Tumour necrosis factor (TNF) and interleukin-1 (IL-1) induce muscle proteolysis through different mechanisms

The purpose of this study was to test the hypothesis that muscle proteolysis induced by TNF or IL-1 is mediated by glucocorticoids. Rats were treated with 300 μg kg−1 of recombinant human preparations of IL-1α (rIL-1α) or TNFα (rTNFα) divided into three equal intraperitoneal doses given over 16 h. Two hours before each cytokine injection, rats were given 5 mg kg−1 of the glucocorticoid receptor blocker mifepristone RU 38486, by gavage or were gavaged with the vehicle. Eighteen hours after the first cytokine injection, total and myofibrillar protein breakdown rates were determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Total and myofibrillar proteolytic rates were increased following injection of rIL-1α or rTNFα. Proteolysis induced by rIL-1α was not altered by treatment with RU 38486. In contrast, the glucocorticoid receptor blocker inhibited the proteolytic effect of rTNFα. The results suggest that the proteolytic effect of TNF is mediated by glucocorticoids and that IL-1 induces muscle proteolysis through a glucocorticoid independent pathway

The Functions of Auxilin and Rab11 in Drosophila Suggest That the Fundamental Role of Ligand Endocytosis in Notch Signaling Cells Is Not Recycling

Notch signaling requires ligand internalization by the signal sending cells. Two endocytic proteins, epsin and auxilin, are essential for ligand internalization and signaling. Epsin promotes clathrin-coated vesicle formation, and auxilin uncoats clathrin from newly internalized vesicles. Two hypotheses have been advanced to explain the requirement for ligand endocytosis. One idea is that after ligand/receptor binding, ligand endocytosis leads to receptor activation by pulling on the receptor, which either exposes a cleavage site on the extracellular domain, or dissociates two receptor subunits. Alternatively, ligand internalization prior to receptor binding, followed by trafficking through an endosomal pathway and recycling to the plasma membrane may enable ligand activation. Activation could mean ligand modification or ligand transcytosis to a membrane environment conducive to signaling. A key piece of evidence supporting the recycling model is the requirement in signaling cells for Rab11, which encodes a GTPase critical for endosomal recycling. Here, we use Drosophila Rab11 and auxilin mutants to test the ligand recycling hypothesis. First, we find that Rab11 is dispensable for several Notch signaling events in the eye disc. Second, we find that Drosophila female germline cells, the one cell type known to signal without clathrin, also do not require auxilin to signal. Third, we find that much of the requirement for auxilin in Notch signaling was bypassed by overexpression of both clathrin heavy chain and epsin. Thus, the main role of auxilin in Notch signaling is not to produce uncoated ligand-containing vesicles, but to maintain the pool of free clathrin. Taken together, these results argue strongly that at least in some cell types, the primary function of Notch ligand endocytosis is not for ligand recycling

Discovery and Characterization of 2-Anilino-4- (Thiazol-5-yl)Pyrimidine Transcriptional CDK Inhibitors as Anticancer Agents

The main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins. We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i.e., CDK7 and especially CDK9. The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation. This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups. We describe the characterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells. A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5-[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H-thiazol-2-one, with anticancer activity in animal models

How Does Socioeconomic Development Affect COPD Mortality? An Age-Period-Cohort Analysis from a Recently Transitioned Population in China

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of death, particularly in developing countries. Little is known about the effects of economic development on COPD mortality, although economic development may potentially have positive and negative influences over the life course on COPD. We took advantage of a unique population whose rapid and recent economic development is marked by changes at clearly delineated and identifiable time points, and where few women smoke, to examine the effect of macro-level events on COPD mortality. Methods: We used Poisson regression to decompose sex-specific COPD mortality rates in Hong Kong from 1981 to 2005 into the effects of age, period and cohort. Results: COPD mortality declined strongly over generations for people born from the early to mid 20th century, which was particularly evident for the first generation to grow up in a more economically developed environment for both sexes. Population wide COPD mortality decreased when air quality improved and increased with increasing air pollution. COPD mortality increased with age, particularly after menopause among women. Conclusions: Economic development may reduce vulnerability to COPD by reducing long-lasting insults to the respiratory system, such as infections, poor nutrition and indoor air pollution. However, some of these gains may be offset if economic development results in increasing air pollution or increasing smoking. © 2011 Chen et al.published_or_final_versio

The Functions of Auxilin and Rab11 in Drosophila Suggest That the Fundamental Role of Ligand Endocytosis in Notch Signaling Cells Is Not Recycling

Notch signaling requires ligand internalization by the signal sending cells. Two endocytic proteins, epsin and auxilin, are essential for ligand internalization and signaling. Epsin promotes clathrin-coated vesicle formation, and auxilin uncoats clathrin from newly internalized vesicles. Two hypotheses have been advanced to explain the requirement for ligand endocytosis. One idea is that after ligand/receptor binding, ligand endocytosis leads to receptor activation by pulling on the receptor, which either exposes a cleavage site on the extracellular domain, or dissociates two receptor subunits. Alternatively, ligand internalization prior to receptor binding, followed by trafficking through an endosomal pathway and recycling to the plasma membrane may enable ligand activation. Activation could mean ligand modification or ligand transcytosis to a membrane environment conducive to signaling. A key piece of evidence supporting the recycling model is the requirement in signaling cells for Rab11, which encodes a GTPase critical for endosomal recycling. Here, we use Drosophila Rab11 and auxilin mutants to test the ligand recycling hypothesis. First, we find that Rab11 is dispensable for several Notch signaling events in the eye disc. Second, we find that Drosophila female germline cells, the one cell type known to signal without clathrin, also do not require auxilin to signal. Third, we find that much of the requirement for auxilin in Notch signaling was bypassed by overexpression of both clathrin heavy chain and epsin. Thus, the main role of auxilin in Notch signaling is not to produce uncoated ligand-containing vesicles, but to maintain the pool of free clathrin. Taken together, these results argue strongly that at least in some cell types, the primary function of Notch ligand endocytosis is not for ligand recycling

Prevalence of Influenza A viruses in wild migratory birds in Alaska: Patterns of variation in detection at a crossroads of intercontinental flyways

<p>Abstract</p> <p>Background</p> <p>The global spread of the highly pathogenic avian influenza H5N1 virus has stimulated interest in a better understanding of the mechanisms of H5N1 dispersal, including the potential role of migratory birds as carriers. Although wild birds have been found dead during H5N1 outbreaks, evidence suggests that others have survived natural infections, and recent studies have shown several species of ducks capable of surviving experimental inoculations of H5N1 and shedding virus. To investigate the possibility of migratory birds as a means of H5N1 dispersal into North America, we monitored for the virus in a surveillance program based on the risk that wild birds may carry the virus from Asia.</p> <p>Results</p> <p>Of 16,797 birds sampled in Alaska between May 2006 and March 2007, low pathogenic avian influenza viruses were detected in 1.7% by rRT-PCR but no highly pathogenic viruses were found. Our data suggest that prevalence varied among sampling locations, species (highest in waterfowl, lowest in passerines), ages (juveniles higher than adults), sexes (males higher than females), date (highest in autumn), and analytical technique (rRT-PCR prevalence = 1.7%; virus isolation prevalence = 1.5%).</p> <p>Conclusion</p> <p>The prevalence of low pathogenic avian influenza viruses isolated from wild birds depends on biological, temporal, and geographical factors, as well as testing methods. Future studies should control for, or sample across, these sources of variation to allow direct comparison of prevalence rates.</p