Gene expression and epigenetic markers of prion diseases

Epigenetics, meaning the variety of mechanisms underpinning gene regulation and chromatin states, plays a key role in normal development as well as in disease initiation and progression. Epigenetic mechanisms like alteration of DNA methylation, histone modifications, and non-coding RNAs, have been proposed as biomarkers for diagnosis, classification, or monitoring of responsiveness to treatment in many diseases. In prion diseases, the profound associations with human aging, the effects of cell type and differentiation on in vitro susceptibility, and recently identified human risk factors, all implicate causal epigenetic mechanisms. Here, we review the current state of the art of epigenetics in prion diseases and its interaction with genetic determinants. In particular, we will review recent advances made by several groups in the field profiling DNA methylation and microRNA expression in mammalian prion diseases and the potential for these discoveries to be exploited as biomarkers

Blandy-les-Tours – Le château

À la suite d’une première évaluation réalisée en 1995 et consistant en deux tranchées, une seconde opération d’évaluation réalisée à la demande expresse de l’architecte en chef des Monuments historiques, sur prescription du Service régional de l’archéologie, a été menée avec un double but. Il s’agissait de fournir des données scientifiques et d’évaluer l’impact d’aménagements éventuels. L’évaluation de 1998 a porté sur environ 800 m2 situés exclusivement dans la partie sud du château entre l’..

El problema del <i>continuum</i> y sus implicancias en la teoría leibniziana de la sustancia

El problema del contínuum juega un papel decisivo en el desarrollo de la metafísica leibniciana de madurez. En los 70, dicho problema asomaba en sus intentos de explicar la naturaleza de la materia y la unión alma-cuerpo desde una perspectiva geométrico-mecanicista. Más tarde, la cuestión reaparece en la discusión con Arnauld sobre la unidad sustancial. Al hacer de la unidad real el criterio definitorio de la sustancia, Leibniz expulsa lo continuo al ámbito de lo ideal. Con este paso, su sistema se encamina hacia una ontología monadológica y hacia un esquema metafísico articulado en tres niveles (real, fenoménico e ideal).The problem of the continuum has a central part in the development of Leibnizian mature system. It appears, early in the 70s, when he intends to explain matter and its union with the soul from a geometric-mechanistic perspective. The same question reappears later, in the debate with Arnauld on substantial unity. In defining substance in terms of real unity, Leibniz expels continuity to the ideal realm. In doing so, he puts his system on the way to both, a monadological ontology and a metaphysical scheme articulated in three levels (real, phenomenal and ideal).Departamento de Filosofí

El argumento ontológico, la necesidad absoluta y el problema de la contingencia en Leibniz

Con el fin de conciliar la contingencia del mundo creado con la perfección divina, Leibniz propuso tempranamente una teoría modal que distinguía dos clases de necesidad: absoluta e hipotética. Sin embargo, la noción del Ens perfectissimum elaborada para su versión del argumento ontológico entraña una seria amenaza para aquella primera defensa de la contingencia. Pues dicha noción, junto con otros presupuestos de la metafísica leibniziana, implica que el enunciado Dios elige lo mejor es necesario en sentido absoluto. Y esta consecuencia pone a su filosofía a un paso del necesitarismo. Contra la interpretación de Rescher, la concepción leibniziana de Dios conlleva el carácter absolutamente necesario de su perfección moral y de su elección de lo mejor.In order to reconcile the actual world’s contingency with divine perfection, Leibniz early proposed a modal theory that distinguished two sorts of necessity: absolute and hypothetical. However, the notion of Ens Perfectissimum developed for his version of the ontological argument entails a serious threat to that first defense of contingency. Because that notion, within the framework of Leibniz’s metaphysics, implies the absolute necessity of the proposition “God chooses the best”. And this consequence leads his philosophy to the edge of necessitarianism. Contrary to what Nicholas Rescher holds on the subject, the leibnizian conception of God entails the absolute necessity of both his moral perfection and his choice of the best.Fil: Escobar Viré, Maximiliano. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

El problema del <i>continuum</i> y sus implicancias en la teoría leibniziana de la sustancia

El problema del contínuum juega un papel decisivo en el desarrollo de la metafísica leibniciana de madurez. En los 70, dicho problema asomaba en sus intentos de explicar la naturaleza de la materia y la unión alma-cuerpo desde una perspectiva geométrico-mecanicista. Más tarde, la cuestión reaparece en la discusión con Arnauld sobre la unidad sustancial. Al hacer de la unidad real el criterio definitorio de la sustancia, Leibniz expulsa lo continuo al ámbito de lo ideal. Con este paso, su sistema se encamina hacia una ontología monadológica y hacia un esquema metafísico articulado en tres niveles (real, fenoménico e ideal).The problem of the continuum has a central part in the development of Leibnizian mature system. It appears, early in the 70s, when he intends to explain matter and its union with the soul from a geometric-mechanistic perspective. The same question reappears later, in the debate with Arnauld on substantial unity. In defining substance in terms of real unity, Leibniz expels continuity to the ideal realm. In doing so, he puts his system on the way to both, a monadological ontology and a metaphysical scheme articulated in three levels (real, phenomenal and ideal).Departamento de Filosofí

