Chantal Guihenneuc-Jouyaux’s research while affiliated with Paris Descartes University and other places

SET is a multifunctional protein, but when present in the cytoplasm, acts as a powerful inhibitor of phosphatase 2A (PP2A). We previously observed that in CA1 of Down syndrome (DS) patients, the level of SET is increased, SET is translocated to the cytoplasm and associated with the hyperphosphorylation of tau at ser202/thr205. The presence of SET in the cytoplasm in DS brains may play a role in the progression of the disease. Here, we show that in CA1 of 3 months old Ts65Dn mice modelling DS, SET level is increased, SET is translocated to the cytoplasm, associated with tau hyperphosphorylations at ser202/thr205 and with amyloid precursor protein caspase cleaved as observed in Alzheimer disease brains. Tau hyperphosphorylation at ser356 and activation of other PP2A targets such as the mammalian target of rapamycin and adenosine monophosphate protein kinases were also observed, suggesting deleterious mechanisms. We propose Ts65Dn mice as a model for therapeutic approaches focused on SET overexpression and its cytoplasmic translocation in order to slow down disease progression.

For the years 2008–2013, particles of diameter <10 and 2.5 μm (PM10 and PM2.5, respectively), NOx, SO2, and O3 concentrations at urban, suburban, rural, and traffic sites in the Paris metropolitan area were analyzed. Strong spatial variability at traffic and rural sites and relatively uniform profiles at urban and suburban sites for PM10, PM2.5, and O3 were observed. The O3 weekend effect was induced by lower NOx emissions during the weekend, and favored volatile organic compounds (VOCs)-limited atmospheric conditions. In conjunction with low ambient temperature, these conditions could also favor increased formation of secondary particulate nitrates in winter. Winter air pollution events were associated with multiple pollutants, whereas those observed in spring were caused by high PM10 and PM2.5 levels. Backward trajectory analyses showed the contribution of sources in Western and Central Europe on days with high PM10, PM2.5, and O3, and a local/national component for NOx and SO2.

To account for the dynamic aspects of carcinogenesis, we propose a compartmental hidden Markov model in which each person is healthy, asymptomatically affected, diagnosed, or deceased. Our model is illustrated using the example of smoking-induced lung cancer. The model was fitted on a case-control study nested in the European Prospective Investigation into Cancer and Nutrition study, including 757 incident cases and 1524 matched controls. Estimation was done through a Markov Chain Monte Carlo algorithm, and simulations based on the posterior estimates of the parameters were used to provide measures of model fit. We performed sensitivity analyses to assess robustness of our findings. After adjusting for its impact on exposure duration, age was not found to independently drive the risk of lung carcinogenesis, whereas age at starting smoking in ever-smokers and time since cessation in former smokers were found to be influential. Our data did not support an age-dependent time to diagnosis. The estimated time between onset of malignancy and clinical diagnosis ranged from 2 to 4 years. Our approach yielded good performance in reconstructing individual trajectories in both cases (sensitivity >90%) and controls (sensitivity >80%). Our compartmental model enabled us to identify time-varying predictors of risk and provided us with insights into the dynamics of smoking-induced lung carcinogenesis. Its flexible and general formulation enables the future incorporation of disease states, as measured by intermediate markers, into the modeling of the natural history of cancer, suggesting a large range of applications in chronic disease epidemiology.

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.

Although formaldehyde is a common indoor pollutant, its impact on respiratory symptoms in childhood remains unclear. The aim of this study was to examine the relation between domestic formaldehyde exposure and occurrence of coughing, one of the most prevalent respiratory symptoms during the first year of life of infants from the PARIS birth cohort involving 3840 healthy full-term babies. The presence of respiratory symptoms, including dry cough at night apart from a cold or chest infection in the past 12 months was reported on a standardized health questionnaire. Formaldehyde exposure was estimated for all infants using a predictive model established from data (both repeated measurements and information about determinants of levels) collected in a random sample of infants from the cohort. An unconditional logistic regression was fitted to study the relation between annual domestic formaldehyde exposure and dry cough at night, adjusting for all potential risk factors/confounders. The prevalence of dry cough at night was 14.9%. Parental history of allergy was found to modify the relation between environmental factors and dry cough. Cockroaches, used mattresses, and family stressor events were associated with dry cough in infants with parental allergy history. Conversely, domestic formaldehyde exposure tended to increase occurrence of dry cough at night only among babies without parental history of allergy (adjusted OR per 10µg/m(3) increase in levels, single imputation approach: 1.45, 95% CI: 1.08-1.96, and Bayesian approach: 1.12, 0.91-1.36). This study suggests that the impact of indoor environmental exposure on dry cough at night in infancy is different depending on the presence or not of parental history of allergy.

We consider the problem of combining opinions from different experts in an explicitly model-based way to construct a valid subjective prior in a Bayesian statistical approach. We propose a generic approach by considering a hierarchical model accounting for various sources of variation as well as accounting for potential dependence between experts. We apply this approach to two problems. The first problem deals with a food risk assessment problem involving modelling dose-response for Listeria monocytogenes contamination of mice. Two hierarchical levels of variation are considered (between and within experts) with a complex mathematical situation due to the use of an indirect probit regression. The second concerns the time taken by PhD students to submit their thesis in a particular school. It illustrates a complex situation where three hierarchical levels of variation are modelled but with a simpler underlying probability distribution (log-Normal).

The levels of molecules crucial for signal transduction processing change in the brain with aging. Lipid rafts are membrane microdomains involved in cell signaling. We describe here substantial biophysical and biochemical changes occurring within the rafts in hippocampus neurons from aging wild-type rats and mice. Using continuous sucrose density gradients, we observed light-, medium-, and heavy raft subpopulations in young adult rodent hippocampus neurons containing very low levels of amyloid precursor protein (APP) and almost no caveolin-1 (CAV-1). By contrast, old rodents had a homogeneous age-specific high-density caveolar raft subpopulation containing significantly more cholesterol (CHOL), CAV-1, and APP. C99-APP-Cter fragment detection demonstrates that the first step of amyloidogenic APP processing takes place in this caveolar structure during physiological aging of the rat brain. In this age-specific caveolar raft subpopulation, levels of the C99-APP-Cter fragment are exponentially correlated with those of APP, suggesting that high APP concentrations may be associated with a risk of large increases in beta-amyloid peptide levels. Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced these age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: CHOL, CAV-1, and APP concentrations were significantly lower and the C99-APP-Cter fragment was less abundant in the heavy raft subpopulation than in controls. Thus, we report substantial changes in raft structures during the aging of rodent hippocampus and describe new and promising areas of investigation concerning the possible protective effect of citrulline on brain function during aging.