76 research outputs found

    Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1- and Cathepsin B-Independent Necrosis

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    Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasome in macrophages, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis. These are mediated through caspase-1 and cathepsin-B, respectively. Human monocyte-derived macrophages were infected with virulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in strongly enhanced release of IL-1β, while a low MOI gave no IL-1β response. The infected macrophages were collected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane was determined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensive DNA fragmentation, loss of mitochondrial membrane potential, loss of plasma membrane integrity, and HMGB1 release. Although we observed plasma membrane permeabilization and IL-1β release from infected cells, the cell death induced by Mtb was not dependent on caspase-1 or cathepsin B. It was, however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches a threshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process

    Energy Demand and Temperature: A Dynamic Panel Analysis

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    This paper is a first attempt to investigate the effect of climate on the demand for different energy vectors from different final users. The ultimate motivation for this is to arrive to a consistent evaluation of the impact of climate change on key consumption goods and primary factors such as energy vectors. This paper addresses these issues by means of a dynamic panel analysis of the demand for coal, gas, electricity, oil and oil products by residential, commercial and industrial users in OECD and (a few) non-OECD countries. It turns out that temperature has a very different influence on the demand of energy vectors as consumption goods and on their demand as primary factors. In general, residential demand responds negatively to temperature increases, while industrial demand is insensitive to temperature increases. As to the service sector, only electricity demand displays a mildly significant negative elasticity to temperature changes

    TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

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    NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohns disease. We found that TRIM27 expression is increased in Crohns disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus. We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases.Funding Agencies|German Research Foundation (DFG)|SFB670-NG01|Swedish Society of Medicine||Regional Research Council of South-East Sweden (FORSS)||Swedish Research Council division of Medicine||Gustav V 90th anniversary foundation||Italian Telethon Foundation||DFG|SE 1122/2-1|</p

    The Nontradable Share Reform in the Chinese Stock Market

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    Nontradable shares (NTS) are an unparalleled feature of the ownership structure of Chinese listed companies and represented a major hurdle to domestic financial market development. After some failed attempts, in 2005 the Chinese authorities have launched a structural reform program aiming at eliminating NTS. In this paper, we evaluate the stock price effects of the actual implementation of this reform in 368 firms. The NTS reform generated a statistically significant 8 percent positive abnormal return over the event window, adjusting prices for the compensation requested by tradable shareholders. Results are consistent with the expectation of improved economic fundamentals such as better corporate governance and enhanced liquidity

    Ethnic Minorities Rewarded: Ethnostratification on the Wage Market in Belgium

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    Several previous researches have confirmed the hypothesis of ethnostratification, which holds that the labour market is divided into different ethnic layers. While people of a European origin are over-represented in the top layers (the primary market), people with non-European roots and/or nationalities are more concentrated in bottom layers (the secondary market). Relative to the primary market, this secondary market is characterized by a higher chance of unemployment, lower wages, poorer working conditions and greater job insecurity. This paper deals with a very important condition of work: the wage. Does origin have an impact on the level of wage? We make a distinction between nine origin groups: Belgians, North en West Europeans, South Europeans (from Greece, Spain, Portugal), Italians, East Europeans, Moroccans, Turks, Sub Sahara Africans and Asians. The first part of this article briefly describes the database used for the analyses and presents a few general figures for the total Belgian population. In the second part we examine the impact of origin on wage levels. For each origin group we will give an overview of the average daily wages and the partition over the wage classes. For the weaker populations, gender and age are taken into account. Finally, by means of a regression analysis, we will examine the influence of origin while controlling a few other variables that may influence the wage level

    Eliciting the Demand for Long Term Care Coverage: A Discrete Choice Modelling Analysis

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    We evaluate the demand for long term care (LTC) insurance prospects in a stated preference context, by means of the results of a choice experiment carried out on a representative sample of the Emilia-Romagna population. Choice modelling techniques have not been used yet for studying the demand for LTC services. In this paper these methods are first of all used in order to assess the relative importance of the characteristics which define some hypothetical insurance programmes and to elicit the willingness to pay for some LTC coverage prospects. Moreover, thanks to the application of a nested logit specification with partial degeneracy, we are able to model the determinants of the preference for status quo situations where no systematic cover for LTC exists. On the basis of this empirical model, we test for the effects of a series of socio-demographic variables as well as personal and household health state indicators

    Entry and Exit Strategies in Migration Dynamics

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    This work is devoted to study the role of combined entry and exit strategies in the migration process. We develop a real option model in which the community of immigrants in the host country is described as a club and the immigrants benefits is a U-shaped function, depending on the dimension of the district. There exist two threshold levels: the first one triggers the migration choice, while the second triggers the return to the country of origin. The theoretical results show that the phenomenon of hysteresis is amplified by the existence of a community both in the entry case and in the exit case. Furthermore, the community can reduce the minimum wage level required to trigger both exit and entry: this fact could explain why in some cases we observe migration inflows with a low wage differential and also with underunemployment. We show also some possible further extensions of the model: in one case we introduce a possible way to select the entrants skills and in another case we show some theoretical implementations to include possible policy shocks in the migrants choice

    Participatory Approach in Decision Making Processes for Water Resources Management in the Mediterranean Basin

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    This paper deals with the comparative analysis of different policy options for water resources management in three south-eastern Mediterranean countries. The applied methodology follows a participatory approach throughout its implementation and is supported by the use of three different software packages dealing with water allocation budget, water quality simulation, and Multi Criteria Analysis, respectively. The paper briefly describes the general objectives of the SMART project and then presents the three local case studies, the valuation objectives and the applied methodology - developed as a general replicable framework suitable for implementation in other decision-making processes. All the steps needed for a correct implementation are therefore described. Following the conceptualisation of the problem, the choice of the appropriate indicators as well as the calculation of their weighting and value functions are detailed. The paper concludes with the results of the Multi Criteria and the related Sensitivity Analyses performed, showing how the different policy responses under consideration can be assessed and furthermore compared through case studies thanks to their relative performances. The adopted methodology was found to be an effective operational approach for bridging scientific modelling and policy making by integrating the model outputs in a conceptual framework that can be understood and utilised by non experts, thus showing concrete potential for participatory decision making
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