Juvenile Delinquency in Switzerland Over 50 Years: Assessing Trends beyond Statistics

The general public seems to be convinced that juvenile delinquency has massively increased over the last decades. However, this assumption is much less popular among academics and some media where doubts about the reality of this trend are often expressed. In the present paper, trends are followed using conviction statistics over 50 years, police and victimization data since the 1980s, and self-report data collected since 1992. All sources consistently point to a massive increase of offending among juveniles, particularly for violent offences during the 1990s. Given that trends were similar in most European countries, explanations should be sought at the European rather than the national level. The available evidence points to possible effects of increased opportunities for property offences since 1950, and although causality remains hard to prove, effects of increased exposure to extreme media violence since 198

FEDSM2008-55143 EULER-EULER LARGE-EDDY SIMULATION APPROACH FOR NON ISOTHERMAL PARTICLE-LADEN TURBULENT JET

ABSTRACT This paper presents an Euler-Euler Large-Eddy Simulation (LES) approach for the numerical modeling of non isothermal dispersed turbulent two-phase flows. The proposed approach is presented and validated by a priori tests from an EulerLagrange database, provided using discrete particle simulation (DPS) of the particle phase coupled with direct numerical simulation (DNS) of the turbulent carrier flow, in a non isothermal particle-laden temporal jet configuration. A statistical approach, the Mesoscopic Eulerian Formalism (MEF) [Février et al., J. Fluid Mech., 2005, vol. 533, pp. 1-46], is used to write local and instantaneous Eulerian equations for the dispersed phase and then, by spatial averaging, to derive the LES equations governing the filtered variables. In this work, the MEF approach is extended to scalar variables transported by the particles in order to develop LES for reactive turbulent dispersed two-phase flows with mass and heat turbulent transport. This approach leads to separate the instantaneous particle temperature distribution in a Mesoscopic Eulerian field, shared by all the particles, and a Random Uncorrelated distribution which may be characterized in terms of Eulerian fields of particle moments such as the uncorrelated temperature variance. In this paper, the DPS-DNS numerical database is presented, LES Eulerian equations for the dispersed phase are derived in the frame of the Mesoscopic approach and models for the unresolved subgrid and random uncorrelated terms are proposed and a priori tested using the DPS-DNS database

Functional Discretization of Space Using Gaussian Processes for Road Intersection

International audienceThis paper propose a new framework to discretize the space within and around a cross intersection. The main purpose of our approach is to capture the manner in which drivers manoeuvre in an intersection in order to facilitate and understand the decision-making tasks. Gaussian processes are used to learn and predict the most likely trajectories taken by multiple drivers in different situations. The merging and crossing areas are found by searching for the overlap between two predicted trajectories, whereas the area approaching the intersection is discretized by using the most probable occupancy. The generated areas are stored in a map. It was possible to show the correlation between this discretization and the drivers’ behaviour by looking at how the proposed framework also discretizes the velocity profile, which can then be applied to decision making

Probabilistic Decision-Making at Road Intersections: Formulation and Quantitative Evaluation

International audienceAs drivers approach a road intersection, they must decide whether to cross it or to come to a stop. For this purpose, drivers make a situation assessment and adapt their behaviour accordingly. When this task is performed by a computer, the available information is partial and uncertain. Any decision requires the system to use this information as well as taking into account the behaviour of other drivers to avoid collisions. However, metrics such as collision rate can remain low in an interactive environment because of other driver’s actions. Consequently, evaluation metrics must depend on other driving aspects. In this paper a decision-making mechanism and metrics to evaluate such a system at road intersection crossing are presented. For the former, a Partially Observable Markov Decision Process is used to model the system with respect to uncertainties in the behaviour of other drivers. For the latter, different key performance indicators are defined to evaluate the resulting behaviour of the system with different configurations and scenarios. The approach is demonstrated within an automotive grade simulator. It has showed at times, that whilst the vehicle can cross safely the intersection, it might not satisfy other key performance indicators related to highway code

Título: Arte de la montea

Sign.: []1, [asterisco]2, A-Q2.Las h. de grab. calc

Illuminating hydrological processes at the soil-vegetation-atmosphere interface with water stable isotopes

Funded by DFG research project “From Catchments as Organised Systems to Models based on Functional Units” (FOR 1Peer reviewedPublisher PDFPublisher PD

RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement

V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Mécanismes moléculaires impliqués dans la rechute des leucémies aiguës lymphoblastiques T

T-cell acute lymphoblastic leukemia (T-ALL) account for approximately 20% of childhood and adult ALL. Despite recent therapeutic progress, T-ALL remain associated with a poorer prognosis than B-ALL, particularly at relapse. This is partly due to a more limited therapeutic armamentarium and partly because T-ALL are associated with a high degree of oncogenic heterogeneity, which makes their individualizations for optimal therapeutic stratification complex. During the last decade we have for the first time established a prognostic classification of T-ALL based on the alteration profile of 5 genes; NOTCH1, FBXW7, N-K-RAS and PTEN. This stratification was based on the identification of each alteration by old sequencing techniques (SANGER). The development of high-throughput sequencing techniques (NGS, Next Generation Sequencing) in recent years has greatly enriched our knowledge of T oncogenesis. NGS approach allows rapid and exhaustive analysis of the alteration profile of a very large number of genes involved in T cell oncogenesis. The work carried out during my thesis focused on the identification of these new molecular alterations involved in the process of T-ALL oncogenesis and relapse. We were thus able to identify for the first time the unfavorable prognostic impact associated with alterations of the transcription factor IKZF1, the epigenetic regulator IDH2 and the tumor suppressor TP53 in T-ALL. This new complex prognostic classification is now based on the alteration profile of the NOTCH1, FBXW7, N-K RAS, PI3KCA, PIK3R1, PTEN, DNMT3A, TP53, and IKZF1 genes. From a therapeutic point of view, the identification of these alterations could also lead to propose innovative therapies in T-ALL; targeting IDH1/2 alterations with specific inhibitors, restoring TP53 activity with APR-246 or targeting PI3K pathway alterations. Finally, based on our previous observations that highlighted the favorable prognosis associated with NOTCH1 mutations present in about 70% of T-ALL, we sought to explain this paradox. Thus, we demonstrated by different and complementary experimental approaches (in particular by using mouse models of T-ALL exposed to chemotherapy in vivo and single cell RNA sequencing approaches) that mutated NOTCH1 T-ALL, under chemotherapy pressure (CT), presented a decrease in the rate of leukemia-initiating cells (LIC) whereas this rate of LIC was increased in wild-type NOTCH1 patients after exposure to CT. By promoting the proliferation of blast cells via c-MYC in particular, NOTCH1 activation could sensitize LICs to the activity of CT, thus leading to a reduction in their proportion after exposure to cytotoxic drugs. This result helps to explain the higher proportion of relapses observed in the wild-type NOTCH1 T-ALL group and constitutes a new innovative therapeutic approach based on the CT susceptibility induced by the activation of this oncogenic pathway. In conclusion, my work has led to the identification of new molecular alterations involved in relapsed T-ALL allowing to establish a new molecular prognostic stratification. At the same time, the identification of these new alterations but also the susceptibility to chemotherapy induced by the activation of the NOTCH1 pathway offers new opportunities for this disease whose prognosis remains unfavorable.Les leucémies aiguës lymphoblastiques T (LAL-T) représentent environ 20% des LAL de l'enfant et de l'adulte. Malgré les progrès thérapeutiques récents elles demeurent associées à un pronostic plus sombre que les formes B notamment en cas de rechute. Ce constat s'explique d'une part en raison d'un arsenal thérapeutique plus restreint et d'autre part car les LAL-T sont des hémopathies présentant une grande hétérogénéité oncogénique rendant complexe leur individualisation en vue d'une stratification thérapeutique optimale. Au cours de la dernière décennie nous avons pour la première fois établi une classification pronostique des LAL-T s'appuyant sur le profil d'altérations de 5 gènes ; NOTCH1, FBXW7, N-K-RAS et PTEN. Cette stratification reposait sur l'identification de chaque altération par des techniques de séquençages anciennes (SANGER). Le développement des techniques de séquençage à haut débit (NGS, Next Generation Sequencing) au cours des dernières années a contribué à enrichir grandement nos connaissances sur l'oncogenèse T. Cette approche par NGS permettant de réaliser rapidement et de façon exhaustive l'analyse du profil d'altération d'un très grand nombre de gènes impliqués dans l'oncogenèse T. Les travaux menés au cours de ma thèse se sont articulés autour de la mise en évidence de ces nouvelles altérations moléculaires impliquées dans les processus d'oncogenèse des LAL-T et de la survenue de rechutes. Nous avons ainsi pu identifier pour la première fois l'impact pronostic défavorable associé aux altérations du facteur de transcription IKZF1, du régulateur épigénétique IDH2 et du suppresseur de tumeur TP53 dans les LAL-T. La mise en évidence de ces nouvelles altérations nous a conduit à proposer une nouvelle stratification moléculaire des LAL-T à l'heure du séquençage à haut débit Cette nouvelle classification pronostique complexe s'appuie maintenant sur le profil d'altérations des gènes NOTCH1, FBXW7, N-K RAS, PI3KCA, PIK3R1, PTEN, DNMT3A, TP53, et IKZF1. D'un point de vue thérapeutique, l'identification de ces altérations pourraient également conduire à proposer des thérapies innovantes dans les LAL-T; cibler spécifiquement les altérations d'IDH1/2, restaurer l'activité de TP53 avec l'APR-246 ou encore cibler les altérations de la voie PI3K. Enfin, en s'appuyant sur nos observations précédentes ayant mise en évidence le pronostic favorable associé aux mutations de NOTCH1 présentes dans environ 70% des LAL-T, nous avons cherché à expliquer ce paradoxe. Ainsi, nous avons démontré par différentes approches expérimentales complémentaires (notamment par utilisation de modèles murins de LAL-T exposés à de la chimiothérapie (CT) in vivo et des approches en single cell RNA sequencing) que les LAL-T NOTCH1 muté, sous pression de la CT présentaient une diminution du taux de cellules initiatrices de leucémies (LIC) alors que ce taux de LIC était augmenté chez les patients NOTCH1 sauvage après exposition à la CT. En favorisant la prolifération des cellules blastiques via notamment c-MYC, l'activation de NOTCH1 sensibiliserait les LIC à l'activité de la CT conduisant ainsi à une réduction de leur proportion après exposition aux drogues cytotoxiques. Ce résultat contribue à expliquer la proportion de rechutes plus élevée observée dans le groupe de LAL-T NOTCH1 sauvage et constitue une nouvelle approche thérapeutique innovante s'appuyant sur la susceptibilité à la CT induite par l'activation de cette voie oncogénique. En conclusion, mes travaux ont conduit à l'identification de nouvelles altérations moléculaires impliquées dans les rechutes des LAL-T permettant d'établir une nouvelle stratification pronostique moléculaire. Dans le même temps, l'identification de ces nouvelles altérations mais également de la susceptibilité à la chimiothérapie induite par l'activation de la voie NOTCH1 offrent de nouvelles opportunités pour ces hémopathies dont le pronostic reste défavorable particulièrement en situation de rechute