The roles of TL1A and Pno1 in the pathogenesis of rheumatoid arthritis

La polyarthrite rhumatoïde (PR) est une maladie auto-immune chronique. Elle est caractérisée par une inflammation persistante touchant de multiples petites articulations, causant douleurs, rougeurs, gonflements et déformations. Des études menées auprès de patients et d’animaux ont démontré que certains auto-anticorps, cytokines et enzymes tissue-déstructives sont des médiateurs importants dans le développement de la PR. Au cours des deux dernières décennies, les traitements de fond (DMARDs en anglais) ont été démontrés très efficaces pour traiter la PR. D'autre part, des effets secondaires ont été rapportés pour ces traitements, par exemple l'augmentation du risque d'infections opportunistes. L’objectif de ce travail est d’acquérir des connaissances sur le rôle du TL1A (TNF-like molécule 1 A; TNFSF15) et son partenaire Nob1 (Pno1 ; YOR145c) dans la pathogenèse de la PR afin de découvrir de nouveaux médicaments contre ces molécules dans l'avenir. TL1A est un membre de la famille du TNF. Il déclenche des signaux co-stimulateurs via le récepteur de mort 3 (DR3) et induit la prolifération ainsi que la production des cytokines pro inflammatoires par les lymphocytes. Des données multiples suggèrent l'implication de la cascade TL1A-DR3 dans plusieurs maladies auto-immunes. Donc, nous avons proposé les hypothèses suivantes:1) la production locale de TL1A dans les articulations est un composant d’un cercle vicieux qui aggrave la PR; 2) dans la PR, la production de TL1A dans les organes lymphoïde augmente la production d’auto-anticorps pathogénique. Au cours de ce travail, nous avons démontré que la TL1A aggrave la maladie chez les souris où l’arthrite a été induite par le collagène (AIC). Par ailleurs, nous avons constaté que l’expression de TL1A est élevée dans les tissus atteints de PR ainsi que dans les ganglions lymphatiques drainant de la souris AIC. Mécaniquement, nous avons découvert que la TL1A est induite par le TNF-α et IL-17 produits par les cellules T in vitro. Ces résultats montrent directement que les TL1A-DR3 jouent un rôle essentiel dans la pathogenèse de la PR. De plus, afin de poursuivre notre étude, la TL1A a été génétiquement supprimée dans les souris (TL1A KO). Nous avons montré que les souris TL1A KO n’ont aucune anomalie apparente et aucun dysfonctionnement du système immunitaire dans des conditions normales. Cependant, ces souris manifestent des AIC améliorées et une réduction significative des niveaux d'anticorps, anti-collagène du type II i dans le sérum. Nous avons trouvé que les ganglions lymphatiques de drainage (dLNs) de souris KO étaient plus petites avec une cellularité inférieure comparativement aux souris WT de 14 jours après l’immunisation. De plus, nous avons découvert que le DR3 a été exprimé par les cellules plasmatiques dans l’étape de la différenciation terminale et ces cellules surviennent mieux en présence de TL1A. La conclusion de cette étude apporte des nouvelles connaissances sur le rôle de TL1A qui amplifie les réponses humorales d’AIC. Nous avons suggéré que TL1A pourrait augmenter la réponse d’initiation d'anticorps contre collagène II (CII) ainsi que prolonger la survie des cellules plasmatiques. Une autre molécule qui nous intéresse est Pno1. Des études antérieures menées chez la levure ont suggéré que Pno1 est essentielle pour la néogénèse du protéasome et du ribosome Le protéasome étant crucial pour la différenciation terminale des cellules plasmatiques pendant les réponses humorales chez les mammifères, nous avons donc supposé que Pno1 joue un rôle dans la production d'anticorps pathogenique dans la PR via la voie du protéasome. Nous avons donc généré des souris génétiquement modifiées pour Pno1 afin d’étudier la fonction de Pno1 in vivo. Cependant, une mutation non-sens dans le Pno1 provoque une létalité embryonnaire à un stade très précoce chez les souris. D'autre part, une réduction de 50% de Pno1 ou une surexpression de Pno1 n’ont aucun effet ni sur le fonctionnent des cellules T et B, ni sur les activités du protéasome ainsi que sur la réponse humorale dans l’AIC. Ces résultats suggèrent que Pno1 est une molécule essentielle sans redondance. Par conséquent, il n’est pas une cible appropriée pour le développement de médicaments thérapeutiques. En conclusion, nos études ont révélé que la TL1A n’est pas essentielle pour maintenir les fonctions du système immunitaire dans des conditions normales. En revanche, il joue un rôle critique dans la pathogenèse de la PR en favorisant l'inflammation locale et la réponse humorale contre des auto-antigènes. Par conséquent, une inhibition de la TL1A pourrait être une stratégie thérapeutique pour le traitement de la PR. Au contraire, Pno1 est essentiel pour la fonction normale des cellules. Une délétion totale pourrait entraîner des conséquences graves. Il n’est pas une cible appropriée pour développer des médicaments de la PR.

The effects of administration of a nuclear factor kappa-B inhibitor on pulmonary endothelial dysfunction after cardiopulmonary bypass: impact on oxygenation and hemodynamics and development of therapeutic and preventive modalities in a porcine model

Introduction: La circulation extracorporelle (CEC) peut entraîner une dysfonction endothéliale pulmonaire et l’hypertension pulmonaire. Le SN50 agit au niveau de la signalisation cellulaire pour prévenir ces réactions à la CEC et pourrait renverser la dysfonction endothéliale pulmonaire post-CEC sans effets néfastes sur l’hémodynamie. Méthodes: Quatre groups de porcs ont reçu un parmi quatre traîtements avant de subir 90 minutes de CEC et 60 minutes de reperfusion: (1) milrinone nébulisé; (2) sildenafil nébulisé; (3) placebo nébulisé; et (4) SN-50 intraveineux. Un monitoring hémodynamique invasif a été utilisé. La réactivité vasculaire des artères pulmonaires de deuxième ordre a été évaluée face à l’acétylcholine et la bradykinine. Résultats: Le sildénafil produit une augmentation significative de la pression de l’artère pulmonaire (PAP) moyenne à 60 minutes de reperfusion par rapport au début de la chirurgie. Les relaxations dépendantes de l’endothélium face à la bradykinine étaient meilleurs dans les groupes milrinone et SN-50 et surtout dans le groupe sildénafil par rapport au groupe placébo. Le SN-50 produisait de moins bonnes relaxations dépendantes de l’endothélium face à l’acétylcholine que les autres traitements incluant placébo. Conclusion: Le sildénafil prévient mieux la dysfonction endothéliale pulmonaire que les autres traitements. Les bénéfices du SN-50 sont possiblement sous-estimés vu que la dose n’a pas pu être ajustée à la durée de CEC. Le sildenafil inhalé mérite une étude plus importante chez l’humain et le SN-50 dans un model de CEC animal.

Bivariate distributions with weighted marginals and reliablity modelling

In this paper, a family of bivariate distributions whose marginals are weighted distributions in the original variables is studied. The relationship between the failure rates of the derived and original models are obtained. These relationships are used to provide some characterizations of specific bivariate models

Many-body theory of laser-induced ultrafast demagnetization and angular momentum transfer in ferromagnetic transition metals

