Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis.

As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1β in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulence-associated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1β in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1-dependent manner. However, during TB, MTB promotes NLRP3- and caspase-1-independent IL-1β release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models.

Memorial exercises in honor of William Boyd Allison : in Hall of House of Representatives, State Capitol, Des Moines, Iowa, Tuesday, September 8, 1908

Program of the memorial in honor of William Boyd Allison, senior Senator of the State of Iowa, who died at his home in Dubuque, Iowa, August 4, 1908. It includes full text of remarks presented at the memorial by dignitaries in attendance.

Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver.

AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated the effect of a short-term overexpression of AMPK specifically in the liver by adenovirus-mediated transfer of a gene encoding a constitutively active form of AMPKalpha2 (AMPKalpha2-CA). Hepatic AMPKalpha2-CA expression significantly decreased blood glucose levels and gluconeogenic gene expression. Hepatic expression of AMPKalpha2-CA in streptozotocin-induced and ob/ob diabetic mice abolished hyperglycemia and decreased gluconeogenic gene expression. In normal mouse liver, AMPKalpha2-CA considerably decreased the refeeding-induced transcriptional activation of genes encoding proteins involved in glycolysis and lipogenesis and their upstream regulators, SREBP-1 (sterol regulatory element-binding protein-1) and ChREBP (carbohydrate response element-binding protein). This resulted in decreases in hepatic glycogen synthesis and circulating lipid levels. Surprisingly, despite the inhibition of hepatic lipogenesis, expression of AMPKalpha2-CA led to fatty liver due to the accumulation of lipids released from adipose tissue. The relative scarcity of glucose due to AMPKalpha2-CA expression led to an increase in hepatic fatty acid oxidation and ketone bodies production as an alternative source of energy for peripheral tissues. Thus, short-term AMPK activation in the liver reduces blood glucose levels and results in a switch from glucose to fatty acid utilization to supply energy needs.

The Political Economy of Active Labor-Market Policy

Active labor-market policies (ALMPs) have developed significantly over the past two decades across Organization for Economic Cooperation and Development (OECD) countries, with substantial cross-national differences in terms of both extent and overall orientation. The objective of this article is to account for cross-national variation in this policy field. It starts by reviewing existing scholarship concerning political, institutional, and ideational determinants of ALMPs. It then argues that ALMP is too broad a category to be used without further specification, and it develops a typology of four different types of ALMPs: incentive reinforcement, employment assistance, occupation, and human capital investment. These are discussed and examined through ALMP expenditure profiles in selected countries. The article uses this typology to analyze ALMP trajectories in six Western European countries and shows that the role of this instrument changes dramatically over time. It concludes that there is little regularity in the political determinants of ALMPs. In contrast, it finds strong institutional and ideational effects, nested in the interaction between the changing economic context and existing labor-market policies.

Organisational reforms in active welfare states: A comparative analysis of the turn to 'single gateways' in Western Europe

Based on the case of reforms aimed at integrating the provision of income protection and employment services for jobless people in Europe, this thesis seeks to understand the reasons which may prompt governments to engage in large-scale organisational reforms. Over the last 20 years, several European countries have indeed radically redesigned the organisational structure of their welfare state by merging or bundling existing front-line offices in charge of benefit payment and employment services together into 'one-stop' agencies. Whereas in academic and political debates, these reforms are generally presented as a necessary and rational response to the problems and inconsistencies induced by fragmentation in a context of the reorientation of welfare states towards labour market activation, this thesis shows that the agenda setting of these reforms is in fact the result of multidimensional political dynamics. More specifically, the main argument of this thesis is that these reforms are best understood not so such from the problems induced by organisational compartmentalism, whose political recognition is often controversial, but from the various goals that governments may simultaneously achieve by means of their adoption. This argument is tested by comparing agenda-setting processes of large-scale reforms of coordination in the United Kingdom (Jobcentre Plus), Germany (Hartz IV reform) and Denmark (2005 Jobcentre reform), and contrasting them with the Swiss case where the government has so far rejected any coordination initiative involving organisational redesign. This comparison brings to light the importance, for the rise of organisational reforms, of the possibility to couple them with the following three goals: first, goals related to the strengthening of activation policies; second, institutional goals seeking to redefine the balance of responsibilities between the central state and non-state actors, and finally electoral goals for governments eager to maintain political credibility. The decisive role of electoral goals in the three countries suggests that these reforms are less bound by partisan politics than by the particular pressures facing governments arrived in office after long periods in opposition.