15 research outputs found
Inducible and constitutive heat shock gene expression responds to modification of Hsp70 copy number in Drosophila melanogaster but does not compensate for loss of thermotolerance in Hsp70 null flies
<p>Abstract</p> <p>Background</p> <p>The heat shock protein Hsp70 promotes inducible thermotolerance in nearly every organism examined to date. Hsp70 interacts with a network of other stress-response proteins, and dissecting the relative roles of these interactions in causing thermotolerance remains difficult. Here we examine the effect of <it>Hsp70 </it>gene copy number modification on thermotolerance and the expression of multiple stress-response genes in <it>Drosophila melanogaster</it>, to determine which genes may represent mechanisms of stress tolerance independent of Hsp70.</p> <p>Results</p> <p><it>Hsp70 </it>copy number in four strains is positively associated with <it>Hsp70 </it>expression and inducible thermotolerance of severe heat shock. When assayed at carefully chosen temperatures, <it>Hsp70 </it>null flies are almost entirely deficient in thermotolerance. In contrast to expectations, increasing <it>Hsp70 </it>expression levels induced by thermal pretreatment are associated with increasing levels of seven other inducible <it>Hsps </it>across strains. In addition, complete <it>Hsp70 </it>loss causes upregulation of the inducible <it>Hsps </it>and six constitutive stress-response genes following severe heat shocks.</p> <p>Conclusion</p> <p>Modification of <it>Hsp70 </it>copy number quantitatively and qualitatively affects the expression of multiple other stress-response genes. A positive association between absolute expression levels of <it>Hsp70 </it>and other <it>Hsps </it>after thermal pretreatment suggests novel regulatory mechanisms. Severe heat shocks induce both novel gene expression patterns and almost total mortality in the <it>Hsp70 </it>null strain: alteration of gene expression in this strain does not compensate for <it>Hsp70 </it>loss but suggests candidates for overexpression studies.</p
Reactions of Low-Valent Group V Dicarbonyl Phosphine Complexes with Carbon-Based Electrophiles To Produce Metal Alkyl, Acyl, Carbyne, and Acetylene Complexes.
Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ‑Secretase Modulator
This work describes
the demonstration of a kilogram-scale synthesis
of a γ-secretase modulator from a plant-sterol-derived starting
material. Key to developing a synthetic route capable of delivering
a kilogram of the target compound was the development of a four-reaction
telescope process and a selective O-alkylation of a triol intermediate.
These improvements enabled the successful delivery of kilogram-scale
batches of API for preclinical development studies
Initial Optimization of a New Series of γ‑Secretase Modulators Derived from a Triterpene Glycoside
The discovery of a new series of γ-secretase modulators
is
disclosed. Starting from a triterpene glycoside γ-secretase
modulator that gave a very low brain-to-plasma ratio, initial SAR
and optimization involved replacement of a pendant sugar with a series
of morpholines. This modification led to two compounds with significantly
improved central nervous system (CNS) exposure