An electronic theory is developed, which describes the ultrafast demagnetization in itinerant ferromagnets following the absorption of a femtosecond laser pulse. The present work intends to elucidate the microscopic physics of this ultrafast phenomenon by identifying its fundamental mechanisms. In particular, it aims to reveal the nature of the involved spin excitations and angular-momentum transfer between spin and lattice, which are still subjects of intensive debate. In the first preliminary part of the thesis the initial stage of the laser-induced demagnetization process is considered. In this stage the electronic system is highly excited by spin-conserving elementary excitations involved in the laser-pulse absorption, while the spin or magnon degrees of freedom remain very weakly excited. The role of electron-hole excitations on the stability of the magnetic order of one- and two-dimensional 3d transition metals (TMs) is investigated by using ab initio density-functional theory. The results show that the local magnetic moments are remarkably stable even at very high levels of local energy density and, therefore, indicate that these moments preserve their identity throughout the entire demagnetization process. In the second main part of the thesis a many-body theory is proposed, which takes into account these local magnetic moments and the local character of the involved spin excitations such as spin fluctuations from the very beginning. In this approach the relevant valence 3d and 4p electrons are described in terms of a multiband model Hamiltonian which includes Coulomb interactions, interatomic hybridizations, spin-orbit interactions, as well as the coupling to the time-dependent laser field on the same footing. An exact numerical time evolution is performed for small ferromagnetic TM clusters. The dynamical simulations show that after ultra-short laser pulse absorption the magnetization of these clusters decreases on a time scale of hundred femtoseconds. In particular, the results reproduce the experimentally observed laser-induced demagnetization in ferromagnets and demonstrate that this effect can be explained in terms of the following purely electronic non-adiabatic mechanism: First, on a time scale of 10–100 fs after laser excitation the spin-orbit coupling yields local angular-momentum transfer between the spins and the electron orbits, while subsequently the orbital angular momentum is very rapidly quenched in the lattice on the time scale of one femtosecond due to interatomic electron hoppings. In combination, these two processes result in a demagnetization within hundred or a few hundred femtoseconds after laser-pulse absorption.

Workforce Issues in the Greater Boston Health Care Industry: Implications for Work and Family

Interviews with more than 40 leaders in the Boston area health care industry have identified a range of broadly-felt critical problems. This document synthesizes these problems and places them in the context of work and family issues implicit in the organization of health care workplaces. It concludes with questions about possible ways to address such issues. The defining circumstance for the health care industry nationally as well as regionally at present is an extraordinary reorganization, not yet fully negotiated, in the provision and financing of health care. Hoped-for controls on increased costs of medical care – specifically the widespread replacement of indemnity insurance by market-based managed care and business models of operation--have fallen far short of their promise. Pressures to limit expenditures have produced dispiriting conditions for the entire healthcare workforce, from technicians and aides to nurses and physicians. Under such strains, relations between managers and workers providing care are uneasy, ranging from determined efforts to maintain respectful cooperation to adversarial negotiation. Taken together, the interviews identify five key issues affecting a broad cross-section of occupational groups, albeit in different ways: Staffing shortages of various kinds throughout the health care workforce create problems for managers and workers and also for the quality of patient care. Long work hours and inflexible schedules place pressure on virtually every part of the healthcare workforce, including physicians. Degraded and unsupportive working conditions, often the result of workplace "deskilling" and "speed up," undercut previous modes of clinical practice. Lack of opportunities for training and advancement exacerbate workforce problems in an industry where occupational categories and terms of work are in a constant state of flux. Professional and employee voices are insufficiently heard in conditions of rapid institutional reorganization and consolidation. Interviewees describe multiple impacts of these issues--on the operation of health care workplaces, on the well being of the health care workforce, and on the quality of patient care. Also apparent in the interviews, but not clearly named and defined, is the impact of these issues on the ability of workers to attend well to the needs of their families--and the reciprocal impact of workers' family tensions on workplace performance. In other words, the same things that affect patient care also affect families, and vice versa. Some workers describe feeling both guilty about raising their own family issues when their patients' needs are at stake, and resentful about the exploitation of these feelings by administrators making workplace policy. The different institutions making up the health care system have responded to their most pressing issues with a variety of specific stratagems but few that address the complexities connecting relations between work and family. The MIT Workplace Center proposes a collaborative exploration of next steps to probe these complications and to identify possible locations within the health care system for workplace experimentation with outcomes benefiting all parties.

Inverse Metabolic Engineering of Synechocystis PCC 6803 for Improved Growth Rate and Poly-3-hydroxybutyrate Production

Synechocystis PCC 6803 is a photosynthetic bacterium that has the potential to make bioproducts from carbon dioxide and light. Biochemical production from photosynthetic organisms is attractive because it replaces the typical bioprocessing steps of crop growth, milling, and fermentation, with a one-step photosynthetic process. However, low yields and slow growth rates limit the economic potential of such endeavors. Rational metabolic engineering methods are hindered by limited cellular knowledge and inadequate models of Synechocystis. Instead, inverse metabolic engineering, a scheme based on combinatorial gene searches which does not require detailed cellular models, but can exploit sequence data and existing molecular biological techniques, was used to find genes that (1) improve the production of the biopolymer poly-3-hydroxybutyrate (PHB) and (2) increase the growth rate. A fluorescence activated cell sorting assay was developed to screen for high PHB producing clones. Separately, serial sub-culturing was used to select clones that improve growth rate. Novel gene knock-outs were identified that increase PHB production and others that increase the specific growth rate. These improvements make this system more attractive for industrial use and demonstrate the power of inverse metabolic engineering to identify novel phenotype-associated genes in poorly understood systems.

Systems Design: Activity and Sequence modelling using Visual Paradigm

This lab follows the lectures 'System Design: http://www.edshare.soton.ac.uk/9653/ and http://www.edshare.soton.ac.uk/6280/ . Students use Visual Paradigm for UML to build Activity and Sequence models through project examples: Library, Plant Nursery and a Health Spa

Evaluación e intervención interdisciplinaria del dolor en Unidades de Cuidado Intensivo

El dolor es un problema importante para los pacientes hospitalizados en las UCI porque genera malestar y distrés. Además, la investigación ha demostrado que en algunos pacientes críticos el dolor agudo puede persistir después de alta y convertirse en crónico. La gestión eficaz del dolor en pacientes críticos requiere un enfoque interdisciplinario, que incorpore la visión y trabajo de expertos que representan una amplia variedad de especialidades clínicas. Así, la utilización de la intervención psicológica en el tratamiento del dolor es una parte integral de un enfoque global. Basado en una revisión de la evidencia científica, se identifican y señalan: (1) los tipos de dolor más comunes; (2) las características del dolor; (3) las patologías más frecuentes asociadas con la presencia de dolor; (4) los procedimientos que generan dolor en la UCI; (5) los métodos de evaluación del dolor; (6) la intervención del mismo y; (7) la contribución del psicólogo en la evaluación y manejo del dolor con el paciente, los familiares y los profesionales de la salud. La revisión realizada indica que los procesos psicológicos influyen tanto en la experiencia del dolor como en los resultados del tratamiento, por lo tanto la integración de los principios psicológicos en el tratamiento del dolor parecen tener potencial mejora de los resultados beneficiando la salud del paciente.

Impulsivity: A view from the behavioral neuroscience and developmental psychology

Impulsivity has been linked to three main factors: performing without direct involvement of the frontal lobe functions, an increase in the speed of response, and the acquisition of immediate gratification. This behavioral inhibition deficit involves a variety of behaviors including aspects of hyperexcitability, behavioral disinhibition and higher order decision making. Although by tradition, the definition of this executive function has been conceptualized from a psychopathological view, currently, the wide variety of neuropsychological, developmental and animal models assessment techniques encourage us to establish dialogues that integrate the knowledge of these theoretical perspectives for the interpretation and understanding of impulsivity.

