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Muscleblind-like 1 activates insulin receptor exon 11 inclusion by enhancing U2AF65 binding and splicing of the upstream intron

Alternative splicing regulates developmentally and tissue-specific gene expression programs, disruption of which have been implicated in numerous diseases. Muscleblind-like 1 (MBNL1) regulates splicing transitions, which are disrupted on loss of MBNL1 function in myotonic dystrophy type 1 (DM1). One such event is MBNL1-mediated activation of insulin receptor exon 11 inclusion, ...

GEneSTATION 1.0: a synthetic resource of diverse evolutionary and functional genomic data for studying the evolution of pregnancy-associated tissues and phenotypes

Mammalian gestation and pregnancy are fast evolving processes that involve the interaction of the fetal, maternal and paternal genomes. Version 1.0 of the GEneSTATION database (http://genestation.org) integrates diverse types of omics data across mammals to advance understanding of the genetic basis of gestation and pregnancy-associated phenotypes and to accelerate the translation ...

The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function

The Rbfox family of RNA-binding proteins is highly conserved with established roles in alternative splicing (AS) regulation. High-throughput studies aimed at understanding transcriptome remodeling have revealed skeletal muscle as displaying one of the largest number of AS events. This finding is consistent with requirements for tissue-specific protein isoforms needed to sustain ...

Ribonuclease L and metal-ion–independent endoribonuclease cleavage sites in host and viral RNAs

Ribonuclease L (RNase L) is a metal-ion–independent endoribonuclease associated with antiviral and antibacterial defense, cancer and lifespan. Despite the biological significance of RNase L, the RNAs cleaved by this enzyme are poorly defined. In this study, we used deep sequencing methods to reveal the frequency and location of RNase L cleavage sites within host and viral RNAs. To ...

When should we commence dialysis? The story of a lingering problem and today's scene after the IDEAL study

Over the last 15–20 years, there has been an increasing trend for dialysis to be commenced earlier in the development of chronic kidney disease (CKD). The drivers for initiation of dialysis at higher levels of renal function are complex but were primarily based on the assumption that by improving solute and water clearances with earlier dialysis, morbidity, mortality and quality of ...

Cerebrospinal Fluid Exposure of Efavirenz and Its Major Metabolites When Dosed at 400 mg and 600 mg Once Daily: A Randomized Controlled Trial

Background. The optimal penetration of antiretroviral agents into the central nervous system may be a balance between providing adequate drug exposure to inhibit human immunodeficiency virus (HIV) replication while avoiding concentrations associated with neuronal toxicities. Methods. Cerebrospinal fluid (CSF) exposure of efavirenz and the metabolites 7-hydroxy (7OH) and 8-hydroxy ...

CUGBP2 directly interacts with U2 17S snRNP components and promotes U2 snRNA binding to cardiac troponin T pre-mRNA

the tissuespecific splicing factors Fox-1 and Fox-2. Genes Dev ., 22 , 2550 - 2563 . 41. Castle , J.C. , Zhang , C. , Shah , J.K. , Kulkarni , A.V. , Kalsotra , A. , Cooper , T.A. and Johnson , J.M

Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes

α-Synuclein plays a central causative role in Parkinson's disease (PD). Increased expression of the P-type ATPase ion pump PARK9/ATP13A2 suppresses α-Synuclein toxicity in primary neurons. Our data indicate that ATP13A2 encodes a zinc pump; neurospheres from a compound heterozygous ATP13A2−/− patient and ATP13A2 knockdown cells are sensitive to zinc, whereas ATP13A2 over-expression ...

Free Protein S Level as a Risk Factor for Coronary Heart Disease and Stroke in a Prospective Cohort Study of Healthy United Kingdom Men

Laboratories, Department of Medicine, Royal Free and University College Medical School, University of London, London, United Kingdom (Gie Ken-Dror, Jackie A. Cooper, Steve E. Humphries, Fotios Drenos, Helen A

Identification of MBNL1 and MBNL3 domains required for splicing activation and repression

Muscleblind-like 1 (MBNL1) is a splicing regulator that controls developmentally regulated alternative splicing of a large number of exons including exon 11 of the Insulin Receptor (IR) gene and exon 5 of the cardiac Troponin T (cTNT) gene. There are three paralogs of MBNL in humans, all of which promote IR exon 11 inclusion and cTNT exon 5 skipping. Here, we identify a cluster of ...

