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Objective: The range uncertainty in proton radiotherapy is a limiting factor to achieve optimum dose conformity to the tumour volume. Ionoacoustics is a promising approach for in-situ range verification, which would allow to reduce the size of the irradiated volume relative to the tumour volume. The energy deposition of a pulsed proton beam leads to an acoustic pressure wave (ionoacoustics), the detection of which allows conclusion about the distance between the Bragg peak and the acoustic detector. This information can be transferred into a co-registered ultrasound image, marking the Bragg peak position relative to the surrounding anatomy. Approach: A CIRS 3D abdominal phantom was irradiated with 126 MeV protons at a clinical proton therapy centre. Acoustic signals were recorded on the beam axis distal to the Bragg peak with a Cetacean C305X hydrophone. The ionoacoustic measurements were processed with a correlation filter using simulated filter templates. The hydrophone was rigidly attached to an ultrasound device (Interson GP-C01) recording ultrasound images of the irradiated region. Main results: The time of flight obtained from ionoacoustic measurements were transferred to an ultrasound image by means of an optoacoustic calibration measurement. The Bragg peak position was marked in the ultrasound image with a statistical uncertainty of σ=0.5 mm of 24 individual measurements depositing 1.2 Gy at the Bragg peak. The difference between the evaluated Bragg peak position and the one obtained from irradiation planning (1.0 mm) is smaller than the typical range uncertainty (∼4 mm) at the given penetration depth (∼10 cm). Significance: The measurements show that it is possible to determine the Bragg peak position of a clinical proton beam with submillimetre precision and transferring the information to an ultrasound image of the irradiated region. The dose required for this is smaller than that used for a typical irradiation fraction.

Objective: The purpose of this systematic literature review is to appraise contemporary research literature examining the effects of mentoring on graduate registered nurses’ transition to practice objectively and systematically. These areas, specifically examined, are competence, job satisfaction, and retention. Three themes emerged from the research in this area. The themes are informal mentoring effectiveness, the extent of mentoring, and mentoring efficacy. Methods: The PRISMA method was implemented. Articles reviewed were written in English and published between December 2015 and December 2020 and obtained from the Griffith University Library electronic catalogue. A quality assessment of each record not excluded in the title and abstract analysis was undertaken using the method described by Kmet.[1] Those with a quality rating of 16 as a minimum are included in this systematic literature review. Results: Three quantitative, two qualitative and two - method research studies emerged after applying inclusion criteria, selection, and quality assessment. The analysis demonstrated the positive effects of mentoring on all three avenues with one mixed-method study that documented a downward trend in job satisfaction at six months. Conclusions: Mentoring is an effective transition to practice strategy for novice nurses. It affects competence, job satisfaction and retention positively. Retention and resignation rates worsen following 12 months of employment. Robust and rigorous studies are essential to justify long-term mentoring programs’ cost-effectiveness.

International audience; Purpose: Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy.Methods: GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans.Results: When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT).Conclusions: Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.

International audience; The valence of new information influences learning rates in humans: good news tends to receive more weight than bad news. We investigated this learning bias in four experiments, by systematically manipulating the source of required action (free versus forced choices), outcome contingencies (low versus high reward) and motor requirements (go versus no-go choices). Analysis of model-estimated learning rates showed that the confirmation bias in learning rates was specific to free choices, but was independent of outcome contingencies. The bias was also unaffected by the motor requirements, thus suggesting that it operates in the representational space of decisions, rather than motoric actions. Finally, model simulations revealed that learning rates estimated from the choice-confirmation model had the effect of maximizing performance across low- and high-reward environments. We therefore suggest that choice-confirmation bias may be adaptive for efficient learning of action–outcome contingencies, above and beyond fostering person-level dispositions such as self-esteem.

International audience; The wine industry must face many challenges because of climate change. One of them is the increase in temperatures and droughts events. These changes sometimes lead to yield losses and can also impact the quality of the wine produced (e.g., increased alcohol content). The management of available water is also a sensitive issue as water requirements for vineyard irrigation are quickly increasing in the south of France. In this context, there is a need for a decision tool that can help evaluate the vine water status through the entire growth season at a large scale. To address this issue, we have previously developed a model (see Laroche-Pinel et al. 2021a) which predicts the vine Stem Water Potential (Ψstem) using Sentinel-2 (S2) images. This model was developed based on a field campaign over three years. The present study now aims to investigate the feedback of winegrowers on the outputs of our model. Therefore, it was applied on the plots of five wine estates that do not belong to the set used in the initial paper. The qualitative results show interesting spatial and temporal consistency in accordance with winegrower knowledge, irrigation data, and weather forecast. The predicted Ψstemhighlights spatial variability in vine fields where a water source emerges and reflects the differences between vine fields with a drip or sparkling irrigation or without an irrigation system. The predicted Ψstem also clearly reacts to a peak in temperature. According to their feedback, three of the five winegrowers would be glad to use this service in the years to come.

