Phosphorylation of CARMA1 by HPK1 is critical for NF-kappaB activation in T cells.

Activation of the NF-kappaB pathway in T cells is required for induction of an adaptive immune response. Hematopoietic progenitor kinase (HPK1) is an important proximal mediator of T-cell receptor (TCR)-induced NF-kappaB activation. Knock-down of HPK1 abrogates TCR-induced IKKbeta and NF-kappaB activation, whereas active HPK1 leads to increased IKKbeta activity in T cells. Yet, the precise molecular mechanism of this process remains elusive. Here, we show that HPK1-mediated NF-kappaB activation is dependent on the adaptor protein CARMA1. HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. In addition, CARMA1 S551A or S5549A/S551A point mutants failed to restore HPK1-mediated and TCR-mediated NF-kappaB activation and IL-2 expression in CARMA1-deficient T cells. Thus, we identify HPK1 as a kinase specific for CARMA1 and suggest HPK1-mediated phosphorylation of CARMA1 as an additional regulatory mechanism tuning the NF-kappaB response upon TCR stimulation.

Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.

Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation, decidualization, and placentation, whether there is a common molecular link that coordinates these processes remains unknown. By exploiting genetic, molecular, pharmacological, and physiological approaches, we show here that the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) delta plays a central role at various stages of pregnancy, whereas maternal PPARdelta is critical to implantation and decidualization, and embryonic PPARdelta is vital for placentation. Using trophoblast stem cells, we further elucidate that a reciprocal relationship between PPARdelta-AKT and leukemia inhibitory factor-STAT3 signaling pathways serves as a cell lineage sensor to direct trophoblast cell fates during placentation. This novel finding of stage-specific integration of maternal and embryonic PPARdelta signaling provides evidence that PPARdelta is a molecular link that coordinates implantation, decidualization, and placentation crucial to pregnancy success. This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans.

T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension.

This article introduces a new interface for T-Coffee, a consistency-based multiple sequence alignment program. This interface provides an easy and intuitive access to the most popular functionality of the package. These include the default T-Coffee mode for protein and nucleic acid sequences, the M-Coffee mode that allows combining the output of any other aligners, and template-based modes of T-Coffee that deliver high accuracy alignments while using structural or homology derived templates. These three available template modes are Expresso for the alignment of protein with a known 3D-Structure, R-Coffee to align RNA sequences with conserved secondary structures and PSI-Coffee to accurately align distantly related sequences using homology extension. The new server benefits from recent improvements of the T-Coffee algorithm and can align up to 150 sequences as long as 10,000 residues and is available from both http://www.tcoffee.org and its main mirror http://tcoffee.crg.cat.

Structure and kinematics of the Siviez-Mischabel nappe in the Mattertal (western Alps of Switzerland) = Structure et cinématique de la nappe de Siviez-Mischabel le long de la vallée de Zermatt (Alpes de Suisse occidentale)

