Retrovirus-induced target cell activation in the early phases of infection: the mouse mammary tumor virus model.

Mouse mammary tumor virus (MMTV) infects B lymphocytes and expresses a superantigen on the cell surface after integration of its reverse-transcribed genome. Superantigen-dependent B- and T-cell activation becomes detectable 2 to 3 days after infection. We show here that before this event, B cells undergo a polyclonal activation which does not involve massive proliferation. This first phase of B-cell activation is T cell independent. Moreover, during the first phase of activation, when only a small fraction of B cells is infected by MMTV(SW), viral DNA is detected only in activated B cells. Such a B-cell activation is also seen after injection of murine leukemia virus but not after injection of vaccinia virus, despite the very similar kinetics and intensity of the immune response. Since retroviruses require activated target cells to induce efficient infection, these data suggest that the early polyclonal retrovirus-induced target cell activation might play an important role in the establishment of retroviral infections.

Teaching, research and service: Experience and opinions of accounting Spanish academics

Research, teaching and service are the main activities carried out in almost all European universities. Previous research, which has been mainlycentred in North-American universities, has found solid results indicatingthat research and teaching are not equally valued when deciding on facultypromotion. This conclusion creates a potential conflict for accountingacademics on how to distribute working time in order to accomplish personalcareer objectives. This paper presents the results of a survey realisedin two European countries: Spain and the United Kingdom, which intendedto explore the opinions and personal experience of accounting academicsworking in these countries. Specifically, we focus on the following issues:(i) The impact of teaching and service on time available for research;(ii) The integration of teaching and research; (iii) The perceived valueof teaching and research for career success and (iv) The interaction betweenprofessional accounting and accounting research. The results show thatboth in Spain and in the United Kingdom there is a conflict between teachingand research, which has its origin in the importance attached to researchactivities on promotion decisions. It also seems evident that so far, theconflict is being solved in favour of research in prejudice of teaching.

National Adaptation Programme of Action on Climate Change - 2008 - 2012

The archipelago of Cape Verde is made up of ten islands and nine islets and is located between latitudes 14º 28' N and 17º 12' N and longitudes 22º 40' W and 25º 22' W. It is located approximately 500 km from the Senegal coast in West Africa (Figure 1). The islands are divided into two groups: Windward and Leeward. The Windward group is composed of the islands of Santo Antão, São Vicente, Santa Luzia, São Nicolau, Sal and Boavista; and the Leeward group is composed of the islands Maio, Santiago, Fogo and Brava. The archipelago has a total land surface of 4,033 km2 and an Economic Exclusive Zone (ZEE) that extends for approximately 734,000 km2. In general, the relief is very steep, culminating with high elevations (e.g. 2,829 m on Fogo and 1,979 m on Santo Antão). The surface area, geophysical configuration and geology vary greatly from one island to the next. Cape Verde, due to its geomorphology, has a dense and complex hydrographical network. However, there are no permanent water courses and temporary water courses run only during the rainy season. These temporary water courses drain quickly towards the main watersheds, where, unless captured by artificial means, continue rapidly to lower areas and to the sea. This applies equally to the flatter islands. The largest watershed is Rabil with an area of 199.2 km2. The watershed areas on other islands extend over less than 70 km2. Cape Verde is both a least developed country (LDC) and a small island development state (SIDS). In 2002, the population of Cape Verde was estimated at approximately 451,000, of whom 52% were women and 48% men. The population was growing at an average 2.4% per year, and the urban population was estimated at 53.7 %. Over the past 15 years, the Government has implemented a successful development strategy, leading to a sustained economic growth anchored on development of the private sector and the integration of Cape Verde into the world economy. During this period, the tertiary sector has become increasingly important, with strong growth in the tourism, transport, banking and trade sectors. Overall, the quality of life indicators show substantial improvements in almost all areas: housing conditions, access to drinking water and sanitation, use of modern energy in both lighting and cooking, access to health services and education. Despite these overall socio-economic successes, the primary sector has witnessed limited progress. Weak performance in the primary sector has had a severe negative impact on the incomes and poverty risks faced by rural workers1. Moreover, relative poverty has increased significantly during the past decade. The poverty profile shows that: (i) extreme poverty is mostly found in rural areas, although it has also increased in urban areas; (ii) poverty is more likely to occur when the head of the household is a woman; (iii) poverty increases with family size; (iv) education significantly affects poverty; (v) the predominantly agricultural islands of Santo Antão and Fogo have the highest poverty rates; (vi) unemployment affects the poor more than the nonpoor; (vii) agriculture and fisheries workers are more likely to be poor than those in other sectors. Therefore, the fight against poverty and income inequalities remains one of the greatest challenges for Cape Verde authorities. The various governments of Cape Verde over the last decade have demonstrated a commitment to improving governance, notably by encouraging a democratic culture that guarantees stability and democratic changes without conflicts. This democratic governance offers a space for a wider participation of citizens in public management and consolidates social cohesion. However, there are some remaining challenges related to democratic governance and the gains must be systematically monitored. Finally, it is worth emphasizing that the country’s insularity has stimulated a movement to decentralized governance, although social inequalities and contrasts from one island to the next constitute, at the same time, challenges and opportunities.

Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation.

Although Drosophila systemic immunity is extensively studied, little is known about the fly's intestine-specific responses to bacterial infection. Global gene expression analysis of Drosophila intestinal tissue to oral infection with the Gram-negative bacterium Erwinia carotovora revealed that immune responses in the gut are regulated by the Imd and JAK-STAT pathways, but not the Toll pathway. Ingestion of bacteria had a dramatic impact on the physiology of the gut that included modulation of stress response and increased stem cell proliferation and epithelial renewal. Our data suggest that gut homeostasis is maintained through a balance between cell damage due to the collateral effects of bacteria killing and epithelial repair by stem cell division. The Drosophila gut provides a powerful model to study the integration of stress and immunity with pathways associated with stem cell control, and this study should prove to be a useful resource for such further studies.

The role of phylogeny in the spatial distributions and assembly of mountain plant communities.

A major challenge in community ecology is a thorough understanding of the processes that govern the assembly and composition of communities in time and space. The growing threat of climate change to the vascular plant biodiversity of fragile ecosystems such as mountains has made it equally imperative to develop comprehensive methodologies to provide insights into how communities are assembled. In this perspective, the primary objective of this PhD thesis is to contribute to the theoretical and methodological development of community ecology, by proposing new solutions to better detect the ecological and evolutionary processes that govern community assembly. As phylogenetic trees provide by far, the most advanced tools to integrate the spatial, ecological and evolutionary dynamics of plant communities, they represent the cornerstone on which this work was based. In this thesis, I proposed new solutions to: (i) reveal trends in community assembly on phylogenies, depicted by the transition of signals at the nodes of the different species and lineages responsible for community assembly, (ii) contribute to evidence the importance of evolutionarily labile traits in the distribution of mountain plant species. More precisely, I demonstrated that phylogenetic and functional compositional turnover in plant communities was driven by climate and human land use gradients mostly influenced by evolutionarily labile traits, (iii) predict and spatially project the phylogenetic structure of communities using species distribution models, to identify the potential distribution of phylogenetic diversity, as well as areas of high evolutionary potential along elevation. The altitudinal setting of the Diablerets mountains (Switzerland) provided an appropriate model for this study. The elevation gradient served as a compression of large latitudinal variations similar to a collection of islands within a single area, and allowed investigations on a large number of plant communities. Overall, this thesis highlights that stochastic and deterministic environmental filtering processes mainly influence the phylogenetic structure of plant communities in mountainous areas. Negative density-dependent processes implied through patterns of phylogenetic overdispersion were only detected at the local scale, whereas environmental filtering implied through phylogenetic clustering was observed at both the regional and local scale. Finally, the integration of indices of phylogenetic community ecology with species distribution models revealed the prospects of providing novel and insightful explanations on the potential distribution of phylogenetic biodiversity in high mountain areas. These results generally demonstrate the usefulness of phylogenies in inferring assembly processes, and are worth considering in the theoretical and methodological development of tools to better understand phylogenetic community structure.

