1,795 research outputs found

    LF+ in Coq for fast-and-loose reasoning

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    We develop the metatheory and the implementation, in Coq, of the novel logical framework LF+ and discuss several of its applications. LF+ generalises research work, carried out by the authors over more than a decade, on Logical Frameworks conservatively extending LF and featuring lock-type constructors L-P(N:sigma)[center dot]. Lock-types capture monadically the concept of inhabitability up-to. They were originally introduced for factoring-out, postponing, or delegating to external tools the verification of time-consuming judgments, which are morally proof-irrelevant, thus allowing for integrating different sources of epistemic evidence in a unique Logical Framework. Besides introducing LF+ and its "shallow" implementation in Coq, the main novelty of the paper is to show that lock-types are also a very flexible tool for expressing in Type Theory several diverse cognitive attitudes and mental strategies used in ordinary reasoning, which essentially amount to reasoning up-to, as in e.g. Typical Ambiguity provisos or co-inductive Coq proofs. In particular we address the encoding of the emerging paradigm of fast-and-loose reasoning, which trades off efficiency for correctness. This paradigm, implicitly used normally in naive Set Theory, is producing considerable impact also in computer architecture and distributed systems, when branch prediction and optimistic concurrency control are implemented

    Electron irradiation: from test to material tayloring

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    In this article, we report some examples of how high-energy electron irradiation can be used as a tool for shaping material properties turning the generation of point-defects into an advantage beyond the presumed degradation of the properties. Such an approach is radically different from what often occurs when irradiation is used as a test for radiation hard materials or devices degradation in harsh environments. We illustrate the potential of this emerging technique by results obtained on two families of materials, namely semiconductors and superconductors

    Supercritical Antisolvent Precipitation of Quercetin Systems: Preliminary Experiments

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    Flavonoids have attracted a lot of attention due to their antioxidant, antitumor and antibacterial activities. Quercetin (3,5,7,3,4-pentahydroxyflavone) is a polyphenolic flavonoid that shows several biological effects including a strong inhibitory effect on the growth of several human and animal cancer cell lines and enhances the antiproliferative effect of cisplatin both in-vitro and in-vivo. In spite of a variety of its biological effects. Quercetin is very poorly soluble in water, which has limited its absorption upon oral administration. As known, the solubility of drug is often due to the increase of the surface/volume ratio which implies the increase of the number of surface atoms (or molecules) with respect to the number of bulk atoms (or molecules). With this aim, we investigated the use of supercritical antisolvent (SAS) technique for Quercetin microparticles generation finding the best operative conditions through the Peng Robinson’s Equation of State. The obtained simulation behaviors were confirmed by experimental precipitation: the physicochemical characterizations of the samples were also performe

    D028 L’expression des gĂšnes PAI-1, tPA et uPA est fortement rĂ©gulĂ©e pendant la diffĂ©renciation des cellules souches embryonnaires en myocytes et adipocytes

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    PAI-1 est l’inhibiteur physiologique des activateurs du plasminogĂšne uPA et tPA et inhibe le complexe formĂ© entre uPA et son rĂ©cepteur, et par voie de consĂ©quence, entre la vitronectine et l’intĂ©grine alphav beta3. PAI-1 est impliquĂ© dans l’adhĂ©sion et la migration des cellules endothĂ©liales, dans la diffĂ©renciation adipocytaire et dans la rĂ©ponse Ă  l’insuline; in vivo, il facilite la thrombose, la fibrose et le remodelage tissulaire. Des taux Ă©levĂ©s circulants de PAI-1 reprĂ©sentent un biomarqueur de l’obĂ©sitĂ© centrale et sont un facteur pronostic du diabĂšte de type 2. Les propriĂ©tĂ©s biologiques de PAI-1 ont conduit Ă  l’hypothĂšse que PAI-1 serait impliquĂ© directement dans le dĂ©veloppement du tissu adipeux. Notre objectif est d’évaluer les rĂŽles spĂ©cifiques des gĂšnes PAI-1, uPA et tPA dans les mĂ©canismes molĂ©culaires de la diffĂ©renciation des cellules souches embryonnaires (cellules ES) de souris dans diffĂ©rents lignages.IndĂ©tectables Ă  l’état indiffĂ©renciĂ©, les expressions de PAI-1, uPA et tPA et les activitĂ©s enzymatiques uPA et tPA sont fortement rĂ©gulĂ©es durant la diffĂ©renciation des cellules ES. Les activitĂ©s uPA et tPA sont rapidement augmentĂ©es durant la phase prĂ©coce de dĂ©termination du processus, sans expression dĂ©tectable de PAI-1. Puis, l’expression de PAI-1 augmente progressivement dans les surnageants de culture des cellules bien diffĂ©renciĂ©es, corrĂ©lant avec une inhibition concomittante des activitĂ©s uPA et tPA. Des expĂ©riences d’immunohistochimie montrent que PAI-1 est exprimĂ© Ă  la fois dans les myotubes et dans les adipocytes matures.Le rĂŽle potentiel de ces rĂ©gulations successives est analysĂ© par la construction de lignĂ©es de cellules ES surexprimant le cDNA de PAI- 1 dĂšs l’état indiffĂ©renciĂ©. Les effets d’une surexpression ectopique de PAI-1 Ă  diffĂ©rent temps pendant la diffĂ©renciation des cellules ES sont recherchĂ©s.De plus, le traitement prĂ©coce des cellules ES en diffĂ©renciation par l’amiloride, inhibiteur spĂ©cifique d’uPA, provoque une diminution de la myogĂ©nĂšse et une augmentation de la diffĂ©renciation adipocytaire. Par contre ces effets ne sont pas retrouvĂ©s en traitant les cellules par l’EACA, inhibiteur de la plasmine ou le DMA, un dĂ©rivĂ© inactif de l’amiloride

