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Abstract Background Incorporating interprofessional collaboration within healthcare is critical to delivery of patient-centered care. Interprofessional Education (IPE) programs are key to promoting such collaboration. The ‘Public Health Service' (PHS) in France is a mandatory IPE initiative that embodies this collaborative spirit, bringing together students from varied health undergraduate training programs—nursing, physiotherapy, pharmacy, midwifery, and medicine— in a common training program focused on primary prevention. The aim of the study was to assess the experience and attitudes of students in the five health training programs regarding the interest of IPEs in the PHS. Methods A cross-sectional survey was administered to 823 students from the 2022–2023 cohort at a French university. The questionnaire was designed with 12 Likert-scale questions specifically created to evaluate the students' experiences, knowledge, and attitudes focused on IPE during the practical seminars, school interventions, and the overall PHS. Additionally, an open-ended question was utilized to gather qualitative data. Statistical analyses assessed satisfaction levels across undergraduate training programs, while thematic analysis was applied to the qualitative responses. Results Within the surveyed cohort, 344 students responded to the survey. The findings showed that students were satisfied with the interprofessional collaboration, both in practical teaching sessions (75% satisfaction) and in primary prevention projects conducted in schools (70% satisfaction), despite their having faced challenges with coordination. Pharmacy students, in particular, highlighted the need for adjustments in program scheduling. The qualitative feedback underscored the positive value of IPE, notwithstanding the organizational difficulties stemming from different academic timetables. Conclusion The student feedback indicated a high level of satisfaction with the interprofessional work carried out in both the practical teaching and the primary prevention projects. To further enhance the educational impact and address the scheduling complexities, it is recommended that program refinements be made based on student feedback and pedagogical best practices.

Abstract Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.

This paper proposes a design-oriented DC model for MOS transistors in advanced nanometric technologies, based on only six parameters. The proposed model is based on the inversion charge and includes the main short-channel effects for accurately describing the behavior of the transistor DC drain current in all regions (linear to saturation) and regimes of operation (weak to strong inversion). The proposed model is critically compared to existing inversion charge-based models, highlighting the main limitations of previous models presented in the literature and the advantages and disadvantages of our proposal. Then, regarding the model implementation, previously presented inversion charge-based models require a numerical solver to link the transistor’s DC current to its DC node voltages. In this work, we propose an innovative approach to model implementation via the analytical approximation of the Lambert function’s principal branch. Thanks to this approximation, the proposed design-oriented model offers for the first time an analytical single-piece expression of the drain current as an explicit function of the transistor node voltages. The validity of both the proposed transistor DC model and its analytical single-piece implementation is confirmed through simulation and measurement results, using the industrial production-level model UTSOI2 as a reference. The evaluations were conducted on MOS transistors with lengths of 30nm, 60nm, and 150nm in STMicroelectronics 28nm FD-SOI CMOS technology, to validate our results in minimum length, intermediate length, and long transistors in the selected technology. The proposed model achieves an average error of less than 6% in drain current evaluation compared to industry-standard models such as UTSOI2, while significantly reducing computational complexity.

Salicornia europaea L. is a halophilic plant species belonging to Chenopodiaceae, whose shoots are used as a vegetable. Since the shoots can be eaten raw, the objective of the present study was to investigate possible controls on the abundance of human pathogenic microorganisms (HPMOs) in the shoots as a health risk. For this reason, the molecular-chemical composition of shoots, site-specific soil organic matter (bulk and rhizosphere), and soil pH and salinity were analyzed. Plant and soil samples were taken from two test sites with differing salinity levels in France (a young and an old marsh). We hypothesized that the chemical traits of plants and soils could suppress or promote HPMOs and, thus, serve as risk indicators for food quality. The chemical traits of shoots and bulk and rhizosphere soil were measured through thermochemolysis using gas chromatography/mass spectrometry (GC/MS). The densities of cultivable HPMOs (Salmonella enterica, Escherichia coli, and Listeria monocytogenes) were determined in plant shoots, rhizosphere soil, and bulk soil using selective media. Negative correlations between lignin content in the shoots and the abundance of S. enterica, as well as between lignin content in bulk soil and the abundance of E. coli, are explained by the lignin-based rigidity and its protective effect on the cell wall. In the shoot samples, the content of lipids was positively correlated with the abundance of E. coli. The abundance of E. coli, S. enterica, and L. monocytogenes in bulk soil decreased with increasing soil pH, which is linked to increased salinity. Therefore, soil salinity is proposed as a tool to decrease HPMO contamination in S. europaea and ensure its food safety.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Abstract Background Transposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryogenesis to innate immune responses. Because of their repetitive nature, TEs have the potential to form CRE platforms enabling the coordinated and genome-wide regulation of protein-coding genes by only a handful of trans-acting transcription factors (TFs). Results Here, we directly test this hypothesis through mathematical modeling and demonstrate that differences in expression at protein-coding genes alone are sufficient to estimate the magnitude and significance of TE-contributed cis-regulatory activities, even in contexts where TE-derived transcription fails to do so. We leverage hundreds of overexpression experiments and estimate that, overall, gene expression is influenced by TE-embedded CREs situated within approximately 500 kb of promoters. Focusing on the cis-regulatory potential of TEs within the gene regulatory network of human embryonic stem cells, we find that pluripotency-specific and evolutionarily young TE subfamilies can be reactivated by TFs involved in post-implantation embryogenesis. Finally, we show that TE subfamilies can be split into truly regulatorily active versus inactive fractions based on additional information such as matched epigenomic data, observing that TF binding may better predict TE cis-regulatory activity than differences in histone marks. Conclusion Our results suggest that TE-embedded CREs contribute to gene regulation during and beyond gastrulation. On a methodological level, we provide a statistical tool that infers TE-dependent cis-regulation from RNA-seq data alone, thus facilitating the study of TEs in the next-generation sequencing era.

Low and high beta frequency rhythms were observed in the motor cortex, but their respective sources and behavioral correlates remain unknown. We studied local field potentials (LFPs) during pre-cued reaching behavior in macaques. They contained a low beta band (20 Hz) dominant in dorsal premotor cortex (PMd). Low beta correlated positively with reaction time (RT) from visual cue onset and negatively with uninstructed hand postural micro-movements throughout the trial. High beta reflected temporal task prediction, with selective modulations before and during cues, which were enhanced in moments of increased focal attention when the gaze was on the work area. This double-dissociation in sources and behavioral correlates of motor cortical low and high beta, with respect to both task-instructed and spontaneous behavior, reconciles the largely disparate roles proposed for the beta rhythm, by suggesting band-specific roles in both movement control and spatiotemporal attention.

A functional trait-based approach is crucial for understanding ecosystem function, persistence, and protection. Vegetation in inland salt marsh habitats has been recognized as unique on a European scale and is legally protected under the Natura 2000 network. Despite long-term international protection, this continues to decline. The concept of inland salt marsh protection refers to vegetation in the sense of syntaxonomical units. However, no link has been found between syntaxonomical and functional concepts of vegetation. We aimed to identify functional traits that are distinctive to individual vegetation units and to link these traits to environmental factors. We hypothesized that a) syntaxonomical vegetation units are also functional units in terms of their functional traits, and b) environmental factors determine the functional traits of vegetation patches. We considered a set of traits from the CLO-PLA and LEDA databases responsible for the persistence, regeneration, and dispersability of approximately 400 species recorded in 874 plots classified into nine vegetation classes and five associations typical of salt marshes. We found that the syntaxonomical vegetation units were also functional. The most important factors separating vegetation classes and salt marsh plant associations are the functional traits responsible for plant persistence. The values of these traits were generally negatively correlated with soil salinity and positively correlated with soil moisture and abandonment of mowing or grazing. Traits related to regeneration, such as seed number and seed number per shoot, also play essential roles in grouping species into individual associations. The classes specific to salt marshes, Therosalicornietea and Festuco-Puccinelietea, had the lowest persistence potential and were thus the most sensitive to environmental changes. The most sensitive association seemed to be Salicornietum ramossissimae. Therefore, significant attention should be paid to protecting this vegetation type. Puccinellio distantis-Spergularietum salinae and Agrostio stoloniferae-Juncetum ranarii had significantly lower stability and higher regenerative ability. Therefore, their regeneration must be easier and more effective. Triglochino maritimae-Glaucetum maritimae and Scorzonero parviflorae-Juncetum gerardi associations had low regeneration ability. The functional pattern of the analyzed vegetation may play a crucial role in the effective protection and restoration of endangered natural saline habitats.

At the cell surface, the actin cytoskeleton and the plasma membrane interact reciprocally in a variety of processes related to the remodeling of the cell surface. The actin cytoskeleton has been known to modulate membrane organization and reshape the membrane. To this end, actin-membrane linking molecules play a major role in regulating actin assembly and spatially direct the interaction between the actin cytoskeleton and the membrane. While studies in cells have provided a wealth of knowledge on the molecular composition and interactions of the actin-membrane interface, the complex molecular interactions make it challenging to elucidate the precise actions of the actin-membrane linkers at the interface. Synthetic reconstituted systems, consisting of model membranes and purified proteins, have been a powerful approach to elucidate how actin-membrane linkers direct actin assembly to drive membrane shape changes. In this review, we will focus only on several actin-membrane linkers that have been studied by using reconstitution systems. We will discuss the design principles of these reconstitution systems and how they have contributed to the understanding of the cellular functions of actin-membrane linkers. Finally, we will provide a perspective on future research directions in understanding the intricate actin-membrane interaction.

This paper analyses the impact of the COVID-19 pandemic crisis on professional regulatory change in two Canadian provinces, drawing on ecological theory. The dataset, constructed using web-scraping techniques, includes all laws and by-law modifications concerning regulated professions enacted during the first 18 months of the pandemic in Quebec and British Columbia. Data show that the crisis prompted regulatory changes but that the impact and nature of these changes varied depending on the structure of the ecology of professional regulation in each province. Furthermore, crisis-related concerns were more likely to induce or accelerate durable changes if they intersected with pre-existing, ongoing professional projects. Our findings have implications for theorizing crisis-related regulatory change and demonstrate the value of a comparative approach to studying professional ecologies and state-profession interfaces.

BackgroundSeoul virus (SEOV) is an orthohantavirus primarily carried by rats. In humans, it may cause hemorrhagic fever with renal syndrome (HFRS). Its incidence is likely underestimated and given the expansion of urban areas, a better knowledge of SEOV circulation in rat populations is called for. Beyond the need to improve human case detection, we need to deepen our comprehension of the ecological, epidemiological, and evolutionary processes involved in the transmission of SEOV.Methodology / principal findingsWe performed a comprehensive serological and molecular characterization of SEOV in Rattus norvegicus in a popular urban park within a large city (Lyon, France) to provide essential information to design surveillance strategies regarding SEOV. We sampled rats within the urban park of 'La Tête d'Or' in Lyon city from 2020 to 2022. We combined rat population genetics, immunofluorescence assays, SEOV high-throughput sequencing (S, M, and L segments), and phylogenetic analyses. We found low structuring of wild rat populations within Lyon city. Only one sampling site within the park (building created in 2021) showed high genetic differentiation and deserves further attention. We confirmed the circulation of SEOV in rats from the park with high seroprevalence (17.2%) and high genetic similarity with the strain previously described in 2011 in Lyon city.Conclusion/significanceThis study confirms the continuous circulation of SEOV in a popular urban park where the risk for SEOV transmission to humans is present. Implementing a surveillance of this virus could provide an efficient early warning system and help prepare risk-based interventions. As we reveal high gene flow between rat populations from the park and the rest of the city, we advocate for SEOV surveillance to be conducted at the scale of the entire city.

Cet article rend compte d’une recherche-action conduite avec les concepteurs d’une IA émotionnelle qui tentaient de s’éloigner du modèle de capture des technologies affectives. Un tel déplacement implique de rattacher une approche critique et des pratiques d’intervention. Saisir et faire agir forment un couple qui vient compléter une éthique des devoirs ou des conséquences, non plus en aidant les concepteurs à arbitrer entre des principes ou des calculs, mais en leur offrant de repartir de leurs expériences, et celles de leurs usagers, pour concevoir une innovation socialement désirable. Cette promesse est rendue possible par une éthique en situations, un cadrage opérationnel permettant de saisir, par la voie d’une ethnographie sensible, ce qui est à disposition dans les situations vécues par les usagers et par les concepteurs ; de mettre à leur disposition, par des approches participatives, des objets intermédiaires facilitant la transition vers des imaginaires autres ; et de se tenir à disposition pour des médiations nouvelles, en s’appuyant sur des méthodes créatives et projectives.

