PALB2 self-interaction controls homologous recombination.

PALB2 is essential for BRCA2 anchorage to nuclear structures and for homologous recombinational repair of DNA double-strand breaks. Here, we report that the N-terminal coiled-coil motif of PALB2 regulates its self-association and homologous recombination. Monomeric PALB2 shows higher efficiency to bind DNA and promotes RAD51 filament formation with or without the inhibitory effect of Replication Protein A. Moreover, overexpression of the PALB2 coiled-coil domain severely affects RAD51 loading to DNA damage sites suggesting a competition between PALB2 self-interaction and PALB2-BRCA1 interaction. In the presence of DNA damage, the switch between PALB2-PALB2 and PALB2-BRCA1 interactions allows the activation of HR. Controlling HR via PALB2 self-interactions could be important to prevent aberrant recombination in normal conditions and activate DNA repair when required

Les cadres de l’encadrement : la gouvernance intermédiaire des systèmes éducatifs en question

La notion de « cadre » est de développement récent dans les organisations publiques, non pas que la hiérarchie des rôles et des statuts en ait été absente, loin de là, mais parce que le fonctionnement bureaucratique qui imprègne leur tradition s’accommodait mal de l’existence d’une forme de responsabilité associant engagement dans l’action collective et autonomie d’action. Ce sont les dénonciations et les défis auxquels l’administration de l’action publique a eu à répondre au tournant des ann..

Les cadres de l’encadrement : la gouvernance intermédiaire des systèmes éducatifs en question

La notion de « cadre » est de développement récent dans les organisations publiques, non pas que la hiérarchie des rôles et des statuts en ait été absente, loin de là, mais parce que le fonctionnement bureaucratique qui imprègne leur tradition s’accommodait mal de l’existence d’une forme de responsabilité associant engagement dans l’action collective et autonomie d’action. Ce sont les dénonciations et les défis auxquels l’administration de l’action publique a eu à répondre au tournant des ann..

Interactions between BRCA2 and RAD51 for promoting homologous recombination in Leishmania infantum.

In most organisms, the primary function of homologous recombination (HR) is to allow genome protection by the faithful repair of DNA double-strand breaks. The vital step of HR is the search for sequence homology, mediated by the RAD51 recombinase, which is stimulated further by proteins mediators such as the tumor suppressor BRCA2. The biochemical interplay between RAD51 and BRCA2 is unknown in Leishmania or Trypanosoma. Here we show that the Leishmania infantum BRCA2 protein possesses several critical features important for the regulation of DNA recombination at the genetic and biochemical level. A BRCA2 null mutant, generated by gene disruption, displayed genomic instability and gene-targeting defects. Furthermore, cytological studies show that LiRAD51 can no longer localize to the nucleus in this mutant. The Leishmania RAD51 and BRCA2 interact together and the purified proteins bind single-strand DNA. Remarkably, LiBRCA2 is a recombination mediator that stimulates the invasion of a resected DNA double-strand break in an undamaged template by LiRAD51 to form a D-loop structure. Collectively, our data show that LiBRCA2 and LiRAD51 promote HR at the genetic and biochemical level in L. infantum, the causative agent of visceral leishmaniasis

Diphtheria in Lao PDR: insufficient coverage or ineffective vaccine?

Background During late 2012 and early 2013 several outbreaks of diphthe-ria were notified in the North of the Lao People’s Democratic Republic. The aim of this study was to determine whether the re-emergence of this vaccine-preventable disease was due to insufficient vaccination coverage or reduction of vaccine effectiveness within the affected regions. Methods A serosurvey was conducted in the Huaphan Province on a cluster sampling of 132 children aged 12–59 months. Serum samples, socio-demographic data, nutri-tional status and vaccination history were collected when available. Anti-diphtheria and anti-tetanus IgG antibody levels were measured by ELISA. Results Overall, 63.6% of participants had detectable diphtheria antibodies and 71.2% tetanus antibodies. Factors independently associated with non-vaccination against diphtheria were the distance from the health centre (OR: 6.35 [95% CI: 1.4–28.8], p = 0.01), the Lao Theung ethnicity (OR: 12.2 [95% CI:1,74–85, 4], p = 0.01) and the lack of advice on vac-cination given at birth (OR: 9.8 [95% CI: 1.5–63.8], (p = 0.01) while the level of maternal edu-cation was a protective factor (OR: 0.08 [95% CI: 0.008–0.81], p = 0.03). Most respondents claimed financial difficulties as the main reason for non-vaccination. Out of 55 children whose vaccination certificates stated that they were given all 3 doses of diphtheria-containing vaccine, 83.6% had diphtheria antibodies and 92.7% had tetanus antibodies. Furthermore, despite a high prevalence of stunted and underweight children (53% and 25.8%, respectively), the low levels of anti-diphtheria antibodies were not correlated to the nutritional status. Conclusions Our data highlight a significant deficit in both the vaccination coverage and diphtheria vaccine effectiveness within the Huaphan Province. Technical defi-ciencies in the methods of storage and distribution of vaccines as well as unreliability of vac-cination cards are discussed. Several hypotheses are advanced to explain such a decline in immunity against diphtheria and recommendations are provided to prevent future outbreaks

