103 research outputs found
Prevention and Promotion for Better Mental Health Fund: Evaluation of Projects to Support a Borough-Wide Trauma-Informed Initiative in Tower Hamlets
Prevention and Promotion for Better Mental Health Fund: London Borough of Newham Local Evaluation Report
La globalización y el malestar en la democracia
El origen de este texto es una conferencia en el VII Congreso de la FES (Salamanca, 20-22 de septiembre de 2001) con el título "Estados, mercados y ciudadanía". Publicado en: Revista Internacional de Filosofía Política, 20: 5-24, 2002.En años recientes se ha convertido en un lugar común la idea de que los ciudadanos de los países democráticos, independientemente de que apoyen esta forma de gobierno por encima de cualquier otra, otorgan un nivel de confianza muy bajo a las instituciones de la democracia
representativa, desde los partidos y los parlamentos hasta los gobiernos (Nye et al., 1997; Norris, 1999; Pharr y Putnam, 2000). En América Latina, además, los alarmantes resultados del Latinobarómetro de 2001 (Economist, 2001) hicieron temer que, ante la mala marcha de la economía, la insatisfacción de los ciudadanos pudiera conducir de forma imparable a la erosión del apoyo a la propia democracia.Proyecto Desconfianza Política y Gobernación Democrática (BSO2000-
1082) del Plan Nacional de I+D (Ministerio de Ciencia y Tecnología, España)Peer reviewe
Detection in coincidence of gravitational wave bursts with a network of interferometric detectors (I): Geometric acceptance and timing
Detecting gravitational wave bursts (characterised by short durations and
poorly modelled waveforms) requires to have coincidences between several
interferometric detectors in order to reject non-stationary noise events. As
the wave amplitude seen in a detector depends on its location with respect to
the source direction and as the signal to noise ratio of these bursts are
expected to be low, coincidences between antennas may not be so likely. This
paper investigates this question from a statistical point of view by using a
simple model of a network of detectors; it also estimates the timing precision
of a detection in an interferometer which is an important issue for the
reconstruction of the source location, based on time delays.Comment: low resolution figure 1 due to file size problem
Characterization of a Natural Mutator Variant of Human DNA Polymerase l which Promotes Chromosomal Instability by Compromising NHEJ
PLoS ONE 4(10): e7290.Background: DNA polymerase lambda (Poll) is a DNA repair polymerase, which likely plays a role in base excision repair
(BER) and in non-homologous end joining (NHEJ) of DNA double-strand breaks (DSB).
Principal Findings: Here, we described a novel natural allelic variant of human Poll (hPoll) characterized by a single
nucleotide polymorphism (SNP), C/T variation in the first base of codon 438, resulting in the amino acid change Arg to Trp.
In vitro enzyme activity assays of the purified W438 Poll variant revealed that it retained both DNA polymerization and
deoxyribose phosphate (dRP) lyase activities, but had reduced base substitution fidelity. Ectopic expression of the W438
hPoll variant in mammalian cells increases mutation frequency, affects the DSB repair NHEJ pathway, and generates
chromosome aberrations. All these phenotypes are dependent upon the catalytic activity of the W438 hPoll.
