Apr 9;7(15). Epub 2021 Apr 9.

Weatherall Institute of Molecular Medicine MRC Molecular Haematology Unit, University of Oxford John Radcliffe Hospital, Oxford OX3 9DS, UK.

Intracellular antibodies are tools that can be used directly for target validation by interfering with properties like protein-protein interactions. An alternative use of intracellular antibodies in drug discovery is developing small-molecule surrogates using antibody-derived (Abd) technology. We previously used this strategy with an in vitro competitive surface plasmon resonance method that relied on high-affinity antibody fragments to obtain RAS-binding compounds. Read More

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Rapid methodologies for assessing colonization and effector-mediated hypersensitive response in kiwifruit.

Mol Plant Microbe Interact 2021 Apr 9. Epub 2021 Apr 9.

Plant and Food Research Ltd, 1413, 120 Mt Albert road, Sandringham, Auckland, New Zealand, 1142;

The infection of in kiwifruit is currently assessed by numerous methodologies, each with their own limitations. Most studies are based on either a laborious method of growth quantification of the pathogen or qualitative assessments by visual scoring following stem or cutting inoculation. Additionally, when assessing for resistance against specific pathogen effectors, confounding interactions between multiple genes in the pathogen can make mapping resistance phenotypes nearly impossible. Read More

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Identification and selectivity profiling of small-molecule degraders via multi-omics approaches.

Cell Chem Biol 2021 Mar 29. Epub 2021 Mar 29.

CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address:

The therapeutic modality of targeted protein degradation promises to overcome limitations of traditional pharmacology. Small-molecule degraders recruit disease-causing proteins to E3 ubiquitin ligases, prompting their ubiquitination and degradation by the proteasome. The discovery, mechanistic elucidation, and selectivity profiling of novel degraders are often conducted in cellular systems. Read More

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Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2.

Cell Rep 2021 04 23;35(1):108959. Epub 2021 Mar 23.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7. Read More

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Screening a Natural Product-Inspired Library for Anti- Activities.

Molecules 2021 Mar 24;26(7). Epub 2021 Mar 24.

School of Biological Sciences, Victoria University of Wellington, Wellington 6140, New Zealand.

is a genus of microorganisms that cause devastating dieback and root-rot diseases in thousands of plant hosts worldwide. The economic impact of diseases on crops and native ecosystems is estimated to be billions of dollars per annum. These invasive pathogens are extremely difficult to control using existing chemical means, and the effectiveness of the few treatments available is being jeopardized by increasing rates of resistance. Read More

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3D Model Characterization by 2D and 3D Imaging in t(14;18)-Positive B-NHL: Perspectives for In Vitro Drug Screens in Follicular Lymphoma.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, CEDEX 1, 31037 Toulouse, France.

Follicular lymphoma (FL) is an indolent B cell lymphoproliferative disorder of transformed follicular center B cells, which accounts for 20-30 percent of all non-Hodgkin lymphoma (NHL) cases. Great advances have been made to identify the most relevant targets for precision therapy. However, no relevant models for in vitro studies have been developed or characterized in depth. Read More

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Shiga Toxins: An Update on Host Factors and Biomedical Applications.

Toxins (Basel) 2021 Mar 18;13(3). Epub 2021 Mar 18.

Department of Urology, Boston Children's Hospital, Boston, MA 02115, USA.

Shiga toxins (Stxs) are classic bacterial toxins and major virulence factors of toxigenic and enterohemorrhagic (EHEC). These toxins recognize a glycosphingolipid globotriaosylceramide (Gb3/CD77) as their receptor and inhibit protein synthesis in cells by cleaving 28S ribosomal RNA. They are the major cause of life-threatening complications such as hemolytic uremic syndrome (HUS), associated with severe cases of EHEC infection, which is the leading cause of acute kidney injury in children. Read More

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Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs-First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor.

Viruses 2021 Mar 10;13(3). Epub 2021 Mar 10.

Department of Global Health, University of Washington, Seattle, WA 98109, USA.

