Control of the proliferation of activated CD4+ T cells by connexins.

As expression of Cxs in cells of the immune system increases upon cellular activation, we investigated whether Cxs and especially CxHcs play a major role during T cell-mediated responses. In particular, we studied the expression of Cx43Hc following CD4(+) T cell stimulation using flow cytometry, real-time PCR, and Western blot analysis. We showed that expression of Cx43 and its phosphorylated isoforms increased in response to the engagement of CD3 and CD28. Cx43Hcs were found to be involved in sustaining proliferation of T cells, as assessed by cell cycle staining, thymidine incorporation assays, and CFSE analysis of cells exposed to mimetic peptide inhibitors of the plasma membrane Cx channels and antibodies generated to an extracellular region of Cx. The reduction of T cell proliferation mediated by Cx channel inhibitors suppressed cysteine uptake but not cytokine production. We conclude that upon antigen recognition, T cells require CxHc to sustain their clonal expansion.

Novel acid phosphatase in Candida glabrata suggests selective pressure and niche specialization in the phosphate signal transduction pathway.

Evolution through natural selection suggests unnecessary genes are lost. We observed that the yeast Candida glabrata lost the gene encoding a phosphate-repressible acid phosphatase (PHO5) present in many yeasts including Saccharomyces cerevisiae. However, C. glabrata still had phosphate starvation-inducible phosphatase activity. Screening a C. glabrata genomic library, we identified CgPMU2, a member of a three-gene family that contains a phosphomutase-like domain. This small-scale gene duplication event could allow for sub- or neofunctionalization. On the basis of phylogenetic and biochemical characterizations, CgPMU2 has neofunctionalized to become a broad range, phosphate starvation-regulated acid phosphatase, which functionally replaces PHO5 in this pathogenic yeast. We determined that CgPmu2, unlike ScPho5, is not able to hydrolyze phytic acid (inositol hexakisphosphate). Phytic acid is present in fruits and seeds where S. cerevisiae grows, but is not abundant in mammalian tissues where C. glabrata grows. We demonstrated that C. glabrata is limited from an environment where phytic acid is the only source of phosphate. Our work suggests that during evolutionary time, the selection for the ancestral PHO5 was lost and that C. glabrata neofunctionalized a weak phosphatase to replace PHO5. Convergent evolution of a phosphate starvation-inducible acid phosphatase in C. glabrata relative to most yeast species provides an example of how small changes in signal transduction pathways can mediate genetic isolation and uncovers a potential speciation gene.

Surface-to-air signals.

Powerful volatile regulators of gene expression, pheromones and other airborne signals are of great interest in biology. Plants are masters of volatile production and release, not just from flowers and fruits, but also from vegetative tissues. The controlled release of bouquets of volatiles from leaves during attack by herbivores helps plants to deter herbivores or attract their predators, but volatiles have other roles in development and in the control of defence gene expression. Some of these roles may include long-distance signalling within and perhaps between plants.

Foods, nutrients and the risk of oral and pharyngeal cancer.

Background:Besides tobacco and alcohol, dietary habits may have a relevant role in oral cavity and pharyngeal (OCP) cancer.Methods:We analysed the role of selected food groups and nutrients on OCP cancer in a case-control study carried out between 1997 and 2009 in Italy and Switzerland. This included 768 incident, histologically confirmed squamous cell carcinoma cases and 2078 hospital controls. Odds ratios (ORs) were estimated using logistic regression models including terms for tobacco, alcohol and other relevant covariates.Results:Significant inverse trends in risk were observed for all vegetables (OR=0.19, for the highest vs the lowest consumption) and all fruits (OR=0.39), whereas significant direct associations were found for milk and dairy products (OR=1.50), eggs (OR=1.71), red meat (OR=1.55), potatoes (OR=1.85) and desserts (OR=1.68), although trends in risk were significant only for potatoes and desserts. With reference to nutrients, significant inverse relations were observed for vegetable protein (OR=0.45, for the highest vs the lowest quintile), vegetable fat (OR=0.54), polyunsaturated fatty acids (OR=0.53), α-carotene (OR=0.51), β-carotene (OR=0.28), β-cryptoxanthin (OR=0.37), lutein and zeazanthin (OR=0.34), vitamin E (OR=0.26), vitamin C (OR=0.40) and total folate (OR=0.34), whereas direct ones were observed for animal protein (OR=1.57), animal fat (OR=2.47), saturated fatty acids (OR=2.18), cholesterol (OR=2.29) and retinol (OR=1.88). Combinations of low consumption of fruits and vegetables, and high consumption of meat with high tobacco and alcohol, led to 10- to over 20-fold excess risk of OCP cancer.Conclusion:Our study confirms and further quantifies that a diet rich in fruits and vegetables and poor in meat and products of animal origin has a favourable role against OCP cancer.

Prediction of cross-recognition of peptide-HLA A2 by Melan-A-specific cytotoxic T lymphocytes using three-dimensional quantitative structure-activity relationships.

