Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products

BACKGROUND: Atherosclerosis is an inflammatory disease in which a perpetuated activation of NFkappaB via the RAGE (receptor for advanced glycation end products)-MAPK signalling pathway may play an important pathogenetic role. As recently S100 proteins have been identified as ligands of RAGE, we sought to determine the effects of the proinflammatory heterodimer of S100A8/S100A9 on the RAGE-NFkappaB mediated induction of proinflammatory gene expression. METHODS: Human umbilical vein endothelial cells (HUVEC) were preincubated for 72 h with AGE-albumin or unmodified albumin for control, whereas AGE-albumin induction resulted in an upregulation of RAGE. Following this preactivation, cells were stimulated for 48 h with heterodimeric human recombinant S100A8/S100A9. RESULTS: Heterodimeric S100A8/S100A9 enhanced secretion of IL-6, ICAM-1, VCAM-1 and MCP1 in AGE-albumin pretreated HUVEC in a dose dependent manner. These effects could not be detected after stimulation with the homodimeric proteins S100A8, S100A9, S100A1 and S100B. The effects of heterodimeric S100A8/S100A9 were reduced by inhibition of the MAP-kinase pathways ERK1/2 and p38 by PD 98059 and SB 203580, respectively. CONCLUSION: The heterodimeric S100A8/S100A9 might therefore play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure, pathophysiological entities associated with a high AGE burden. Thus, blocking heterodimeric S100A8/S100A9 might represent a novel therapeutic modality in treating atherosclerosis

Political opportunity structures, democracy, and civil war

Theories of mobilization suggest that groups are more likely to resort to violence in the presence of political opportunity structures that afford greater prospects for extracting concessions from the government or better opportunities to topple ruling governments. However, existing efforts to consider the possible influences of political opportunity structures on incentives for violence and civil war empirically have almost invariably relied upon measures of democracy to proxy for the hypothesized mechanisms, most notably the argument that the opposing effects of political accommodation and repression will give rise to an inverted U-shaped relationship between democracy and the risk of civil war. The authors detail a number of problems with measures of democracy as proxies for political opportunity structures and develop alternative measures based on the likely risks that political leaders will lose power in irregular challenges and their implications for the incentives for resort to violence. The authors evaluate empirically how the security with which leaders hold office influences the prospects of violent civil conflict. The findings indicate that recent irregular leader entry and transitions indeed increase the risk of conflict onset, while democratic institutions are found to decrease the risk of civil war, after controlling for the new measures of state weakness. </jats:p

Working on common ground

Meeting: World Commission on Environment and Development, Public Hearing, 26-27 May 1986, Ottawa, ON, CARelated to DAP 87-4249 under which IDRC supported the WCED to acquire and duplicate original papers, submissions, tapes and transcripts, became the depository of all original archival materials and received the right to microfiche the collection for broader disseminatio

Pathways toward a Decarbonized Future—Impact on Security of Supply and System Stability in a Sustainable German Energy System

Pathways leading to a carbon neutral future for the German energy system have to deal with the expected phase-out of coal-fired power generation, in addition to the shutdown of nuclear power plants and the rapid ramp-up of photovoltaics and wind power generation. An analysis of the expected impact on electricity market, security of supply, and system stability must consider the European context because of the strong coupling—both from an economic and a system operation point of view—through the cross-border power exchange of Germany with its neighbors. This analysis, complemented by options to improve the existing development plans, is the purpose of this paper. We propose a multilevel energy system modeling, including electricity market, network congestion management, and system stability, to identify challenges for the years 2023 and 2035. Out of the results, we would like to highlight the positive role of innovative combined heat and power (CHP) solutions securing power and heat supply, the importance of a network congestion management utilizing flexibility from sector coupling, and the essential network extension plans. Network congestion and reduced security margins will become the new normal. We conclude that future energy systems require expanded flexibilities in combination with forward planning of operation

Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

Cardiac-restricted overexpression of the Ca(2+)-binding protein S100A1 has been shown to lead to increased myocardial contractile performance in vitro and in vivo. Since decreased cardiac expression of S100A1 is a characteristic of heart failure, we tested the hypothesis that S100A1 gene transfer could restore contractile function of failing myocardium. Adenoviral S100A1 gene delivery normalized S100A1 protein expression in a postinfarction rat heart failure model and reversed contractile dysfunction of failing myocardium in vivo and in vitro. S100A1 gene transfer to failing cardiomyocytes restored diminished intracellular Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) load mechanistically due to increased SR Ca(2+) uptake and reduced SR Ca(2+) leak. Moreover, S100A1 gene transfer decreased elevated intracellular Na(+) concentrations to levels detected in nonfailing cardiomyocytes, reversed reactivated fetal gene expression, and restored energy supply in failing cardiomyocytes. Intracoronary adenovirus-mediated S100A1 gene delivery in vivo to the postinfarcted failing rat heart normalized myocardial contractile function and Ca(2+) handling, which provided support in a physiological context for results found in myocytes. Thus, the present study demonstrates that restoration of S100A1 protein levels in failing myocardium by gene transfer may be a novel therapeutic strategy for the treatment of heart failure