Search

PRSS1 and PRSS2 constitute the only functional copies of a tandemly-arranged five-trypsinogen-gene cluster (i.e., PRSS1, PRSS3P1, PRSS3P2, TRY7 and PRSS2) on chromosome 7q35. Variants in PRSS1 and PRSS2, including missense and copy number variants (CNVs), have been reported to predispose to or protect against chronic pancreatitis (CP). We wondered whether a common trypsinogen pseudogene deletion CNV (that removes two of the three trypsinogen pseudogenes, PRSS3P2 and TRY7) might be associated with CP causation/predisposition.We analyzed the common PRSS3P2 and TRY7 deletion CNV in a total of 1536 CP patients and 3506 controls from France, Germany, India and Japan by means of quantitative fluorescent multiplex polymerase chain reaction.We demonstrated that the deletion CNV variant was associated with a protective effect against CP in the French, German and Japanese cohorts whilst a trend toward the same association was noted in the Indian cohort. Meta-analysis under a dominant model yielded a pooled odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.89; p = 0.005) whereas an allele-based meta-analysis yielded a pooled OR of 0.84 (95% CI 0.77-0.92; p = 0.0001). This protective effect is explicable by reference to the recent finding that the still functional PRSS3P2/TRY7 pseudogene enhancers upregulate pancreatic PRSS2 expression.The common PRSS3P2 and TRY7 deletion CNV was associated with a reduced risk for CP. This finding provides additional support for the emerging view that dysregulated PRSS2 expression represents a discrete mechanism underlying CP predisposition or protection.

In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson’s disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.

International audience; Background & aims: Based on platelets and liver stiffness measurements, the Baveno VI criteria (B6C), the expanded B6C (EB6C), and the ANTICIPATE score can be used to rule out varices needing treatment (VNT) in patients with compensated chronic liver disease. We aimed to improve these tests by including data on the ratio of platelets to liver stiffness.Methods: In a retrospective analysis of data from 10 study populations, collected from 2004 through 2018, we randomly assigned data from 2368 patients with chronic liver disease of different etiologies to a derivation population (n = 1579; 15.1% with VNT, 50.2% with viral hepatitis, 28.9% with nonalcoholic fatty liver disease, 20.8% with alcohol-associated liver disease, with model for end-stage liver disease scores of 9.5 ± 3.0, and 93.0% with liver stiffness measurements ≥10 kPa) or a validation population (n = 789). Test results were compared with results from a sequential algorithm (VariScreen). VariScreen incorporated data on platelets or liver stiffness measurements and then the ratio of platelets to liver stiffness measurement, adjusted for etiology, patient sex, and international normalized ratio.Results: In the derivation population, endoscopies were spared for 23.9% of patients using the B6C (VNT missed in 2.9%), 24.3% of patients using the ANTICIPATE score (VNT missed in 4.6%), 34.5% of patients using VariScreen (VNT missed in 2.9%), and 41.9% of patients using the EB6C (VNT missed in 10.9%). Differences in spared endoscopy rates were significant (P ≤ .001), except for B6C vs ANTICIPATE and in missed VNT only for EB6C vs the others (P ≤ .009). VariScreen was the only safe test regardless of sex or etiology (missed VNT ≤5%). Moreover, VariScreen secured screening without missed VNT in patients with model for end-stage liver disease scores higher than 10. This overall strategy performed better than a selective strategy restricted to patients with compensated liver disease. Test performance and safety did not differ significantly among populations.Conclusions: In a retrospective study of data from 2368 patients with chronic liver disease, we found that the B6C are safe whereas the EB6C are unsafe, based on missed VNT. The VariScreen algorithm performed well in patients with chronic liver disease of any etiology or severity. It is the only test that safely rules out VNT and can be used in clinical practice.

