Rif1 maintains telomeres and mediates DNA repair by encasing DNA ends

In yeast, Rif1 is part of the telosome, where it inhibits telomerase and checkpoint signaling at chromosome ends. In mammalian cells, Rif1 is not telomeric, but it suppresses DNA end resection at chromosomal breaks, promoting repair by nonhomologous end joining (NHEJ). Here, we describe crystal structures for the uncharacterized and conserved ∼125-kDa N-terminal domain of Rif1 from Saccharomyces cerevisiae (Rif1-NTD), revealing an α-helical fold shaped like a shepherd's crook. We identify a high-affinity DNA-binding site in the Rif1-NTD that fully encases DNA as a head-to-tail dimer. Engagement of the Rif1-NTD with telomeres proved essential for checkpoint control and telomere length regulation. Unexpectedly, Rif1-NTD also promoted NHEJ at DNA breaks in yeast, revealing a conserved role of Rif1 in DNA repair. We propose that tight associations between the Rif1-NTD and DNA gate access of processing factors to DNA ends, enabling Rif1 to mediate diverse telomere maintenance and DNA repair functions

Les mécanismes d'action antidépressive de l'électroconvulsivothérapie (hypothèses neurobiologiques)

L électroconvulsivothérapie (ECT) reste le traitement le plus efficace de la dépression. Son mécanisme d action n est pas totalement élucidé. La convergence d effets neurobiologiques induis par ce traitement dans le cadre des hypothèses monoaminergiques, neurotrophiques et anticonvulsivantes permettent de progresser dans la compréhension de son efficacité antidepressive. Les modifications du système monoaminergique ne semblent pas être une voie biologique fondamentale de l action antidépressive de l ECT. En revanche, comme le suggèrent les connaissances actuelles, le mécanisme d action de l ECT relève probablement d un double mécanisme. Le premier, neurotrophique permet de compenser l atrophie cérébrale due à la dépression et aux facteurs de stress, et le second, anticonvulsivant, par le recrutement de processus inhibiteurs de l activité cérébrale détermine l efficacité antidépressive par la durée de sa période réfractaire. Sur le plan biologique, le neuropeptide Y dont la synthèse est stimulée par le brain derived neurotrophic factor pourrait expliquer cette double action et semble être une piste importante de compréhension du mécanisme d action neurobiologique de l ECT. Mais la recherche dans ce domaine reste limitée techniquement, du fait de la restriction à l étude cérébrale in vivo chez l homme. L extrapolation des résultats obtenus chez l animal doit être prudente. La recherche systématique d une corrélation de l ECT et des chimiothérapies limite la pertinence des résultats. Le développement de techniques de neuroimagerie cérébrale performantes permettra dans le futur de progresser dans la compréhension des mécanismes neurobiologiques chez l homme. D autant que le traitement de la dépression est une priorité de santé publique dans les années à venir.AMIENS-BU Santé (800212102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Effects of depression and cognitive impairment on quality of life in older adults with schizophrenia spectrum disorder: Results from a multicenter study

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Psychiatric symptoms and mortality in older adults with major psychiatric disorders: results from a multicenter study

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A comprehensive model of predictors of quality of life in older adults with schizophrenia: results from the CSA study

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Late-onset and nonlate-onset schizophrenia: A comparison of clinical characteristics in a multicenter study

International audienceObjectives Data are scarce regarding the potential clinical differences between non-late onset schizophrenia (NLOS, i.e., disorder occurring before 40 years of age), late-onset schizophrenia (LOS, occurring between ages 40 and 60 years) and very-late-onset schizophrenia-like psychosis (VLOSLP, occurring after 60 years of age). Furthermore, previous research compared LOS patients with non-age matched NLOS patients. In this study, we sought to examine potential clinical differences between patients of similar age with LOS and NLOS. Methods/Design This is a cross-sectional multicentre study that recruited in- and outpatients older adults (aged >= 55 years) with an ICD-10 diagnosis of schizophrenia or schizoaffective disorder with NLOS and LOS. Sociodemographic and clinical characteristics, comorbidity, psychotropic medications, quality of life, functioning, and mental health care utilization were drawn for comparison. Results Two hundred seventy-two participants (79.8%) had NLOS, 61 (17.9%) LOS, and 8 (2.3%) VLOSLP. LOS was significantly and independently associated with greater severity of emotional withdrawal and lower severity of depression (all p < 0.05). However, the magnitude of these associations was modest, with significant adjusted odds ratios ranging from 0.71 to 1.24, and there were no significant between-group differences in other characteristics. Conclusion In an age-matched multicenter sample of elderly patients with schizophrenia, older adults with LOS were largely similar to older adults with NLOS in terms of clinical characteristics. The few differences observed may be at least partially related to symptom fluctuation with time. Implications of these findings for pharmacological and nonpharmacological management is yet to be determined

Psychiatric and physical outcomes of long-term use of lithium in older adults with bipolar disorder and major depressive disorder: A cross-sectional multicenter study

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Association between antithrombotic treatment and outcomes at 1-year follow-up in patients with atrial fibrillation: the EORP-AF General Long-Term Registry

International audienceAims In recent years, stroke prevention in patients with atrial fibrillation (AF) has radically changed, with increasing use of non-vitamin K antagonist oral anticoagulants (NOACs). Contemporary European data on AF thromboprophylaxis are needed. Methods and results We report 1-year follow-up data from the EURObservational Research Programme in Atrial Fibrillation (EORP-AF) General Long-Term Registry. Outcomes were assessed according to antithrombotic therapy. At 1-year follow-up, 9663 (88.0%) patients had available data for analysis: 586 (6.1%) were not treated with any antithrombotic; 681 (7.0%) with antiplatelets only; 4066 (42.1%) with vitamin K antagonist (VKA) only; 3167 (32.8%) with NOACs only; and 1163 (12.0%) with antiplatelet and oral anticoagulant. At 1-year follow-up, there was a low rate of stroke (0.7%) and any thromboembolic event (TE) (1.2%), while haemorrhagic events occurred in 222 patients (2.3%). Cardiovascular (CV) death and all-cause death occurred in 3.9% and 5.2% of patients, respectively. Cumulative survival for all the three main outcomes considered was highest amongst patients treated only with NOACs (P &lt; 0.0001). Multivariable-adjusted Cox regression analysis found that VKA or NOACs use was independently associated with a lower risk for any TE/acute coronary syndrome/CV death, while all treatments were independently associated with a lower risk for CV death and all-cause death. Conclusion The 1-year follow-up of EORP-AF General Long-Term Registry reported a low occurrence of thromboembolic and haemorrhagic events, although mortality was high. Both VKA and NOACs were associated with a lower risk of all main adverse outcomes. All treatments were associated with a lower risk for CV death and all-cause death

The SAMe-TT2R2 score and quality of anticoagulation in atrial fibrillation: a simple aid to decision-making on who is suitable (or not) for vitamin K antagonists

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