Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis

The Necrotic Signal Induced by Mycophenolic Acid Overcomes Apoptosis-Resistance in Tumor Cells

The amount of inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP), is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA) are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42.Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA–mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL–overexpressing cells). All tested cells remained sensitive to MPA–mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers.These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells

Importance of the difference in surface pressures of the cell membrane in doxorubicin resistant cells that do not express Pgp and ABCG2

P-glycoprotein (Pgp) represents the archetypal mechanism of drug resistance. But Pgp alone cannot expel drugs. A small but growing body of works has demonstrated that the membrane biophysical properties are central to Pgp-mediated drug resistance. For example, a change in the membrane surface pressure is expected to support drug–Pgp interaction. An interesting aspect from these models is that under specific conditions, the membrane is predicted to take over Pgp concerning the mechanism of drug resistance especially when the surface pressure is high enough, at which point drugs remain physically blocked at the membrane level. However it remains to be determined experimentally whether the membrane itself could, on its own, affect drug entry into cells that have been selected by a low concentration of drug and that do not express transporters. We demonstrate here that in the case of the drug doxorubicin, alteration of the surface pressure of membrane leaflets drive drug resistance

Early Prediction of Blood Loss and Postpartum Hemorrhage after Vaginal Delivery by Ultrasound Measurement of Intrauterine Content.

The ability of ultrasound to predict postpartum hemorrhage remains poorly described. The aim of this study was to evaluate whether ultrasound measurement of intrauterine content can predict blood loss and postpartum hemorrhage after vaginal delivery. We used a preliminary prospective monocentric study of 201 women who delivered vaginally after 34 wk of gestation. Measurements were performed 30-45 min after normal vaginal delivery according to strict ultrasonographic criteria. Analysis of the relationship between ultrasound measurements and hemoglobin loss showed a strong linear correlation (R² = 0.59 and R² = 0.4 for isthmic and fundal measurements). The maximal value between the fundal and isthmic measurements seems to provide the best accuracy to predict loss of hemoglobin higher than 3 g/dL (area under the curve [AUC] of the receiver operating characteristic curve, 0.9; 95% confidence interval [CI], [0.76-0.97]) and post-partum hemorrhage (AUC, 0.99; 95%CI, [0.984-0.99]). In case of intrauterine content >2 cm (135/201), the risks of loss of hemoglobin higher than 3 g/dL (5/135 vs. 0/66) and post-partum hemorrhage (11/135 vs. 0/66) were increased, all the more if the intrauterine content was >4 cm (4/16 and 11/16, respectively). Considering the maximal measurement, the most optimal cut-off value for clinical practice could be 2.4 cm (sensibility 100%, specificity 57%) and 4.1 cm (sensibility 100%, specificity 97%) for loss of hemoglobin higher than 3 g/dL and post-partum hemorrhage, respectively

Un système numérique de cryptographie basé sur les propriétés des signaux chaotiques discrets

- Nous présentons ici un cryptosystème numérique. Les algorithmes de cryptage proposés reposent sur l'utilisation des propriétés de suites chaotiques qui sont générées par des récurrences non inversibles de dimension 2. L'implémentation de ces algorithmes a été réalisée sur DSP. Cette réalisation effective du système nous a permis tout d'abord une première validation expérimentale, via la détermination de temps de calcul prohibitifs pour les attaques à force brute. Elle nous a aussi permis de mettre en évidence le problème de la représentation du chaos sur des machines discrètes, et de dégager certaines caractéristiques nécessaires aux récurrences utilisées afin de pouvoir continuer plus avant l'analyse de leur utilisation en cryptographie

Post-modified FAU zeolites as efficient catalysts for the synthesis of coumarins

Herein, the effect of various treatments subjected to FAU zeolites to introduce mesoporosity has been examined on their efficiency as catalyst in the cyclisation of O-aryl 3-arylpropynoic acid ester to its corresponding coumarin. The addition of bio-sourced lignin residues in the alkaline desilication treatment induced the generation of supplementary mesoporosity, thus offering an optimal micro- and mesopores combination with respect to targeted activity and selectivity. The so-called bio-sourced secondary template (BSST) concept in the design of zeolite-based catalysts could be assessed. The use of renewable wood feedstocks can therefore be a valuable strategy for the zeolite post-modification, thus for the design of porous zeolite catalysts. © 2020 Elsevier B.V.1

Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist

International audienceA novel pyridine derivative, 8-4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl -8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs

La radioprotection sur EPR : présentation comparée des instructions françaises et finlandaises et des démarches d’optimisation à la conception

À l’occasion de l’évaluation du rapport préliminaire de sûreté du réacteur EPR de Flamanville 3 (France), l’IRSN a souhaité dresser un bilan de l’historique de l’EPR, depuis les années 1990 jusqu’à l’autorisation de construction d’un réacteur EPR en Finlande puis en France ainsi que des instructions menées sur les aspects liés à la prise en compte de la radioprotection des travailleurs. Ce bilan présente les objectifs de dose retenus par les exploitants à la conception, la démarche globale d’optimisation mise en œuvre ainsi qu’une comparaison des démarches d’analyse française et finlandaise. En France, par exemple, EDF a réalisé des études approfondies d’optimisation sur les activités à fort enjeu « radioprotection » (calorifuge, logistique de chantier, robinetterie, ouverture/fermeture de la cuve, générateur de vapeur, évacuation du combustible et conditionnement des déchets). Cette démarche repose (en France) sur un processus itératif d’optimisation. Une comparaison des objectifs de dose collective des EPR français et finlandais par rapport aux doses reçues sur d’autres réacteurs à eau sous pression (Konvoi allemands, tranches du parc français, ...) est également présentée. Cette synthèse, élaborée par l’IRSN en collaboration avec EDF et l’autorité de sûreté nucléaire finlandaise STUK, reflète plus de 15 ans d’études et de partenariat en matière de radioprotection, dans le cadre du projet EPR