Compendium of projects in the European nanosafety cluster

This is the second edition of the compendium. Since the first edition a number of important initiatives have been launched in the shape of large projects targeting integration of research infrastructure and new technology for toxicity studies and exposure monitoring.The demand for research in the area of human health and environmental safety management of nanotechnologies is present since a decade and identified by several landmark reports and studies. Several guidance documents have been published. It is not the intention of this compendium to report on these as they are widely available.It is also not the intention to publish scientific papers and research results as this task is covered by scientific conferences and the peer reviewed press.The intention of the compendium is to bring together researchers, create synergy in their work, and establish links and communication between them mainly during the actual research phase before publication of results. Towards this purpose we find useful to give emphasis to communication of projects strategic aims, extensive coverage of specific work objectives and of methods used in research, strengthening human capacities and laboratories infrastructure, supporting collaboration for common goals and joint elaboration of future plans, without compromising scientific publication potential or IP Rights.These targets are far from being achieved with the publication in its present shape. We shall continue working, though, and hope with the assistance of the research community to make significant progress. The publication will take the shape of a dynamic, frequently updated, web-based document available free of charge to all interested parties. Researchers in this domain are invited to join the effort, communicating the work being done. [Auteurs]

Constructive thinking skills and impulsivity dimensions in conduct and substance use disorders: differences and relationships in an adolescents' sample.

Impact of conduct disorder (CD) and substance use disorder (SUD) on constructive thinking skills and impulsivity was explored. 71 offending adolescents were assessed for CD and SUD. Furthermore, the constructive thinking inventory, the immediate and delayed memory tasks and the UPPS impulsive behaviour scale were administered. Results showed that youths with CD, independently from SUD, presented higher personality impulsivity (urgency) and altered constructive thinking skills (categorical thinking and personal superstitious thinking). Furthermore, trait-impulsivity explained variation in constructive thinking skills. The implications of these results were discussed.

Improved growth with bioabsorbable sutures in both high- and low-pressure zones.

BACKGROUND: Compromised growth after operation remains a significant problem in the cardiovascular field. Some benefit of absorbable suture materials has been demonstrated for arterial anastomoses. However, for the low-pressure zone, few data are available. METHODS: To assess growth in high- versus low-pressure zones we transected the abdominal aorta (high-pressure zone) as well as the inferior vena cava (low-pressure zone) in 10 young mongrel dogs using for reanastomosis 7-0 nonabsorbable versus absorbable running sutures in random order. RESULTS: All animals survived and were evaluated over 12 months including body weight (gain, 212% +/- 45% for nonabsorbable versus 218% +/- 8% for absorbable; not significant), angiography, and, after elective sacrifice, detailed studies of aorta and vena cava. Systematic complication of angiographic data at 12 months showed at the suture level an area of 13.8 mm2 for nonabsorbable versus 24.3 +/- 14.4 mm2 for absorbable sutures in the high-pressure zone as compared with 12.9 +/- 4.9 mm2 for nonabsorbable versus 25.3 +/- 15.4 mm2 for absorbable sutures in the low-pressure zone. Residual lumen, calculated as a function of the area above and below the suture, accounted for 35% +/- 10% for nonabsorbable versus 92% +/- 12% for absorbable sutures (p < 0.001) in the high-pressure zone as compared with 37% +/- 13% for nonabsorbable versus 75% +/- 15% for absorbable sutures (p < 0.003) in the low-pressure zone (high versus low, not significant). Poststenotic dilatation accounted for 199% +/- 22% for nonabsorbable versus 126% +/- 43% for absorbable sutures (p < 0.01) in the high-pressure zone. In the low-pressure zone, poststenotic dilatation remained below the inflow area, and the residual poststenotic lumen accounted for 52% +/- 14% for nonabsorbable versus 77% +/- 16% for absorbable sutures (p < 0.004). Macroscopic, light, and scanning electron microscopic studies confirmed different growth patterns in high- versus low-pressure zones. CONCLUSIONS: Aortic narrowing resulted in poststenotic dilatation and unrestricted outflow path (hourglass-type stenosis). Caval narrowing was followed by restriction of poststenotic outflow path (funnel-type stenosis). Absorbable suture material allows for superior growth in both high- and low-pressure zones.

Predicting the deleterious effects of mutation load in fragmented populations.

Human-induced habitat fragmentation constitutes a major threat to biodiversity. Both genetic and demographic factors combine to drive small and isolated populations into extinction vortices. Nevertheless, the deleterious effects of inbreeding and drift load may depend on population structure, migration patterns, and mating systems and are difficult to predict in the absence of crossing experiments. We performed stochastic individual-based simulations aimed at predicting the effects of deleterious mutations on population fitness (offspring viability and median time to extinction) under a variety of settings (landscape configurations, migration models, and mating systems) on the basis of easy-to-collect demographic and genetic information. Pooling all simulations, a large part (70%) of variance in offspring viability was explained by a combination of genetic structure (F(ST)) and within-deme heterozygosity (H(S)). A similar part of variance in median time to extinction was explained by a combination of local population size (N) and heterozygosity (H(S)). In both cases the predictive power increased above 80% when information on mating systems was available. These results provide robust predictive models to evaluate the viability prospects of fragmented populations.