Introduction Inadequate bowel preparation before colonoscopy has a 20–30% rate and impedes on the quality of the procedure. The aim of this study was to develop a predictive score of inadequate bowel preparation, using a patient questionnaire on potential risk factors. Methods In this single center study, consecutive patients with colonoscopy indication were enrolled. The primary outcome was inadequate bowel preparation defined by Boston Bowel Preparation Scale (BBPS) score Results A total of 561 patients were included. Inadequate bowel preparation was seen in 25.0% of cases. Seven risk factors were selected into the prediction model of inadequate bowel preparation: diabetes or obesity, irregular physical activity, cirrhosis, use of antidepressants or neuroleptics, use of opiate medication, history of surgery and history of inadequate bowel preparation. The risk score, named PREPA-CO, had an AUROC of 0.621, adequately predicted bowel cleanliness in 68.3% of cases, with a specificity of 75.8% and a negative predictive value of 80.8%. Conclusion We developed a predictive score named “Prepa-Co”, allowing the identification of patients at high risk of inadequate bowel preparation. In clinical practice, this score could help tailor the prescription of the preparation to the patient.

International audience; BACKGROUND & AIMS: Large oesophageal varice (LEV) screening is recommended in cirrhosis. We performed a prospective study to improve non-invasive LEV screening.DESIGN: 287 patients with cirrhosis had upper gastrointestinal endoscopy (LEV reference), oesophageal capsule endoscopy (ECE), liver elastography and blood marker analyses. CirrhoMeter (cirrhosis blood test), the most accurate non-invasive LEV test, was segmented for cirrhosis (reference comparator) or LEV. VariScreen, a sequential and partially minimally invasive diagnostic algorithm, was developed by multivariate analysis. It uses CirrhoMeter first, then ECE if CirrhoMeter cannot rule LEV out or in, and finally endoscopy if CirrhoMeter+ECE combination remains uninformative.RESULTS: Diagnostic effectiveness rates for LEV were: cirrhosis-segmented CirrhoMeter: 14.6%, LEV-segmented CirrhoMeter: 34.6%, ECE: 60.6% and VariScreen: 66.4% (P≤.001 for overall or pair comparison). The respective missed LEV rates were: 2.8%, 5.6%, 8.3% and 5.6% (P=.789). Spared endoscopy rates were, respectively: 15.6%, 36.0%, 70.6% and 69%, (PCONCLUSION: VariScreen algorithm significantly reduced the missed LEV rate with ECE by 87%, ECE use by 38% and endoscopy requirement by 69%, and even 86% in compensated cirrhosis.

Obesity epidemic continues to spread and obesity rates are increasing in the world. In addition to public health effort to reduce obesity, there is a need to better understand the underlying biology to enable more effective treatment and the discovery of new pharmacological agents. Abhydrolase domain-containing protein 11 (ABHD11) is a serine hydrolase enzyme, localized in mitochondria, that can synthesize the endocannabinoid 2-arachidonoyl glycerol (2AG) in vitro. In vivo preclinical studies demonstrated that knock-out ABHD11 mice have a similar 2AG level as WT mice and exhibit a lean metabolic phenotype. Such mice resist to weight gain in Diet Induced Obesity studies (DIO) and display normal biochemical plasma parameters. Metabolic and transcriptomic analyses on serum and tissues of ABHD11 KO mice from DIO studies show a modulation in bile salts associated with reduced fat intestinal absorption. These data suggest that modulating ABHD11 signaling pathway could be of therapeutic value for the treatment of metabolic disorders.

