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Lentic waters are biogeochemical reactors, producing and receiving carbon (C) originally fixed by the terrestrial and aquatic biosphere, which is then buried in sediments or respired back to the atmosphere in the forms of carbon dioxide (CO2) and one of the more potent greenhouse gas (GHG) methane (CH4). Additionally, lakes serve as archives of terrestrial and aquatic carbon processes within their sediments, enabling the reconstruction of historical changes spanning thousands of years. These changes encompass alterations in land cover, indicated by pollen records, soil carbon erosion and shifts in lake productivity resulting from changes in land use and climate. Both the burial of C in lakes and the emissions of GHGs are recognised as important components of Earth's climate system, yet they remain poorly understood and constrained due to inadequate quantities and qualities of observations. In the case of GHG emissions from lakes, observations are often sporadic, failing to capture the significant spatial and temporal variations in emissions across diverse lentic systems. To address this challenge, process-based models that incorporate the interconnected biogeochemical processes occurring within lakes and their watersheds would arguably be the best tool to extrapolate from site-level observations to regional and finally global scales, to quantify the anthropogenic impact on these fluxes and to reconstruct long-term shifts in emissions and burial due to changes in land cover and climate. However, the development and evaluation of such models is hampered by the lack of observations in sufficient quality. In this project, we bring together a unique consortium of specialists in aquatic ecology, biogeochemistry, palynology, sedimentology and modelling of terrestrial and aquatic biogeochemistry. This project will put forth a national programme of systematic, long-term observations of lake GHG and C cycling processes of unmet detail, consistency and quality. First, at 40 pilot sites spanning typological and environmental gradients, there will be a comprehensive data acquisition endeavour to evaluate biological processes and mesological factors influencing the sequestration or recycling of organic carbon. This effort will be complemented with a synthesis of existing data (WP1). Second, based on well-dated sediment records, which include both newly-acquired and synthesised existing data, variability of lake C burial and their climate and land-use controls will be reconstructed over the past 150 years (WP2). For 15 of these pilot sites, reconstruction will go back until the mid-Holocene (5,000 years BP), allowing us to shed light on the anthropogenic perturbation of the C cycle in this earlier part of human history, which is commonly excluded from this type of research due to lack of information. The activities of these first two WPs will result in an open-source national database, guaranteeing valorisation of our research far beyond this project. In WP3, we will use the land surface model (LSM) ORCHIDEE C-lateral to assess C cycling in the terrestrial biosphere and the mobilisation of biospheric C into lakes, which is possible due to an explicit representation of soil C leaching and erosion processes and a downscaling scheme permitting us to assess C exports from watersheds at sub-grid scale. While LSMs are used to assess evolution of biospheric C budgets from the beginning of the Industrial Period, we will use it to hindcast the evolution since the mid-Holocene, using lake sediment records for model validation. Moreover, we will develop a new process-based lake C model supported by the database established in WPs 1 and 2, which we will couple to ORCHIDEE C-lateral to simulate lake C burial and GHG emissions in response to climate and processes in the lake watershed. This model set-up will first be used to better constrain contemporary large-scale lake GHG emissions and to disentangle the anthropogenic perturbation of these fluxes from the natural background flux. These estimates will be revolutionary, as they will allow attributing part of lake GHG emissions to anthropogenic emissions for national GHG budget reporting. Then, these models will be emulated to reconstruct evolution of lake GHG budgets and C budgets of the whole lake watershed since the mid-Holocene. While simulations will first be performed at the scales of France and Europe, the development of international partnerships to implement observations from other biomes (WP4) will finally support simulations at the global scale.

