IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25.

IL-2 is crucial to T cell homeostasis, especially of CD4(+) T regulatory cells and memory CD8(+) cells, as evidenced by vigorous proliferation of these cells in vivo following injections of superagonist IL-2/anti-IL-2 antibody complexes. The mechanism of IL-2/anti-IL-2 antibody complexes is unknown owing to a lack of understanding of IL-2 homeostasis. We show that IL-2 receptor alpha (CD25) plays a crucial role in IL-2 homeostasis. Thus, prolongation of IL-2 half-life and blocking of CD25 using antibodies or CD25-deficient mice led in combination, but not alone, to vigorous IL-2-mediated T cell proliferation, similar to IL-2/anti-IL-2 antibody complexes. These data suggest an unpredicted role for CD25 in IL-2 homeostasis.

Effect of Emotion and Personality on Deviation from Purely Rational Decision-Making

Human decision-making has consistently demonstrated deviation from "pure" rationality. Emotions are a primary driver of human actions and the current study investigates how perceived emotions and personality traits may affect decision-making during the Ultimatum Game (UG). We manipulated emotions by showing images with emotional connotation while participants decided how to split money with a second player. Event-related potentials (ERPs) from scalp electrodes were recorded during the whole decision-making process. We observed significant differences in the activity of central and frontal areas when participants offered money with respect to when they accepted or rejected an offer. We found that participants were more likely to offer a higher amount of money when making their decision in association with negative emotions. Furthermore, participants were more likely to accept offers when making their decision in association with positive emotions. Honest, conscientious, and introverted participants were more likely to accept offers. Our results suggest that factors others than a rational strategy may predict economic decision-making in the UG.

Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA.

Clustering of alphavbeta3 integrin after interaction with the RGD-like integrin-binding sequence present in neuronal Thy-1 triggers formation of focal adhesions and stress fibers in astrocytes via RhoA activation. A putative heparin-binding domain is present in Thy-1, raising the possibility that this membrane protein stimulates astrocyte adhesion via engagement of an integrin and the proteoglycan syndecan-4. Indeed, heparin, heparitinase treatment and mutation of the Thy-1 heparin-binding site each inhibited Thy-1-induced RhoA activation, as well as formation of focal adhesions and stress fibers in DI TNC(1) astrocytes. These responses required both syndecan-4 binding and signaling, as evidenced by silencing syndecan-4 expression and by overexpressing a syndecan-4 mutant lacking the intracellular domain, respectively. Furthermore, lack of RhoA activation and astrocyte responses in the presence of a PKC inhibitor or a dominant-negative form of PKCalpha implicated PKCalpha and RhoA activation in these events. Therefore, combined interaction of the astrocyte alphavbeta3-integrin-syndecan-4 receptor pair with Thy-1, promotes adhesion to the underlying matrix via PKCalpha- and RhoA-dependent pathways. Importantly, signaling events triggered by such receptor cooperation are shown here to be the consequence of cell-cell rather than cell-matrix interactions. These observations are likely to be of widespread biological relevance because Thy-1-integrin binding is reportedly relevant to melanoma invasion, monocyte transmigration through endothelial cells and host defense mechanisms.

Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

BACKGROUND: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. METHODS: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (psi) and population attributable risks (PAR). RESULTS: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (psi = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). CONCLUSIONS: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases.

Interaction of alpha-melanotropin with central dopamine systems: role of hormonal state and molecular structure

The tubero-infundibular and nigrostriatal DA neurone systems of rats respond to systemic (i.p.) injection of alpha-MSH (2-100 microgram/kg). The response of the tubero-infundibular (arcuate) DA neurones, an increase in cellular fluorescence intensity which can be interpreted as a sign of increased neuronal activity, is essentially the same in males, estrogen-progesterone-pretreated ovariectomized females and hypophysectomized males, whereas the type of response elicited by alpha-MSH in the nigral DA neurones depends upon the hormonal state of the animal. Differences between the two DA neurone groups exist also with regard to the effects of peptide fragments containing the two active sites of the alpha-MSH molecule. Results of lesion experiments in the lower brainstem (area postrema) and of blockade of muscarinic mechanisms by atropine further point to differences in the mechanisms underlying the peptide effects on the two neurone systems. The reaction of the tubero-infundibular DA system (which controls the pars intermedia of the pituitary) can be considered to reflect the activation of a feedback mechanism on MSH secretion, while the functional counterpart of the changes observed in the nigral system remains unknown at the present time.

