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Sepsis is a state of disrupted inflammatory homeostasis that is often initiated by infection. The development and progression of sepsis is multi-factorial, and affects the cardiovascular, immunological and endocrine systems of the body. The complexity of sepsis makes the clinical study of sepsis and sepsis therapeutics difficult. Animal models have been developed in an effort to create reproducible systems for studying sepsis pathogenesis and preliminary testing of potential therapeutic agents. However, demonstrated benefit from a therapeutic agent in animal models has rarely been translated into success in human clinical trials. This review summarizes the common animal sepsis models and highlights how results of recent human clinical trials might affect their use.

Sepsis is a state of disrupted inflammatory homeostasis that is often initiated by infection. The development and progression of sepsis is multi-factorial, and affects the cardiovascular, immunological and endocrine systems of the body. The complexity of sepsis makes the clinical study of sepsis and sepsis therapeutics difficult. Animal models have been developed in an effort to create reproducible systems for studying sepsis pathogenesis and preliminary testing of potential therapeutic agents. However, demonstrated benefit from a therapeutic agent in animal models has rarely been translated into success in human clinical trials. This review summarizes the common animal sepsis models and highlights how results of recent human clinical trials might affect their use.

In recent decades, an increasing persistence of atmospheric circulation patterns has been observed. In the course of the associated long-lasting anticyclonic summer circulations, heatwaves and drought spells often coincide, leading to so-called hotter droughts. Previous hotter droughts caused a decrease in agricultural yields and an increase in tree mortality. Thus, they had a remarkable effect on carbon budgets and negative economic impacts. Consequently, a quantification of ecosystem responses to hotter droughts and a better understanding of the underlying mechanisms are crucial. In this context, the European hotter drought of the year 2018 may be considered a key event. As a first step towards the quantification of its causes and consequences, we here assess anomalies of atmospheric circulation patterns, maximum temperature, and climatic water balance as potential drivers of ecosystem responses which are quantified by remote sensing using the MODIS vegetation indices (VIs) normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI). To place the drought of 2018 within a climatological context, we compare its climatic features and remotely sensed ecosystem response with the extreme hot drought of 2003. The year 2018 was characterized by a climatic dipole, featuring extremely hot and dry weather conditions north of the Alps but comparably cool and moist conditions across large parts of the Mediterranean. Analysing the ecosystem response of five dominant land cover classes, we found significant positive effects of climatic water balance on ecosystem VI response. Negative drought impacts appeared to affect an area 1.5 times larger and to be significantly stronger in July 2018 compared to August 2003, i.e. at the respective peak of drought. Moreover, we found a significantly higher sensitivity of pastures and arable land to climatic water balance compared to forests in both years. We explain the stronger coupling and higher sensitivity of ecosystem response in 2018 by the prevailing climatic dipole: while the generally water-limited ecosystems of the Mediterranean experienced above-average climatic water balance, the less drought-adapted ecosystems of central and northern Europe experienced a record hot drought. In conclusion, this study quantifies the drought of 2018 as a yet unprecedented event, outlines hotspots of drought-impacted areas in 2018 which should be given particular attention in follow-up studies, and provides valuable insights into the heterogeneous responses of the dominant European ecosystems to hotter drought.

The complement system plays an important role in mediating tissue injury after oxidative stress. The role of mannose-binding lectin (MBL) and the lectin complement pathway (LCP) in mediating complement activation after endothelial oxidative stress was investigated. iC3b deposition on hypoxic (24 hours; 1% O(2))/reoxygenated (3 hours; 21% O(2)) human endothelial cells was attenuated by N-acetyl-D-glucosamine or D-mannose, but not L-mannose, in a dose-dependent manner. Endothelial iC3b deposition after oxidative stress was also attenuated in MBL-deficient serum. Novel, functionally inhibitory, anti-human MBL monoclonal antibodies attenuated MBL-dependent C3 deposition on mannan-coated plates in a dose-dependent manner. Treatment of human serum with anti-MBL monoclonal antibodies inhibited MBL and C3 deposition after endothelial oxidative stress. Consistent with our in vitro findings, C3 and MBL immunostaining throughout the ischemic area at risk increased during rat myocardial reperfusion in vivo. These data suggest that the LCP mediates complement activation after tissue oxidative stress. Inhibition of MBL may represent a novel therapeutic strategy for ischemia/reperfusion injury and other complement-mediated disease states.