Abstract Images collected during NASA’s Double Asteroid Redirection Test (DART) mission provide the first resolved views of the Didymos binary asteroid system. These images reveal that the primary asteroid, Didymos, is flattened and has plausible undulations along its equatorial perimeter. At high elevations, its surface is rough and contains large boulders and craters; at low elevations its surface is smooth and possesses fewer large boulders and craters. Didymos’ moon, Dimorphos, possesses an intimate mixture of boulders, several asteroid-wide lineaments, and a handful of craters. The surfaces of both asteroids include boulders that are large relative to their host body, suggesting that both asteroids are rubble piles. Based on these observations, our models indicate that Didymos has a surface cohesion ≤ 1 Pa and an interior cohesion of ∼10 Pa, while Dimorphos has a surface cohesion of

Abstract Planetary defense efforts rely on estimates of the mechanical properties of asteroids, which are difficult to constrain accurately from Earth. The mechanical properties of asteroid material are also important in the interpretation of the Double Asteroid Redirection Test (DART) impact. Here we perform a detailed morphological analysis of the surface boulders on Dimorphos using images, the primary data set available from the DART mission. We estimate the bulk angle of internal friction of the boulders to be 32.7 ± 2. 5° from our measurements of the roundness of the 34 best-resolved boulders ranging in size from 1.67–6.64 m. The elongated nature of the boulders around the DART impact site implies that they were likely formed through impact processing. Finally, we find striking similarities in the morphology of the boulders on Dimorphos with those on other rubble pile asteroids (Itokawa, Ryugu and Bennu). This leads to very similar internal friction angles across the four bodies and suggests that a common formation mechanism has shaped the boulders. Our results provide key inputs for understanding the DART impact and for improving our knowledge about the physical properties, the formation and the evolution of both near-Earth rubble-pile and binary asteroids.

Abstract Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA.

Roadside revegetation practices have evolved significantly in recent decades, spurred by the need for more reliable and cost-efficient operations and escalating concerns regarding biodiversity integration into large land-planning projects. While the use of rich and locally-sourced seed mixtures for revegetation is being considered with a rising interest to provide ecosystem services and resiliency, their efficacy in meeting practitioners' erosion-control expectations remains underexplored. This study addresses this gap by investigating the erosion-control potential of six seed mixtures, categorized into three compositions with varying levels of richness (Standard < Competitive < Biodiversity) and sourced from local and non-local origins, in a controlled greenhouse environment. To do so, we assessed the effect of these modalities on vegetation cover, plant density and root biomass production over a period of 118 days. During the establishment phase, while the effect of the origin on cover was not conclusive, the richer Biodiversity composition achieved faster ground cover, attributed to the presence of large-leaved forbs. The overall density of plants was lower in the richer mix compared to the two others, but significantly higher in its local version. The findings underscored trade-offs between vegetation cover and density, driven by intra- and inter-specific competition processes, particularly related to access to light. Root biomass production was influenced by the origin of the seeds, with local mixes yielding higher biomass, particularly visible in the richer composition. In spite of growing conditions supposed to favour cultivars, wild and locally-sourced seeds showed promising results, advocating for their broader adoption in roadside revegetation efforts. These findings provide insights for practitioners to optimize revegetation strategies and enhance roadside ecosystem resilience in the face of changing environmental conditions. In situ field trials should now be carried out to confirm these promising results obtained under controlled conditions for roadside management and ecological restoration.

Abstract Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.

A 44-year-old woman suffered a carotid dissection causing a deep and superficial right middle cerebral artery stroke in October 2013, despite undergoing thrombolysis and thrombectomy. Sixteen months later, massive left upper extremity impairment persisted. She then agreed to embark upon a guided self-rehabilitation contract (GSC). This GSC is a moral contract where the physician or therapist identifies specific muscles, particularly hypo-extensible and disabling that act as antagonists to functional activities. The physician or therapist then teaches and prescribes quantified daily high-load self-stretch postures for these muscles, alternating with repeated maximal amplitude movement exercises against their resistance. In turn, the patient commits to practicing the prescribed program and to delivering a diary of the stretch postures and alternating movement exercises performed each day. Over 4 years of GSC, the patient practiced upon prescription against a total of seven upper limb antagonists to common functional movements: shoulder extensors, shoulder internal rotators, elbow flexors, elbow pronators, wrist and finger flexors, and interossei muscles. She manually filled up her diary 99% of the days. Each day, she practiced an average of 20 min of high-load static self-stretch per muscle, alternating with about 50 maximal active efforts against the resistance of each targeted muscle's resistance. Overall, her mean static self-stretch time was 81 ± 2 (mean ± SEM) min/day, and her mean number of active maximal efforts was 285 ± 78/day, for a total daily self-rehabilitation time of over 2 h a day. Five years after her stroke, she had recovered all left upper extremity use in daily activities and resumed her previous job as a nurse's aide. She now spontaneously uses her left hand in most tasks. Functional MRI (March 2020) demonstrated bilateral primary motor and motor supplementary area activation upon left-hand exercise. Prolonged static self-stretch increased muscle extensibility (muscle plasticity) while maximal amplitude, alternating movement training reduced co-contraction in these muscles (neural plasticity). The Modified Frenchay Scale assessment was video-recorded by the clinician at each visit, allowing qualitative and quantitative evaluation of the functional capacities. The two videos of the first and last clinic visits have been uploaded and are available.

Abstract The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State Belgium for the pesticide active substance Pythium oligandrum strain B301 and the considerations as regards the inclusion of the substance in Annex IV of Regulation (EC) No 396/2005 are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions were reached on the basis of the evaluation of the representative uses of Pythium oligandrum strain B301 as a resistance inducer/elicitor to control trunk diseases on grapevines. The reliable endpoints, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Abstract The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State The Netherlands for the pesticide active substance 1‐methylcyclopropene are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council for an amendment in approval conditions. The current approval of 1‐methylcyclopropene includes the specific provision ‘Only uses as plant growth regulator for post‐harvest storage in sealable warehouse may be authorised’. The applicant AgroFresh Holding France SAS submitted, in accordance with Article 7 of Reg. (EC) 1107/2009, an application to remove this specific provision in order to allow member states to authorise the use of products containing 1‐methylcyclopropene on outdoor crops pre‐harvest. The conclusions were reached on the basis of the evaluation of the representative use(s) of 1‐methylcyclopropene as a plant growth regulator via spray application on pome fruit. The reliable endpoints, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Abstract The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State, The Netherlands for the pesticide active substance Phthorimaea operculella granulovirus are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions were reached on the basis of the evaluation of the representative uses of Phthorimaea operculella granulovirus as an insecticide on tomato (field and greenhouse uses) and on potato (field use) via spraying (tractor drawn or knapsack sprayers) or overhead irrigation. The reliable endpoints, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed.

Abstract The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State Poland and co‐rapporteur Member State Hungary for the pesticide active substance triclopyr (variant triclopyr‐butotyl) and the assessment of applications for maximum residue levels (MRLs) are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of triclopyr (variant triclopyr‐butotyl) as a herbicide on established pasture and non‐recreational amenity grassland (field use). MRLs were assessed in rice. The reliable end points, appropriate for use in regulatory risk assessment and the proposed MRLs, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Summary: CREB-regulated transcription co-activator (CRTC) is activated by Calcineurin (CaN) to regulate gluconeogenic genes. CaN also has roles in cardiac hypertrophy. Here, we explore a cardiac-autonomous role for CRTC in cardiac hypertrophy. In Drosophila, CRTC mutants exhibit severe cardiac restriction, myofibrillar disorganization, fibrosis, and tachycardia. Cardiac-specific CRTC knockdown (KD) phenocopies mutants, and cardiac overexpression causes hypertrophy. CaN-induced hypertrophy in Drosophila is reduced in CRTC mutants, suggesting that CRTC mediates the effects. RNA sequencing (RNA-seq) of CRTC-KD and -overexpressing hearts reveals contraregulation of metabolic genes. Genes with conserved CREB sites include the fly ortholog of Sarcalumenin, a Ca2+-binding protein. Cardiac manipulation of this gene recapitulates the CRTC-KD and -overexpression phenotypes. CRTC KD in zebrafish also causes cardiac restriction, and CRTC KD in human induced cardiomyocytes causes a reduction in Srl expression and increased action potential duration. Our data from three model systems suggest that CaN-CRTC-Sarcalumenin signaling represents an alternate, conserved pathway underlying cardiac function and hypertrophy.