Streptomycetes are Gram-positive actinobacteria largely represented in the plant root microbiota. The genetic determinants involved in the presence of Streptomyces in the rhizosphere are mostly unknown but can rely on the ability to release phytohormones, degrade plant cell-wall polysaccharides and produce specialised metabolites. Here we sequenced the genome of the rhizospheric and plant defence-stimulating strain Streptomyces sp. AgN23. We found out that it belongs to the soil and plant root dwelling S. violaceusniger clade. The genome annotation of AgN23 revealed the ability of the bacterium to synthesise auxin, a major regulator of plant development, to degrade plant cell wall with a large repertoire of carbohydrate degrading enzymes and to produce antimicrobials (rustmicin, mediomycin, niphimycin, nigericin) and plant bioactive compounds (nigericin, echosides, elaiophylin) through a set of biosynthetic gene clusters. We also found that these genomic features are well-conserved among members of the S. violaceusniger clade. In addition, AgN23 display original events of biosynthetic gene clusters acquisitions and losses which may account for its beneficial effect on plants. Taken together, our work supports the hypothesis that hydrolytic enzymes and specialised metabolites repertoires underpin the interaction of bacteria belonging to the S. violaceusniger clade with plant roots within the rhizosphere.Impact statementStreptomycetes are filamentous Gram-positive bacteria universally found around and within host plant tissues. These actinobacteria have been extensively investigated for their tremendous ability to produce diverse specialised metabolites (e.g., antibiotics). By contrast their impact on host plant physiology is widely neglected. Whether specific lineage of Streptomyces colonise host plant and what are the underlying molecular mechanisms is poorly documented. Here we report a chromosome-scale assembly of AgN23 genome, a Streptomyces sp. strain previously characterised for its ability to activate the plant immune system. This reference sequence enabled us to position AgN23 in the S. violaceusniger clade from which several representatives have been isolated worldwide from the rhizosphere of unrelated plants. Comparative genomic studies suggest that S. violaceusniger spp. produce a prominent CAZyome with expansion of plant cell wall degrading enzymes families and a conserved specialised metabolism acting on host plant physiology and its rhizospheric microbiota. These genomic features may underly S. violaceusniger spp. adaptation to the rhizopsheric niche.Data summaryThe raw reads sequences of AgN23 genome are available at NCBI on the Sequence Read Archive portal for PacBio and MiSeq data (SRR13990229 and SRR14028548 respectively). The Genome assembly is available on the NCBI nucleotide portal under the accession NZ_CP007153.1. This genome sequence was uploaded on the MicroScope platform for genome annotation and analysis (https://mage.genoscope.cns.fr/microscope/home/index.php) [1]. The RNA-seq raw reads are archived in the NCBI Bioproject PRJNA745930. The following eight supplementary tables are included in the online version of this article.Supplementary Information 1: Genomes used in this study. The accession number used from the NCBI portal, name, size, number of contigs as well as the level of completeness of the assembly are indicated.Supplementary Information 2: List of the single copy core genes used by autoMLST to build the phylogenetic tree in Figure 1.Supplementary information 3: Annotation of AgN23 full chromosome. For each gene the frame of translation, sequence length and position on the chromosome are indicated. All genes were annotated according to the Microscope platform, see materials and methods. In addition, the expression for each gene is reported in transcripts per million (TPM) based on the the RNA-seq data from three biological replicates.Supplementary Information 4: Genomes having a Mash-based estimated ANI (Average Nucleotide Identity) superior or egal to 80% according to autoMLST.Supplementary Information 5: Prediction of the CAZyme encoding genes using HMMER dbCAN2. The genes are sorted according their CAZy families. For each gene, the begin position on the chromosome, the CAZy category, the annotation, the expression level in transcripts per million (TPM) and the predicted targets of the putative enzymes are described.Supplementary Information 6: Gene identified by antiSMASH in the region containing a biosynthetic gene cluster. Expression levels in transcripts per million (TPM) are indicated for each gene. Annotated central bioynthetic genes are indicated as Y. Those are the ones used for the calculation of mean BGC expression in Table 2.Supplementary Information 7: Annotation of AgN23 genes putatively involved in biosynthetic pathways for Auxins related phytohomones. Expression levels in transcripts per million (TPM) are indicated for each gene. The genes were detected by blasting reference KEGG sequences for each KEGG ONTOLOGY against AgN23 genes. A cut off of 70% identity and 40% coverage was applied to detect positive hits. These biosynthetic pathways and the KEGG ONTOLOGY are indicated in column F and G.Supplementary Information 8: Inspection of BiG-FAM hits with AgN23 BGCs to identify homologous BGCs found outside the S. violaceusniger clade. BiG-FAM distance higher than 900 were excluded from the analysis.The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.

The presence of putative stem/progenitor cells has been suggested in adult peripheral nervous system (PNS) tissue, including the dorsal root ganglion (DRG). To date, their identification and fate in pathophysiological conditions have not been addressed. Combining multiple in vitro and in vivo approaches, we identified the presence of stem cells in the adult DRG satellite glial population, and progenitors were present in the DRGs and sciatic nerve. Cell-specific transgenic mouse lines highlighted the proliferative potential of DRG stem cells and progenitors in vitro. DRG stem cells had gliogenic and neurogenic potentials, whereas progenitors were essentially gliogenic. Lineage tracing showed that, under physiological conditions, adult DRG stem cells maintained DRG homeostasis by supplying satellite glia. Under pathological conditions, adult DRG stem cells replaced DRG neurons lost to injury in addition of renewing the satellite glial pool. These novel findings open new avenues for development of therapeutic strategies targeting DRG stem cells for PNS disorders.

