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Dans certaines maladies métaboliques héréditaires, les vomissements peuvent apparaître comme un symptôme étant au premier plan, en particulier les anomalies du cycle de l'urée, qui sont habituellement diagnostiqués en période néonatale ou dans l'enfance. Nous en rapportons un cas de révélation tardive par un état de mal convulsif. Nous rapportons le cas d'une patiente âgée de 13 ans, qui a été hospitalisé pour prise en charge d'un état de mal convulsif et un retard staturo-pondéral. L'interrogatoire a révélé la notion de vomissements chroniques avec des troubles du comportement, ralentissement idéomoteur et céphalées. L'examen a trouvé une ataxie. La ponction lombaire et le scanner cérébral sont normaux. Une ammoniémie nettement augmentée est mise en évidence 75 micromoles/l (11-50). La chromatographie des acides aminés dans le sang a montré une augmentation de la glutamine et de l'alanine, La chromatographie des acides aminés dans les urines a montré une augmentation des acides aminés basiques évoquant un déficit du cycle de l'urée par déficit de l'enzyme Argininosuccinate lyase. La patiente a été traité en urgence par une alimentation exclusivement glucidolipidique, et par benzoate de sodium permettant une amélioration de l'état clinique, et une reprise de poids. Les crises convulsives ont été maîtrisées par le phénobarbital. L'enquête familiale a trouvé une soeur âgée de 20 ans suivie depuis l'âge de 3 ans pour crises convulsives traité par le phénobarbital dont le bilan métabolique réalisé dans notre service a objectivé la même anomalie du cycle de l'urée que sa soeur. A tout âge, devant une encéphalopathie avec épilepsie, vomissement, stagnation pondérale et hyperammoniémie, il faut penser à un déficit du cycle de l'urée. Le diagnostic est très souvent posé lors d'un accès neuro-digestif aigue associant vomissements, troubles de conscience et/ou crises convulsives. [ABSTRACT FROM AUTHOR]

Programmed necrosis induced by DNA alkylating agents, such as MNNG, is a caspase-independent mode of cell death mediated by apoptosis-inducing factor (AIF). After poly(ADP-ribose) polymerase 1, calpain, and Bax activation, AIF moves from the mitochondria to the nucleus where it induces chromatinolysis and cell death. The mechanisms underlying the nuclear action of AIF are, however, largely unknown. We show here that, through its C-terminal proline-rich binding domain (PBD, residues 543–559), AIF associates in the nucleus with histone H2AX. This interaction regulates chromatinolysis and programmed necrosis by generating an active DNA-degrading complex with cyclophilin A (CypA). Deletion or directed mutagenesis in the AIF C-terminal PBD abolishes AIF/H2AX interaction and AIF-mediated chromatinolysis. H2AX genetic ablation or CypA downregulation confers resistance to programmed necrosis. AIF fails to induce chromatinolysis in H2AX or CypA-deficient nuclei. We also establish that H2AX is phosphorylated at Ser139 after MNNG treatment and that this phosphorylation is critical for caspase-independent programmed necrosis. Overall, our data shed new light in the mechanisms regulating programmed necrosis, elucidate a key nuclear partner of AIF, and uncover an AIF apoptogenic motif. [ABSTRACT FROM AUTHOR]

In nuclear physics experiments, a decision maker named as “trigger” gives a bit pattern which allows the fired detectors identification. As the data acquisition dead time is greater than the time between physical events, timing information is essential. We add to the trigger function a Time to Digital Converter (TDC) in order to make a separation between events. The paper describes the architecture chosen for the TDC and illustrates the contribution of each element to the TDC performance. An eight-bit counter is used for the dynamic range of the TDC (in microsecond) associated to a delay line improving the resolution (in nanosecond). The study shows that exploiting the two system clock states (high and low) allows to reduce the number of delay line cells. The Differential Nonlinearity Measurements are given for different resolutions (1, 2 and 5 ns) and illustrate the clock period, the clock duty cycle and the delay line contributions to the TDC performances. [Copyright &y& Elsevier]

Discusses the isolation and characterization of the steroidogenesis-stimulating protein (STP) from medium conditioned rat Sertoli cells cultured in the presence of follicle-stimulating hormone (FSH). Effect of STP on steroidogenesis; Identification of the 28- and 38-kD proteins; Regulation of the abundance of messenger RNAs encoding the proteins.