The R&D activities for the linear collider TPC (LC-TPC) are currently working on the adoption of the micro pattern devices for the gaseous amplification stage. Several beam tests have been carried out at DESY with a 5 GeV electron beam in a 1 T superconducting magnet. We worked on a large prototype TPC with an end-plate that was built, for the first time, using seven resistive bulk Micromegas modules. During experiments, reduced signal sensitivity was observed at the boundary of these modules. Electrostatic field distortion near the module boundaries was considered to be the possible major reason behind these observations. In the present work, we will explore this hypothesis through numerical simulation. Our aim has been to understand the origin of distortions observed close to the edges of the test beam modules and to explore the possibility of using the Garfield simulation framework for investigating a phenomenon as complex as distortion.

Insert your english abstract here.A new versatile facility LEETECH for detector R&D, tests and calibration is designed and constructed. It uses electrons produced by the photoinjector PHIL at LAL, Orsay and provides a powerful tool for wide range R&D studies of different detector concepts delivering “monochromatic” samples of low energy electrons with adjustable energy and intensity. Among other innovative instrumentation techniques, LEETECH will be used for testing various gaseous tracking detectors and studying new Micromegas/InGrid concept which has very promising characteristics of spatial resolution and can be a good candidate for particle tracking and identification. In this paper the importance and expected characteristics of such facility based on detailed simulation studies are addressed.

Highlights CD73 is the key ectoenzyme involved in the generation of AMP-derived adenosine, which contributes to immunosuppression in the MM BM milieu. Blocking CD73 activity with a potent, selective, orally bioavailable CD73 inhibitor ORIC-533 decreases adenosine generation, overcomes immune suppression, and restores immune cell-mediated MM cell lysis. Based on these preclinical studies, a multi-center clinical trial of ORIC-533 has been initiated in patients with relapsed refractory MM (NCT05227144).

Abstract The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Greece, and co‐rapporteur Member State, France, for the pesticide active substance paraffin oil are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of paraffin oil as an acaricide and insecticide on potatoes, ornamentals (flower bulbs) and orchards (pear/apple), on pome fruit and stone fruit, on field and permanent protected fruiting vegetables and on field and permanent protected roses and on citrus. The reliable end points appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Abstract The conclusions of the EFSA following the peer review of the initial risk assessment carried out by the competent authority of the rapporteur Member State, Spain, for the pesticide active substance difenoconazole are reported. The context of the peer review was that requested by the European Commission following the submission and evaluation of confirmatory information with regard to the consumer risk assessment. The conclusions were reached on the basis of the evaluation of the representative uses of difenoconazole as a fungicide on pome fruit, carrot, wheat, barley, triticale, rye and oats. The reliable endpoints concluded as being appropriate for use in regulatory risk assessment, derived from the available studies and/or literature in the dossier peer reviewed, are presented. Concerns were not identified.

Abstract The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Finland, and co‐rapporteur Member State, Estonia, for the pesticide active substance mepiquat (evaluated variant mepiquat chloride) are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of mepiquat chloride as a plant growth regulator on cereals and grass (field uses). The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified.

Abstract The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Belgium, and co‐rapporteur Member State, Austria, for the pesticide active substance lenacil are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of lenacil as a herbicide on sugar and fodder beet (field use). The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αβ T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αβ T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion in organs and blood was higher after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection was prevented when masking γδ T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire composed of a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. This better survival potential of TCM cells was confirmed by a detailed scRNASeq analysis of the two γδ T cell memory subsets which also revealed their similarity to classically adaptive αβ CD8 T cells. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches.

Le Fake Art n’est pas l’Art Fake : l’article vise à montrer que les artefacts numériques natifs sont fictionnels en ce que, ni faux, ni copie ni réplique pures, ils mettent en tension des traits des régimes autographique et allographique. Ensuite, il s’agit de s’interroger sur la dimension « imaginaire » de l’œuvre d’art numérique, à travers la mise en avant des notions de « fiction artistique », de simulation et de simulacre : passer de la fiction artistique à l’œuvre-simulacre et au virtuel, est-ce dépasser les oppositions « vrai vs faux » et « réel vs imaginaire » et mettre l’accent sur la puissance créatrice ? In fine, nous défendons l’idée de la fiction-façonnage, qui attire l’attention sur la fabrication de l’artefact numérique.

