Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells

<p>Abstract</p> <p>Background</p> <p>Dendritic cells (DCs) connect innate and adaptive immunity, and are necessary for an efficient CD4⁺and CD8⁺T cell response after infection with <it>Mycobacterium tuberculosis </it>(Mtb). We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival.</p> <p>Results</p> <p>Infection of DCs with live Mtb (H37Ra or H37Rv) led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth.</p> <p>Conclusions</p> <p>Human DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity.</p

Recent advances in the transesterification of β-keto esters

The ability to selectively transesterify β-keto esters is a useful transformation in organic synthesis. The increasing interest in transesterification for the synthesis of compounds of pharmaceutical importance, as well as for biodiesel production, has led to the development of a variety of different approaches. This article aims to summarise recent advances in the transesterifications of β-keto esters. Particular interest has been paid to methodologies with minimal environmental impact

Mesenchymal chondroprogenitor cell origin and therapeutic potential

Mesenchymal progenitor cells, a multipotent adult stem cell population, have the ability to differentiate into cells of connective tissue lineages, including fat, cartilage, bone and muscle, and therefore generate a great deal of interest for their potential use in regenerative medicine. During development, endochondral bone is formed from a template of cartilage that transforms into bone; however, mature articular cartilage remains in the articulating joints, where its principal role is reducing friction and dispersing mechanical load. Articular cartilage is prone to damage from sports injuries or ageing, which regularly progresses to more serious joint disorders, such as osteoarthritis. Osteoarthritis is a degenerative joint disease characterized by the thinning and eventual wearing of articular cartilage, and affects millions of people worldwide. Due to low chondrocyte motility and proliferative rates, and complicated by the absence of blood vessels, cartilage has a limited ability to self-repair. Current pharmaceutical and surgical interventions fail to generate repair tissue with the mechanical and cellular properties of native host cartilage. The long-term success of cartilage repair will therefore depend on regenerative methodologies resulting in the restoration of articular cartilage that closely duplicates the native tissue. For cell-based therapies, the optimal cell source must be readily accessible with easily isolated, abundant cells capable of collagen type II and sulfated proteoglycan production in appropriate proportions. Although a cell source with these therapeutic properties remains elusive, mesenchymal chondroprogenitors retain their expansion capacity with the promise of reproducing the structural or biomechanical properties of healthy articular cartilage. As current knowledge regarding chondroprogenitors is relatively limited, this review will focus on their origin and therapeutic application

Evaluation of the Efficacy and Safety of a Marine-Derived Bacillus Strain for Use as an In-Feed Probiotic for Newly Weaned Pigs

peer-reviewedForty eight individual pigs (8.7±0.26 kg) weaned at 28±1 d of age were used in a 22-d study to evaluate the effect of oral administration of a Bacillus pumilus spore suspension on growth performance and health indicators. Treatments (n = 16) were: (1) non-medicated diet; (2) medicated diet with apramycin (200 mg/kg) and pharmacological levels of zinc oxide (2,500 mg zinc/kg) and (3) B. pumilus diet (non-medicated diet + 1010 spores/day B. pumilus). Final body weight and average daily gain tended to be lower (P = 0.07) and feed conversion ratio was worsened (P<0.05) for the medicated treatment compared to the B. pumilus treatment. Ileal E. coli counts were lower for the B. pumilus and medicated treatments compared to the non-medicated treatment (P<0.05), perhaps as a result of increased ileal propionic acid concentrations (P<0.001). However, the medicated treatment reduced fecal (P<0.001) and cecal (P<0.05) Lactobacillus counts and tended to reduce the total cecal short chain fatty acid (SCFA) concentration (P = 0.10). Liver weights were lighter and concentrations of liver enzymes higher (P<0.05) in pigs on the medicated treatment compared to those on the non-medicated or B. pumilus treatments. Pigs on the B. pumilus treatment had lower overall lymphocyte and higher granulocyte percentages (P<0.001) and higher numbers of jejunal goblet cells (P<0.01) than pigs on either of the other two treatments or the non-medicated treatment, respectively. However, histopathological examination of the small intestine, kidneys and liver revealed no abnormalities. Overall, the B. pumilus treatment decreased ileal E. coli counts in a manner similar to the medicated treatment but without the adverse effects on growth performance, Lactobacillus counts, cecal SCFA concentration and possible liver toxicity experienced with the medicated treatment.The study was funded by the Higher Education Authority/Institutes of Technology Ireland Technological Sector Research Strand III Programme

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.