Fruit development can be viewed as the succession of three main steps consisting of the fruit initiation, growth and ripening. These processes are orchestrated by different factors, notably the successful fertilization of flowers, the environmental conditions and the hormones whose action is coordinated by a large variety of transcription factors. Among the different transcription factor families, TEOSINTE BRANCHED 1, CYCLOIDEA, PROLIFERATING CELL FACTOR (TCP) family has received little attention in the frame of fruit biology despite its large effects on several developmental processes and its action as modulator of different hormonal pathways. In this respect, the comprehension of TCP functions in fruit development remains an incomplete puzzle that needs to be assembled. Building on the abundance of genomic and transcriptomic data, this review aims at collecting available TCP expression data to allow their integration in the light of the different functional genetic studies reported so far. This reveals that several Class I TCP genes, already known for their involvement in the cell proliferation and growth, display significant expression levels in developing fruit, although clear evidence supporting their functional significance in this process remains scarce. The extensive expression data compiled in our study provide convincing elements that shed light on the specific involvement of Class I TCP genes in fruit ripening, once these reproductive organs acquire their mature size. They also emphasize their putative role in the control of specific biological processes such as fruit metabolism and hormonal dialogue.

Radiotherapy is recommended for the treatment of brain tumors such as glioblastoma (GBM) and brain metastases. Various curative and palliative scenarios suggest improved local-regional control. Although the underlying mechanisms are not yet clear, additional therapeutic effects have been described, including proximity and abscopal reactions at the treatment site. Clinical and preclinical data suggest that the immune system plays an essential role in regulating the non-targeted effects of radiotherapy for GBM. This article reviews current biological mechanisms for regulating the non-targeted effects caused by external and internal radiotherapy, and how they might be applied in a clinical context. Optimization of therapeutic regimens requires assessment of the complexity of the host immune system on the activity of immunosuppressive or immunostimulatory cells, such as glioma-associated macrophages and microglia. This article also discusses recent preclinical models adapted to post-radiotherapy responses.This narrative review explores and discusses the current status of immune responses both locally via the ''bystander effect'' and remotely via the ''abscopal effect''. Preclinical and clinical observations demonstrate that unirradiated cells, near or far from the irradiation site, can control the tumor response. Nevertheless, previous studies do not address the problem in its global context, and present gaps regarding the link between the role of the immune system in the control of non-targeted effects for different types of radiotherapy and different fractionation schemes applied to GBM. This narrative synthesis of the scientific literature should help to update and critique available preclinical and medical knowledge. Indirectly, it will help formulate new research projects based on the synthesis and interpretation of results from a non-systematic selection of published studies.

Perceptual measures, such as intelligibility and speech disorder severity, are widely used in the clinical assessment of speech disorders in patients treated for oral or oropharyngeal cancer. Despite their widespread usage, these measures are known to be subjective and hard to reproduce. Therefore, an M-Health assessment based on an automatic prediction has been seen as a more robust and reliable alternative. Despite recent progress, these automatic approaches still remain somewhat theoretical, and a need to implement them in real clinical practice rises. Hence, in the present work we introduce SAMI, a clinical mobile application used to predict speech intelligibility and disorder severity as well as to monitor patient progress on these measures over time. The first part of this work illustrates the design and development of the systems supported by SAMI. Here, we show how deep neural speaker embeddings are used to automatically regress speech disorder measurements (intelligibility and severity), as well as the training and validation of the system on a French corpus of head and neck cancer. Furthermore, we also test our model on a secondary corpus recorded in real clinical conditions. The second part details the results obtained from the deployment of our system in a real clinical environment, over the course of several weeks. In this section, the results obtained with SAMI are compared to an a posteriori perceptual evaluation, conducted by a set of experts on the new recorded data. The comparison suggests a high correlation and a low error between the perceptual and automatic evaluations, validating the clinical usage of the proposed application.

RÉSUMÉCirculant dans les arènes internationales, le concept de Solutions fondées sur la Nature (SfN) est apparu au cours de la dernière décennie dans les politiques environnementales et des risques liés à l’eau. Les SfN doivent permettre de répondre à des défis sociétaux tout en préservant ou favorisant la biodiversité. Nous proposons ici de suivre l’institutionnalisation du concept en France en nous appuyant sur des méthodes de sciences humaines et sociales. Au niveau national, nous identifions une institutionnalisation assez forte du concept dans les politiques publiques à travers différents vecteurs d’intégration. Les cas d’étude montrent des modalités d’appropriation du concept variables à l’échelle locale, oscillant entre une absence de mobilisation du concept malgré des pratiques qui semblent similaires à la définition de l’UICN, à un usage du concept stratégique dans certains contextes. Afin d’expliquer cette différence d’appropriation, nous avançons deux hypothèses. La première concerne l’« innovation conceptuelle » que représente les SfN, qui semble adaptée aux modes de fonctionnement des politiques publiques à l’échelle nationale, mais qui trouve certaines limites dans sa déclinaison à l’échelle locale. La seconde concerne les instruments d’action publique mobilisés pour promouvoir le concept, qui ne semblent pas permettre d’aboutir à un processus d’intéressement des acteurs locaux.

IntroductionAddressing relevant determinants for preserved person-centered rehabilitation in mental health is still a major challenge. Little research focuses on factors associated with psychiatric hospitalization in exclusive outpatient settings. Some variables have been identified, but evidence across studies is inconsistent. This study aimed to identify and confirm factors associated with hospitalization in a specific outpatient population.MethodsA retrospective monocentric case-control study with 617 adult outpatients (216 cases and 401 controls) from a French community-based care facility was conducted. Participants had an index outpatient consultation between June 2021 and February 2023. All cases, who were patients with a psychiatric hospitalization from the day after the index outpatient consultation and up to 1 year later, have been included. Controls have been randomly selected from the same facility and did not experience a psychiatric hospitalization in the 12 months following the index outpatient consultation. Data collection was performed from electronic medical records. Sociodemographic, psychiatric diagnosis, historical issues, lifestyle, and follow-up-related variables were collected retrospectively. Uni- and bivariate analyses were performed, followed by a multivariable logistic regression.ResultsVisit to a psychiatric emergency within a year (adjusted odds ratio (aOR): 13.02, 95% confidence interval (CI): 7.32–23.97), drug treatment discontinuation within a year (aOR: 6.43, 95% CI: 3.52–12.03), history of mental healthcare without consent (aOR: 5.48, 95% CI: 3.10–10.06), medical follow-up discontinuation within a year (aOR: 3.17, 95% CI: 1.70–5.95), history of attempted suicide (aOR: 2.50, 95% CI: 1.48–4.30) and unskilled job (aOR: 0.26, 95% CI: 0.10–0.65) are the independent variables found associated with hospitalization for followed up outpatients.ConclusionsPublic health policies and tools at the local and national levels should be adapted to target the identified individual determinants in order to prevent outpatients from being hospitalized.