Influenza viruses transcribe and replicate their genome in the nucleus of the infected cells, two functions that are supported by the viral RNA-dependent RNA-polymerase (FluPol). FluPol displays structural flexibility related to distinct functional states, from an inactive form to conformations competent for replication and transcription. FluPol machinery is constituted by a structurally-invariant core comprising the PB1 subunit stabilized with PA and PB2 domains, whereas the PA endonuclease and PB2 C-domains can pack in different configurations around the core. To get insights into the functioning of FluPol, we selected single-domain nanobodies (VHHs) specific of the influenza A FluPol core. When expressed intracellularly, some of them exhibited inhibitory activity on type A FluPol, but not on the type B one. The most potent VHH (VHH16) binds PA and the PA-PB1 dimer with an affinity below the nanomolar range. Ectopic intracellular expression of VHH16 in virus permissive cells blocks multiplication of different influenza A subtypes, even when induced at late times post-infection. VHH16 was found to interfere with the transport of the PA-PB1 dimer to the nucleus, without affecting its handling by the importin β RanBP5 and subsequent steps in FluPol assembly. Using FluPol mutants selected after passaging in VHH16-expressing cells, we identified the VHH16 binding site at the interface formed by PA residues with the N-terminus of PB1, overlapping or close to binding sites of two host proteins, ANP32A and RNA-polymerase II RPB1 subunit which are critical for virus replication and transcription, respectively. These data suggest that the VHH16 neutralization is likely due to several activities, altering the import of the PA-PB1 dimer into the nucleus as well as inhibiting specifically virus transcription and replication. Thus, the VHH16 binding site represents a new Achilles' heel for FluPol and as such, a potential target for antiviral development.

Acetabular dysplasia is a hip condition characterized by abnormal development of the acetabulum, which can be present from birth or develop during childhood and may persist into adulthood. Mild or borderline acetabular dysplasia frequently is associated with cam-type femoroacetabular impingement in adults. Over time, the association of impingement and abnormal contact can lead to hip pain, cartilage damage, labral tears, and an increased risk of developing hip osteoarthritis. Several surgical treatments have been proposed: arthroscopic capsular plication, periacetabular osteotomy, or shelf acetabuloplasty. As mini-invasive shelf acetabuloplasty procedure has already proven its effectiveness, an arthroscopic shelf acetabuloplasty represents a less-invasive, less-risky procedure and allows during the same procedure to perform intra-articular resection of the femoral cam, labrum repair and capsular plication. This Technical Note describes an original technique of arthroscopic shelf acetabuloplasty that combines an outside-in arthroscopic approach for the intra-articular procedure (labral repair, femoroplasty, capsular plication) and an endoscopic shelf acetabulopasty with a tricortical iliac crest autograft secure with a single cannulated screw.

Objective This study aimed at investigating the relationship between occupational exposure to external ionising radiation and central nervous system (CNS) tumours mortality in healthcare workers working in France.Design and setting The Occupational Radiation-Induced Cancer in Medical staff (ORICAMs) nested case–control study was conducted based on the dosimetric records of the national register of occupational dosimetry (Système d’information de la surveillance de l’exposition aux rayonnements ionisants).Participants and methods 33 CNS tumour deaths occurred between 2002 and 2012 among the ORICAMs cohort composed of 164 015 healthcare workers. Each case was matched to five controls alive at the time of the corresponding case’s death, based on sex, year of birth, date of enrolment in the cohort and duration of follow-up. All participants were badge monitored for external radiation exposure, expressed in Hp(10). Conditional logistic regression was used to analyse the dose–response relationship between radiation dose and CNS mortality.Results Cases were exposed to a mean cumulative career radiation dose of 5.8±13.7 (max: 54.3) millisievert (mSv) compared with 4.1±15.2 (142.2) mSv for controls. No statistically significant association was found between CNS tumour mortality and cumulative whole-body career dose (OR=1.00, 95% CI 0.98 to 1.03), duration of exposure (OR=1.03; 95% CI 0.95 to 1.12) or age at first exposure (OR=0.98; 95% CI 0.91 to 1.06).Conclusion We found no evidence of an association between external radiation exposure and CNS tumour risk in healthcare workers. Limitations of the study include low statistical power and short duration of follow-up.

