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In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC , has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC -associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Una joven se ve atrapada por las más oscuras pesadillas, una mezcla de los inventos de su subconsciente con los recuerdos de su infancia. Condenada a repetir su muerte, cae una y otra vez en un infierno a merced de un demonio, hasta que algo rompe con el ciclo de su pesadilla.

Restoring damaged β-cells in diabetic patients by harnessing the plasticity of other pancreatic cells raises the questions of the efficiency of the process and of the functionality of the new Insulin-expressing cells. To overcome the weak regenerative capacity of mammals, we used regeneration-prone zebrafish to study β-cells arising following destruction. We show that most new insulin cells differ from the original β-cells as they coexpress Somatostatin and Insulin. These bihormonal cells are abundant, functional and able to normalize glycemia. Their formation in response to β-cell destruction is fast, efficient, and age-independent. Bihormonal cells are transcriptionally close to a subset of δ-cells that we identified in control islets and that are characterized by the expression of somatostatin 1.1 (sst1.1) and by genes essential for glucose-induced Insulin secretion in β-cells such as pdx1, slc2a2 and gck. We observed in vivo the conversion of monohormonal sst1.1-expressing cells to sst1.1+ ins + bihormonal cells following β-cell destruction. Our findings support the conclusion that sst1.1 δ-cells possess a pro-β identity enabling them to contribute to the neogenesis of Insulin-producing cells during regeneration. This work unveils that abundant and functional bihormonal cells benefit to diabetes recovery in zebrafish.

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its non-coding gene,RNU4ATAC, has been found mutated in Taybi-Linder (MOPD1/TALS), Roifman (RFMN) and Lowry-Wood syndromes (LWS). These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy and immunodeficiency. Here, we report a homozygousRNU4ATACmutation in the Stem II domain, n.16G>A, in two unrelated patients presenting with both typical traits of the Joubert syndrome (JBTS), a well-characterized ciliopathy, and of TALS/RFMN/LWS, thus widening the clinical spectrum ofRNU4ATAC-associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. This finding is supported by alterations of primary cilium function in TALS and JBTS/RFMN fibroblasts, as well as byu4ataczebrafish model, which exhibit ciliopathy-related phenotypes and ciliary defects. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Cet article présente une recension des écrits concernant l’utilisation de technologies pour soutenir l’intervention auprès des personnes présentant un polyhandicap. La recension a permis de rassembler et de catégoriser les articles selon le type de technologie utilisé et les domaines d’intervention visés. Les études révèlent que ces technologies offrent un potentiel intéressant pour soutenir l’intervention auprès des personnes présentant un polyhandicap. Le coût, la complexité et la disponibilité de ces outils demeurent néanmoins des obstacles importants à l’utilisation de telles interventions innovatrices. Les enjeux sont discutés et des recommandations sont proposées pour les recherches futures., This article presents a review of the literature on the use of technologies to support intervention with people with multiple disabilities. The literature review was used to gather and categorize articles according to the type of technology used and the areas of intervention targeted. The studies indicate that these technologies have significant potential to support intervention for persons with multiple disabilities. However, the cost, complexity and availability of these tools remain significant barriers to the use of such innovative interventions. The issues are discussed and recommendations are proposed for future research.

Aim In many parts of the world, there is growing concern about youth homelessness. Homeless youth are particularly vulnerable to psychological distress, substance use and mental disorders, and premature mortality caused by suicide and drug overdose. However, their access to and use of mental health care is very limited. Methods The Réseau d'intervention de proximité auprès des jeunes (RIPAJ), a Montreal network of over 20 community stakeholders providing a wide array of cohesive services, was created to ease homeless youth's access to mental health and psychosocial services. Its philosophy is that there should be no “wrong door” or “wrong timing” for youth seeking help. In 2014, the network partnered with the pan‐Canadian transformational research initiative, ACCESS Esprits ouverts. Results Created through this partnership, ACCESS Esprits ouverts RIPAJ has been promoting early identification through outreach activities targeting homeless youth and agencies that serve them. An ACCESS Clinician was hired to promote and rapidly respond to help‐seeking and referrals. By strengthening connections within RIPAJ and using system navigation, the site is working to facilitate youth's access to timely appropriate care and eliminate age‐based transitions between services. A notable feature of our program, that is not usually evident in homelessness services, has been the engagement of the youth in service planning and design and the encouragement of contact with families and/or friends. Conclusion Challenges remain including eliminating any remaining age‐related transitions of care between adolescent and adult services; and the sustainability of services transformation and network coordination. Nonetheless, this program serves as an example of an innovative, much‐needed, community‐oriented model for improving access to mental health care for homeless youth.

Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536–539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52−/− cells. Altogether, our findings allow a better comprehensive genotype–phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.

The huge increase in the availability of bacterial genomes led us to a point in which we can investigate and query pan-genomes, for example, the full set of genes of a given bacterial species or clade. Here, we used a data set of 1,311 high-quality genomes from the human pathogen Pseudomonas aeruginosa, 619 of which were newly sequenced, to show that a pan-genomic approach can greatly refine the population structure of bacterial species, provide new insights to define species boundaries, and generate hypotheses on the evolution of pathogenicity. The 665-gene P. aeruginosa core genome presented here, which constitutes only 1% of the entire pan-genome, is the first to be in the same order of magnitude as the minimal bacterial genome and represents a conservative estimate of the actual core genome. Moreover, the phylogeny based on this core genome provides strong evidence for a five-group population structure that includes two previously undescribed groups of isolates. Comparative genomics focusing on antimicrobial resistance and virulence genes showed that variation among isolates was partly linked to this population structure. Finally, we hypothesized that horizontal gene transfer had an important role in this respect, and found a total of 3,010 putative complete and fragmented plasmids, 5% and 12% of which contained resistance or virulence genes, respectively. This work provides data and strategies to study the evolutionary trajectories of resistance and virulence in P. aeruginosa.

In situ synchrotron radiation diffraction was performed during the compression of as-cast Mg&ndash, 3Nd&ndash, Zn alloys with different amounts (0, 0.5, 1, and 2 wt %) of Zn addition at room temperature. During the tests, the acoustic emission signals of the samples were recorded. The results show that the addition of Zn decreased the strength of the alloys but, at the same time, increased their ductility. In the earlier stages of deformation, twin formation and basal slip were the dominant deformation mechanisms. The twins tended to grow during the entire compression stage, however, the formation of new twins dominated only at the beginning of the plastic deformation. In order to accommodate the strain levels, the alloys containing Zn underwent nonbasal slip in the later stages of deformation. This can be attributed to the presence of precipitates containing Zn in the microstructure, inhibiting twin growth.

Youth homelessness is a complex phenomenon as well as an important public health issue often compounded by mental illness of varying severity, in turn creating numerous deleterious consequences. While emergency health services usage remains high, access to mental health services is arduous and conventional interventions often fall short on providing integrated care and seldom lead to sustained positive outcomes for this group. From this observation, clinicians in Montreal, Canada, initiated collaborative meetings, eventually attended by a growing number of institutional and community stakeholders working with homeless youth. Acknowledging the unique needs of this population, the Reseau d'intervention de proximite aupres des Jeunes de la Rue (RIPAJ) or Montreal Homeless Youth Network was created to engage and seamlessly connect youth with the right resources within the network including mental health services amongst others. The genesis, philosophy and unique features of RIPAJ that allow for effective and cohesive interventions as well as future directions are discussed.

Recent data from several studies and surveys confirm that our society has entered the digital and information age. Some authors mention that information and communication technologies (ICT) have the potential to enhance people’s power to act and promote equal citizen participation. These elements are particularly important for people living with intellectual disability (ID). However, it seems that the use of ICT is challenging for these people and that a digital divide has gradually formed between them and the connected citizen. The general objective of this theoretical article is to identify and illustrate the dimensions that must be taken into account to promote the digital participation of people with ID. The model is based on a qualitative analysis of scientific publications using a conceptual-style matrix (Miles & Huberman, 2003). The coding categories were derived from two main sources: the accessibility pyramid and the Human Development Model - Disability Creation Process. Five challenges or conditions associated with digital inclusion were identified: access to digital devices, sensorimotor, cognitive and technical requierements and the comprehension of codes and conventions. For each one, the obstacles and facilitators identified in the literature are described. These reflections and principles led us to propose a model in the shape of a gear. The proper operation of the gear system depends on the fit between individual resources and environmental support. The model is a first step to understand the digital inclusion of people with ID.

Resume Les centres d’investigation clinique (CIC) sont des structures de recherche clinique academiques appartenant a un reseau national, coordonne par l’Institut national de la sante et de la recherche medicale (Inserm) et la Direction generale de l’offre de soins (DGOS), comportant des groupes de travail et des reseaux thematiques. Le groupe « Harmonisation des procedures des CIC » (HPCIC) a elabore un manuel de bonnes pratiques professionnelles, presente dans cet article. Le manuel a ete elabore par consensus, relu par les coordonnateurs des CIC, des experts externes, et valide par des representants des deux tutelles Inserm et DGOS. Le manuel de bonnes pratiques professionnelles des CIC est un guide, structure en 2 parties : une premiere partie abordant la gestion generale d’une structure CIC (commune a l’ensemble des CIC), et une deuxieme partie traitant de la partie operationnelle, des activites-metier gerees par les CIC : la gestion d’etudes cliniques (fonctions de coordination d’etudes, investigation clinique, gestion des donnees, analyse statistique, et valorisation). Le manuel est mis a disposition des CIC, et de toute structure academique qui souhaiterait l’utiliser. Il servira de base a des auto-evaluations, audits croises entre les CIC puis externes des CIC. Cette demarche reflete une volonte d’harmoniser les pratiques et procedures des CIC au niveau national, afin de garantir une qualite optimale dans la realisation des etudes.

En 1954, dans les Ardennes belges, le procès de 14 éducateurs du pénitencier de Saint-Hubert constitue le point d’orgue d’un scandale paradoxalement peu médiatisé. Malgré la réaction de quelques journaux qui déplorent la « loi du silence », des pressions sont exercées sur la majorité des médias : les hommes et les institutions mis en cause sont protégés d’une exposition trop menaçante. Pourtant, cette affaire remet en question les pratiques professionnelles et tout l’édifice de la politique de protection de l’enfance fondé sur la loi de 1912. In 1954, in the Belgian Ardennes, the trial of 14 youth workers from the Saint-Hubert prison marked the climax of a scandal, which was poorly covered by the media. Besides coverage from a few newspapers condemning the “omertà”, most media were under a lot of pressure: the suspected men and institutions were protected from what could have been a threatening exposure. Yet, this affair questioned professional standards and the whole of the childhood protection policies based on the 1912 law.

Resume La difficulte essentielle des adolescents souffrant d’anorexie mentale tient a leur personnalite et a leur incapacite a gerer les conflits. Les relations de ces patients avec les autres sont similaires a celles qu’elles entretiennent avec la nourriture : les deux sont caracterisees par un aspect paradoxal : une alternance entre une furieuse avidite pour la relation et une capacite d’isolement, de retrait et d’intolerance a la solitude ; une grande sensibilite a l’attitude et a l’opinion des autres ; des difficultes a gerer la relation affective et a trouver une suffisamment bonne distance ; une oscillation entre une anxiete due a la separation et une anxiete due a la crainte de l’intrusion ; la coexistence d’attente exacerbee avec la capacite d’etre facilement influencable et dans le meme temps une capacite d’opposition et refus de l’echange. Globalement ces caracteristiques se regroupent dans le concept de dependance. Chez tous ces patients il y a une predisposition a une dependance exageree, avec un manque d’autonomie. La signification pathologique de ces conduites, ces enjeux et les consequences therapeutiques seront discutees.