A model of conglomeration and synergy traps

We present a model of conglomeration motivated by technology synergies and strategic reductions in variable costs in the face of competitive pressures. The resulting firm integration is neither horizontal nor vertical but rather congeneric integration of firms in related industries. We endogenize the industrial conglomeration structure and examine the effects of competition between conglomerates, and between a conglomerate and independent firms. We show that there is an equilibrium synergy trap in which conglomerates are formed to exploit economies of scope, but resulting profits are lower than under the status quo. We also show that strategic firm integration can occur even in the presence of diseconomies of scope. The model helps to explain features of recent mergers and acquisitions experience.

NOTCH1 can initiate NF-κB activation via cytosolic interactions with components of the T cell Signalosome.

T cell stimulation requires the input and integration of external signals. Signaling through the T cell receptor (TCR) is known to induce formation of the membrane-tethered CBM complex, comprising CARMA1, BCL10, and MALT1, which is required for TCR-mediated NF-κB activation. TCR signaling has been shown to activate NOTCH proteins, transmembrane receptors also implicated in NF-κB activation. However, the link between TCR-mediated NOTCH signaling and early events leading to induction of NF-κB activity remains unclear. In this report, we demonstrate a novel cytosolic function for NOTCH1 and show that it is essential to CBM complex formation. Using a model of skin allograft rejection, we show in vivo that NOTCH1 acts in the same functional pathway as PKCθ, a T cell-specific kinase important for CBM assembly and classical NF-κB activation. We further demonstrate in vitro NOTCH1 associates physically with PKCθ and CARMA1 in the cytosol. Unexpectedly, when NOTCH1 expression was abrogated using RNAi approaches, interactions between CARMA1, BCL10, and MALT1 were lost. This failure in CBM assembly reduced inhibitor of kappa B alpha phosphorylation and diminished NF-κB-DNA binding. Finally, using a luciferase gene reporter assay, we show the intracellular domain of NOTCH1 can initiate robust NF-κB activity in stimulated T cells, even when NOTCH1 is excluded from the nucleus through modifications that restrict it to the cytoplasm or hold it tethered to the membrane. Collectively, these observations provide evidence that NOTCH1 may facilitate early events during T cell activation by nucleating the CBM complex and initiating NF-κB signaling.

Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease.

In adult mammals, neural progenitors located in the dentate gyrus retain their ability to generate neurons and glia throughout lifetime. In rodents, increased production of new granule neurons is associated with improved memory capacities, while decreased hippocampal neurogenesis results in impaired memory performance in several memory tasks. In mouse models of Alzheimer's disease, neurogenesis is impaired and the granule neurons that are generated fail to integrate existing networks. Thus, enhancing neurogenesis should improve functional plasticity in the hippocampus and restore cognitive deficits in these mice. Here, we performed a screen of transcription factors that could potentially enhance adult hippocampal neurogenesis. We identified Neurod1 as a robust neuronal determinant with the capability to direct hippocampal progenitors towards an exclusive granule neuron fate. Importantly, Neurod1 also accelerated neuronal maturation and functional integration of new neurons during the period of their maturation when they contribute to memory processes. When tested in an APPxPS1 mouse model of Alzheimer's disease, directed expression of Neurod1 in cycling hippocampal progenitors conspicuously reduced dendritic spine density deficits on new hippocampal neurons, to the same level as that observed in healthy age-matched control animals. Remarkably, this population of highly connected new neurons was sufficient to restore spatial memory in these diseased mice. Collectively our findings demonstrate that endogenous neural stem cells of the diseased brain can be manipulated to become new neurons that could allow cognitive improvement.

