Synthese von Vitamin-A-Methyläther

Summary Preliminary report on the synthesis of vitamin A methyl ether starting from 4-trimethylcyclohexenyl-2-methyl-butenal and 1-methoxy-3-methyl-pentenin.     

Mögliche Beziehungen der optischen Aktivität zum Problem des Alterns

Summary The solubilities and other properties of compounds made by combination of optically active components, e.g. the solubilities of the salts made from the dextro-form of an acid and the dextro- or the laevo-form of a base are in some instancesextremely different. It is a consequence of these differences that in a living organism, containing optically active substance,the degree of optical purity of these substances is of outmost importance. The presence of undesired antipodes of any kind might fundamentally disturb the metabolism. It is also known that living organisms at least partly and continuously produce the optically active substances needed bysynthesis from optically inactive material.A kinetical and thermodynamical study of the conditions under which optically active substances can, with use of optically active catalysers, be synthetized from inactive material, shows that the degree of optical purity of the material synthetized is, even under the most favorable conditions, maximum in the beginning of the synthesis andis bound to decay when the synthesis is, chemically speaking,completed and if the synthetized material is left in contact with the catalyzer. Thus a racemization of the synthetized active material occurs in which the catalyzer which has originally produced this active substance actively accelerates the deterioration of its state of optical purity.The means are discussed by which the organism is able to delay this loss of optical purity; and it is shown that all poosible means to do so are indeed used by the organism. As these means can delay but never completely avoid the decay of optical purity, this decay, even if it be slow, i.e.an ageing of optical purity, is a necessity in the course of the life of a living organism. As a loss of optical purity must disturb the normal metabolism, this must, even if no other events occur, limit the individual life.Experimental evidence which would check the prediction of decay of optical purity with age is incomplete; in several instances, however, the experimental technique permits us to detect and to follow the occurrence of finite small amounts of undesired antipodes, e.g. of some amino acids in the proteins of living organisms.

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Vortrag, gehalten vor der Schweizerischen Gerontologischen Gesellschaft in Basel am 11. Dezember 1954.     

Vaccination against and treatment of tuberculosis, the leishmaniases and AIDS: perspectives from basic immunology and immunity to chronic intracellular infections

The occurrence of infectious disease represents a failure of the immune system, a failure that must be prevented by effective vaccination or remedied by treatment. Vaccination against acute diseases such as smallpox and polio are very effective, due to the rapid and increased immune response of vaccinated individuals upon natural infection. In contrast, effective vaccination against intracellular pathogens that cause chronic diseases, such as the leishmaniases, tuberculosis and AIDS, has not been achieved. Clinical observations suggest cell-mediated, Th1 responses, exclusive of antibody production and the generation of Th2 cells, are optimally protective against these intracellular pathogens. Effective vaccination must ensure the generation of such a protective response. We explore here whether understanding very broad features of the regulation of the immune response can accommodate modern findings on the immunological features of these diseases, and provide a perspective within which strategies for effective vaccination and treatment can be developed.     

Studies on muscle fibre splitting in skeletal muscle

Summary Autoradiographic, stereological and histological studies have been carried out to determine the origin of muscle fibre splitting which supposedly occurs during muscle hypertrophy. The results obtained clearly indicate that the supposedly split fibres are a transient response probably derived from satellite cells and are not derived from pre-existing fibres by true splitting. Similarly, increases in muscle fibre size are not achieved by recruitment of satellite structures as indicated by lack of myonuclear recruitment.Acknowledgment. This work was carried out with the aid of a grant from the Medical Research Council of Great Britain. The authors are grateful for the excellent technical assistance of Miss H. Caulton, M.J. Wild and M. Fenner.     

Structural basis of bacterial defense against g-type lysozyme-based innate immunity

Gram-negative bacteria can produce specific proteinaceous inhibitors to defend themselves against the lytic action of host lysozymes. So far, four different lysozyme inhibitor families have been identified. Here, we report the crystal structure of the Escherichia coli periplasmic lysozyme inhibitor of g-type lysozyme (PliG-Ec) in complex with Atlantic salmon g-type lysozyme (SalG) at a resolution of 0.95 Å, which is exceptionally high for a complex of two proteins. The structure reveals for the first time the mechanism of g-type lysozyme inhibition by the PliG family. The latter contains two specific conserved regions that are essential for its inhibitory activity. The inhibitory complex formation is based on a double ‘key-lock’ mechanism. The first key-lock element is formed by the insertion of two conserved PliG regions into the active site of the lysozyme. The second element is defined by a distinct pocket of PliG accommodating a lysozyme loop. Computational analysis indicates that this pocket represents a suitable site for small molecule binding, which opens an avenue for the development of novel antibacterial agents that suppress the inhibitory activity of PliG.     

PPAR γ partial agonist, KR-62776, inhibits adipocyte differentiation via activation of ERK

Indenone KR-62776 acts as an agonist of PPARγ without inducing obesity in animal models and cells. X-ray crystallography reveals that the indenone occupies the binding pocket in a different manner than rosiglitazone. 2-Dimensional gel-electrophoresis showed that the expression of 42 proteins was altered more than 2.0-fold between KR-62776- or rosiglitazone-treated adipocyte cells and control cells. Rosiglitazone down-regulated the expression of ERK1/2 and suppressed the phosphorylation of ERK1/2 in these cells. However, the expression of ERK1/2 was up-regulated in KR-62776-treated cells. Phosphorylated ERK1/2, activated by indenone, affects the localization of PPARγ, suggesting a mechanism for indenone-inhibition of adipogenesis in 3T3-L1 preadipocyte cells. The preadipocyte cells are treated with ERK1/2 inhibitor PD98059, a large amount of the cells are converted to adipocyte cells. These results support the conclusion that the localization of PPARγ is one of the key factors explaining the biological responses of the ligands. Received 04 March 2009; received after revision 13 March 2009; accepted 17 March 2009     

A p-menthane derivative isolated from culture filtrates ofFusicoccum amygdali,Del.

Summary From culture filtrates ofFusicoccum amygdali, Del., a new compound, whose structure corresponds to 1,2,3-trihydroxy-p-menthane, has been isolated. Its discovery is of some interest since, to our knowledge, it is the first time that a monoterpenoid is isolated from a microorganism.     

Synaptic vesicle depletion and glutamate uptake in a nerve-muscle preparation of the locust,Locusta migratoria L

Summary Excitatory terminals, depleted of their synaptic vesicles by stimulation at high frequency, were incubated in the radiolabelled putative neurotransmitter, L-glutamate. Quantitative electron microscope autoradiography revealed that the axoplasm of these recovering terminals had accumulated the³H L-glutamate.Acknowledgment. The authors wish to thank Dr N. M. Blackett for running the computer analyses of the autoradiographical results. R. P. Botham gratefully acknowledges the SRC for financial assistance.