Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease

Linking Ethnic Identification to Organisational Solidarity

This paper investigates the process through which ethnic identification (EI) influences employees’ sense of organisational solidarity (OS). A survey of 1525 employees working in different ministries of a state government in Nigeria was collected and analysed by means of a regression to investigate EI-OS relationships. As expected, EI was a significant determinant of OS with co-worker social support explaining the rationale for EI-OS relationship. The conceptualisation of OS as a composite construct that manifest in employees’ self-efficacy, organisational self-identity and employee voice behaviours is novel. The study provides evidence from an under researched area to further generalise existing debates

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

A national cross-sectional survey of public perceptions of the COVID-19 pandemic: Self-reported beliefs, knowledge, and behaviors

INTRODUCTION: Efforts to mitigate the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing Corona Virus Disease-19 (COVID-19) have largely relied on broad compliance with public health recommendations yet navigating the high volume of evolving information can be challenging. We assessed self-reported public perceptions related to COVID-19 including, beliefs (e.g., severity, concerns, health), knowledge (e.g., transmission, information sources), and behaviors (e.g., physical distancing) to understand perspectives in Canada and to inform future public health initiatives. METHODS: We administered a national online survey aiming to obtain responses from 2000 adults in Canada. Respondent sampling was stratified by age, sex, and region. We used descriptive statistics to summarize responses and tested for regional differences using chi-squared tests, followed by weighted logistic regression. RESULTS: We collected 1,996 eligible questionnaires between April 26th and May 1st, 2020. One-fifth (20%) of respondents knew someone diagnosed with COVID-19, but few had tested positive themselves (0.6%). Negative impacts of pandemic conditions were evidenced in several areas, including concerns about healthcare (e.g. sufficient equipment, 52%), pandemic stress (45%), and worsening social (49%) and mental/emotional (39%) health. Most respondents (88%) felt they had good to excellent knowledge of virus transmission, and predominantly accessed (74%) and trusted (60%) Canadian news television, newspapers/magazines, or non-government news websites for COVID-19 information. We found high compliance with distancing measures (80% reported self-isolating or always physical distancing). We identified associations between region and self-reported beliefs, knowledge, and behaviors related to COVID-19. DISCUSSION: We found that information about COVID-19 is largely acquired through domestic news sources, which may explain high self-reported compliance with prevention measures. The results highlight the broader impact of a pandemic on the general public's overall health and wellbeing, outside of personal infection. The study findings should be used to inform public health communications during COVID-19 and future pandemics

Implementing and evaluating shared decision-making before transcatheter aortic valve implantation with a dedicated pathway and questionnaire

Aims: Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement for patients with aortic valve stenosis. The choice between TAVI, surgery, or a conservative approach should be based upon multiple factors including clinical considerations, technical feasibility, and informed patient preference. In this context, engaging patients in a shared decision-making (SDM) process becomes essential, but this practice is generally underused. Methods and results: To comply with the European and UK national guidelines, in January 2023 we established a structured SDM pathway in which patients are offered virtual/physical decision aids and after 1 week are invited to a meeting to reach a shared decision. From December 2022 to June 2023, a custom-developed questionnaire was prospectively administered to 23 patients prior to, and 38 patients after, the implementation of the SDM pathway. The answers to 12 core questions were recorded on a Likert scale (1-5). Global satisfaction, as measured by mean Likert score, was significantly higher for the post-SDM group than for the pre-SDM group (4.46 ± 0.14 vs. 3.78 ± 0.30, P < 0.001). The percentage of positive (Likert 4-5) responses was significantly higher in the post-SDM group (289/312, 92.6% vs. 155/234, 66.2%, P < 0.001). The percentage of negative (Likert 1-2) responses was significantly lower in the post-SDM group (5/312, 1.6% vs. 53/234, 22.6%, P < 0.001). Conclusion: The SDM pathway proved effective in delivering SDM in compliance with national and international guidance. A similar approach leveraging digital technology to minimize cost and enhance patient convenience could be implemented for other treatments and across other institutions

Lump-Sum Bonus Satisfaction: Testing the Construct Validity of a New Pay Satisfaction Dimension