Cardiac paraganglioma: diagnostic work up and review of the literature.

Paraganglioma of the heart are potentially invasive, highly vascularized tumors for which complete resection may be curative. Derived from the cardiac wall in most instances, resectability can be assessed after integration of the data provided by MRI in T2 sequence, and coronarography. A fully documented case of a large cardiac pheochromocytoma of the left atrium and AV groove is reported and the pertinent literature on the subject is here presented.

Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era.

PURPOSE OF REVIEW: Many chemotherapeutic drugs, including fluoropyrimidines, platinums, CPT-11, taxanes and adriamycin have single-agent activity in advanced gastric cancer. Although combination chemotherapy has been shown to be more effective than single agents, response rates between 30 and 50% have not fulfilled their promise as progression-free survival from the best combinations ranges between 3 and 7 months and overall survival between 8 and 11 months. The development of targeted therapies in gastric cancer clearly stays behind the integration of these novel agents into new treatment concepts for patients with colorectal cancer. This review summarizes the experience and major recent advances in the development of targeted therapies in advanced gastric cancer. RECENT FINDINGS: Recent publications on targeted therapies in gastric cancer are limited to nonrandomized phase I or II trials. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors epidermal growth factor receptor 1 and HER2. SUMMARY: Adequately powered, randomized phase III trials are necessary to define the clinical role of targeted therapies in advanced gastric cancer. Biomarker studies to correlate with treatment outcomes will be critical to identify patients who benefit most from chemotherapy and targeted therapy.

A protein interaction atlas for the nuclear receptors: properties and quality of a hub-based dimerisation network.

BACKGROUND: The nuclear receptors are a large family of eukaryotic transcription factors that constitute major pharmacological targets. They exert their combinatorial control through homotypic heterodimerisation. Elucidation of this dimerisation network is vital in order to understand the complex dynamics and potential cross-talk involved. RESULTS: Phylogeny, protein-protein interactions, protein-DNA interactions and gene expression data have been integrated to provide a comprehensive and up-to-date description of the topology and properties of the nuclear receptor interaction network in humans. We discriminate between DNA-binding and non-DNA-binding dimers, and provide a comprehensive interaction map, that identifies potential cross-talk between the various pathways of nuclear receptors. CONCLUSION: We infer that the topology of this network is hub-based, and much more connected than previously thought. The hub-based topology of the network and the wide tissue expression pattern of NRs create a highly competitive environment for the common heterodimerising partners. Furthermore, a significant number of negative feedback loops is present, with the hub protein SHP [NR0B2] playing a major role. We also compare the evolution, topology and properties of the nuclear receptor network with the hub-based dimerisation network of the bHLH transcription factors in order to identify both unique themes and ubiquitous properties in gene regulation. In terms of methodology, we conclude that such a comprehensive picture can only be assembled by semi-automated text-mining, manual curation and integration of data from various sources.

The geographical concentration of industry across Spanish Regions, 1856-1995

New economic geography models show that there may be a strong relationship between economic integration and the geographical concentration of industries. Nevertheless, this relationship is neither unique nor stable, and may follow a ?-shaped pattern in the long term. The aim of the present paper is to analyze the evolution of the geographical concentration of manufacturing across Spanish regions during the period 1856-1995. We construct several geographical concentration indices for different points in time over these 140 years. The analysis is carried out at two levels of aggregation, in regions corresponding to the NUTS-II and NUTS-III classifications. We confirm that the process of economic integration stimulated the geographical concentration of industrial activity. Nevertheless, the localization coefficients only started to fall after the beginning of the integration of the Spanish Economy into the international markets in the mid-70s, and this new path was not interrupted by Spain¿s entry in the European Union some years later