Résumé Cette étude porte sur le flanc inverse de la nappe de Siviez-Mischabel et sur les unités tectoniques sous jacentes (zone de Stalden supérieur et zone Houillère) dans la vallée menant à Zermatt. L'étude structurale du granite permien de Randa (orthogneiss oeillé) permet de mieux comprendre les effets de la déformation alpine sur les roches de socle. La cartographie détaillée de l'orthogneiss et de son encaissant, ainsi que l'étude lithostratigraphique des terrains sédimentaires associés permettent de proposer un schéma structural et cinématique du flanc inverse de la nappe de Siviez-Mischabel et de mieux comprendre ses relations avec les unités tectoniques sous-jacentes. L'analyse structurale de l'orthogneiss de Randa et de son encaissant révèle la superposition de plusieurs phases de déformation ductile. Cet orthogneiss formé sous des conditions métamorphiques du faciès schiste vert possède une forte schistosité alpine avec au moins deux linéations d'extension. La première, L1, orientée NW-SE est associée à la mise en place de la nappe. La seconde, L2, orientée SW-NE, se corrèle au cisaillement ductile du Simplon. La quantification de la déformation au moyen de la méthode de Fry sur les faciès porphyriques donne des ellipses à rapports axiaux compris entre 1.9 et 5.3, en accord avec les valeurs obtenues par d'autres marqueurs {tourmalines étirées, fibres). Les valeurs mesurées parallèlement à L1 ou L2 sont très semblables. La méthode de Fry a nécessité une étude théorique préalable afin de vérifier son applicabilité aux orthogneiss oeillés. La méthode requiert une distribution spatiale homogène et isotrope des marqueurs utilisés. Les tests statistiques effectués ont révélé que les phénocristaux de feldspath alcalin satisfont à cette condition et qu'ils peuvent être utilisés comme marqueur de la déformation au moyen de la méthode de Fry. Les valeurs obtenues révèlent l'importance du cisaillement ductile du Simplon sur la géométrie de la nappe dans la région d'étude. Le levé cartographique a permis d'améliorer la lithostratigraphie de la base de la nappe de Siviez-Mischabel. Trois formations en position renversée peuvent être observées sous les gneiss formant le coeur de la nappe. Ces trois formations forment le coeur du synclinal de St-Niklaus qui connecte la nappe de Siviez-Mischabel à la zone de Stalden supérieur. La datation par U-Pb de zircons détritiques et magmatiques par LA-ICP-MS permet de contraindre l'âge des formations observées (probablement Carbonifère à Trias précoce). Ces données ont des répercussions importantes sur la structure de la nappe dans la région, prouvant l'existence de plusieurs plis avec des séries normales et renversées bien préservées. La définition et la datation de ces formations, ainsi que leur identification dans la-Zone- Houillère avoisinante permettent de mieux comprendre la géométrie initiale et les relations tectoniques des nappes du Pennique moyen dans la vallée de Zermatt. Summary This study investigates the overturned limb of the Siviez-Mischabel nappe and underlying tectonic units (Upper Stalden zone and Houillère zone) in the Mattertal area. Detailed structural analysis in the Permian Randa granite (augen orthogneiss) allows a better understanding of the Alpine deformation effects on basement rocks. Detailed mapping of this orthogneiss and surrounding rocks, and the study of the lithostratigraphy in the related sedimentary horizons allow the proposition of a structural and kinematic model for the overturned limb of the Siviez-Mischabel and to better understand the relations with the underlying tectonic units. The structural analysis of the Randa orthogneiss and surrounding rocks revealed the superposition of several phases of ductile deformation. This orthogneiss formed under greenschist facies metamorphic conditions displays a strong Alpine foliation with at least two stretching lineations. The first lineation, L1, is oriented NW-SE and is related to the nappe emplacement northward. The second one, L2, is related to the Simplon ductile shear zone. Strain estimation using the Fry method has been performed on porphyritic facies of the Randa orthogneiss. The obtained ellipses have axial ratios varying between 1.9 and 5.3, in agreement with strain estimation obtained from other markers (stretched turmalines, fringes). The strain values are very similar if measured parallel to L1 or to L2. A theoretical approach was necessary to verify the relevant application of the Fry method to augen orthogneiss. This method requires that the distribution of the used markers has to be homogeneous and isotropic. Statistical tests have been done and revealed that K-feldspar phenocrysts satisfy these conditions and can be used as strain markers with the Fry method. The obtained strain measurements revealed the importance of the Simplon ductile shear zone on the geometry of the nappe in the studied area. Mapping has improved the lithostratigraphy at the base of the Siviez-Mischabel nappe. Three overturned formations can be observed below the gneisses forming the core of the nappe. These three formations form the St-Niklaus syncline, which connects the Siviez-Mischabel nappe to the underlying Upper Stalden zone. U-Pb dating of detrital and magmatic zircons by LA-ICPMS allowed the age of the observed formations to be constrained (presumably Carboniferous to Early Triassic). This data has critical implications for nappe structure in the region, composed of few recumbent folds with well preserved normal and overturned limbs. The definition and dating of these formations, as well as their identification in the adjacent "Houillère Zone" improve the understanding of the geometry and tectonic relations of the Middle Penninic nappes in the Mattertal.

