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Inflation of viscous magma intrusions in Earth's shallow crust often induces strain and fracturing within heterogeneous host rocks and dome‐shaped ground deformation. Most geodetic models nevertheless consider homogeneous, isotropic, and linear‐elastic media wherein stress patterns indicate the potential for failure, but without simulating actual fracturing. We present a two‐dimensional Discrete Element Method (DEM) application to simulate magma recharge in a pre‐existing laccolith intrusion. In DEM models, fractures can propagate during simulations. We systematically investigate the effect of the host rock toughness (resistance to fracturing), stiffness (resistance to deformation) and the intrusion depth, on intrusion‐induced stress, strain, displacement and spatial fracture distribution. Our results show that the spatial fracture distribution varies between two end‐members: (a) for high stiffness or low toughness host rock or a shallow intrusion: extensive cracking, multiple vertical surface fractures propagating downward and two inward‐dipping highly cracked shear zones that connect the intrusion tip with the surface; and (b) for low stiffness or high toughness host rock or a deeper intrusion: limited cracking, one central vertical fracture initiated at the surface, and two inward‐dipping fractures at the intrusion tips. Abrupt increases in surface displacement magnitude occur in response to fracturing, even at constant magma injection rates. Our modeling application provides a novel approach to considering host rock mechanical strength and fracturing during viscous magma intrusion and associated dome‐shaped ground deformation, with important implications for interpreting geodetic signals at active volcanoes and the exploitation of geothermal reservoirs and mineral deposits. Most viscous magmas are stored and solidified in the upper 1–2 km of Earth's crust and rarely reach the surface to produce explosive volcanic eruptions. At such shallow depths, these viscous magmas often form intrusions with a flat base and dome‐shaped roof, or “laccoliths.” To accommodate the emplaced volume, the deformation of the host rock produces dome‐shaped ground uplift at the surface. Geological and geophysical observations show that laccolith emplacement often coincides with intense host rock fracturing. However, most of the numerical laccolith emplacement models ignore that fracturing and severely simplify the mechanical response of the host rock. To assess the effect of host rock fracturing on ground deformation, we designed a two‐dimensional Discrete Element Method (DEM) application, which can simulate the fracturing of the host rock during magma injection. We found that varying the strength of the host rock and/or the intrusion depth controls the spatial distribution of fracturing and magnitude of the ground uplift. Our results help to understand complex interplays between the depth of magma injection and the mechanical properties of host rocks, and to improve the modeling tools used to routinely monitor magmatic activity. We present a two‐dimensional Discrete Element Method model that simulates host rock fracturing during the inflation of a magmatic laccolithThe host rock toughness and stiffness along with source depth control spatial fracture distribution between two end‐membersAt a constant injection rate, the vertical displacement maximum and lateral extent show sudden changes in response to host rock fracturing We present a two‐dimensional Discrete Element Method model that simulates host rock fracturing during the inflation of a magmatic laccolith The host rock toughness and stiffness along with source depth control spatial fracture distribution between two end‐members At a constant injection rate, the vertical displacement maximum and lateral extent show sudden changes in response to host rock fracturing

Geological mapping in the Ogaden region of SE Ethiopia, integrated with aeromagnetic data, has revealed a large dyke swarm extending SSE more than 600 km from the southern Afar margin across the Somali Plate to the Ethiopia–Somalia border. 40Ar/39Ar age dating shows that emplacement occurred at 24–27 Ma, contemporaneous with early rifting and dyking in the Red Sea. Slab-pull forces generated at the Zagros subduction zone strained the lithosphere in the Afro-Arabian plate, and dyking began to extend south from the Red Sea at c.27 Ma, extending across Afar, fed by a plume-related magma source, rather than the rift-related source prevailing along the Red Sea. Immediately south of the Afar margin, the dyke system was emplaced along the Precambrian Marda Fault Zone, and the continuation across the Ogaden may have been controlled by lithospheric weakness associated with a splay of the Marda Fault. We suggest that the Ogaden Dyke Swarm is a zone of crustal dilation continuing the Red Sea trend across the Horn of Africa and constituting the original third ‘arm’ of the Afar triple junction. Geochemical and geochronological analyses indicate that basaltic outpourings from the Ogaden Dyke Swarm flowed at least as far east as the Ethiopia–Somalia border and emanated from the same magma source as the Ethiopian flood basalts, which had erupted earlier at c.30 Ma. Dykes are emergent only occasionally and are marked at the surface by linear sand-filled troughs varying from 2 to 20 m deep caused by tensional collapse above the dyke tip. Magnetic anomalies associated with the dykes vary in width up to 1 km and likely identify dyke zones.Supplementary material:Geological map of the Marda Fault Zone and surroundings; argon dating analytical protocol and isotopic data corrected from baseline; petrographic description of representative samples of the Ogaden Dyke Swarm and analytical protocol used for geochemistry are available at http://www.geolsoc.org.uk/SUP18829.