Oxidative stress increases endothelial mannose-binding lectin (MBL) binding and activates the lectin complement pathway (LCP). However, the molecular mechanism of MBL binding to the endothelium after oxidative stress is unknown. Intermediate filaments have been previously reported to activate the classical complement pathway in an antibody-independent manner. We investigated whether oxidative stress increases human umbilical vein endothelial cell (HUVEC) cytokeratin 1 (CK1) expression and activates the LCP via MBL binding to CK1. Reoxygenation (3 hours, 21% O(2)) of hypoxic HUVECs (24 hours, 1% O(2)) significantly increased CK1 mRNA (in situ hybridization) and membrane protein expression [enzyme-linked immunosorbent assay (ELISA)/confocal microscopy]. Incubating human serum (HS) with N-acetyl-D-glucosamine or anti-human MBL monoclonal antibody attenuated MBL and C3 deposition on purified CK1 (ELISA). CK1 and MBL were co-immunoprecipitated from hypoxic HUVECs reoxygenated in HS. Treatment with anti-human cytokeratin Fab fragments attenuated endothelial MBL and C3 deposition after oxidative stress (ELISA/confocal microscopy). We conclude that: 1) endothelial oxidative stress increases CK1 expression, MBL binding, and C3 deposition; 2) inhibition of MBL attenuates purified CK1-induced complement activation; and 3) anti-human cytokeratin Fab fragments attenuate endothelial MBL and C3 deposition after oxidative stress. These results suggest that MBL binding to endothelial cytokeratins may mediate LCP activation after oxidative stress.

We analyze the B → ππ, πK modes in the light of the most recent B-factory data, and obtain the following new results: (i) the modes prefer γ = (74±6)°, which - together with |Vub/Vcb| - allows us to determine the \"true\" unitarity triangle and to search for CP-violating new-physics contributions to B0d- mixing; (ii) the B → πK puzzle reflected in particular by the low experimental value of the ratio Rn of the neutral B → πK rates persists and still favors new physics in the electroweak penguin sector with a new CP-violating phase ϕ ~ –90°, although now also ϕ ~ +90° can bring us rather close to the data; (iii) the mixing-induced CP asymmetry is a sensitive probe of the sign of this phase, and would currently favor ϕ ~ +90°, as well as the direct CP asymmetry of , which suffers, however, from large hadronic uncertainties; (iv) we investigate the sensitivity of our B → πK analysis to large non-factorizable SU(3)-breaking effects and find that their impact is surprisingly small so that it is indeed exciting to speculate on new physics; (v) assuming that new physics enters through Z0 penguins, we study the interplay between B → πK and rare B, K decays and point out that the most recent B-factory constraints for the latter have interesting implications, bringing us to a few scenarios for the future evolution of the data, where also the mixing-induced CP violation in plays a prominent rôle.

CpG oligodeoxynucleotides (ODNs) may prevent mortality from infection. We have identified a therapeutic benefit in treating sepsis with phosphorothioate ODN sequences containing the CpG motif. Sepsis was induced in rats by cecal ligation and puncture (CLP), and treatment with CpG ODNs reduced sepsis mortality from 80% to 15% during a 108-h period. Protection from mortality was dose dependent. Bacterial load in peritoneal fluid was reduced in CpG ODN–treated versus non-CpG ODN–treated rats after CLP. Lung injury, as determined by total myeloperoxidase activity, was also reduced in CpG ODN–treated versus non-CpG ODN–treated rats after CLP. Indirect evidence suggests that CpG-induced expression of interleukin (IL)–23 as levels of p40—but not p35—were significantly increased in both plasma and peritoneal lavage fluid in CpG ODN–treated versus non-CpG ODN–treated rats 24 h after CLP. Anti–IL-17 antibody inhibited the CpG-mediated prevention of mortality. These data suggest that IL-17 may mediate CpG-inducible host defenses during intraabdominal sepsis