Pyrone-based inhibitors of metalloproteinase types 2 and 3 may work as conformation-selective inhibitors.

Matrix metalloproteinases are zinc-containing enzymes capable of degrading all components of the extracellular matrix. Owing to their role in human disease, matrix metalloproteinase have been the subject of extensive study. A bioinorganic approach was recently used to identify novel inhibitors based on a maltol zinc-binding group, but accompanying molecular-docking studies failed to explain why one of these inhibitors, AM-6, had approximately 2500-fold selectivity for MMP-3 over MMP-2. A number of studies have suggested that the matrix-metalloproteinase active site is highly flexible, leading some to speculate that differences in active-site flexibility may explain inhibitor selectivity. To extend the bioinorganic approach in a way that accounts for MMP-2 and MMP-3 dynamics, we here investigate the predicted binding modes and energies of AM-6 docked into multiple structures extracted from matrix-metalloproteinase molecular dynamics simulations. Our findings suggest that accounting for protein dynamics is essential for the accurate prediction of binding affinity and selectivity. Additionally, AM-6 and other similar inhibitors likely select for and stabilize only a subpopulation of all matrix-metalloproteinase conformations sampled by the apo protein. Consequently, when attempting to predict ligand affinity and selectivity using an ensemble of protein structures, it may be wise to disregard protein conformations that cannot accommodate the ligand

La persona adecuada en el momento adecuado: los miembros del comité de auditoría y la calidad de la información financiera

We analyze some personal characteristics of the members of the audit committee of the Spanish listed firms and the relation between these characteristics and earnings management. We find a non-linear relation with tenure, so that long tenures can initially compromise the directors’ independence but, after a given threshold, longer tenures improve the expertise of the members. Serving in too many boards has a negative influence on the ability of directors to detect earnings management, and higher academic background and more diverse professional background improve the directors’ abilities.En el presente trabajo analizamos la relación entre algunas características personales de los miembros del comité de auditoría de las empresas cotizadas españolas y la gestión del resultado. Nuestros resultados muestran una relación no lineal con la antigüedad en el consejo: mientras que en los primeros estadios una mayor duración puede comprometer la independencia de los consejeros, llega un punto en el que la mayor antigüedad en el comité incrementa su experiencia. Formar parte de un número excesivo de consejos redunda en una menor capacidad de los consejeros para detectar la gestión del resultado. Una formación académica más elevada y una experiencia profesional más diversa contribuyen a mejorar la calidad de la información financiera

Intrinsic noise and two-dimensional maps: Quasicycles, quasiperiodicity, and chaos

We develop a formalism to describe the discrete-time dynamics of systems containing an arbitrary number of interacting species. The individual-based model, which forms our starting point, is described by a Markov chain, which in the limit of large system sizes is shown to be very well-approximated by a Fokker-Planck-like equation, or equivalently by a set of stochastic difference equations. This formalism is applied to the specific case of two species: one predator species and its prey species. Quasi-cycles --- stochastic cycles sustained and amplified by the demographic noise --- previously found in continuous-time predator-prey models are shown to exist, and their behavior predicted from a linear noise analysis is shown to be in very good agreement with simulations. The effects of the noise on other attractors in the corresponding deterministic map, such as periodic cycles, quasiperiodicity and chaos, are also investigated.Comment: 21 pages, 12 figure

Applications of an exact counting formula in the Bousso-Polchinski Landscape

The Bousso-Polchinski (BP) Landscape is a proposal for solving the Cosmological Constant Problem. The solution requires counting the states in a very thin shell in flux space. We find an exact formula for this counting problem which has two simple asymptotic regime one of them being the method of counting low $\Lambda$ states given originally by Bousso and Polchinski. We finally give some applications of the extended formula: a robust property of the Landscape which can be identified with an effective occupation number, an estimator for the minimum cosmological constant and a possible influence on the KKLT stabilization mechanism.Comment: 43 pages, 11 figures, 2 appendices. We have added a new section (3.4) on the influence of the fraction of non-vanishing fluxes in the KKLT mechanism. Other minor changes also mad

Suppressing escape events in maps of the unit interval with demographic noise

We explore the properties of discrete-time stochastic processes with a bounded state space, whose deterministic limit is given by a map of the unit interval. We find that, in the mesoscopic description of the system, the large jumps between successive iterates of the process can result in probability leaking out of the unit interval, despite the fact that the noise is multiplicative and vanishes at the boundaries. By including higher-order terms in the mesoscopic expansion, we are able to capture the non-Gaussian nature of the noise distribution near the boundaries, but this does not preclude the possibility of a trajectory leaving the interval. We propose a number of prescriptions for treating these escape events, and we compare the results with those obtained for the metastable behavior of the microscopic model, where escape events are not possible. We find that, rather than truncating the noise distribution, censoring this distribution to prevent escape events leads to results which are more consistent with the microscopic model. The addition of higher moments to the noise distribution does not increase the accuracy of the final results, and it can be replaced by the simpler Gaussian noise.Comment: 14 pages, 13 figure