Il n’existe pas de recommandation concernant l’intervention à réaliser en cas de tumeur de l’angle colique gauche (TACG) en occlusion. Quatre procédures se discutent : stomie de proche amont (SA), colectomie angulaire gauche (CAG), hémicolectomie gauche (HG) vraie et colectomie subtotale (CST). Le but de cette étude multicentrique était de comparer les résultats périopératoires, histologiques et de survie de ces interventions.

Le traitement de l’adénocarcinome gastrique cT2N0M0 consiste en une chimiothérapie suivi d’une gastrectomie oncologique, ou une chirurgie d’emblée dans certains cas. Le but de cette étude est d’évaluer si la chimiothérapie preopératoire offre un bénéfice chez ces patients.

T-cell antigen receptor-induced signaling requires both ZAP-70 and Lck protein-tyrosine kinases. One essential function of Lck in this process is to phosphorylate ZAP-70 and up-regulate its catalytic activity. We have previously shown that after T-cell antigen receptor stimulation, Lck binds to ZAP-70 via its Src homology 2 (SH2) domain (LckSH2) and, more recently, that Tyr319 of ZAP-70 is phosphorylated in vivo and plays a positive regulatory role. Here, we investigated the possibility that Tyr319 mediates the SH2-dependent interaction between Lck and ZAP-70. We show that a phosphopeptide encompassing the motif harboring Tyr319, YSDP, interacted with LckSH2, although with a lower affinity compared with a phosphopeptide containing the optimal binding motif, YEEI. Moreover, mutation of Tyr319 to phenylalanine prevented the interaction of ZAP-70 with LckSH2. Based on these results, a gain-of-function mutant of ZAP-70 was generated by changing the sequence Y319SDP into Y319EEI. As a result of its increased ability to bind LckSH2, this mutant induced a dramatic increase in NFAT activity in Jurkat T-cells, was hyperphosphorylated, and displayed a higher catalytic activity compared with wild-type ZAP-70. Collectively, our findings indicate that Tyr319-mediated binding of the SH2 domain of Lck is crucial for ZAP-70 activation and consequently for the propagation of the signaling cascade leading to T-cell activation.

Following T cell antigen receptor (TCR) engagement, the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. These events have been implicated in both positive and negative regulation of ZAP-70 activity and in coupling this PTK to downstream signaling pathways in T cells. We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. Indeed, overexpression in Jurkat cells and in a murine T cell hybridoma of a ZAP-70 mutant in which Tyr319 was replaced by phenylalanine (ZAP-70-Y319F) dramatically impaired anti-TCR-induced activation of the nuclear factor of activated T cells and interleukin-2 production, respectively. Surprisingly, an analogous mutation of Tyr315 had little or no effect. The inhibitory effect of ZAP-70-Y319F correlated with a substantial loss of its activation-induced tyrosine phosphorylation and up-regulation of catalytic activity, as well as with a decreased in vivo capacity to phosphorylate known ZAP-70 substrates, such as SLP-76 and LAT. Collectively, our data reveal the pivotal role of Tyr319 phosphorylation in the positive regulation of ZAP-70 and in TCR-mediated signaling.