The chemical burden on the environment and human population is increasing. Consequently, regulatory risk assessment must keep pace to manage, reduce, and prevent adverse impacts on human and environmental health associated with hazardous chemicals. Surveillance of chemicals of known, emerging, or potential future concern, entering the environment-food-human continuum is needed to document the reality of risks posed by chemicals on ecosystem and human health from a one health perspective, feed into early warning systems and support public policies for exposure mitigation provisions and safe and sustainable by design strategies. The use of less-conventional sampling strategies and integration of full-scan, high-resolution mass spectrometry and effect-directed analysis in environmental and human monitoring programmes have the potential to enhance the screening and identification of a wider range of chemicals of known, emerging or potential future concern. Here, we outline the key needs and recommendations identified within the European Partnership for Assessment of Risks from Chemicals (PARC) project for leveraging these innovative methodologies to support the development of next-generation chemical risk assessment.

The pine processionary moth Thaumetopoea pityocampa is a defoliating lepidopter that develops during winter. The larvae are gregarious and bear urticating setae that are harmful to humans and vertebrates. They shelter in conspicuous silk tents that are easy to detect. We here present a dataset comprising tree characterization and tent counts from 3 agglomerations in France located in regions with different climatic environments. The studied trees belong to various conifer species that are potential hosts for the caterpillars. In each site, we defined clusters as one target tree and its 10–62 nearest neighbors, and surveyed each tree within the clusters by informing: tree species, coordinates, size, number of tents. We characterized a total of 3690 trees, including 2009 trees in Orléans (grouped in 68 clusters), 359 trees in La Baule (18 clusters) and 1322 trees in Montpellier (52 clusters). We provide the raw data characterizing each individual tree, graphs showing the prevalence and mean number of tents for the tree species included in the survey, and maps allowing to locate each tree. This dataset brings information about host preference of the pine processionary moth and will be useful as a baseline to study spatio-temporal variability of host-insect relationships. It can also be informative for decision-makers and managers of urban greenings to avoid trees that are likely to be heavily infested for plantation in proximity to vulnerable people.

Abstract The role of antiviral treatment in coronavirus disease 2019 hospitalized patients is controversial. To address this question, we analyzed simultaneously nasopharyngeal viral load and the National Early Warning Score 2 (NEWS‐2) using an effect compartment model to relate viral dynamics and the evolution of clinical severity. The model is applied to 664 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020‐000936‐23) randomly assigned to either standard of care (SoC) or SoC + remdesivir. Then we use the model to simulate the impact of antiviral treatments on the time to clinical improvement, defined by a NEWS‐2 score lower than 3 (in patients with NEWS‐2

Abstract Ubiquitin widely modifies proteins, thereby regulating most cellular functions. The complexity of ubiquitin signalling necessitates unbiased methods enabling global detection of dynamic protein ubiquitylation. Here, we describe UBIMAX (UBiquitin target Identification by Mass spectrometry in X enopus egg extracts), which enriches ubiquitin-conjugated proteins and quantifies regulation of protein ubiquitylation under precise and adaptable conditions. We benchmark UBIMAX by investigating DNA double-strand break-responsive ubiquitylation events, identifying previously known targets and revealing the actin-organizing protein Dbn1 as a major target of DNA damage-induced ubiquitylation. We find that Dbn1 is targeted for proteasomal degradation by the SCFβ-Trcp1 ubiquitin ligase, in a conserved mechanism driven by ATM-mediated phosphorylation of a previously uncharacterized β-Trcp1 degron containing an SQ motif. We further show that this degron is sufficient to induce DNA damage-dependent protein degradation of a model substrate. Collectively, we demonstrate UBIMAX’s ability to identify targets of stimulus-regulated ubiquitylation and reveal an SCFβ-Trcp1-mediated ubiquitylation mechanism controlled directly by the apical DNA damage response kinases.

Abstract Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg−1 of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3–7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities.

Abstract Background In France, rural general practitioner (GP) numbers could reduce by 20% between 2006 and 2030 if no measures are taken to address primary care access difficulties. In countries such as Australia, the USA and Canada, intrinsic and extrinsic factors associated with GPs practising in rural areas include rural upbringing and rural training placements. However, the health systems and rural area definition differ between these countries and France making result extrapolation difficult. These factors must be studied in the context of the French heath system, to design strategies to improve rural GP recruitment and retention. This study aims to identify the intrinsic and extrinsic factors associated with GPs practising in rural areas in France. Methods This case–control study was conducted between May and September 2020. Included GPs practised in Brittany, France, and completed a self-administered questionnaire. The cases were rural GPs and controls were urban GPs. National references defined rural and urban areas. Comparisons between rural and urban groups were conducted using univariate and multivariate analyses to identify factors associated with practising in a rural area. Results The study included 341 GPs, of which 146 were in the rural group and 195 in the urban group. Working as a rural GP was significantly associated with having a rural upbringing (OR = 2.35; 95% CI [1.07–5.15]; p = 0.032), completing at least one undergraduate general medicine training placement in a rural area (OR = 3.44; 95% CI [1.18–9.98]; p

Since the beginning of Russia’s “Special Military Operation”, the dividing line between the “war front” and the “words front” has neither been clear nor rigid, due to the linguistic and cultural proximity between the direct actors of the conflict and the total character of hybrid warfare that tends to darken and soften the distinction between the front and the back to the point that the battlefield leaves the fury of the ground to penetrate the minds, the hearts, and the tongues. This paper attempts to highlight the impact of language on perceptions and representations in the context of the Russia-Ukraine war. It analyses the polarization of language and the weaponisation of identity markers with the aim of understanding the process of constructing the enemy from both Russian and Ukrainian parties by identifying the key elements at the foundations of their collective narratives.

