Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement

Background: The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cellular processes, including cell migration. Mutations in TTC7A have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. Objectives: This study investigates the impact of TTC7A deficiency in immune homeostasis. In particular, the role of the TTC7A/phosphatidylinositol 4 kinase type III α pathway in the control of leukocyte migration and actin dynamics. Methods: Microfabricated devices were leveraged to study cell migration and actin dynamics of murine and patient-derived leukocytes under confinement at the single-cell level. Results: We show that TTC7A-deficient lymphocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositide signaling, leading to the downregulation of the phosphoinositide 3-kinase/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamics. TTC7A-associated phenotype resulted in impaired cell motility, accumulation of DNA damage, and increased cell death in dense 3-dimensional gels in the presence of chemokines. Conclusions: These results highlight a novel role of TTC7A as a critical regulator of lymphocyte migration. Impairment of this cellular function is likely to contribute to the pathophysiology underlying progressive immunodeficiency in patients.</p

Abnormal Wnt and PI3Kinase Signaling in the Malformed Intestine of lama5 Deficient Mice

Laminins are major constituents of basement membranes and are essential for tissue homeostasis. Laminin-511 is highly expressed in the intestine and its absence causes severe malformation of the intestine and embryonic lethality. To understand the mechanistic role of laminin-511 in tissue homeostasis, we used RNA profiling of embryonic intestinal tissue of lama5 knockout mice and identified a lama5 specific gene expression signature. By combining cell culture experiments with mediated knockdown approaches, we provide a mechanistic link between laminin α5 gene deficiency and the physiological phenotype. We show that laminin α5 plays a crucial role in both epithelial and mesenchymal cell behavior by inhibiting Wnt and activating PI3K signaling. We conclude that conflicting signals are elicited in the absence of lama5, which alter cell adhesion, migration as well as epithelial and muscle differentiation. Conversely, adhesion to laminin-511 may serve as a potent regulator of known interconnected PI3K/Akt and Wnt signaling pathways. Thus deregulated adhesion to laminin-511 may be instrumental in diseases such as human pathologies of the gut where laminin-511 is abnormally expressed as it is shown here

Targeting surface nucleolin with a multivalent pseudopeptide delays development of spontaneous melanoma in RET transgenic mice

<p>Abstract</p> <p>Background</p> <p>The importance of cell-surface nucleolin in cancer biology was recently highlighted by studies showing that ligands of nucleolin play critical role in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal tail of nucleolin, the HB-19 pseudopeptide, we recently reported that HB-19 treatment markedly suppressed the progression of established human breast tumor cell xenografts in the athymic nude mice without apparent toxicity.</p> <p>Methods</p> <p>The <it>in vivo </it>antitumoral action of HB-19 treatment was assessed on the spontaneous development of melanoma in the RET transgenic mouse model. Ten days old RET mice were treated with HB-19 in a prophylactic setting that extended 300 days. In parallel, the molecular basis for the action of HB-19 was investigated on a melanoma cell line (called TIII) derived from a cutaneous nodule of a RET mouse.</p> <p>Results</p> <p>HB-19 treatment of RET mice caused a significant delay in the onset of cutaneous tumors, several-months delay in the incidence of large tumors, a lower frequency of cutaneous nodules, and a reduction of visceral metastatic nodules while displaying no toxicity to normal tissue. Moreover, microvessel density was significantly reduced in tumors recovered from HB-19 treated mice compared to corresponding controls. Studies on the melanoma-derived tumor cells demonstrated that HB-19 treatment of TIII cells could restore contact inhibition, impair anchorage-independent growth, and reduce their tumorigenic potential in mice. Moreover, HB-19 treatment caused selective down regulation of transcripts coding matrix metalloproteinase 2 and 9, and tumor necrosis factor-α in the TIII cells and in melanoma tumors of RET mice.</p> <p>Conclusions</p> <p>Although HB-19 treatment failed to prevent the development of spontaneous melanoma in the RET mice, it delayed for several months the onset and frequency of cutaneous tumors, and exerted a significant inhibitory effect on visceral metastasis. Consequently, HB-19 could provide a novel therapeutic agent by itself or as an adjuvant therapy in association with current therapeutic interventions on a virulent cancer like melanoma.</p

Modélisation analytique de la puissance thermique générée par les courants de couplage à l'intérieur d'un composite supraconducteur

International audienceLorsqu'un composite supraconducteur est dans un environnement à champ magnétique variable, des courants dits de couplage sont induits. Ceux-ci, en traversant les parties résistives du composite, génèrent une puissance thermique locale. Le but de la présente contribution est de présenter un modèle permettant de calculer analytiquement et de manière précise le terme source de l'équation de la chaleur associé à cet échauffement à tout instant et en tout point de l'espace. Le modèle est ensuite appliqué à un brin réel et les résultats des simulations sont présentés et commentés

ASC2018-3LPo2A-03

International audienceIn spite of their complex geometry, CICCs have to be modelled with a rather simple description for coupling losses when operating in transient regime. Difficulties to predict AC losses in superconducting cable have already been shown in previous models such as the new analytical one developed at CEA named COLISEUM (after COupling Losses analytIcal Staged cablEs Unified Model) and CEA heuristic one MPAS. In this paper, we present a parametric analysis for coupling losses in superconducting strands and cables subjected to time-varying transverse magnetic field by using the recently developed COLISEUM. This analysis aims at understanding trends of the model in a broad domain of investigation and their associated limits of application. We show that for a wide range of parameters, it is possible to reduce this model of four time constants to a smaller subset. This reduction brings simplifications to the current COLISEUM and enables it to be consistent with the number of time constants considered in the MPAS model from CEA

Void Fraction Influence on CICCs Coupling Losses: Analysis of Experimental Results With MPAS Model

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Analytical Modelling of CICCs Coupling Losses: Broad Investigation of Two-Stage Model

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Analytical coupling losses modelling with COLISEUM: generalized approach upgraded to all stages

International audiencePredicting analytically the coupling losses generated in a cable for fusion magnets is still a significant challenge. Difficulties are related to the complex geometry of the system: several multi-strand stages embedded in one another with different twist pitches length, difficulty to model multiplets of strands, including compaction to the final shape. A two-stage analytical geometry based model (COLISEUM) has previously been developed at CEA. We try to extend it to any n-stage cables We detail here an iterative enhancement method to an n-stage model. We validated it against experimental data and shown that it is robust enough to fit our measured coupling losses. Finally, this upgraded model can be used to assess coupling losses in fusion n-stage cables in a particularly precise way from only geometrical information and analytical tools

AC coupling losses in CICCs: analytical modeling at different stages

International audienceCable-in-conduit conductors (CICCs) are composed of a large number of strands (superconducting composites and copper strands) twisted together in several stages with different twist pitches. They are widely used in large fusion tokamaks such as JT-60SA or ITER. However, because of their complex transposed geometry at a strand scale, the knowledge of ac coupling losses in these conductors is limited and still has some improvement margins to capture its complexity while the prediction of their behavior under transient regimes (e.g., central solenoid) is of first importance to assess a safe operation in tokamaks. Consequently, we have carried out an in-depth theoretical generic study of a single stage of a CICC and analytically derived the expression of coupling losses using physical parameters (time constant and partial shielding coefficient) determined from electromagnetic and geometrical properties. Our approach has been inspired by the MPAS model (extensively used on the experimental ITER database) but starts from the analytical description of a single stage and aims at reaching the CICC scale in an iterative way