Contribution of the gap junction proteins Connexin40 and Connexin43 to the control of blood pressure

Summary Cells in tissues and organs coordinate their activities by communicating with each other through intercellular channels named gap junctions. These channels are conduits between the cytoplasmic compartments of adjacent cells, allowing the exchange of small molecules which may be crucial for hormone secretion. Renin is normally secreted in a regulated manner by specific cells of the juxtaglomerular apparatus located within the renal cortex. Gap junctional communication may be requisite to maintain an accurate functioning in coordination of renin-producing cells, more especially as renin is of paramount importance for the control of blood pressure. Connexin43 (Cx43) and Cx40 form gap junctions that link in vivo the cells of the juxtaglomerular apparatus. Cx43 links the endothelial cells, whereas gap junctions made of Cx40 connect the endothelial cells, the renin secreting cells, as well as the endothelial cells of to the renin-secreting cells of the afferent arteriole. The observation that loss of Cx40 results in chronic hypertension associated with altered vasomotion and signal conduction along arterioles, has lead us to suggest that connexins may contribute to control blood pressure by participating to the integration of various mechanical, osmotic and electrochemical stimuli involved in the control of renin secretion and by mediating the adaptive changes of the vascular wall induced by elevated blood pressure and mechanical stress. We therefore postulated that the absence of Cx40 could have deleterious effects on the coordinated functioning of the renin-containing cells, hence accounting for hypertension. In the first part of my thesis, we reported that Cx40-deficient mice (Cx40) are hypertensive due to increased plasma renin levels and numbers of renin-producing cells. Besides, we demonstrated that prostaglandins and nitric oxide, which are possible mediators in the regulation of renin secretion by the macula densa, exert a critical role in the mechanisms controlling blood pressure ín Cx40 knockout hypertensive mice. In view of previous studies that stated avessel-specifc increase in the expression of Cx43 during renin-dependent hypertension, we hypothesized that Cx43 channels are particularly well-matched to integrate the response of cells constituting the vascular wall to hypertensive conditions. Using transgenic mice in which Cx43 was replaced by Cx32, we revealed that the replacement of Cx43 by Cx32 is associated with decreased expression and secretion of renin and prevent the renin-dependent hypertension which is normally induced in the 2K1C model. To gain insights into the regulation of connexins in two separate tissues exposed to the same fluid pressure, the second part of my thesis work was dedicated to the study of the impact of chronic hypertension and related hypertrophy on the expression of the cardiovascular connexins (Cx40, Cx37, Cx43 and Cx45) in mouse aorta and heart. Our results documented that the expression of connexins is differentially regulated in mouse aorta. according to the models of hypertension. Thus, blood pressure induces mechanical forces that differentially alter the expression of vascular connexins in order to respond to an adaptation of the aortic wall observed under pathological conditions. Altogether these data provide the first evidences that intercellular communication mediated by gap junctions is required for a proper renin secretion from the juxtaglomerular apparatus in order to control blood pressure.

Analysis, modelling and classification of geospatial data using machine learning

The research considers the problem of spatial data classification using machine learning algorithms: probabilistic neural networks (PNN) and support vector machines (SVM). As a benchmark model simple k-nearest neighbor algorithm is considered. PNN is a neural network reformulation of well known nonparametric principles of probability density modeling using kernel density estimator and Bayesian optimal or maximum a posteriori decision rules. PNN is well suited to problems where not only predictions but also quantification of accuracy and integration of prior information are necessary. An important property of PNN is that they can be easily used in decision support systems dealing with problems of automatic classification. Support vector machine is an implementation of the principles of statistical learning theory for the classification tasks. Recently they were successfully applied for different environmental topics: classification of soil types and hydro-geological units, optimization of monitoring networks, susceptibility mapping of natural hazards. In the present paper both simulated and real data case studies (low and high dimensional) are considered. The main attention is paid to the detection and learning of spatial patterns by the algorithms applied.