El problema de la contingencia en Leibniz hacia 1690: importancia, interpretaciones actuales y modelos alternativos de fundamentación

En 1686 Leibniz propuso su “solución definitiva” al problema de la contingencia. Pero las tensiones que siguió afrontando su metafísica modal evidencian la presencia de modelos alternativos de fundamentación. Así, hacia 1690, su teoría del análisis infinito debió complementarse con la tesis de la indemostrabilidad de lo óptimo.In 1686, Leibniz put forward his “definitive solution” to the problem of contingency. However, his modal metaphysics kept on facing some difficulties which arose from alternative explicative frameworks. Hence, by 1690, his theory of infinite analysis had to be supplemented with the statement of indemonstrability of the best.Fil: Escobar Viré, Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Towards the Fully-coupled Numerical Modelling of Floating Wind Turbines

AbstractThe aim of this study is to model the interactions between fluids and solids using fully nonlinear models. Non- linearity is important in the context of floating wind turbines, for example, to model breaking waves impacting on the structure and the effect of the solid's elasticity. The fluid- and solid-dynamics equations are solved using two unstructured finite-element models, which are coupled at every time step. Importantly, the coupling ensures that the action-reaction principle is satisfied at a discrete level, independently of the order of representation of the discrete fields. To the authors’ knowledge, the present algorithm is novel in that it can simultaneously handle: (i) non- matching fluid and solid meshes, (ii) different polynomial orders of the basis functions on each mesh, and (iii) different fluid and solid time steps. First, results are shown for the flow past a fixed actuator-disk immersed in a uniform flow and representing a wind turbine. The present numerical results for the velocity deficit induced by the disk are shown to be in good agreement with the semi-analytical solution, for three values of thrust coefficients. The presence of a non-zero fluid viscosity in the numerical simulation affects wake recovery and fluid entrainment around the disk. Second, the dynamic response of a cylindrical pile is computed when placed at an interface between air and water. The results qualitatively demonstrate that the present models are applicable to the modelling of multiple fluids interacting with a floating solid. This work provides a first-step towards the fully coupled simulation of offshore wind turbines supported by a floating spar

Probabilistic surrogate modeling of offshore wind-turbine loads with chained Gaussian processes

Heteroscedastic Gaussian process regression, based on the concept of chained Gaussian processes, is used to build surrogates to predict site-specific loads on an offshore wind turbine. Stochasticity in the inflow turbulence and irregular waves results in load responses that are best represented as random variables rather than deterministic values. Moreover, the effect of these stochastic sources on the loads depends strongly on the mean environmental conditions -- for instance, at low mean wind speeds, inflow turbulence produces much less variability in loads than at high wind speeds. Statistically, this is known as heteroscedasticity. Deterministic and most stochastic surrogates do not account for the heteroscedastic noise, giving an incomplete and potentially misleading picture of the structural response. In this paper, we draw on the recent advancements in statistical inference to train a heteroscedastic surrogate model on a noisy database to predict the conditional pdf of the response. The model is informed via 10-minute load statistics of the IEA-10MW-RWT subject to both aero- and hydrodynamic loads, simulated with OpenFAST. Its performance is assessed against the standard Gaussian process regression. The predicted mean is similar in both models, but the heteroscedastic surrogate approximates the large-scale variance of the responses significantly better.Comment: 10 pages. To be published in the IOP Journal of Physics: Conference Series. To be presented at TORQUE 202

Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway.

Hutchinson-Gilford progeria syndrome (HGPS) is an incurable premature aging disease. Identifying deregulated biological processes in HGPS might thus help define novel therapeutic strategies. Fibroblasts from HGPS patients display defects in nucleocytoplasmic shuttling of the GTP-bound form of the small GTPase Ran (RanGTP), which leads to abnormal transport of proteins into the nucleus. We report that microtubule stabilization in HGPS cells sequestered the nonclassical nuclear import protein Transportin-1 (TNPO1) in the cytoplasm, thus affecting the nuclear localization of its cargo, including the nuclear pore protein NUP153. Consequently, nuclear Ran, nuclear anchorage of the nucleoporin TPR, and chromatin organization were disrupted, deregulating gene expression and inducing senescence. Inhibiting N-acetyltransferase 10 (NAT10) ameliorated HGPS phenotypes by rebalancing the nuclear to cytoplasmic ratio of TNPO1. This restored nuclear pore complex integrity and nuclear Ran localization, thereby correcting HGPS cellular phenotypes. We observed a similar mechanism in cells from healthy aged individuals. This study identifies a nuclear import pathway affected in aging and underscores the potential for NAT10 inhibition as a possible therapeutic strategy for HGPS and perhaps also for pathologies associated with normal aging