Palliative surgical procedures to restore shoulder function in obstetric brachial palsy. Critical analysis of Narakas' series.

Dr. Narakas intended to study a series of 61 cases of shoulder sequelae of obstetric palsy. His vast experience would have enriched our clinical knowledge of this ailment. The authors carry on with that study to clarify his therapeutic approach and share the benefit of his experience.

Tumor localization of radiolabeled antibodies against carcinoembryonic antigen in patients with carcinoma: a critical evaluation.

Purified, [131I]-labeled goat antibodies against carcinoembryonic antigen, which have been shown to localize in human carcinoma in nude mice, were injected into 27 patients with carcinoma. Patients were scanned with a scintillation camera at various intervals. In 11 patients, radioactivity was detectable in the tumor 48 hours after injection. Computerized subtraction of blood-pool radioactivity provided clearer pictures in positive cases, but in 16 patients the scans remained doubtful or negative. To study the specificity of [131I]-antibody localization, we gave some patients simultaneous injections of [125I]-labeled normal IgG. Both isotopes were measured by means of scintillation counting in tumors and normal tissues recovered after surgery. The results demonstrated that only the anti-CEA antibodies localized in tumors. However, the total antibody-derived radioactivity in the tumor was only about 0.001 of the injected dose. We conclude that, despite the present demonstration of specificity, this method of tumor detection is not yet clinically useful.

Rab3D is critical for secretory granule maturation in PC12 cells.

Neuropeptide- and hormone-containing secretory granules (SGs) are synthesized at the trans-Golgi network (TGN) as immature secretory granules (ISGs) and complete their maturation in the F-actin-rich cell cortex. This maturation process is characterized by acidification-dependent processing of cargo proteins, condensation of the SG matrix and removal of membrane and proteins not destined to mature secretory granules (MSGs). Here we addressed a potential role of Rab3 isoforms in these maturation steps by expressing their nucleotide-binding deficient mutants in PC12 cells. Our data show that the presence of Rab3D(N135I) decreases the restriction of maturing SGs to the F-actin-rich cell cortex, blocks the removal of the endoprotease furin from SGs and impedes the processing of the luminal SG protein secretogranin II. This strongly suggests that Rab3D is implicated in the subcellular localization and maturation of ISGs.

Personalized drug administrations using Support Vector Machine

The decision-making process regarding drug dose, regularly used in everyday medical practice, is critical to patients' health and recovery. It is a challenging process, especially for a drug with narrow therapeutic ranges, in which a medical doctor decides the quantity (dose amount) and frequency (dose interval) on the basis of a set of available patient features and doctor's clinical experience (a priori adaptation). Computer support in drug dose administration makes the prescription procedure faster, more accurate, objective, and less expensive, with a tendency to reduce the number of invasive procedures. This paper presents an advanced integrated Drug Administration Decision Support System (DADSS) to help clinicians/patients with the dose computing. Based on a support vector machine (SVM) algorithm, enhanced with the random sample consensus technique, this system is able to predict the drug concentration values and computes the ideal dose amount and dose interval for a new patient. With an extension to combine the SVM method and the explicit analytical model, the advanced integrated DADSS system is able to compute drug concentration-to-time curves for a patient under different conditions. A feedback loop is enabled to update the curve with a new measured concentration value to make it more personalized (a posteriori adaptation).

Répercussions de l'agression sur le métabolisme et la composition corporelle chez l'individu obèse : Nutrition de l'obèse agressé. [Repercussions of injury on metabolic and body composition factors in obese individuals : Nutrition and obese critical patients]