The concerning increase in HIV-1 resistance argues for prioritizing the development of host-targeting antiviral drugs because such drugs can offer high genetic barriers to the selection of drug-resistant viral variants. Targeting host proteins could also yield drugs that act on viral life cycle events that have proven elusive to inhibition, such as intracellular events of HIV-1 immature capsid assembly. Here, we review small molecule inhibitors identified primarily through HIV-1 self-assembly screens and describe how all act either narrowly post-entry or broadly on early and late events of the HIV-1 life cycle. Read More

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Genotype to Phenotype: CRISPR Gene Editing Reveals Genetic Compensation as a Mechanism for Phenotypic Disjunction of Morphants and Mutants.

Int J Mol Sci 2021 Mar 27;22(7). Epub 2021 Mar 27.

Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA.

Forward genetic screens have shown the consequences of deleterious mutations; however, they are best suited for model organisms with fast reproductive rates and large broods. Furthermore, investigators must faithfully identify changes in phenotype, even if subtle, to realize the full benefit of the screen. Reverse genetic approaches also probe genotype to phenotype relationships, except that the genetic targets are predefined. Read More

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Next-generation yeast-two-hybrid analysis with Y2H-SCORES identifies novel interactors of the MLA immune receptor.

PLoS Comput Biol 2021 Apr 2;17(4):e1008890. Epub 2021 Apr 2.

Program in Bioinformatics & Computational Biology, Iowa State University, Ames, Iowa, United States of America.

Protein-protein interaction networks are one of the most effective representations of cellular behavior. In order to build these models, high-throughput techniques are required. Next-generation interaction screening (NGIS) protocols that combine yeast two-hybrid (Y2H) with deep sequencing are promising approaches to generate interactome networks in any organism. Read More

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High-throughput fitness screening and transcriptomics identify a role for a type IV secretion system in the pathogenesis of Crohn's disease-associated Escherichia coli.

Nat Commun 2021 04 1;12(1):2032. Epub 2021 Apr 1.

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.

Adherent-invasive Escherichia coli (AIEC) are pathogenic bacteria frequently isolated from patients who have Crohn's disease (CD). Despite the phenotypic differences between AIEC and commensal E. coli, comparative genomic approaches have been unable to differentiate these two groups, making the identification of key virulence factors a challenge. Read More

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Competitive SPR using an intracellular anti-LMO2 antibody identifies novel LMO2-interacting compounds.

J Immunol Methods 2021 Mar 29;494:113051. Epub 2021 Mar 29.

Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK. Electronic address:

The use of intracellular antibodies as templates to derive surrogate compounds is an important objective because intracellular antibodies can be employed initially for target validation in pre-clinical assays and subsequently employed in compound library screens. LMO2 is a T cell oncogenic protein activated in the majority of T cell acute leukaemias. We have used an inhibitory intracellular antibody fragment as a competitor in a small molecule library screen using competitive surface plasmon resonance (cSPR) to identify compounds that bind to LMO2. Read More

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Multidisciplinary Approaches Identify Compounds that Bind to Human ACE2 or SARS-CoV-2 Spike Protein as Candidates to Block SARS-CoV-2-ACE2 Receptor Interactions.

mBio 2021 03 30;12(2). Epub 2021 Mar 30.

Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Read More

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Identification of cancer driver genes using Sleeping Beauty transposon mutagenesis.

Cancer Sci 2021 Mar 30. Epub 2021 Mar 30.

Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Cancer genome sequencing studies have identified driver genes for a variety of different cancers and helped to understand the genetic landscape of human cancer. It is still challenging, however, to identify cancer driver genes with confidence simply from genetic data alone. In vivo forward genetic screens using Sleeping Beauty (SB) transposon mutagenesis provides another powerful genetic tool for identifying candidate cancer driver genes in wild type and sensitized mouse tumors. Read More

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Application of CRISPR screens to investigate mammalian cell competition.

Brief Funct Genomics 2021 Mar 30. Epub 2021 Mar 30.

Cell competition is defined as the context-dependent elimination of cells that is mediated by intercellular communication, such as paracrine or contact-dependent cell signaling, and/or mechanical stresses. It is considered to be a quality control mechanism that facilitates the removal of suboptimal cells from both adult and embryonic tissues. Cell competition, however, can also be hijacked by transformed cells to acquire a 'super-competitor' status and outcompete the normal epithelium to establish a precancerous field. Read More

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Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions.

