Joyce Apsel on To Plead Our Own Cause: Personal Stories by Today\u27s Slaves. Edited by Kevin Bales and Zoe Trodd (Ithaca, NY: Cornell University Press, 2008). 260pp.

A review of: To Plead Our Own Cause: Personal Stories by Today\u27s Slaves. Edited by Kevin Bales and Zoe Trodd (Ithaca, NY: Cornell University Press, 2008). 260pp

Joyce Apsel on Peace: A History of Movements and Ideas. By David Cortright. New York: Cambridge University Press, 2008. 376pp.

A review of: Peace: A History of Movements and Ideas. By David Cortright. New York: Cambridge University Press, 2008. 376pp

Joyce Apsel on The Oxford Handbook of Genocide Studies. Edited by Donald Bloxham & A. Dirk Moses. New York, NY: Oxford University Press, 2010. 675pp.

A review of: The Oxford Handbook of Genocide Studies. Edited by Donald Bloxham & A. Dirk Moses. New York, NY: Oxford University Press, 2010. 675pp

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

Lower Complexity Bounds for Lifted Inference

One of the big challenges in the development of probabilistic relational (or probabilistic logical) modeling and learning frameworks is the design of inference techniques that operate on the level of the abstract model representation language, rather than on the level of ground, propositional instances of the model. Numerous approaches for such "lifted inference" techniques have been proposed. While it has been demonstrated that these techniques will lead to significantly more efficient inference on some specific models, there are only very recent and still quite restricted results that show the feasibility of lifted inference on certain syntactically defined classes of models. Lower complexity bounds that imply some limitations for the feasibility of lifted inference on more expressive model classes were established early on in (Jaeger 2000). However, it is not immediate that these results also apply to the type of modeling languages that currently receive the most attention, i.e., weighted, quantifier-free formulas. In this paper we extend these earlier results, and show that under the assumption that NETIME =/= ETIME, there is no polynomial lifted inference algorithm for knowledge bases of weighted, quantifier- and function-free formulas. Further strengthening earlier results, this is also shown to hold for approximate inference, and for knowledge bases not containing the equality predicate.Comment: To appear in Theory and Practice of Logic Programming (TPLP

Evidence for Adiabatic Magnetization of cold Dy_N Clusters

Magnetic properties of Dy_N clusters in a molecular beam generated with a liquid helium cooled nozzle are investigated by Stern-Gerlach experiments. The cluster magnetizations \mu_z are measured as a function of magnetic field (B = 0 - 1.6T) and cluster size (16 < N < 56). The most important observation is the saturation of the magnetization \mu_z(B) at large field strengths. The magnetization approaches saturation following the power law |\mu_z-\mu_0| proportional to 1/\sqrt{B}, where \mu_0 denotes the magnetic moment. This gives evidence for adiabatic magnetization.Comment: 4 pages, 3 figure

Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2

The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)→Akt→mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease