Celiac disease:From genetic variation to molecular culprits

Coeliakie (CeD) is een auto-immuunziekte die veroorzaakt door gluten bij genetisch gevoelige individuen.. Het doel van dit proefschrift was om meer inzicht te krijgen in de functie van enkele van de CeD-kandidaat genen én de biologische mechanismen waar deze genen bij betrokken zijn. Hoofdstuk 1 geeft een overzicht van de voornaamste celtypes, cytokines, immuun moleculen en genetische- en omgevingsfactoren die zouden kunnen bijdragen aan CeD. In hoofdstuk 2 bestuderen we de rol die LPP, een slecht gekenmerkt eiwit in darmepitheelcellen. We vonden dat LPP bijdraagt aan de ziekte via zowel non-immuun als immuun functies van darmepitheelcellen. In hoofdstuk 3 hebben we 118 CeD-geassocieerde kandidaat genen geïdentificeerd door middel van expression quantitative trait loci (eQTL) analyse en statistische om eQTL genen aan een genetisch risico op CeD te koppelen. In hoofdstuk 4 hebben we onderzocht hoe cytokines, die verhoogd zijn in weefsels die door auto-immuunziektes zijn aangedaan (IFNb, Il-15 en IL-21), de genexpressie profiel van Intra-epitheliale cytotoxische lymfocyten (IE-CTLs) veranderen. In een poging om de rol van lncRNAs in het aangeboren immuunsysteem beter te begrijpen, hebben we lncRNAs (RP11-291B21.2) gekarakteriseerd in IEL-CTLs (hoofdstuk 6). We vonden dat deze lncRNA een rol zou kunnen spelen in T-cel activatie. Tenslotte heb ik In hoofdstuk 7 de belangrijkste bevindingen van dit proefschrift samengevat. Verder bespreek ik enkele tekortkomingen in het vaststellen van kandidaat genen en biologische mechanismen geassocieerd met CeD. Daarnaast bespreek ik hoe nieuwe technologieën kunnen worden gebruikt om deze tekortkomingen te overkome.Celiac disease (CeD) is an autoimmune disease triggered by gluten in genetically susceptible individuals. The aim of this thesis was to gain more insight into the function of some of the CeD candidate genes and the biological mechanisms in which these genes are involved. Chapter 1 provides an overview of the main cell types, cytokines, immune molecules and genetic and environmental factors that could contribute to CeD. In chapter 2 we study the role of LPP, a poorly characterized protein in intestinal epithelial cells. We found that LPP contributes to the disease through both non-immune and immune functions of intestinal epithelial cells. In chapter 3, we identified 118 CeD-associated candidate genes by expression quantitative trait loci (eQTL) analysis and statistics to link eQTL genes to a genetic risk of CeD. In chapter 4 we investigated how cytokines, which are elevated in tissues affected by autoimmune diseases (IFNb, Il-15 and IL-21), alter the gene expression profile of Intra-epithelial cytotoxic lymphocytes (IE-CTLs). In an effort to better understand the role of lncRNAs in the innate immune system, we characterized lncRNAs (RP11-291B21.2) in IEL-CTLs (Chapter 6). We found that this lncRNA could play a role in T cell activation. Finally, in Chapter 7 I summarized the main findings of this thesis. Furthermore, I discuss some shortcomings in the determination of candidate genes and biological mechanisms associated with CeD. In addition, I discuss how new technologies can be used to overcome these shortcomings

The value of information : the impact of European Union bank stress tests on stock markets

We tested whether the 2010, 2011 and 2014 European Union bank stress tests produced useful and real information to the market. Using an augmented capital asset pricing model, we analyzed the impact of the information disclosures on each stress test (announcement, methodology and results events) on the stock market returns and risk of banks. Our approach allows an integrated analysis, as a sample of 41 banks that participated in all three stress tests was used. The most significant event was the methodology disclosure, in terms of its impact on risk and returns. In contrast, the results events did not have much impact in the stock market when considering the entire sample of banks. On the other hand, after dividing the sample of banks into two groups (those that passed the 2014 European Union stress test vs. those that failed), we observed a significant reaction of the stock markets in both groups. These findings are consistent with the hypothesis that stress tests provide real and valuable information to the markets about the banking system. A significant part of that information is conveyed by announcement and methodology eventsinfo:eu-repo/semantics/publishedVersio

