Ovarian cancer molecular pathology.

Peer reviewe

Revised Morning Loops of the Arabidopsis Circadian Clock Based on Analyses of Direct Regulatory Interactions

The network structure of the plant circadian clock is complex and direct regulatory interactions between individual components have proven particularly difficult to predict from genetic analyses. Here, we systematically investigate in vivo binding interactions between the morning-specific transcription factor, LATE ELONGATED HYPOCOTYL (LHY) and the promoters of other components of the network. We then demonstrate the functionality of these interactions by testing the responsiveness of the target gene to an ethanol-induced change in expression level of the LHY protein. We uncover novel, negative autoregulatory feedback loops from LHY and the closely related CIRCADIAN CLOCK ASSOCIATED-1 (CCA1) onto their own and each other’s expression. Furthermore we show that LHY acts as a repressor of all other clock components, including PSEUDO-RESPONSE REGULATORs (PRRs) 9 and 7, which were previously thought to be positive regulatory targets. These experimental results lead to a substantial revision of the morning loops of the clock

Chronic and remitting trajectories of depressive symptoms in the elderly. Characterization and risk factors: Trajectories of depressive symptoms in the elderly

International audienceAimsIn elderly general population sub-syndromal clinically significant levels of depressive symptoms are highly prevalent and associated with high co-morbidity and increased mortality risk. However changes in depressive symptoms over time and etiologic factors have been difficult to characterize notably due to methodological shortcomings. Our objective was to differentiate trajectories of depressive symptoms over 10 years in community-dwelling elderly men and women using statistical modelling methods which take into account intra-subject correlation and individual differences as well as to examine current and life-time risk factors associated with different trajectories. MethodsParticipants aged 65 and over were administered standardised questionnaires and underwent clinical examinations at baseline and after 2, 4, 7 and 10 years. Trajectories over time of the Center for Epidemiologic Studies Depression scores were modelled in 517 men and 736 women separately with latent class mixed models which include both a linear mixed model to describe latent classes of trajectories and a multinomial logistic model to characterize the latent trajectories according to baseline covariates (socio-demographic, lifestyle, clinical, genetic characteristics and stressful life events). ResultsIn both genders two different profiles of symptom changes were observed over the 10-year follow-up. For 9.1% of men and 25% of women a high depressive symptom trajectory was found with a trend toward worsening in men. The majority of the remaining men and women showed decreasing symptomatology over time, falling from clinically significant to very low levels of depressive symptoms. In large multivariate class membership models, mobility limitations (odds ratio (OR)=4.5, 95% confidence interval (CI) 1.6-12.9 and OR=4.9, 95% CI 2.3-10.7, in men and women respectively), ischemic pathologies (OR=2.9, 95% CI 1.0-8.3 and OR=3.1, 95%CI 1.0-9.9), and recent stressful events (OR=4.5, 95% CI 1.1-18.5, OR=3.2, 95%CI 1.6-6.2) were associated with a poor symptom course in both gender as well as diabetes in men (OR=3.5, 95% CI 1.1-10.9) and childhood traumatic experiences in women (OR=3.1, 95% CI 1.6-5.8). ConclusionsThis prospective study was able to differentiate patterns of chronic and remitting depressive symptoms in elderly people with distinct symptom courses and risk factors for men and women. These findings may inform prevention programmes designed to reduce the chronic course of depressive symptomatology

Differences in locomotor behavior revealed in mice deficient for the calcium-binding proteins parvalbumin, calbindin D-28k or both

We investigated the role of the two calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) in the locomotor activity and motor coordination using null-mutant mice for PV (PV−/−), CB (CB−/−) or both proteins (PV−/−CB−/−). These proteins are expressed in distinct, mainly non-overlapping populations of neurons of the central and peripheral nervous system and PV additionally in fast-twitch muscles. In a test measuring repeated locomotor activity during 18–20 days, the analysis revealed a slightly increased activity in mice lacking either protein, while the lack of both decreased the number of beams crossed during active periods. An increase in the characteristic speed during the first 8 days could be attributed to PV-deficiency, while the elimination of CB in CB−/− and double-KO mice decreased the percentage of fast movements at all time points. In the latter, additionally a reduction of the fastest speed was observed. The alterations in locomotor activity (fast movements, fastest speed) strongly correlate with the impairment in locomotor coordination in mice deficient for CB evidenced in the runway assay and the rotarod assay. The graded locomotor phenotype (CB > PV) is qualitatively correlated with alterations in Purkinje cell firing reported previously in these mice. The presence or absence of either protein did not affect the spontaneous locomotor activity when animals were placed in a novel environment and tested only once for 30 min. In summary, the lack of these calcium-binding proteins yields characteristic, yet distinct phenotypes with respect to locomotor activity and coordination