Resume Introduction L’Observatoire dedie au Cancer des OMEDITs Bretagne et Pays de la Loire a mene une enquete visant a connaitre et cartographier les pratiques actuelles de prise en charge des patients par Voie Orale antiCancereuse (VOC) en inter-region. Methode Quarante-huit etablissements de cancerologie ont recu en juillet et octobre 2016 un questionnaire concernant la prise en charge des VOC : de la prescription par le specialiste en cancerologie, a l’intervention du pharmacien (analyse et entretien pharmaceutique), au suivi par l’infirmier (IDE), ainsi que le financement de cette activite et le ressenti des acteurs sur cette organisation en place. Resultats Cinquante-sept professionnels de 31 etablissements dont les plus representatifs, ont repondu a l’enquete. La moitie des etablissements realise une analyse pharmaceutique pour une partie ou l’ensemble des prescriptions de VOC et seul 30 % realise un entretien pharmaceutique. La consultation IDE est par contre plus largement implantee (74 % des etablissements) ainsi que le suivi telephonique (67 %). Plus de 90 % des professionnels pensent que l’organisation en place pourrait etre amelioree et davantage securisee par, notamment, l’implication plus forte des pharmaciens, le developpement d’outils pour les IDE (pour le suivi, l’education therapeutique…) et par l’amelioration du lien ville–hopital. Conclusion Cette enquete montre la variabilite de la prise en charge des patients sous VOC en raison de l’insuffisance de moyens octroyes pour garantir l’equite et la perennite de l’organisation en place. Le lien ville–hopital pourrait encore etre optimise pour securiser la prise en charge des patients.

Objective. Image guidance and precise irradiation are fundamental to ensure the reliability of small animal oncology studies. Accurate positioning of the animal and the in-beam monitoring of the delivered radio-therapeutic treatment necessitate several imaging modalities. In the particular context of proton therapy with a pulsed beam, information on the delivered dose can be retrieved by monitoring the thermoacoustic waves resulting from the brief and local energy deposition induced by a proton beam (ionoacoustics). The objective of this work was to fabricate a multimodal phantom (x-ray, proton, ultrasound, and ionoacoustics) allowing for sufficient imaging contrast for all the modalities. Approach. The phantom anatomical parts were extracted from mouse computed tomography scans and printed using polylactic acid (organs) and a granite/polylactic acid composite (skeleton). The anatomical pieces were encapsulated in silicone rubber to ensure long term stability. The phantom was imaged using x-ray cone-beam computed tomography, proton radiography, ultrasound imaging, and monitoring of a 20 MeV pulsed proton beam using ionoacoustics. Main results. The anatomical parts could be visualized in all the imaging modalities validating the phantom capability to be used for multimodal imaging. Ultrasound images were simulated from the x-ray cone-beam computed tomography and co-registered with ultrasound images obtained before the phantom irradiation and low-resolution ultrasound images of the mouse phantom in the irradiation position, co-registered with ionoacoustic measurements. The latter confirmed the irradiation of a tumor surrogate for which the reconstructed range was found to be in reasonable agreement with the expectation. Significance. This study reports on a realistic small animal phantom which can be used to investigate ionoacoustic range (or dose) verification together with ultrasound, x-ray, and proton imaging. The co-registration between ionoacoustic reconstructions of the impinging proton beam and x-ray imaging is assessed for the first time in a pre-clinical scenario.

Accurate knowledge of the exact stopping location of ions inside the patient would allow full exploitation of their ballistic properties for patient treatment. The localized energy deposition of a pulsed particle beam induces a rapid temperature increase of the irradiated volume and leads to the emission of ionoacoustic (IA) waves. Detecting the time-of-flight (ToF) of the IA wave allows inferring information on the Bragg peak location and can henceforth be used for in-vivo range verification. A challenge for IA is the poor signal-to-noise ratio at clinically relevant doses and viable machines. We present a frequency-based measurement technique, labeled as ionoacoustic tandem phase detection (iTPD) utilizing lock-in amplifiers. The phase shift of the IA signal to a reference signal is measured to derive the ToF. Experimental IA measurements with a 3.5 MHz lead zirconate titanate (PZT) transducer and lock-in amplifiers were performed in water using 22 MeV proton bursts. A digital iTPD was performed in-silico at clinical dose levels on experimental data obtained from a clinical facility and secondly, on simulations emulating a heterogeneous geometry. For the experimental setup using 22 MeV protons, a localization accuracy and precision obtained through iTPD deviates from a time-based reference analysis by less than 15 μm. Several methodological aspects were investigated experimentally in systematic manner. Lastly, iTPD was evaluated in-silico for clinical beam energies indicating that iTPD is in reach of sub-mm accuracy for fractionated doses < 5 Gy. iTPD can be used to accurately measure the ToF of IA signals online via its phase shift in frequency domain. An application of iTPD to the clinical scenario using a single pulsed beam is feasible but requires further development to reach

