370 research outputs found
Designing a Resilient Waterscape Using a Living Lab and catalyzing Polycentric Governance
The both polycentric governance and Living Labs concepts are based on decentralized participatory planning, co-design, and decisionmaking. While the concept of Living Lab is still emerging, the Isar-Plan (2000 ~ 2011) pioneered the approach for selecting, co-designing, and implementing nature-based solutions along the Isar River in Munich, Germany. Despite multiple governing authorities involved in the decisionmaking process of the Isar-Plan, the polycentric governance that led to the success of the project has to date not been analyzed. This paper presents the results of an ex-post-analysis of the Isar-Plan restoration planning process based on stakeholder interviews and a literature review. The contribution describes the evolution of Isar-Plan governance arrangements and discusses the Living Lab approaches to cooperative governance. The analysis demonstrates how polycentricity facilitated trust, learning, and the co-design of a resilient waterscape. The paper concludes that Living Labs can be a way of applying polycentric governance when autonomous and multi-scale decision-makers are collaboratively involved in the design of policy solutions, and vice-versa
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Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis
Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions: Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary
Vascular CXCR4 Expression – a Novel Antiangiogenic Target in Gastric Cancer?
BACKGROUND:
G-protein-coupled receptors (GPCRs) are prime candidates for novel cancer prevention and treatment strategies. We searched for differentially expressed GPCRs in node positive gastric carcinomas.
METHODOLOGY/PRINCIPAL FINDINGS:
Differential expression of GPCRs in three node positive vs. three node negative intestinal type gastric carcinomas was analyzed by gene array technology. The candidate genes CXCL12 and its receptor CXCR4 were validated by real-time reverse-transcription polymerase chain reaction in an independent set of 37 gastric carcinomas. Translation was studied by immunohistochemistry in 347 gastric carcinomas using tissue microarrays as well as in 61 matching lymph node metastases. Protein expression was correlated with clinicopathological patient characteristics and survival. 52 GPCRs and GPCR-related genes were up- or down-regulated in node positive gastric cancer, including CXCL12. Differential expression of CXCL12 was confirmed by RT-PCR and correlated with local tumour growth. CXCL12 immunopositivity was negatively associated with distant metastases and tumour grade. Only 17% of gastric carcinomas showed CXCR4 immunopositive tumour cells, which was associated with higher local tumour extent. 29% of gastric carcinomas showed CXCR4 positive tumour microvessels. Vascular CXCR4 expression was significantly associated with higher local tumour extent as well as higher UICC-stages. When expressing both, CXCL12 in tumour cells and CXCR4 in tumour microvessels, these tumours also were highly significantly associated with higher T- and UICC-stages. Three lymph node metastases revealed vascular CXCR4 expression while tumour cells completely lacked CXCR4 in all cases. The expression of CXCL12 and CXCR4 had no impact on patient survival.
CONCLUSIONS/SIGNIFICANCE:
Our results substantiate the significance of GPCRs on the biology of gastric carcinomas and provide evidence that the CXCL12-CXCR4 pathway might be a novel promising antiangiogenic target for the treatment of gastric carcinomas
Diatom-inferred salinity records from the Arctic Siverian margin: Implications for fluvial runoff patterns during the Holocene
Diatom assemblages were employed to study temporal changes of Siberian river runoff on the Laptev Sea shelf. Using a correlation between freshwater diatoms (%) in core-top sediments and summer surface water salinities from the inner Kara Sea, salinity conditions were reconstructed for a site northeast of the Lena River Delta (present water depth 32 m) since 9 calendar years (cal) ka. The reconstruction indicate a strong, near-coastal, and river-influenced environment at the site until about 8.6 cal ka. Corroborated by comparison with other proxy records from further to the east, surface salinities increased from 9 to 14 until about 7.4 cal ka, owing to ongoing global sea level rise and synchronous southward shift of the coastline. Although riverine water became less influential at the site since then, salinities still varied between 12.5 and 15, particularly during the last 3.5 kyr. These more recent salinity fluctuations agree well with reconstructions from just north of the Lena Delta, emphasizing the strong linkage between shelf hydrography and riverine discharge patterns in Arctic Siberia
Human Intestinal Cells Modulate Conjugational Transfer of Multidrug Resistance Plasmids between Clinical Escherichia coli Isolates.
Bacterial conjugation in the human gut microbiota is believed to play a major role in the dissemination of antibiotic resistance genes and virulence plasmids. However, the modulation of bacterial conjugation by the human host remains poorly understood and there is a need for controlled systems to study this process. We established an in vitro co-culture system to study the interaction between human intestinal cells and bacteria. We show that the conjugation efficiency of a plasmid encoding an extended spectrum beta-lactamase is reduced when clinical isolates of Escherichia coli are co-cultured with human intestinal cells. We show that filtered media from co-cultures contain a factor that reduces conjugation efficiency. Protease treatment of the filtered media eliminates this inhibition of conjugation. This data suggests that a peptide or protein based factor is secreted on the apical side of the intestinal cells exposed to bacteria leading to a two-fold reduction in conjugation efficiency. These results show that human gut epithelial cells can modulate bacterial conjugation and may have relevance to gene exchange in the gut
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