Downstream of the plant circadian clock : output pathways for the control of physiology and development

The plant circadian clock controls many aspects of growth and development, allowing an individual to adapt its physiology and metabolism in anticipation of diurnal and seasonal environmental changes. Circadian regulation of hormone levels and hormonal signalling modulates many features of development, including daily growth patterns and the breaking of seed dormancy. The clock also plays a role in seasonal day-length perception, allowing plants to optimally time key development transitions, such as reproduction. Moreover, the clock restricts (gates) the sensitivity of a plant's response to environmental cues, such as light and stress, to specific times of the day, ensuring that the plant can distinguish between normal fluctuations and longer-term changes. The central oscillator controls many of these output pathways via rhythmic gene expression, with several of the core clock components encoding transcription factors. Post-transcriptional processes are also likely to make an important contribution to the circadian regulation of output pathways. The plant circadian clock plays a role in regulating fitness, hybrid vigour and numerous stress responses. Thus elucidating the complexities of the circadian output mechanisms and their regulation may provide new avenues for crop enhancement

Patterns of selective serotonin reuptake inhibitor use andrisk of falls and fractures in community-dwelling elderly people. The Three-City cohort

International audiencePurpose: Increased risk of falls and fractures has been reported in elderly users of selective serotonin reuptake inhibitors (SSRIs). However, biases were insufficiently addressed notably temporality between exposure and outcome and confounding by residual depression. Our objective was to examine the associations between SSRIs and fall or fracture incidence focusing on their chronic use and different types of SSRIs.Methods: The population-based cohort included participants aged 65 years and above, who had not fallen before inclusion (n=6,599) or free of recent fracture (n=6823) and followed-up twice over 4 years. New fall and fracture events were self-reported and defined as at least two falls and one fracture, respectively, during the previous 2-years. SSRI users were compared with those taking no antidepressants. Hazard ratios (HR) were estimated using Cox models with delayed entry and adjusted for many confounders including residual depressive symptoms.Results: Incidence of falls was 19.3% over 4 years and that of fractures 9.5%. After multi-adjustment, SSRI intake was significantly associated with a higher risk of falls (HR, 95% CI = 1.58, 1.23-2.03) and fractures (HR, 95% CI = 1.61, 1.16-2.24). The risks were significantly increased by 80% in those continuing the treatment over 4 years. Citalopram intake only was at significant risk for falls and fluoxetine for fractures. Conclusions: In this large community-dwelling elderly sample, SSRI users were at higher risk of falls and fractures. This association was not due to reverse causality or residual depressive symptoms. Different SSRI drugs may have specific adverse effects on falls and fractures

Antidepressant use and cognitive decline in community-dwelling elderly people – The Three-City Cohort

International audienceAbstractBackgroundCognitive impairment is very common in late-life depression, principally affecting executive skills and information processing speed. The aim of the study was to examine the effect of antidepressant treatment on cognitive performances over a 10-year period.MethodsThe community-based cohort included 7381 participants aged 65 years and above. Five cognitive domains (verbal fluency, psychomotor speed, executive function, visuospatial skills and global cognition) were assessed up to five times over 10 years of follow-up. Treatment groups included participants under a specific antidepressant class at both baseline and the first follow-up and their follow-up cognitive data were considered until the last consecutive follow-up with a report of antidepressant use of the same class. Linear mixed models were used to compare baseline cognitive performance and cognitive decline over time according to antidepressant treatment. The models were adjusted for multiple confounders including residual depressive symptoms assessed by the Center for Epidemiologic Studies-Depression scale.ResultsAt baseline, 4.0% of participants were taking antidepressants. Compared to non-users, tricyclic antidepressant users had lower baseline performances in verbal fluency, visual memory and psychomotor speed, and selective serotonin reuptake inhibitor users in verbal fluency and psychomotor speed. For the two other cognitive abilities, executive function and global cognition, no significant differences were found at baseline irrespective of the antidepressant class. Regarding changes over time, no significant differences were observed in comparison with non-users whatever the cognitive domain, except for a slight additional improvement over the follow-up in verbal fluency skills for tricyclic antidepressant users.ConclusionsIn this large elderly general population cohort, we found no evidence for an association between antidepressant use and post-treatment cognitive decline over 10 years of follow-up in various cognitive domains

Genetic and Transcriptomic Bases of Intestinal Epithelial Barrier Dysfunction in Inflammatory Bowel Disease

Intestinal barrier defects are common in patients with inflammatory bowel disease (IBD). To identify which components could underlie these changes, we performed an in-depth analysis of epithelial barrier genes in IBD.status: publishe