Molecular mechanisms involved in cisplatin cytotoxicity

cis-diamminedichloroplatinum(II) or cisplatin is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin cross-links to DNA, forming intra- and interstrand adducts, which bend and unwind the duplex and attract high-mobility-group domain and other proteins. Presumably due to a shielding effect caused by these proteins, the cisplatin-modified DNA is poorly repaired. The resulting DNA damage triggers cell-cycle arrest and apoptosis. Although it is still debatable whether the clinical success of cisplatin relies primarily on its ability to trigger apoptosis, at least two distinct pathways have been proposed to contribute to cisplatin-induced apoptosis in vitro. One involves the tumour-suppressor protein p53, the other is mediated by the p53-related protein p73. Coupling cisplatin damage to apoptosis requires mismatch repair activity, and recent observations further suggest involvement of the homologous recombinatorial repair system. At present it is generally accepted that abortive attempts to repair the DNA lesions play a key role in the cytotoxicity of the drug, and loss of the mismatch repair activity is known to cause cisplatin resistance, a major problem in antineoplastic therapy. Clearly, a better understanding of the signalling networks involved in cisplatin toxicity should provide a rational basis for the development of new therapeutic strategies.     

Diversity of IL-17-producing T lymphocytes

Interleukin (IL)-17 is a pro-inflammatory cytokine that plays critical roles in host defense against extracellular bacteria and fungi and also in the pathogenesis of autoimmune diseases. While CD4+ TCRαβ+ T helper (Th) 17 cells are the best-described cellular source of IL-17, many innate-like T cells are in fact potent producers of IL-17. Given the increasing interest in therapeutic modulation of the IL-17 axis, it is crucial to better understand the cellular origins of IL-17 in various infection and diseases settings. While the diverse population of IL-17-producing T cells share many common characteristics, notable differences also exist. In this review, we discuss the heterogeneity of IL-17-producing T cell types focusing on their development, regulation, and function.     

The adoption of self-induction by telephony, 1886–1889

Through 1886 to 1889 understanding of the mechanism of telephone transmission was transformed from an electrostatic and traditional view to an electrodynamic one conforming with Maxwell's scheme. Observed at the level of commercial application this painful adjustment occurred via a sequence of controversies connected with self-induction—on techniques of telephony, on electrical measurement, on lightning conductors and on matters of professional ethics—in which the parts played by evidence, by theory, and by authority were strangely mixed. The well-known confrontation of O. Heaviside and W. H. Preece was at the centre of the debate. An open division between traditionalists and progressives amongst electrical engineers was provoked, and the effectiveness of mathematical theory as against pure pragmatism at the practical level had in the end to be conceded.     

Pro-sequence of subtilisin can guide the refolding of denatured subtilisin in an intermolecular process

Subtilisin E, an alkaline serine protease consisting of a single polypeptide chain of 275 amino acids is produced from a pre-pro-protein. The pre-sequence functions as the signal peptide for protein secretion across the membrane. Deletion of the pro-sequence yields mature but inactive subtilisin: the 77-amino acid pro-sequence must precede the mature subtilisin to guide the latter into an active conformation. Pro-subtilisin denatured in 6 M guanidine-HCl can be self-processed to the active enzyme intramolecularly, with concomitant cleavage of the pro-sequence, when dialysed against renaturing buffer. We have constructed an active-centre mutant of pro-subtilisin (Asp 32----Asn) which is not processed to active enzyme, unlike the wild-type pro-subtilisin, because intramolecular processing is prevented. Here we report an intermolecular pathway for the refolding of the inactive mature protein to an active enzyme in vitro with the aid of exogenously added pro-sequence. We establish conditions under which the mature inactive form, as well as acid-denatured subtilisins Carlsberg and BPN', can be renatured by the mutant pro-subtilisin.     

Presence of maxillary canine teeth in mule deer in Utah

Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} During the winters of 1980–1984 winter mortality of mule deer fawns in central Utah was assessed. It was determined that the winter mortality ratio for female fawns as compared to males was 156:100. This mortality factor should be taken into consideration by game and range managers when determining harvest recommendations.          

Effects of logging on habitat quality and feeding patterns of Abert squirrels

Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} In 1973 a timber harvest of ponderosa pine ( Pinus ponderosa ) was conducted in an area southeast of Monticello, Utah, that is inhabited by Abert squirrels ( Sciurus aberti ). Abert squirrel dietary habits, foraging patterns, and population densities were compared in the timber harvest area and in an adjacent nonharvested area. Squirrel feeding patterns and preferences were visually determined by physical evidence of past feeding. Live-trapping and field-marking of animals were used to determine population density and trends in the two areas. Squirrels fed in only 26.3% of sampled plots on the timber harvest areas, while 42.7% of the uncut area plots showed use (P 50 acres) by clear-cut methods commonly employed by management agencies.     

Nuclear pores. can they expand and contract to regulate nucleocytoplasmic exchange?

Summary Recent evidence has revived the idea that translocation of macromolecules between nucleus and cytoplasm may be regulated via expansion and contraction of the entire diameter of the nuclear pore complex. The present investigation does not support this hypothesis.Acknowledgments. We are indebted to Dr J.H.M. Willison for discussion of his and Dr Rajaraman's results before their publication. We also wish to thank Dr C. Thurston, Dr D.H. Williamson and Dr K. Lambert for providing some of the specimens used in this investigation. N.J. Severs acknowledges the support of the Science Research Council and the Cancer Research Campaign.     

Praemia

Ohne Zusammenfassung