Étude des relations pharmacodynamiques, pharmacogénétiques et pharmacocinétiques des immunosuppresseurs anticalcineurines chez les transplantés hépatiques

Calcineurin inhibitors (CNI) are the immunosuppressants most employed in solid organ transplantation and despite their toxicity and suboptimal efficacy they will remain the first therapeutic option for time ahead. Their effects show huge intra- and inter-individual variability, not explained by differences in drug doses, concentrations or areas under the concentration-time curve, limiting the benefits of therapeutic drug monitoring and suggesting that other factors contribute to response variability. As CNI target T cell function, CNI concentration in lymphocytes was studied as a surrogate marker of the immune function. Actually, intra-lymphocyte TAC levels in liver transplant patients were better associated with acute rejection than whole blood levels, probably because they integrate potential inter-individual variations of drug entry into the lymphocytes. In the same line, previous studies showed that intrahepatic TAC levels displayed excellent correlation with the Banff rejection scores, whereas trough blood levels did not. Both may represent interesting, although difficult to assess, pharmacokinetic biomarkers. To qualify as an index of CNI immunosuppressive activity, a pharmacodynamic biomarker should be directly affected by drug activity, i.e. not too far from the drug target and at the same time close to its clinical effects. As a large amount of evidence supports the concept that T cell suppression is the key mechanism by which CNI achieve immunosuppression to prevent cellular rejection, T cell function and activation are attractive candidates for pharmacodynamic monitoring strategies. However, so far no single pharmacodynamic (PD) biomarker has met all the ideal requirements, i.e. non-invasiveness, reliability, sensitivity, specificity, reproducibility and short analytical time. Objectives and populations To search for suitable PD biomarkers, i.e., with high specificity for calcineurin inhibition and most affected by inter-individual variability, our works aimed at exploring the pharmacodynamics of CNI, the strength and variability of signal translation along the calcineurin pathway, as well as the steps where sources of internal (genetic) or external variability are the most influential. In order to achieve this, we assessed simultaneously NFAT1 translocation into the nucleus of peripheral blood mononuclear cells (PBMC) (NFTA1 being the main NAFT isoform in resting and activated lymphocytes), the intracellular expression of IL-2 in CD3+, CD4+ and CD8+ T cell subsets and the membrane expression of CD25 (IL-2Rα), a surface marker of T cells activation, in T cells at large. A non-interventional clinical trial was set up in healthy volunteers, patients registered on a liver transplantation waiting list (WLP) and liver transplant recipients (LTR). A different question was addressed in each group: The healthy volunteer study (n=35): explored TAC PD along the calcineurin pathway by exposing PBMC ex-vivo; modelled signal translation along this cascade; examined the interindividual variability of TAC PD parameters; and investigated the sources of the variability observed and their contribution at each step of the calcineurin pathway. Furthermore, it allowed us to evaluate the analytical variability of our techniques as well as the intra-individual variability of TAC PD parameters. WLP (n=19) were enrolled to confirm in patients with liver diseases the results obtained in healthy volunteers, as well as to test the potential influence of their initial disease on the ex-vivo pharmacodynamics of TAC. The aims of the transversal study of LTR on CNI (n=80) were to further explore the interindividual variability in the PD of CNI in realistic clinical conditions, i.e. in situations of residual PD activities under tacrolimus or cyclosporine exposure, and the potential pharmacogenetic (PG) sources of such variability. The (still small) group of liver transplant patients (n=6) enrolled immediately before transplantation and followed-up with serial monitoring along the first year post-transplantation was intended to explore the relationships between CNI PD and clinical responses. In summary, IL-2 and CD25 in CD8+ T cells and CD25 in CD4+ T cells may be reliable biomarkers of CNI activity, with the largest inter-individual variability. Moreover, a few clinical cases suggest that NFAT1 levels in PBMC nuclei might help to anticipate infection episodes, while Tregs diminution and high levels of IL-2 expression in CD8+ T cells might predict acute cellular rejection.Agencia Nacional de Investigación e InnovaciónPEDECIBA QuímicaService de Coopération Sientífique et d´Action Culturelle de l´Ambassade de France en UruguayU1248 INSERM, IPPRITT (Individual Profiling and Preventions of Risks with Immunosuppressive Therapies and Transplantation) Université de Limoges, FranceFacultad de Química, UdelaRCHU de Limoges - Hôpital Dupuytren - SERVICE DE PHARMACOLOGIE - TOXICOLOGIE ET PHARMACOVIGILANC