Purpose The aims of this work are to study the response of a small-gap plane-parallel ionization chamber in the presence of charge multiplication and suggest an experimental method to determine the product of the recombination correction factor (ks) and the charge multiplication correction factor (kCM) in order to investigate the latter. Methods Experimental data were acquired in scanned proton beams and in a Cobalt-60 beam. Measurements were carried out using an IBA PPC05 chambers of which the electrode gap is 0.6 mm. The study is based on the determination of Jaffe plots by operating the chambers at different voltages. Experimental results are compared to theoretical equations describing initial and volume recombination as well as charge multiplication for continuous and pulsed beams. Results Results obtained in protons and Cobalt-60 with the same PPC05 chamber indicate that the charge multiplication effect is independent of the beam quality, while results obtained in different proton beams with two different PPC05 chambers show that the charge multiplication effect is chamber dependent. Conclusions The approach to be taken when using a small-gap plane-parallel ionization chamber with a high voltage (e.g. 300 V or 500 V) for reference dosimetry in scanned proton beams depends on which correction factors were applied to the chamber response during its calibration in terms of absorbed dose to water: - if ks and kCM are applied during the calibration, the user can use a linear extrapolation method (e.g. two-voltage method or 3VL-method) to determine the product of ks and kCM in the user beam. - if ks and kCM are not applied during the calibration: the user can neglect kCM and determine ks in the user beams using a linear interpolation of the chamber response. In both cases, it is recommended to use the ionization chamber at the same operating voltage used during its ND,w-calibration. Another solution consists of operating the PPC05 chamber at a lower voltage (e.g. 50 V) with larger ks and smaller kCM and determining the product of both factors with higher accuracy using a linear extrapolation method.

International audience; PurposeGATE‐RTion is a validated version of GATE for clinical use in the field of light ion beam therapy. This paper describes the GATE‐RTion project and illustrates its potential through clinical applications developed in three European centers delivering scanned proton and carbon ion treatments.MethodsGATE‐RTion is a collaborative framework provided by the OpenGATE collaboration. It contains a validated GATE release based on a specific Geant4 version, a set of tools to integrate GATE into a clinical environment and a network for clinical users.ResultsThree applications are presented: Proton radiography at the Centre Antoine Lacassagne (Nice, France); Independent dose calculation for proton therapy at the Christie NHS Foundation Trust (Manchester, UK); Independent dose calculation for protons and carbon ions at the MedAustron Ion Therapy center (Wiener Neustadt, Austria).ConclusionsGATE‐RTion builds the bridge between researchers and clinical users from the OpenGATE collaboration in the field of Light Ion Beam Therapy. The applications presented in three European facilities using three completely different machines (three different vendors, cyclotron‐ and synchrotron‐based systems, protons, and carbon ions) demonstrate the relevance and versatility of this project.

International audience; In the cerebral cortex, GABAergic interneurons and oligodendrocyte lineage cells share different characteristics and interact despite being neurons and glial cells, respectively. These two distinct cell types share common embryonic origins and are born from precursors expressing similar transcription factors. Moreover, they highly interact with each other through different communication mechanisms during development. Notably, cortical oligodendrocyte precursor cells (OPCs) receive a major and transient GABAergic synaptic input, preferentially from parvalbumin-expressing interneurons, a specific interneuron subtype recently recognized as highly mye-linated. In this review, we highlight the similarities and interactions between GABAergic interneurons and oligodendrocyte lineage cells in the cerebral cortex and suggest potential roles of this intimate interneuron-oligodendroglia relationship in cortical construction. We also propose new lines of research to understand the role of the close link between interneurons and oligodendroglia during cortical development and in pathological conditions such as schizophrenia.

The valence of new information influences learning rates in humans: good news tends to receive more weight than bad news. We investigated this learning bias in four experiments, by systematically manipulating the source of required action (free versus forced choices), outcome contingencies (low versus high reward) and motor requirements (go versus no-go choices). Analysis of model-estimated learning rates showed that the confirmation bias in learning rates was specific to free choices, but was independent of outcome contingencies. The bias was also unaffected by the motor requirements, thus suggesting that it operates in the representational space of decisions, rather than motoric actions. Finally, model simulations revealed that learning rates estimated from the choice-confirmation model had the effect of maximizing performance across low- and high-reward environments. We therefore suggest that choice-confirmation bias may be adaptive for efficient learning of action-outcome contingencies, above and beyond fostering person-level dispositions such as self-esteem.

Positivity bias refers to learning more from positive than negative events. This learning asymmetry could either reflect a preference for positive events in general, or be the upshot of a more general, and perhaps, ubiquitous, “choice-confirmation” bias, whereby agents preferentially integrate information that confirms their previous decision. We systematically compared these two theories with 3 experiments mixing free- and forced-choice conditions, featuring factual and counterfactual learning and varying action requirements across “go” and “no-go” trials. Computational analyses of learning rates showed clear and robust evidence in favour of the “choice-confirmation” theory: participants amplified positive prediction errors in free-choice conditions while being valence-neutral on forced-choice conditions. We suggest that a choice-confirmation bias is adaptive to the extent that it reinforces actions that are most likely to meet an individual’s needs, i.e. freely chosen actions. In contrast, outcomes from unchosen actions are more likely to be treated impartially, i.e. to be assigned no special value in self-determined decisions.