A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.This work was supported by the National Institutes of Health (R37AI054503, LR, R01NS082567, CBM, 5F30HL110455, RB, 1DP2-OD008614, DMT), the Wellcome Trust (LR), the National Institute of Health Research Cambridge Biomedical Research Centre (LR), the Health Research Board of Ireland (HRA_POR/2013/387, MO’S and CSA/2012/16, JK), and The Royal City of Dublin Hospital Trust (Grant 146, JK).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cell.2016.02.034

Wet scavenging of soluble gases in DC3 deep convective storms using WRF-Chem simulations and aircraft observations

We examine wet scavenging of soluble trace gases in storms observed during the Deep Convective Clouds and Chemistry (DC3) field campaign. We conduct high-resolution simulations with the Weather Research and Forecasting model with Chemistry (WRF-Chem) of a severe storm in Oklahoma. The model represents well the storm location, size, and structure as compared with Next Generation Weather Radar reflectivity, and simulated CO transport is consistent with aircraft observations. Scavenging efficiencies (SEs) between inflow and outflow of soluble species are calculated from aircraft measurements and model simulations. Using a simple wet scavenging scheme, we simulate the SE of each soluble species within the error bars of the observations. The simulated SEs of all species except nitric acid (HNO_3) are highly sensitive to the values specified for the fractions retained in ice when cloud water freezes. To reproduce the observations, we must assume zero ice retention for formaldehyde (CH_2O) and hydrogen peroxide (H_2O_2) and complete retention for methyl hydrogen peroxide (CH_3OOH) and sulfur dioxide (SO_2), likely to compensate for the lack of aqueous chemistry in the model. We then compare scavenging efficiencies among storms that formed in Alabama and northeast Colorado and the Oklahoma storm. Significant differences in SEs are seen among storms and species. More scavenging of HNO_3 and less removal of CH_3OOH are seen in storms with higher maximum flash rates, an indication of more graupel mass. Graupel is associated with mixed-phase scavenging and lightning production of nitrogen oxides (NO_x), processes that may explain the observed differences in HNO_3 and CH_3OOH scavenging

TRAIL-Expressing Monocyte/Macrophages Are Critical for Reducing Inflammation and Atherosclerosis.

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease

Choosing Short: An Explanation of the Similarities and Dissimilarities in the Distribution Patterns of Binding and Covaluation

Covaluation is the generalization of coreference introduced by Tanya Reinhart. Covaluation distributes in patterns that are very similar yet not entirely identical to those of binding. On a widespread view, covaluation and binding distribute similarly because binding is defined in terms of covaluation. Yet on Reinhart's view, binding and covaluation are not related that way: binding pertains to syntax, covaluation does not. Naturally, the widespread view can easily explain the similarities between binding and covaluation, whereas Reinhart can easily explain the dissimilarities. Reciprocally, the widespread view finds it harder to explain the dissimilarities, whereas Reinhart finds it harder to explain the similarities. Reinhart and others have proposed more than one explanation of the similarities, but as I argue, these explanations do not work. Hence although I adopt Reinhart's view, I propose a new explanation of the similarities and dissimilarities between binding and covaluation: While Reinhart has invoked semantic structure only to explain dissimilarities, I do so to explain both similarities and dissimilarities at once. Finally, I examine in light of this approach the topics of language acquisition, only-constructions, the identity predicate, the Partee/Bach/Higginbotham problem, the Dahl puzzle and its recent versions by Roelofsen

A queer politics of emotion: reimagining sexualities and schooling

peer-reviewedThis paper draws together Hochschild’s (1979; 1983) concepts of emotional labour and feeling rules with Ahmed’s affective economies (2004a, 2004b; 2008; 2010) and queer phenomenology (2006a, 2006b) as a way to address wider questions about sexuality and schooling. It highlights the value of the everyday politics of emotion for elucidating and clarifying the specificities, pertinence and complementarities of Hochschild’s and Ahmed’s work for reimagining the relationship between sexualities and schooling. The combination of their approaches allows for a focus on the individual, bodily management of emotions while demonstrating the connectedness of bodies and spaces. It enables disruption of ‘inclusive’ and ‘progressive’ educational approaches that leave heterosexuality uninterrupted and provides insight into how power works in and across the bodies, discourses, practices, relations and spaces of schools to maintain a collective orientation towards heterosexuality. It also counters linear narratives of progressive change, elucidating how change is a hopeful but messy process of simultaneous constraint, transgression and transformation. Key moments from a three-year study with LGBT-Q teachers entering into civil partnerships (CP) in Ireland serve as exploratory examples of the theoretical ideas put forward in this paper.ACCEPTEDpeer-reviewe

WS16.1 Clinical Outcomes of Real-World Kalydeco (CORK) study – Investigating the impact of CFTR potentiation on the intestinal microbiota, exocrine pancreatic function and intestinal inflammation prospectively over 12 months

peer-reviewedAbstracts of the 38th European Cystic Fibrosis ConferenceObjectives Ivacaftor is effective in the treatment of patients with CF and the G551D gating mutation. We present faecal analysis results of the CORK cohort, a single-centre, adult (n = 20), prospective, longitudinal study of G551D clinical responders (median follow-up 12 months), examining the gut microbiota, exocrine pancreatic function and intestinal inflammation on a 3 monthly basis after commencing treatment