The AGATA collaboration has a long-standing leadership in the development of front-end electronics for high resolution γ -ray spectroscopy using large volume high purity germanium detectors. For two decades, the AGATA collaboration has been developing state-of-the-art digital electronics processing with high resolution sampling ADC, high-speed signal transfer and fast readout to a high throughput computing (HTC) farm for on-line pulse shape analysis. The collaboration is presently addressing the next challenge of equipping a 4 π array with more than 6000 channels in high resolution mode, generating approximately 10 MHz of total trigger requests, coupled to a large variety of complementary instruments. A next generation of front-end electronics, presently under design, is based on industrial products (System on Module FPGA's), has higher integration and lower power consumption. In this contribution, the conceptual design of the new electronics is presented. The results of the very first tests of the pre-production electronics are presented as well as future perspectives. [ABSTRACT FROM AUTHOR]

This paper presents the design of the NEDA (Neutron Detector Array) electronics, a first attempt to involve the use of digital electronics in large neutron detector arrays. Starting from the front-end modules attached to the PMTs (PhotoMultiplier Tubes) and ending up with the data processing workstations, a comprehensive electronic system capable of dealing with the acquisition and pre-processing of the neutron array is detailed. Among the electronic modules required, we emphasize the front-end analog processing, the digitalization, digital pre-processing and communications firmware, as well as the integration of the GTS (Global Trigger and Synchronization) system, already used successfully in AGATA (Advanced Gamma Tracking Array). The NEDA array will be available for measurements in 2016. [ABSTRACT FROM PUBLISHER]

The Myocardin-related transcription factor A [MRTFA, also known as Megakaryoblastic Leukemia 1 (MKL1))] is a major actor in the epithelial to mesenchymal transition (EMT). We have previously shown that activation and nuclear accumulation of MRTFA mediate endocrine resistance of estrogen receptor alpha (ERα) positive breast cancers by initiating a partial transition from luminal to basal-like phenotype and impairing ERα cistrome and transcriptome. In the present study, we deepen our understanding of the mechanism by monitoring functional changes in the receptor's activity. We demonstrate that MRTFA nuclear accumulation down-regulates the expression of the unliganded (Apo-)ERα and causes a redistribution of the protein localization from its normal nuclear place to the entire cell volume. This phenomenon is accompanied by a shift in Apo-ERα monomer/dimer ratio towards the monomeric state, leading to significant functional consequences on ERα activities. In particular, the association of Apo-ERα with chromatin is drastically decreased, and the remaining ERα binding sites are substantially less enriched in ERE motifs than in control conditions. Monitored by proximity Ligation Assay, ERα interactions with P160 family coactivators are partly impacted when MRTFA accumulates in the nucleus, and those with SMRT and NCOR1 corepressors are abolished. Finally, ERα interactions with kinases such as c-src and PI3K are increased, thereby enhancing MAP Kinase and AKT activities. In conclusion, the activation and nuclear accumulation of MRTFA in ERα positive breast cancer cells remodels both ERα location and functions by shifting its activity from nuclear genome regulation to extra-nuclear non-genomic signaling. • MRTFA is a master regulator of actin dynamic and cellular motile functions. • Nuclear translocation of MRTFA is associated with endocrine resistance. • Nuclear translocation of MRTFA down-regulates ERα and relocates it to the whole cell. • Nuclear translocation of MRTFA induces a shift in Apo-ERα monomer/dimer ratio towards the monomeric state. • Nuclear translocation of MRTFA abolishes ERα interactions with corepressors and promotes ER interactions with kinases. [ABSTRACT FROM AUTHOR]

