Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta

The two subunits of core binding factor (Runx1 and CBFbeta) play critical roles in hematopoiesis and are frequent targets of chromosomal translocations found in leukemia. The binding of the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein to Runx1 is essential for leukemogenesis, making this a viable target for treatment. We have developed inhibitors with low micromolar affinity which effectively block binding of Runx1 to CBFbeta. NMR-based docking shows that these compounds bind to CBFbeta at a site displaced from the binding interface for Runx1, that is, these compounds function as allosteric inhibitors of this protein-protein interaction, a potentially generalizable approach. Treatment of the human leukemia cell line ME-1 with these compounds shows decreased proliferation, indicating these are good candidates for further development.     

Fucci: street lights on the road to mitosis

Tracking cell-cycle progression in live cells within their endogenous environment has been an outstanding challenge. In a recent issue of Cell, Sakaue-Sawano et al. describe Fucci, a technique designed to track cell-cycle progression with high spatiotemporal resolution in a multicellular context.     

Auditory efferent activation in CBA mice exceeds that of C57s for varying levels of noise

The medial olivocochlear efferent (MOC) system enhances signals in noise and helps mediate auditory attention. Contralateral suppression (CS) of distortion product otoacoustic emissions (DPOAEs) has revealed age-related MOC declines. Here, differences in CS as a function of contralateral noise intensity (43-67 dB sound pressure level) were measured; 2f1-f2 DPOAE grams were recorded for young adult CBA and C57 mice. In CBAs, CS was a monotonic function of contralateral noise level. The C57s showed normal hearing, measured with DPOAE amplitudes and auditory brainstem response thresholds, but showed little CS, suggesting a loss of efferent dynamics preceding any deficiencies of the afferent auditory system.     

Complex systems analysis of series of blackouts: cascading failure, critical points, and self-organization

We give an overview of a complex systems approach to large blackouts of electric power transmission systems caused by cascading failure. Instead of looking at the details of particular blackouts, we study the statistics and dynamics of series of blackouts with approximate global models. Blackout data from several countries suggest that the frequency of large blackouts is governed by a power law. The power law makes the risk of large blackouts consequential and is consistent with the power system being a complex system designed and operated near a critical point. Power system overall loading or stress relative to operating limits is a key factor affecting the risk of cascading failure. Power system blackout models and abstract models of cascading failure show critical points with power law behavior as load is increased. To explain why the power system is operated near these critical points and inspired by concepts from self-organized criticality, we suggest that power system operating margins evolve slowly to near a critical point and confirm this idea using a power system model. The slow evolution of the power system is driven by a steady increase in electric loading, economic pressures to maximize the use of the grid, and the engineering responses to blackouts that upgrade the system. Mitigation of blackout risk should account for dynamical effects in complex self-organized critical systems. For example, some methods of suppressing small blackouts could ultimately increase the risk of large blackouts.     

Investigation of the interactions between alkanethiol self-assembled monolayers and a liquid overlayer using impedance spectroscopy

We report on changes in the complex impedance response of a quartz crystal microbalance (QCM) that result from the growth of an alkanethiol monolayer on the electrodes of the device. The purpose of this work is to understand the evolution of the interactions between alkanethiol-gold monolayers and a liquid overlayer as a function of time after initial deposition by evaluating the position, shape, and linewidth of the impedance spectra associated with the monolayer formation. We relate the complex impedance response of the QCM to the mass and viscosity of the monolayer through an established equivalent circuit model. The data show the organization of alkanethiol SAMs occurs at approximately the same rate for aliphatic chain lengths in the range of C(9)-C(16), as long as the thiol is readily soluble in the solvent system used. Our data are consistent with SAM annealing being mediated by the sulfur-gold adsorption and desorption equilibrium. Additionally, we have found that examination of a C(18) SAM is limited by the deposition conditions and thiol solubility. Bulk deposition was confirmed visually and related to the evolution of the peak position and shape changes with deposition time.     

An efficient method for the N-arylation of phenylurea via copper catalyzed amidation

The coupling reaction of phenylurea with different functionalized aryl halides in the presence of air stable CuI,N,N-dimethylethylenediamine as a ligand,and K₃PO₄ as a base gives symmetrical and unsymmetrical diarylureas in relatively high yields.This method is milder than the palladium catalyzed arylation and avoids the use of toxic phosphine ligands.