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Abstract DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.

Mediterranean forests represent critical areas that are increasingly affected by the frequency of droughts and fires, anthropic activities and land use changes. Optical remote sensing data give access to several essential biodiversity variables, such as species traits (related to vegetation biophysical and biochemical composition), which can help to better understand the structure and functioning of these forests. However, their reliability highly depends on the scale of observation and the spectral configuration of the sensor. Thus, the objective of the SENTHYMED/MEDOAK experiment is to provide datasets from leaf to canopy scale in synchronization with remote sensing acquisitions obtained from multi-platform sensors having different spectral characteristics and spatial resolutions. Seven monthly data collections were performed between April and October 2021 (with a complementary one in June 2023) over two forests in the north of Montpellier, France, comprised of two oak endemic species with different phenological dynamics (evergreen: Quercus ilex and deciduous: Quercus pubescens) and a variability of canopy cover fractions (from dense to open canopy). These collections were coincident with satellite multispectral Sentinel-2 data and one with airborne hyperspectral AVIRIS-Next Generation data. In addition, satellite hyperspectral PRISMA and DESIS were also available for some dates. All these airborne and satellite data are provided from free online download websites. Eight datasets are presented in this paper from thirteen studied forest plots: (1) overstory and understory inventory, (2) 687 canopy plant area index from Li-COR plant canopy analyzers, (3) 1475 in situ spectral reflectances (oak canopy, trunk, grass, limestone, etc.) from ASD spectroradiometers, (4) 92 soil moistures and temperatures from IMKO and Campbell probes, (5) 747 leaf-clip optical data from SPAD and DUALEX sensors, (6) 2594 in-lab leaf directional-hemispherical reflectances and transmittances from ASD spectroradiometer coupled with an integrating sphere, (7) 747 in-lab measured leaf water and dry matter content, and additional leaf traits by inversion of the PROSPECT model and (8) UAV-borne LiDAR 3-D point clouds. These datasets can be useful for multi-scale and multi-temporal calibration/validation of high level satellite vegetation products such as species traits, for current and future imaging spectroscopic missions, and by fusing or comparing both multispectral and hyperspectral data. Other targeted applications can be forest 3-D modelling, biodiversity assessment, fire risk prevention and globally vegetation monitoring.

Abstract Background The demand for 68Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, 68Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([68Ga]Ga-FAPI-46) in late-phase studies, whereas [68Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach. Results Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 ± 5% for [68Ga]Ga-FAPI-46 and 46 ± 7% for [68Ga]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC were 98.2 ± 0.2% and 98.4 ± 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including 68Ga trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers. Conclusions The microfluidic-based approach enabled the implementation of radiosynthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC on the iMiDEV™ microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2–3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [68Ga]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.

Abstract Background TGFβ induces several cell phenotypes including senescence, a stable cell cycle arrest accompanied by a secretory program, and epithelial-mesenchymal transition (EMT) in normal epithelial cells. During carcinogenesis cells lose the ability to undergo senescence in response to TGFβ but they maintain an EMT, which can contribute to tumor progression. Our aim was to identify mechanisms promoting TGFβ-induced senescence escape. Methods In vitro experiments were performed with primary human mammary epithelial cells (HMEC) immortalized by hTert. For kinase library screen and modulation of gene expression retroviral transduction was used. To characterize gene expression, RNA microarray with GSEA analysis and RT-qPCR were used. For protein level and localization, Western blot and immunofluorescence were performed. For senescence characterization crystal violet assay, Senescence Associated-β-Galactosidase activity, EdU staining were conducted. To determine RSK3 partners FLAG-baited immunoprecipitation and mass spectrometry-based proteomic analyses were performed. Proteosome activity and proteasome enrichment assays were performed. To validate the role of RSK3 in human breast cancer, analysis of METABRIC database was performed. Murine intraductal xenografts using MCF10DCIS.com cells were carried out, with histological and immunofluorescence analysis of mouse tissue sections. Results A screen with active kinases in HMECs upon TGFβ treatment identified that the serine threonine kinase RSK3, or RPS6KA2, a kinase mainly known to regulate cancer cell death including in breast cancer, reverted TGFβ-induced senescence. Interestingly, RSK3 expression decreased in response to TGFβ in a SMAD3-dependent manner, and its constitutive expression rescued SMAD3-induced senescence, indicating that a decrease in RSK3 itself contributes to TGFβ-induced senescence. Using transcriptomic analyses and affinity purification coupled to mass spectrometry-based proteomics, we unveiled that RSK3 regulates senescence by inhibiting the NF-κΒ pathway through the decrease in proteasome-mediated IκBα degradation. Strikingly, senescent TGFβ-treated HMECs display features of epithelial to mesenchymal transition (EMT) and during RSK3-induced senescence escaped HMECs conserve EMT features. Importantly, RSK3 expression is correlated with EMT and invasion, and inversely correlated with senescence and NF-κΒ in human claudin-low breast tumors and its expression enhances the formation of breast invasive tumors in the mouse mammary gland. Conclusions We conclude that RSK3 switches cell fate from senescence to malignancy in response to TGFβ signaling.

Abstract DNA ligase I (LigI), the predominant enzyme that joins Okazaki fragments, interacts with PCNA and Pol δ. LigI also interacts with UHRF1, linking Okazaki fragment joining with DNA maintenance methylation. Okazaki fragments can also be joined by a relatively poorly characterized DNA ligase IIIα (LigIIIα)-dependent backup pathway. Here we examined the effect of LigI-deficiency on proteins at the replication fork. Notably, LigI-deficiency did not alter the kinetics of association of the PCNA clamp, the leading strand polymerase Pol ε, DNA maintenance methylation proteins and core histones with newly synthesized DNA. While the absence of major changes in replication and methylation proteins is consistent with the similar proliferation rate and DNA methylation levels of the LIG1 null cells compared with the parental cells, the increased levels of LigIIIα/XRCC1 and Pol δ at the replication fork and in bulk chromatin indicate that there are subtle replication defects in the absence of LigI. Interestingly, the non-replicative histone H1 variant, H1.0, is enriched in the chromatin of LigI-deficient mouse CH12F3 and human 46BR.1G1 cells. This alteration was not corrected by expression of wild type LigI, suggesting that it is a relatively stable epigenetic change that may contribute to the immunodeficiencies linked with inherited LigI-deficiency syndrome.

