| 1. |
- Brütt, Katharina, et al.
(författare)
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Competition and moral behavior: A meta-analysis of forty-five crowd-sourced experimental designs
- 2023
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Ingår i: Proceedings of the National Academy of Sciences - PNAS. - : National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 120:23
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Tidskriftsartikel (refereegranskat)abstract
- Does competition affect moral behavior? This fundamental question has been debated among leading scholars for centuries, and more recently, it has been tested in experimental studies yielding a body of rather inconclusive empirical evidence. A potential source of ambivalent empirical results on the same hypothesis is design heterogeneity-variation in true effect sizes across various reasonable experimental research protocols. To provide further evidence on whether competition affects moral behavior and to examine whether the generalizability of a single experimental study is jeopardized by design heterogeneity, we invited independent research teams to contribute experimental designs to a crowd-sourced project. In a large-scale online data collection, 18,123 experimental participants were randomly allocated to 45 randomly selected experimental designs out of 95 submitted designs. We find a small adverse effect of competition on moral behavior in a meta-analysis of the pooled data. The crowd-sourced design of our study allows for a clean identification and estimation of the variation in effect sizes above and beyond what could be expected due to sampling variance. We find substantial design heterogeneity-estimated to be about 1.6 times as large as the average standard error of effect size estimates of the 45 research designs-indicating that the informativeness and generalizability of results based on a single experimental design are limited. Drawing strong conclusions about the underlying hypotheses in the presence of substantive design heterogeneity requires moving toward much larger data collections on various experimental designs testing the same hypothesis.
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| 2. |
- Dold, Stefan, et al.
(författare)
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Cholestatic liver damage is mediated by lymphocyte function antigen-1-dependent recruitment of leukocytes.
- 2008
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Ingår i: Surgery. - : Elsevier BV. - 1532-7361 .- 0039-6060. ; 144:3, s. 385-393
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The role of specific adhesion molecules in cholestasis-induced leukocyte recruitment in the liver is not known. Therefore, the aim of our experimental study was to evaluate the role of lymphocyte function antigen-1 (LFA-1) in cholestatic liver injury. METHODS: C57BL/6 mice underwent bile duct ligation for 12 hours. Mice were pretreated with an anti-LFA-1 antibody or control antibody. Subsequently, hepatic accumulation of leukocytes and sinusoidal perfusion were determined by means of intravital fluorescence microscopy. Hepatocellular damage was monitored by measuring serum levels of alanine aminotransferase and aspartate aminotransferase. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. RESULTS: Bile duct ligation provoked clear-cut recruitment of leukocytes and liver damage, as indicated by increased serum activities of liver enzymes and sinusoidal perfusion failure. Neutrophils expressed greater levels of LFA-1 and inhibition of LFA-1 significantly decreased serum activity of alanine aminotransferase and aspartate aminotransferase levels in cholestatic mice. Immunoneutralization of LFA-1 reduced leukocyte adhesion in postsinusoidal venules that had been induced by bile duct ligation, whereas leukocyte rolling and sinusoidal accumulation were not changed. Moreover, blocking LFA-1 function restored sinusoidal perfusion in cholestatic animals. CONCLUSION: These findings demonstrate an important role of LFA-1 in supporting cholestasis-induced leukocyte recruitment in the liver. Thus, targeting LFA-1 may help to protect against pathologic inflammation and liver damage in cholestatic liver diseases.
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| 3. |
- Dold, Stefan, et al.
(författare)
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P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice.
- 2010
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 59, s. 291-298
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Leukocytes mediate hepatocellular injury in obstructive cholestasis. The aim of the present study was to define the role of P-selectin glycoprotein ligand-1 (PSGL-1) in cholestasis-induced leukocyte recruitment and liver damage. METHODS: C57BL/6 mice were pre-treated with an anti-PSGL-1 antibody or a control antibody prior to bile duct ligation (BDL) for 12 h. Hepatic recruitment of leukocytes and sinusoidal perfusion were determined by means of intravital fluorescence microscopy. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of CXC chemokines were determined by ELISA. RESULTS: BDL caused significant hepatocellular damage indicated by increased serum activities of ALT and AST as well as decreased sinusoidal perfusion and clear-cut hepatic infiltration of leukocytes. Administration of the anti-PSGL-1 antibody reduced BDL-induced levels of ALT by 78% and AST by 77%. Inhibition of PSGL-1 decreased BDL-provoked leukocyte rolling and adhesion in post-sinusoidal venules by more than 81%. Moreover, we found that immunoneutralisation of PSGL-1 restored sinusoidal perfusion and decreased hepatic formation of CXC chemokines in cholestatic mice. CONCLUSIONS: Our novel data show that PSGL-1 plays an important role in cholestatic liver damage by regulating leukocyte rolling in post-sinusoidal venules. Consequently, interference with PSGL-1 attenuates cholestasis-provoked leukocyte adhesion and extravasation in the liver. Thus, inhibition of PSGL-1 may help to protect against hepatocellular damage in cholestatic diseases.
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| 4. |
- Dold, Stefan, et al.
(författare)
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Simvastatin protects against cholestasis-induced liver injury.
- 2009
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 156, s. 466-474
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage. Experimental approach: C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg.kg(-1)) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined. Key results: Administration of 0.2 mg.kg(-1) simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg.kg(-1) simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation. Conclusions and implications: These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.
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| 5. |
- Laschke, MW, et al.
