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The reported selective serotonin Re-uptake Inhibitor Litoxetine was used as the starting point in the design of a range of potential SSRIs with high ease of synthetic accessibility. Preparation and subsequent optimization yielded a range of potent and highly selective SSRIs.  相似文献   
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Summary The effect of water-miscible cosolvents on biotransformations of poorly water-soluble substrates by immobilized cells was investigated, using 1-dehydrogenation of hydrocortisone by Arthrobacter simplex as a model. Criteria for solvent selection on the basis of retention of enzymic activity were postulated and tested. Diols were considered to be the most suitable group of solvents. Substrate solubility increased tenfold in 30% (v/v) ethylene glycol, but reaction rates were significantly slower in such solutions. This was mainly caused by a decrease of oxygen solubility in the presence of the cosolvent and conformational changes imposed on the intracellular enzyme by cosolvent molecules penetrating the cell. The inhibition could be eliminated by the addition of an artificial electron acceptor, phenazine methosulphate (PMS). Reaction rates faster than those for substrate suspensions (no cosolvent added) could thus be achieved. Immobilization of Arthrobacter simplex in cross-linked polyacrylamide hydrazide gave high retentions of activity. PMS exhibited toxic effects on the entrapped cells, leading to reduced activity after extended use.  相似文献   
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The mechanisms underlying loss of oestrogen responsiveness in breast cancer are not well-defined. Potential mechanisms include loss of receptor expression, alterations in the oestrogen receptor (ER) gene producing proteins with abnormal function, or changes to receptor-dependent or -independent pathways controlling cell proliferation. Examination by Southern analysis of the ER gene in a series of ER-negative and -positive breast tumour biopsies failed to provide evidence of gross rearrangements and in only only one of thirty seven tumour DNA samples was significant gene amplification observed. No restriction fragment length polymorphisms were detected for the restriction enzymes EcoRI, Pst I or Hind III. Methylation of the ER gene as assessed by Hpa II and Msp I restriction enzyme digests varied between tumours but the degree of methylation was not correlated with levels of expression of the receptor protein. Similar findings applied in a series of ER-negative and -positive breast cancer cell lines and clonal lines of MCF-7 cells, which were developed as an in vitro model for the acquisition of oestrogen and antioestrogen resistance. In this model there was no evidence that changes to ER receptor function and/or structure at the level of the ER gene, mRNA, ligand binding, and ability to induce progesterone receptor might account for the development of hormone resistance. However, the ability of ER to interact with a DNA sequence containing the vitellogenin promoter oestrogen response element, as assessed by gel retardation assay, was impaired in the clone showing the greatest degree of oestrogen and antioestrogen resistance.  相似文献   
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Summary A combination of simple membrane theory and statical analysis has been used to determine how stresses are carried in echinoid skeletons. Sutures oriented circumferentially are subject principally to compression. Those forming radial zig-zags are subject to compression near the apex and tension near the ambitus. Radial and circumferential sutures in Eucidaris are equally bound with collagen fibers but in Diadema, Tripneustes, Psammechinus, Arbacia and other regular echinoids, most radial sutures are more heavily bound, and thus stronger in tension. Psammechinus, Tripneustes and several other echinoids have radial sutures thickened by ribs which increase the area of interlocking trabeculae. Ribs also increase flexural stiffness and carry a greater proportion of the stress. Further, ribs effectively draw stress from weaker areas pierced by podial pores, and increase the total load which can be sustained.Allometry indicates that regular echinoids become relatively higher at the apex as size increases, thus reducing ambital stresses. Some spatangoids with very high domes (eg Agassizia) maintain isometry, but others (eg Meoma) become flatter with size. Both holectypoids (Echinoneus) and cassiduloids (Apatopygus) maintain a constant height to diameter relationship. Flattening, and consequently ambital tensile stress, is greatest in the clypeasteroids. In this group the formation of internal buttresses which preferentially carry stress, reaches maximum development. A notable exception, however, is the high domed Clypeaster rosaceus.In this analysis it was assumed that local buckling or bending does not occur. The test of some echinoids (e.g. Diadematoida) have relatively wide sutures swathed in collagen, which allows local deformation. Others (e.g. Arbacia) have rigid sutures with reduced collagen. In Psammechinus and other members of the Order Echinoida, in addition to rib formation, inner and outer surface trabeculae are thickened so that the individual plates are stiffened. Some spatangoids (Meoma, Paleopneustes) have extensive sutural collagen, but the cassiduloid Apatopygus has collagen confined to junctions of sutures, and elsewhere the joints are strengthened and stiffened by fusion of trabeculae. Fusion of surface trabeculae is almost complete in the holectypoid, Echinoneus, and the sutures are obscured.  相似文献   
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