DNA methylation on CpGs regulates transcription in mammals, both by decreasing the binding of methylation-repelled factors and by increasing the binding of methylation-attracted factors. Among the latter, zinc finger proteins have the potential to bind methylated CpGs in a sequence-specific context. The protein ZBTB38 is unique in that it has two independent sets of zinc fingers, which recognize two different methylated consensus sequences in vitro. Here, we identify the binding sites of ZBTB38 in a human cell line, and show that they contain the two methylated consensus sequences identified in vitro. In addition, we show that the distribution of ZBTB38 sites is highly unusual: while 10% of the ZBTB38 sites are also bound by CTCF, the other 90% of sites reside in closed chromatin and are not bound by any of the other factors mapped in our model cell line. Finally, a third of ZBTB38 sites are found upstream of long and active CpG islands. Our work therefore validates ZBTB38 as a methyl-DNA binder in vivo and identifies its unique distribution in the genome.

DNMT1 is an essential for maintaining genomic DNA methylation. Here, we report the cryo-EM structure of DNMT1 bound to ubiquitinated H3 and hemimethylated DNA, revealing structural insight into the activation mechanism of DNMT1.

Abstract Introduction A wide range of arbuscular mycorrhizal fungi (AMF) can be applied to agricultural soils as biofertilizers for increasing crop growth and yield. Current research also shows that AMF can stimulate plant defences against a range of herbivores and pathogens. However, to date, the efficient use of AMF in agriculture is largely impaired by our inability to predict the performance of different AMF‐plant complexes in variable environments. For instance, AMFs by increasing plant foraging capacity might alleviate allocation constraints in relation to growth versus defences. However, whether this effect occurs might depend on the in situ conditions. The main goal of this study was to investigate the context‐dependency of the ability of AMF to modulate plant growth and resistance against herbivores under variable soil water availability. Materials and Methods To address our goal, we performed a greenhouse experiment for measuring the effect of different AMF inocula (Funneliformis mosseae, Rhizophagus irregularis, or both) on tomato plants (Solanum lycopersicum) growth and defences against an insect herbivore under two conditions: a normal watering regime or drought conditions. We measured the functional, physiological and chemical traits of the plants. Results We found that AMF presence generally decreased plant growth, but increased chemical defences and resistance against generalist caterpillars. Such growth‐defence trade‐off was nonetheless dependent on the identity of the mycorrhizal inoculum and on soil water content. Under drought, inoculated tomato plants lowered their investment to defence and noninoculated plants lowered their growth. Conclusion This study highlights the influence of abiotic factors and fungal identity on plant–AMF–herbivore interactions. In a broader sense, our results point to the necessity of finding AMF species that have reduced context‐dependency to climatic factors, for more widespread use in organic agriculture.

On 19 September 2021, the Cumbre Vieja volcano (renamed Tajogaite) erupted on the island of La Palma (Canary Islands). One month after the eruption, a multidisciplinary team conducted an in situ geomorphological, geographical and socio-environmental diagnosis to complement the remote monitoring of the crisis management and impacts of the eruption. The impacts of the lava flows and the ash fallout led to the evacuation of more than 7,000 people, had a heavy and lasting impact on the agricultural and touristic sectors, and imposed a territorial reorganisation. The analysis of the crisis management reveals that the eruption surprised by its location and duration; the island was prepared for an eruptive crisis but not for a long, multiform and multiphase territorial crisis.

IntroductionComparable indicators on complete cancer prevalence are increasingly needed in Europe to support survivorship care planning. Direct measures can be biased by limited registration time and estimates are needed to recover long term survivors. The completeness index method, based on incidence and survival modelling, is the standard most validated approach.MethodsWithin this framework, we consider two alternative approaches that do not require any direct modelling activity: i) empirical indices derived from long established European registries; ii) pre-calculated indices derived from US-SEER cancer registries. Relying on the EUROCARE-6 study dataset we compare standard vs alternative complete prevalence estimates using data from 62 registries in 27 countries by sex, cancer type and registration time.ResultsFor tumours mostly diagnosed in the elderly the empirical estimates differ little from standard estimates (on average less than 5% after 10-15 years of registration), especially for low prognosis cancers. For early-onset cancers (bone, brain, cervix uteri, testis, Hodgkin disease, soft tissues) the empirical method may produce substantial underestimations of complete prevalence (up to 20%) even when based on 35-year observations. SEER estimates are comparable to the standard ones for most cancers, including many early-onset tumours, even when derived from short time series (10-15 years). Longer observations are however needed when cancer-specific incidence and prognosis differ remarkably between US and European populations (endometrium, thyroid or stomach).DiscussionThese results may facilitate the dissemination of complete prevalence estimates across Europe and help bridge the current information gaps.

18F-labelled radiopharmaceuticals are indispensable in positron emission tomography. The critical step in the preparation of 18F-labelled tracers is the anhydrous F-18 nucleophilic substitution reaction, which involves [18F]F− anions generated in aqueous media by the cyclotron. For this, azeotropic drying by distillation is widely used in standard synthesisers, but microfluidic systems are often not compatible with such a process. To avoid this step, several methods compatible with aqueous media have been developed. We summarised the existing approaches and two of them have been studied in detail. [18F]fluoride elution efficiencies have been investigated under different conditions showing high 18F-recovery. Finally, a large scope of precursors has been assessed for radiochemical conversion, and these hydrous labelling techniques have shown their potential for tracer production using a microfluidic approach, more particularly compatible with iMiDEV™ cassette volumes.