Objectives The perspective of general practitioners’ (GPs) on retirement and the factors influencing their attitude towards retirement have been previously investigated. However, while the number of GPs has been declining for many years in France, leading to the emergence of medical deserts, the impact on their patients remains to be explored. The aim of this study was to understand patients’ perceptions of their GP’s retirement.Design A semistructured interview-based qualitative study was conducted, using Interpretative Phenomenological Analysis.Setting Interviews were conducted in two general practices located in Essonne, Ile-de-France, France, between January and April 2014.Participants Thirteen women and five men, aged 21–94 years, were included in this study. Exclusion criteria were the non-declaration of the physician as the declared doctor and being under 18 years of age.Results The GP–patient relationship is a link that is built up over time, over the course of several consultations. Patients choose their GP based on qualities or skills they value. In this way, the physician chosen is unique for their patients; this choice reflects a certain loyalty to their physician. The interaction with the family sphere reinforces this relationship through the multiple links created during care. When a GP retires, this link is broken. Patients’ reactions can range from indifference to real grief.Conclusion This study confirms the importance of the link between the GPs and their patients and highlights the need to prepare patients for their GP’s retirement.

The year 2022 was marked by the mpox outbreak caused by the human monkeypox virus (MPXV), which is approximately 98% identical to the vaccinia virus (VACV) at the sequence level with regard to the proteins involved in DNA replication. We present the production in the baculovirus-insect cell system of the VACV DNA polymerase holoenzyme, which consists of the E9 polymerase in combination with its co-factor, the A20-D4 heterodimer. This led to the 3.8 Å cryo-electron microscopy (cryo-EM) structure of the DNA-free form of the holoenzyme. The model of the holoenzyme was constructed from high-resolution structures of the components of the complex and the A20 structure predicted by AlphaFold 2. The structures do not change in the context of the holoenzyme compared to the previously determined crystal and NMR structures, but the E9 thumb domain became disordered. The E9-A20-D4 structure shows the same compact arrangement with D4 folded back on E9 as observed for the recently solved MPXV holoenzyme structures in the presence and the absence of bound DNA. A conserved interface between E9 and D4 is formed by a cluster of hydrophobic residues. Small-angle X-ray scattering data show that other, more open conformations of E9-A20-D4 without the E9-D4 contact exist in solution using the flexibility of two hinge regions in A20. Biolayer interferometry (BLI) showed that the E9-D4 interaction is indeed weak and transient in the absence of DNA although it is very important, as it has not been possible to obtain viable viruses carrying mutations of key residues within the E9-D4 interface.

Abstract Background The ATM kinase constitutes a master regulatory hub of DNA damage and activates the p53 response pathway by phosphorylating the MDM2 protein, which develops an affinity for the p53 mRNA secondary structure. Disruption of this interaction prevents the activation of the nascent p53. The link of the MDM2 protein—p53 mRNA interaction with the upstream DNA damage sensor ATM kinase and the role of the p53 mRNA in the DNA damage sensing mechanism, are still highly anticipated. Methods The proximity ligation assay (PLA) has been extensively used to reveal the sub-cellular localisation of the protein—mRNA and protein–protein interactions. ELISA and co-immunoprecipitation confirmed the interactions in vitro and in cells. Results This study provides a novel mechanism whereby the p53 mRNA interacts with the ATM kinase enzyme and shows that the L22L synonymous mutant, known to alter the secondary structure of the p53 mRNA, prevents the interaction. The relevant mechanistic roles in the DNA Damage Sensing pathway, which is linked to downstream DNA damage response, are explored. Following DNA damage (double-stranded DNA breaks activating ATM), activated MDMX protein competes the ATM—p53 mRNA interaction and prevents the association of the p53 mRNA with NBS1 (MRN complex). These data also reveal the binding domains and the phosphorylation events on ATM that regulate the interaction and the trafficking of the complex to the cytoplasm. Conclusion The presented model shows a novel interaction of ATM with the p53 mRNA and describes the link between DNA Damage Sensing with the downstream p53 activation pathways; supporting the rising functional implications of synonymous mutations altering secondary mRNA structures.