Abstract Background Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats. Results First, in vitro studies confirmed that H2030-BrM3 cells respond to hypoxia with increasing expression of HIF-1, HIF-2 and their target genes. Proteomic analyses revealed, among expression changes, proteins associated with metabolism, oxidative stress, metal response and hypoxia signaling in particular in cortical BM. [64Cu][Cu(ATSM)] PET revealed a significant uptake by cortical BM (p

Abstract Background Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis. Methods The dynamics of lung uptake of 18F-labeled FAPI ([18F]FAPI-74) was assessed in the bleomycin mouse model at various time points and using different concentrations of bleomycin by PET/CT. FAPα was measured in BALFs from these bleomycin-treated and control mice. FAPα levels were also assessed in BALFs from controls and patients with idiopathic pulmonary fibrosis (IPF). Results Bleomycin-treated mice presented a significantly higher uptake of [18F]FAPI-74 during lung fibrinogenesis (days 10 and 16 after instillation) compared to control mice. No significant difference was observed at initial inflammatory phase (3 days) and when fibrosis was already established (28 days). [18F]FAPI-74 tracer was unable to show a dose-response to bleomycin treatment. On the other hand, BALF FAPα levels were steeply higher in bleomycin-treated mice at day 10 and a significant dose-response effect was observed. Moreover, FAPα levels were strongly correlated with lung fibrosis as measured by the modified Aschroft histological analysis, hydroxyproline and the percentage of weight loss. Importantly, higher levels of FAPα were observed in IPF patients where the disease was progressing as compared to stable patients and controls. Moreover, patients with FAPα BALF levels higher than 192.5 pg/mL presented a higher risk of progression, transplantation or death compared to patients with lower levels. Conclusions Our preclinical data highlight a specific increase of [18F]FAPI-74 lung uptake during the fibrotic phase of the bleomycin murine model. The measurement of FAPα in BALF appears to be a promising marker of the fibrotic activity in preclinical models of lung fibrosis and in IPF patients. Further studies are required to confirm the role of FAPα in BALF as biomarker of IPF activity and assess the relationship between FAPα levels in BALF and [18F]FAPI-74 uptake on PET/CT in patients with fibrotic lung disease.

Abstract The SHI RELATED SEQUENCE (SRS) family plays a vital role in the development of multiple plant organs such as floral meristem determinacy, organ morphogenesis, and signal transduction. Nevertheless, there is little understanding of the biological significance of tomato SRS family at this point. Our research identified eight SlSRS family members and classified them into three subfamilies based on phylogenetics, conserved motifs, and characteristic domain analysis. The intraspecies and interspecies collinearity analysis revealed clues of SRS family evolution. Many cis-elements related to hormones, stresses, and plant development can be found in the promoter region of SlSRS genes. All of eight SlSRS proteins were located in the nucleus and possessed transcriptional activity, half of which were transcriptional activators, and the other half were transcriptional repressors. Except for SlSRS1, which showed high transcript accumulation in vegetative organs, most SlSRS genes expressed ubiquitously in all flower organs. In addition, all SlSRS genes could significantly respond to at least four different plant hormones. Further, expression of SlSRS genes were regulated by various abiotic stress conditions. In summary, we systematically analyzed and characterized the SlSRS family, reviewed the expression patterns and preliminarily investigated the protein function, and provided essential information for further functional research of the tomato SRS genes in the determination of reproductive floral organs and the development of plants, and possibly other plants.

Abstract The observation of a weak proton-emission branch in the decay of the 3174-keV 53mCo isomeric state marked the discovery of proton radioactivity in atomic nuclei in 1970. Here we show, based on the partial half-lives and the decay energies of the possible proton-emission branches, that the exceptionally high angular momentum barriers, $${{{{{{\mathcal{l}}}}}}}_{{{{{{\rm{p}}}}}}}=9$$ l p = 9 and $${{{{{{\mathcal{l}}}}}}}_{{{{{{\rm{p}}}}}}}=7$$ l p = 7 , play a key role in hindering the proton radioactivity from 53mCo, making them very challenging to observe and calculate. Indeed, experiments had to wait decades for significant advances in accelerator facilities and multi-faceted state-of-the-art decay stations to gain full access to all observables. Combining data taken with the TASISpec decay station at the Accelerator Laboratory of the University of Jyväskylä, Finland, and the ACTAR TPC device on LISE3 at GANIL, France, we measured their branching ratios as bp1 = 1.3(1)% and bp2 = 0.025(4)%. These results were compared to cutting-edge shell-model and barrier penetration calculations. This description reproduces the order of magnitude of the branching ratios and partial half-lives, despite their very small spectroscopic factors.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

This paper introduces an evolutionary algorithm for objective functions defined over clouds of points of varying sizes. Such design variables are modeled as uniform discrete measures with finite support and the crossover and mutation operators of the algorithm are defined using the Wasserstein barycenter. We prove that the Wasserstein-based crossover has a contracting property in the sense that the support of the generated measure is included in the closed convex hull of the union of the two parents’ supports. We introduce boundary mutations to counteract this contraction. Variants of evolutionary operators based on Wasserstein barycenters are studied. We compare the resulting algorithm to a more classical, sequence-based, evolutionary algorithm on a family of test functions that include a wind-farm layout problem. The results show that Wasserstein-based evolutionary operators better capture the underlying geometrical structures of the considered test functions and outperform a reference evolutionary algorithm in the vast majority of the cases. The tests indicate that the mutation operators play a major part in the performances of the algorithms.

Background. In the context of increasing antimicrobial resistance (AMR), whole-genome sequencing (WGS) of bacteria is considered a highly accurate and comprehensive surveillance method for detecting and tracking the spread of resistant pathogens. Two primary sequencing technologies exist: short-read sequencing (50–300 base pairs) and long-read sequencing (thousands of base pairs). The former, based on Illumina sequencing platforms (ISPs), provides extensive coverage and high accuracy for detecting single nucleotide polymorphisms (SNPs) and small insertions/deletions, but is limited by its read length. The latter, based on platforms such as Oxford Nanopore Technologies (ONT), enables the assembly of genomes, particularly those with repetitive regions and structural variants, although its accuracy has historically been lower. Results. We performed a head-to-head comparison of these techniques to sequence the K. pneumoniae VS17 isolate, focusing on blaNDM resistance gene alleles in the context of a surveillance program. Discrepancies between the ISP (blaNDM-4 allele identified) and ONT (blaNDM-1 and blaNDM-5 alleles identified) were observed. Conjugation assays and Sanger sequencing, used as the gold standard, confirmed the validity of ONT results. This study demonstrates the importance of long-read or hybrid assemblies for accurate carbapenemase resistance gene identification and highlights the limitations of short reads in the context of gene duplications or multiple alleles. Conclusions. In this proof-of-concept study, we conclude that recent long-read sequencing technology may outperform standard short-read sequencing for the accurate identification of carbapenemase alleles. Such information is crucial given the rising prevalence of strains producing multiple carbapenemases, especially as WGS is increasingly used for epidemiological surveillance and infection control.