Metabolomics is playing an increasingly prominent role in chemical ecology and in the discovery of bioactive natural products (NPs). The identification of metabolites is a common/central objective in both research fields. NPs have significant biological properties and play roles in multiple chemical-ecological interactions. Classically, in pharmacognosy, their chemical structure is determined after a complex process of isolating and interpreting spectroscopic data. With the advent of powerful analytical techniques such as liquid chromatography-mass spectrometry (LC-MS) the annotation process of the specialised metabolome of plants and microorganisms has improved considerably. In this article, we summarise the possibilities opened by these advances and illustrate how we harnessed them in our own research to automate annotations of NPs and target the isolation of key compounds. In addition, we are also discussing the analytical and computational challenges associated with these emerging approaches and their perspective.

Introduction At the end of the treatment, many young breast cancer (BC) survivors face difficulties related to fertility and sexuality, mainly due to the side effects of treatment. Integrating patient needs into medical decisions is becoming increasingly essential for high quality care. To this end, there is a compelling need to elicit patients’ perspectives through qualitative studies, to understand their experiences and needs in the aftermath of cancer. We aim to: (1) identify clinical, social and economic determinants of sexuality and fertility, and describe other living conditions of young BC survivors in France; and (2) explore young women’s experience after BC in relation to clinical and information needs about fertility preservation and sexual health.Methods and analysis This is a mixed-methods, cross-sectional, population-based study. In the quantitative component, women diagnosed with non-metastatic BC between 2009 and 2016 and aged 40 years or younger at diagnosis will be identified through the French network of cancer registries (FRANCIM). Participants will complete self-report questionnaires including standardised measures of sexuality, health-related quality of life (HRQoL), anxiety, depression, social deprivation and social support. Fertility and professional reintegration issues will also be assessed. Sexuality profiles will be identified by ascending hierarchical classification and fertility profiles will be identified by latent class models. Determinants of sexuality, fertility and HRQoL will be identified using a mixed regression model. Subsequently, semistructured interviews will be performed with a sample of 30 women who participated in the quantitative study. Interviews will be recorded, transcribed synthetically and content analysis will be performed, with the aid of NVivo software.Ethics and dissemination This study will be performed in accordance with the declaration of Helsinki. The protocol was approved in October 2020 by the Committee for the Protection of Persons North-West III (20.07.16.44445) and by the French national data protection authority (CNIL-MR003 No1989764-v0).The results of this project will be communicated to the scientific community through publications in international scientific peer-reviewed journals and communications to national and international congresses. Popularised results will also be provided to patient associations. The results of Candy project will also be published on the website of the sponsor, www.cgfl.fr.

Tyrosine kinase inhibitors (TKIs) have been improving the prognosis of patients with chronic myeloid leukemia (CML), but there are still large differences in survival among European countries. This raises questions on the added value of results from population-based studies, which use real-world data, compared to results of randomized controlled trials (RCTs) involving patients with CML. There are also questions about the extent of the findings on RCTs effectiveness for patients in the general population. We compare survival data extracted from our previous systematic review and meta-analysis of CML RCTs with the latest updated population-based survival data of EUROCARE-6, the widest collaborative study on cancer survival in Europe. The EUROCARE-6 CML survival estimated in patients (15–64 years) diagnosed in 2000–2006 vs. 2007–2013 revealed that the prognostic improvement highlighted by RCTs was confirmed in real-world settings, too. The study shows, evaluating for the first time all European regions, that the optimal outcome figures obtained in controlled settings for CML are also achievable (and indeed achieved) in real-world settings with prompt introduction of TKIs in daily clinical practice. However, some differences still persist, particularly in Eastern European countries, where overall survival values are lower than elsewhere, probably due to a delayed introduction of TKIs. Our results suggest an insufficient adoption of adequate protocols in daily clinical practice in those countries where CML survival values remain lower in real life than the values obtained in RCTs. New high-resolution population-based studies may help to identify failures in the clinical pathways followed there.

Abstract Objective To analyze trends in cancer incidence and mortality (France, 1990–2018), with a focus on men-women disparities. Methods Incidence data stemmed from cancer registries (FRANCIM) and mortality data from national statistics (CépiDc). Incidence and mortality rates were modelled using bidimensional penalized splines of age and year (at diagnosis and at death, respectively). Trends in age-standardized rates were summarized by the average annual percent changes (AAPC) for all-cancers combined, 19 solid tumors, and 8 subsites. Sex gaps were indicated using male-to-female rate ratios (relative difference) and male-to-female rate differences (absolute difference) in 1990 and 2018, for incidence and mortality, respectively. Results For all-cancers, the sex gap narrowed over 1990–2018 in incidence (1.6 to 1.2) and mortality (2.3 to 1.7). The largest decreases of the male-to-female incidence rate ratio were for cancers of the lung (9.5 to 2.2), lip - oral cavity - pharynx (10.9 to 3.1), esophagus (12.6 to 4.5) and larynx (17.1 to 7.1). Mixed trends emerged in lung and oesophageal cancers, probably explained by differing risk factors for the two main histological subtypes. Sex incidence gaps narrowed due to increasing trends in men and women for skin melanoma (0.7 to 1, due to initially higher rates in women), cancers of the liver (7.4 to 4.4) and pancreas (2.0 to 1.4). Sex incidence gaps narrowed for colon-rectum (1.7 to 1.4), urinary bladder (6.9 to 6.1) and stomach (2.7 to 2.4) driven by decreasing trends among men. Other cancers showed similar increasing incidence trends in both sexes leading to stable sex gaps: thyroid gland (0.3 to 0.3), kidney (2.2 to 2.4) and central nervous system (1.4 to 1.5). Conclusion In France in 2018, while men still had higher risks of developing or dying from most cancers, the sex gap was narrowing. Efforts should focus on avoiding risk factors (e.g., smoking) and developing etiological studies to understand currently unexplained increasing trends.