The creation and evolution of juvenile institutions in 19th century Belgium corresponds to two approaches, two eras and two reformers (Edouard Ducpétiaux and Jules LeJeune). The first fifty years are dominated by the idea of guilty children, who should be condemned and incarcerated in penitentiaries to be punished and reformed. Then, the image of children in danger who should be protected against the bad influences of their families becomes dominant. The passage from punishment to protection involves the adoption of social and psychological criteria to classify children along new categories. The scope of the institutions is being widened as their mission becomes centered on all types of children "in danger". As institutions become challenged, family placements become more popular and are intended to compensate for the weaknesses and bad influences of the natural family. The legal withdrawal of parental authority (endorsed by Parliament in 1912) is aimed at controlling families of deprived classes of society. The adoption of the medical model for juvenile delinquents becomes a reality with the opening of psychological observation centres in the Écoles de bienfaisance.

The nasopharyngeal Haemophilus influenzae flora of healthy children under the age of 3 years attending day care centers in three distinct French geographic areas was analyzed by sampling during two periods, spring 1999 (May and June) and fall 1999 (November and December). The average carrier rate among 1,683 children was 40.9%. The prevalence of capsulated H. influenzae carriers was 0.4% for type f and 0.6% for type e. No type b strains were found among these children, of whom 98.5% had received one or more doses of anti- Haemophilus b vaccine. Among the strains, 44.5% were TEM-type beta-lactamase producers and nine (1.3%) were beta-lactamase-negative ampicillin-resistant strains. Pulsed-field gel electrophoresis restriction patterns showed a large diversity with 366 Sma I patterns from 663 strains. Among the strains isolated during a given period, 33% were isolated simultaneously in more than one area. In each area, depending on the sampling period, 68 to 72% of the strains had new pulsotypes and persistence of 28 to 32% of the strains was noted. For the 297 beta-lactamase-producing strains, 194 patterns were found. The genomic diversity of these strains was comparable to that of the whole set of strains and does not suggest a clonal diffusion. Among the beta-lactamase-producing strains isolated in November and December, depending on the area, 66 to 73% had new pulsotypes with persistence of only 27 to 33% of the strains. In any given geographic area, colonization by H. influenzae appears to be a dynamic process involving a high degree of genomic heterogeneity among the noncapsulated colonizing strains.

Deux modèles de justice criminelle coexistent tout au long des XVI e , XVII e et XVIII e siècles : celui de la justice royale fondé sur la condamnation et la punition, et celui, plus caché, de la justice réparatrice, fondé sur la négociation et l'accommodement, hérité du Moyen Âge. Mais à partir du XVI e siècle, le souverain qui a monopolisé l'exercice de la justice, le droit de punir, s'est aussi réservé le droit de pardonner. Punir et pardonner constituent ainsi les deux volets complémentaires d'une double stratégie de maintien de l'ordre, fondée à la fois sur l'éclat des supplices et la générosité du pardon. Pour être pardonné, l'accusé doit reconnaître son crime, en demander pardon au souverain. Celui-ci lui accorde sa rémission, moyennant la réparation des dommages causés à la victime, ou à sa famille, et le paiement d'une amende au profit du souverain. La justice réparatrice s'inscrit désormais dans un modèle de « justice imposée » où la négociation est reléguée dans l'accord conclu avec la partie offensée., Two models of criminal justice coexisted during the 16th, 17th and 18th centuries: Royal justice based on condemnation and punishment, and another less prevalent one, of restorative justice (system of compensation). This latter one, inherited from the Middle Ages, is based on negotiation and agreement. However, since the 16th century, the King has kept the monopoly of justice, giving himself the right to punish or to forgive. He practices a double strategy of maintaining public order using both the "spectacle of suffering" and the generosity or forgiving. To be forgiven, the accused has to confess his crime and ask the King for pardon. According to the religious model, the King gives him "letters of remission", with the conditions of compensating the damages caused to the victim's family and the payment of a fine to the King. Since then, restorative justice (compensation system) takes place in a model of imposed justice where negotiation is confined to the agreement made with the offended party.

The Fries rearrangement of phenyl acetate for the paracetamol process is usually performed in hydrofluoric acid (HF). We have optimized this reaction with methane sulfonic acid (MSA), a strong, stable and biodegradable acid, to give para-hydroxyacetophenone with high conversion and selectivity (up to 92% of para-isomer and 8% of ortho-isomer at 100% conversion).

