Postactivation performance enhancement (PAPE) of sprint acceleration performance

Postactivation performance enhancement (PAPE) is a principle that an acute bout of high-intensity voluntary exercise is followed by an enhancement in strength, speed or power production. This study intended to show a direct correlation between intensity, specificity and the outcome of a maximal task of sprint accelerations compared to a previously defined weighted plyometric intervention. In a randomised controlled, double-blind trial, professional footballers undertook 20 m maximal sprint accelerations at a baseline and at 2 and 6 min post-intervention after 1 of 3 interventions; 2 repetitions of 20 m sprint accelerations (S), 3 × 10 alternative leg weighted bounding (P) and control (C). Relative to the baseline there was a significant improvement for S over 10 and 20 m at 2 min of 0.12m.s−1 and 0.11m.s−1 and 6 min of 0.11m.s−1 and 0.12m.s−1. Relative to the baseline P also had a significant improvement over 10 and 20 m at 2 min 0.09m.s−1 and 0.09m.s−1 and 6 min of 0.11m.s−1 and 0.09m.s−1. There was a significant improvement in C between 2 and 6 min post-intervention at 10 and 20 m of 0.06m.s−1 and 0.08m.s−1. This finding suggests a maximal sprint acceleration may enhance the outcome of a subsequent maximal sprint acceleration at 2 min, but the latter results could not be directly attributed to the interventions as previous testing is likely to have influenced these outcomes

Pattern of activation of pelvic floor muscles in men differs with verbal instructions

AimsTo investigate the effect of instruction on activation of pelvic floor muscles (PFM) in men as quantified by transperineal ultrasound imaging (US) and to validate these measures with invasive EMG recordings

Characterisation of the Type III Secretion System EspO effector family in enteric pathogens

Many enteric pathogens employ a type III secretion system to translocate effector proteins directly into the host cell cytoplasm, where they subvert signalling pathways of the intestinal epithelium. Once inside the cell, effector proteins may interact with host cell proteins to control various cellular processes. This enables enteric pathogens to establish their infective niche within the human host. The T3SS effectors EspO of enterohaemorrhagic Escherichia coli and Citrobacter rodentium, OspE of Shigella flexnerie and SopO of Salmonella enterica Serovar Typhimurium are known to interact with integrin-linked kinase to enhance cellular attachment to the substratum. In this project we demonstrate that the EspO family of effectors also interacts with the anti-apoptotic regulator Hax-1 and the co-chaperone DnaJB6. Employing fluorescence microscopy we found that ectopically expressed EspO resides on large cytosolic vacuoles, which stained positive for the endoplasmic reticulum marker CREB3. Moreover, ectopic expression of EspO changed the cellular distribution of endogenous Hax-1, which co-localized with the EspO vacuoles. We found that the EspO orthologs are anti apoptotic, protecting cells from apoptosis triggered by multiple inducers including staurosporine (a global kinase inhibitor), tunicamycin (induces unfolded protein response) and thapsigargin (interferes with Ca2+ homeostasis). Additionally, EspO protects HeLa cells from the apoptosis induced in EPEC infections. Hax-1 depleted HeLa cells by siRNA showed that the anti apoptotic activity of the EspO orthologs is Hax-1 dependent. Using the C. rodentium in-vivo model of EHEC / EPEC infections, we found that deletion of espO results in decreased levels of hyperplasia similar to the uninfected control. The mutant strain also showed low levels of neutrophils and CD4+T cells, whereas the EspO complemented strain showed a dramatic increase in both inflammatory cells. These results suggest new mechanisms unique to the T3SS EspO family of effectors, which might shed new insights regarding the infection strategies followed by enteric pathogens. These results suggest new mechanisms unique to the T3SS EspO family of effectors, which might shed new insights regarding the infection strategies followed by enteric pathogens.Open Acces

Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H–Related Protein-5 (FHR5) Deposition

IgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury. Methods: To elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN. Results: M-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN. Conclusion: Our data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity

Tuberculosis Patients Blood Gene Expression Through Treatment (cured and end-of-treatment patients)