Abstract Purpose The assessment of patient satisfaction during treatment is essential to provide patient-centered high-quality cancer care. Nevertheless, no German instrument assesses patient satisfaction with comprehensive cancer care, which not only includes oncological treatment, but also interpersonal quality of care as well as psychosocial support services. Based on the French REPERES-60, we developed the German Patient Satisfaction with Comprehensive Cancer Care (SCCC) questionnaire. Methods The REPERES-60 was translated and the items were adapted to make it applicable to the German healthcare system and across different tumor entities. Scales of the resulting instrument were extracted via principal axis factoring (PAF). Subsequently, we investigated the reliability (Cronbach’s Alpha, CA), discriminatory power (corrected item-scale correlations) and convergent validity (pre-specified correlations of the SCCC with different outcomes). Results The SCCC consisted of 32 items which were subsequently tested among a sample of 333 patients across different tumor entities (response rate: 47%). Average age was 59 years (standard deviation: 14), 63% were male. PAF revealed four multi-item scales named Competence, Information, Access and Support accounting for 71% of the variance. Two single-items scales assess global satisfaction with medical and psychosocial care, respectively. CA across the multi-item scales ranged from .84 to .96. Discriminatory power was sufficiently high, with all r ≥ .5. Convergent validity was largely verified by negative associations of the four multi-item scales with depressive/anxious symptomatology (r ≥ − .18, p

The objective of our study is to establish an assessment of four volcanic hazards in a country threatened by the eruption of the OlDoinyo Lengai volcano. The last major eruption dates back to 2007-2008 but stronger activity in 2019 has revived the memory of volcanic threats to the Maasai and Bantu communities and human activities (agro-pastoral and tourism). The methods chosen have had to be adapted to the scarce and incomplete data. The volcanic hazards and their probability of occurrence were analysed on the basis of data available in the scientific literature and were supplemented by two field missions combining geography and hydro-geomorphology. Our study enabled us to map the hazards of ash fall, lava flows, lahars and avalanches of debris. Each hazard was spatialised by being ascribed an intensity. They are sometimes synchronous with the eruption sometimes they occur several months or years after a volcanic eruption. The results are the first step towards developing a volcanic risk management strategy, especially for the pastoral communities living around Lengai and for the growing tourist activities in this area.

The intense hurricane season of 2017 in the North Atlantic brought a number of major hurricanes including Hurricane Irma (cat. 5), which landed on the French islands of St. Martin and St. Barthélemy. These two French Overseas Collectivities, separated by a distance of some 20 kilometres, have very different territorial and social characteristics. The study reported in this article is part of a scientific feedback conducted a few weeks after Irma. The social approach to the disaster conducted within this research framework aims to characterise the behaviour and implications of the inhabitants in the experience of the event, placed in a social and territorial context thanks to narrative interviews administered in situ. The comparative approach reveals similar behaviour before and during the hurricane, but individual and collective social and territorial factors guided very distinct post-event reactions.

Las personas trans están entre los miembros más vulnerables de cualquier sociedad y experimentan altos niveles de estigmatización y marginación. El presente artículo tiene como objetivo realizar un análisis de los derechos de las personas transexuales, abordando para ello tanto la jurisprudencia como la legislación en el contexto europeo y latinoamericano. Dentro del nudo cognitivo jurídico internacional y apoyado en la metodología cualitativa se realizó una caracterización de la realidad facto-jurídica de la legislación aplicable a estas personas.

Purpose – This paper focuses on the application of the postal rule to email, due to the controversy surrounding the application of the “instantaneous” test to emails. Methodology/approach/design – This article analyses standards and literature on the formation of contract under English law. Findings – Although the postal rule is an invention of its time, this rule could still play a role regarding emails. Indeed, due to the difficulties in applying the “instantaneous” test to emails, emails would still be subject to the postal rule. Of course, the postal rule in its current form is no more fitting the reality. However, the benefits that such rule provides should not be lost, instead a new rule could be drafted based on the postal rule. Practical implications – This article discusses the possible improvements to the already existing framework. Originality/value – This paper analyses the use of the postal rule to electronic contracts in the UK, a topic that is not much researched but could have great importance when doing electronic business.

Abstract The successful conservation plans of megaherbivores necessitate precisely characterizing their ecological needs in order to optimize reproduction rates and reintroduction plans. The black rhino (Diceros bicornis L.) is among the most endangered species of megaherbivores in Africa and its conservation relies on nature reserves that are bound and habitat‐restricted. Therefore, identifying the optimal amount of space this species needs and the factors driving its habitat use are crucial for establishing reserve priority plans. Knowing that forage selection is an important component linked to herbivore spatial distribution, we combined 5 years of sightings data with observations of rhinos' vegetation type and forage preferences to address their forage selection across multiple spatial scales. We found that black rhinos' spatial distribution was negatively associated with ecosystem productivity, but positively associated with specific vegetation types that contain highly preferred, chemically distinct, plant species. Black rhinos thus occupy their habitat across space and time through selective foraging on preferred plants.

In the aftermath of a disaster, the debris caused by the destruction of property or vegetation become a crucial problem. The increase in the volume of debris, the growing requirements for environmental protection, the cost of waste collection and treatment for local authorities or companies are increasingly complex challenges for lands subject to natural, technological or political disasters (conflicts). The landfall of the cat 5 hurricane Irma and, to a lesser extent Jose, generated an amount of debris estimated up to 60 000 metric tons only for the French part of the island of St. Martin, i.e. 1.7 metric ton per capita. The waste collection and treatment represented a huge challenge. The waste collection took four months whereas the full process (treatment and recycling) was still going on in November 2018. Operations have been hampered by the cyclone itself (destruction of infrastructure and material resources, lack of laborers…) and by the constraints of insularity (low volume to value, lack of storage areas...). On the other hand, Saint-Martin benefits from a single public operator (the collectivity of Saint-Martin) and a recycling and landfill site called “Écosite” with rising skills in waste valorization despite modest funds. The example of Saint-Martin shows all the difficulties of post-cyclonic debris management and emphasizes the dependence of the production of debris and their treatment to the characteristics of the island.

