Modified stiffened panel analysis methods for laser beam and friction stir welded aircraft panels

The introduction of advanced welding methods as an alternative joining process to riveting in the manufacture of primary aircraft structure has the potential to realize reductions in both manufacturing costs and structural weight. Current design and analysis methods for aircraft panels have been developed and validated for riveted fabrication. For welded panels, considering the buckling collapse design philosophy of aircraft stiffened panels, strength prediction methods considering welding process effects for both local-buckling and post-buckling behaviours must be developed and validated. This article reports on the work undertaken to develop analysis methods for the crippling failure of stiffened panels fabricated using laser beam and friction stir welding. The work assesses modifications to conventional analysis methods and finite-element analysis methods for strength prediction. The analysis work is validated experimentally with welded single stiffener crippling specimens. The experimental programme has demonstrated the potential static strength of laser beam and friction stir welded sheet-stiffener joints for post-buckling panel applications. The work undertaken has demonstrated that the crippling behaviour of welded stiffened panels may be analysed considering standard-buckling behaviour. However, stiffened panel buckling analysis procedures must be altered to account for the weld joint geometry and process altered material properties. © IMechE 2006.

Low mating frequency of queens in the stingless bee Scaptotrigona postica and worker maternity of males.

Kin selection models of intracolonial conflict over the maternity of males predict that social hymenopteran workers should favour the production of sons and nephews over brothers when the effective mating frequency (me) of the queen is low (me2. Stingless bees have been used to support these models in that me within the group is considered low and workers are thought often to monopolise the parentage of males. We genetically analysed 20 worker and 20 male pupae from each of 10 colonies of the stingless bee Scaptotrigona postica (= Scaptotrigona aff. depilis) using six microsatellite loci and demonstrate queen monandry in eight nests and apparent low me in the other two. However, four colonies contained an additional matriline, possibly due to queen supersedure (serial polygyny), which complicated their genetic structure. Across colonies, workers were responsible for the maternity of 13% of all males. These data are broadly in agreement with predictions from kin selection theory, though the question remains open as to why workers do not secure a greater share of male maternity in this and other stingless bee species in which workers are more closely related to nephews than brothers.

Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS- and non-TS-targeted chemotherapies

Thymidylate synthase (TS) is responsible for the de novo synthesis of thymidylate, which is required for DNA synthesis and repair and which is an important target for fluoropyrimidines such as 5-fluorouracil (5-FU), and antifolates such as Tomudex (TDX), ZD9331, and multitargeted antifolate (MTA). To study the importance of TS expression in determining resistance to these agents, we have developed an MDA435 breast cancer-derived cell line with tetracycline-regulated expression of TS termed MTS-5. We have demonstrated that inducible expression of TS increased the IC(50) dose of the TS-targeted therapeutic agents 5-FU, TDX, and ZD9331 by 2-, 9- and 24-fold respectively. An IC(50) dose for MTA was unobtainable when TS was overexpressed in these cells, which indicated that MTA toxicity is highly sensitive to increased TS expression levels. The growth inhibitory effects of the chemotherapeutic agents CPT-11, cisplatin, oxaliplatin, and Taxol were unaffected by TS up-regulation. Cell cycle analyses revealed that IC(50) doses of 5-FU, TDX and MTA caused an S-phase arrest in cells that did not overexpress TS, and this arrest was overcome when TS was up-regulated. Furthermore, the S-phase arrest was accompanied by 2- to 4-fold increased expression of the cell cycle regulatory genes cyclin E, cyclin A, and cyclin dependent kinase 2 (cdk2). These results indicate that acute increases in TS expression levels play a key role in determining cellular sensitivity to TS-directed chemotherapeutic drugs by modulating the degree of S-phase arrest caused by these agents. Moreover, CPT-11, cisplatin, oxaliplatin, and Taxol remain highly cytotoxic in cells that overexpress TS.

The Role of Thymidylate Synthase Induction in Modulating p53-regulated Gene Expression in Response to 5-Fluorouracil and Antifolates

Thymidylate synthase (TS) is a critical target for chemotherapeutic agents such as 5-fluorouracil (5-FU) and antifolates such as tomudex (TDX),multitargeted antifolate, and ZD9331. Using the MCF-7 breast cancer line, we have developed p53 wild-type (M7TS90) and null (M7TS90-E6) isogenic lines with inducible TS expression (approximately 6-fold induction compared with control after 48 h). In the M7TS90 line, inducible TS expression resulted in a moderate approximately 3-fold increase in 5-FU IC-50(72 h) dose and a dramatic >20-fold increase in the IC-50(72 h) doses of TDX, multitargeted antifolate, and ZD9331. S-phase cell cycle arrest and apoptosis induced by the antifolates were abrogated by TS induction. In contrast, cell cycle arrest and apoptosis induced by 5-FU was unaffected by TS expression levels. Inactivation of p53 significantly increased resistance to 5-FU and the antifolates with IC-50(72 h) doses for 5-FU and TDX of >100 and >10 microM, respectively, in the M7TS90-E6 cell line. Furthermore, p53 inactivation completely abrogated the cell cycle arrest and apoptosis induced by 5-FU. The antifolates induced S-phase arrest in the p53 null cell line; however, the induction of apoptosis by these agents was significantly reduced compared with p53 wild-type cells. Both inducible TS expression and the addition of exogenous thymidine (10 microM) blocked p53 and p21 induction by the antifolates but not by 5-FU in the M7TS90 cell line. Similarly, inducible TS expression and exogenous thymidine abrogated antifolate but not 5-FU-mediated up-regulation of Fas/CD95 in M7TS90 cells. Our results indicate that in M7TS90 cells, inducible TS expression modulates p53 and p53 target gene expression in response to TS-targeted antifolate therapies but not to 5-FU.