Recently, proton therapy treatments delivered with ultra-high dose rates have been of high scientific interest, and the Faraday cup is a promising dosimetry tool for such experiments. Different institutes use different Faraday cup designs, and either a high voltage guard ring, or the combination of an electric and a magnetic field is employed to minimize the effect of secondary electrons. The authors first investigate these different approaches for beam energies of 70 MeV, 150 MeV, 230 MeV and 250 MeV, magnetic fields between 0 mT and 24 mT and voltages between -1000V to 1000V. When applying a magnetic field, the measured signal is independent of the guard ring voltage, indicating that this setting minimizes the effect of secondary electrons on the reading of the Faraday cup. Without magnetic field, applying the negative voltage however decreases the signal by an energy dependent factor up to 1.3% for the lowest energy tested and 0.4% for the highest energy, showing an energy dependent response. Next, the study demonstrates the application of the Faraday cup up to ultra-high dose rates. Faraday cup measurements with cyclotron currents up to 800nA (dose rates of up to approximately 1000 Gy/s) show that the Faraday cup is indeed dose rate independent. Then, the Faraday cup is applied to commission the primary gantry monitor for high dose rates. Finally, short-term reproducibility of the monitor calibration is quantified within single days, showing a standard deviation of 0.1% (one sigma). In conclusion, the Faraday cup is a promising, dose rate independent tool for dosimetry up to ultra-high dose rates. Caution is however necessary when using a Faraday cup without magnetic field, as a guard ring with high voltage alone can introduce an energy dependent signal offset.

Aim To investigate the feasibility of dose escalation using rapid arc (RA) and Helical Tomotherapy (HT) for patients with upper, middle and distal esophageal carcinomas, even for large tumor volumes. Background In esophageal cancer, for patients with exclusive radio-chemotherapy, local disease control remains poor. Planning study with dose escalation was done for two sophisticated modulated radiotherapy techniques: Rapid arc against Tomotherapy. Materials and methods Six patients treated with a RA simultaneous integrated boost (SIB) of 60 Gy were re-planned for RA and HT techniques with a SIB dose escalated to 70 Gy. Dose volume histogram statistics, conformity indices and homogeneity indices were analyzed. For a given set of normal tissue constraints, the capability of each treatment modality to increase the GTV dose to 70 Gy was investigated. Results Either HT or VMAT may be used to escalate the dose delivered in esophageal tumors while maintaining the spinal cord, lung and heart doses within tolerance. Adequate target coverage was achieved by both techniques. Typically, HT achieved better lung sparing and PTV coverage than did RA. Conclusions Dose escalation for esophageal cancer becomes clinically feasible with the use of RA and HT. This promising result could be explored in a carefully controlled clinical study which considered normal tissue complications and tumor control as endpoints.

International audience; Rapid phenotypic evolution of quantitative traits can occur within years, but its underlying genetic architecture remains uncharacterized. Here we test the theoretical prediction that genes with intermediate pleiotropy drive adaptive evolution in nature. Through a resurrection experiment, we grew Arabidopsis thaliana accessions collected across an 8-year period in six micro-habitats representative of that local population. We then used genome-wide association mapping to identify the single-nucleotide polymorphisms (SNPs) associated with evolved and unevolved traits in each micro-habitat. Finally, we performed a selection scan by testing for temporal differentiation in these SNPs. Phenotypic evolution was consistent across micro-habitats, but its associated genetic bases were largely distinct. Adaptive evolutionary change was most strongly driven by a small number of quantitative trait loci (QTLs) with intermediate degrees of pleiotropy; this pleiotropy was synergistic with the per-trait effect size of the SNPs, increasing with the degree of pleiotropy. In addition, weak selection was detected for frequent micro-habitat-specific QTLs that shape single traits. In this population, A. thaliana probably responded to local warming and increased competition, in part mediated by central regulators of flowering time. This genetic architecture, which includes both synergistic pleiotropic QTLs and distinct QTLs within particular micro-habitats, enables rapid phenotypic evolution while still maintaining genetic variation in wild populations.

Le present essai prend appui sur la caricature d’une interdisciplinarite non raisonnee que nous offrent l’astrologie et son « monisme cosmologique », pour proposer une approche clinique des vastes projets interdisciplinaires bio-anthropologiques, et developper l’analyse du contre-transfert de l’auteur de theories anthropologiques, ou des adeptes qui reprennent ces theories a leur propre compte, comme outil d’interrogation et eventuel critere de refutation. Cette clinique epistemologique est proposee comme susceptible d’offrir de nouvelles occasions de « rencontrer le faux » et d’exploiter les refutations enregistrees, notamment dans la conception du trouble autistique et du developpement de la symbolisation sur lequel il porte.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERK Thr188 autophosphorylation as a regulatory phosphorylation of ERK1/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERK Thr188 phosphorylation permits the impairment of ERK1/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERK Thr188 phosphorylation on cardiomyocyte hypertrophy and cell survival was analyzed in isolated cells and in mice using the mutant ERK2 T188A , which is dominant-negative for ERK Thr188 signaling. ERK2 T188A efficiently attenuated cardiomyocyte hypertrophic responses to phenylephrine and to chronic pressure overload, but it affected neither antiapoptotic ERK1/2 signaling nor overall physiological cardiac function. In contrast to its inhibition of pathological hypertrophy, ERK2 T188A did not interfere with physiological cardiac growth occurring with age or upon voluntary exercise. A preferential role of ERK Thr188 phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERK Thr188 phosphorylation was increased 8.5 ± 1.3-fold in high-gradient, rapidly progressing cases (≥40 mmHg gradient), whereas in low-gradient, slowly progressing cases, the increase was not significant. Because interference with ERK Thr188 phosphorylation ( i ) inhibits pathological hypertrophy and ( ii ) does not impair antiapoptotic ERK1/2 signaling and because ERK Thr188 phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERK Thr188 phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.