Globalisation has not only increased international competition but also led to an increasingly more integrated and evolving legal system. On 23 June 2016, 52 percent of British voters opted to leave the European Union in the hope of ‘regaining their freedom’. The United Kingdom’s decision to leave the European Union has triggered an important political crisis at the same time as raising various questions as to the implications of such a withdrawal. This referendum leaves much uncertainty about the future in many areas, such as competition. Brexit raises particular problems for competition policy and law because of the influence of the European Commission in this field. Indeed, the Commission is the major direct actor, while the national authorities mainly operate within the European framework. Many authors have argued that the implications of the UK’s withdrawal from the European Union depend on the type of agreement that is secured by the UK. However, this article argues that whatever the type of agreement the UK strikes with the EU, EU competition law will still play a predominant role.

Abstract Background Climate change and rising sea level will certainly lead to significant changes in the management of low-lying coastal areas in the coming decades. While the most recent studies in the field of coastal storms-related flooding are increasingly integrated, simultaneously addressing hazards and vulnerability, as well as population risk perception, there is still little work to consider the preparedness of stakeholders to manage crises whose frequency and intensity are likely to increase in the next years. Methods The aim of this paper is to expose the major results of the CRISSIS research program, which proposed a multi-disciplinary approach to the management of coastal flood risk in a town particularly exposed on the French Mediterranean coast. The originality of the project was to offer both an integrated approach to risk by analysing its 3 dimensions (hazard, impact and vulnerability, and representations and perceptions held by populations and stakeholders, or « risk culture ») and a very operational section focused on the evaluation of crisis management measures led by local stakeholders. To achieve this objective, two crisis exercises were organized, the first one to test the assimilation by the municipality staff of existing crisis management procedures and the second to allow local actors to integrate in their crisis management procedures the new risk knowledge data issued from research conducted under the program. Results The project has had three main features; (i) it accurately mapped the submersible areas that present a critical vulnerability, both material and human; (ii) it revelated the poor social representation of marine submersion risk, as well as the obvious lack of awareness of crisis management systems and tools and the behavior to adopt in the event of flooding; (iii) Finally, it highlighted the need, through the crisis exercises, for a better assimilation by the municipality staff of the crisis management procedures defined in the Municipal Rescue Plan. Conclusion The CRISSIS project has demonstrated the usefulness of an integrated and operational approach of coastal flood risk, not only in terms of studying hazards, stakes and vulnerability, but also in terms of crisis management, in particular through the organisation of crisis simulation exercises.

Abstract Background To assess the impact of the participation in screening programme according to the mode of detection on the early diagnosis, treatment, and specific survival outcomes in women with breast cancer. Methods Women diagnosed with invasive breast cancer in Poitou-Charentes region (France) between 2008 and 2009 were classified into three groups, using data linkage of cancer registry, vital statistics and French organized screening programme: the screening programme (SP), interval cancer (IC), and non-screening programme detected cancer (NSP) groups. Specific survival rates were analysed using the Kaplan–Meier method and Cox proportional hazard models. Results Among 1613 patients, 65.7% (n = 1059) participated in a screening programme. The interval cancer rate was 17.1% (n = 181). Tumours in the IC group were diagnosed at a more advanced stage, i.e. with further regional lymph node metastasis or local spread, than those in the SP group (p

Abstract Background The aim of the study was to evaluate the current rate of molecular testing prescription (KRAS codons 12/13, BRAF and microsatellite instability (MSI)) in newly diagnosed colorectal cancer (CRC) patients and to determine which factors influence testing. Methods All incident CRC cases in 2010 were identified in the Poitou-Charentes General Cancer Registry. The exhaustive molecular testing performed was accessed in the French molecular genetics platform. Factors influencing prescription were analyzed using logistic regression. Results Among the 1269 CRCs included in the study, KRAS, BRAF and MSI testing accounted for 35.1%, 10.5% and 10.9%, respectively. KRAS testing was carried out in 65.5% of metastatic CRCs, and 26.1% of non-metastatic CRCs. Among metastatic CRCs, age (

Purpose – This paper focuses on the regulation of copyrights at international level by comparing the situation under the TRIPS agreement in Brazil and in the European Union. Methodology/approach/design – This article analyses standards and literature on regulation, as well as the role of TRIPS agreement. Attention was specially drawn to the market failure theory for justifying regulation, advocated by Baldwin & Cave. The TRIPS agreement will be analysed through Baldwin’s five criteria for good regulation. Findings – The TRIPS agreement substantially widened the scope of governance of copyrights but imposes the WTO view on the matter. Notwithstanding its flaws, the TRIPS agreement remains the most comprehensive international agreement on intellectual property. According to Baldwin’s theory, the TRIPS agreement as a regulation is a good regulation. Indeed, it achieves the major part of the goals it set. However, some of the declared goals have never come to existence and had been replaced by other goals. On the overall, the TRIPS agreement has the capacity to regulate international intellectual property. Originality/value – This paper analyses the TRIPS agreement as a way forward in the harmonization of the rules on intellectual property.

Globalisation, alongside with the growth in trade and wealth has influenced the considerable development of consumer law over the last 50 years. In some countries, consumer rights have been embraced at the highest Constitutional level. For instance, in Brazil, consumer protection has been given a constitutional value. This constitutional value has been reinforced by the approach taken by the Federal Supreme Court of Brazil with regard to that nation’s Consumer Code (CDC). In spite of the existence of a specific federal agency with its own rules to govern civil aviation, the services rendered by airline companies are also subject to the Consumer Code. For an obscure reason, and even though logic would favor application of the Montreal Convention, Brazilian judges prefer to apply the Brazilian Consumer Code to international air service, in cases involving consumers. The conflict between the Montreal Convention and the CDC is limited to one area, which is one of the most important areas regulated by the Convention, namely the civil responsibility of the carrier. This paper demonstrates that the inclusion of consumer rights as Constitutional rights does not improve the standard of consumer protection but instead put a heavy burden on airlines and in the case of the CDC even creates legal uncertainty.