Economía y antropología, diálogos disciplinares

Economía y antropología, diálogos disciplinare

Scale Invariant Interest Points with Shearlets

Shearlets are a relatively new directional multi-scale framework for signal analysis, which have been shown effective to enhance signal discontinuities such as edges and corners at multiple scales. In this work we address the problem of detecting and describing blob-like features in the shearlets framework. We derive a measure which is very effective for blob detection and closely related to the Laplacian of Gaussian. We demonstrate the measure satisfies the perfect scale invariance property in the continuous case. In the discrete setting, we derive algorithms for blob detection and keypoint description. Finally, we provide qualitative justifications of our findings as well as a quantitative evaluation on benchmark data. We also report an experimental evidence that our method is very suitable to deal with compressed and noisy images, thanks to the sparsity property of shearlets

On the Use of Efficient Projection Kernels for Motion-Based Visual Saliency Estimation

In this paper, we investigate the potential of a family of efficient filters—the Gray-Code Kernels (GCKs)—for addressing visual saliency estimation with a focus on motion information. Our implementation relies on the use of 3D kernels applied to overlapping blocks of frames and is able to gather meaningful spatio-temporal information with a very light computation. We introduce an attention module that reasons the use of pooling strategies, combined in an unsupervised way to derive a saliency map highlighting the presence of motion in the scene. A coarse segmentation map can also be obtained. In the experimental analysis, we evaluate our method on publicly available datasets and show that it is able to effectively and efficiently identify the portion of the image where the motion is occurring, providing tolerance to a variety of scene conditions and complexities

Las trasformaciones a través de ventanas territoriales: Quebrada de Humahuaca, Jujuy

El trabajo ensaya el redibujo, construcción y análisis de nuevas cartografías y esquemas interpretativos de algunas ventanas territoriales, en varia escalas de acercamiento, para ciertos centros urbanos de la Quebrada de Humahuaca (Jujuy, Argentina) como un instrumento de conocimiento. En este sentido, esta investigación busca interpretar los procesos morfológicos de transformación de las últimas décadas, en relación a la crisis económica de la Argentina de principios del siglo XXI, la declaratoria de la Quebrada de Humahuaca como Patrimonio de la Humanidad (UNESCO, 2003) y la promoción turística nacional, entre otros acontecimientos que han modificado las lógicas locales. Para esto, estudia los cambios y permanencias en el espacio construido y los distintos tipos de desarrollo urbano –agregación de nuevas manzanas, anexión de nuevos barrios y loteos discontinuos a la mancha urbana o densificación gradual de los usos urbanos, rurales y rururbanos, entre otros- a la luz de la historia reciente de la Quebrada.The paper works on the redraw, construction and analysis of new maps and interpretations in some territorials windows, in various scales, for few urban centers of the Quebrada de Humahuaca (Jujuy, Argentina) as an instrument of knowledge. In this sense, this research is looking to understand the morphological processes of transformation in recent decades, in relation to the economic crisis in Argentina at the beginning of the XXI century, the declaration of the Quebrada de Humahuaca as a World Heritage Site (UNESCO, 2003) and national tourism promotion, among other events that have changed the local’s logics. For this, study the changes and continuities in the territory and the types of urban development -adding new blocks, annexation of new neighborhoods and subdivisions in the urban discontinuous or gradual densification of urban, rural and rururban, among others- knowing the recent history of the Quebrada.Peer Reviewe