This paper proposes a kind of summary of research made from twenty years by historians and jurists about the question of philanthropy, ≪patronage≫, and the origins of the protection of children in Europe. The principal sources are the International Penitentiary Congresses between 1840 and 1914 and the International Congresses of protection of children (1880–1914). Two periods and two generations of philanthropists have to be distinguished. The first one (1840–1850) that we can call the time of the ≪Sainte Alliance≫ of European philanthropists against poverty and criminality, is characterised by individual action of personalities like prisons inspectors (Ducpetiaux in Belgium, Lucas in France) or private philanthropists like Suringar in the Netherlands who travel around Europe to visit reformatories and prisons to compare and promote their own solutions. This is the time of ≪penitentiary tourism≫ and comparison between different models of treatment of juvenile delinquency, based on the concept of ≪guilty c...

OBJECTIVE: To assess the rates of intermediate and high-level resistance to penicillin among Streptococcus pneumoniae isolates and to identify clonal relationship of isolates within the different serotypes by means of pulsed-field gel electrophoresis. METHODS: We studied all clinical isolates obtained between April 1995 and March 1996 from patients admitted to 10 hospitals in eastern France. Antibiotic susceptibility testing and serotyping were performed on all isolates. The genetic polymorphism of isolates susceptible, intermediately resistant and highly resistant to penicillin was studied by using pulsed-field gel electrophoresis with ApaI and SmaI endonucleases. RESULTS: The prevalence of intermediate and high-level resistance was respectively 30.3% and 9.7%. Diminished sensitivity to penicillin was mainly encountered in serotypes 6, 9V, 14 and 23F. The 9V isolates from the different hospitals were genetically closely related, unlike the 23F isolates. Different levels of resistance (MICs from 0.5 to 2 mg/L) were expressed by closely related isolates. Three 9V isolates, three capsular-type 14 isolates and one non-typeable isolate were genetically closely related in studies with the two endonucleases. CONCLUSIONS: The capsular type was not a good indicator of genetic relatedness. The level of penicillin resistance was independent of the clonal classification. Horizontal gene transfer may be the main factor determining the degree of resistance.

Cloud Computing offers great benefits such as reduced IT costs and an improved business agility. Nevertheless, enterprises are still hesitant to put their sensitive data in the cloud as they notably fear privacy issues (e.g., violation of country-based regulations regarding the storage location of a sensitive data). In this context, this paper presents the demonstration of a privacy control technology that allows to protect sensitive files stored, processed, and moved in an IaaS cloud. In our approach, the privacy control is performed within the file system of the Virtual Machines (VM) and allows to control the access done by any application to each sensitive file. It notably covers business applications (e.g., provided by the cloud user) and system applications such as FTP (e.g., to prevent the transfer of a sensitive file in a not authorized country). Moreover, our technology allows to generate tamper-proof traces for any action performed on a sensitive file. In the demonstration, we then also show how the cloud user has a full view of the usage of his sensitive files (e.g., number of copies, storage locations, performed actions). Finally, the demonstration shows these different capabilities through a scenario of file access and cross-country transfer in a multi-platform cloud environment.

Privacy in the cloud is still a strong issue for the large adoption of cloud technologies by enterprises which fear to actually put their sensitive data in the cloud. There is indeed a need to have an efficient access control on the data stored and processed in the cloud infrastructure allowing to support the various business and country-based regulation constraints (e.g., on data location and co-location, data retention duration, data processing, node security level, tracing and audit). In this perspective, this paper presents a novel approach of end-to-end privacy policy enforcement over the cloud infrastructure and based on the sticky policy paradigm (a policy being bound to each sensitive data). In our approach the data protection is performed within the cloud nodes (e.g., within the internal file system of a VM or its attached volume) and is completely transparent for the applications (no need to modify the applications). This paper describes the concept and the proposed end-to-end architecture (from the client to the cloud nodes) as well as an implementation based on the FUSE (Filesystem in Userspace) technology. This implementation is executed on a scenario of data access and transfer control, and is also used to achieve performance evaluations. These evaluations show that, with a reasonable additional computation cost, this approach offers a flexible and transparent way to enforce various privacy constraints within the cloud infrastructure.