La PI3-kinase : De la synapse immunologique au contrôle de la prolifération T

Le contrôle de la quiescence lymphocytaire est un élément essentiel à l’homéostasie du système immunitaire. Cet état quiescent est activement maintenu par des facteurs transcriptionnels nucléaires, de la famille FoxO (Forkhead subgroup O) notamment. Cet équilibre est cependant rompu à la suite de la reconnaissance de l’antigène, ce qui déclenche la division cellulaire. Cet article fait le point des données récemment acquises sur les mécanismes moléculaires impliqués dans ce phénomène. Il décrit ainsi comment la synapse immunologique formée entre un lymphocyte T et une cellule présentant l’antigène constitue une plate-forme d’intégration au sein de laquelle il existe une production continue de 3’-phospho-inositides sous l’impulsion des phosphoinositides-3-kinases. En provoquant l’activation de la sérine-thréonine kinase Akt, ce processus stimule l’exclusion nucléaire des FoxO pour lever le frein permanent qu’ils exercent et permettre l’expansion clonale des cellules T en réponse à l’antigène.T cell clonal expansion contributing to host defense against pathogens is a tightly controlled process to maintain the homeostasis of the immune system. Our understanding of how T cell growth and proliferation are controlled following antigenic stimulation is therefore a major challenge. Antigen recognition occurs when a naive T lymphocyte contacts an antigen-presenting cell. A specialized junction enriched in T-cell receptors, costimulation molecules and signaling adaptors, called the immunological synapse, is then created for several hours between the two cell types. Recent discoveries now clarify the molecular mechanisms used by this organization to control T cell growth and proliferation. It has been established that the immunological synapse functions in fact as an integrative platform where class Ia phosphoinositide-3-kinases (PI3Ks) are recruited and activated to continuously produce high levels of 3’-phosphoinositides. These lipids regulate the localization and the activation of a wide range of PH-domain containing proteins, among which the serine-threonine kinase Akt, a downstream effector of PI3Ks, appears to be a key player. FoxO (Forkhead subgroup O) family members control in various cell systems genes implicated in apoptosis, stress resistance and cell cycle arrest, thereby contributing to maintain quiescence in unstimulated cells. In naïve T cells contacting antigen-presenting cells a rapid but also very prolonged nuclear exclusion of these transcription factors is observed downstream of Akt. Mainly, this compartmentalization process is mandatory to induce T cell growth triggered by the T cell/antigen-presenting cell interaction. These findings demonstrate that to initiate cell cycle progression the formation of the immunological synapse is an undemanding tactic used by primary T cells to securely maintain the 3’-phosphoinositide-dependent mitotic switch governed by the spatial control of FoxO transcription factors

Étude archéozoologique d’une cour d’habitat sur le site des Barbes-et-Fon-Danis à Saint-Laurent-de-Carnols (Gard, fin Ve s. av. J.‑C. début IVe s. av. J.‑C.)

Les fouilles du site des Barbes-et-Fon-Danis à Saint-Laurent-de-Carnols (Gard) ont livré un assemblage faunique datant de la période de transition entre le premier et le deuxième âge du Fer. Les résultats archéozoologiques issus de cette étude apportent avant tout de nouvelles données sur les modes alimentaires et la gestion des déchets d’origine animale pour la 2nde moitié du Ve et la 1ère moitié du IVe s. av. J.‑C. L’échantillon provient d’une cour aménagée en plein air et témoigne de pratiques alimentaires liées à une consommation exclusivement domestique des habitants installés à proximité de cette cour ayant servi de dépotoir. La faune présente témoigne d’un approvisionnement fondé sur une activité d’élevage avec la présence majoritaire de mammifères domestiques classiques (bœuf, caprinés et porc) associée à une activité cynégétique (cerf et sanglier).The excavation of Barbes-et-Fon-Danis at Saint-Laurent-de-Carnols (Gard, France) has provided a faunal assemblage dated at the transition period between the first and the second Iron Age. This archaeozoological study provides new information on dietary practices and the processing of animal waste during the 5th and 4th centuries BC. The sample comes from a courtyard and shows dietary practices related exclusively to the domestic consumption of the close inhabitants of this courtyard which was used as a rubbish dump. The faunal remains indicate a meat supply mainly based on traditional livestock (cattle, sheep, goat and pig), associated to hunting strategies (red deer and boar)

Prominent role of the Ig-like V domain in trans-interactions of nectins. Nectin3 and nectin 4 bind to the predicted C-C'-C"-D beta-strands of the nectin1 V domain.