WOMEN AND DIACONAL MINISTRY. A POSSIBLE MINISTRY FOR A NEW CHURCH

Negli ultimi due anni, l’opinione pubblica cattolica ha affrontato frequentemente la possibilità di ordinare donne diacono. Partendo dall’assenza della questione del diaconato femminile al Concilio, attraverso la richiesta del diaconato in seno ad alcuni sinodi e congressi pastorali europei e nordamericani, il saggio giunge alla riflessione teologica sul ministero ordinato inserendolo nel concetto di popolo di Dio e nella comune missione messianica. Si offre un quadro interpretativo del diaconato tracciando quelle che sono le implicazioni per il dibattito sul diaconato femminile nonché le prospettive per una trasformazione ecclesiale.The twofold question of the possibility and the opportunity to order women deacons in the Catholic Church has been dealt with frequently in the last two years, both on the pages of newspapers and high-disclosure Catholic journals; it has been relaunched on blogs interested in feminine and feminist issues, Christian and not; it is of interest to theologians of various Christian confessions, both men and women, and it involves historians and scholars of ancient Christian literature, as well as experts in sociology of religions and cultural anthropology. The intervention of Msgr. J.P. Durocher in the Synod on the Family, in October 2015, helped hasten the resumption of this question, but it were the request made by a religious sister from the International Union of Superiors General to pope Francis the following May and the manifest willingness shown by the pope to confront the theme that have actually brought the discussion on women deacons / deaconesses back in public context. A Study Commission on the Women’s diaconate, appointed by the pope and set up on August 2nd, 2016, was entrusted with an uneasy task to provide contributions and identify orientations on the subject. In fact, the historical, patristic and theological-systematic research on the subject is already rich with hundreds of contributions, many of which are wide-ranging; from the first post-conciliar time onwards, proposals of reflection from bishops originating in different countries have joined the requests coming from the base of the Church, although in the last two decades the confrontation undoubtedly remained confined to restricted groups of theologians and pastors, more aware of the present ecclesiastic challenges and more informed of the chances offered by the ecclesiastical Tradition. Rebuilding the trajectories of the post-conciliar debate on ministerial ordination of women helps identifying the paradigms and the theological categories adopted to think about the female diaconate and allows to understand the open questions around which the positions of different authors have polarized. The novelty of the teaching of Vatican II on the theological reason of the ordained ministry and on the reinterpretation of the specificity of ministerial figures of bishops, priests and deacons appears, starting precisely from the post-conciliar confrontation, as an indispensable reference horizon in order to propose the figure of “women deacons” as possible and necessary

Análise do capital de giro de uma empresa do setor varejista no estado de Santa Catarina

TCC (Graduação) - Universidade Federal de Santa Catarina. Centro Socioeconômico. Curso de Ciências ContábeisNa gestão empresarial, a administração do capital de giro constitui uma importante tarefa dos administradores financeiros, já que, uma administração inadequada do capital de giro resulta, de modo geral, em graves problemas financeiros, contribuindo assim para a formação de uma situação de insolvência. A partir deste problema, este trabalho propõe a responder quais os indicadores que podem ser empregados para analisar a situação financeira de Curto Prazo da empresa varejista pesquisada, através de Análises de Liquidez, Atividade e do Capital Dinâmico. Foi escolhida para o estudo de caso a empresa Eugênio Raulino Koerich S/A Comércio e Indústria. Após a análise, observou-se que a empresa estudada enquadra-se em um perfil conservador, tendo sua situação financeira sumariamente estável de acordo com os resultados apurados ao longo do período analisado, porem sugerindo-se um estudo que acompanhe as estratégias e o comportamento dos seus indicadores financeiros

Shortcuts for causal discovery of nonlinear models by score matching

The use of simulated data in the field of causal discovery is ubiquitous due to the scarcity of annotated real data. Recently, Reisach et al., 2021 highlighted the emergence of patterns in simulated linear data, which displays increasing marginal variance in the casual direction. As an ablation in their experiments, Montagna et al., 2023 found that similar patterns may emerge in nonlinear models for the variance of the score vector $\nabla \log p_{\mathbf{X}}$, and introduced the ScoreSort algorithm. In this work, we formally define and characterize this score-sortability pattern of nonlinear additive noise models. We find that it defines a class of identifiable (bivariate) causal models overlapping with nonlinear additive noise models. We theoretically demonstrate the advantages of ScoreSort in terms of statistical efficiency compared to prior state-of-the-art score matching-based methods and empirically show the score-sortability of the most common synthetic benchmarks in the literature. Our findings remark (1) the lack of diversity in the data as an important limitation in the evaluation of nonlinear causal discovery approaches, (2) the importance of thoroughly testing different settings within a problem class, and (3) the importance of analyzing statistical properties in causal discovery, where research is often limited to defining identifiability conditions of the model