Purpose – This paper focuses on the regulation of Uber at regional level (Sao Paulo and Brasilia), national level (European Member States) and supranational level (The European Commission initiative), which are often too restrictive. Methodology/approach/design – This article analyses standards and literature on regulation, as well as the role of competition. Attention was specially drawn to the market failure theory for justifying regulation, advocated by Breyer, Ogus and Baldwin & Cave. Due to the fact that there will be an evaluation of the regulations in place, consequentialism, welfarism and Pareto are briefly mentioned. Findings – None of the current regulatory responses, at the exception to Sao Paulo and the initiative by the European Commission that are not based exclusively on market failure theory, are working. Indeed, Uber is still banned in various cities. In others, the regulatory burden is so high that it takes away any incentives that Uber created. Regulation is not the only exit to market failure, competition must play a role. Uber is based on deregulation of the market and to try to regulate such concept with conventional theories will only lead to failures and restrictions. Practical implications – This article discusses the possible improvements to the already existing regulations. Originality/value – This paper correlates the regulation of Uber in Brazil and in Europe, explaining the difficulties these regulations are creating for Uber.

This article aims to show, through the example of Cambodia, how territorial framework is significant for public policies and risk management strategies. Bibliographic research and field observations directed the study case and explore risk management in a developing country which experienced recent political and military history with large consequences in the different institutions and for citizens. This evaluation shows several elements, the difficulties related to low development indicators, a military and political context still weak, difficulties in accessing data, the lack of knowledge about historical events and governance issues. It is also about the standardized approach sometimes not transferable to these territories with specifics characteristics.

IntroductionSarcomas are rare tumours of connective tissue. The exact overall incidence of sarcomas is unknown due to diagnostic difficulties and the various histological subtypes (over 80 subtypes). However, the apparent increasing incidence of sarcomas suggests environmental causes such as pesticides. Except for some specific factors (ie, ionising radiation, vinyl chloride, dioxin and genetic predispositions) the scientific knowledge on the aetiology of sarcomas is sparse and inconsistent. France is a particularly appropriate country to set up a study investigating the causes of sarcoma occurrence due to the French organisation in treatment and care of sarcoma patients, which is highly structured and revolved around national expert networks. The main objective of the ETIOlogy of SARcomas (ETIOSARC) project is to study the role of lifestyle, environmental and occupational factors in the occurrence of sarcomas among adults from a multicentric population-based case–control study.Methods and analysisCases will be all incident patients (older than 18 years) prospectively identified in 15 districts of France covered by a general population-based cancer registry and/or a reference centre in sarcoma’s patient care over a 3-year period with an inclusion start date ranging from February 2019 to January 2020 and histologically confirmed by a second review of the diagnosis. Two controls will be individually matched by sex, age (5 years group) and districts of residence and randomly selected from electoral rolls. A standardised questionnaire will be administered by a trained interviewer in order to gather information about occupational and residential history, demographic and socioeconomic characteristics and lifestyle factors. At the end of the interview, a saliva sample will be systematically proposed. This study will permit to validate or identify already suspected risk factors for sarcomas such as phenoxyherbicides, chlorophenol and to generate new hypothesis to increase our understanding about the genetic and environmental contributions in the carcinogenicity process.Ethics and disseminationThe present study is promoted by the French National Institute of Health and Medical Research (identification number C17-03). This study received National French Ethic committee (CPP Sud Méditerrannée I) approval (identification number 18-31) and French Data Protection Authority (CNIL) approval (identification number 918171). Results of this study will be published in international peer-reviewed journals. Technical appendix, statistical code and dataset will be available in the Dryad repository when collection data are completed.Trial registration numberNCT03670927.

BACKGROUND:The European Society of Breast Cancer Specialists (EUSOMA), which aims to standardize the quality of patient care in Europe, has defined quality indicators (QIs) for breast cancer (BC) care to assess compliance to current care standards. These QIs are a useful tool to evaluate care organizations. Only population-based studies are able to assess health system performance in "real-life" situations. This population-based study aimed to describe compliance with several EUSOMA QIs overall and according to patient and organizational factors in France. METHODS:1 560 adult women with primary invasive non-metastatic BC diagnosed in 2012 were randomly selected among all incident BC from 16 French geographical areas covered by cancer registries. Twelve EUSOMA QIs were selected regarding diagnosis, treatment and staging. RESULTS:The minimum standard as proposed by EUSOMA was met for nine QIs related to pre-operative definitive diagnosis, multidisciplinary discussion and treatment (single surgery, breast conserving surgery (BCS) for small BC (

Telehealth devices are expected to improve quality of care and quality of life of patients living with chronic illness. This article proposes to analyze a telehealth device for cancer patients. Beyond the well-known constraints related to the use of ICT, the article focuses on the relational dimension of the telehealth solution to understand the low use of the device that has been observed. The results are discussed in the light of current discourses in the health field that consider these telehealth solutions as instruments for empowering patients.

Summary: Faithful DNA replication is essential for the maintenance of genome integrity. Incomplete genome replication leads to DNA breaks and chromosomal rearrangements, which are causal factors in cancer and other human diseases. Despite their importance, the molecular mechanisms that control human genome stability are incompletely understood. Here, we report a pathway that is required for human genome replication and stability. This pathway has three components: an E3 ubiquitin ligase, a transcriptional repressor, and a replication protein. The E3 ubiquitin ligase RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38. This repressor negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Cells lacking RBBP6 experience reduced replication fork progression and increased damage at common fragile sites due to ZBTB38 accumulation and MCM10 downregulation. Our results uncover a pathway that ensures genome-wide DNA replication and chromosomal stability. : DNA replication duplicates the genome at every cell cycle. Miotto et al. have now identified a molecular pathway that ensures proper replication of the mammalian genome. Common fragile sites are regions in the mammalian genome that are prone to loss when DNA replication is suboptimal. The new data show that common fragile sites are exquisitely sensitive to the activity of this RBBP6/ZBTB38/MCM10 axis, suggesting that deregulation of these factors may underlie genome instability and human disease.