Cet article étudie les manifestations spatiales de la pratique catholique dans la vallée de la Maurienne, avec comme postulat de départ que la mobilité, à toutes les échelles, constitue une caractéristique majeure au sein d’un ensemble paroissial recomposé. Interroger la structure ecclésiale de la Savoie en général et de la Maurienne en particulier permet ainsi de dresser un état des lieux du socle au sein duquel l’espace catholique, dans la pluralité des acteurs qui le composent, se manifeste afin d’envisager, par la carte, des logiques réticulaires et de polarités aux temporalités diverses. Si la pratique catholique est universelle, son expression n’en est pas moins locale et suppose de prendre en compte les spécificités du contexte social de la vallée où le tourisme domine ainsi que d’envisager les phénomènes d’appropriation, de valorisation et de représentation attachés aux lieux et dont dépend la (dé)construction du territoire de pratique. L’étude vise finalement à poser les jalons d’une géographie du fait religieux en Maurienne. This article aims to present the spatial manifestations of Catholicism throughout the territory of the Maurienne valley, with the presumption that the mobility, at all scales, is a major feature in a reconstructed aggregated parish. Studying the ecclesial structure of Savoie in general and Maurienne in particular allows us to inventory the basic structures through which Catholic space is manifested, with its plurality of actors. It also allows us to map reticular logics and polarities at various moments. Though the practice of Catholicism is universal, its expression remains profoundly contextual. This implies taking into account the specificities of the valley’s social context where tourism dominates. It is equally necessary to consider phenomena such as appropriation, valuation, and representation tied to specific spatial contexts, a necessary step in their (de)construction. Finally, the article lays the foundation for a geographical study of religious practice in Maurienne Este artículo estudia las manifestaciones espaciales del catolicismo en el valle de Maurienne, partiendo de la hipótesis de la existencia de una la movilidad multiesacalar tras la reorganización de las parroquias. Cuestiona la estructura eclesial de Saboya y, particularmente, la del vallre de Maurienne partiendo desde el presupuesto por el que el espacio católico es plural. Cartografiandolo se conocerán mejor su estructura lógica, y se podrán comprender sus diversas polariddes, temporalidad y redes reticulares. Aunqe el catolicismo es universal, su expresión es local al considerar las especificidades del contexto social de un valle donde domina el turismo. También, tiene en cuenta los fenómenos de apropiación, valoración y representación de los lugares, y de lo que se deriva la (de)construcción sobre la práctica del territorio. Con este estudio se pretende fundamentar las bases de una geografía del hecho religioso en Maurienne.

L’ISP-Faculté d’Éducation de l’Institut Catholique de Paris a initié la pratique du journal de recherche depuis trois ans au sein du master 2 MEEF, afin de faciliter le processus de rédaction du mémoire et l’entrée dans la recherche des stagiaires enseignants et cadres d’éducation. Nous avons analysé si autant la pratique que l’outil étaient « significatifs » et « facilitateurs » pour leurs utilisateurs. Plusieurs entretiens semi-directifs ont été menés pour identifier les avantages et les inconvénients, les usages et les réutilisations de cette pratique et de cet outil. Une analyse croisée des entretiens a fait émerger des éléments déterminants : d’abord la difficulté partagée dans l’entrée dans le processus d’écriture. Une fois cette appréhension surmontée, la pratique est intégrée et l’outil utilisé de façon permanente pour la construction et l’écriture du mémoire. En effet, les personnes interviewées ont révélé mieux organiser leurs idées et leur réflexion, problématiser leur sujet et réussir à construire leur mémoire. Enfin, le journal participe à la construction de l’étudiant-chercheur et, sur le long terme, à celle du praticien-réflexif l’intégrant dans sa vie professionnelle ; avec pour conséquence de transformer et/ou de faire évoluer celle-ci. ISP-Faculty of the Catholic Institute of Paris introduced the practice of the research diary since three years in order to facilitate the writing of the Master dissertation and the beginning of the research for the students teachers. We wanted to analyze if this practice and tool were “significant” and “facilitators” for their users. Several semi-directive interviews were led to identify advantages and inconveniences, uses and reuses of this practice and this tool. A crossed analysis of interviews was brought to determining elements: at first the difficulty shared at the beginning of the writing process. Once this apprehension is overcome the practice is integrated and the tool used in a permanent way for construction and writing of dissertation. Indeed, the interviewed people revealed to better organize their ideas and their reflection, problematize their subject and managing to write their dissertation. Finally the research diary participates in the research student’s identity and, on the long term, of the reflexive practitioner. Practice and tool can be integrated into professional life; with for consequence to transform and/or to develop it.

Summary Phosphoribosyltransferases catalyze the displacement of a PRPP α-1′-pyrophosphate to a nitrogen-containing nucleobase. How they control the balance of substrates/products binding and activities is poorly understood. Here, we investigated the human adenine phosphoribosyltransferase (hAPRT) that produces AMP in the purine salvage pathway. We show that a single oxygen atom from the Tyr105 side chain is responsible for selecting the active conformation of the 12 amino acid long catalytic loop. Using in vitro , cellular, and in crystallo approaches, we demonstrated that Tyr105 is key for the fine-tuning of the kinetic activity efficiencies of the forward and reverse reactions. Together, our results reveal an evolutionary pressure on the strictly conserved Tyr105 and on the dynamic motion of the flexible loop in phosphoribosyltransferases that is essential for purine biosynthesis in cells. These data also provide the framework for designing novel adenine derivatives that could modulate, through hAPRT, diseases-involved cellular pathways.

