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MRCKα and MRCKβ (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate the actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, MRCKα and MRCKβ influence cell shape and motility. We report further evidence for MRCKα and MRCKβ contributions to the invasion of cancer cells in 3-dimensional matrix invasion assays. In particular, our results indicate that the combined inhibition of MRCKα and MRCKβ together with inhibition of ROCK kinases results in significantly greater effects on reducing cancer cell invasion than blocking either MRCK or ROCK kinases alone. To probe the kinase ligand pocket, we screened 159 kinase inhibitors in an in vitro MRCKβ kinase assay and found 11 compounds that inhibited enzyme activity >80% at 3 µM. Further analysis of three hits, Y-27632, Fasudil and TPCA-1, revealed low micromolar IC(50) values for MRCKα and MRCKβ. We also describe the crystal structure of MRCKβ in complex with inhibitors Fasudil and TPCA-1 bound to the active site of the kinase. These high-resolution structures reveal a highly conserved AGC kinase fold in a typical dimeric arrangement. The kinase domain is in an active conformation with a fully-ordered and correctly positioned αC helix and catalytic residues in a conformation competent for catalysis. Together, these results provide further validation for MRCK involvement in regulation of cancer cell invasion and present a valuable starting point for future structure-based drug discovery efforts.

Wheatley examines the image of a sow gnawing a child in Chaucer's Knight's Tale. The image is unexpected in the long series of descriptions that focus on adults both as victims and victimizers: here the victim is an innocent child and the victimizer is merely following its natural animal instincts, horrible though they may be. Chaucer may have deployed the image of the sow eating the child as a result of having heard of just such an occurrence in the Norman town of Falaise, an event that was commemorated afterwards in a painting on the wall of a parish church there.

A cell suspension culture of a tobacco (Nicotiana tabacum L. cv. Petit Havana) cell line derived from a cultivar transformed with the Tcyt gene from Agrobacterium, which leads to high endogenous levels of cytokinin, has been established. This cell line shows increased cell aggregation, elongated cells and a 5-fold increase in wall thickness. If allowed to carry on growing it can form a single mass without shedding cells into the medium. When analysed at an earlier growth stage, these cultures were found to produce improved levels of vascular nodule formation than in other systems that employ exogenous cytokinin. This differentiation was optimised with respect to sucrose and auxin signals in order to induce maximum production of cells with thickened walls and a morphology characteristic of fibre cells and tracheids, in addition to cells that remain meristematic. In order to establish the validity of this system for studying secondary wall formation, the walls and associated biosynthetic changes were analysed in these cells by chemical analysis of the walls, changes in activities of enzymes of xylan and monolignol synthesis, and expression of mRNAs coding for enzymes of lignin biosynthesis. The wall composition of the transformed cells was compared with that determined for primary walls from a typical untransformed tobacco cell line. Recovery of wall material was 50% greater in the transformed culture. In this material a major difference was found in the pectin fraction where there was a distinct difference in size distribution together with a lower level of methylation for the transformed line, which may be related to increased adhesiveness. There were increased amounts of xylan, although the ratio of xyloglucan to xylan content was not substantially different due to the mixture of cell types. There was also an increase in cellulose and phenolic components. Increased activity of enzymes involved in the synthesis of xylan as a marker for the secondary wall occurred around the time of tracheid differentiation and coincided with a broad peak of cinnamyl alcohol dehydrogenase activity. The expression of mRNAs coding for enzymes of the general phenylpropanoid pathway, phenylalanine ammonia-lyase, cinnamate 4-hydroxylase, catechol O-methyl transferase was relatively constitutive in the cultures while transcripts of ferulate 5-hydroxylase, cinnamoyl CoA-reductase, cinnamyl alcohol dehydrogenase and lignin peroxidase were induced. The walls of the transformed cells also showed considerable differences in the subset of extractable proteins from that found in primary walls of tobacco when these were subjected to proteomic analysis. Many of these proteins appear to be novel and not present in primary walls. However an Mr-32,000 chitinase, an Mr-34,000 peroxidase, an Mr-65,000 polyphenoloxidase/laccase and possibly an Mr-68,000 xylanase could be identified as well as structural proteins.

The trick evidently persuades Gloucester that he has been saved by a miracle, and he decides to go on living.1 Although Edgar says that his mistreatment of Gloucester is an attempt to cure him of his despair, it remains gratuitous and difficult to explain within the context of the play, so in this essay I would like to move beyond Lear to examine the scene in relation to drama that provides surprising analogues to it: medieval French farce featuring blind men and their cruelly deceptive guides. [...] I would add that the point is equally applicable to the guide figures in the French farces discussed above: they are both good and evil, both cruel and helpful toward their charges. [...] in not only La Farce de l'aveugle et de son varlet tort but also Lear, a guide figure who is capable of cruelty at one moment leads the blind man soon thereafter to a miracle, if, in the words of the pragmatic archbishop of Rheims in Shaw's Saint Joan, A miracle ... is an event which creates faith.

Data from 396 real estate salespeople offer structural model evidence of the antecedence of salesperson cognitive style (Jung, 1971) to adaptive selling behavior, and to sales orientation-customer orientation and self-perceived selling performance. Four hypotheses were supported: Salespeople who prefer information intake by intuiting (rather than sensing) and information processing/decision-making by thinking (rather than feeling) were found to be more likely to practice adaptive selling; the more adaptive selling was practiced, the greater customer orientation became; and the greater the customer orientation, the better the self-perceived selling performance. Implications exist for salesperson training, management, and motivation research.