Nectins form a family of integral molecules that belong to the immunoglobulin superfamily. Their ectodomain is made of three Ig-like domains (V, C, C). This family comprises at least five members, namely nectin1, -2, -3, -4, and poliovirus receptor (PVR), that are involved in different physiological and pathological processes. (i) Nectins are adhesion molecules localized at adherens junctions in epithelial cells. (ii) Some nectins act as poliovirus or alpha-herpesvirus receptors (nectin1). (iii) Nectin1 mutations are involved in orofacial developmental abnormalities in humans. Adhesion properties of nectins are mediated by Ca(2+)-independent homophilic and heterophilic processes through ectodomain trans-interactions. We have described a nectin trans-hetero-interaction network: nectin3 binds to nectin1, nectin2, and PVR; nectin1 also binds to nectin4. In the present study we compared the affinities of the different trans-interactions mediated by nectin1. We found that the K(D) of nectin1/nectin3 and nectin1/nectin4 interactions is 1 and 100 nm, respectively, whereas the K(D) of the nectin1-mediated homophilic interaction is 1 microm. We show that nectin1/nectin3 and nectin1/nectin4 trans-hetero-interactions were mediated through trans V to V domain interactions, whereas C domains contributed to increase the affinity of the interaction. Nectin3 and nectin4 share a common binding region in the nectin1 V domain: (i) nectin3 strongly competed with nectin4 binding, (ii) nectin3 and nectin4 binding to nectin1 was reduced by a number of monoclonal antibodies directed against the nectin1 V domain, and (iii) the glycoprotein D of herpes simplex virus-1 that binds to the V domain of nectin1 reduced nectin3 and nectin4 binding. Finally, using chimeric nectin1/PVR receptors where PVR V domain beta-strands were substituted with the corresponding regions of nectin1, the nectin3 and nectin4 minimal binding region on nectin1 V domain was mapped to the C-C'-C"-D beta-strands

Étude archéozoologique d’une cour d’habitat sur le site des Barbes-et-Fon-Danis à Saint-Laurent-de-Carnols (Gard, fin Ve s. av. J.‑C. début IVe s. av. J.‑C.)

Les fouilles du site des Barbes-et-Fon-Danis à Saint-Laurent-de-Carnols (Gard) ont livré un assemblage faunique datant de la période de transition entre le premier et le deuxième âge du Fer. Les résultats archéozoologiques issus de cette étude apportent avant tout de nouvelles données sur les modes alimentaires et la gestion des déchets d’origine animale pour la 2nde moitié du Ve et la 1ère moitié du IVe s. av. J.‑C. L’échantillon provient d’une cour aménagée en plein air et témoigne de pratiques alimentaires liées à une consommation exclusivement domestique des habitants installés à proximité de cette cour ayant servi de dépotoir. La faune présente témoigne d’un approvisionnement fondé sur une activité d’élevage avec la présence majoritaire de mammifères domestiques classiques (bœuf, caprinés et porc) associée à une activité cynégétique (cerf et sanglier).The excavation of Barbes-et-Fon-Danis at Saint-Laurent-de-Carnols (Gard, France) has provided a faunal assemblage dated at the transition period between the first and the second Iron Age. This archaeozoological study provides new information on dietary practices and the processing of animal waste during the 5th and 4th centuries BC. The sample comes from a courtyard and shows dietary practices related exclusively to the domestic consumption of the close inhabitants of this courtyard which was used as a rubbish dump. The faunal remains indicate a meat supply mainly based on traditional livestock (cattle, sheep, goat and pig), associated to hunting strategies (red deer and boar)

Use of electrochemical techniques to study the corrosion of metals in model fluoride melts

Molten fluorides are appealing coolants for innovative nuclear systems but structural alloys may undergo corrosion at high temperature. Because corrosion primarily occurs via electrochemical reactions, electrochemical techniques are ideal for the study of corrosion thermochemistry and kinetics. Examples are given. An electrochemical series was established using voltammetry in LiF-NaF at 1173 K. Stability increases in the following order: Na, Cr, Fe, Ni, Mo/W, Ag, Au. Various alloys were also classified according to their oxidation resistance. A cathodic protection method was developed to curb the intergranular attack of some nickel alloys in molten LiF-CaF₂-MgF₂-ZrF₄ containing tellurium vapor at 953 K. Voltammetry and polarization resistance measurement were used to estimate the rate of chromium selective dissolution for nickel base alloys immersed in LiF-NaF at 1073 K and 1173 K

DNAM-1 and PVR Regulate Monocyte Migration through Endothelial Junctions

DNAX accessory molecule 1 (DNAM-1; CD226) is a transmembrane glycoprotein involved in T cell and natural killer (NK) cell cytotoxicity. We demonstrated recently that DNAM-1 triggers NK cell–mediated killing of tumor cells upon engagement by its two ligands, poliovirus receptor (PVR; CD155) and Nectin-2 (CD112). In the present paper, we show that PVR and Nectin-2 are expressed at cell junctions on primary vascular endothelial cells. Moreover, the specific binding of a soluble DNAM-1–Fc molecule was detected at endothelial junctions. This binding was almost completely abrogated by anti-PVR monoclonal antibodies (mAbs), but not modified by anti–Nectin-2 mAbs, which demonstrates that PVR is the major DNAM-1 ligand on endothelial cells. Because DNAM-1 is highly expressed on leukocytes, we investigated the role of the DNAM-1–PVR interaction during the monocyte transendothelial migration process. In vitro, both anti–DNAM-1 and anti-PVR mAbs strongly blocked the transmigration of monocytes through the endothelium. Moreover, after anti–DNAM-1 or anti-PVR mAb treatment, monocytes were arrested at the apical surface of the endothelium over intercellular junctions, which strongly suggests that the DNAM-1–PVR interaction occurs during the diapedesis step. Altogether, our results demonstrate that DNAM-1 regulates monocyte extravasation via its interaction with PVR expressed at endothelial junctions on normal cells