Based on the original scientific field of taste communication, the article exposes the setting up of a methodology specific to the communication sciences. Explicating the specificity of the taste and using multidisciplinary tools, we build a communication methodology specific to the communication of sensory attribute.

Mediterranean area has often concerned area is often hit by flash foods. Grabels (city in southern France) experienced flash floods from 6-7th October 2014. During this time the river “Mosson” and its tributaries overflowed and combined with the streaming to damage near 500 homes. To evaluate the event and its impacts, we performed an analysis days after the disaster to identify the main flow and consecutive damages. We identified the floodplain, the development of the flood and others characteristics on morphosedimentary and hydrologics changes. We also estimate damages and impacts on urbanized area.

The diversity of fungi along environmental gradients has been little explored in contrast to plants and animals. Consequently, environmental factors influencing the composition of fungal assemblages are poorly understood. The aim of this study was to determine whether the diversity and composition of leaf and root-associated fungal assemblages vary with elevation and to investigate potential explanatory variables. High-throughput sequencing of the Internal Transcribed Spacer 1 region was used to explore fungal assemblages along three elevation gradients, located in French mountainous regions. Beech forest was selected as a study system to minimise the host effect. The variation in species richness and specific composition was investigated for ascomycetes and basidiomycetes assemblages with a particular focus on root-associated ectomycorrhizal fungi. The richness of fungal communities associated with leaves or roots did not significantly relate to any of the tested environmental drivers, i.e. elevation, mean temperature, precipitation or edaphic variables such as soil pH or the ratio carbon∶nitrogen. Nevertheless, the ascomycete species richness peaked at mid-temperature, illustrating a mid-domain effect model. We found that leaf and root-associated fungal assemblages did not follow similar patterns of composition with elevation. While the composition of the leaf-associated fungal assemblage correlated primarily with the mean annual temperature, the composition of root-associated fungal assemblage was explained equally by soil pH and by temperature. The ectomycorrhizal composition was also related to these variables. Our results therefore suggest that above and below-ground fungal assemblages are not controlled by the same main environmental variables. This may be due to the larger amplitude of climatic variables in the tree foliage compared to the soil environment.

Chromatin-immunoprecipitation (ChIP) is a powerful technique for mapping the protein-DNA interactions that occur in living cells. The critical technical determinant for successful ChIP is the availability of an appropriate, “ChIP-grade” serum. Here we present a technique designed to assess whether sera are suitable for ChIP, and to quantify their efficiency relative to a positive internal reference. This approach is useful as a first step toward ChIP-on-chip or ChIP-sequencing, especially in the case of recently identified proteins for which no binding sites are yet known.

Sustainable agriculture is certainly one of the most important challenges at present, considering both human population demography and evidence showing that crop productivity based on chemical control is plateauing. While the environmental and health threats of conventional agriculture are increasing, ecological research is offering promising solutions for crop protection against herbivore pests. While most research has focused on aboveground systems, several major crop pests are uniquely feeding on roots. We here aim at documenting the current and potential use of several biological control agents, including micro-organisms (viruses, bacteria, fungi, and nematodes) and invertebrates included among the macrofauna of soils (arthropods and annelids) that are used against root herbivores. In addition, we discuss the synergistic action of different bio-control agents when co-inoculated in soil and how the induction and priming of plant chemical defense could be synergized with the use of the bio-control agents described above to optimize root pest control. Finally, we highlight the gaps in the research for optimizing a more sustainable management of root pests.

In France, for a long time, flood risk management has only oriented to controlling flood hazard with structural measures such as dikes. But since 1990’s many events have proved they have not totally efficient measures. So, institutions decided it’s necessary to manage flood risk with others ways like prevention. Risk management is so organize about holistic policies with different stakeholders and societies exposed at risk. Our study have the aim to demonstrate through several examples how flood risk is manage in French Mediterranean area. Post event feedback permit us to evaluate damage and crisis management. This method is use for show if this strategies is efficient or not. This study demonstrate how is risk management in France. Regulations are they efficient, so have they an influence about the reduction of deaths and damages? Individual measures are they more important than collective action? Finally, what policies and strategies are used and effective? The main results about cases studies show that natural event has most important that publics policies and it determines preventive policies.

This paper analyses the fatalities related to two recent floods in France. The first flood event was a nightly sea surge due to Xynthia windstorm on the Atlantic coast in February 2010 the 28th. The second was a flash flood which struck the department of Var in the French Mediterranean region in June 2010 the 15th. The death tolls are respectively 41 and 26 fatalities. The characteristics of each fatality and the circumstances of death are accurately examined. In the first case, elderly people were surprised while they were sleeping and were drowned in their home. In the case of flash flood the characteristics of victims are diversified ; traffic-related deaths are numerous. The demonstration focuses on the factors that explain mortality : water depth, type of housing, vulnerability of people. The paper concludes discussing the effectiveness of prevention measures and caution messages that must be adapted to natural and human local context (age of people, kind of flood…)

The paper addresses irreversible cooperation in research partnerships. It analyzes longitudinal data from various contracts signed by research units of the French National Centre for Scientific Research (CNRS), and companies or public organizations. The contracts signed between 1986 and 2005 are short term ones, which conveys an impression of volatility. But collaboration does not take the same form for laboratories and companies. In the case of laboratory matching, loyalty is an issue as far as contract renewal is concerned. Finally, Social Network Analysis helps understanding similarities between the contracts signed by several big companies with research units, and confirms that “small scientific worlds” do exist.

El siguiente artículo arroja luz sobre el tema de la organización "irreversible" de las alianzas de investigación, a partir de datos longitudinales relativos a los contratos firmados por grupos de investigación del Centre National de la Recherche Scientifique (CNRS) con organismos financiadores (empresas, administraciones) entre 1986 y 2005. Los datos ponen de relieve diferentes aspectos: en primer lugar, los contratos tienden a ser volátiles y efímeros. Además, los laboratorios no presentan el mismo comportamiento que sus asociados en cuanto a cooperación, y cabe señalar que la repetición de los contratos conlleva una cierta "fidelidad" a su asociado. Por último, el análisis de estas alianzas desde el punto de vista de las redes sociales científicas ha puesto de manifiesto la convergencia de los modos de compatibilidad entre las grandes empresas y los grupos del CNRS, e igualmente la existencia de "pequeños mundos científicos".

