Differential effects of natural product microtubule stabilizers on microtubule assembly: single agent and combination studies with taxol, epothilone B, and discodermolide

A systematic comparison has been performed of the morphology and stability of microtubules (MTs) induced by the potent microtubule-stabilizing agents (MSAs) taxol, epothilone B (Epo B), and discodermolide (DDM) under GTP-free conditions. DDM-induced tubulin polymerization occurred significantly faster than that induced by taxol and Epo B. At the same time, tubulin polymers assembled from soluble tubulin by DDM were morphologically distinct (shorter and less ordered) from those induced by either taxol or Epo B, as demonstrated by electron microscopy. Exposure of MSA-induced tubulin polymers to ultrasound revealed the DDM-based polymers to be less stable to this type of physical stress than those formed with either Epo B or taxol. Interestingly, MT assembly in the presence of both DDM and taxol appeared to produce a distinct new type of MT polymer with a mixed morphology between those of DDM- and taxol-induced structures. The observed differences in MT morphology and stability might be related, at least partly, to differences in intramicrotubular tubulin isotype distribution, as DDM showed a different pattern of beta-tubulin isotype usage in the assembly process.

Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice

Pancreatic beta-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in beta-cell insulin receptor knockout (betaIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, approximately 7-mo-old betaIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced beta-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic betaIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic betaIRKOs and to a lesser degree in the nondiabetic betaIRKO group. Pancreatic islets of nondiabetic betaIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in beta-cells leads primarily to profound defects in postnatal beta-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.

Sequential overchoice in product customization

The present study demonstrates how consumers can suffer from sequential overchoice. Customizing a tailor-made suit from combined-attribute choices (e.g., deciding on color and fabric in combination) leads to less satisfaction, more information overload, and less additional consumption than customizing it from single-attribute choices (e.g., deciding on color, then on fabric).

New Product Portfolio Performance in Family Firms

This study investigates the relationship between top management team (TMT) innovation orientation and new product portfolio performance in small and medium-sized family firms by exploring two family firm-specific sources of TMT diversity as moderators: the number of generations involved in the TMT and the ratio of family members in the TMT. Results indicate that family-induced diversity in the TMT has opposing moderating effects. Although a positive relationship exists between TMT innovation orientation and new product portfolio performance when multiple generations are involved in the TMT, TMT innovation orientation and new product portfolio performance experience a negative relationship when the ratio of family members in the TMT is high. The study discusses theoretical and managerial implications of the findings and develops avenues for future research.

Repeatedly experiencing information overload in a product customization: a case of sequential overchoice

The present study demonstrates how consumers can suffer from sequential overchoice. Customizing a tailor-made suit from combined-attribute choices (e.g., deciding on color and fabric in combination) leads to less satisfaction and less additional consumption than customizing it from single-attribute choices (e.g., deciding on color, then on fabric). The effect is mediated by information overload and moderated by consideration set size.