DNA methylation by CcrM activates the transcription of two genes required for the division of Caulobacter crescentus.

DNA methylation regulates many processes, including gene expression, by superimposing secondary information on DNA sequences. The conserved CcrM enzyme, which methylates adenines in GANTC sequences, is essential to the viability of several Alphaproteobacteria. In this study, we find that Caulobacter crescentus cells lacking the CcrM enzyme accumulate low levels of the two conserved FtsZ and MipZ proteins, leading to a severe defect in cell division. This defect can be compensated by the expression of the ftsZ gene from an inducible promoter or by spontaneous suppressor mutations that promote FtsZ accumulation. We show that CcrM promotes the transcription of the ftsZ and mipZ genes and that the ftsZ and mipZ promoter regions contain a conserved CGACTC motif that is critical to their activities and to their regulation by CcrM. In addition, our results suggest that the ftsZ promoter has the lowest activity when the CGACTC motif is non-methylated, an intermediate activity when it is hemi-methylated and the highest activity when it is fully methylated. The regulation of ftsZ expression by DNA methylation may explain why CcrM is essential in a subset of Alphaproteobacteria.

Diagnostic et traitement des tumeurs intra-oculaires chez l'enfant [Diagnosis and treatment of intraocular tumors in the child]

PURPOSE: To remind of the absolute necessity for early diagnosis in the presence of ocular signs in children giving rise to possible intraocular tumours. METHOD: Based on our own experience of intraocular tumours in children, together with findings from the literature, diagnostic criteria and methods of treatment are presented. RESULTS: Retinoblastoma is the predominant cause of intraocular tumours in children, representing over 80% of cases under the age of 15 years. Other diseases may give rise to the same initial signs, usually leukocoria, sometimes strabismus, more rarely other atypical signs. Elements taken into account for diagnosis include age, sex, laterality, heredity, size of the globe, clinical aspect of the tumours, presence of calcifications and vitreous seeding. Full fundus examination under general anaesthetic is usually necessary. Biological examination, ultrasonography, computerized tomography and MRI enable an accurate diagnosis to be made in the majority of doubtful cases. The management of retinoblastoma is adapted for each individual case from the wide range of treatments available. Enucleation, radioactive applicators (...), brachytherapy (...), cryo- and photocoagulation represent classical measures. Primary chemotherapy, combined with other treatments such as thermotherapy, has become the treatment of choice in those cases where external beam radiotherapy has been used up to now, or in some instances before enucleation. Enucleation is usually carried out for medullo-epitheliomas, but brachytherapy may offer an alternative. CONCLUSION: Any unexplained ocular sign in children should be considered as a possible retinoblastoma, making an accurate and certain diagnosis imperative. Early treatment may save not only the life but also the vision of patients carrying this highly malignant lesion.

A microRNA profile of human CD8.

BackgroundRecently, regulatory T (Treg) cells have gained interest in the fields of immunopathology, transplantation and oncoimmunology. Here, we investigated the microRNA expression profile of human natural CD8+CD25+ Treg cells and the impact of microRNAs on molecules associated with immune regulation.MethodsWe purified human natural CD8+ Treg cells and assessed the expression of FOXP3 and CTLA-4 by flow cytometry. We have also tested the ex vivo suppressive capacity of these cells in mixed leukocyte reactions. Using TaqMan low-density arrays and microRNA qPCR for validation, we could identify a microRNA `signature¿ for CD8+CD25+FOXP3+CTLA-4+ natural Treg cells. We used the `TargetScan¿ and `miRBase¿ bioinformatics programs to identify potential target sites for these microRNAs in the 3¿-UTR of important Treg cell-associated genes.ResultsThe human CD8+CD25+ natural Treg cell microRNA signature includes 10 differentially expressed microRNAs. We demonstrated an impact of this signature on Treg cell biology by showing specific regulation of FOXP3, CTLA-4 and GARP gene expression by microRNA using site-directed mutagenesis and a dual-luciferase reporter assay. Furthermore, we used microRNA transduction experiments to demonstrate that these microRNAs impacted their target genes in human primary Treg cells ex vivo.ConclusionsWe are examining the biological relevance of this `signature¿ by studying its impact on other important Treg cell-associated genes. These efforts could result in a better understanding of the regulation of Treg cell function and might reveal new targets for immunotherapy in immune disorders and cancer.