Small and long regulatory RNAs in the immune system and immune diseases

Cellular differentiation is regulated on the level of gene expression and it is known that dysregulation of gene expression can lead to deficiencies in differentiation that contribute to a variety of diseases, particularly of the immune system. Until recently, it was thought that the dysregulation was governed by changes in the binding or activity of a class of proteins called transcription factors. However, the discovery of micro-RNAs and recent descriptions of long noncoding RNAs have given enormous momentum to a whole new field of biology: the regulatory RNAs. In this review, we describe these two classes of regulatory RNAs and summarize what is known about how they regulate aspects of the adaptive and innate immune systems. Finally, we describe what is known about the involvement of micro-RNAs and long noncoding RNAs in three different autoimmune diseases (celiac disease, inflammatory bowel disease, and multiple sclerosis)

Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth

Identification of a population of Foxp3-expressing suppressive macrophages

Propuesta de Supply Chain Management y Logística para la Empresa Molinos Flor Huila Ltda.

Se anexan imágenes representativas de Molinos Florhuila, red estructural y gráficos comparativos.La logística ha sido muy importante en el transcurrir del tiempo, sin embargo, en la última década ha desarrollado estrategias adquiriendo mayor fuerza. Teniendo en cuenta que el mercado actual está siendo cada día más riguroso, que la competencia se ha tornado cada vez más difícil para garantizar la satisfacción de los clientes. y la globalización es un hecho latente para las empresas. Se escoge en consenso con el grupo de trabajo colaborativo, a una excelente empresa colombiana de gran trayectoria y reconocimiento en el mercado nacional, Molinos Florhuila, Siendo esta, una sociedad anónima que genera una fuente constante de empleos directos e indirectos, ofreciendo un producto de alta demanda en los hogares colombianos. Se escoge con el fin de mostrar las diferentes etapas o procesos de la Supply Chain management y logística de Molinos Flor Huila, Proponiendo mejoras a cada uno de los procesos logísticos, dando a conocer qué pueden implementar en la organización, para alcanzar mayores niveles competitivos, a través de la configuración de la red de la empresa, los procesos de enfoque del GSCF, Los procesos de APICS-SCORD,el análisis de la posición de Colombia en términos de logística , la propuesta de una estrategia de aprovisionamiento para aplicar en la empresa, la identificación de modos y medios de transporte , un diseño para el layout del almacén , un modelo de gestión de inventarios y la identificación de los beneficios de implementar estrategias de DRP y TMS y las mega tendencias en SCM y logística.Logistics has been very important over time, however, in the last decade it has developed strategies gaining greater strength. Taking into account that the current market is becoming more rigorous every day, that competition has become increasingly difficult to guarantee customer satisfaction. and globalization is a latent fact for companies. In consensus with the collaborative work group, an excellent Colombian company with a great track record and recognition in the national market, Molinos Florhuila, is chosen. Being this, a corporation that generates a constant source of direct and indirect jobs, offering a product of high demand in Colombian homes. It is chosen in order to show the different stages or processes of the Supply Chain management and logistics of Molinos Flor Huila, proposing improvements to each of the logistics processes, making known what they can implement in the organization, to achieve higher competitive levels, through the configuration of the company's network, the GSCF approach processes, the APICS-SCORD processes, the analysis of Colombia's position in terms of logistics, the proposal of a supply strategy to apply in the company , the identification of modes and means of transport , a design for the warehouse layout , an inventory management model and the identification of the benefits of implementing DRP and TMS strategies and the mega trends in SCM and logistics

Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models

Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regulate gene expression at transcriptional and translational levels. c-KIT proto-oncogene encodes for a tyrosine kinase receptor. It is involved in several physiological processes, but it is also dysregulated in many diseases, including cancer. Two G-rich sequences able to fold into G4, have been identified in c-KIT proximal promoter, thus representing suitable targets for anticancer intervention. Herein, we screened an \u201cin house\u201d library of compounds for the recognition of these G4 elements and we identified three promising ligands. Their G4-binding properties were analyzed and related to their antiproliferative, transcriptional and post-transcriptional effects in MCF7 and HGC27 cell lines. Besides c-KIT, the transcriptional analysis covered a panel of oncogenes known to possess G4 in their promoters. From these studies, an anthraquinone derivative (AQ1) was found to efficiently downregulate c-KIT mRNA and protein in both cell lines. The targeted activity of AQ1 was confirmed using c-KIT\u2013dependent cell lines that present either c-KIT mutations or promoter engineered (i.e., \u3b1155, HMC1.2 and ROSA cells). Present results indicate AQ1 as a promising compound for the target therapy of c-KIT-dependent tumors, worth of further and in depth molecular investigations

SPATIAL ANALYSIS AND CONFLICTS IN ARTISANAL FISHERIES IN THE LITORAL OF OIAPOQUE, AMAPA, BRAZIL

Este estudo localiza os pesqueiros e define as áreas de uso da pesca artesanal, que atuam no litoral do Oiapoque e do Parque Nacional do Cabo Orange, e apresenta o cenário atual dos conflitos ocasionados pelo uso destas áreas por diversos grupos de pescadores que exploram estes ambientes. O levantamento de informações ocorreu através de entrevistas semiestruturadas e não estruturadas à grupos focais, compostos por pescadores e gestores de unidades de conservação, assim como através de mapas participativos, e por georeferenciamento dos pesqueiros (no estuário do rio Oiapoque e litoral do Parque Nacional do Cabo Orange). Foram registrados quinze pesqueiros distribuídos em duas “zonas de pesca” e foram identificados três níveis de conflitos que envolveram os pescadores do município do Oiapoque.Palavras-chave: conflitos e áreas de uso na pesca, litoral do Parque Nacional do Cabo Orange.This study located the fisherie areas and areas areas explored by artisanal fisheries of the litoral of Oiapoque and coast of Cabo Oarange National Park and discuss the current status of the conflicts generated by the use of overlap areas by different fleets in these environments. The data collection was by semi-structured and unstructured interviews to focal groups, of fishermen and managers of protected areas, by participatory maps, and by georeferencing of fishery places (in the estuary of the Oiapoque river and coast of Cabo Orange National Park). Fifteen fishery areas were recorded in two zones and were identified three types of conflict involving fishermen of the Oiapoque Municipality.Keyword: fishing areas conflict; litoral of the National National Park of Cabo Orange

Vivir y morir en Tibanica: reflexiones sobre el poder y el espacio en una aldea muisca tardía de la sabana de Bogotá

This paper studies the relation between feasts and other issues that are traditionally related the power of Muisca chiefs in their communities. The research question deals with the linkage between different dimensions of the social stratification in the the Muisca site of Tibanica, including: feasting itself, health, kinship and nutrition. It is argued that there is no lineal relation between such variables, and that Muisca social organization is best understood from a multidimensional and comparative analysis, recognizing the complexity of the issue at hand. https://doi.org/10.22380/2539472X18En este artículo se estudia la relación entre las actividades de festejos y otras características que usualmente se atribuyen al poder de las élites muiscas. La pregunta de investigación se refiere a la relación entre diferentes dimensiones de análisis de la jerarquización muisca en el sitio tardío de Tibanica: realización de festejos, niveles de salud, parentesco y alimentación. Se concluye que dichas dimensiones de análisis no tienen una relación lineal entre sí, lo cual invita a entender las diferencias sociales en la población muisca desde una perspectiva multidimensional y comparativa, que haga honor a la complejidad del problema. https://doi.org/10.22380/2539472X1

Systematic Prioritization of Candidate Genes in Disease Loci Identifies TRAFD1 as a Master Regulator of IFN gamma Signaling in Celiac Disease

Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD. We used four different in silico approaches-Mendelian randomization inverse variance weighting, COLOC, LD overlap, and DEPICT-to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signaling and T cell activation pathways. Fifty-one of these genes are targets of known drug compounds or likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAF-type zinc finger domain containing 1 (TRAFD1), and were found to be involved in interferon (IFN)gamma signaling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments in a human monocytic cell line that validated the role of TRAFD1 as an immune regulator acting in trans. Our strategy confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and IFN gamma signaling as well as with MHC I antigen processing, both major players of immune activation and CeD pathogenesis

Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits

Effective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans