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Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production.
We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells
The effect of acute sleep deprivation on skeletal muscle protein synthesis and the hormonal environment
Chronic sleep loss is a potent catabolic stressor, increasing the risk of metabolic dysfunction and loss of muscle mass and function. To provide mechanistic insight into these clinical outcomes, we sought to determine if acute sleep deprivation blunts skeletal muscle protein synthesis and promotes a catabolic environment. Healthy young adults (N = 13; seven male, six female) were subjected to one night of total sleep deprivation (DEP) and normal sleep (CON) in a randomized cross-over design. Anabolic and catabolic hormonal profiles were assessed across the following day. Postprandial muscle protein fractional synthesis rate (FSR) was assessed between 13:00 and 15:00 and gene markers of muscle protein degradation were assessed at 13:00. Acute sleep deprivation reduced muscle protein synthesis by 18% (CON: 0.072 ± 0.015% vs. DEP: 0.059 ± 0.014%·h-1, p =.040). In addition, sleep deprivation increased plasma cortisol by 21% (p =.030) and decreased plasma testosterone by 24% (p =.029). No difference was found in the markers of protein degradation. A single night of total sleep deprivation is sufficient to induce anabolic resistance and a procatabolic environment. These acute changes may represent mechanistic precursors driving the metabolic dysfunction and body composition changes associated with chronic sleep deprivation
Phenomenon of declining blood pressure in elderly - high systolic levels are undervalued with Korotkoff method
<p>Abstract</p> <p>Background</p> <p>Systolic blood pressure (SBP) decline has been reported in octogenarians. The aim was to study if it could be observed while measuring SBP with two methods: Korotkoff (K-BP) and Strain-Gauge-Finger-Pletysmography (SG-BP), and which of them were more reliable in expressing vascular burden.</p> <p>Methods</p> <p>A cohort of 703 men from a population of Malmö, Sweden, were included in "Men born in 1914-study" and followed-up at ages: 68 and 81 years. 176 survivors were examined with K-BP and SG-BP at both ages, and 104 of them with Ambulatory Blood Pressure at age 81/82. Ankle Brachial Index (ABI) was measured on both occasions, and Carotid Ultrasound at age 81.</p> <p>Results</p> <p>From age 68 to 81, mean K-BP decreased in the cohort with mean 8.3 mmHg, while SG-BP increased with 13.4 mmHg. K-BP decreased in 55% and SG-BP in 31% of the subjects. At age 81, K-BP was lower than SG-BP in 72% of subjects, and correlated to high K-BP at age 68 (r = --.22; p < .05). SG-BP at age 81 was correlated with mean ambulatory 24-h SBP (r = .480; p < .0001), daytime SBP (r = .416; p < .0001), nighttime SBP (r = .395; p < .0001), and daytime and nighttime Pulse Pressure (r = .452; p < .0001 and r = .386; p < .0001). KB-BP correlated moderately only with nighttime SBP (r = .198; p = .044), and daytime and nightime pulse pressure (r = .225; p = .021 and r = .264; p = .007). Increasing SG-BP from age 68 to 81, but not K-BP, correlated with: 24-h, daytime and nighttime SBP, and mean daytime and nighttime Pulse Pressure. Increasing SG-BP was also predicted by high B-glucose and low ABI at age 68, and correlated with carotid stenosis and low ABI age 81, and the grade of ABI decrease over 13 years.</p> <p>Conclusion</p> <p>In contrast to K-BP, values of SG-BP in octogenarians strongly correlated with Ambulatory Blood Pressure. The SG-BP decline in the last decade was rare, and increasing SG-BP better than K-BP reflected advanced atherosclerosis. It should be aware, that K-BP underdetected 46% of subjects with SG-BP equal/higher than 140 mmHg at age 81, which may lead to biased associations with risk factors due to differential misclassification by age.</p
Socioeconomic status, severity of disease and level of family members’ care in adult surgical intensive care patients: the prospective ECSSTASI study
Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo
We use data from the second science run of the LIGO gravitational-wave
detectors to search for the gravitational waves from primordial black hole
(PBH) binary coalescence with component masses in the range 0.2--.
