Up-regulation of p21(WAF1)/(CIP1) by histone deacetylase inhibitors reduces their cytotoxicity

Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21(+/+) and p21(-/-) cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors.

M. Mangin [Louis, le nouveau] directeur du Muséum [national d'histoire naturelle de Paris] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 58398

Instantáneas : proyectos para atender a la diversidad educativa.

Se analizan los factores determinantes para que un centro sea capaz de responder adecuadamente a la diversidad educativa de sus alumnos. Se presenta el proceso y resultados de un estudio que trata de identificar, analizar y explicar cuales son los principios didácticos, los dispositivos metodológicos y las actitudes educativas que pueden explicar el éxito logrado por siete centros de características muy dispares, en dar una respuesta organizativa y curricular ajustada a la multiplicidad de intereses y necesidades educativas de sus alumnos. Se han elegido ejemplos de siete centros educativos de características diferentes con el fin de ofrecer a los centros ideas, propuestas, actividades y puntos de vista que favorezcan la reflexión y el desarrollo de iniciativas tendentes a encontrar soluciones educativas para todos sus estudiantes, que respondan a los principios de comprensividad e inclusividad.

Search for new phenomena in events with three charged leptons at a center-of-mass energy of 7 TeV with the ATLAS detector

A generic search for anomalous production of events with at least three charged leptons is presented. The search uses a pp-collision data sample at a center-of-mass energy of root s = 7 TeV corresponding to 4.6 fb(-1) of integrated luminosity collected in 2011 by the ATLAS detector at the CERN Large Hadron Collider. Events are required to contain at least two electrons or muons, while the third lepton may either be an additional electron or muon, or a hadronically decaying tau lepton. Events are categorized by the presence or absence of a reconstructed tau-lepton or Z-boson candidate decaying to leptons. No significant excess above backgrounds expected from Standard Model processes is observed. Results are presented as upper limits on event yields from non-Standard-Model processes producing at least three prompt, isolated leptons, given as functions of lower bounds on several kinematic variables. Fiducial efficiencies for model testing are also provided. The use of the results is illustrated by setting upper limits on the production of doubly charged Higgs bosons decaying to same-sign lepton pairs.

Turkey's economy: a story of success with an uncertain future. OSW Commentary No. 120, 2013-11-05

In the decade since the Justice and Development Party (AKP) came to power, Turkey’s economy has become synonymous with success and well-implemented reforms. Economic development has been the basis of both socio-political stability inside the country and of an ambitious foreign policy agenda pursued by the AKP. However, the risks associated with a series of unresolved issues are becoming increasingly apparent. These include the country’s current account deficit, its over-reliance on short-term external financing, and unfinished reforms, for example of the education sector. This leaves Turkey exposed to over-dependence on investors, especially from the West. Consequently, Ankara has become a hostage of its own image as an economically successful state with a stable socio-political system. Any changes to this image would cause capital flight, as exemplified by the outflow of portfolio investment1 and an increase in the cost of external debt2 that followed the nationwide protests over the proposed closure of Gezi Park last summer. In addition, Turkey remains vulnerable to potential changes in investor sentiment towards emerging markets.