    Association of Plasminogen Activator Inhibitor (PAI)-1 (SERPINE1) SNPs With Myocardial Infarction, Plasma PAI-1, and Metabolic Parameters

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    Objective— The purpose of this study was to investigate the effects of plasminogen activator inhibitor-1 (PAI-1) gene (SERPINE1) single nucleotide polymorphisms (SNPs) on the risk of myocardial infarction (MI), on PAI-1 levels, and factors related to the metabolic syndrome. Methods and Results— Eleven SNPs capturing the common genetic variation of the SERPINE1 gene were genotyped in the HIFMECH study. In the 510 male cases and their 543 age-matched controls, a significant gene-smoking interaction was observed. In nonsmokers, the rs7242-G allele was more frequent in cases than in controls (0.486 versus 0.382, P =0.013) whereas the haplotype derived from the rs2227631 (−844A>G)-G and rs2227683-A alleles was ≈3-fold lower in cases than in controls (0.042 versus 0.115, P =0.006). SERPINE1 haplotypes explained 3.5% ( P =0.007) of the variability of PAI-1 levels, which was attributable to the combined effects of 3 SNPs, −844A>G, rs2227666, and rs2227694. The rs6092 (Ala15Thr) and rs7242 SNPs acted additively to explain 4.4% of the variability of plasma insulin levels and 1.6% of the variability of BMI ( P <10 −3 and P =0.023, respectively). Conclusions— SERPINE1 haplotypes are mildly associated with plasma levels of PAI-1 and with the risk of MI in nonsmokers. They are also associated with insulin levels and BMI

    Kinase and channel activity of TRPM6 are co-ordinated by a dimerization motif and pocket interaction

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    Contains fulltext : 138516.pdf (publisher's version ) (Open Access)Mutations in the gene that encodes the atypical channel-kinase TRPM6 (transient receptor potential melastatin 6) cause HSH (hypomagnesaemia with secondary hypocalcaemia), a disorder characterized by defective intestinal Mg2+ transport and impaired renal Mg2+ reabsorption. TRPM6, together with its homologue TRPM7, are unique proteins as they combine an ion channel domain with a C-terminally fused protein kinase domain. How TRPM6 channel and kinase activity are linked is unknown. Previous structural analysis revealed that TRPM7 possesses a non-catalytic dimerization motif preceding the kinase domain. This interacts with a dimerization pocket lying within the kinase domain. In the present study, we provide evidence that the dimerization motif in TRPM6 plays a critical role in regulating kinase activity as well as ion channel activity. We identify mutations within the TRPM6 dimerization motif (Leu1718 and Leu1721) or dimerization pocket (L1743A, Q1832K, A1836N, L1840A and L1919Q) that abolish dimerization and establish that these mutations inhibit protein kinase activity. We also demonstrate that kinase activity of a dimerization motif mutant can be restored by addition of a peptide encompassing the dimerization motif. Moreover, we observe that mutations that disrupt the dimerization motif and dimerization pocket interaction greatly diminish TRPM6 ion channel activity, in a manner that is independent of kinase activity. Finally, we analyse the impact on kinase activity of ten disease-causing missense mutations that lie outwith the protein kinase domain of TRPM6. This revealed that one mutation lying nearby the dimerization motif (S1754N), found previously to inhibit channel activity, abolished kinase activity. These results provide the first evidence that there is structural co-ordination between channel and kinase activity, which is mediated by the dimerization motif and pocket interaction. We discuss that modulation of this interaction could comprise a major regulatory mechanism by which TRPM6 function is controlled

    The alpha subunit of RNA polymerase and transcription antitermination

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    Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72225/1/j.1365-2958.1996.451409.x.pd

    Vemurafenib treatment of pleomorphic xanthoastrocytoma in a child with Down syndrome

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    Brain tumors are the most common solid neoplasms of childhood, but they are very rarely reported in children with Down Syndrome (DS), who develop more commonly different types of malignancies. In particular, we hereby report the case of an 8-years-old child with DS that presented to our attention for neurological and endocrinological issues. Brain imaging revealed the presence of a mass that was partially resected revealing a histological diagnosis of Pleomorphic Xanthoastrocytoma (PXA), a rare WHO grade II tumor extending from the diencephalic region into the surrounding brain tissue. These tumors can harbor the BRAF mutation p.V600E, targetable by the specific inhibitor Vemurafenib. After confirming the presence of the mutation in the tumor, the patient was treated with Vemurafenib. The treatment proved to be effective, leading to a partial response and a stabilization of the disease. Usually, in patients with DS a reduction of the dose of chemotherapeutic drugs is necessary. Vemurafenib was instead well-tolerated as the only observed adverse effect was grade I skin toxicity. This is, to our knowledge, the first case of a PXA reported in a child with DS and the first DS patient treated with Vemurafenib
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