Aspergillus flavus is a cosmopolitan saprophytic fungus that infests several foodstuffs and is associated with adverse effects in humans. In Senegal, significant losses of groundnut production are mainly due to contamination caused by this species. This study evaluated in vitro antifungal activities of Cyperus articulatus, Cyperus rotundus and Lippia alba essential oils against A. flavus isolated from peanut seeds. Essential oils obtained by hydrodistillation of rhizomes of the two Cyperus species and leaves of L. alba were analyzed with GC-DIF and GC-MS. The essential oil yields from C. articulatus, C. rotundus and L. alba were 1.1%, 1.3% and 1.7%, respectively. These three samples had the following chemotypes: (i) mustakone (21.4%)/eudesma-4(15)-7-dien-1β-ol (8.8%)/caryophyllene oxide (5.9%), (ii) caryophyllene oxide (25.2%)/humulene epoxyde 2 (35.0%) and (iii) geranial (46.6%)/neral (34.6%). The three oils tested inhibited the growth of A. flavus at concentrations between 100 and 1000 ppm. The L. alba oil was the most effective with total clearance of A. flavus on PDA. For the essential oils of C. rotundus (93.65%) and C. articulatus (78.11%), the highest inhibition rates were obtained with a 1000 ppm dose. Thus, L. alba oil could be used safely as an effective protector of groundnuts against A. flavus.

With the growing trend of urbanisation and the growing number of people migrating to cities, the demand for the development and construction of new buildings and infrastructure has risen, meaning that the construction industry must adapt to these trends. Growing demands with shorter deadlines for an industry already known for its high costs and late delivery means that productivity must be increased without increasing costs. The solution for this might lie in the application of the Lean philosophy to the construction industry. This paper analyses the application of the Lean philosophy in order to increase the productivity of construction work for an airport project. This paper highlights the potential for enhancing productivity in construction workplaces by concurrently fostering continuous improvement and sustainability through the implementation of the A3 methodology and Lean principles, resulting in waste reduction and increased value.

Abstract In the last two decades, safety concerns about general anesthesia (GA) arose from studies documenting brain cell death in various pharmacological conditions and animal models. Nowadays, a thorough characterization of sevoflurane-induced apoptosis in the entire neonatal mouse brain would help identify and further focus on underlying mechanisms. We performed whole-brain mapping of sevoflurane-induced apoptosis in post-natal day (P) 7 mice using tissue clearing and immunohistochemistry. We found an anatomically heterogenous increase in cleaved-caspase-3 staining. The use of a novel P7 brain atlas showed that the neocortex was the most affected area, followed by the striatum and the metencephalon. Histological characterization in cortical slices determined that post-mitotic neurons were the most affected cell type and followed inter- and intracortical gradients with maximal apoptosis in the superficial layers of the posterodorsal cortex. The unbiased anatomical mapping used here allowed us to confirm sevoflurane-induced apoptosis in the perinatal period, neocortical involvement, and indicated striatal and metencephalic damage while suggesting moderate hippocampal one. The identification of neocortical gradients is consistent with a maturity-dependent mechanism. Further research could then focus on the interference of sevoflurane with neuronal migration and survival during development.

Abstract Patient reported outcomes measures (PROMS) are important endpoints to measure patient health status in the perioperative setting. However, there are no good tools to measure PROMS in the pediatric surgical population. Patients 7 to 17 years old undergoing surgery were included and followed up for 1 day after surgery (POD1). At POD1 the patients were asked to rate their overall postoperative recovery using a 100-mm visual analog scale (VAS). The primary outcome was the pediatric QoR-15 score on postoperative day 1 (POD1). 150 patients completed the study. The mean (SD) pediatric QoR-15F scores were 132.1 (14.1) and 111.0 (27.0), preoperatively and on POD1, respectively. Convergent validity confirmed with Pearson (r) correlation between the postoperative pediatric QoR-15F and the patient-rated global recovery assessment was 0.72 (95% confidence interval [0.63–0.79]; p

Abstract Background Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. Materials and methods The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. Results Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13–9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23–11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07–33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76–10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01–4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42–1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. Conclusion PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.

Abstract Quadruped robots require robust and general locomotion skills to exploit their mobility potential in complex and challenging environments. In this work, we present an implementation of a robust end-to-end learning-based controller on the Solo12 quadruped. Our method is based on deep reinforcement learning of joint impedance references. The resulting control policies follow a commanded velocity reference while being efficient in its energy consumption and easy to deploy. We detail the learning procedure and method for transfer on the real robot. We show elaborate experiments. Finally, we present experimental results of the learned locomotion on various grounds indoors and outdoors. These results show that the Solo12 robot is a suitable open-source platform for research combining learning and control because of the easiness in transferring and deploying learned controllers.

Abstract Background Healthcare-associated infections involving Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) phenotype are associated with impaired patient-centered outcomes and poses daily therapeutic challenges in most of intensive care units worldwide. Over the recent years, four innovative β-lactam/β-lactamase inhibitor (BL/BLI) combinations (ceftolozane–tazobactam, ceftazidime–avibactam, imipenem–relebactam and meropenem–vaborbactam) and a new siderophore cephalosporin (cefiderocol) have been approved for the treatment of certain DTR-GNB infections. The literature addressing their microbiological spectrum, pharmacokinetics, clinical efficacy and safety was exhaustively audited by our group to support the recent guidelines of the French Intensive Care Society on their utilization in critically ill patients. This narrative review summarizes the available evidence and unanswered questions on these issues. Methods A systematic search for English-language publications in PUBMED and the Cochrane Library database from inception to November 15, 2022. Results These drugs have demonstrated relevant clinical success rates and a reduced renal risk in most of severe infections for whom polymyxin- and/or aminoglycoside-based regimen were historically used as last-resort strategies—namely, ceftazidime–avibactam for infections due to Klebsiella pneumoniae carbapenemase (KPC)- or OXA-48-like-producing Enterobacterales, meropenem–vaborbactam for KPC-producing Enterobacterales, ceftazidime–avibactam/aztreonam combination or cefiderocol for metallo-β-lactamase (MBL)-producing Enterobacterales, and ceftolozane–tazobactam, ceftazidime–avibactam and imipenem–relebactam for non-MBL-producing DTR Pseudomonas aeruginosa. However, limited clinical evidence exists in critically ill patients. Extended-infusion scheme (except for imipenem–relebactam) may be indicated for DTR-GNB with high minimal inhibitory concentrations and/or in case of augmented renal clearance. The potential benefit of combining these agents with other antimicrobials remains under-investigated, notably for the most severe presentations. Other important knowledge gaps include pharmacokinetic information in particular situations (e.g., pneumonia, other deep-seated infections, and renal replacement therapy), the hazard of treatment-emergent resistance and possible preventive measures, the safety of high-dose regimen, the potential usefulness of rapid molecular diagnostic tools to rationalize their empirical utilization, and optimal treatment durations. Comparative clinical, ecological, and medico-economic data are needed for infections in whom two or more of these agents exhibit in vitro activity against the causative pathogen. Conclusions New BL/BLI combinations and cefiderocol represent long-awaited options for improving the management of DTR-GNB infections. Several research axes must be explored to better define the positioning and appropriate administration scheme of these drugs in critically ill patients.

Abstract Background The frequency of chromosomal rearrangements in Canadian breeding boars has been estimated at 0.91 to 1.64%. These abnormalities are widely recognized as a potential cause of subfertility in livestock production. Since artificial insemination is practiced in almost all intensive pig production systems, the use of elite boars carrying cytogenetic defects that have an impact on fertility can lead to major economic losses. To avoid keeping subfertile boars in artificial insemination centres and spreading chromosomal defects within populations, cytogenetic screening of boars is crucial. Different techniques are used for this purpose, but several issues are frequently encountered, i.e. environmental factors can influence the quality of results, the lack of genomic information outputted by these techniques, and the need for prior cytogenetic skills. The aim of this study was to develop a new pig karyotyping method based on fluorescent banding patterns. Results The use of 207,847 specific oligonucleotides generated 96 fluorescent bands that are distributed across the 18 autosomes and the sex chromosomes. Tested alongside conventional G-banding, this oligo-banding method allowed us to identify four chromosomal translocations and a rare unbalanced chromosomal rearrangement that was not detected by conventional banding. In addition, this method allowed us to investigate chromosomal imbalance in spermatozoa. Conclusions The use of oligo-banding was found to be appropriate for detecting chromosomal aberrations in a Canadian pig nucleus and its convenient design and use make it an interesting tool for livestock karyotyping and cytogenetic studies.

Abstract Dengue (DENV) and chikungunya (CHIKV) viruses are among the most preponderant arboviruses. Although primarily transmitted through the bite of Aedes aegypti mosquitoes, Aedes albopictus and Aedes malayensis are competent vectors and have an impact on arbovirus epidemiology. Here, to fill the gap in our understanding of the molecular interactions between secondary vectors and arboviruses, we used transcriptomics to profile the whole-genome responses of A. albopictus to CHIKV and of A. malayensis to CHIKV and DENV at 1 and 4 days post-infection (dpi) in midguts. In A. albopictus, 1793 and 339 genes were significantly regulated by CHIKV at 1 and 4 dpi, respectively. In A. malayensis, 943 and 222 genes upon CHIKV infection, and 74 and 69 genes upon DENV infection were significantly regulated at 1 and 4 dpi, respectively. We reported 81 genes that were consistently differentially regulated in all the CHIKV-infected conditions, identifying a CHIKV-induced signature. We identified expressed immune genes in both mosquito species, using a de novo assembled midgut transcriptome for A. malayensis, and described the immune architectures. We found the JNK pathway activated in all conditions, generalizing its antiviral function to Aedines. Our comprehensive study provides insight into arbovirus transmission by multiple Aedes vectors.

Abstract Dystrophic muscle is characterized by necrosis/regeneration cycles, inflammation, and fibro-adipogenic development. Conventional histological stainings provide essential topographical data of this remodeling but may be limited to discriminate closely related pathophysiological contexts. They fail to mention microarchitecture changes linked to the nature and spatial distribution of tissue compartment components. We investigated whether label-free tissue autofluorescence revealed by Synchrotron deep ultraviolet (DUV) radiation could serve as an additional tool for monitoring dystrophic muscle remodeling. Using widefield microscopy with specific emission fluorescence filters and microspectroscopy defined by high spectral resolution, we analyzed samples from healthy dogs and two groups of dystrophic dogs: naïve (severely affected) and MuStem cell-transplanted (clinically stabilized) animals. Multivariate statistical analysis and machine learning approaches demonstrated that autofluorescence emitted at 420–480 nm by the Biceps femoris muscle effectively discriminates between healthy, dystrophic, and transplanted dog samples. Microspectroscopy showed that dystrophic dog muscle displays higher and lower autofluorescence due to collagen cross-linking and NADH respectively than that of healthy and transplanted dogs, defining biomarkers to evaluate the impact of cell transplantation. Our findings demonstrate that DUV radiation is a sensitive, label-free method to assess the histopathological status of dystrophic muscle using small amounts of tissue, with potential applications in regenerative medicine.

Abstract The Paris Agreement plans for “net‐zero” carbon dioxide (CO2) emissions during the second half of the 21st century. However, reducing emissions from some sectors is challenging, and “net‐zero” permits carbon dioxide removal (CDR) activities. One CDR scheme is ocean alkalinity enhancement (OAE), which proposes dissolving basic minerals into seawater to increase its buffering capacity for CO2. While modeling studies have often investigated OAE at basin or global scale, some proposals focus on readily accessible coastal shelves, with TA added through the dissolution of seafloor olivine sands. Critically, by settling and dissolving sands on shallow seafloors, this retains the added TA in near‐surface waters in direct contact with atmospheric CO2. To investigate this, we add dissolved TA at a rate of ∼29 Teq y−1 to the global shelves (

ABSTRACTTuberculosis remains the most pervasive infectious disease and the recent emergence of drug-resistant strains emphasizes the need for more efficient drug treatments. A key feature of pathogenesis, conserved between the human pathogen Mycobacterium tuberculosis and the model pathogen Mycobacterium marinum, is the metabolic switch to lipid catabolism and altered expression of virulence genes at different stages of infection. This study aims to identify genes involved in sustaining viable intracellular infection. We applied transposon sequencing (Tn-Seq) to M. marinum, an unbiased genome-wide strategy combining saturation insertional mutagenesis and high-throughput sequencing. This approach allowed us to identify the localization and relative abundance of insertions in pools of transposon mutants. Gene essentiality and fitness cost of mutations were quantitatively compared between in vitro growth and different stages of infection in two evolutionary distinct phagocytes, the amoeba Dictyostelium discoideum and the murine BV2 microglial cells. In the M. marinum genome, 57% of TA sites were disrupted and 568 genes (10.2%) were essential, which is comparable to previous Tn-Seq studies on M. tuberculosis and M. bovis. Major pathways involved in the survival of M. marinum during infection of D. discoideum are related to DNA damage repair, lipid and vitamin metabolism, the type VII secretion system (T7SS) ESX-1, and the Mce1 lipid transport system. These pathways, except Mce1 and some glycolytic enzymes, were similarly affected in BV2 cells. These differences suggest subtly distinct nutrient availability or requirement in different host cells despite the known predominant use of lipids in both amoeba and microglial cells.IMPORTANCEThe emergence of biochemically and genetically tractable host model organisms for infection studies holds the promise to accelerate the pace of discoveries related to the evolution of innate immunity and the dissection of conserved mechanisms of cell-autonomous defenses. Here, we have used the genetically and biochemically tractable infection model system Dictyostelium discoideum/Mycobacterium marinum to apply a genome-wide transposon-sequencing experimental strategy to reveal comprehensively which mutations confer a fitness advantage or disadvantage during infection and compare these to a similar experiment performed using the murine microglial BV2 cells as host for M. marinum to identify conservation of virulence pathways between hosts.

ObjectivesThough the rise of big data in the field of occupational health offers new opportunities especially for cross-cutting research, they raise the issue of privacy and security of data, especially when linking sensitive data from the field of insurance, occupational health or compensation claims. We aimed to validate a large, blinded synthesized database developed from the CONSTANCES cohort by comparing associations between three independently selected outcomes, and various exposures.MethodsFrom the CONSTANCES cohort, a large synthetic dataset was constructed using the avatar method (Octopize) that is agnostic to the data primary or secondary data uses. Three main analyses of interest were chosen to compare associations between the raw and avatar dataset: risk of stroke (any stroke, and subtypes of stroke), risk of knee pain and limitations associated with knee pain. Logistic models were computed, and a qualitative comparison of paired odds ratio (OR) was made.ResultsBoth raw and avatar datasets included 162,434 observations and 19 relevant variables. On the 172 paired raw/avatar OR that were computed, including stratified analyses on sex, more than 77% of the comparisons had a OR difference ≤0.5 and less than 7% had a discrepancy in the statistical significance of the associations, with a Cohen's Kappa coefficient of 0.80.ConclusionsThis study shows the flexibility and the multiple usage of a synthetic database created with the avatar method in the particular field of occupational health, which can be shared in open access without risking re-identification and privacy issues and help bring new insights for complex phenomenon like return to work.

BackgroundGlenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets.Methods and patientsGARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population.ResultsBetween December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively.ConclusionsTherapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications.

Rodents are recognized as the main reservoirs of Leptospira spp. Rats, in particular, serve as hosts for the widely predominant Leptospira interrogans serovar Icterohaemorrhagiae, found worldwide. Several studies have shown the importance of other reservoirs, such as mice or hedgehogs, which harbor other leptospires' serovars. Nevertheless, our knowledge of circulating Leptospira spp. in reservoirs other than rats remains limited. In this context, we proposed an eco-health approach to assess the health hazard associated with leptospires in urban green spaces, where contacts between human/small mammals and domestic animals are likely. We studied the prevalence, the diversity of circulating strains, and epidemiology of pathogenic Leptospira species in small terrestrial mammal communities (rodents and shrews), between 2020-2022, in two parks in Lyon metropolis, France. Our study showed a significant carriage of Leptospira spp. in small terrestrial mammals in these parks and unveiled a global prevalence rate of 11.4%. Significant variations of prevalence were observed among the small mammal species (from 0 to 26.1%), with Rattus norvegicus exhibiting the highest infection levels (26.1%). We also observed strong spatio-temporal variations in Leptospira spp. circulation in its reservoirs. Prevalence seems to be higher in the peri-urban park and in autumn in 2021 and 2022. This is potentially due to differences in landscape, abiotic conditions and small mammal communities' composition. Our study suggests an important public health relevance of rats and in a lesser extent of other rodents (Apodemus spp., Clethrionomys glareolus and Mus musculus) as reservoirs of L. interrogans, with rodent species carrying specific serogroups/serovars. We also emphasize the potential hazard associated between the shrew Crocidura russula and L. kirschneri. Altogether, these results improve our knowledge about the prevalence of leptospirosis in an urban environment, which is an essential prerequisite for the implementation of prevention of associated risks.

The study aimed to investigate the chemical composition and antimicrobial and antioxidant activities of the essential oil from dried seeds of Xylopia aethiopica. The essential oil was obtained by hydrodistillation and analyzed by GC/FID and GC/MS. The essential oil yield was 1.35%. Forty-nine compounds were identified in the essential oil with 1,8-cineole (16.3%), β-pinene (14.8%), trans-pinocarveol (9.1%), myrtenol (8.3%), α-pinene (5.9%), and terpinen-4-ol (5.6%) as major components. The antimicrobial activity of this essential oil was studied using disk diffusion and broth microdilution methods on four bacteria (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa) and one fungus (Candida albicans). The essential oil exhibited excellent activity against S. aureus, E. faecalis, and C. albicans and moderate activity against E. coli. Among all strains tested, C. albicans showed the best sensitivity with a MIC of 50 mg/mL. The antioxidant activity was examined using a DPPH-free radical scavenging assay. The essential oil of X. aethiopica showed low antioxidant activity (IC50 = 784.604 ± 0.320 mg/mL) compared to that of ascorbic acid and the reference compound (IC50 = 0.163 ± 0.003 mg/mL). The results indicate that consumption of X. aethiopica seeds can reduce the virulence of food-borne pathogens and their resistance to antibiotics.

Shape vectorization is a key stage of the digitization of large-scale historical maps, especially city maps that exhibit complex and valuable details. Having access to digitized buildings, building blocks, street networks and other geographic content opens numerous new approaches for historical studies such as change tracking, morphological analysis and density estimations. In the context of the digitization of Paris atlases created in the 19th and early 20th centuries, we have designed a supervised pipeline that reliably extract closed shapes from historical maps. This pipeline is based on a supervised edge filtering stage using deep filters, and a closed shape extraction stage using a watershed transform. It relies on probable multiple suboptimal methodological choices that hamper the vectorization performances in terms of accuracy and completeness. Objectively investigating which solutions are the most adequate among the numerous possibilities is comprehensively addressed in this paper. The following contributions are subsequently introduced: (i) we propose an improved training protocol for map digitization; (ii) we introduce a joint optimization of the edge detection and shape extraction stages; (iii) we compare the performance of state-of-the-art deep edge filters with topology-preserving loss functions, including vision transformers; (iv) we evaluate the end-to-end deep learnable watershed against Meyer watershed. We subsequently design the critical path for a fully automatic extraction of key elements of historical maps. All the data, code, benchmark results are freely available at https://github.com/soduco/Benchmark_historical_map_vectorization.