Hepatitis B virus in the Lao People’s Democratic Republic: a cross sectional serosurvey in different cohorts

Background Despite hepatitis B vaccination at birth and at 6, 10 and 14 weeks of age, hepatitis B virus (HBV) infection continues to be endemic in the Lao People’s Democratic Republic (PDR). We carried out a cross-sectional serological study in infants, pre-school children, school pupils and pregnant women to determine their burden of disease, risk of infection and vaccination status. Methods A total of 2471 participants between 9 months and 46 years old were recruited from urban (Vientiane Capital, Luang Prabang), semi-urban (Boulhikhamxai and Savannakhet) and remote rural areas (Huaphan). All sera were tested for anti-HBs and anti-HBc. Sera testing positive for anti-HBc alone were further tested for the presence of HBsAg. Results A low prevalence of HBsAg (0.5%) was detected among infants from Vientiane and Luang Prabang, indicating some success of the vaccination policy. However, only 65.6% had protective anti-HBs antibodies, suggesting that vaccination coverage or responses remain sub-optimal, even in these urban populations. In pre-school children from remote areas in Huaphan, 21.2% were positive for anti-HBc antibodies, and 4.6% were for HBsAg positive, showing that a significant proportion of children in these rural regions have early exposure to HBV. In pre-school children with 3 documented HBV vaccinations, only 17.0% (15/55) were serologically protected. Among school-children from semi-urban regions of Luang Prabang, Boulhikhamxai and Savannakhet provinces, those below the age of 9 who were born after HBV vaccine introduction had anti-HBc and HBsAg prevalence of 11.7% and 4.1%, respectively. The prevalence increased to 19.4% and 7.8% of 10–14 year olds and to 27% and 10.2% of 15–19 year olds. Pregnant women from Luang Prabang and Vientiane had very high anti-HBc and HBsAg prevalence (49.5% and 8.2%), indicating high exposure and risk of onward vertical transmission to the unborn infant. Conclusions Overall, the results demonstrate a dramatic deficiency in vaccination coverage and vaccine responses and/or documentation within the regions of Lao PDR studied, which included urbanized areas with better health care access. Timely and effective hepatitis B vaccination coverage is needed in Lao PDR

MRI Findings in 77 Children with Non-Syndromic Autistic Disorder

International audienceBACKGROUND: The clinical relevance of MR scanning in children with autism is still an open question and must be considered in light of the evolution of this technology. MRI was judged to be of insufficient value to be included in the standard clinical evaluation of autism according to the guidelines of the American Academy of Neurology and Child Neurology Society in 2000. However, this statement was based on results obtained from small samples of patients and, more importantly, included mostly insufficient MRI sequences. Our main objective was to evaluate the prevalence of brain abnormalities in a large group of children with a non-syndromic autistic disorder (AD) using T1, T2 and FLAIR MRI sequences. METHODOLOGY: MRI inspection of 77 children and adolescents with non-syndromic AD (mean age 7.4+/-3.6) was performed. All met the DSM-IV and ADI -R criteria for autism. Based on recommended clinical and biological screenings, we excluded patients with infectious, metabolic or genetic diseases, seizures or any other neurological symptoms. Identical MRI inspections of 77 children (mean age 7.0+/-4.2) without AD, developmental or neurological disorders were also performed. All MRIs were acquired with a 1.5-T Signa GE (3-D T1-FSPGR, T2, FLAIR coronal and axial sequences). Two neuroradiologists independently inspected cortical and sub-cortical regions. MRIs were reported to be normal, abnormal or uninterpretable. PRINCIPAL FINDINGS: MRIs were judged as uninterpretable in 10% (8/77) of the cases. In 48% of the children (33/69 patients), abnormalities were reported. Three predominant abnormalities were observed, including white matter signal abnormalities (19/69), major dilated Virchow-Robin spaces (12/69) and temporal lobe abnormalities (20/69). In all, 52% of the MRIs were interpreted as normal (36/69 patients). CONCLUSIONS: An unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in non-syndromic autism. These results could contribute to further etiopathogenetic research into autism

Les disparités territoriales dans l'accès aux formations d'élite: La situation des Pays de la Loire au regard des autres régions françaises

La formation des élites demeure un sujet controversé entre les partisans de la suppression des grandes écoles, de leur fusion au sein des universités ou de leur maintien. Alors que dans la plupart des autres pays l’Université assure seule la formation des élites, le système français est organisé de telle sorte qu’une partie des futures élites administratives, managériales, intellectuelles, politiques et scientifiques est sélectionnée, préparée et formée dans des structures non universitaires : les « grandes écoles » et les classes préparatoires aux grandes écoles (CPGE). Autre particularité du système : ces classes préparatoires relèvent de l’enseignement supérieur alors qu’elles se situent dans des établissements d’enseignement secondaire. Instituées au XVIIIe siècle (Belhoste, 2003), elles accueillent actuellement 81135 étudiants, soit 3,5% des étudiants (RERS, 2010). Leur représentation n’a quasiment pas évolué depuis 1970 (3,8%), malgré une croissance forte des effectifs, notamment durant la période 1985-1995 avec la création de nouvelles divisons, essentiellement dans les filières scientifiques et dans une moindre mesure, économiques et commerciales.Ces classes suscitent de vives critiques : plus coûteuses – le coût moyen d’un préparationnaire était en 2007 de 15080 euros contre 9120 euros pour un étudiant des universités – , faisant preuve d’une faible ouverture sociale (Euriat et Thélot, 1995 ; Duru-Bellat et Kieffer, 2008) – 51,1% d’enfants de cadre supérieur en 2009 vs 29,7% à l’Université – , territorialement inéquitables (Bodin, 2007) – les effectifs sont concentrés en Ile-de-France et dans les grandes métropoles régionales – et d’une « productivité » moyenne (Michaut, à paraître) – sur 100 néo-inscrits en CPGE scientifiques , seuls 50% intégreront une grande école en deux années de préparation et la situation est bien plus problématique dans la filière littéraire avec seulement 8% d’intégrés (Lemaire, 2008). A l’inverse, les « gardiens du temple » défendent un modèle d’excellence à la française qui favorise l’apprentissage de certaines compétences chez les étudiants, leur assurant ainsi une meilleure insertion professionnelle et de meilleurs salaires (Adangnikou, 2007 ; Giret, 2009).Les recherches se sont, jusqu’à présent, essentiellement focalisées sur le territoire national, sans faire apparaitre les éventuelles spécificités des « prépas de proximité » ou des CPGE des établissements privés. De même, les caractéristiques, les conditions de travail et les représentations des enseignants qui font souvent figure d’élites dans le corps professoral du secondaire ont été peu étudiées. Ce rapport offre des éléments de réponse en s’appuyant sur les recherches entreprises par des chercheurs du Centre de recherche en éducation de Nantes (CREN-Université de Nantes), du Centre Nantais en sociologie (CENS-Université de Nantes), du Laboratoire de Recherche en Education et Formation (LAREF-Université Catholique de l’Ouest), du Laboratoire d'Economie et de Sociologie du Travail (LEST-CNRS) et de l’Observatoire sociologique du changement (OSC- Sciences.Po). Il éclaire également les débats sur les projets de réformes en cours (30% de boursiers en CPGE, dispositif d’ouverture sociale) et aborde de nouvelles problématiques, notamment l’endorecrutement des établissements.La recherche est articulée autour de quatre axes :- les disparités territoriales de recrutement des classes préparatoires aux grandes écoles ;- les conditions d’études et les parcours scolaires des étudiants des filières d’excellence ;- Les stratégies des personnels des lycées ;- Les politiques d'ouverture sociale et les dispositifs innovants de l’Education nationale, des collectivités territoriales et des établissements d'enseignement

Coupling Complete Blood Count and Steroidomics to Track Low Doses Administration of Recombinant Growth Hormone: An Anti-Doping Perspective

Growth Hormone (GH) under its human recombinant homologue (rhGH), may be abused by athletes to take advantage of its well-known anabolic and lipolytic properties; hence it is prohibited in sports by the World Anti-Doping Agency. Due to the rapid turnover of rhGH, anti-doping screening tests have turned to monitor two endocrine biomarkers (IGF-I and P-III-NP), but unfortunately, they show population-wise variability, limiting the identification rate of rhGH users. Previous studies have evidenced the numerous effects of GH on human physiology, especially in hematopoiesis and steroidogenesis. In this work, aiming to discover novel physiological rhGH biomarkers, we analyzed the complete blood count and the steroidomics profile of healthy, physically active, young males treated either with EPO + rhGH or EPO + placebo. The time-trends of these two physiological routes have been analyzed through geometric trajectory analysis (GTA) and OPLS-DA. Individuals supplemented with micro-doses of rhGH exhibited different leukopoietic and steroidal profiles compared to the control population, suggesting a role of the rhGH in both pathways. In the article, hypotheses on the observed differences are discussed according to the most recent literature and compared to results in animal models. The use of leukopoietic and steroidal biomarkers together with endocrine biomarkers (IGF-1 and P-III-NP) allows to correctly classify over 98% of samples with no false positives, miss-classifying only one single sample (false negative) over a total of 56; a promising result, if compared to the current rhGH detection strategies