Développement de la communication intentionnelle gestuelle à partir des usages culturels des objets dans l'interaction triadique enfant-objet-adulte

Pour que deux protagonistes parviennent à communiquer, ils doivent non seulement partager les signes verbaux et/ou non verbaux qu'ils utilisent, mais ils doivent également parvenir à accéder à l'intention communicative de chacun. Ce dernier aspect de la communication a été intimement lié aux significations et aux connaissances que les protagonistes partagent (angl. common ground). Malgré le fait que l'importance des significations partagées ait été soulignée dans la littérature concernant la communication entre adultes, cet aspect n'a pas été étudié en ce qui concerne le développement précoce de la communication. Dans le présent travail, nous suggérons d'investiguer le lien entre les significations partagées entre le jeune enfant et l'adulte et la capacité de l'enfant à communiquer de manière intentionnelle via des gestes. En nous appuyant sur l'approche de la Pragmatique de l'Objet (Moro & Rodríguez, 2005), nous suggérons que les connaissances concernant l'usage culturel de l'objet que construit progressivement l'enfant représentent un type de significations que l'enfant partage avec autrui. 12 dyades mère-enfant ont été enregistrées à l'aide d'une caméra lors d'interactions avec quatre objets. Les observations ont eu lieu au domicile des familles et ont été conduites chaque deuxième mois lorsque les enfants ont été âgés de 8 à 16 mois (groupe 1) et de 16 à 24 mois (groupe 2). Les observations ont été codées pour le niveau de maîtrise de l'usage culturel par l'enfant ainsi que pour la production de gestes par l'enfant et par l'adulte. Nous avons trouvé que plus l'enfant maîtrise les usages culturels des objets, plus il produit de gestes, et plus ces gestes remplissent une fonction communicative explicite. Concernant les gestes de l'adulte, les résultats dévoilent que plus l'enfant maîtrise les usages conventionnels des objets, plus l'adulte adresse des gestes communicatifs à l'enfant, plus ses gestes sont produits de manière complexe et plus l'intention des gestes communicatifs de l'adulte est complexe. Pris ensemble, ces résultats suggèrent que le partage de significations sur l'usage culturel des objets représente un type de connaissances communes qui permettent au bébé et à ses protagonistes de communiquer.

Interaction between widening of diameter of abdominal aorta and cardiovascular risk factors and atherosclerosis burden.

The aim of this study was to investigate influence of traditional cardiovascular risk factors (CVRF) and subclinical atherosclerosis (ATS) burden on early stages of abdominal aortic diameter (AAD) widening among adults. 2,052 consecutive patients (P) (39 % women), mean age 52 ± 13 years, were prospectively screened for CVRF, ATS, and AAD. B-mode ultrasound was used to evaluate the largest AAD and to detect carotid and femoral atherosclerotic plaques. Mean AAD was 15.2 ± 2.8 mm. Atherosclerotic plaques were detected in 71 % of patients. Significant univariate correlation between AAD, traditional CVRF, and ABS was found. However, multiple regression analysis showed that only seven of them were significantly and weakly correlated with AAD (R² = 0.27, p < 0.001). On the other hand, a multivariate logistic analysis was used to evaluate CVRF impact on enlarged AAD ≥25 mm (EAAD) as compared to those with AAD <25 mm. These factors did not account for more than 30 % of interaction (R² = 0.30, p = 0.001). Furthermore, despite a large proportion of patients with high number of CVRF, and subclinical ATS, rate of patients with AAD ≥25 mm was low (1 %) and scattered regardless their CHD risk score or ATS burden. In conclusion, these results suggest that although some traditional CVRF and presence of ATS are associated with early stages of EAAD, other determinants still need to be identified for a better understanding of abdominal aortic aneurysm pathogenesis.

Shaping the interaction landscape of bioactive molecules.

MOTIVATION: Most bioactive molecules perform their action by interacting with proteins or other macromolecules. However, for a significant fraction of them, the primary target remains unknown. In addition, the majority of bioactive molecules have more than one target, many of which are poorly characterized. Computational predictions of bioactive molecule targets based on similarity with known ligands are powerful to narrow down the number of potential targets and to rationalize side effects of known molecules. RESULTS: Using a reference set of 224 412 molecules active on 1700 human proteins, we show that accurate target prediction can be achieved by combining different measures of chemical similarity based on both chemical structure and molecular shape. Our results indicate that the combined approach is especially efficient when no ligand with the same scaffold or from the same chemical series has yet been discovered. We also observe that different combinations of similarity measures are optimal for different molecular properties, such as the number of heavy atoms. This further highlights the importance of considering different classes of similarity measures between new molecules and known ligands to accurately predict their targets. CONTACT: olivier.michielin@unil.ch or vincent.zoete@unil.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Immunothérapie: une nouvelle arme contre le cancer de la prostate [Immunotherapy: a therapeutic revolution against prostate cancer?].

The interaction between the immune system and cancer was an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of sipuleucel-T and ipilimumab stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies under development are therapeutic vaccination strategies, such as sipuleucel-T and PROSTVAC-VF, or immune checkpoint blockade of CTLA-4. Improved understanding of the immune responses generated by the development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide new treatment options in prostate cancer.

Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex.

Cytotoxic T cell (CTL) activation by antigen requires the specific detection of peptide-major histocompatibility class I (pMHC) molecules on the target-cell surface by the T cell receptor (TCR). We examined the effect of mutations in the antigen-binding site of a Kb-restricted TCR on T cell activation, antigen binding and dissociation from antigen.These parameters were also examined for variants derived from a Kd-restricted peptide that was recognized by a CTL clone. Using these two independent systems, we show that T cell activation can be impaired by mutations that either decrease or increase the binding half-life of the TCR-pMHC interaction. Our data indicate that efficient T cell activation occurs within an optimal dwell-time range of TCR-pMHC interaction. This restricted dwell-time range is consistent with the exclusion of either extremely low or high affinity T cells from the expanded population during immune responses.