234 research outputs found
La PI3-kinase : De la synapse immunologique au contrÎle de la prolifération T
Le contrĂŽle de la quiescence lymphocytaire est un Ă©lĂ©ment essentiel Ă lâhomĂ©ostasie du systĂšme immunitaire. Cet Ă©tat quiescent est activement maintenu par des facteurs transcriptionnels nuclĂ©aires, de la famille FoxO (Forkhead subgroup O) notamment. Cet Ă©quilibre est cependant rompu Ă la suite de la reconnaissance de lâantigĂšne, ce qui dĂ©clenche la division cellulaire. Cet article fait le point des donnĂ©es rĂ©cemment acquises sur les mĂ©canismes molĂ©culaires impliquĂ©s dans ce phĂ©nomĂšne. Il dĂ©crit ainsi comment la synapse immunologique formĂ©e entre un lymphocyte T et une cellule prĂ©sentant lâantigĂšne constitue une plate-forme dâintĂ©gration au sein de laquelle il existe une production continue de 3â-phospho-inositides sous lâimpulsion des phosphoinositides-3-kinases. En provoquant lâactivation de la sĂ©rine-thrĂ©onine kinase Akt, ce processus stimule lâexclusion nuclĂ©aire des FoxO pour lever le frein permanent quâils exercent et permettre lâexpansion clonale des cellules T en rĂ©ponse Ă lâantigĂšne.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 3â-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 naĂŻve 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 3â-phosphoinositide-dependent mitotic switch governed by the spatial control of FoxO transcription factors
Ătude archĂ©ozoologique dâune cour dâhabitat sur le site des Barbes-et-Fon-Danis Ă Saint-Laurent-de-Carnols (Gard, fin Ve s. av. J.âC. dĂ©but IVe s. av. J.âC.)
Les fouilles du site des Barbes-et-Fon-Danis Ă Saint-Laurent-de-Carnols (Gard) ont livrĂ© un assemblage faunique datant de la pĂ©riode de transition entre le premier et le deuxiĂšme Ăąge du Fer. Les rĂ©sultats archĂ©ozoologiques issus de cette Ă©tude apportent avant tout de nouvelles donnĂ©es sur les modes alimentaires et la gestion des dĂ©chets dâorigine animale pour la 2nde moitiĂ© du Ve et la 1Ăšre moitiĂ© du IVe s. av. J.âC. LâĂ©chantillon provient dâune cour amĂ©nagĂ©e en plein air et tĂ©moigne de pratiques alimentaires liĂ©es Ă une consommation exclusivement domestique des habitants installĂ©s Ă proximitĂ© de cette cour ayant servi de dĂ©potoir. La faune prĂ©sente tĂ©moigne dâun approvisionnement fondĂ© sur une activitĂ© dâĂ©levage avec la prĂ©sence majoritaire de mammifĂšres domestiques classiques (bĆuf, caprinĂ©s et porc) associĂ©e Ă une activitĂ© cynĂ©gĂ©tique (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
Ătude archĂ©ozoologique dâune cour dâhabitat sur le site des Barbes-et-Fon-Danis Ă Saint-Laurent-de-Carnols (Gard, fin Ve s. av. J.âC. dĂ©but IVe s. av. J.âC.)
Les fouilles du site des Barbes-et-Fon-Danis Ă Saint-Laurent-de-Carnols (Gard) ont livrĂ© un assemblage faunique datant de la pĂ©riode de transition entre le premier et le deuxiĂšme Ăąge du Fer. Les rĂ©sultats archĂ©ozoologiques issus de cette Ă©tude apportent avant tout de nouvelles donnĂ©es sur les modes alimentaires et la gestion des dĂ©chets dâorigine animale pour la 2nde moitiĂ© du Ve et la 1Ăšre moitiĂ© du IVe s. av. J.âC. LâĂ©chantillon provient dâune cour amĂ©nagĂ©e en plein air et tĂ©moigne de pratiques alimentaires liĂ©es Ă une consommation exclusivement domestique des habitants installĂ©s Ă proximitĂ© de cette cour ayant servi de dĂ©potoir. La faune prĂ©sente tĂ©moigne dâun approvisionnement fondĂ© sur une activitĂ© dâĂ©levage avec la prĂ©sence majoritaire de mammifĂšres domestiques classiques (bĆuf, caprinĂ©s et porc) associĂ©e Ă une activitĂ© cynĂ©gĂ©tique (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-CaFâ-MgFâ-ZrFâ 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 cellâmediated 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-1âFc molecule was detected at endothelial junctions. This binding was almost completely abrogated by anti-PVR monoclonal antibodies (mAbs), but not modified by antiâNectin-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-1âPVR interaction during the monocyte transendothelial migration process. In vitro, both antiâDNAM-1 and anti-PVR mAbs strongly blocked the transmigration of monocytes through the endothelium. Moreover, after antiâDNAM-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-1âPVR 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 laitiÚres portant l'haplotype " fertil+/+ " ou " fertil-/- " pour un QTL de fertilité femelle situé sur le chromosome 3
Au cours de ces derniĂšres annĂ©es, la fertilitĂ© des vaches laitiĂšres hautes productrices a fortement diminuĂ©, notamment en race Prim'Holstein. Cette baisse de fertilitĂ© est en partie liĂ©e Ă une intense sĂ©lection de la productivitĂ© laitiĂšre. Des Ă©tudes rĂ©alisĂ©es par des gĂ©nĂ©ticiens ont mis en Ă©vidence plusieurs QTLs (Quantitative Trait Locus) de fertilitĂ© femelle chez la vache laitiĂšre. Nous avons choisi d'Ă©tudier des vaches laitiĂšres homozygotes Ă l'haplotype favorable "fertil+/+" ou dĂ©favorable "fertil-/-" pour un QTL de fertilitĂ© femelle situĂ© sur le chromosome 3 (QTL-Fert-F-BTA3), ce QTL Ă©tant impliquĂ© dans les Ă©checs prĂ©coces de la gestation. Plusieurs paramĂštres ont Ă©tĂ© Ă©tudiĂ©s sur quarante cinq gĂ©nisses puis sur quarante et une vaches en premiĂšre lactation. Nous avons observĂ© que les primipares "fertil-/-" ont perdu plus de poids que les primipares "fertil+/+" dans les sept premiĂšres semaines aprĂšs vĂȘlage. Dans cette mĂȘme pĂ©riode, la production laitiĂšre ainsi que l'ingĂ©rĂ© alimentaire des primipares "fertil-/-" ont Ă©tĂ© infĂ©rieurs Ă ceux des primipares "fertil+/+". GrĂące aux profils de progestĂ©rone plasmatique, nous avons constatĂ© que les animaux "fertil+/+" ont repris leur activitĂ© ovarienne plus vite que les animaux "fertil-/-" aprĂšs le vĂȘlage. Nous avons enfin constatĂ© un meilleur taux de rĂ©ussite Ă la premiĂšre insĂ©mination artificielle pour les animaux "fertil+/+" que pour les animaux "fertil-/-". La perte de poids aprĂšs vĂȘlage plus importante chez les animaux "fertil-/-" pourrait expliquer un allongement de l'inactivitĂ© ovarienne post-partum et une fertilitĂ© 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
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