The analysis requires a signal to be found in the data from both LIGO
observatories, according to a set of coincidence criteria. No inspiral signals
were found. Assuming a spherical halo with core radius 5 kpc extending to 50
kpc containing non-spinning black holes with masses in the range 0.2--, we place an observational upper limit on the rate of PBH coalescence
of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.
Identification of a Transcription Factor Controlling pH-Dependent Organic Acid Response in Aspergillus niger.
Acid formation in Aspergillus niger is known to be subjected to tight regulation, and the acid production profiles are fine-tuned to respond to the ambient pH. Based on transcriptome data, putative trans-acting pH responding transcription factors were listed and through knock out studies, mutants exhibiting an oxalate overproducing phenotype were identified. The yield of oxalate was increased up to 158% compared to the wild type and the corresponding transcription factor was therefore entitled Oxalic Acid repression Factor, OafA. Detailed physiological characterization of one of the ΔoafA mutants, compared to the wild type, showed that both strains produced substantial amounts of gluconic acid, but the mutant strain was more efficient in re-uptake of gluconic acid and converting it to oxalic acid, particularly at high pH (pH 5.0). Transcriptional profiles showed that 241 genes were differentially expressed due to the deletion of oafA and this supported the argument of OafA being a trans-acting transcription factor. Furthermore, expression of two phosphoketolases was down-regulated in the ΔoafA mutant, one of which has not previously been described in fungi. It was argued that the observed oxalate overproducing phenotype was a consequence of the efficient re-uptake of gluconic acid and thereby a higher flux through glycolysis. This results in a lower flux through the pentose phosphate pathway, demonstrated by the down-regulation of the phosphoketolases. Finally, the physiological data, in terms of the specific oxygen consumption, indicated a connection between the oxidative phosphorylation and oxalate production and this was further substantiated through transcription analysis
Spontaneous focal activation of invariant natural killer T (iNKT) cells in mouse liver and kidney
<p>Abstract</p> <p>Background</p> <p>Invariant natural killer T (iNKT) cells differ from other T cells by their hyperactive effector T-cell status, in addition to the expression of NK lineage receptors and semi-invariant T-cell receptors. It is generally agreed that the immune phenotype of iNKT cells is maintained by repeated activation in peripheral tissues although no explicit evidence for such iNKT cell activity <it>in vivo </it>has so far been reported.</p> <p>Results</p> <p>We used an interferon (IFN)-γ-inducible cytoplasmic protein, Irga6, as a histological marker for local IFN-γ production. Irga6 was intensely expressed in small foci of liver parenchymal cells and kidney tubular epithelium. Focal Irga6 expression was unaffected by germ-free status or loss of TLR signalling and was totally dependent on IFN-γ secreted by T cells in the centres of expression foci. These were shown to be iNKT cells by diagnostic T cell receptor usage and their activity was lost in both CD1 d and Jα-deficient mice.</p> <p>Conclusions</p> <p>This is the first report that supplies direct evidence for explicit activation events of NKT cells <it>in vivo </it>and raises issues about the triggering mechanism and consequences for immune functions in liver and kidney.</p
Effects of Low-Dose Drinking Water Arsenic on Mouse Fetal and Postnatal Growth and Development
© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 7 (2012): e38249, doi:10.1371/journal.pone.0038249.Arsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level). C57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and health of the dams were assessed by a variety of measurements. Birth outcomes including litter weight, number of pups, and gestational length were unaffected. However, exposure during the in utero and postnatal period resulted in significant growth deficits in the offspring after birth, which was principally a result of decreased nutrients in the dam's breast milk. Cross-fostering of the pups reversed the growth deficit. Arsenic exposed dams displayed altered liver and breast milk triglyceride levels and serum profiles during pregnancy and lactation. The growth deficits in the F1 offspring resolved following separation from the dam and cessation of exposure in male mice, but did not resolve in female mice up to six weeks of age. Exposure to As at the current U.S. drinking water standard during critical windows of development induces a number of adverse health outcomes for both the dam and offspring. Such effects may contribute to the increased disease risks observed in human populations.This work was supported by National Institute of Environmental Health Sciences at the National Institutes of Health grants 1F32 ES019070 (CDK-H) and P42 ES007373 (BPJ, JWH, RIE and CDK-H, Dartmouth Superfund Research Program Project Grant, Project 2 and Pilot Project)
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