Increasing block tariffs seek a cross-subsidy mechanism between the water network users, based on the common assumption of a low water price elasticity. In Manaus, the capital city of the Brazilian state of Amazonas, where most of the 1.6 million dwellers are supplied through a municipal water network, a substantial consumption drop followed the tariff increase of 2004. This drop questions the cross-subsidy capacity of the current structure. We see this 31.51% tariff increase as a natural experiment applied to the whole network user population of Manaus, and this allows us to measure the impact on monthly consumption of metered households, using month-on-month differences between years 2003 and 2004.

Dans un contexte de ressources budgetaires limitees et suite au constat que la croissance et l’aide publique au developpement ne beneficiaient pas forcement aux pauvres, la communaute internationale a eu recours a des outils specifiques permettant d’atteindre en priorite les pauvres. Le ciblage des politiques de lutte contre la pauvrete est l’un de ces outils. Cet article vise a dresser un bilan des experiences de ciblage menees dans les pays en developpement. Il cherche pour cela a degager les facteurs de reussite ou d’echec de ces experiences et fait le point sur les questions qui font toujours debat.Classification JEL : I38, O12, H23

This chapter is presenting the various strategies used to find pertinent compounds as starting points for optimization up to a drug. The discovery strategies from the historical ones to the most modern approaches are reviewed. They consist into mainly five approaches: the improvement of already existing drugs, the systematic screening, the exploitation of observed biological activities, the attempts towards rational design and the target protein structure-based approaches. These strategies are not mutually exclusive and can be appropriately applied and combined.

SummaryRod-derived cone viability factor (RdCVF) is an inactive thioredoxin secreted by rod photoreceptors that protects cones from degeneration. Because the secondary loss of cones in retinitis pigmentosa (RP) leads to blindness, the administration of RdCVF is a promising therapy for this untreatable neurodegenerative disease. Here, we investigated the mechanism underlying the protective role of RdCVF in RP. We show that RdCVF acts through binding to Basigin-1 (BSG1), a transmembrane protein expressed specifically by photoreceptors. BSG1 binds to the glucose transporter GLUT1, resulting in increased glucose entry into cones. Increased glucose promotes cone survival by stimulation of aerobic glycolysis. Moreover, a missense mutation of RdCVF results in its inability to bind to BSG1, stimulate glucose uptake, and prevent secondary cone death in a model of RP. Our data uncover an entirely novel mechanism of neuroprotection through the stimulation of glucose metabolism.

gamma-aminobutyric acid type A (GABAA) receptors comprise a subfamily of ligand-gated ion channels whose activity can be modulated by ligands acting at the benzodiazepine binding site on the receptor. The benzodiazepine binding site was characterized using a site-directed mutagenesis strategy in which amino acids of the alpha5 subunit were substituted by their corresponding alpha1 residues. Given the high affinity and selectivity of alpha1-containing compared with alpha5-containing GABAA receptors for zolpidem, mutated alpha5 subunits were co-expressed with beta2 and gamma2 subunits, and the affinity of recombinant receptors for zolpidem was measured. One alpha5 mutant (bearing P162T, E200G, and T204S) exhibited properties similar to that of the alpha1 subunit, notably high affinity zolpidem binding and potentiation by zolpidem of GABA-induced chloride current. Two of these mutations, alpha5P162T and alpha5E200G, might alter binding pocket conformation, whereas alpha5T204S probably permits formation of a hydrogen bond with a proton acceptor in zolpidem. These three amino acid substitutions also influenced receptor affinity for CL218872. Our data thus suggest that corresponding amino acids of the alpha1 subunit, particularly alpha1-Ser204, are the crucial residues influencing ligand selectivity at the binding pocket of alpha1-containing receptors, and a model of this binding pocket is presented.

Conformational analysis by NOESY NMR spectroscopy and Distance Geometry of an ω1 selective (zolpidem) and a non selective (saripidem) ligand of ω modulatory sites suggests that the single set of conformations observed with zolpidem could be account for its ω1 selective properties. The methodology applied in this study appears to be a powerful technique to explore conformational space of non-peptidic ligands of GABA a receptor subtypes.

We describe a family of seven boys affected by Lesch-Nyhan disease with various phenotypes. Further investigations revealed a mutation c.203T>C in the gene encoding HGprt of all members, with substitution of leucine to proline at residue 68 (p.Leu68Pro). Thus patients from this family display a wide variety of symptoms although sharing the same mutation. Mutant HGprt enzyme was prepared by site-directed mutagenesis and the kinetics of the enzyme revealed that the catalytic activity of the mutant was reduced, in association with marked reductions in the affinity towards phosphoribosylpyrophosphate (PRPP). Its Km for PRPP was increased 215-fold with hypoxanthine as substrate and 40-fold with guanine as substrate with associated reduced catalytic potential. Molecular modeling confirmed that the most prominent defect was the dramatically reduced affinity towards PRPP. Our studies suggest that the p.Leu68Pro mutation has a strong impact on PRPP binding and on stability of the active conformation. This suggests that factors other than HGprt activity per se may influence the phenotype of Lesch-Nyhan patients.

Crystal structures of 5-(5-methylthien-2-yl)-2′-deoxyuridine (I), 5-(5-thien-2-yl)-2′-deoxyuridine (II) and 5-(5-bromothien-2-yl)-2′-deoxyuridine (III) have been obtained from data collected on a four-circle Enraf-Nonius diffractometer (CAD-4 system). Space group, unit/cell parameters and finalR indices are:I, monoclinic,P21,a=9.105(2),b=20.819(2),c=7.932(2) A, β=98.79(2)°,R=5.7%;II, monoclinic,P21,a=8.720(4),b=20.793(4),c=7.884(4) A, β=95.06(2)°,R=5.8%;III, monoclinic,P21,a=9.260(2),b=41.655(7),c=7.926(2) A, β=97.996(13)°,R=9.4%. Structural properties of the title compounds are compared with those of 5-(5-chlorothien-2-yl)-2′-deoxyuridine (IV) previously reported in order to explain their affinity for HSV-1 thymidine kinase and their eventual interaction with viral DNA polymerase. The main structural features observed are the coplanarity of the uracil and thienyl cycles stabilized by a S−O intramolecular interaction and the formation of dimeric intermolecular H bonds between two uracil moieties.

The crystal structures of 5-(5-furan-2-yl)-2'-deoxyuridine (II), 5-(5-bromofuran-2-yl)-2'-deoxyuridine (IV) and 5-(3-bromothien-2-yl)-2'-deoxyuridine (V) have been studied in order to explain the different affinity of the compounds for the herpes simplex virus type 1 (HSV-1) thymidine kinase. These compounds present a variable affinity according to the position of the heteroatom substituting the five-membered ring. An unfavourable substitution in the five-membered ring for interaction with the HSV-1 thymidine kinase has been identified.

Structural and electronic characteristics of 5-(5-chlorothien-2-yl)-2′-deoxyuridine ( I ), 5-(furan-2-yl)-2′-deoxyuridine ( II ), 5-(5-bromofuran-2-yl)-2′-deoxyuridine ( III ), 5-(3-bromoisoxazol-5-yl)-2′-deoxyuridine ( V ) and 5-(isoxazol-5-yl)-2′-deoxyuridine ( IV ) have been determined and compared to the BVDU ( VI ) characteristics in order to explain their respective affinity for the herpes simplex virus type 1 thymidine kinase (TK). Molecular structure of 5-(5-chlorothien-2-yl)-2′-deoxyuridine has been obtained using single crystal X-ray crystallography. Electrostatic potential maps, energy and topology of frontier orbitals were computed at the ab initio MO STO-3G and STO-3G∗ level. These studies reveal that the electrostatic potential energy maps are clearly dependent on the affinity of the compound for the enzyme.