Direct evidence of nuclear Argonaute distribution during transcriptional silencing links the actin cytoskeleton to nuclear RNAi machinery in human cells

Mammalian RNAi machinery facilitating transcriptional gene silencing (TGS) is the RNA-induced transcriptional gene silencing-like (RITS-like) complex, comprising of Argonaute (Ago) and small interfering RNA (siRNA) components. We have previously demonstrated promoter-targeted siRNA induce TGS in human immunodeficiency virus type-1 (HIV-1) and simian immunodeficiency virus (SIV), ...

Molecular Analysis of Household Transmission of Giardia lamblia in a Region of High Endemicity in Peru

Background. Giardia lamblia is ubiquitous in multiple communities of nonindustrialized nations. Genotypes A1, A2, and B (Nash groups 1, 2, and 3, respectively) are found in humans, whereas genotypes C and D are typically found in dogs. However, genotypes A and B have occasionally been identified in dogs. Methods. Fecal Giardia isolates from 22 families and their dogs, living in ...

CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1

The neuromuscular disease myotonic dystrophy type I (DM1) affects multiple organ systems with the major symptoms being severe muscle weakness, progressive muscle wasting and myotonia. The causative mutation in DM1 is a CTG repeat expansion in the 3′-untranslated region of the DM protein kinase (DMPK) gene. RNA transcribed from the expanded allele contains the expanded CUG repeats ...

Identification of CELF splicing activation and repression domains in vivo

CUG-BP and ETR-3 like factor (CELF) proteins are regulators of pre-mRNA alternative splicing. We created a series of truncation mutants to identify the regions of CELF proteins that are required to activate and to repress alternative splicing of different exons. This analysis was performed in parallel on two CELF proteins, ETR-3 (CUG-BP2, NAPOR, BRUNOL3) and CELF4 (BRUNOL4). We ...

Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion within the 3′-untranslated region of the DMPK gene. The predominant mechanism of pathogenesis is a toxic gain of function of CUG repeat containing RNA transcribed from the expanded allele. The molecular mechanisms by which the RNA containing expanded repeats produce pathogenic effects include: sequestration of ...

Disease Progression and Fatal Outcomes in HIV-Infected Patients during Interruption of Antiretroviral Treatment

0 David A. Cooper, Sean Emery, and Damien V. Cordery National Centre in HIV Epidemiology and Clinical Research, University of New South Wales , Sydney, Australia - To the EditorSeveral recent

A bichromatic fluorescent reporter for cell-based screens of alternative splicing

Alternative splicing is the primary source of proteome complexity in metazoans and its regulation shapes the proteome in response to shifting physiological requirements. We developed a bichromatic splicing reporter that uses a peculiar feature of some fluorescent protein coding regions to express two different fluorescent proteins from a single alternative splicing event. The ...

Simplification of Antiretroviral Therapy with Tenofovir-Emtricitabine or Abacavir-Lamivudine: A Randomized, 96-Week Trial

Background. There are 2 once-daily, fixed-dose-combination, dual-nucleoside analogue tablets: tenofovir 300 mg-emtricitabine 200 mg (TDF-FTC) and abacavir 600 mg-lamivudine 300 mg (ABC-3TC). Which fixed-dose-combination tablet is more effective and safe is uncertain. Methods. We compared TDF-FTC and ABC-3TC in a randomized, open-label, 96-week trial in which either ...

Mediators of Innate and Adaptive Immune Responses Differentially Affect Immune Restoration Disease Associated with Mycobacterium tuberculosis in HIV Patients Beginning Antiretroviral Therapy

Background. Initiation of antiretroviral therapy (ART) in human immunodeficiency virus patients with treated or unrecognized Mycobacterium tuberculosis infection may result in tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) or ART-associated tuberculosis (ART-TB), respectively. Both conditions appear to be immune restoration disease but their ...

Global regulation of alternative splicing during myogenic differentiation

alternative splicing in the human genome? Trends Genet ., 20 , 68 - 71 . 22. Castle , J.C. , Zhang , C. , Shah , J.K. , Kulkarni , A.V. , Kalsotra , A. , Cooper , T.A. and Johnson , J.M. ( 2008 ) Expression of