Oscillations in the expression of a self-repressed gene induced by a slow transcriptional dynamics

We revisit the dynamics of a gene repressed by its own protein in the case where the transcription rate does not adapt instantaneously to protein concentration but is a dynamical variable. We derive analytical criteria for the appearance of sustained oscillations and find that they require degradation mechanisms much less nonlinear than for infinitely fast regulation. Deterministic predictions are also compared with stochastic simulations of this minimal genetic oscillator

Oscillations in the expression of a self-repressed gene induced by a slow transcriptional dynamics

We revisit the dynamics of a gene repressed by its own protein in the case where the transcription rate does not adapt instantaneously to protein concentration but is a dynamical variable. We derive analytical criteria for the appearance of sustained oscillations and find that they require degradation mechanisms much less nonlinear than for infinitely fast regulation. Deterministic predictions are also compared with stochastic simulations of this minimal genetic oscillator

Contribution au développement de microcapteurs intégrés de viscoélasticité de fluides

Les propriétés viscoélastiques des fluides déterminent leur écoulement. L étude de ces propriétés a de nombreuses applications industrielles et académiques qui concernent la matière dite molle (polymères, colloïdes, tensioactifs, protéines, ...). L approche proposée permet d'étudier ces propriétés sur une gamme de fréquence allant de 1 à 100 kHz. La méthode utilise la mesure de la vibration d une microstructure actionnée électromagnétiquement et immergée dans le fluide à caractériser. La réponse en fréquence du système mécanique, mesurée optiquement ou électriquement, est caractéristique du milieu dans lequel la structure est immergée. Une méthode analytique dédiée aux micropoutres, pour l extraction des propriétés rhéologiques du milieu, a été améliorée tout au long de la thèse.La méthode analytique développée, pour être appliquée, nécessite la précision d un système optique complexe pour mesurer sans artefact les propriétés mécaniques de l interaction micropoutre-liquide. Ainsi les liquides opaques ne peuvent être caractérisés avec cette approche. De plus la mesure peut difficilement être intégrée dans un dispositif portable tout-électronique. Afin de pallier ces difficultés et de proposer une mesure de la viscoélasticité en milieu opaque, la stratégie de mesure du capteur jusqu au traitement des signaux ont été réévalués : (1) des microstructures en U ont été fabriquées, (2) une méthode de mesure intégrée a été mise en place et (3) une méthode de traitement à fréquence unique a été utilisée. Finalement, un liquide opaque viscoélastique, le yaourt, a pu être caractérisé in-situ tout au long de la fermentation lactique permettant de démontrer la validité et l applicabilité de la méthode mise en œuvre pour le suivi en temps réel de la viscoélasticité.The study of viscoelastic properties has many industrial and academic applications related to "soft matter" like polymers, colloids, surfactants or proteins. The present approach measures these properties in a frequency range from 1 to 100 kHz. The method uses the measurement of the vibration of a microstructure actuated electromagnetically and immersed in the fluid that has to be characterized. The frequency response of the mechanical system, which is measured optically or electrically, is characteristic of the environment in which the structure is immersed in. An analytical method dedicated to microcantilevers for the extraction of the rheological properties has been improved during this PhD thesis.The analytical method developed requires the accuracy of a complex optical system for measuring without artifact the mechanical properties of microcantilever-liquid interaction. Thus opaque liquids cannot be characterized with this sytem. In addition, the measurement cannot easily be integrated. To overcome these difficulties and provide the measurement of viscoelasticity into opaque medium, some strategy was reassessed: (1) U shaped microstructures were fabricated; (2) an integrated measurement method was developed and (3) a single frequency method was used to calculate the viscoelasticity.Finally, a viscoelastic and opaque liquid, such as yogurt, has been characterized in situ during the lactic fermentation to demonstrate the validity and the applicability of the method for the real-time monitoring of viscoelasticity.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Precision-Cut Liver Slices of Salmo salar as a tool to investigate the oxidative impact of CYP1A-mediated PCB 126 and 3-methylcholanthrene metabolism

a b s t r a c t Fish isolated cell systems have long been used to predict in vivo toxicity of man-made chemicals. In present study, we tested the suitability of Precision-Cut Liver Slices (PCLS) as an alternative to these models that allows the evaluation of a global tissue response to toxicants, to investigate oxidative stress response to cytochrome P450 1A (CYP1A) induction in fish liver. PCLS of Salmo salar were exposed for 21 h to increasing doses of 3-methylcholanthrene (3-MC) and Polychlorobiphenyl 126 (PCB 126). 3-MC (25 lM) strongly induced CYP1A transcription. In dose-response analysis (25-100 lM), EROD activity was strongly increased at intermediate 3-MC concentrations. We found the counter-intuitive decline of EROD at the highest 3-MC doses to result from reversible competition with ethoxyresorufin. No increases of H 2 O 2 production, antioxidant enzymes activities or oxidative damage to lipids were found with 3-MC treatments. PCLS subjected to PCB 126 (2-200 nM) showed increased contamination levels and a parallel increased CYP1A mRNA synthesis and EROD activity. H 2 O 2 production tended to increase but no oxidative damage to lipids was found. As antioxidant enzymes activities declined at the highest PCB 126 dose, it is suggested that longer incubation periods could be required to generate oxidative stress in PCLS