(english) Fiscal constraints and policy changes to improve the effectiveness of programmes in reducing poverty have gradually led the international community to use tools to reach the poor. Poverty reduction policy targeting is one of them. This paper reviews targeted poverty alleviation policies in developing countries and seeks to identify the key factors that affect their performances. _________________________________ (français) Dans un contexte de ressources budgétaires limitées et suite au constat que la croissance et l’aide publique au développement ne bénéficiaient pas forcément aux pauvres, la communauté internationale a eu recours à des outils spécifiques permettant d’atteindre en priorité les pauvres. Le ciblage des politiques de lutte contre la pauvreté est l’un de ces outils. Cet article vise à dresser un bilan des expériences de ciblage menées dans les pays en développement. Il cherche pour cela à dégager les facteurs de réussite ou d’échec de ces expériences et fait le point sur les questions qui font toujours débat.

Vanishing white matter (VWM) disease, also known as childhood ataxia with central nervous system hypomyelination (CACH) syndrome, is an autosomal recessive transmitted leukodystrophy. Classically characterised by early childhood onset, adult onset formed with slower progression have been recently recognized. The course of neurological impairment is usually progressive with possible occasional episodes of acute deterioration following febrile illnesses or head trauma. Neurological features are dominated by cerebellar ataxia and spasticity with relatively preserved mental abilities. Brain MRI shows diffuse abnormal signal of the cerebral white matter and cystic degeneration. Mutations in one of the genes coding for the five subunits of the translation factor eukaryotic initiation factor 2B (eIF2B) have been identified. We report here on two sisters affected by adult onset VWM with variable phenotypic expression. The proband is remarkable by the very late age of the disease onset (age of 42). A homozygous p.Arg113His mutation in the eIF2B ɛ gene was identified. This mutation had been recurrently associated with adult onset VWM establishing phenotype–genotype correlations. We will show an important intra-familial phenotypic variability and discuss it in the light of recent molecular progresses. External precipitating factors are contributing for some of the differences observed.

(english) Increasing block tariffs seek a cross-subsidy mechanism between the water network users, based on the common assumption of weak water price elasticity. In Manaus, the capital city of the Brazilian state of Amazonas where most of the 1.6 million dwellers are supplied through the municipal water network, a substantial consumption drop followed the tariff increase of 2004. This drop questions the cross-subsidy capacity of the current structure. We see this 31.51% tariff increase as a natural experiment applied to the whole network user population of Manaus and this allows us to measure the impact on monthly consumption of metered households, using month per month differences between years 2003 and 2004. _________________________________ (français) Les structures tarifaires progressives par tranche de consommation en eau cherchent à établir des péréquations entre les usagers du réseau d’approvisionnement, ceci sous l’hypothèse d’élasticités faibles au prix de l’eau. A Manaus, capitale de l’Etat d’Amazonas au Brésil où résident 1,6 million de personnes majoritairement approvisionnées par le réseau municipal, la dernière hausse du prix de l’eau, appliquée uniformément à chaque tranche de consommation en janvier 2004, a conduit à une baisse significative des consommations, remettant en cause la capacité de subventions croisées de la structure tarifaire. L’exploitation de cette hausse de 31,51 % du tarif, comme un choc naturel subi par l’ensemble des usagers du réseau d’approvisionnement de Manaus, permet d’en mesurer l’impact sur les consommations mensuelles en eau des ménages équipés de compteurs par différence mois à mois entre les années 2004 et 2003.

Amisulpride, sultopride and sulpiride (Figure 1) are antagonists of the D2-like dopamine receptors, which are members of a large family of receptors that interact with specific intracellular signalling pathways through coupling with G proteins. These compounds are substituted benzamides and present a high degree of selectivity for D2 and D3 versus D1 and D4 dopaminergic receptor subtypes. Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).

Qui sont les agents locaux mediateurs de securite ? Recrutes sur des criteres ethniques (issus de familles immigrees), de territoire (banlieues) et d’âge (jeunes adultes), ils œuvrent a la securisation des transports publics. Leur engagement base sur une valorisation de l’ethique republicaine prepare-t-il une insertion professionnelle plus consistante ou les conduit-il vers les impasses des dispositifs d’insertion ?