Cocylisierungsreaktionen mit Olefin- und Alkinkomplexen des Titanocens und Zirkonocens

Available from TIB Hannover: DW 4690 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Thromboinflammation in Brain Ischemia:Recent Updates and Future Perspectives

Despite decades of promising preclinical validation and clinical translation, ischemic stroke still remains as one of the leading causes of death and disability worldwide. Within its complex pathophysiological signatures, thrombosis and inflammation, that is, thromboinflammation, are highly interconnected processes leading to cerebral vessel occlusion, inflammatory responses, and severe neuronal damage following the ischemic event. Hence, we here review the most recent updates on thromboinflammatory-dependent mediators relevant after stroke focusing on recent discoveries on platelet modulation, a potential regulation of the innate and adaptive immune system in thromboinflammation, utterly providing a thorough up-to-date overview of all therapeutic approaches currently undergoing clinical trial

A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation

Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX2 to be a major therapeutic target in stroke. Systematic review and MA of all available NOX2(-/y) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX2 as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias

Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke.

lschemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a calciumactivated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found that reoxygenation or calcium overload increased brain ROS levels in a NOX5-dependent manner. In vivo, postischemic ROS formation, infarct volume, and functional outcomes were worsened in NOXS-KI mice. Of clinical and therapeutic relevance, in a human blood-barrier model, pharmacological NOX inhibition also prevented acute reoxygenationinduced leakage. Our data support further evaluation of poststroke recanalization in the presence of NOX inhibition for limiting stroke-induced damage

Neue Olefin-Polymere mittels neuer Metallocen-Ziegler-Katalysatoren

The potential of metallocene catalyst for the industrial production of novel polyolefin materials by 1-olefin homo- and copolymerization has been studied using besides lanthanoid (La, Y) metallocenes mainly ansa-zirconcenes as the catalysts with special regard to rac-Me_2Si(2-MeBenz[e]Ind_2)ZrCl_2. As a result of systematic variation of the metallocene structure it is shown that at a given central metal ion the polymerization behaviour is mainly governed by steric factors while electronic factors only play a marginal role. The effect of #alpha#-substituents leading to increased molecular weights is contributed to the suppression of the #beta#-H transfer to a coordinated olefin. Stereo faults in the isospezific propylene polymerization are caused by an isomerization reaction. The equilibrium between active and potentially active polyemerization sites can be influenced by adding water or a cocatalyst. The crystallization of metallocene-homopropylene is strongly influenced by insertion faults giving even the #gamma# modification at the high levels of insertion faults. By heterogenization of rac-Me_2Si(2-MeBenz[2]Ind_2)ZrCl_2 on silica pretreated with methylalumoxane a supported metallocene-based Ziegler catalyst for continuous gas phase polymerization was prepared. Homopolypropylene obtained by such a polymerization process is characterized by a lower melting point, improved optical properties and outstanding organoleptics. This novel material is especially suited for transparent thin-layer injection moulding, preparation of pp-fibres and biaxially-oriented pp-films. (WEN)SIGLEAvailable from TIB Hannover: F97B695+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells

Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders