Bacillus Calmette-Guérin Induces PD-L1 Expression on Antigen-Presenting Cells via Autocrine and Paracrine Interleukin-STAT3 Circuits

Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB), and is also used as an immunotherapy for bladder cancer and other malignancies due to its immunostimulatory properties. Mycobacteria spp., however, are well known for their numerous immune evasion mechanisms that limit the true potential of their therapeutic use. One such major mechanism is the induction of programmed death ligand-1 (PD-L1), which mitigates adaptive immune responses. Here, we sought to unravel the molecular pathways behind PD-L1 up-regulation on antigen-presenting cells (APCs) by BCG. We found that infection of APCs with BCG induced PD-L1 up-regulation, but that this did not depend on direct infection, suggesting a soluble mediator for this effect. BCG induced potent quantities of IL-6 and IL-10, and the downstream transcription factor STAT3 was hyper-phosphorylated. Intracellular analyses revealed that levels of PD-L1 molecules were associated with the STAT3 phosphorylation state, suggesting a causal link. Neutralisation of the IL-6 or IL-10 cytokine receptors dampened STAT3 phosphorylation and BCG-mediated up-regulation of PD-L1 on APCs. Pharmacological inhibition of STAT3 achieved the same effect, confirming an autocrine-paracrine cytokine loop as a mechanism for BCG-mediated up-regulation of PD-L1. Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. These novel findings could lead to refinement of BCG as both a vaccine for infectious disease and as a cancer immunotherapy

Intraspecfic variation in cold-temperature metabolic phenotypes of Arabidopsis lyrata ssp petraea

Atmospheric temperature is a key factor in determining the distribution of a plant species. Alongside this, plant populations growing at the margin of their range may exhibit traits that indicate genetic differentiation and adaptation to their local abiotic environment. We investigated whether geographically separated marginal populations of Arabidopsis lyrata ssp. petraea have distinct metabolic phenotypes associated with exposure to cold temperatures. Seeds of A. petraea were obtained from populations along a latitudinal gradient, namely Wales, Sweden and Iceland and grown in a controlled cabinet environment. Mannose, glucose, fructose, sucrose and raffinose concentrations were different between cold treatments and populations, especially in the Welsh population, but polyhydric alcohol concentrations were not. The free amino acid compositions were population specific, with fold differences in most amino acids, especially in the Icelandic populations, with gross changes in amino acids, particularly those associated with glutamine metabolism. Metabolic fingerprints and profiles were obtained. Principal component analysis (PCA) of metabolite fingerprints revealed metabolic characteristic phenotypes for each population and temperature. It is suggested that amino acids and carbohydrates were responsible for discriminating populations within the PCA. Metabolite fingerprinting and profiling has proved to be sufficiently sensitive to identify metabolic differences between plant populations at different atmospheric temperatures. These findings show that there is significant natural variation in cold metabolism among populations of A. l. petraea which may signify plant adaptation to local climates

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

Background Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups

Mucosal Therapy of Multi-Drug Resistant Tuberculosis With IgA and Interferon-γ

New evidence has been emerging that antibodies can be protective in various experimental models of tuberculosis. Here, we report on protection against multidrug-resistant Mycobacterium tuberculosis (MDR-TB) infection using a combination of the human monoclonal IgA 2E9 antibody against the alpha-crystallin (Acr, HspX) antigen and mouse interferon-gamma in mice transgenic for the human IgA receptor, CD89. The effect of the combined mucosal IgA and IFN-γ; treatment was strongest (50-fold reduction) when therapy was applied at the time of infection, but a statistically significant reduction of lung bacterial load was observed even when the therapy was initiated once the infection had already been established. The protection involving enhanced phagocytosis and then neutrophil mediated killing of infected cells was IgA isotype mediated, because treatment with an IgG version of 2E9 antibody was not effective in human IgG receptor CD64 transgenic mice. The Acr antigen specificity of IgA antibodies for protection in humans has been indicated by their elevated serum levels in latent tuberculosis unlike the lack of IgA antibodies against the virulence-associated MPT64 antigen. Our results represent the first evidence for potential translation of mucosal immunotherapy for the management of MDR-TB

Factors influencing quality of life following lower limb amputation for peripheral arterial occlusive disease: a systematic review of the literature

Background: The majority of lower limb amputations are undertaken in people with peripheral arterial occlusive disease,\ud and approximately 50% have diabetes. Quality of life is an important outcome in lower limb amputations; little is known\ud about what influences it, and therefore how to improve it.\ud Objectives: The aim of this systematic review was to identify the factors that influence quality of life after lower limb\ud amputation for peripheral arterial occlusive disease.\ud Methods: MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science and Cochrane databases were searched to identify\ud articles that quantitatively measured quality of life in those with a lower limb amputation for peripheral arterial occlusive\ud disease. Articles were quality assessed by two assessors, evidence tables summarised each article and a narrative\ud synthesis was performed.\ud Study design: Systematic review.\ud Results: Twelve articles were included. Study designs and outcome measures used varied. Quality assessment scores\ud ranged from 36% to 92%. The ability to walk successfully with a prosthesis had the greatest positive impact on quality\ud of life. A trans-femoral amputation was negatively associated with quality of life due to increased difficulty in walking\ud with a prosthesis. Other factors such as older age, being male, longer time since amputation, level of social support and\ud presence of diabetes also negatively affected quality of life.\ud Conclusion: Being able to walk with a prosthesis is of primary importance to improve quality of life for people with lower\ud limb amputation due to peripheral arterial occlusive disease. To further understand and improve the quality of life of this\ud population, there is a need for more prospective longitudinal studies, with a standardised outcome measure