BackgroundMBD5 and MBD6 are two uncharacterized mammalian proteins that contain a putative Methyl-Binding Domain (MBD). In the proteins MBD1, MBD2, MBD4, and MeCP2, this domain allows the specific recognition of DNA containing methylated cytosine; as a consequence, the proteins serve as interpreters of DNA methylation, an essential epigenetic mark. It is unknown whether MBD5 or MBD6 also bind methylated DNA; this question has interest for basic research, but also practical consequences for human health, as MBD5 deletions are the likely cause of certain cases of mental retardation.Principal findingsHere we report the first functional characterization of MBD5 and MBD6. We have observed that the proteins colocalize with heterochromatin in cultured cells, and that this localization requires the integrity of their MBD. However, heterochromatic localization is maintained in cells with severely decreased levels of DNA methylation. In vitro, neither MBD5 nor MBD6 binds any of the methylated sequences DNA that were tested.ConclusionsOur data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization.

The paper addresses irreversible cooperation in research partnerships. It analyzes longitudinal data from various contracts signed by research units of the French National Centre for Scientific Research (CNRS), and companies or public organizations. The contracts signed between 1986 and 2005 are short term ones, which conveys an impression of volatility. But collaboration does not take the same form for laboratories and companies. In the case of laboratory matching, loyalty is an issue as far as contract renewal is concerned. Finally, SocialNetwork Analysis helps understanding similarities between the contracts signed by several big companies with research units, and confirms that “small scientific worlds” do exist.

Abstract Background The care itinerary for cancer involves difficulties that occur in several different areas, whether in the diagnostic procedures, in surgery, or in adjuvant treatment. The aim of this work was to obtain a valid instrument measuring satisfaction among patients with breast cancer and exploring their care itinerary overall. Methods Development phase: Patient focus groups were implemented in two French regions in order to identify areas of satisfaction in relation to the different phases of care provision in breast cancer. On the basis of the literature and the themes and wordings derived from the focus groups, the patients identified several areas of satisfaction, which they found to be partially covered in an American satisfaction measure that has been validated in the French general population (the Consumer Satisfaction Survey in its French version, CSS-VF, 39 items). The patient focus groups suggested adaptation of certain dimensions of this instrument to the potential care providers (37 items) and produced 45 new items in six areas. Validation phase: Using a large sample of patients (cohort of 820 women with invasive non-metastatic breast cancer) approached one month after treatment, this phase selected items that were comprehensible (non-response rate < 10%), non-redundant (r < 0.80) and reproducible (test-retest conducted on a sub-sample of 166 patients). The dimensions were identified by factor analysis on the selected items. Divergent and discriminant validity were assessed (relationships with quality of life questionnaire, comparisons between extreme groups). Results Results were in favour of not inserting additional broken-down items into the CSS-VF and retaining 21 new items. The factor analysis found the initial structure of the CSS-VF (39 items in 9 dimensions) and the 21 new items divide up into four dimensions (listening abilities and information provided by doctors, organisation and follow-up of medical care provision, psychological support, material environment). No redundancy was observed between new items and CSS-VF items. Internal consistency was high. Divergent and discriminant validity were satisfactory. Conclusion Adding four new dimensions to the CSS-VF yielded a valid 60-item instrument for assessment of care provided in breast cancer. These promising results now require further investigations of its responsiveness and its robustness in other linguistic, cultural and healthcare settings.

The hurricane season 2017 in the North Atlantic was intense. The events recalled the exposure of the West Indies to these phenomena sometimes devastating, such as the cyclone Irma which caused heavy losses on the French islands of Saint-Martin and Saint-Barthélemy. The post-event phase sometimes gives rise to an experience feedback (RETEX), which reports on the steps and management processes of the event. RETEX is widely conducted with institutions but leaves to hear the people. This study is based on a scientific RETEX in which the individual dimension of crisis management is integrated, by asking to what extent do individuals participate (or not) in crisis management (directly and indirectly) and how? The scientist team went to meet populations to assess how they lived and prepared themselves to cope with TC Irma in order to present the invest of populations in crisis management. The acknowledgment of populations about natural hazards is fine, and they also know recommendations to cope with cyclone. However, TC Irma was more strong that the reference event (Luis in 1955) for which the populations were prepared. Damage revealed and/or increased existing vulnerabilities which raise the question of built back processes.

This article looks back at the 2017 hurricane season, which strongly impacted the Lesser Antilles, particularly during the passage of Hurricane Irma over the islands of Saint-Martin and Saint-Barthélemy. It presents the main results of a collective and multi-dimensional scientific feedback, conducted over five years as part of the ANR TIREX research project. In addition to the many lessons learned, the project explores ways of transferring scientific knowledge to the population and decision-makers, and questions the practice of RETEX in general. In particular, TIREX contributes to improve hurricane warnings, to identify inherited vulnerability factors, to understand the damage processes related to wind and sea, to monitor the dynamics of territorial and human recovery at the individual and collective levels, and more generally to strengthen the adaptation and response capacities of Lesser Antilles societies in the face of hurricanes.

The ways the personal networks of cancer patients operate have seldom been studied. We analyze here how the personal relationships and networks of people with serious and long-term illnesses are activated. We adapted the “quantified narrative method” to the study of 12 cases. A total of 317 personal relationships were mobilized by these patients in order to access different types of resources: emotional support, help with daily tasks, information on the disease or on cancer care protocols, etc. The patients’ personal networks appear to be very flexible depending on the phases of cancer treatment. The networks are activated especially during the care phase, at key moments such as surgery or the beginning of chemotherapy. In addition, the nature of the relationships also evolve during the illness: colleagues turn into counselors and certain family members become daily life assistants. In some cases, relationships fall apart, sometimes breaking up entirely.