The cross-recognition of peptides by cytotoxic T lymphocytes is a key element in immunology and in particular in peptide based immunotherapy. Here we develop three-dimensional (3D) quantitative structure-activity relationships (QSARs) to predict cross-recognition by Melan-A-specific cytotoxic T lymphocytes of peptides bound to HLA A*0201 (hereafter referred to as HLA A2). First, we predict the structure of a set of self- and pathogen-derived peptides bound to HLA A2 using a previously developed ab initio structure prediction approach [Fagerberg et al., J. Mol. Biol., 521-46 (2006)]. Second, shape and electrostatic energy calculations are performed on a 3D grid to produce similarity matrices which are combined with a genetic neural network method [So et al., J. Med. Chem., 4347-59 (1997)] to generate 3D-QSAR models. The models are extensively validated using several different approaches. During the model generation, the leave-one-out cross-validated correlation coefficient (q (2)) is used as the fitness criterion and all obtained models are evaluated based on their q (2) values. Moreover, the best model obtained for a partitioned data set is evaluated by its correlation coefficient (r = 0.92 for the external test set). The physical relevance of all models is tested using a functional dependence analysis and the robustness of the models obtained for the entire data set is confirmed using y-randomization. Finally, the validated models are tested for their utility in the setting of rational peptide design: their ability to discriminate between peptides that only contain side chain substitutions in a single secondary anchor position is evaluated. In addition, the predicted cross-recognition of the mono-substituted peptides is confirmed experimentally in chromium-release assays. These results underline the utility of 3D-QSARs in peptide mimetic design and suggest that the properties of the unbound epitope are sufficient to capture most of the information to determine the cross-recognition.

Who eats healthily ? A population based study among young Swiss residents

Rapport de synthèseCette recherche s'intéresse à investiguer d'une part si les résidents en Suisse entre 15 et 24 ans suivent les recommandations nutritionnelles actuelles et d'autre part, s'il y a des différences entre ceux en surpoids et ceux en poids normal. Les données sont tirées de l'Enquête Suisse sur la Santé ESS 2007. Pour notre étude, seules les 1813 personnes âgées entre 15 et 24 ans ont été sélectionnées.Dans une première analyse bivariée, l'adhérence aux recommandations alimentaires a été comparée entre hommes et femmes. Les quantités proposées par le questionnaire ESS sont: 1 à 2 portions de fruits, 3 portions de légumes et 3 portions de produits laitiers par jour, ainsi qu'un maximum de 5 portions de viande et au moins une portion de poisson par semaine. Ces quantités sont en accord avec les recommandations de la Société Suisse de Nutrition.L'adhérence aux recommandations alimentaires est plutôt basse quelque soit le genre, en particulier pour les légumes et les produits laitiers. Les femmes ont tendance à manger les quantités recommandées de fruits, légumes et viande, tandis que les hommes ont tendance à manger la quantité recommandée de produits laitiers. Pour le poisson aucune différence n'a été observée entre personnes du sexe opposé.Ensuite, les personnes en surpoids ont été comparées dans une analyse bivariée aux personnes en poids normal, en fonction du sexe. Plusieurs facteurs ont été considérés: participation à une activité physique avec essoufflement pendant au mois 20 minutes et au moins 4 jours par semaine, attitude envers leur poids corporel (satisfaction avec le poids, désir de perdre du poids et régime suivi pour perdre du poids), consommation d'alcool, de cigarettes et présence d'un état dépressif majeur. Finalement, des facteurs potentiellement confondants (âge, nationalité et lieu de domicile) ont été inclus dans une analyse multivariée.Concernant l'adhérence aux recommandations alimentaires, la seule différence significative est une consommation de légumes plus basse chez les femmes en surpoids. Seulement 4.2% des femmes en surpoids mangent 3 portions de légumes ou plus par jour comparé à 18.1% des femmes avec un poids normal. La consommation de produits laitiers est très basse dans tous les groupes, seulement environ 10% des répondants mangent les 3 portions recommandées de produits laitiers.Pour le niveau d'activité physique, aucune différence significative n'a été observée. L'analyse bivariée montre que les femmes en surpoids mangent moins de légumes, sont moins satisfaites de leur corps et ont plus souvent suivi un régime pour perdre du poids. Cependant elles ne souhaitent pas plus souvent perdre du poids en comparaison des femmes en poids normal. Les hommes en surpoids sont moins satisfaits de leur corps, désirent plus souvent perdre du poids, mais n'ont pas plus souvent suivi un régime que les hommes ayant un poids normal.Ces résultats montrent qu'il est difficile de suivre les recommandations alimentaires pour les 15-24 ans. Une recherche plus approfondie est nécessaire afin de déterminer comment ces recommandations pourraient être mieux adaptées à la vie quotidienne des jeunes. La faible consommation de produits laitiers est préoccupante, vu que la période entre l'adolescence et l'âge adulte est un moment crucial pour le développement de la densité osseuse. De nouvelles stratégies doivent être trouvées pour améliorer la consommation de produits laitiers chez les jeunes. Comme le comportement alimentaire et l'attitude envers le poids corporel diffèrent beaucoup selon le sexe, les programmes de prévention de surpoids devraient cibler les jeunes spécifiquement par sexe.

MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma.

Myeloid cell leukemia-1 (MCL1) is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared with germinal center B-cell-like DLBCL patient samples (P=2.7 × 10(-10)). Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; P=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization data of 203 DLBCL samples and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1-positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.