Identification of a small molecule yeast TORC1 inhibitor with a flow cytometry-based multiplex screen

TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high throughput flow cytometry multiplexed screen using five GFPtagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose-response analysis to alter GFP expression in one or more clones. To validate the concept of the high throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in an analogous manner to rapamycin. We have shown that CID 3528206 inhibited yeast cell growth, and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC50s of 150 nM and 3.9 μM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors

The cricket and the ant : organizational tradeoffs in changing environments

Organizations face tradeoffs when they adopt strategies in changing resource environments. The type of tradeoff depends on the type of resource change. The paper gives an organizational tradeoff model for quantitative change. I call that the "Cricket and Ant" (CA), because the pertaining strategies resemble to the cricket and ant behavior in La Fontaine’s famous fable. I demonstrate that organizational ecology’s niche theory and U-.-strategist theory obtain as special cases of CA; their predictions on selection derive as theorems, if their respective boundary conditions are represented in the formal model. New selection conclusions also derive, prone to empirical testing.

The cricket and the ant : organizational tradeoffs in changing environments

Organizations face tradeoffs when they adopt strategies in changing resource environments. The type of tradeoff depends on the type of resource change. The paper gives an organizational tradeoff model for quantitative change. I call that the "Cricket and Ant" (CA), because the pertaining strategies resemble to the cricket and ant behavior in La Fontaine’s famous fable. I demonstrate that organizational ecology’s niche theory and U-.-strategist theory obtain as special cases of CA; their predictions on selection derive as theorems, if their respective boundary conditions are represented in the formal model. New selection conclusions also derive, prone to empirical testing.