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Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially,thedevelopmentoffibrosisandportalhypertensioninNAFLDpatientsrequirestreatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. Asexpected,WDinducedobesityandliverfibrosisasconfirmedbySiriusRedandOilRed O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increasedduringfeedingofWD,indicatinginfiltrationofmacrophagesintotheliver,eventhoughthis increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
Purpose of the Review: This review aims to summarize the current knowledge of the extracellular matrix remodeling during hepatic fibrosis. We discuss the diverse interactions of the extracellular matrix with hepatic cells and the surrounding matrix in liver fibrosis, with the focus on the molecular pathways and the mechanisms that regulate extracellular matrix remodeling.
Recent Findings: The extracellular matrix not only provides structure and support for the cells, but also controls cell behavior by providing adhesion signals and by acting as a reservoir of growth factors and cytokines.
Summary: Hepatic fibrosis is characterized by an excessive accumulation of extracellular matrix. During fibrogenesis, the natural remodeling process of the extracellular matrix varies, resulting in the excessive accumulation of its components, mainly collagens. Signals released by the extracellular matrix induce the activation of hepatic stellate cells, which are the major source of extracellular matrix and most abundant myofibroblasts in the liver.
Im Gegensatz zu Adorno wird Walter Benjamins Theorie […] kaum mit Musik in Verbindung gebracht, sondern vor allem für ihr Bilddenken geschätzt. Auch wenn im Ursprung des Deutschen Trauerspiels, in den Erinnerungsszenen der Berliner Kindheit, den Häuser- und Gedankenschluchten der Passagenarbeit und nicht zuletzt in seinem Briefwechsel durchaus von Musik die Rede ist, rücken Klänge seltener in den Mittelpunkt seiner Schriften und sind in der Rezeption bisher auch weniger beachtet worden. Ohnedies wird derjenige enttäuscht, der gerade von Benjamin – so reizvoll es sein mag, sich solchen Gegenständen widmende Essays zu imaginieren – die Exegese des gängigen musikalischen Kanons erwartet: Keine Abhandlung zu Schuberts Streichquintett schließt an die Interpretation der Wahlverwandschaften an und ebenso vergeblich sucht man nach die Erwägungen zum Trauerspiel auf die Affektkontrolle der opera seria oder die des Kraus-Essays auf die Musik des Fackel-Habitués Arnold Schönberg übertragenden Arbeiten. Dennoch kommt Musik, Klage und Tönen in Benjamins Reflexionen eine nicht unerhebliche Bedeutung zu. Selten drängen sie sich lautstark in den Vordergrund, erlauben aber – zumal in einer Zeit, in der auch die professionelle Auseinandersetzung mit Musik die ideale Beständigkeit musikalischer Werke und ihrer Texte zunehmend in Zweifel zieht – theoretische Einsichten, über die das auf andere Dinge gerichtete Ohr des Experten achtlos hinweggeht. In Ergänzung zur wohlbekannten epistemischen und poetischen Rolle seiner Sprach- und Denkbilder unternimmt dieser Band den ersten systematisch angelegten Versuch, sowohl den kultur- und medienhistorischen Zusammenhängen von Benjamins akustischen Motiven nachzugehen als auch ihre ästhetische Relevanz für die gegenwärtige Produktion und Reproduktion von Klängen zu reflektieren.
Zwei Jahre nach dem Beginn des Zweiten Weltkriegs veröffentlichte der franko-amerikanische Historiker Jacques Barzun eine ideengeschichtliche Anatomie des 19. Jahrhunderts mit dem aufsehenerregenden Titel 'Darwin, Marx and Wagner'. Eine mit Absolutheitsanspruch verfochtene deterministische Weltsicht betrachtet sein Buch, dessen narrativen Ausgangspunkt die just ins Jahr der Vollendung der 'Tristan'-Partitur (1859) fallende Veröffentlichung von 'The Origin of Species' und der 'Kritik der politischen Ökonomie' bildet, als ein anhaltend problematisches Erbe der mit jenen drei "representatives of the dominant tradition" verbundenen Umwälzungen in den Künsten, Natur- und Sozialwissenschaften: "Their thought embraces the three great relations that cause us the deepest concern - science and religion, science and society, society and art - and it is from them that on these subjects we have learned what we most familiarly know." Gegen solchen von der weltgeschichtlichen Lage geprägten (liberalen) Skeptizismus kann zwar zum einen auf jene die "ewige Wiederkehr des Gleichen" progressiv durchbrechende Zielgerichtetheit verwiesen werden, die Wagners auf ein multilaterales "Ende" zulaufende Musikdramen mit dem Telos von Marx’ Gesellschafts- und Darwins Naturbeobachtung teilen. Aber auch diejenigen Kopplungen und ideengeschichtlichen Synergieeffekte, die sich in - sich neu formierenden - Problemzusammenhängen wie der (Musik-)Psychologie niederschlagen, lassen sich Barzuns düsterer Zeitgeistdiagnose entgegenstellen. Der vorliegende Aufsatz steht also nicht nur vor der bislang unbewältigten Aufgabe, das Werk eines bedeutenden Komponisten in den Kontext der Wissenschaftsgeschichte zu stellen. Zugleich geht es darum, gewöhnlich nicht ins Blickfeld der Musikwissenschaft fallende Textgattungen und Diskurse für die musikalische Analyse und Historiographie des ausgehenden 19. Jahrhunderts fruchtbar zu machen.