There are both practical and theoretical reasons to measure lump-sum bonus satisfaction. The practical need for such a measure stems from its increased use as a component in modern compensation practices. Based on the means of administering and allocating lump-sum bonuses, a theoretical case can be built suggesting that lump-sum bonus satisfaction constitutes a separate component of pay satisfaction fitting into the Pay Satisfaction Questionaire\u27s (PSQ) theoretical framework. We develop 4 questions that complement the PSQ, and use a series of techniques to test the convergent and discriminant validity of the measure. Empirical evidence shows that bonus-related items are more related to the lump-sum bonus satisfaction measure than other PSQ dimensions. We also demonstrate that the dimension of lump-sum bonus satisfaction has a substantive relationship with attitudinal variables beyond that provided by pay level variables and the PSQ. The development of this measure should foster greater accuracy when assessing pay satisfaction levels and the effects of lump-sum bonus pay policies

Aging effect on nectar production in two clones of Asclepias syriaca

In common milkweed ( Asclepias syriaca ), flower nectar volumes, concentration and sugar production varied according to the age of the sampled blossoms. In individual blossoms, nectar production peaked daily at 0800 hr. Peak production during the life of the flower occurred on the second day of flowering, 50 h after anthesis, and nectar production ceased after 120 h. The amount and quality of nectar were affected by microclimatic conditions and varied between clones. However, the same secretory patterns were found in all flowers studied. This age dependent nectar secretion combined with the sequential mode of flowering found on a single stem, results in substantial reward for extended periods to nectar feeders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47744/1/442_2004_Article_BF00378227.pd

Dystrophin deficiency in canine X-linked muscular dystrophy in Japan (CXMDJ) alters myosin heavy chain expression profiles in the diaphragm more markedly than in the tibialis cranialis muscle

<p>Abstract</p> <p>Background</p> <p>Skeletal muscles are composed of heterogeneous collections of muscle fiber types, the arrangement of which contributes to a variety of functional capabilities in many muscle types. Furthermore, skeletal muscles can adapt individual myofibers under various circumstances, such as disease and exercise, by changing fiber types. This study was performed to examine the influence of dystrophin deficiency on fiber type composition of skeletal muscles in canine X-linked muscular dystrophy in Japan (CXMD_J), a large animal model for Duchenne muscular dystrophy.</p> <p>Methods</p> <p>We used tibialis cranialis (TC) muscles and diaphragms of normal dogs and those with CXMD_Jat various ages from 1 month to 3 years old. For classification of fiber types, muscle sections were immunostained with antibodies against fast, slow, or developmental myosin heavy chain (MHC), and the number and size of these fibers were analyzed. In addition, MHC isoforms were detected by gel electrophoresis.</p> <p>Results</p> <p>In comparison with TC muscles of CXMD_J, the number of fibers expressing slow MHC increased markedly and the number of fibers expressing fast MHC decreased with growth in the affected diaphragm. In populations of muscle fibers expressing fast and/or slow MHC(s) but not developmental MHC of CXMD_Jmuscles, slow MHC fibers were predominant in number and showed selective enlargement. Especially, in CXMD_Jdiaphragms, the proportions of slow MHC fibers were significantly larger in populations of myofibers with non-expression of developmental MHC. Analyses of MHC isoforms also indicated a marked increase of type I and decrease of type IIA isoforms in the affected diaphragm at ages over 6 months. In addition, expression of developmental (embryonic and/or neonatal) MHC decreased in the CXMD_Jdiaphragm in adults, in contrast to continuous high-level expression in affected TC muscle.</p> <p>Conclusion</p> <p>The CXMD_Jdiaphragm showed marked changes in fiber type composition unlike TC muscles, suggesting that the affected diaphragm may be effectively adapted toward dystrophic stress by switching to predominantly slow fibers. Furthermore, the MHC expression profile in the CXMD_Jdiaphragm was markedly different from that in <it>mdx </it>mice, indicating that the dystrophic dog is a more appropriate model than a murine one, to investigate the mechanisms of respiratory failure in DMD.</p

Toxicity Associated with Stavudine Dose Reduction from 40 to 30 mg in First-Line Antiretroviral Therapy

To compare the incidence and timing of toxicity associated with the use of a reduced dose of stavudine from 40 to 30 mg in first-line antiretroviral therapy (ART) for HIV treatment and to investigate associated risk factors