Improved Production of Bioactive Glucosylmannosyl-Glycerolipid by Sponge-Associated <Emphasis Type="Italic">Microbacterium</Emphasis> Species

The marine Microbacterium species HP2 (DSM 12583), isolated from the sponge Halichondria panicea, is able to produce a glucosylmannosyl-glycerolipid when grown on a complex medium with glucose. Optimizing the carbon sources in shake flask experiments has shown that glycerol affords the highest specific glycoglycerolipid production. The product yield approached 300 mg/L or 25 mg/g biomass upon scaling up in a 40-L bioreactor volume. The native diglycosyl-glycerolipid GGL.2 strongly inhibited growth of the tumor cell lines HM02 and Hep G2 (50% inhibition at 0.4 to 3 µg/mL), while the related deacylated compound (GG.2) showed a potent anti-tumor-promoting activity.     

Pseudomonas cepacia lipase: Studies on aggregation,purification and on the cleavage of olive oil

Summary To purify the extracellular lipase ofPseudomonas cepacia DSM 50181 and to disintegrate molecular aggregation, the presence of i-propanol (70% per volume) was necessary. The molecular weight was determined to be 33,000 D. Concerning the hydrolytic activity of the pure enzyme towards olive oil additional free fatty acids inhibited the reaction.     

Analysing overexpression of l-valine biosynthesis genes in pyruvate-dehydrogenase-deficient Corynebacterium glutamicum

l-Valine biosynthesis was analysed by comparing different plasmids in pyruvate-dehydrogenase-deficient Corynebacterium glutamicum strains in order to achieve an optimal production strain. The plasmids contained different combinations of the genes ilvBNCDE encoding for the l-valine forming pathway. It was shown that overexpression of the ilvBN genes encoding acetolactate synthase is obligatory for efficient pyruvate conversion and to prevent l-alanine as a by-product. In contrast to earlier studies, overexpression of ilvE encoding transaminase B is favourable in pyruvate-dehydrogenase-negative strains. Its amplification enhanced l-valine formation and avoided extra- and intracellular accumulation of ketoisovalerate.     

Anti-acetylcholine-receptor antibody concentrations after thymectomy in patients with myasthenia gravis.

Serum concentrations of anti-acetylcholine-receptor (anti-AChR) antibody were measured in patients with myasthenia gravis. In those patients undergoing thymectomy concentrations were measured before and after the operation to see whether there might be a connection between the thymus and antibody production. We found no correlation between antibody concentration and either thymectomy or duration and severity of the disease before the operation. Our results suggest that if anti-AChR antibodies are the principal pathogenic factor in myasthenia gravis then immunological and neurophysical variables other than the total serum anti-AChR antibody concentration contribute to the severity of the disease.     

Goldspotted oak borer effects on tree health and colonization patterns at six newly‐established sites

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Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation

Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data. Unlike previous models, the current model takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, and possesses some unique features, including a blood flow component and a portfolio of drug action mechanisms. This study aimed to use the model to compare the mechanism of action of rivaroxaban with that of warfarin, and to evaluate the efficacy and safety of different rivaroxaban doses with other anticoagulants included in the model. Rather than reproducing known standard clinical measurements, such as the prothrombin time and activated partial thromboplastin time clotting tests, the anticoagulant benchmarking was based on a simulation of physiologically plausible clotting scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity for tissue factor concentration inducing clotting, and a steep concentration-effect relationship, rapidly flattening towards higher inhibitor concentrations, both suggesting a broad therapeutic window. The predicted dosing window is highly accordant with the final dose recommendation based upon extensive clinical studies.     

TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms

The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFκB-mediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFκB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival.