Plasma extracellular vesicles in people living with HIV and type 2 diabetes are related to microbial translocation and cardiovascular risk

HIV and type 2 diabetes (T2D) are both associated with gut microbiota alterations, low-grade endotoxemia and increased cardiovascular risk. We investigated the potential role of plasma extracellular vesicles (EVs) in relation to these processes. Plasma EVs were isolated by size exclusion chromatography in fasting individuals with HIV and T2D (n = 16), T2D only (n = 14), HIV only (n = 20) or healthy controls (n = 19), and characterized by transmission electron microscopy, western blot, nanoparticle tracking analysis and quantitative proteomics. The findings were compared to gut microbiota alterations, lipopolysaccharide levels and cardiovascular risk profile. Individuals with concomitant HIV and T2D had higher plasma EV concentration, which correlated closely with plasma lipopolysaccharides, triglycerides and Framingham score, but not with gut microbiota alterations. Proteomic analyses identified 558 human proteins, largely related to cardiometabolic disease genes and upstream regulation of inflammatory pathways, including IL-6 and IL-1 beta, as well as 30 bacterial proteins, mostly from lipopolysaccharide-producing Proteobacteria. Our study supports that EVs are related to microbial translocation processes in individuals with HIV and T2D. Their proteomic content suggests a contributing role in low-grade inflammation and cardiovascular risk development. The present approach for exploring gut-host crosstalk can potentially identify novel diagnostic biomarkers and therapeutic targets.Peer reviewe

S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells

<p>Abstract</p> <p>Background</p> <p>The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 (psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 (calgranulin A) and S100A9 (calgranulin B) are expressed in ductal carcinoma <it>in situ </it>(DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression.</p> <p>Methods</p> <p>We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test.</p> <p>Results</p> <p>We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment.</p> <p>Conclusion</p> <p>Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.</p

Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis

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Transcriptome Analysis of Neisseria meningitidis in Human Whole Blood and Mutagenesis Studies Identify Virulence Factors Involved in Blood Survival

During infection Neisseria meningitidis (Nm) encounters multiple environments within the host, which makes rapid adaptation a crucial factor for meningococcal survival. Despite the importance of invasion into the bloodstream in the meningococcal disease process, little is known about how Nm adapts to permit survival and growth in blood. To address this, we performed a time-course transcriptome analysis using an ex vivo model of human whole blood infection. We observed that Nm alters the expression of ≈30% of ORFs of the genome and major dynamic changes were observed in the expression of transcriptional regulators, transport and binding proteins, energy metabolism, and surface-exposed virulence factors. In particular, we found that the gene encoding the regulator Fur, as well as all genes encoding iron uptake systems, were significantly up-regulated. Analysis of regulated genes encoding for surface-exposed proteins involved in Nm pathogenesis allowed us to better understand mechanisms used to circumvent host defenses. During blood infection, Nm activates genes encoding for the factor H binding proteins, fHbp and NspA, genes encoding for detoxifying enzymes such as SodC, Kat and AniA, as well as several less characterized surface-exposed proteins that might have a role in blood survival. Through mutagenesis studies of a subset of up-regulated genes we were able to identify new proteins important for survival in human blood and also to identify additional roles of previously known virulence factors in aiding survival in blood. Nm mutant strains lacking the genes encoding the hypothetical protein NMB1483 and the surface-exposed proteins NalP, Mip and NspA, the Fur regulator, the transferrin binding protein TbpB, and the L-lactate permease LctP were sensitive to killing by human blood. This increased knowledge of how Nm responds to adaptation in blood could also be helpful to develop diagnostic and therapeutic strategies to control the devastating disease cause by this microorganism

Transcriptional Profiling of Serogroup B Neisseria meningitidis Growing in Human Blood: An Approach to Vaccine Antigen Discovery

Neisseria meningitidis is a nasopharyngeal commensal of humans which occasionally invades the blood to cause septicaemia. The transcriptome of N. meningitidis strain MC58 grown in human blood for up to 4 hours was determined and around 10% of the genome was found to be differentially regulated. The nuo, pet and atp operons, involved in energy metabolism, were up-regulated, while many house-keeping genes were down-regulated. Genes encoding protein chaperones and proteases, involved in the stress response; complement resistant genes encoding enzymes for LOS sialylation and biosynthesis; and fHbp (NMB1870) and nspA (NMB0663), encoding vaccine candidates, were all up-regulated. Genes for glutamate uptake and metabolism, and biosynthesis of purine and pyrimidine were also up-regulated. Blood grown meningococci are under stress and undergo a metabolic adaptation and energy conservation strategy. The localisation of four putative outer membrane proteins encoded by genes found to be up-regulated in blood was assessed by FACS using polyclonal mouse antisera, and one (NMB0390) showed evidence of surface expression, supporting its vaccine candidacy

Propagation of Dry Habitat Fern Species Using Spore Collections from Historic Herbarium Specimens

Spores sourced from historic herbarium specimens have been used to introduce wild-collected material to the Royal Botanic Garden Edinburgh (RBGE) living plant collection. The ability of dry habitat ferns to maintain spore viability for prolonged periods makes it possible to grow plants from the historically important RBGE herbarium collections. The factors that affect the ability of spores to germinate from herbarium collections are described. Three fern species from the Pteridaceae – Actiniopteris semiflabellata, Anogramma leptophylla and Aleuritopteris scioana – which were not previously in cultivation at RBGE were germinated from herbarium material of different ages. Germination was observed from all three species. Plants produced in this experiment were accessed into the RBGE living plant collection for future horticultural research and germination trials

Beneficial effects of regular physical activity motivated at work on blood pressure and lipid status

Originales[ES] Introducción: La inactividad física se ha incrementado de forma considerable en la sociedad actual pudiendo acarrear efectos perjudiciales para la salud. El ejercicio físico regular motivado en el trabajo podría ser una intervención de promoción de la salud y preventiva con beneficios a corto y largo plazo, por lo que es importante documentar sus efectos fisiológicos. Material y métodos: Estudio de corte transversal que representa la primera parte de un estudio prospectivo donde 121 trabajadores viales, de mantenimiento y de oficina (42 mujeres y 79 hombres) recibieron un programa de motivación de actividad física. Se registró el grado de actividad física previa y actual. Se estudió el índice de masa corporal (IMC), la frecuencia cardíaca (FC), tensión arterial sistólica y diastólica (TAS, TAD), el pérfil lipídico, niveles de proteína C reactiva (PCR) y hemoglobina glicosilada (HbA1c). La captación máxima de oxígeno fue cuantificada por medio de ergoespirometría. Análisis de regresión lineal fueron utilizados para estudiar asociaciones entre las variables de estudio con la respectiva inclusión de variables de confusión.Resultados: Las mujeres presentaron un pérfil lipídico más favorable y valores de IMC y tensión arterial menores en comparación con los hombres. La actividad física regular más de dos veces por semana estuvo asociada a niveles menores de colesterol total (p = 0,013 para 2-3 veces/semana; p = 0,025 para ≥4 vez / semana) y lipoproteínas de baja densidad (LDL) (p = 0,015 para 2-3 veces/emana; p = 0,022 para ≥4 veces / semana). Los valores de TAD eran más bajos en el grupo de los que reportó actividad física regular al menos cuatro veces por semana (p = 0,026). El efecto de la actividad física regular sobre la TAD fue másevidente en hombres que en mujeres (p = 0,01). Los niveles autoreportados de actividad física mostraron correlación con los niveles de captación máxima de oxígeno medidos.Conclusión: El pérfil lipídico y los niveles de tensión arterial fueron más favorables en aquellos individuos que reportaron actividad física de forma regular a comparación de aquellos con bajos niveles de actividad física semanal. La actividad física autoreportada se hallaba asociada a los niveles de captación máxima de oxígeno medidos. [EN] Introduction: Physical inactivity is increasing considerably in the modern society and may lead to adverse health effects. Physical exercise motivated at work could be a health promotion and preventive intervention at work with short and long-term benefits. Therefore it is important to document its physiological effects. Material and methods: This cross-sectional study represents the first part of a prospective study where 121 road workers, maintenance and office (42 women and 79 men) participated in a motivational program for physical activity. Background data and level of physical activity were collected by a questionnaire. Body mass index (BMI), Maximal oxygen uptake, blood pressure, and blood samples (lipids, C-reactive protein and glycosylated hemoglobin) were obtained. Linear regression analysis was performed to study associations between the study variables with the inclusion of confounding variables. Results: A more favorable lipid status, BMI values, and lower blood pressure were found among women. Regular physical activity more than twice a week was associated with lower levels of total cholesterol (p = 0,013 twice a week; p = 0,025 more than 4 times a week), and low density lipoprotein(LDL) (p = 0,015 twice a week; p = 0,022 more than 4 times a week). Diastolic blood pressure (dBP) was lower in the group who reported regular physical activity at least four times a week (p = 0,026). The effect of regular physical activity on dBP was more evident in men than in women (p = 0,01). The intensity of self-reported physical activity was associated with the measured levels of maximal oxygen uptake.Conclusion: Exercise several times a week was associated with a more favorable lipid status and lower blood pressure compared to lower weekly activity. The intensity of self-reported physical activity was associated to the measured levels of maximal oxygen uptake.N

A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women

Development and application of statistical models for medical scientific researc