Conclusions: The expression of a cancer-related natural variant of one specialized DNA polymerase can be associated to
generic instability at the cromosomal level, probably due a defective NHEJ. These results establish that chromosomal
aberrations can result from mutations in specialized DNA repair polymerases.This work was supported by Ministerio de Ciencia y Tecnologia Grants BFU2006-14390/BMC, CONSOLIDER CSD2007-00015 and Comunidad Autonoma
de Madrid Grants P2006/BIO-0306 to L.B., by INCa ‘‘Checkpol’’, ARC, and ‘‘Ligue contre le Cancer (Region Midi-Pyrenees)’’ to J-S.H., by the Division of Intramural
Research, NIEHS, NIH, DHHS to T.A.K., by SAF2002-02265 to A.V., and by an institutional grant to Centro de Biologia Molecular ‘‘Severo Ochoa’’ from Fundacion
Ramon Areces. G.T. was recipient of a fellowship from the Ministerio de Educacion y Ciencia. A.V. is an Investigator of the Ramon y Cajal ProgramPeer reviewe
Mechanism of double-base lesion bypass catalyzed by a Y-family DNA polymerase
As a widely used anticancer drug, cis-diamminedichloroplatinum(II) (cisplatin) reacts with adjacent purine bases in DNA to form predominantly cis-[Pt(NH3)2{d(GpG)-N7(1),-N7(2)}] intrastrand cross-links. Drug resistance, one of the major limitations of cisplatin therapy, is partially due to the inherent ability of human Y-family DNA polymerases to perform translesion synthesis in the presence of DNA-distorting damage such as cisplatin–DNA adducts. To better understand the mechanistic basis of translesion synthesis contributing to cisplatin resistance, this study investigated the bypass of a single, site-specifically placed cisplatin-d(GpG) adduct by a model Y-family DNA polymerase, Sulfolobus solfataricus DNA polymerase IV (Dpo4). Dpo4 was able to bypass this double-base lesion, although, the incorporation efficiency of dCTP opposite the first and second cross-linked guanine bases was decreased by 72- and 860-fold, respectively. Moreover, the fidelity at the lesion decreased up to two orders of magnitude. The cisplatin-d(GpG) adduct affected six downstream nucleotide incorporations, but interestingly the fidelity was essentially unaltered. Biphasic kinetic analysis supported a universal kinetic mechanism for the bypass of DNA lesions catalyzed by various translesion DNA polymerases. In conclusion, if human Y-family DNA polymerases adhere to this bypass mechanism, then translesion synthesis by these error-prone enzymes is likely accountable for cisplatin resistance observed in cancer patients
The E1A-Associated p400 Protein Modulates Cell Fate Decisions by the Regulation of ROS Homeostasis
The p400 E1A-associated protein, which mediates H2A.Z incorporation at specific promoters, plays a major role in cell fate decisions: it promotes cell cycle progression and inhibits induction of apoptosis or senescence. Here, we show that p400 expression is required for the correct control of ROS metabolism. Depletion of p400 indeed increases intracellular ROS levels and causes the appearance of DNA damage, indicating that p400 maintains oxidative stress below a threshold at which DNA damages occur. Suppression of the DNA damage response using a siRNA against ATM inhibits the effects of p400 on cell cycle progression, apoptosis, or senescence, demonstrating the importance of ATM–dependent DDR pathways in cell fates control by p400. Finally, we show that these effects of p400 are dependent on direct transcriptional regulation of specific promoters and may also involve a positive feedback loop between oxidative stress and DNA breaks since we found that persistent DNA breaks are sufficient to increase ROS levels. Altogether, our results uncover an unexpected link between p400 and ROS metabolism and allow deciphering the molecular mechanisms largely responsible for cell proliferation control by p400
Cohesin Protects Genes against γH2AX Induced by DNA Double-Strand Breaks
Chromatin undergoes major remodeling around DNA double-strand breaks (DSB) to promote repair and DNA damage response (DDR) activation. We recently reported a high-resolution map of γH2AX around multiple breaks on the human genome, using a new cell-based DSB inducible system. In an attempt to further characterize the chromatin landscape induced around DSBs, we now report the profile of SMC3, a subunit of the cohesin complex, previously characterized as required for repair by homologous recombination. We found that recruitment of cohesin is moderate and restricted to the immediate vicinity of DSBs in human cells. In addition, we show that cohesin controls γH2AX distribution within domains. Indeed, as we reported previously for transcription, cohesin binding antagonizes γH2AX spreading. Remarkably, depletion of cohesin leads to an increase of γH2AX at cohesin-bound genes, associated with a decrease in their expression level after DSB induction. We propose that, in agreement with their function in chromosome architecture, cohesin could also help to isolate active genes from some chromatin remodelling and modifications such as the ones that occur when a DSB is detected on the genome
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