The Role of IRE1α in the Degradation of Insulin mRNA in Pancreatic β-Cells

The endoplasmic reticulum (ER) is a cellular compartment for the biosynthesis and folding of newly synthesized secretory proteins such as insulin. Perturbations to ER homeostasis cause ER stress and subsequently activate cell signaling pathways, collectively known as the Unfolded Protein Response (UPR). IRE1α is a central component of the UPR. In pancreatic β-cells, IRE1α also functions in the regulation of insulin biosynthesis.Here we report that hyperactivation of IRE1α caused by chronic high glucose treatment or IRE1α overexpression leads to insulin mRNA degradation in pancreatic β-cells. Inhibition of IRE1α signaling using its dominant negative form prevents insulin mRNA degradation. Islets from mice heterozygous for IRE1α retain expression of more insulin mRNA after chronic high glucose treatment than do their wild-type littermates.These results reveal a role of IRE1α in insulin mRNA expression under ER stress conditions caused by chronic high glucose. The rapid degradation of insulin mRNA could provide immediate relief for the ER and free up the translocation machinery. Thus, this mechanism would preserve ER homeostasis and help ensure that the insulin already inside the ER can be properly folded and secreted. This adaptation may be crucial for the maintenance of β-cell homeostasis and may explain why the β-cells of type 2 diabetic patients with chronic hyperglycemia stop producing insulin in the absence of apoptosis. This mechanism may also be involved in suppression of the autoimmune type 1 diabetes by reducing the amount of misfolded insulin, which could be a source of “neo-autoantigens.

Mapping patterns of complementary and alternative medicine use in cancer: An explorative cross-sectional study of individuals with reported positive "exceptional" experiences

<p>Abstract</p> <p>Background</p> <p>While the use of complementary and alternative medicine (CAM) among cancer patients is common and widespread, levels of commitment to CAM vary. "Committed" CAM use is important to investigate, as it may be associated with elevated risks and benefits, and may affect use of biomedically-oriented health care (BHC). Multiple methodological approaches were used to explore and map patterns of CAM use among individuals postulated to be committed users, voluntarily reporting exceptional experiences associated with CAM use after cancer diagnosis.</p> <p>Method</p> <p>The verbatim transcripts of thirty-eight unstructured interviews were analyzed in two steps. First, manifest content analysis was used to elucidate and map participants' use of CAM, based on the National Center for Complementary Medicine (NCCAM)'s classification system. Second, patterns of CAM use were explored statistically using principal component analysis.</p> <p>Findings</p> <p>The 38 participants reported using a total of 274 specific CAM (median = 4) consisting of 148 different therapeutic modalities. Most reported therapies could be categorized using the NCCAM taxonomy (n = 224). However, a significant number of CAM therapies were not consistent with this categorization (n = 50); consequently, we introduced two additional categories: <it>Spiritual/health literature </it>and <it>Treatment centers</it>. The two factors explaining the largest proportion of variation in CAM usage patterns were a) number of CAM modalities used and b) a category preference for <it>Energy therapies </it>over the categories <it>Alternative Medical Systems </it>and <it>Treatment centers </it>or vice versa.</p> <p>Discussion</p> <p>We found considerable heterogeneity in patterns of CAM use. By analyzing users' own descriptions of CAM in relation to the most commonly used predefined professional taxonomy, this study highlights discrepancies between user and professional conceptualizations of CAM not previously addressed. Beyond variations in users' reports of CAM, our findings indicate some patterns in CAM usage related to number of therapies used and preference for different CAM categories.</p

Assessing control of postural stability in community-living older adults using performance-based limits of stability

<p>Abstract</p> <p>Background</p> <p>Balance disability measurements routinely used to identify fall risks in frail populations have limited value in the early detection of postural stability deficits in community-living older adults. The objectives of the study were to 1) measure performance-based limits of stability (LOS) in community-living older adults and compare them to theoretical LOS computed from data proposed by the Balance Master^®system, 2) explore the feasibility of a new measurement approach based on the assessment of postural stability during weight-shifting tasks at performance-based LOS, 3) quantify intra-session performance variability during multiple trials using the performance-based LOS paradigm.</p> <p>Methods</p> <p>Twenty-four healthy community-living older adults (10 men, 14 women) aged between 62 to 85 (mean age ± sd, 71.5 ± 6 yrs) participated in the study. Subjects' performance-based LOS were established by asking them to transfer their body weight as far as possible in three directions (forward, right and left) without changing their base of support. LOS were computed as the maximal excursion of the COP in each direction among three trials. Participants then performed two experimental tasks that consisted in controlling, with the assistance of visual feedback, their centre of pressure (COP) within two predefined targets set at 100% of their performance-based LOS. For each tasks 8 trials were performed. Ground reaction forces and torques during performance-based LOS evaluation and experimental tasks were recorded with a force plate. Sway area and medio-lateral mean COP displacement speed variables were extracted from force plate recordings.</p> <p>Results</p> <p>Significant differences between theoretical LOS computed from maximum leaning angles derived from anthropometric characteristics and performance-based LOS were observed. Results showed that a motor learning effect was present as the participants optimized their weight-shifting strategy through the first three trials of each task using the visual biofeedback provided on their COP. Reliable measures of control of postural stability at performance-based LOS can be obtained after two additional trials after the learning phase (0.69 > ICC > 1.0).</p> <p>Conclusion</p> <p>Establishing performance-based LOS instead of relying on estimations of theoretical LOS offers a more individualized and realistic insight on the true LOS of an individual. Performance-based LOS can be used as targets during weight-shifting postural tasks with real time visual feedback of the COP displacement to assess postural stability of community-living older adults. In order to obtain reliable results, a learning phase allowing subjects to learn how to control their COP displacement is needed.</p

A controlled study of team-based learning for undergraduate clinical neurology education

<p>Abstract</p> <p>Background</p> <p>Team-based learning (TBL), a new active learning method, has not been reported for neurology education. We aimed to determine if TBL was more effective than passive learning (PL) in improving knowledge outcomes in two key neurology topics - neurological localization and neurological emergencies.</p> <p>Methods</p> <p>We conducted a modified crossover study during a nine-week internal medicine posting involving 49 third-year medical undergraduates, using TBL as the active intervention, compared against self-reading as a PL control, for teaching the two topics. Primary outcome was the mean percentage change in test scores immediately after (post-test 1) and 48 hours after TBL (post-test 2), compared to a baseline pre-test. Student engagement was the secondary outcome.</p> <p>Results</p> <p>Mean percentage change in scores was greater in the TBL versus the PL group in post-test 1 (8.8% vs 4.3%, p = 0.023) and post-test 2 (11.4% vs 3.4%, p = 0.001). After adjustment for gender and second year examination grades, mean percentage change in scores remained greater in the TBL versus the PL group for post-test 1 (10.3% vs 5.8%, mean difference 4.5%,95% CI 0.7 - 8.3%, p = 0.021) and post-test 2 (13.0% vs 4.9%, mean difference 8.1%,95% CI 3.7 - 12.5%, p = 0.001), indicating further score improvement 48 hours post-TBL. Academically weaker students, identified by poorer examination grades, showed a greater increase in scores with TBL versus strong students (p < 0.02). Measures of engagement were high in the TBL group, suggesting that continued improvements in scores 48 hours post-TBL may result from self-directed learning.</p> <p>Conclusions</p> <p>Compared to PL, TBL showed greater improvement in knowledge scores, with continued improvement up to 48 hours later. This effect is larger in academically weaker students. TBL is an effective method for improving knowledge in neurological localization and neurological emergencies in undergraduates.</p

A transcription factor contributes to pathogenesis and virulence in streptococcus pneumoniae

To date, the role of transcription factors (TFs) in the progression of disease for many pathogens is yet to be studied in detail. This is probably due to transient, and generally low expression levels of TFs, which are the central components controlling the expression of many genes during the course of infection. However, a small change in the expression or specificity of a TF can radically alter gene expression. In this study, we combined a number of quality-based selection strategies including structural prediction of modulated genes, gene ontology and network analysis, to predict the regulatory mechanisms underlying pathogenesis of Streptococcus pneumoniae (the pneumococcus). We have identified two TFs (SP_0676 and SP_0927 [SmrC]) that might control tissue-specific gene expression during pneumococcal translocation from the nasopharynx to lungs, to blood and then to brain of mice. Targeted mutagenesis and mouse models of infection confirmed the role of SP_0927 in pathogenesis and virulence, and suggests that SP_0676 might be essential to pneumococcal viability. These findings provide fundamental new insights into virulence gene expression and regulation during pathogenesis.Layla K. Mahdi, Esmaeil Ebrahimie, David L. Adelson, James C. Paton, Abiodun D. Ogunniy

Enriched job design, high involvement management and organizational performance: The mediating roles of job satisfaction and well-being

The relationship between organizational performance and two dimensions of the 'high performance work system' - enriched job design and high involvement management (HIM) - is widely assumed to be mediated by worker well-being. We outline the basis for three models: mutual-gains, in which employee involvement increases well-being and this mediates its positive relationship with performance; conflicting outcomes, which associates involvement with increased stress for workers, accounting for its positive performance effects; and counteracting effects, which associates involvement with increased stress and dissatisfaction, reducing its positive performance effects. These are tested using the UK's Workplace Employment Relations Survey 2004. Job satisfaction mediates the relationship between enriched job design and four performance indicators, supporting the mutual gains model; but HIM is negatively related to job satisfaction and this depresses a positive relationship between HIM and the economic performance measures, supporting a counteracting effects model. Finally, HIM is negatively related to job-related anxiety-comfort and enriched job design is unrelated to it. © The Author(s) 2012

Production of a reference transcriptome and transcriptomic database (PocilloporaBase) for the cauliflower coral, Pocillopora damicornis

<p>Abstract</p> <p>Background</p> <p>Motivated by the precarious state of the world's coral reefs, there is currently a keen interest in coral transcriptomics. By identifying changes in coral gene expression that are triggered by particular environmental stressors, we can begin to characterize coral stress responses at the molecular level, which should lead to the development of more powerful diagnostic tools for evaluating the health of corals in the field. Furthermore, the identification of genetic variants that are more or less resilient in the face of particular stressors will help us to develop more reliable prognoses for particular coral populations. Toward this end, we performed deep mRNA sequencing of the cauliflower coral, <it>Pocillopora damicornis</it>, a geographically widespread Indo-Pacific species that exhibits a great diversity of colony forms and is able to thrive in habitats subject to a wide range of human impacts. Importantly, <it>P. damicornis </it>is particularly amenable to laboratory culture. We collected specimens from three geographically isolated Hawaiian populations subjected to qualitatively different levels of human impact. We isolated RNA from colony fragments ("nubbins") exposed to four environmental stressors (heat, desiccation, peroxide, and hypo-saline conditions) or control conditions. The RNA was pooled and sequenced using the 454 platform.</p> <p>Description</p> <p>Both the raw reads (n = 1, 116, 551) and the assembled contigs (n = 70, 786; mean length = 836 nucleotides) were deposited in a new publicly available relational database called PocilloporaBase <url>http://www.PocilloporaBase.org</url>. Using BLASTX, 47.2% of the contigs were found to match a sequence in the NCBI database at an E-value threshold of ≤.001; 93.6% of those contigs with matches in the NCBI database appear to be of metazoan origin and 2.3% bacterial origin, while most of the remaining 4.1% match to other eukaryotes, including algae and amoebae.</p> <p>Conclusions</p> <p><it>P. damicornis </it>now joins the handful of coral species for which extensive transcriptomic data are publicly available. Through PocilloporaBase <url>http://www.PocilloporaBase.org</url>, one can obtain assembled contigs and raw reads and query the data according to a wide assortment of attributes including taxonomic origin, PFAM motif, KEGG pathway, and GO annotation.</p

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Forward-Backward Asymmetry in the B -> K(*) mu+ mu- Decay and First Observation of the Bs -> phi mu+ mu- Decay

We reconstruct the rare decays $B^+ \to K^+\mu^+\mu^-$, $B^0 \to K^{*}(892)^0\mu^+\mu^-$, and $B^0_s \to \phi(1020)\mu^+\mu^-$ in a data sample corresponding to $4.4 {\rm fb^{-1}}$ collected in $p\bar{p}$ collisions at $\sqrt{s}=1.96 {\rm TeV}$ by the CDF II detector at the Fermilab Tevatron Collider. Using $121 \pm 16$ $B^+ \to K^+\mu^+\mu^-$ and $101 \pm 12$ $B^0 \to K^{*0}\mu^+\mu^-$ decays we report the branching ratios. In addition, we report the measurement of the differential branching ratio and the muon forward-backward asymmetry in the $B^+$ and $B^0$ decay modes, and the $K^{*0}$ longitudinal polarization in the $B^0$ decay mode with respect to the squared dimuon mass. These are consistent with the theoretical prediction from the standard model, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the $B^0_s \to \phi\mu^+\mu^- decay and measure its branching ratio${\mathcal{B}}(B^0_s \to \phi\mu^+\mu^-) = [1.44 \pm 0.33 \pm 0.46] \times 10^{-6}$using$27 \pm 6$signal events. This is currently the most rare$B^0_s$ decay observed.Comment: 7 pages, 2 figures, 3 tables. Submitted to Phys. Rev. Let