La réponse métabolique de l'obèse apparemment « sainen situation d'agression aiguë (polytraumatisés, traumatisés crâniens, patients chirurgicaux, grands brûlés, opérations électives) ne se distingue pas ou peu de celle de l'individu non-obèse. Cependant, les complications médicales liées à l'agression (insuffisances respiratoire et cardiaque, bronchopneumonie, infections de plaies, thrombophlébites et embolies) demeurent plus importantes chez l'obèse morbide que chez l'individu de poids normal. Grâce à l'inflation de ses réserves énergétiques, l'obèse apparemment sain est avantagé, par rapport au sujet mince, au cours d'une agression nutritionnelle chronique telle que le jeûne prolongé. Le facteur fonctionnel limitant la survie dépend avant tout de la composition corporelle initiale et du degré d'adaptation métabolique (et comportementale) en particulier du degré de conservation de la masse maigre par rapport à la masse grasse. La mobilisation accrue de la masse grasse associée à la perte de poids chez l'obèse (par rapport à son homologue non-obèse) est favorable à une prolongation de la vie, car, en brûlant davantage de graisse corporelle, la part des protéines corporelles endogènes utilisée à des fins énergétiques est plus faible. Il s'ensuit chez l'obèse qu'un niveau de masse maigre critique pour la survie n'est atteint qu'après une réduction très marquée de ses réserves énergétiques. En revanche, le sujet mince perd davantage de masse maigre lors de l'amaigrissement et, par conséquent, son métabolisme de repos diminuera plus rapidement que celui du sujet obèse. Cela peut constituer un avantage énergétique évident en termes d'économie d'énergie consécutive à l'adaptation métabolique, mais un inconvénient majeur quant à la durée de la survie. The metabolic response of « apparently healthyobese individuals following acute injury (multiple trauma, head injury and surgical patients, extended burns, elective surgery) is not dramatically different from that of a non-obese individuals. However, the medical complications following the injury (respiratory and cardiac insufficiency, broncho-pneumonia, infections of wounds, trombophlebitis and embolism) are more prevalent in morbid obese patients than in individuals of normal body weight. Because of a large increase in their individuals energy store, "apparently healthy" obese individuals have an advantage over very lean subjects when exposed to a chronic nutritional aggression such as total fasting. The functional limiting factor for survival depends primarily on initial body composition and the magnitude of metabolic adaptation (including behavioral adaptation). The key factor is the extent to which the fat-free mass is maintained (versus to the fat mass) during weight loss. The increased proportion of body fat mobilized during weight loss in obese patients, compared with their non-obese counterparts, favors prolonged survival, because more adipose tissue is burned off, the fraction of body protein endogenously utilized for energy purpose individuals, is smaller. This implies that obese individuals do not reach a fat-free mass "critical" for their survival until their energy stores reach very low values. In contrast, lean subject tend to lose more fat-free mass during weight loss than obese subjects and, as a result, their energy expenditure drops more rapidly. This may offer a potential advantage in terms of energy economy (more energy saving) but a major disadvantage in terms of duration of survival.

Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation.

Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.

Extension of Murray's law using a non-Newtonian model of blood flow.

BACKGROUND: So far, none of the existing methods on Murray's law deal with the non-Newtonian behavior of blood flow although the non-Newtonian approach for blood flow modelling looks more accurate. MODELING: In the present paper, Murray's law which is applicable to an arterial bifurcation, is generalized to a non-Newtonian blood flow model (power-law model). When the vessel size reaches the capillary limitation, blood can be modeled using a non-Newtonian constitutive equation. It is assumed two different constraints in addition to the pumping power: the volume constraint or the surface constraint (related to the internal surface of the vessel). For a seek of generality, the relationships are given for an arbitrary number of daughter vessels. It is shown that for a cost function including the volume constraint, classical Murray's law remains valid (i.e. SigmaR(c) = cste with c = 3 is verified and is independent of n, the dimensionless index in the viscosity equation; R being the radius of the vessel). On the contrary, for a cost function including the surface constraint, different values of c may be calculated depending on the value of n. RESULTS: We find that c varies for blood from 2.42 to 3 depending on the constraint and the fluid properties. For the Newtonian model, the surface constraint leads to c = 2.5. The cost function (based on the surface constraint) can be related to entropy generation, by dividing it by the temperature. CONCLUSION: It is demonstrated that the entropy generated in all the daughter vessels is greater than the entropy generated in the parent vessel. Furthermore, it is shown that the difference of entropy generation between the parent and daughter vessels is smaller for a non-Newtonian fluid than for a Newtonian fluid.