MuRF1 mono-ubiquitinates TRα to inhibit T3-induced cardiac hypertrophy in vivo

Thyroid hormone (TH) is recognized for its role in cellular metabolism and growth and participates in homeostasis of the heart. T3 activates pro-survival pathways including Akt and mTOR. Treatment with T3 after myocardial infarction is cardioprotective and promotes elements of physiological hypertrophic response after cardiac injury. Although T3 is known to benefit the heart, very little about its regulation at the molecular level has been described to date. The ubiquitin proteasome system (UPS) regulates nuclear hormone receptors such as estrogen, progesterone, androgen, and glucocorticoid receptors by both degradatory and non-degradatory mechanisms. However, how the UPS regulates T3-mediated activity is not well understood. In this study, we aim to determine the role of the muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) in regulating T3-induced cardiomyocyte growth. An increase in MuRF1 expression inhibits T3-induced physiological cardiac hypertrophy, whereas a decrease in MuRF1 expression enhances T3’s activity both in vitro and in cardiomyocytes in vivo. MuRF1 interacts directly with TRα to inhibit its activity by posttranslational ubiquitination in a non-canonical manner. We then demonstrated that a nuclear localization apparatus that regulates/inhibits nuclear receptors by sequestering them within a subcompartment of the nucleus was necessary for MuRF1 to inhibit T3 activity. This work implicates a novel mechanism that enhances the beneficial T3 activity specifically within the heart, thereby offering a potential target to enhance cardiac T3 activity in an organ-specific manner

The Nuclear Pore Complex Mediates Binding of the Mig1 Repressor to Target Promoters

All eukaryotic cells alter their transcriptional program in response to the sugar glucose. In Saccharomyces cerevisiae, the best-studied downstream effector of this response is the glucose-regulated repressor Mig1. We show here that nuclear pore complexes also contribute to glucose-regulated gene expression. NPCs participate in glucose-responsive repression by physically interacting with Mig1 and mediating its function independently of nucleocytoplasmic transport. Surprisingly, despite its abundant presence in the nucleus of glucose-grown nup120Δ or nup133Δ cells, Mig1 has lost its ability to interact with target promoters. The glucose repression defect in the absence of these nuclear pore components therefore appears to result from the failure of Mig1 to access its consensus recognition sites in genomic DNA. We propose that the NPC contributes to both repression and activation at the level of transcription

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon¹⁻³. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses⁴⁻⁹. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.Keywords: Ecology, Environmental scienc

The Transcription Factor Gcr1 Stimulates Cell Growth by Participating in Nutrient-Responsive Gene Expression on a Global Level

Transcriptomic reprogramming is critical to the coordination between growth and cell cycle progression in response to changing extracellular conditions. In Saccharomyces cerevisiae, the transcription factor Gcr1 contributes to this coordination by supporting maximum expression of G1 cyclins in addition to regulating both glucose-induced and glucose-repressed genes. We report here the comprehensive genome-wide expression profiling of gcr1Δ cells. Our data show that reduced expression of ribosomal protein genes in gcr1Δ cells is detectable both 20 min after glucose addition and in steady-state cultures of raffinose-grown cells, showing that this defect is not the result of slow growth or growth on a repressing sugar. However, the large cell phenotype of the gcr1Δ mutant occurs only in the presence of repressing sugars. GCR1 deletion also results in aberrant derepression of numerous glucose repressed loci; glucose-grown gcr1Δ cells actively respire, demonstrating that this global alteration in transcription corresponds to significant changes at the physiological level. These data offer an insight into the coordination of growth and cell division by providing an integrated view of the transcriptomic, phenotypic, and metabolic consequences of GCR1 deletion

Coiled Coil Structures and Transcription: An Analysis of the \u3ci\u3eS. cerevisiae\u3c/i\u3e coilome

The α-helical coiled coil is a simple but widespread motif that is an integral feature of many cellular structures. Coiled coils allow monomeric building blocks to form complex assemblages that can serve as molecular motors and springs. Previous parametrically delimited analyses of the distribution of coiled coils in the genomes of diverse organisms, including Escherichia coli, Saccharomyces cerevisiae, Arabidopsis thaliana, Caenorhabditis elegans and Homo sapiens, have identified conserved biological processes that make use of this versatile motif. Here we present a comprehensive inventory of the set of coiled coil proteins in S. cerevisiae by combining multiple coiled coil prediction algorithms with extensive literature curation. Our analysis of this set of proteins, which we call the coilome, reveals a wider role for this motif in transcription than was anticipated, particularly with respect to the category that includes nucleocytoplasmic shuttling factors involved in transcriptional regulation. We also show that the constitutively nuclear yeast transcription factor Gcr1 is homologous to the mammalian transcription factor MLL3, and that two coiled coil domains conserved between these homologs are important for Gcr1 dimerization and function. These data support the hypothesis that coiled coils are required to assemble structures essential for proper functioning of the transcriptional machinery