Caractérisation phénotypique des vaches laitières portant l'haplotype " fertil+/+ " ou " fertil-/- " pour un QTL de fertilité femelle situé sur le chromosome 3

Au cours de ces dernières années, la fertilité des vaches laitières hautes productrices a fortement diminué, notamment en race Prim'Holstein. Cette baisse de fertilité est en partie liée à une intense sélection de la productivité laitière. Des études réalisées par des généticiens ont mis en évidence plusieurs QTLs (Quantitative Trait Locus) de fertilité femelle chez la vache laitière. Nous avons choisi d'étudier des vaches laitières homozygotes à l'haplotype favorable "fertil+/+" ou défavorable "fertil-/-" pour un QTL de fertilité femelle situé sur le chromosome 3 (QTL-Fert-F-BTA3), ce QTL étant impliqué dans les échecs précoces de la gestation. Plusieurs paramètres ont été étudiés sur quarante cinq génisses puis sur quarante et une vaches en première lactation. Nous avons observé que les primipares "fertil-/-" ont perdu plus de poids que les primipares "fertil+/+" dans les sept premières semaines après vêlage. Dans cette même période, la production laitière ainsi que l'ingéré alimentaire des primipares "fertil-/-" ont été inférieurs à ceux des primipares "fertil+/+". Grâce aux profils de progestérone plasmatique, nous avons constaté que les animaux "fertil+/+" ont repris leur activité ovarienne plus vite que les animaux "fertil-/-" après le vêlage. Nous avons enfin constaté un meilleur taux de réussite à la première insémination artificielle pour les animaux "fertil+/+" que pour les animaux "fertil-/-". La perte de poids après vêlage plus importante chez les animaux "fertil-/-" pourrait expliquer un allongement de l'inactivité ovarienne post-partum et une fertilité plus faible chez ces animaux par rapport aux animaux "fertil+/+"

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators

Nectin-4 is a new histological and serological tumor associated marker for breast cancer

Abstract Introduction Breast cancer is a complex and heterogeneous disease at the molecular level. Evolution is difficult to predict according to classical histoclinical prognostic factors. Different studies highlight the importance of large-scale molecular expression analyses to improve taxonomy of breast cancer and prognostic classification. Identification of new molecular markers that refine this taxonomy and improve patient management is a priority in the field of breast cancer research. Nectins are cell adhesion molecules involved in the regulation of epithelial physiology. We present here Nectin-4/PVRL4 as a new histological and serological tumor associated marker for breast carcinoma. Methods Expression of Nectin-4 protein was measured on a panel of 78 primary cells and cell lines from different origins and 57 breast tumors by FACS analysis and immunohistochemistry (IHC), respectively. mRNA expression was measured by quantitative PCR. Serum Nectin-4 was detected by ELISA and compared with CEA and CA15.3 markers, on panels of 45 sera from healthy donors, 53 sera from patients with non-metastatic breast carcinoma (MBC) at diagnosis, and 182 sera from patients with MBC. Distribution of histological/serological molecular markers and histoclinical parameters were compared using the standard Chi-2 test. Results Nectin-4 was not detected in normal breast epithelium. By contrast, Nectin-4 was expressed in 61% of ductal breast carcinoma vs 6% in lobular type. Expression of Nectin-4 strongly correlated with the basal-like markers EGFR, P53, and P-cadherin, and negatively correlated with the luminal-like markers ER, PR and GATA3. All but one ER/PR-negative tumors expressed Nectin-4. The detection of Nectin-4 in serum improves the follow-up of patients with MBC: the association CEA/CA15.3/Nectin-4 allowed to monitor 74% of these patients compared to 67% with the association CEA/CA15.3. Serum Nectin-4 is a marker of disease progression, and levels correlate with the number of metastases (P = 0.038). Serum Nectin-4 is also a marker of therapeutic efficiency and correlates, in 90% of cases, with clinical evolution. Conclusion Nectin-4 is a new tumor-associated antigen for breast carcinoma. Nectin-4 is a new bio-marker whose use could help refine breast cancer taxonomy and improve patients' follow-up. Nectin-4 emerges as a potential target for breast cancer immunotherapy.http://deepblue.lib.umich.edu/bitstream/2027.42/112418/1/12885_2007_Article_723.pd