University of Graz

About: University of Graz is a education organization based out in Graz, Steiermark, Austria. It is known for research contribution in the topics: Population & Context (language use). The organization has 17934 authors who have published 37489 publications receiving 1110980 citations. The organization is also known as: Carolo Franciscea Graecensis & Karl Franzens Universität.

STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation

Abstract: Stromal interaction molecule (STIM1) and ORAI1 are key components of the Ca2+ release-activated Ca2+ (CRAC) current having an important role in T-cell activation and mast cell degranulation. CRAC channel activation occurs via physical interaction of ORAI1 with STIM1 when endoplasmic reticulum Ca2+ stores are depleted. Here we show, utilizing a novel STIM1-derived Forster resonance energy transfer sensor, that the ORAI1 activating small fragment (OASF) undergoes a C-terminal, intramolecular transition into an extended conformation when activating ORAI1. The C-terminal rearrangement of STIM1 does not require a functional CRAC channel, suggesting interaction with ORAI1 as sufficient for this conformational switch. Extended conformations were also engineered by mutations within the first and third coiled-coil domains in the cytosolic portion of STIM1 revealing the involvement of hydrophobic residues in the intramolecular transition. Corresponding full-length STIM1 mutants exhibited enhanced interaction with ORAI1 inducing constitutive CRAC currents, even in the absence of store depletion. We suggest that these mutant STIM1 proteins imitate a physiological activated state, which mimics the intramolecular transition that occurs in native STIM1 upon store depletion.

Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis.

Abstract: Over the past decade, inflammation-induced alterations at the hepatocellular, bile ductular and ductal level have been linked to different clinical presentations of cholestasis in sepsis. In this Review, the authors give a comprehensive overview of the molecular and cellular mechanisms that underlie sepsis-associated cholestasis and the potential clinical and therapeutic implications that these mechanisms have for critically ill patients. Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis. This article gives a comprehensive overview of the molecular and cellular mechanisms of sepsis-associated cholestasis. Recent advances in the understanding of intrahepatic cholestasis have allowed us to delineate the molecular mechanisms that underlie sepsis-associated cholestasis and to describe their potential clinical and therapeutic applications. The mechanisms and clinical presentation of sepsis-associated liver injury vary according to the severity of the bacterial infection. Proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation. Ischemic liver injury and, rarely, progressive sclerosing cholangitis can also be found in patients with septic shock, or major trauma with systemic inflammatory response syndrome. Treatment is mainly focused on eradication of the underlying infection and managing the sepsis. The use of ursodeoxycholic acid or extracorporeal liver support as treatments for sepsis-associated cholestasis is under investigation, but neither can be recommended in routine clinical practice at present. Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation.

Asymmetric Synthesis of Optically Pure Pharmacologically Relevant Amines Employing ω-Transaminases

Abstract: Various w-transaminases were tested for the synthesis of enantiomerically pure amines from the corresponding ketones employing d -o rl-alanine as amino donor and lactate dehydrogenase to remove the side-product pyruvate to shift the unfav- ourable reaction equilibrium to the product side. Both enantiomers, (R)- and (S)-amines, could be pre- pared with up to 99% ee and > 99% conversions within 24 h at 50 mM substrate concentration. The activity and stereoselectivity of the amination reac- tion depended on the w-transaminase and substrate employed; furthermore the co-solvent significantly influenced both the stereoselectivity and activity of the transaminases. Best results were obtained by em- ploying ATA-117 to obtain the (R)-enantiomer and ATA-113 or ATA-103 to access the (S)-enantiomer with 15% v v 1 DMSO.