The protein-tyrosine kinase ZAP-70 is implicated, together with the Src kinase p56(lck), in controlling the early steps of the T-cell antigen receptor (TCR) signaling cascade. To help elucidate further the mechanism by which ZAP-70 regulates these initial events, we used a dominant-negative mutant approach. We overexpressed in the Jurkat T-cell line ZAP-70 mutated on Tyr-492 and Tyr-493 in the putative regulatory loop of its kinase domain. This mutant inhibited TCR-induced activation of nuclear factor of activated T cells by interfering with both intracellular calcium increase and Ras-regulated activation of extracellular signal-regulated kinases. Moreover, TCR-induced phosphorylation of pp36-38, thought to play a role upstream of these pathways, was found to be reduced. In contrast, overexpression of wild-type ZAP-70 induced constitutive activation of nuclear factor of activated T cells. The ZAP-70 mutant studied here could be phosphorylated on tyrosine when associated to the TCR zeta chain and was able to bind p56(lck). This result demonstrates that Tyr-492 and Tyr-493 are not responsible for the Src homology domain 2-mediated association of p56(lck) with ZAP-70. Our data are most consistent with a model in which recruitment to the TCR allows ZAP-70 autophosphorylation and binding to p56(lck), which in turn phosphorylates Tyr-492 and/or Tyr-493 with consequent up-regulation of the ZAP-70 kinase activity. ZAP-70 will then be able to effectively control phosphorylation of its substrates and lead to gene activation.

Biliary amphipathic anionic polypeptide (APF) the major protein of the pigment-lipoprotein complex in bile, and calcium-binding protein (CBP) from gallstones are both small (less than 10 kDa), highly acidic, amphipathic proteins present in bile and closely associated also with pigmented areas in human gallstones. Polyclonal antibodies against APF have shown cross-reactivity with plasma high density lipoproteins (HDL). This study examines the hypothesis that APF and CBP might be closely related or even identical, and might also share common epitopes with the larger apoA-I (23 kDa). To assess this, immunoreactivity of the three delipidated, highly purified proteins was determined against a panel of 12 monoclonal antibodies (MAbs) prepared against APF and a panel of 4 MAbs against apoA-I. APF was isolated from bile by zonal ultracentrifugation. CBP was isolated from proteins precipitated from bile by CaCl2, as well as from the calcium bilirubinate shells of cholesterol gallstones, by extraction successively with methyl-t-butyl ether, methanol, and Na2EDTA, followed by Sephadex G-25 chromatography and two-stage preparative SDS-PAGE. ApoA-I was prepared by two types of chromatography: Sephacryl S200 chromatography and heparin-chromatographic immunoaffinity. Specific polyclonal antibodies to APF and apoA-I were prepared from immunized rabbits. MAbs to APF and apoA-I were prepared by immunization of mice, using standard hybridoma technique. Western blotting of APF and CBP in 15% SDS-PAGE yielded one band with an apparent molecular weight of 6.5 kDa, which, along with apoA-I, was immunostained by polyclonal antibodies to APF and apoA-I. Using 12 MAbs against APF with three types of ELISA (direct antigen binding, competitive antigen displacement, and epitope competition between antibodies), it was shown that APF and delipidated apoA-I shared six epitopes, three of which were detected also on the surface of intact HDL particles. Six other epitopes were present in APF but not apoA-I, four of which were exposed on the surface of HDL. Four MAbs against apoA-I reacted with APF and CBP. Amino acid analyses of APF and CBP were similar with 20-23% acidic and 7-11% basic amino acids and low contents of cysteine, methionine, and tyrosine; both differed from apoA-I in containing isoleucine and cysteine. Using ELISA and one MAb (no. 32) against APF, this polypeptide was detected in human plasma HDL, the pigment-lipoprotein complex in the bile of humans, dogs, and rats, and in both pigment and cholesterol gallstones.(ABSTRACT TRUNCATED AT 400 WORDS)

L’extériorisation trans-anale du côlon avec anastomose colo-anale différée (ACAD) avait été étudiée en cas de problèmes rectaux complexes. Peu de résultats étant disponibles, il s’agissait donc d’évaluer les résultats cliniques et fonctionnels de l’ACAD en situation pelvienne complexe.