Implementación de cópulas para la estimación del valor en riesgo

La dependencia entre las series financieras, es un parámetro fundamental para la estimación de modelos de Riesgo. El Valor en Riesgo (VaR) es una de las medidas más importantes utilizadas para la administración y gestión de Riesgos Financieros, en la actualidad existen diferentes métodos para su estimación, como el método por simulación histórica, el cual no asume ninguna distribución sobre los retornos de los factores de riesgo o activos, o los métodos paramétricos que asumen normalidad sobre las distribuciones. En este documento se introduce la teoría de cópulas, como medida de dependencia entre las series, se estima un modelo ARMA-GARCH-Cópula para el cálculo del Valor en Riesgo de un portafolio compuesto por dos series financiera, la tasa de cambio Dólar-Peso y Euro-Peso. Los resultados obtenidos muestran que la estimación del VaR por medio de copulas es más preciso en relación a los métodos tradicionales.

Natural resource windfalls and efficiency of local government expenditures: evidence from Peru

We study the role of natural resource windfalls in explaining the efficiency of public expenditures. Using a rich dataset of expenditures and public good provision for 1,836 municipalities in Peru for period 2001-2010, we estimate a non-monotonic relationship between the efficiency of public good provision and the level of natural resource transfers. Local governments that were extremely favored by the boom of mineral prices were more efficient in using fiscal windfalls whereas those benefited with modest transfers were more inefficient. These results can be explained by the increase in political competition associated with the boom. However, the fact that increases in efficiency were related to reductions in public good provision casts doubts about the beneficial effects of political competition in promoting efficiency.

Modeling and Mapping Golden-winged Warbler Abundance to Improve Regional Conservation Strategies

Conservation planning requires identifying pertinent habitat factors and locating geographic locations where land management may improve habitat conditions for high priority species. I derived habitat models and mapped predicted abundance for the Golden-winged Warbler (Vermivora chrysoptera), a species of high conservation concern, using bird counts, environmental variables, and hierarchical models applied at multiple spatial scales. My aim was to understand habitat associations at multiple spatial scales and create a predictive abundance map for purposes of conservation planning for the Golden-winged Warbler. My models indicated a substantial influence of landscape conditions, including strong positive associations with total forest composition within the landscape. However, many of the associations I observed were counter to reported associations at finer spatial extents; for instance, I found Golden-winged Warblers negatively associated with several measures of edge habitat. No single spatial scale dominated, indicating that this species is responding to factors at multiple spatial scales. I found Golden-winged Warbler abundance was negatively related with Blue-winged Warbler (Vermivora cyanoptera) abundance. I also observed a north-south spatial trend suggestive of a regional climate effect that was not previously noted for this species. The map of predicted abundance indicated a large area of concentrated abundance in west-central Wisconsin, with smaller areas of high abundance along the northern periphery of the Prairie Hardwood Transition. This map of predicted abundance compared favorably with independent evaluation data sets and can thus be used to inform regional planning efforts devoted to conserving this species.

A tale of two elements: P1ncP1 and RTO

The and RT0 finite element schemes are among the most promising low order elements for use in unstructured mesh marine and lake models. They are both free of spurious elevation modes, have good dispersive properties and have a relatively low computational cost. In this paper, we derive both finite element schemes in the same unified framework and discuss their respective qualities in terms of conservation, consistency, propagation factor and convergence rate. We also highlight the impact that the local variables placement can have on the model solution. The main conclusion that we can draw is that the choice between elements is highly application dependent. We suggest that the element is better suited to purely hydrodynamical applications while the RT0 element might perform better for hydrological applications that require scalar transport calculations.

Introduction. Stochastic physics and climate modelling

Finite computing resources limit the spatial resolution of state-of-the-art global climate simulations to hundreds of kilometres. In neither the atmosphere nor the ocean are small-scale processes such as convection, clouds and ocean eddies properly represented. Climate simulations are known to depend, sometimes quite strongly, on the resulting bulk-formula representation of unresolved processes. Stochastic physics schemes within weather and climate models have the potential to represent the dynamical effects of unresolved scales in ways which conventional bulk-formula representations are incapable of so doing. The application of stochastic physics to climate modelling is a rapidly advancing, important and innovative topic. The latest research findings are gathered together in the Theme Issue for which this paper serves as the introduction.

Geostatistical Tools for Validation of Satellite and NWP Model Rainfall