Insights Into the Effects of Mucosal Epithelial and Innate Immune Dysfunction in Older People on Host Interactions With Streptococcus pneumoniae

In humans, nasopharyngeal carriage of Streptococcus pneumoniae is common and although primarily asymptomatic, is a pre-requisite for pneumonia and invasive pneumococcal disease (IPD). Together, these kill over 500,000 people over the age of 70 years worldwide every year. Pneumococcal conjugate vaccines have been largely successful in reducing IPD in young children and have had considerable indirect impact in protection of older people in industrialized country settings (herd immunity). However, serotype replacement continues to threaten vulnerable populations, particularly older people in whom direct vaccine efficacy is reduced. The early control of pneumococcal colonization at the mucosal surface is mediated through a complex array of epithelial and innate immune cell interactions. Older people often display a state of chronic inflammation, which is associated with an increased mortality risk and has been termed ‘Inflammageing’. In this review, we discuss the contribution of an altered microbiome, the impact of inflammageing on human epithelial and innate immunity to S. pneumoniae, and how the resulting dysregulation may affect the outcome of pneumococcal infection in older individuals. We describe the impact of the pneumococcal vaccine and highlight potential research approaches which may improve our understanding of respiratory mucosal immunity during pneumococcal colonization in older individuals

Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylateinhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents

Cooperative secretions facilitate host range expansion in bacteria

The majority of emergent human pathogens are zoonotic in origin, that is, they can transmit to humans from other animals. Understanding the factors underlying the evolution of pathogen host range is therefore of critical importance in protecting human health. There are two main evolutionary routes to generalism: organisms can tolerate multiple environments or they can modify their environments to forms to which they are adapted. Here we use a combination of theory and a phylogenetic comparative analysis of 191 pathogenic bacterial species to show that bacteria use cooperative secretions that modify their environment to extend their host range and infect multiple host species. Our results suggest that cooperative secretions are key determinants of host range in bacteria, and that monitoring for the acquisition of secreted proteins by horizontal gene transfer can help predict emerging zoonoses

Variable protection against experimental broiler necrotic enteritis after immunization with the C-terminal fragment of Clostridium perfringens alpha-toxin and a non-toxic NetB variant

This is the final version of the article. Available from the publisher via the DOI in this record.Necrotic enteritis toxin B (NetB) is a pore-forming toxin produced by Clostridium perfringens and has been shown to play a key role in avian necrotic enteritis, a disease causing significant costs to the poultry production industry worldwide. The aim of this work was to determine whether immunization with a non-toxic variant of NetB (NetB W262A) and the C-terminal fragment of C. perfringens alpha-toxin (CPA247-370) would provide protection against experimental necrotic enteritis. Immunized birds with either antigen or a combination of antigens developed serum antibody levels against NetB and CPA. When CPA247-370 and NetB W262A were used in combination as immunogens, an increased protection was observed after oral challenge by individual dosing, but not after in-feed-challenge

Folding of xylan onto cellulose fibrils in plant cell walls revealed by solid-state NMR

Exploitation of plant lignocellulosic biomass is hampered by our ignorance of the molecular basis for its properties such as strength and digestibility. Xylan, the most prevalent non-cellulosic polysaccharide, binds to cellulose microfibrils. The nature of this interaction remains unclear, despite its importance. Here we show that the majority of xylan, which forms a threefold helical screw in solution, flattens into a twofold helical screw ribbon to bind intimately to cellulose microfibrils in the cell wall. $^{13}$C solid-state magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy, supported by in silico predictions of chemical shifts, shows both two- and threefold screw xylan conformations are present in fresh Arabidopsis stems. The twofold screw xylan is spatially close to cellulose, and has similar rigidity to the cellulose microfibrils, but reverts to the threefold screw conformation in the cellulose-deficient irx3 mutant. The discovery that induced polysaccharide conformation underlies cell wall assembly provides new principles to understand biomass properties.This work was part supported by BBSRC Grant BB/G016240/1 via The BBSRC Sustainable Bioenergy Cell Wall Sugars Programme. ODB and ERdA are grateful to CNPq for financial support for this work via Grants # 159341/2011-6 and 206278/2014-4. ACP is grateful to the Royal Society for a Newton International Fellowship. PD is supported by the Leverhulme Trust grant for the Centre for Natural Material Innovation. The UK 850 MHz solid-state NMR Facility used in this research was funded by EPSRC and BBSRC, as well as the University of Warwick including via part funding through Birmingham Science City Advanced Materials Projects 1 and 2 supported by Advantage West Midlands (AWM) and the European Regional Development Fund (ERDF). (Contract reference PR140003 for work after 5 January 2015). DFT calculations of NMR parameters were performed at the Centre for Scientific Computing at the University of Warwick

The role of Isocitrate Lyase (ICL1) in the metabolic adaptation of Candida albicans biofilms

Background A major characteristic of Candida biofilm cells that differentiates them from free-floating cells is their high tolerance to antifungal drugs. This high resistance is attributed to particular biofilm properties, including the accumulation of extrapolymeric substances, morphogenetic switching, and metabolic flexibility. Objectives This study evaluated the roles of metabolic processes (in particular the glyoxylate cycle) on biofilm formation, antifungal drug resistance, morphology, and cell wall components. Methods Growth, adhesion, biofilm formation, and cell wall carbohydrate composition were quantified for isogenic Candida albicans ICL1/ICL1, ICL1/icl1, and icl1/icl1 strains. The morphology and topography of these strains were compared by light microscopy and scanning electron microscopy. FKS1 (glucan synthase), ERG11 (14-α-demethylase), and CDR2 (efflux pump) mRNA levels were quantified using qRT-PCR. Results The ICL1/icl1 and icl1/icl1 strains formed similar biofilms and exhibited analogous drug-tolerance levels to the control ICL1/ICL1 strains. Furthermore, the drug sequestration ability of β-1, 3-glucan, a major carbohydrate component of the extracellular matrix, was not impaired. However, the inactivation of ICL1 did impair morphogenesis. ICL1 deletion also had a considerable effect on the expression of the FKS1, ERG11, and CDR2 genes. FKS1 and ERG11 were upregulated in ICL1/icl1 and icl1/icl1 cells throughout the biofilm developmental stages, and CDR2 was upregulated at the early phase. However, their expression was downregulated compared to the control ICL1/ICL1 strain. Conclusions We conclude that the glyoxylate cycle is not a specific determinant of biofilm drug resistance

Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders

Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Background The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Methods In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. Results A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .)

Fatigue and Recovery Time Course After Female Soccer Matches: A Systematic Review And Meta-analysis.

BACKGROUND: This study aimed to analyze the extent of fatigue responses after female soccer matches and the ensuing recovery time course of performance, physiological, and perceptual responses. METHODS: Three databases (PubMed, Web of Science, and SPORTDiscus) were searched in October 2020 and updated in November 2021. Studies were included when participants were female soccer players, regardless of their ability level. Further, the intervention was an official soccer match with performance, physiological, or perceptual parameters collected pre- and post-match (immediately, 12 h, 24 h, 48 h, or 72 h-post). RESULTS: A total of 26 studies (n = 465 players) were included for meta-analysis. Most performance parameters showed some immediate post-match reduction (effect size [ES] = - 0.72 to - 1.80), apart from countermovement jump (CMJ; ES = - 0.04). Reduced CMJ performance occurred at 12 h (ES = - 0.38) and 24 h (ES = - 0.42) and sprint at 48 h post-match (ES = - 0.75). Inflammatory and immunological parameters responded acutely with moderate-to-large increases (ES = 0.58-2.75) immediately post-match. Creatine kinase and lactate dehydrogenase alterations persisted at 72 h post-match (ES = 3.79 and 7.46, respectively). Small-to-moderate effects were observed for increased cortisol (ES = 0.75) and reduced testosterone/cortisol ratio (ES = -0.47) immediately post-match, while negligible to small effects existed for testosterone (ES = 0.14) and estradiol (ES = 0.34). Large effects were observed for perceptual variables, with increased fatigue (ES = 1.79) and reduced vigor (ES = - 0.97) at 12 h post-match, while muscle soreness was increased immediately post (ES = 1.63) and at 24 h post-match (ES = 1.00). CONCLUSIONS: Acute fatigue exists following female soccer matches, and the performance, physiological, and perceptual parameters showed distinctive recovery timelines. Importantly, physical performance was recovered at 72 h post-match, whereas muscle damage markers were still increased at this time point. These timelines should be considered when planning training and match schedules. However, some caution should be advised given the small number of studies available on this population. REGISTRATION: The protocol for this systematic review was pre-registered on the International Prospective Register of Systematic Reviews (PROSPERO, Registration Number: CRD42021237857)