(författare)
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Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis
- 2008
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 153:1, s. 148-156
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Tidskriftsartikel (refereegranskat)abstract
- Background:Although it is well known that extrahepatic cholestasis induces liver damage, the mechanisms are still not completely understood. The aim of the present study was to evaluate the role of platelets and P-selectin in cholestasis-induced liver injury.Experimental approach:C57BL/6 mice underwent bile duct ligation (BDL) and pretreatment with an anti-GP1balpha antibody, which depletes platelets, an anti-P-selectin antibody or a control antibody. Hepatic platelet and leukocyte recruitment as well as microvascular perfusion were determined by intravital fluorescence microscopy.Key results:BDL caused significant liver damage and sinusoidal perfusion failure. BDL further induced hepatic platelet accumulation with widespread intravascular platelet aggregates, increased platelet adhesion in postsinusoidal venules and massive platelet accumulation in liver sinusoids. Administration of the anti-GP1balpha antibody reduced systemic platelet count by 90%. Depletion of platelets in BDL mice not only abolished accumulation and adhesion of platelets in sinusoids and venules but also restored sinusoidal perfusion and reduced liver enzymes by more than 83%. Platelet depletion further reduced BDL-associated sinusoidal leukocyte accumulation by 48% although leukocyte-endothelium interactions in venules were not affected. Immunoneutralization of P-selectin also inhibited hepatic microvascular accumulation of platelets and leukocytes, and protected against cholestasis-provoked hepatocellular damage.Conclusions and implications:Platelets play an important role in BDL-induced liver injury by promoting leukocyte recruitment and deteriorating microvascular perfusion. Moreover, our findings demonstrate that cholestasis-induced accumulation of platelets is mediated by P-selectin. Thus, targeting platelet accumulation may be a useful strategy against liver damage associated with obstructive jaundice.British Journal of Pharmacology advance online publication, 19 November 2007; doi:10.1038/sj.bjp.0707578.
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| 6. |
- Laschke, Matthias, et al.
(författare)
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Rho-Kinase Inhibitor Attenuates Cholestasis-Induced CXC Chemokine Formation, Leukocyte Recruitment, and Hepatocellular Damage in the Liver.
- 2010
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 159, s. 666-673
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the present experimental study, we analyzed the role of Rho-kinase during obstructive cholestasis by studying the effect of the Rho-kinase inhibitor Y-27632 on hepatic CXC chemokine formation, leukocyte recruitment and hepatocellular damage. MATERIALS AND METHODS: C57BL/6 mice underwent bile duct ligation (BDL) to induce obstructive cholestasis. Mice were pretreated with Y-27632 (1 and 10mg/kg) or the vehicle PBS. Sham-operated animals served as controls. After 12h, hepatic accumulation of leukocytes and sinusoidal perfusion were determined using intravital fluorescence microscopy. Hepatocellular damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). CXC chemokines in the liver were analyzed by ELISA. RESULTS: Administration of 10mg/kg of Y-27632 protected against cholestasis-induced hepatocellular damage indicated by a more than 87% reduction of ALT and AST in BDL mice. Moreover, this Rho-kinase inhibitor significantly decreased BDL-induced production of CXC chemokines by 44-83% and leukocyte recruitment by 60%. Finally, treatment with Y-27632 restored sinusoidal perfusion in cholestatic animals. CONCLUSIONS: Our findings indicate that the Rho-kinase signaling pathway plays a key role in the pathophysiology of cholestatic liver injury. Thus, targeting Rho-kinase activity may represent a new therapeutic approach in the treatment of inflammation and liver injury in cholestatic liver diseases.
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| 7. |
- Laschke, Matthias, et al.
(författare)
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The Rho-kinase inhibitor Y-27632 inhibits cholestasis-induced platelet interactions in the hepatic microcirculation.
- 2009
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Ingår i: Microvascular Research. - : Elsevier BV. - 1095-9319 .- 0026-2862. ; 78, s. 95-99
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Tidskriftsartikel (refereegranskat)abstract
- Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. Emerging data suggest that platelets may play an important role in tissue damage and inflammation. Herein, we characterized the platelet response in cholestatic liver injury and evaluated the role of Rho-kinase signaling. For this purpose, C57BL/6 mice were treated with the Rho-kinase inhibitor Y-27632 (10 mg/kg) and vehicle before undergoing bile duct ligation (BDL) for 12 h. Platelet rolling and adhesion, formation of platelet aggregates as well as microvascular perfusion in the liver were analyzed using intravital fluorescence microscopy. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Administration of Y-27632 reduced the BDL-associated increase of ALT and AST by 95% and 89%, respectively. The inhibition of Rho-kinase also reduced cholestasis-induced platelet rolling and adhesion by more than 46% and 73% in postsinusoidal venules and platelet adhesion in sinusoids by 60%. In addition, Y-27632 decreased platelet aggregation in hepatic sinusoids and postsinusoidal venules by 69% and 81%. BDL caused a significant reduction of hepatic microvascular perfusion. Importantly, pretreatment with Y-27632 restored sinusoidal perfusion in cholestatic animals. Our findings demonstrate that Rho-kinase regulates multiple aspects of platelet interaction in the microcirculation of cholestatic animals. Moreover, inhibition of Rho-kinase signaling not only attenuates platelet responses but also maintains microvascular perfusion and protects against hepatocellular injury in cholestasis. Thus, targeting Rho-kinase signaling may be an effective way to protect against platelet-mediated liver injury in obstructive jaundice.
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