Background Accurate assessment of treatment efficacy would facilitate clinical trials of new anti-tuberculosis drugs. TB patients exhibit altered peripheral immunity which reverts during successful treatment. We hypothesised that these changes could be observed in whole blood transcriptome profiles. Methods Ex vivo blood samples from 27 pulmonary TB patients were assayed at diagnosis and during conventional treatment. RNA was processed and hybridised to Affymetrix GeneChips, to determine expression of over 47,000 transcripts. Findings There were significant changes in expression of over 4,000 genes during treatment. Rapid, large scale changes were detected, with down-regulated expression of ~1,000 genes within the first week, including inflammatory markers such as the complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B cell markers, transcription factors and signalling molecules. Interpretation The expression of many genes is drastically altered during TB disease, with components of the humoral immune response being markedly affected. The treatment-induced restoration reflects the simultaneous suppression and activation of different immune responses in TB. The rapid initial down-regulation of expression of inflammatory mediators coincides with rapid killing of actively dividing bacilli, whereas slower delayed changes occur as drugs act on dormant bacilli and as lung pathology resolves. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity. Ex vivo blood samples analysed during TB treatment. These samples are from 9 successfully cured patients at diagnosis and end-of-treatment at 26 weeks

Tuberculosis Patients Blood Gene Expression Through Treatment

Accurate assessment of treatment efficacy would facilitate clinical trials of new anti-tuberculosis drugs. TB patients exhibit altered peripheral immunity which reverts during successful treatment. We hypothesised that these changes could be observed in whole blood transcriptome profiles. Methods Ex vivo blood samples from 27 pulmonary TB patients were assayed at diagnosis and during conventional treatment. RNA was processed and hybridised to Affymetrix GeneChips, to determine expression of over 47,000 transcripts. Findings There were significant changes in expression of over 4,000 genes during treatment. Rapid, large scale changes were detected, with down-regulated expression of ~1,000 genes within the first week, including inflammatory markers such as the complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B cell markers, transcription factors and signalling molecules. Interpretation The expression of many genes is drastically altered during TB disease, with components of the humoral immune response being markedly affected. The treatment-induced restoration reflects the simultaneous suppression and activation of different immune responses in TB. The rapid initial down-regulation of expression of inflammatory mediators coincides with rapid killing of actively dividing bacilli, whereas slower delayed changes occur as drugs act on dormant bacilli and as lung pathology resolves. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity. Ex vivo blood samples analysed for 27 first episode pulmonary TB patients, at diagnosis and after 1, 2, 4 and 26 weeks of treatment

Targeting the TLR co-receptor CD14 with TLR2-derived peptides modulates immune responses to pathogens

Dysregulation of Toll-like receptor (TLR) responses to pathogens can lead to pathological inflammation or to immune hyporesponsiveness and susceptibility to infections, and may affect adaptive immune responses. TLRs are therefore attractive therapeutic targets. We assessed the potential of the TLR co-receptor CD14 as a target for therapeutics by investigating the magnitude of its influence on TLR responses. We studied the interaction of CD14 with TLR2 by conducting peptide screening and site-directed mutagenesis analysis and found TLR2 leucine-rich repeats 5, 9, 15, and 20 involved in interaction with CD14. Peptides representing these regions interacted with CD14 and enhanced TLR2- and TLR4-mediated proinflammatory responses to bacterial pathogens in vitro. Notably, the peptides’ immune boosting capacity helped to rescue proinflammatory responses of immunosuppressed sepsis patients ex vivo. In vivo, peptide treatment increased phagocyte recruitment and accelerated bacterial clearance in murine models of Gram-negative and Gram-positive bacterial peritonitis. Up-modulating CD14’s co-receptor activity with TLR2-derived peptides also enhanced antigen-induced dendritic cell (DC) maturation and interleukin-2 production and, most notably, differentially affected DC cytokine profile upon antigen stimulation, promoting a T helper 1–skewed adaptive immune response. Biochemical, cell imaging, and molecular docking studies showed that peptide binding to CD14 accelerates microbial ligand transfer from CD14 to TLR2, resulting in increased and sustained ligand occupancy of TLR2 and receptor clustering for signaling. These findings reveal the influence that CD14 exerts on TLR activities and describe a potential therapeutic strategy to amplify responses to different pathogens mediated by different TLRs by targeting the common TLR co-receptor, CD14