Optimizing the care management of patients is a major issue for our society. In Brittany-Pays-de-la-Loire (almost 10% of French population), an observatory of cancer has been created in 2003. Its main objective was the follow-up of expensive drugs. The knowledge of the use of these drugs in clinical practice has led to development of a thesaurus of good use. Thus, regular exchanges between clinicians have almost totally reduced not medically justified prescriptions by the thesaurus after and before administration to patient. The thesaurus has given away to national guidelines from 2007. For example, in these two regions, optimization of the use of gemcitabine and bevacizumab has allowed to save respectively 2.5 millions euros between 2005 and 2008 and 3 millions euros between 2009 and 2010 (breast cancer only). Optimizing the use of anticancer drugs has allowed a real health economy without any bad impact on patient management. Respecting medical ethics, the main objective remains to optimize health care. This highly participation of clinicians currently allows to reflect together on the relevance of the last chemotherapy.

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Background Brevibacterium strains are widely used for the manufacturing of surface-ripened cheeses, contributing to the breakdown of lipids and proteins and producing volatile sulfur compounds and red-orange pigments. The objective of the present study was to perform comparative genomic analyses in order to better understand the mechanisms involved in their ability to grow on the cheese surface and the differences between the strains. Results The genomes of 23 Brevibacterium strains, including twelve strains isolated from cheeses, were compared for their gene repertoire involved in salt tolerance, iron acquisition, bacteriocin production and the ability to use the energy compounds present in cheeses. All or almost all the genomes encode the enzymes involved in ethanol, acetate, lactate, 4-aminobutyrate and glycerol catabolism, and in the synthesis of the osmoprotectants ectoine, glycine-betaine and trehalose. Most of the genomes contain two contiguous genes encoding extracellular proteases, one of which was previously characterized for its activity on caseins. Genes encoding a secreted triacylglycerol lipase or involved in the catabolism of galactose and D-galactonate or in the synthesis of a hydroxamate-type siderophore are present in part of the genomes. Numerous Fe3+/siderophore ABC transport components are present, part of them resulting from horizontal gene transfers. Two cheese-associated strains have also acquired catecholate-type siderophore biosynthesis gene clusters by horizontal gene transfer. Predicted bacteriocin biosynthesis genes are present in most of the strains, and one of the corresponding gene clusters is located in a probable conjugative transposon that was only found in cheese-associated strains. Conclusions Brevibacterium strains show differences in their gene repertoire potentially involved in the ability to grow on the cheese surface. Part of these differences can be explained by different phylogenetic positions or by horizontal gene transfer events. Some of the distinguishing features concern biotic interactions with other strains such as the secretion of proteases and triacylglycerol lipases, and competition for iron or bacteriocin production. In the future, it would be interesting to take the properties deduced from genomic analyses into account in order to improve the screening and selection of Brevibacterium strains, and their association with other ripening culture components. Electronic supplementary material The online version of this article (10.1186/s12864-017-4322-1) contains supplementary material, which is available to authorized users.

L’autisme, considere comme l’un des syndromes des Troubles envahissant du developpement, est lui meme multiple. Mais il l’est apparemment moins dans ses manifestations symptomatiques, synchroniques – dont la formulation reste a clarifier – que dans ses formes d’evolution syndromiques ou diachroniques qui excluent d’en deduire quelque etiologie exclusive. Les trois alterations qualitatives repertoriees par les classifications actuelles ne paraissent pas plus coherentes que les deux symptomes pathognomoniques proposes par Kanner. Ces alterations, comme les deficiences reperees lors des tests d’evaluation, ne resistent pas aux observations lors de suivis prolonges. Les hypotheses etiologiques biogenetiques ou psychogenetiques sont tout au plus envisageables pour certains cas et ne peuvent etre generalisees. Mais la convergence des symptomes relevant d’etiologies tres variees ne peut qu’interroger nos modeles de representation de la symbolisation comme de son developpement normal ou pathologique. La precocite des troubles autistiques, au regard d’autres troubles psychotiques, est averee mais reste relative, d’autant que les signes precoces, avant 2 a 3 ans, ne sont le plus souvent que des indicateurs de risques. Le delai, entre les premieres apparitions d’expressions symboliques et l’âge permettant le diagnostic, incite a penser qu’il s’agit moins d’un probleme d’emergence ou d’acces a la dimension symbolique que de la consolidation de cette symbolisation. Si la conception de l’autisme primaire normal apparait aujourd’hui refutee, il reste a tenir compte des formes particulieres d’investissement et d’attachement autistiques.

Pierre-Marie Vidal : Merci beaucoup. Le public va nous dire s’il est de moins en moins couru de voter pour les candidats de son camp ! Stephane Rozes doit nous quitter d’ici une demi-heure, donc entamons le debat avec la salle autour des deux interventions qui viennent d’avoir lieu. Thierry Vedel nous parlera ensuite d’une autre facon de s’emanciper de son camp et de ses leaders politiques grâce aux nouvelles technologies et aux blogs. Stephane Rozes : J’en profite pour m’excuser aupres de no...