Risk Factors for Pharyngocutaneous Fistula After Total Pharyngolaryngectomy

Purpose:To evaluate the risk factors of pharyngocutaneous fistula after total pharyngolaryngectomy (TPL) in orderto reduce theirincidence and propose a perioperative rehabilitation protocol.Materials and Methods:This was a multicenter retrospectivestudy based on 456 patients operated for squamous cell carcinoma by total laryngectomy or TPL. Sociodemographic, medical,surgical, carcinologic, and biological risk factors were studied. Reactive C protein was evaluated on post-op day 5. Patients weredivided into a learning population and a validation population with patients who underwent surgery between 2006 and 2013 andbetween 2014 and 2016, respectively. A risk score of occurrence of salivary fistula was developed from the learning population dataand then applied on the validation population (temporal validation).Objective:To use a preoperative risk score in order tomodify practices and reduce the incidence of pharyngocutaneous fistula.Results:Four hundred fifty-six patients were included,328 in the learning population and 128 in the validation population. The combination of active smoking over 20 pack-years, ahistory of cervical radiotherapy, mucosal closure in separate stitches instead of running sutures, and the placement of a pedicleflap instead of a free flap led to a maximum risk of post-op pharyngocutaneous fistula after TPL. The risk score was discriminantwith an area under the receiver operating characteristic curve of 0.66 (95% confidence interval [CI]¼0.59-0.73) and 0.70 (95% CI¼0.60-0.81) for the learning population and the validation population, respectively.Conclusion:A preoperative risk score couldbe used to reduce the rate of pharyngocutaneous fistula after TPL by removing 1 or more of the 4 identified risk factors

Prevalence and Clinical Associations of Antiphospholipid Antibodies in Systemic Sclerosis: New Data From a French Cross-Sectional Study, Systematic Review, and Meta-Analysis

Objectives: Antiphospholipid antibodies (aPL) can be present in the sera of systemic sclerosis (SSc) patients. This study aimed to determine the prevalence of aPL in a cross-sectional study of SSc patients, to assess their clinical associations, to perform a systematic review of published reports and a meta-analysis to estimate the worldwide prevalence of aPL in SSc.Methods: Two-hundred and forty-nine SSc patients were consecutively tested once for lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2glycoprotein I (anti-β2GpI) antibodies. Clinical associations with aPL positivity were studied using a logistic regression model. A systematic review of the literature was carried out in PubMed and Embase. Meta-analysis was performed using number of aPL positive (at least one of the three antibodies positive) and negative patients. Meta-regression was used to study potential factors explaining the heterogeneity between studies.Results: In our cross-sectional study, aPL positivity was found in 16 patients (prevalence 6.4%; 95%CI [3.8–10.4]). In multivariate analysis, there was a significant association between aPL positivity and venous thrombosis (VT) (OR 6.25 [1.18–33.00]; p = 0.028) and miscarriage (OR 5.43; 95%CI [1.31–22.13]; p = 0.017). Twenty-four studies were included in the meta-analysis, representing a total population of 3036 SSc patients. The overall pooled prevalence of aPL in SSc was 14% (9–20) with a high degree of heterogeneity among studies.Conclusion: This study found a prevalence of aPL positivity in our SSc population of 6.4% (3.8–10.4) and an overall worldwide pooled prevalence of 14% (9–20). In our SSc population, aPL positivity was associated with VT and miscarriage. These data provide additional insights into the role of aPL in the vasculopathy observed in SSc

Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders

Cytochrome P450 (CYP) enzymes for which there is no functional information are considered "orphan" CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, suggesting involvement in brain and in early development. Moreover, hyperactivity is reported in humans with chromosome 2 microdeletions including CYP20A1. We examined CYP20A1 in zebrafish, including impacts of chemical exposure on expression. Zebrafish CYP20A1 cDNA was cloned, sequenced, and aligned with cloned human CYP20A1 and predicted vertebrate orthologs. CYP20A1s share a highly conserved N-terminal region and unusual sequences in the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including the liver, heart, gonads, spleen and brain, as well as the eye and optic nerve. Putative binding sites in proximal promoter regions of CYP20A1s, and response of zebrafish CYP20A1 to selected nuclear and xenobiotic receptor agonists, point to up-regulation by agents involved in steroid hormone response, cholesterol and lipid metabolism. There also was a dose-dependent reduction of CYP20A1 expression in embryos exposed to environmentally relevant levels of methylmercury. Morpholino knockdown of CYP20A1 in developing zebrafish resulted in behavioral effects, including hyperactivity and a slowing of the optomotor response in larvae. The results suggest that altered expression of CYP20A1 might be part of a mechanism linking methylmercury exposure to neurobehavioral deficits. The expanded information on CYP20A1 brings us closer to "deorphanization" CYP20A1 functions and its roles in health and disease

Seabirds reveal mercury distribution across the North Atlantic

Author contributionsC.A. and J.F. designed research; C.A., B. Moe, A.T., S.D., V.S.B., B. Merkel, J.Å., and J.F. performed research; C.A., B. Moe, M.B.-F., A.T., S.D., V.S.B., B. Merkel, J.Å., J.L., C.P.-P., and J.F. analyzed data; C.A., B.M., V.S.B., and J.F. sample and data collection, data coordination and management, statistical methodology; H.S. sample and data contribution and Data coordination and management; D.G., M.B.-F., F. Amélineau, F. Angelier, T.A.-N., O.C., S.C.-D., J.D., K.E., K.E.E., A.E., G.W.G., M.G., S.A.H., H.H.H., M.K.J., Y. Kolbeinsson, Y. Krasnov, M.L., J.L., S.-H.L., B.O., A.P., C.P.-P., T.K.R., G.H.S., P.M.T., T.L.T., and P.B. sample and data contribution; A.T., P.F. and S.D. sample and data contribution and statistical methodology; J.Å. statistical methodology; J.F. supervision; and C.A., B. Moe, H.S., D.G., A.T., S.D., V.S.B., B. Merkel, J.Å., F. Amélineau, F. Angelier, T.A.-N., O.C., S.C.-D., J.D., K.E., K.E.E., A.E., P.F., G.W.G., M.G., S.A.H., H.H.H., Y. Kolbeinsson, Y. Krasnov, S.-H.L., B.O., A.P., T.K.R., G.H.S., P.M.T., T.L.L., P.B., and J.F. wrote the paper.Peer reviewe

Mode shifting between storage and recall based on novelty detection in oscillating hippocampal circuits.

ABSTRACT: It has been suggested that hippocampal mode shifting between a storage and a retrieval state might be under the control of acetylcholine (ACh) levels, as set by an autoregulatory hippocampo-septohippocampal loop. The present study investigates how such a mechanism might operate in a large-scale connectionist model of this circuitry that takes into account the major hippocampal subdivisions, oscillatory population dynamics and the time scale on which ACh exerts its effects in the hippocampus. The model assumes that hippocampal mode shifting is regulated by a novelty signal generated in the hippocampus. The simulations suggest that this signal originates in the dentate. Novel patterns presented to this structure lead to brief periods of depressed firing in the hippocampal circuitry. During these periods, an inhibitory influence of the hippocampus on the septum is lifted, leading to increased firing of cholinergic neurons. The resulting increase in ACh release in the hippocampus produces network dynamics that favor learning over retrieval. Resumption of activity in the hippocampus leads to the reinstatement of inhibition. Despite theta-locked rhythmic firing of ACh neurons in the septum, ACh modulation in the model fluctuates smoothly on a time scale of seconds. It is shown that this is compatible with the time scale on which memory processes take place. A number of strong predictions regarding memory function are derived from the model. © 2004 Wiley-Liss, Inc. KEY WORDS: acetylcholine; computational modeling; hippocampus; medial septum; memor

Regards comparatistes sur la réforme de la responsabilité civile: le rapprochement des responsabilités contractuelle et délictuelle dans l’avant-projet de réforme, abordé sous l’angle du droit compare

This article is a comparative study of the Dutch and French legal systems regarding four major points of the French governmental reform project for civil liability : concurrence of actions; limitation and exemption clauses; causation; the obligation to mitigate your own damage. It also addresses the following issues: the question of damages to the environment, and the role of transitional provisions. Through these different areas of study, this article shows that the traditional distinction between contractual and tortuous liability is not necessarily relevant and may even prove a nuisance in certain cases. The contribution is followed by a reaction of Mme. De Cabarrus, magistrate at the French Ministry of Justice