Boletín digital Montañeros de Aragón: Epoca IV Número 51 - julio - agosto 2016

A novel layered lead titanate with the approximate composition PbTiO2(CO3)0.3(NO3)0.35(OH) has been synthesized hydrothermally under acidic conditions. The structure has been solved and refined from X-ray and neutron powder diffraction data in the space group P -3 1 m, with cell dimensions a = 5.1787(5) Å and c = 8.5222(7) Å. The titanate layers possess a gibbsite-like structure: lead cations and oxyanions such as carbonate and nitrate are included between the layers. Upon heating the solid loses water, carbon dioxide and nitrogen dioxide and converts via a poorly crystalline intermediate phase to the perovskite PbTiO3. The conversion is complete by 550°C; continued heating results in an increase in crystallinity

The Atlantic Ocean at the last glacial maximum: 1. Objective mapping of the GLAMAP sea-surface conditions

Recent efforts of the German paleoceanographic community have resulted in a unique data set of reconstructed sea-surface temperature for the Atlantic Ocean during the Last Glacial Maximum, plus estimates for the extents of glacial sea ice. Unlike prior attempts, the contributing research groups based their data on a common definition of the Last Glacial Maximum chronozone and used the same modern reference data for calibrating the different transfer techniques. Furthermore, the number of processed sediment cores was vastly increased. Thus the new data is a significant advance not only with respect to quality, but also to quantity. We integrate these new data and provide monthly data sets of global sea-surface temperature and ice cover, objectively interpolated onto a regular 1°x1° grid, suitable for forcing or validating numerical ocean and atmosphere models. This set is compared to an existing subjective interpolation of the same base data, in part by employing an ocean circulation model. For the latter purpose, we reconstruct sea surface salinity from the new temperature data and the available oxygen isotope measurements

Inhibition of Fungi and Gram-Negative Bacteria by Bacteriocin BacTN635 Produced by Lactobacillus plantarum sp. TN635

The aim of this study was to evaluate 54 lactic acid bacteria (LAB) strains isolated from meat, fermented vegetables and dairy products for their capacity to produce antimicrobial activities against several bacteria and fungi. The strain designed TN635 has been selected for advanced studies. The supernatant culture of this strain inhibits the growth of all tested pathogenic including the four Gram-negative bacteria (Salmonella enterica ATCC43972, Pseudomonas aeruginosa ATCC 49189, Hafnia sp. and Serratia sp.) and the pathogenic fungus Candida tropicalis R2 CIP203. Based on the nucleotide sequence of the 16S rRNA gene of the strain TN635 (1,540 pb accession no FN252881) and the phylogenetic analysis, we propose the assignment of our new isolate bacterium as Lactobacillus plantarum sp. TN635 strain. Its antimicrobial compound was determined as a proteinaceous substance, stable to heat and to treatment with surfactants and organic solvents. Highest antimicrobial activity was found between pH 3 and 11 with an optimum at pH = 7. The BacTN635 was purified to homogeneity by a four-step protocol involving ammonium sulfate precipitation, centrifugal microconcentrators with a 10-kDa membrane cutoff, gel filtration Sephadex G-25, and C18 reverse-phase HPLC. SDS-PAGE analysis of the purified BacTN635, revealed a single band with an estimated molecular mass of approximately 4 kDa. The maximum bacteriocin production (5,000 AU/ml) was recorded after a 16-h incubation in Man, Rogosa, and Sharpe (MRS) medium at 30 °C. The mode of action of the partial purified BacTN635 was identified as bactericidal against Listeria ivanovii BUG 496 and as fungistatic against C. tropicalis R2 CIP203

Risk factors for high anti-HHV-8 antibody titers (≥1:51,200) in black, HIV-1 negative South African cancer patients: a case control study

Background: Infection with human herpesvirus 8 (HHV-8) is the necessary causal agent in the development of Kaposi's sarcoma (KS). Infection with HIV-1, male gender and older age all increase risk for KS. However, the geographic distribution of HHV-8 and KS both prior to the HIV/AIDS epidemic and with HIV/AIDS suggest the presence of an additional co-factor in the development of KS. Methods: Between January 1994 and October 1997, we interviewed 2576 black in-patients with cancer in Johannesburg and Soweto, South Africa. Blood was tested for antibodies against HIV-1 and HHV-8 and the study was restricted to 2191 HIV-1 negative patients. Antibodies against the latent nuclear antigen of HHV-8 encoded by orf73 were detected with an indirect immunofluorescence assay. We examined the relationship between high anti-HHV-8 antibody titers (≥1:51,200) and sociodemographic and behavioral factors using unconditional logistic regression models. Variables that were significant at p = 0.10 were included in multivariate analysis. Results: Of the 2191 HIV-1 negative patients who did not have Kaposi's sarcoma, 854 (39.0%) were positive for antibodies against HHV-8 according to the immunofluorescent assay. Among those seropositive for HHV-8, 530 (62.1%) had low titers (1:200), 227 (26.6%) had medium titers (1:51,200) and 97 (11.4%) had highest titers (1:204,800). Among the 2191 HIV-1 negative patients, the prevalence of high anti-HHV-8 antibody titers (≥1:51,200) was independently associated with increasing age (ptrend = 0.04), having a marital status of separated or divorced (p = 0.003), using wood, coal or charcoal as fuel for cooking 20 years ago instead of electricity (p = 0.02) and consuming traditional maize beer more than one time a week (p = 0.02; p-trend for increasing consumption = 0.05) although this may be due to chance given the large number of predictors considered in this analysis. Conclusions: Among HIV-negative subjects, patients with high anti-HHV-8 antibody titers are characterized by older age. Other associations that may be factors in the development of high anti- HHV-8 titers include exposure to poverty or a low socioeconomic status environment and consumption of traditional maize beer. The relationship between these variables and high anti- HHV-8 titers requires further, prospective study