BIO-INSPIRED COMPUTATIONAL TECHNIQUES APPLIED TO THE CLUSTERING AND VISUALIZATION OF SPATIO-TEMPORAL GEOSPATIAL DATA

The coverage and volume of geo-referenced datasets are extensive and incessantly¦growing. The systematic capture of geo-referenced information generates large volumes¦of spatio-temporal data to be analyzed. Clustering and visualization play a key¦role in the exploratory data analysis and the extraction of knowledge embedded in¦these data. However, new challenges in visualization and clustering are posed when¦dealing with the special characteristics of this data. For instance, its complex structures,¦large quantity of samples, variables involved in a temporal context, high dimensionality¦and large variability in cluster shapes.¦The central aim of my thesis is to propose new algorithms and methodologies for¦clustering and visualization, in order to assist the knowledge extraction from spatiotemporal¦geo-referenced data, thus improving making decision processes.¦I present two original algorithms, one for clustering: the Fuzzy Growing Hierarchical¦Self-Organizing Networks (FGHSON), and the second for exploratory visual data analysis:¦the Tree-structured Self-organizing Maps Component Planes. In addition, I present¦methodologies that combined with FGHSON and the Tree-structured SOM Component¦Planes allow the integration of space and time seamlessly and simultaneously in¦order to extract knowledge embedded in a temporal context.¦The originality of the FGHSON lies in its capability to reflect the underlying structure¦of a dataset in a hierarchical fuzzy way. A hierarchical fuzzy representation of¦clusters is crucial when data include complex structures with large variability of cluster¦shapes, variances, densities and number of clusters. The most important characteristics¦of the FGHSON include: (1) It does not require an a-priori setup of the number¦of clusters. (2) The algorithm executes several self-organizing processes in parallel.¦Hence, when dealing with large datasets the processes can be distributed reducing the¦computational cost. (3) Only three parameters are necessary to set up the algorithm.¦In the case of the Tree-structured SOM Component Planes, the novelty of this algorithm¦lies in its ability to create a structure that allows the visual exploratory data analysis¦of large high-dimensional datasets. This algorithm creates a hierarchical structure¦of Self-Organizing Map Component Planes, arranging similar variables' projections in¦the same branches of the tree. Hence, similarities on variables' behavior can be easily¦detected (e.g. local correlations, maximal and minimal values and outliers).¦Both FGHSON and the Tree-structured SOM Component Planes were applied in¦several agroecological problems proving to be very efficient in the exploratory analysis¦and clustering of spatio-temporal datasets.¦In this thesis I also tested three soft competitive learning algorithms. Two of them¦well-known non supervised soft competitive algorithms, namely the Self-Organizing¦Maps (SOMs) and the Growing Hierarchical Self-Organizing Maps (GHSOMs); and the¦third was our original contribution, the FGHSON. Although the algorithms presented¦here have been used in several areas, to my knowledge there is not any work applying¦and comparing the performance of those techniques when dealing with spatiotemporal¦geospatial data, as it is presented in this thesis.¦I propose original methodologies to explore spatio-temporal geo-referenced datasets¦through time. Our approach uses time windows to capture temporal similarities and¦variations by using the FGHSON clustering algorithm. The developed methodologies¦are used in two case studies. In the first, the objective was to find similar agroecozones¦through time and in the second one it was to find similar environmental patterns¦shifted in time.¦Several results presented in this thesis have led to new contributions to agroecological¦knowledge, for instance, in sugar cane, and blackberry production.¦Finally, in the framework of this thesis we developed several software tools: (1)¦a Matlab toolbox that implements the FGHSON algorithm, and (2) a program called¦BIS (Bio-inspired Identification of Similar agroecozones) an interactive graphical user¦interface tool which integrates the FGHSON algorithm with Google Earth in order to¦show zones with similar agroecological characteristics.