Es sind weit mehr als jene sprichwörtlichen Siebensachen, die ein ghanaischer Oberschüler beim Eintritt in eines der zahlreichen Internate des Landes mitzubringen hat. Ein zuvor ausgehändigter "prospectus" verzeichnet so nützliche und notwendige Dinge wie Bügeleisen, Wassereimer, Buschmesser, Scheuerbürste, Schaumstoffmatratze und einiges andere mehr. Was die Bekleidung betrifft, so findet sich auf dieser Liste neben "white trousers for church service" und "khaki trousers" auch ein ausdrücklich mit dem Zusatz "school supply" versehenes "pair of khaki shorts": Bis heute identifizieren sich "school boys" in Ghana durch sowohl den klimatischen Bedingungen als auch einer impliziten sozialen Hierarchie genügende kurze Hosen, für die sich im informellen Idiom die Bezeichnung 'school knickers' durchgesetzt hat.
The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.
Background and Aims: Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear.
Methods: Hepatic CC-chemokine ligand 2 (CCL2) expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl4 for 7 weeks). Next, hepatic RNA levels of CCL2 were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension.
Results: In this mouse model of fibrotic hepatitis, hepatic expression of CCL2 (P = 0.009) and the amount of F4/80 positive cells in the liver (P < 0.001) significantly increased after induction of hepatitis by CCl4 compared to control animals. Moreover, strong correlation of hepatic CCL2 expression and F4/80 positive cells were seen (P = 0.023). Furthermore, in human liver explants, hepatic transcription levels of CCL2 correlated with the MELD score of the patients, and thus disease severity (P = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (P = 0.028) and correlation of hepatic CCL2 expression (R = 0.69, P = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte CCL2 expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (P = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (P = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both P = 0.039).
Conclusion: Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.
Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the leading causes of liver disease worldwide. To identify disease-specific pathomechanisms, we analyzed the lipidome, metabolome and immune cell recruitment in livers in both diseases. Mice harboring ASH or NASH had comparable disease severities regarding mortality rate, neurological behavior, expression of fibrosis marker and albumin levels. Lipid droplet size was higher in NASH than ASH and qualitative differences in the lipidome were mainly based on incorporation of diet-specific fatty acids into triglycerides, phosphatidylcholines and lysophosphatidylcholines. Metabolomic analysis showed downregulated nucleoside levels in both models. Here, the corresponding uremic metabolites were only upregulated in NASH suggesting stronger cellular senescence, which was supported by lower antioxidant levels in NASH as compared to ASH. While altered urea cycle metabolites suggest increased nitric oxide synthesis in both models, in ASH, this depended on increased L-homoarginine levels indicating a cardiovascular response mechanism. Interestingly, only in NASH were the levels of tryptophan and its anti-inflammatory metabolite kynurenine upregulated. Fittingly, high-content immunohistochemistry showed a decreased macrophage recruitment and an increased polarization towards M2-like macrophages in NASH. In conclusion, with comparable disease severity in both models, higher lipid storage, oxidative stress and tryptophan/kynurenine levels were seen in NASH, leading to distinct immune responses.
Near equilibrium potential energy and dipole moment functions have been calculated for the electronic ground state of the XeH+ ion from highly correlated SCEP/CEPA electronic wavefunctions. The following spectroscopic constants for 132XeH+ are obtained: Re= 1.611 ± 0.005 Å, ωe = 2313 ± 50cm-1, ωexe = 41 ± 5cm-1 and D0(Xe+ + H) = 3.90 ± 0.1 eV.
Infrared transition dipole matrix elements and probability coefficients for 132XeH+ and 132XeD+ are given. The electric dipole moment functions of the protonated rare gas atoms HeH+ to XeH+ are discussed.