The levels in Sn-129 populated from the beta(-) decay of In-129 isomers were investigated at the ISOLDE facility of CERN using the newly commissioned ISOLDE Decay Station (IDS). The lowest 1/2(+) state and the 3/2(+) ground state in 129Sn are expected to have configurations dominated by the neutron s(1/2) (l = 0) and d(3/2) (l = 2) single-particle states, respectively. Consequently, these states should be connected by a somewhat slow l-forbidden M1 transition. Using fast-timing spectroscopy we havemeasured the half-life of the 1/2(+) 315.3-keV state, T-1/2 = 19(10) ps, which corresponds to a moderately fast M1 transition. Shell-model calculations using the CD-Bonn effective interaction, with standard effective charges and g factors, predict a 4-ns half-life for this level. We can reconcile the shell-model calculations to the measured T-1/2 value by the renormalization of the M1 effective operator for neutron holes.

Oligodendrocytes are the myelin-forming cells of the vertebrate CNS. Little is known about the molecular control of region-specific oligodendrocyte development. Here, we show that oligodendrogenesis in the mouse rostral hindbrain, which is organized in a metameric series of rhombomere-derived (rd) territories, follows a rhombomere-specific pattern, with extensive production of oligodendrocytes in the pontine territory (r4d) and delayed and reduced oligodendrocyte production in the prepontine region (r2d, r3d). We demonstrate that segmental organization of oligodendrocytes is controlled byHoxgenes, namelyHoxa2andHoxb2. Specifically,Hoxa2loss of function induced a dorsoventral enlargement of theOlig2/Nkx2.2-expressing oligodendrocyte progenitor domain, whereas conditionalHoxa2overexpression in theOlig2+domain inhibited oligodendrogenesis throughout the brain. In contrast,Hoxb2deletion resulted in a reduction of the pontine oligodendrogenic domain. CompoundHoxa2−/−/Hoxb2−/−mutant mice displayed the phenotype ofHoxb2−/−mutants in territories coexpressingHoxa2andHoxb2(rd3, rd4), indicating thatHoxb2antagonizesHoxa2during rostral hindbrain oligodendrogenesis. This study provides the firstin vivoevidence thatHoxgenes determine oligodendrocyte regional identity in the mammalian brain.

Aims Activation of the β1-adrenergic receptor and its G protein, Gs, induces cardiac hypertrophy. However, activation of classic Gαs effectors, adenylyl cyclases (AC) and protein kinase A, is not sufficient for induction of hypertrophy, which suggests the involvement of additional pathway(s) activated by Gs. Recently, we discovered that βγ subunits of Gq induce phosphorylation of the extracellular regulated kinases 1 and 2 (Erk1/2) at threonine188 and thereby induce hypertrophy. Here we investigated whether β-adrenergic receptors might also induce cardiac hypertrophy via ErkThr188 phosphorylation. Methods and results β-Adrenergic receptor activation induced ErkThr188 phosphorylation in mouse hearts and in neonatal cardiomyocytes. Inhibition of Erk1/2 or overexpression of ErkThr188 phosphorylation-deficient mutants (Erk2T188A and Erk2T188S) significantly attenuated β–adrenergic cardiomyocyte hypertrophy in vitro . Erk activity was stimulated by both isoproterenol and the direct AC activator forskolin, but only isoproterenol induced ErkThr188 phosphorylation. ErkThr188 phosphorylation required Gβγ released from Gs and was prevented by Gβγ inhibition. Similarly, isoproterenol, but not forskolin, induced nuclear accumulation of Erk and cardiomyocyte hypertrophy. Long-term application of isoproterenol in mice caused left ventricular hypertrophy and cardiac remodelling, and this was reduced in Erk2T188S transgenic mice, supporting the physiological relevance of ErkThr188 phosphorylation. Conclusions Activation of Gs by β-adrenergic receptors leads to (i) canonical Erk1/2 activation via AC, and (ii) release of Gβγ, which then associates with activated Erk1/2 and induces ErkThr188 phosphorylation, causing nuclear accumulation of Erk and ultimately cardiomyocyte hypertrophy. These findings reveal a new pathway critically involved in β-adrenergically mediated cardiac hypertrophy and may yield new therapeutic strategies against hypertrophic remodelling.

Boundary cap cells (BC), which express the transcription factor Krox20, participate in the formation of the boundary between the central nervous system and the peripheral nervous system. To study BC stemness, we developed a method to purify and amplify BC in vitro from Krox20 Cre/+ , R26R YFP/+ mouse embryos. We show that BC progeny are EGF/FGF2-responsive, form spheres, and express neural crest markers. Upon growth factor withdrawal, BC progeny gave rise to multiple neural crest and CNS lineages. Transplanted into the developing murine forebrain, they successfully survived, migrated, and integrated within the host environment. Surprisingly, BC progeny generated exclusively CNS cells, including neurons, astrocytes, and myelin-forming oligodendrocytes. In vitro experiments indicated that a sequential combination of ventralizing morphogens and glial growth factors was necessary to reprogram BC into oligodendrocytes. Thus, BC progeny are endowed with differentiation plasticity beyond the peripheral nervous system. The demonstration that CNS developmental cues can reprogram neural crest-derived stem cells into CNS derivatives suggests that BC could serve as a source of cell type-specific lineages, including oligodendrocytes, for cell-based therapies to treat CNS disorders.