Proc Natl Acad Sci U S A 2021 Apr;118(14)

Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada

Genetic screens can identify synthetic lethal (SL) interactions and uncover potential anticancer therapeutic targets. However, most SL screens have utilized knockout or knockdown approaches that do not accurately mimic chemical inhibition of a target protein. Here, we test whether missense mutations can be utilized as a model for a type of protein inhibition that creates a dominant gain-of-function cytotoxicity. Read More

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Application of a small molecule inhibitor screen approach to identify CXCR4 downstream signaling pathways that promote a mesenchymal and fulvestrant-resistant phenotype in breast cancer cells.

Oncol Lett 2021 May 16;21(5):380. Epub 2021 Mar 16.

Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Chemokine receptor 4 (CXCR4) and its ligand stromal-derived factor 1 (SDF-1) have well-characterized functions in cancer metastasis; however, the specific mechanisms through which CXCR4 promotes a metastatic and drug-resistant phenotype remain widely unknown. The aim of the present study was to demonstrate the application of a phenotypic screening approach using a small molecule inhibitor library to identify potential CXCR4-mediated signaling pathways. The present study demonstrated a new application of the Published Kinase Inhibitor Set (PKIS), a library of small molecule inhibitors from diverse chemotype series with varying levels of selectivity, in a phenotypic medium-throughput screen to identify potential mechanisms to pursue. Read More

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Excess weight in adolescents and associated factors: data from the ERICA study.

J Pediatr (Rio J) 2021 Mar 26. Epub 2021 Mar 26.

Universidade Federal de Pernambuco, Centro de Ciências da Saúde, Departamento de Nutrição, Recife, PE, Brazil.

Objective: To estimate the prevalence of excessive weight and to identify associations with socioeconomic, demographic, biological, and lifestyle factors in adolescents.

Methods: It is a cross-sectional school-based study, with a stratified and complex sample. The evaluated individuals were adolescents (2404), aged 12-17 years old, participating in the Study of Cardiovascular Risk Factors in Adolescents (ERICA). Read More

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Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project.

Genet Med 2021 Mar 26. Epub 2021 Mar 26.

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Purpose: Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population. Read More

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Ultra-fast proteomics with Scanning SWATH.

Nat Biotechnol 2021 Mar 25. Epub 2021 Mar 25.

Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK.

Accurate quantification of the proteome remains challenging for large sample series and longitudinal experiments. We report a data-independent acquisition method, Scanning SWATH, that accelerates mass spectrometric (MS) duty cycles, yielding quantitative proteomes in combination with short gradients and high-flow (800 µl min) chromatography. Exploiting a continuous movement of the precursor isolation window to assign precursor masses to tandem mass spectrometry (MS/MS) fragment traces, Scanning SWATH increases precursor identifications by ~70% compared to conventional data-independent acquisition (DIA) methods on 0. Read More

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Key Variables for Effective eHealth Designs for Individuals With and Without Mental Health Disorders: 2^12-4 Fractional Factorial Experiment.

J Med Internet Res 2021 Mar 24;23(3):e23137. Epub 2021 Mar 24.

Behavioral Health, VA Pittsburgh Health Care System, Department of Veterans Affairs, Pittsburgh, PA, United States.

Background: eHealth applications not only offer the potential to increase service convenience and responsiveness but also expand the ability to tailor services to improve relevance, engagement, and use. To achieve these goals, it is critical that the designs are intuitive. Limited research exists on designs that work for those with a severe mental illness (SMI), many of whom have difficulty traveling for treatments, reject or infrequently seek treatment, and tend to discontinue treatments for significant periods. Read More

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A first-generation pediatric cancer dependency map.

Nat Genet 2021 04 22;53(4):529-538. Epub 2021 Mar 22.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Read More

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High-Throughput Discovery of Targeted, Minimally Complex Peptide Surfaces for Human Pluripotent Stem Cell Culture.

ACS Biomater Sci Eng 2021 04 22;7(4):1344-1360. Epub 2021 Mar 22.

Department of Bioengineering, University of California, Berkeley, Berkeley, California 94720, United States.

Human pluripotent stem cells harbor an unlimited capacity to generate therapeutically relevant cells for applications in regenerative medicine. However, to utilize these cells in the clinic, scalable culture systems that activate defined receptors and signaling pathways to sustain stem cell self-renewal are required; and synthetic materials offer considerable promise to meet these needs. development of materials that target novel pathways has been stymied by a limited understanding of critical receptor interactions maintaining pluripotency. Read More

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