The effects of some progestins on fish reproduction have been recently reported revealing the hazard of this class of steroidal pharmaceuticals. However, their effects at the central nervous system level have been poorly studied until now. Notwithstanding, progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. Herein, we investigated the effects of a large set of synthetic ligands of the nuclear progesterone receptor on the glial-specific expression of the zebrafish brain aromatase ( cyp19a1b ) using zebrafish mechanism-based assays. Progesterone and 24 progestins were first screened on transgenic cyp19a1b- GFP zebrafish embryos. We showed that progesterone, dydrogesterone, drospirenone and all the progesterone-derived progestins had no effect on GFP expression. Conversely, all progestins derived from 19-nortesterone induced GFP in a concentration-dependent manner with EC 50 ranging from the low nM range to hundreds nM. The 19-nortestosterone derived progestins levonorgestrel (LNG) and norethindrone (NET) were further tested in a radial glial cell context using U251-MG cells co-transfected with zebrafish ER subtypes (zfERα, zfERβ1 or zfERβ2) and cyp19a1b promoter linked to luciferase. Progesterone had no effect on luciferase activity while NET and LNG induced luciferase activity that was blocked by ICI 182,780. Zebrafish-ERs competition assays showed that NET and LNG were unable to bind to ERs, suggesting that the effects of these compounds on cyp19a1b require metabolic activation prior to elicit estrogenic activity. Overall, we demonstrate that 19-nortestosterone derived progestins elicit estrogenic activity by inducing cyp19a1b expression in radial glial cells. Given the crucial role of radial glial cells and neuro-estrogens in early development of brain, the consequences of exposure of fish to these compounds require further investigation. [ABSTRACT FROM AUTHOR]

This paper presents the final design and results of the FADC Mezzanine for the EXOGAM (EXOtic GAMma array spectrometer) and NEDA (Neutron Detector Array) detectors. The measurements performed include those of studying the effective number of bits, the energy resolution using HP-Ge detectors, as well as timing histograms and n/\gamma discrimination performance. Finally, the conclusion shows how a common digitizing device has been integrated in the experimental environment of two very different detectors which combine both low-noise acquisition and fast sampling rates. Not only the integration fulfilled the expected specifications on both systems, but it also showed how a study of synergy between detectors could lead to the reduction of resources and time by applying a common strategy. [ABSTRACT FROM PUBLISHER]

The existence of a link between estrogen deprivation and osteoarthritis (OA) in postmenopausal women suggests that 17β-estradiol (17β-E) may be a modulator of cartilage homeostasis. Here, we demonstrate that 17β-E stimulates, via its receptor human estrogen receptor α 66 (hERα66), type II collagen expression in differentiated and dedifferentiated (reflecting the OA phenotype) articular chondrocytes. Transactivation of type II collagen gene ( COL2A1) by ligand-independent transactivation domain (AF-1) of hERα66 was mediated by 'GC' binding sites of the −266/−63-bp promoter, through physical interactions between ERα, Sp1/Sp3, Sox9, and p300, as demonstrated in chromatin immunoprecipitation (ChIP) and Re-Chromatin Immuno-Precipitation (Re-ChIP) assays in primary and dedifferentiated cells. 17β-E and hERα66 increased the DNA-binding activities of Sp1/Sp3 and Sox-9 to both COL2A1 promoter and enhancer regions. Besides, Sp1, Sp3, and Sox-9 small interfering RNAs (siRNAs) prevented hERα66-induced transactivation of COL2A1, suggesting that these factors and their respective cis-regions are required for hERα66-mediated COL2A1 up-regulation. Our results highlight the genomic pathway by which 17β-E and hERα66 modulate Sp1/Sp3 heteromer binding activity and simultaneously participate in the recruitment of the essential factors Sox-9 and p300 involved respectively in the chondrocyte-differentiated status and COL2A1 transcriptional activation. These novel findings could therefore be attractive for tissue engineering of cartilage in OA, by the fact that 17β-E could promote chondrocyte redifferentiation. Key messages: • 17β-E up-regulates type II collagen gene expression in articular chondrocytes. • An ERα66/Sp1/Sp3/Sox-9/p300 protein complex mediates this stimulatory effect. • This heteromeric complex interacts and binds to Col2a1 promoter and enhancer in vivo. • Our findings highlight a new regulatory mechanism for 17β-E action in chondrocytes. • 17β-E might be an attractive candidate for cartilage engineering applications. [ABSTRACT FROM AUTHOR]

In addition to soluble factors, mechanical constraints and extracellular matrix stiffness are important regulators of cell fate that are mediated by cytoskeletal modifications. The EMT (epithelial-mesenchymal transition) that occurs during normal development and malignant progression is a typical example of the phenotypic switch associated with profound actin remodelling and changes in gene expression. For instance, actin dynamics control motile cell functions in EMT, in part, through regulating the subcellular localization of the myocardin-related transcription factor MKL1 (megakaryoblastic leukaemia translocation 1), a co-activator of SRF (serum-responsive factor). In the present paper, we show that MKL1 participates also to the control of the cellular switch between growth and quiescence. Experimental disconnection between MKL1 and G-actin (globular actin), by using an MKL1 mutant or enhancing the F (filamentous)-/Gactin ratio, generates a widely open chromatin state and a global increase in biosynthetic activity, classically associated with cell growth. Conversely, G-actin accumulation favours nuclear condensation and cell quiescence. These large-scale chromatin changes rely upon extensive histone modifications, exemplified by that of H3K9 (H3 Lys9) shifting from trimethylation, a heterochromatin mark, to acetylation, a mark of euchromatin. The present study provides the first evidence for a global reversible hetero/euchromatinization phenomenon triggered by the actin/MKL1 signalling pathway. [ABSTRACT FROM AUTHOR]

This work describes new electronics for the EXOGAM2 (HP-Ge detector array) and NEDA (BC501A-based neutron detector array). A new digitizing card with high resolution has been designed for gamma-ray and neutron spectroscopy experiments. The higher bandwidth requirement of the NEDA signals, together with the necessity for accuracy, require a high sampling rate in order to preserve the shape for real-time Pulse Shape Analysis (PSA). [ABSTRACT FROM AUTHOR]

Although involved in processes leading to the emergence and development of hormone-dependent breast cancers, the estrogen receptor a (ERα) also prevents transformed cells from progressing toward a more aggressive phenotype. The transcriptional activity of ERα is mediated through two transactivation functions, called activation function 1 and 2, whose respective involvement varies in a cell-specific manner. Here, we identify the Rho/megakaryoblastic leukemia 1 (MKL1) signaling pathway as a main actor in controlling the cell-specific activity of both transactivation functions of ERα. Notably, we show that, when the coregulator MKL1 is sequestered in an inactive form by unpolymerized actin, the transcriptional activity of ERα mainly relies on the activation function 1. The activation of MKL1, which results from its dissociation from unpolymerized actin, promoted by the ability of Rho to support polymeric actin accumulation, silences the activation function 1 of ERα and allows the receptor to mainly act through its activation function 2. Importantly, this switch in the respective contribution exerted by both transactivation functions is correlated with an impaired ability of ERα to efficiently transactivate estrogen-regulated reporter genes. MKL1 is further shown to be present on estrogen-responsive genes in vivo. Interestingly, the Rho/MKL1 signaling pathway is activated during the epithelial-mesenchymal transition. A reduced transactivation efficiency of ERα, resulting from the activation of this pathway, may therefore suppress the protective role exerted by ERα toward tumor progression and invasiveness. [ABSTRACT FROM AUTHOR]

Objectives. To investigate the mechanisms by which cytokines and 17β-oestradiol (17β-E2) modulate gene expression and activity of uridine diphosphoglucose dehydrogenase (UGDH), a key enzyme of GAG synthesis in articular chondrocytes. [ABSTRACT FROM PUBLISHER]

Abstract: The estrogen receptor alpha (ERα) is key in regulating normal breast development and function and is closely involved in the onset and progress of cancers. ERα transcriptional activity is mediated through two activation functions, AF1 and AF2, whose activity is tightly regulated in a cell-specific manner through yet unknown processes. Here, we demonstrate that cell–cell junctions generate cell permissiveness to AF1 through an up-regulation of the activity of an AF1 sub-region termed box 1. Moreover, the loss of E-cadherin expression is shown to silence the AF1 activity of ERα, allowing the receptor to mainly act through its AF2. This switch from an AF1 to an AF2 cell permissiveness also consequently results in the attenuation of ERα activity. Therefore, a loss of cell–cell junctions, a key process that occurs during the epithelial–mesenchymal transition, should have a broad impact on ERα transcriptional functions. [Copyright &y& Elsevier]

Three different Artificial Neural Network architectures have been applied to perform neutron/ γ discrimination in neda based on waveform and time-of-flight information. Using the coincident γ -rays from agata , we have been able to measure and compare on real data the performances of the Artificial Neural Networks as classifiers. While the general performances are quite similar for the data set we used, differences, in particular related to the computing times, have been highlighted. One of the Artificial Neural Network architecture has also been found more robust to time misalignment of the waveforms. Such a feature is of great interest for online processing of waveforms. [ABSTRACT FROM AUTHOR]

We have developed a new telescope array, dedicated to the study of direct reactions of exotic nuclei on light targets in inverse kinematics. This device, called MUST2, is briefly described, and the results of the first tests performed with an alpha source and Ni beams at 10 and 75 MeV/ u on a CDH target are presented. [ABSTRACT FROM AUTHOR]