La comprehension de notre specificite humaine peut prendre appui a la fois sur une interrogation des opinions et theories que nous « prenons a notre compte », et sur une hermeneutique croisant le plus grand nombre d'indices ethologiques et anthropologiques (psychopathologiques compris). Lethologie a apporte deux refutations scientifiques majeures: l'une contredit la conception de « l'animal-machine » ; l'autre refute l'hypothese de quelque « animal pre-humain » qui montrerait aujourd'hui des conduites symboliques. De son cote, l'anthropologie a amplement refute les hypotheses de quelque « demi-humain », « demi-langue » ou « demi-culture ». Cette discontinuite psychique peut se formuler en termes de secondeite des systemes signaletiques ethologiques, et en tierceite des structures symboliques anthropologiques. Elle eclaire le fonctionnement autistique en tant que « trouble envahissant de la tierceite » et, en retour, elle se voit confirmee.

During development, boundary cap cells (BC) and neural crest cell (NCC) derivatives generate Schwann cells (SC) of the spinal roots and a subpopulation of neurons and satellite cells in the dorsal root ganglia. Despite their stem-like properties, their therapeutic potential in the diseased central nervous system (CNS) was never explored. The aim of this work was to explore BC therapeutic potential for CNS remyelination. We derived BC from Krox20Cre × R26RYfp embryos at E12.5, when Krox20 is exclusively expressed by BC. Combining microdissection and cell fate mapping, we show that acutely isolated BC are a unique population closely related but distinct from NCC and SC precursors. Moreover, when grafted in the demyelinated spinal cord, BC progeny expands in the lesion through a combination of time-regulated processes including proliferation and differentiation. Furthermore, when grafted away from the lesion, BC progeny, in contrast to committed SC, show a high migratory potential mediated through enhanced interactions with astrocytes and white matter, and possibly with polysialylated neural cell adhesion molecule expression. In response to demyelinated axons of the CNS, BC progeny generates essentially myelin-forming SC. However, in contact with axons and astrocytes, some of them generate also myelin-forming oligodendrocytes. There are two primary outcomes of this study. First, the high motility of BC and their progeny, in addition to their capacity to remyelinate CNS axons, supports the view that BC are a reservoir of interest to promote CNS remyelination. Second, from a developmental point of view, BC behavior in the demyelinated CNS raises the question of the boundary between central and peripheral myelinating cells.

Over the past two decades, basic research has revealed a complex network of regulatory mechanisms that control the ERK1/2-signaling cascade. ERK1/2 mediate cardiac hypertrophy, a major risk factor for the development of arrhythmias, heart failure and sudden death, but also beneficial effects, e.g. protection of the heart from cell death and ischemic injury. Selective targeting of these ambiguous ERK functions could provide a powerful tool in the treatment of cardiac disease. This short review will discuss new mechanistic insights into ERK1/2-dependent development of cardiac hypertrophy and the prospect to translate this knowledge into future therapeutic strategies.

Notre reperage semiologique quant a la maniere dont les autistes traitent et maltraitent les principales Formes symboliques (personnes, objets et signes langagiers) aboutit au constat que leur trouble les amene a rompre les relations structurales triadiques entre ces diverses formes, pour les faire fonctionner sur un mode dyadique de collage de signaux a des stimuli sources de sensations. Ce reperage nous a amene a ouvrir le cadre psychotherapeutique a des jeux d’appropriation, par l’enfant, des relations triadiques entre les personnes. Un cas clinique permet d’illustrer la dynamique de tels jeux et jusqu’a leurs limites – eclairant du meme coup le fonctionnement autistique. L’alteration autistique nous parait formulable en terme de double fonctionnement psychique ou d’oscillations plus ou moins frequentes et prolongees, entre ouvertures a notre monde de formes symboliques tierceisees, et fermetures dans leur monde autistique de-tierceise ou desymbolise. Ce reperage nous amene a interroger en retour ce verrou de la symbolisation qui nous preserverait de retourner dans le monde autistique des simples sensations.

We describe a focused beam-stop array (BSA) for the measurement of object scatter in imaging systems that utilize x-ray beams in the megavoltage (MV) energy range. The BSA consists of 64 doubly truncated tungsten cone elements of 0.5 cm maximum diameter that are arranged in a regular array on an acrylic slab. The BSA is placed in the accessory tray of a medical linear accelerator at a distance of approximately 50 cm from the focal spot. We derive an expression that allows us to estimate the scatter in an image taken without the array present, given image values in a second image with the array in place. The presence of the array reduces fluence incident on the imaged object. This leads to an object-dependent underestimation bias in the scatter measurements. We apply corrections in order to address this issue. We compare estimates of the flat panel detector response to scatter obtained using the BSA to those derived from Monte Carlo simulations. We find that the two estimates agree to within 10% in terms of RMS error for 30 cm x 30 cm water slabs in the thickness range of 10-30 cm. Larger errors in the scatter estimates are encountered for thinner objects, probably owing to extrafocal radiation sources. However, RMS errors in the estimates of primary images are no more than 5% for water slab thicknesses in the range of 1-30 cm. The BSA scatter estimates are also used to correct cone beam tomographic projections. Maximum deviations of central profiles of uniform water phantoms are reduced from 193 to 19 HU after application of corrections for scatter, beam hardening, and lateral truncation that are based on the BSA-derived scatter estimate. The same corrections remove the typical cupping artifact from both phantom and patient images. The BSA proves to be a useful tool for quantifying and removing image scatter, as well as for validating models of MV imaging systems.