Sociologie des céramistes d'art en France : l'invention d'un groupe socio-professionnel : pratiques et manières d'être

Cette thèse voudrait expliquer l'émergence et l'autonomisation d'un groupe professionnel récent en France, celui des céramistes d'art, « inventé » au milieu du XXe siècle, et qui s'est largement développé après 1968. Il s'agit d'analyser l'apparition d'un groupe social dans la division du travail, puis sa capacité à assurer les moyens de sa reproduction et de sa pérennisation, tant par l'étude de ses dynamiques internes que par ses rapports à l'hors-groupe. Au-delà de l'aspect monographique, cette recherche interroge la professionnalisation de cet espace du travail artistique peu légitime culturellement, et les obstacles à celle-ci (définition des frontières, contrôle des pratiques). Les normes professionnelles - émergentes, codifiées, transmises, défendues ou contestées - constituant le point d'entrée de cette recherche : liant du groupe, elles sont aussi révélatrices de ses transformations, clivages internes et modes d'institutionnalisation. Dans cette optique, la recherche restitue la diversité des dimensions du métier en tenant ensemble travail et hors- travail : sociogenèse du métier, rapport des céramistes d'art au travail artistique et à la culture légitime, engagement dans les organisations professionnelles (associatives et syndicales), récèption des politiques publiques qui concernent le secteur. Cette recherche réaffirme ainsi la centralité du travail comme espace au carrefour de plusieurs espaces sociaux et de plusieurs types d'investissements, c'est-à-dire comme un rapport social général et non comme enclave sociale que l'on pourrait appréhender par elle-même. La thèse montre aussi que l'hybridité constitutive du métier, entre art et artisanat, constitue l'une des bases de sa professionnalisation : la contestation des principes et des critères de légitimité culturelle en sont les manifestations majeures. Enfin, l'étude de la politisation chez les différentes unités-générationnelles qui composent le métier met en évidence la portée instituante de l'auto-organisation associative et les modes de constitution d'une identité collective. Elle révèle également la présence de l'Etat en filigrane, par opposition ou par coopération. Tels sont les multiples fondements de cette professionnalisation multi-située et constamment évolutive évolutive. Cette recherche repose essentiellement sur des observations - directes et participantes - dans les lieux de vie, de travail et de socialisation des céramistes d'art, et sur 62 entretiens semi-directifs. En plus de l'enquête ethnographique, la thèse s'appuie sur les résultats d'une enquête par questionnaire (218 répondants) et de la documentation professionnelle (archives syndicales, compte-rendu associatifs, supports de communication, etc.).

Formation of virus-like clusters is an intrinsic property of the tumor necrosis factor family member BAFF (B cell activating factor).

The oligomeric state of BAFF (B cell activing factor), a tumor necrosis factor (TNF) family cytokine that plays a critical role in B cell development and survival, has been the subject of recent debate. Myc-tagged BAFF starting at residue Gln136 was previously reported to crystallize as trimers at pH 4.5, whereas a histidine-tagged construct of BAFF, starting at residue Ala134, formed a virus-like cluster containing 60 monomers when crystallized at pH 9.0. The formation of the BAFF 60-mer was pH dependent, requiring pH &gt;or= 7.0. More recently, 60-mer formation was suggested to be artificially induced by the histidine tag, and it was proposed that BAFF, like all other TNF family members, is trimeric. We report here that a construct of BAFF with no amino-terminal tag (Ala134-BAFF) can form a 60-mer in solution. Using size exclusion chromatography and static light scattering to monitor trimer to 60-mer ratios in BAFF preparations, we find that 60-mer formation is pH-dependent and requires histidine 218 within the DE loop of BAFF. Biacore measurements established that the affinity of Ala134-BAFF for the BAFF receptor BAFFR/BR3 is similar to that of myc-Gln136-BAFF, which is exclusively trimeric in solution. However, Ala134-BAFF is more efficacious than myc-Gln136-BAFF in inducing B cell proliferation in vitro. We additionally show that BAFF that is processed and secreted by 293T cells transfected with full-length BAFF, or by a histiocytic lymphoma cell line (U937) that expresses BAFF endogenously, forms a pH-dependent 60-mer in solution. Our results indicate that the formation of the 60-mer in solution by the BAFF extracellular domain is an intrinsic property of the protein, and therefore that this more active form of BAFF may be physiologically relevant.

High cardiovascular morbidity and mortality in myofibrillar myopathies due to DES gene mutations: a 10-year longitudinal study.

To determine incidence and type of major cardiac adverse events in patients with mutated desmin (DES) gene, we retrospectively reviewed baseline medical information, and examined the long-term outcomes of 28 DES patients (17 men, baseline mean age=37.7±14.4 years [min=9, max=71]) from 19 families. Baseline studies revealed skeletal muscle involvement in 21 patients and cardiac abnormalities in all but one patient. Over a mean follow-up of 10.4±9.4 years [min=1, max=35], cardiac death occurred in three patients, death due to cardiac comorbidities in two, one or more major cardiac adverse events in 13 patients. Among the 19 patients with mild conduction defects at baseline, eight developed high-degree conduction blocks requiring permanent pacing. Cardiac involvement was neither correlated with the type of DES mutation nor with the severity of skeletal muscle involvement. Our study underscores that in DES patients in-depth cardiac investigations are needed to prevent cardiac conduction system disease.

Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength.

A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone - and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION: The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS: Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS: As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS: This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

Beta-catenin Status in P?aediatric Medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics.

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for beta-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/beta-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2 months) from diagnosis. All three patients with focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de-escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved.