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Summary: Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT1A) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT1A from AgRP neurons causes RMR adaptation. Extracellular patch-clamp recordings identify distinct cellular responses of individual AgRP neurons from lean mice to Ang-II: no response, inhibition via AT1A and Gαi, or stimulation via Ang-II type 2 (AT2) receptors and Gαq. Following diet-induced obesity, a subset of Ang-II/AT1A-inhibited AgRP neurons undergo a spontaneous G-protein “signal switch,” whereby AT1A stop inhibiting the cell via Gαi and instead begin stimulating the cell via Gαq. DREADD-mediated activation of Gαi, but not Gαq, in AT1A-expressing AgRP cells stimulates RMR in lean and obese mice. Thus, loss of AT1A-Gαi coupling within the AT1A-expressing AgRP neuron subtype represents a molecular mechanism contributing to RMR adaptation.

Objectives Women of low socioeconomic status have been described as having suboptimal prenatal care, which in turn has been associated with poor pregnancy outcomes. Many types of conditional cash transfer (CCT) programmes have been developed, including programmes to improve prenatal care or smoking cessation during pregnancy, and their effects demonstrated. However, ethical critiques have included paternalism and lack of informed choice. Our objective was to determine if women and healthcare professionals (HPs) shared these concerns.Design Prospective qualitative research.Setting We included economically disadvantaged women, as defined by health insurance data, who participated in the French NAITRE randomised trial assessing a CCT programme during prenatal follow-up to improve pregnancy outcomes. The HP worked in some maternities participating in this trial.Participants 26 women, 14 who received CCT and 12 who did not, mostly unemployed (20/26), and - 7 HPs.Interventions We conducted a multicentre cross-sectional qualitative study among women and HPs who participated in the NAITRE Study to assess their views on CCT. The women were interviewed after childbirth.Results Women did not perceive CCT negatively. They did not mention feeling stigmatised. They described CCT as a significant source of aid for women with limited financial resources. HP described the CCT in less positive terms, for example, expressing concern about discussing cash transfer at their first medical consultation with women. Though they emphasised ethical concerns about the basis of the trial, they recognised the importance of evaluating CCT.Conclusions In France, a high-income country where prenatal follow-up is free, HPs were concerned that the CCT programme would change their relationship with patients and wondered if it was the best use of funding. However, women who received a cash incentive said they did not feel stigmatised and indicated that these payments helped them prepare for their baby’s birth.Trial registration number NCT02402855

Summary: The balance of phospho-signaling at the outer kinetochore is critical for forming accurate attachments between kinetochores and the mitotic spindle and timely exit from mitosis. A major player in determining this balance is the PP2A-B56 phosphatase, which is recruited to the kinase attachment regulatory domain (KARD) of budding uninhibited by benzimidazole 1-related 1 (BUBR1) in a phospho-dependent manner. This unleashes a rapid, switch-like phosphatase relay that reverses mitotic phosphorylation at the kinetochore, extinguishing the checkpoint and promoting anaphase. Here, we demonstrate that the C-terminal pseudokinase domain of human BUBR1 is required to promote KARD phosphorylation. Mutation or removal of the pseudokinase domain results in decreased PP2A-B56 recruitment to the outer kinetochore attenuated checkpoint silencing and errors in chromosome alignment as a result of imbalance in Aurora B activity. Our data, therefore, elucidate a function for the BUBR1 pseudokinase domain in ensuring accurate and timely exit from mitosis.

Because of poor self-healing ability, joint cartilage can undergo irreversible degradation in the course of various diseases or after injury. A promising approach for cartilage engineering consists of using of mesenchymal stem cells (MSC) and a differentiation factor combined with an injectable carrier biomaterial. We describe here a novel synthesis route for native collagen microspheres that does not involve the use of potentially toxic crosslinking agents. An emulsion was formed between a type I collagen solution and perfluorinated oil, stabilised by a biocompatible triblock perfluorinated copolymer surfactant. Spherical microparticles of fibrillar collagen were formed through a sol-gel transition induced by ammonia vapours. Electron microscopy observations showed that these self-cross-linked microspheres were constituted by a gel of striated collagen fibrils. Microspheres that were loaded with transforming growth factor beta (TGF-β)3 progressively released this differentiation factor over a four weeks period. Human MSC rapidly adhered to TGF-β3-loaded microspheres and, after 21 d of culture, exhibited typical chondrocyte morphology and produced an uncalcified matrix made of the predominant cartilage components, aggrecan and type II collagen, but devoid of the hypertrophic marker type X collagen. Subcutaneous co-injection of MSC and TGF-β3-loaded microspheres in mice consistently led to the formation of a cartilage-like tissue, which was however hypertrophic, calcified and vascularised. In conclusion, we developed cross-linker free collagen microspheres that allowed chondrogenic differentiation of MSC in vitro and in vivo.

Achieving target coverage levels for mass drug administration (MDA) is essential to elimination and control efforts for several neglected tropical diseases (NTD). To ensure program goals are met, coverage reported by drug distributors may be validated through household coverage surveys that rely on respondent recall. This is the first study to assess accuracy in such surveys.Recall accuracy was tested in a series of coverage surveys conducted at 1, 6, and 12 months after an integrated MDA in Togo during which three drugs (albendazole, ivermectin, and praziquantel) were distributed. Drug distribution was observed during the MDA to ensure accurate recording of persons treated during the MDA. Information was obtained for 506, 1131, and 947 persons surveyed at 1, 6, and 12 months, respectively. Coverage (defined as the percentage of persons taking at least one of the MDA medications) within these groups was respectively 88.3%, 87.4%, and 80.0%, according to the treatment registers; it was 87.9%, 91.4% and 89.4%, according to survey responses. Concordance between respondents and registers on swallowing at least one pill was >95% at 1 month and >86% at 12 months; the lower concordance at 12 months was more likely due to difficulty matching survey respondents with the year-old treatment register rather than inaccurate responses. Respondents generally distinguished between pills similar in appearance; concordance for recall of which pills were taken was over 80% in each survey.In this population, coverage surveys provided remarkably consistent coverage estimates for up to one year following an integrated MDA. It is not clear if similar consistency will be seen in other settings, however, these data suggest that in some settings coverage surveys might be conducted as much as one year following an MDA without compromising results. This might enable integration of post-MDA coverage measurement into large, multipurpose, periodic surveys, thereby conserving resources.

The anatomical distribution of PACAP-like immunoreactivity was investigated in sensory and peripheral organs of the zebrafish, Danio rerio, during the pharyngula, hatching and larval periods, by using indirect immunofluorescence methods. First PACAP-like immunoreactive (ir) elements appeared during the pharyngula period, at 24 hours post fertilization (hpf), within the most superficial layer of the retina and the dorsal aorta. At 48 hpf, additional ir cells were found in the olfactory placode and esophagus. At 72 hpf (hatching period), PACAP-like immunoreactivity was first detected in the ganglion cell layer of the retina, the otic sensory epithelium, pharyngeal arches, swim bladder and pancreatic progenitor cells. During day 5 of larval development, new groups of ir cells appeared in the liver, whereas no ir elements were observed in the olfactory placode. Subsequently, at day 13 of larval development, additional ir elements were found for the first time in some gut epithelial cells while those previously observed in the retina and otic sensory epithelium were absent. The transient expression of PACAP-like ir material in sensory organs suggests that the peptide could be implicated in neurotrophic activities and neurosensorial connections in the migration and/or differentiation processes. The appearance of PACAP-like ir elements in peripheral organs at different developmental stages, indicates that this peptide could be involved in the control of more specific functions as soon as these peripheral structures begin to operate.

This article, titled "DES SOLUTIONS D'ICI POUR FAIRE FACE À L'ÉBULLITION CLIMATIQUE," provides a comprehensive overview of various solutions to address the challenges posed by climate change. It highlights inspiring and relevant examples of improvements that can be made to enhance the climate resilience of both urban and rural environments. The article also explores plausible climate scenarios for the end of the century, emphasizing the investments required to ensure the health and safety of populations and ecosystems. It acknowledges the increasing frequency and intensity of extreme weather events, such as ice storms, floods, wildfires, and heatwaves, which have become the new normal in Quebec. Additionally, it discusses less tangible but equally harmful phenomena, including erosion, invasive species, and soil and water acidification. The article concludes by presenting innovative solutions to reduce Quebec's greenhouse gas emissions. It emphasizes the need for a multisectoral approach to address the dual challenges of the climate crisis and biodiversity protection. The article is part of the mission of Réseau Environnement, an organization that aims to guide public policies and address the climate crisis. The article also mentions the upcoming Quebec Environmental Technologies Exhibition (STEQ) in April 2024, which will showcase promising environmental innovations. The article encourages the sharing and implementation of these solutions to mitigate the effects of climate change and promote climate adaptation within communities. [Extracted from the article]

Screening patients for the possibility of sleep apnoea, one of the most common forms of sleep-disordered breathing, requires measurement of respiration. We propose a simple method to estimate the amplitude modulation of a respiratory tidal volume, using a semi-quantitative measure of respiration based on thoracic impedance (TI). Because respiratory volume changes may be accommodated by varying displacements of the rib cage (RC) and abdomen (AB), the latter produced by outward motion of the diaphragm, it is necessary for any useful measure of respiration to be closely related to both RC and AB displacements. Because the relative contributions of RC and AB displacements to respiratory tidal volume vary in different body positions, the present measurements were recorded from subjects in supine, and right and left lateral decubitus postures. We observed a clear linear relationship between TI and both RC and AB signals in all three body positions. There were no statistically significant differences between observed relationships between TI and AB and between TI and RC, and these relationships were independent of the body position. TI sensors appear to be a useful candidate for a simple method of screening for sleep apnoea, especially in a cardiology clinical setting. Further investigation is warranted for the refinement of algorithms to detect changes in amplitude modulation occurring with apnoeas and to remove artefacts due to gross body movements. [ABSTRACT FROM AUTHOR]

Abstract  Germins and germin-like proteins (GLPs) are members of a superfamily of proteins widely distributed in plants. Their localization within the extracellular matrix and in some cases their hydrogen peroxide-producing activity suggests that these proteins are involved in cell wall metabolism during stress responses and developmental processes. Several very highly conserved conifer GLPs have been identified in somatic embryo tissues. In order to gain more knowledge on their potential involvement in the development of this particular tissue, we have characterized a new GLP gene, LmGER1 in hybrid larch. Anti-GLP immunserum and in-gel activity analyses suggested the presence of superoxide dismutase activity in apoplastic proteins from larch somatic embryos. These results could indicate a possible role for LmGER1 in this physiological process. The expression of LmGER1 has been followed during the maturation of somatic embryos and in different organs of young plantlets by homologous transformation with a promoter-gus construct. This promoter was activated in the root cap of young embryos and, later on, in the cotyledons and in the vascular procambium and xylem. Furthermore, the importance of this gene in embryo development was evaluated by transforming embryonal masses with a gene construct encoding a hairpin RNA leading to gene silencing. The potential role of LmGER1 in cross-linking of cell wall components is discussed. [ABSTRACT FROM AUTHOR]

We prove that a unital surjective spectral isometry between von Neumann algebras one of which is of type I is a Jordan isomorphism. This is based on a study of some hereditary properties of spectral isometries. [ABSTRACT FROM AUTHOR]

Refining the role of apex predators in marine food webs is a necessary step in predicting the consequences of their global decline under the footprint of fishing activities. White sharks (Carcharodon carcharias) are vulnerable predators, performing large migrations and able to forage on a variety of prey in different habitats. In the Northeast Pacific, juvenile and adult white sharks are found seasonally at the same aggregation sites, such as Guadalupe Island off Mexico. While adults are thought to target local pinniped colonies, very few predator-prey interactions have been documented and the diet of juveniles in this area remains poorly understood. Here we used carbon/nitrogen stable isotopes and fatty acids to characterize the trophic ecology of white sharks at Guadalupe Island. In contrast to the ontogenetic trophic shift paradigm, we detected no influence of size on muscle stable isotope and fatty acid composition, revealing no significant dietary variation between juvenile and adult sharks. Stable isotopes did not allow definitive conclusions to be drawn regarding the diet of white sharks at Guadalupe Island, due to significant variability in the contribution of different potential prey depending on the trophic discrimination factors used. However, most sharks were rich in polyunsaturated fatty acids (such as long-chain omega 3), suggesting a local diet of mainly pelagic prey (potentially large fish or cephalopods). A few individuals appeared to show recent consumption of pinnipeds, with higher proportions of saturated and monounsaturated fatty acids. These individual differences in fatty acid composition could reflect an ecological trade-off between consumption of prey rich in fat (marine mammals) versus prey rich in polyunsaturated fatty acids (pelagic prey), respectively meeting the energetic and physiological needs of white sharks. Although ontogenetic trophic changes were not able to be discerned, our results provide new insights into the physiological drivers of predator-prey interactions, which can benefit the definition of conservation strategies in a changing ocean., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sarcopenia is a devastating disease for older adults, but it lacks accessible and reliable tools for measuring total appendicular skeletal muscle mass (ASMM). Two-dimensional muscle ultrasound (US) has been developed for its bedside clinical advantages and feasibility but lacks standardization and prediction performance. We previously validated a new 3D-US technique to measure muscle volume (MV) at bedside and applied it in a geriatric rehabilitation setting. Objectives were to analyse the concordance between 3D-US MV and ASMM and compare concordance between 3D-US MV and 2D-US parameters with ASMM., Methods: Participants were recruited in a Geriatric rehabilitation ward in Nantes, France, from May to October 2022. Exclusion criteria were as follows: oedema in the lower limbs or recent history of unilateral lower limb damage or stroke. ASMM was measured with bioelectrical impedance analysis; 3D-US and 2D-US acquisitions were performed on three muscles of the right lower limb. Measures of strength (hand grip, knee extension and ankle dorsiflexion) were also recorded. Reliability of 3D-US MV measurements on 10 participants was high (ICC = 0.99). We used Lin's concordance correlation coefficients (CCC) and bias correction factor for agreement between variables and linear regression models for prediction equations., Results: Fifty-eight participants had an interpretable ASMM of whom 17 (29%) had a diagnosis of sarcopenia. Volumes of TA, RF and VL were all significantly concordant with ASMM measured by BIA (all p values < 0.001), with CCCs respectively of 0.72, 0.61 and 0.60. MV were all significantly concordant with isometric strength (p values < 0.001). Concordance and correlation with ASMM were higher with 3D-US than 2D-US measurements regardless of the muscle. Prediction of ASMM reached an adjusted R 2 of 0.8 with tibialis anterior volume, biometrics and 2D measurements., Conclusions: This study was the first to use 3D-US in a geriatric setting and develop a model to predict ASMM in very old hospitalized patients. MV measurements with 3D-US proved to be reliable and more concordant with appendicular muscle mass and strength than 2D parameters., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Human land-use intensification threatens arthropod (for example, insect and spider) biodiversity across aquatic and terrestrial ecosystems. Insects and spiders play critical roles in ecosystems by accumulating and synthesizing organic nutrients such as polyunsaturated fatty acids (PUFAs). However, links between biodiversity and nutrient content of insect and spider communities have yet to be quantified. We relate insect and spider richness to biomass and PUFA-mass from stream and terrestrial communities encompassing nine land uses. PUFA-mass and biomass relate positively to biodiversity across ecosystems. In terrestrial systems, human-dominated areas have lower biomass and PUFA-mass than more natural areas, even at equivalent levels of richness. Aquatic ecosystems have consistently higher PUFA-mass than terrestrial ecosystems. Our findings reinforce the importance of conserving biodiversity and highlight the distinctive benefits of aquatic biodiversity.

Background/aims: Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings., Methods: We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8 + T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts., Results: We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8 + T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice., Conclusion: ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response via STING activation., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Background: Despite many efforts to provide children with legal existence over the last decades, 1 in 4 children under the age of 5 (166 million) do not officially exist, with limited possibility to enjoy their human rights. In Latin America and the Caribbean, Haiti has one of the highest rates of undocumented births. This study aimed to analyze the prevalence and the determinant factors of undocumented childhood in Haiti., Methods: For analysis of undocumented childhood and related socioeconomic determinants, data from the 2016/17 Haiti demographic and health survey were used. The prevalence and the associated factors were analyzed using descriptive statistics and the binary logistic regression model., Results: The prevalence of undocumented childhood in Haiti was 23% (95% CI: 21.9-24.0) among children under-five. Among the drivers of undocumented births, mothers with no formal education (aOR = 3.88; 95% CI 2.21-6.81), children aged less than 1 year (aOR = 20.47; 95% CI 16.83-24.89), children adopted or in foster care (aOR = 2.66; 95% CI 1.67-4.24), children from the poorest regions like "Artibonite" (aOR = 2.19; 95% CI 1.63-2.94) or "Centre" (aOR = 1.51; 95% CI 1.09-2.10) or "Nord-Ouest" (aOR = 1.61; 95% CI 1.11-2.34), children from poorest households (aOR = 6.25; 95% CI 4.37-8.93), and children whose mothers were dead (aOR = 2.45; 95% CI 1.33-4.49) had higher odds to be undocumented., Conclusion: According to our findings, there is an institutional necessity to bring birth documentation to underprivileged households, particularly those in the poorest regions where socioeconomic development programs are also needed. Interventions should focus on uneducated mothers who are reknown for giving birth outside of medical facilities. Therefore, an awareness campaign should be implemented to influence the children late-registering behavior., (© 2024. The Author(s).)

Abstract: Reliability of muscle thickness assessed in B-mode ultrasound has been confirmed in adults but remains a less direct assessment of muscle mass than muscle volume (MV). The aim of this prospective monocentric study was to assess the interday reliability of MV determined by the 2D-panoramic ultrasound in older hospitalized patients.Ten participants hospitalized in geriatric ward (mean age = 84) underwent 2 sessions of panoramic ultrasound scanning 1 week apart for MV assessment and DXA for leg lean mass (LLM) assessment when it was possible. The interday reliability of MV assessed using the intraclass correlation coefficient (ICC) was excellent, whatever was the muscle analyzed: ICC = 0.99 for tibialis anterior; ICC = 0.99 for vastus lateralis; ICC = 1 for rectus femoris. The pilot analysis of its association with leg lean mass revealed a good association between the vastus lateralis MV and LLM, but this needs to be confirmed on a larger number of participants (Pearson correlation coefficient = 0.91, P = 0.03).The 2D-panoramic ultrasound system for the determination of MV was reliable in older hospitalized patients with measurements performed on the patient's bed. MV seemed to be more correlated to LLM than muscle thickness. Future research will need to reduce the data processing time maybe with automation of data measurement., Competing Interests: Disclosure: All authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Over the past decade, the Amazon basin has faced numerous infectious epidemics. Our comprehension of the actual extent of these infections during pregnancy remains limited. This study aimed to clarify the clinical and epidemiological features of emerging and re-emerging infectious diseases during pregnancy in western French Guiana and along the Maroni River over the previous nine years., Methods: This retrospective cohort study enrolled pregnant women living in west French Guiana territory and giving birth in the only local referral center after 22 weeks of gestation between 2013 and 2021. Data on symptomatic or asymptomatic biologically confirmed emerging or re-emerging diseases during pregnancy was collected., Results: Six epidemic waves were experienced during the study period, including 498 confirmed Zika virus infections (2016), 363 SARS-CoV-2 infections (2020-2021), 87 chikungunya virus infections (2014), 76 syphilis infections (2013-2021), and 60 dengue virus infections (2013-2021) at different gestational ages. Furthermore, 1.1% (n = 287) and 1.4% (n = 350) of pregnant women in west French Guiana were living with HIV and HTLV, respectively. During the study period, at least 5.5% (n = 1,371) faced an emerging or re-emerging infection during pregnancy., Conclusion: These results highlight the diversity, abundance, and dynamism of emerging and re-emerging infectious agents faced by pregnant women in the Amazon basin. Considering the maternal and neonatal adverse outcomes associated with these infections, increased efforts are required to enhance diagnosis, reporting, and treatment of these conditions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Single particle analysis from cryogenic transmission electron microscopy (cryo-EM) is particularly attractive for complexes for which structure prediction remains intractable, such as antibody-antigen complexes. Here we obtain the detailed structure of a particularly difficult complex between human epidermal growth factor receptor 2 (HER2) and the antigen-binding fragments from two distinct therapeutic antibodies binding to distant parts of the flexible HER2, pertuzumab and trastuzumab (HTP). We highlight the strengths and limitations of current data processing software in dealing with various kinds of heterogeneities, particularly continuous conformational heterogeneity, and in describing the motions that can be extracted from our dataset. Our HTP structure provides a more detailed view than the one previously available for this ternary complex. This allowed us to pinpoint a previously overlooked loop in domain IV that may be involved both in binding of trastuzumab and in HER2 dimerization. This finding may contribute to explain the synergistic anticancer effect of the two antibodies. We further propose that the flexibility of the HTP complex, beyond the difficulties it causes for cryo-EM analysis, actually reflects regulation of HER2 signaling and its inhibition by therapeutic antibodies. Notably we obtain our best data with ultra-thin continuous carbon grids, showing that with current cameras their use to alleviate particle misdistribution is compatible with a protein complex of only 162 kDa. Perhaps most importantly, we provide here a dataset for such a smallish protein complex for further development of software accounting for continuous conformational heterogeneity in cryo-EM images., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Environmental and behavioral factors are responsible for 12.6 million deaths annually and contribute to 25% of deaths and chronic diseases worldwide. Through the One Health initiative, the World Health Organization and other international health organizations plan to improve these indicators to create healthier environments by 2030. To meet this challenge, training primary care professionals should be the priority of national policies. General practitioners (GPs) are ready to become involved but need in-depth training to gain and apply environmental health (EH) knowledge to their practice. In response, we designed the Primary Care Environment and Health (PCEH) online course in partnership with the Occitanie Regional Health Agency in France. This course was used to train GP residents from the Montpelier-Nimes Faculty of Medicine in EH knowledge. The course was organized in 2 successive parts: (1) an asynchronous e-learning modular course focusing on EH knowledge and tools and (2) 1 day of face-to-face sessions., Objective: This study assessed the impact of the e-learning component of the PCEH course on participants' satisfaction, knowledge, and behavior changes toward EH., Methods: This was a pilot before-and-after study. Four modules were available in the 6-hour e-learning course: introduction to EH, population-based approach (mapping tools and resources), clinical cases, and communication tools. From August to September 2021, we recruited first-year GP residents from the University of Montpellier (N=130). Participants' satisfaction, knowledge improvements for 19 EH risks, procedure to report EH risks to health authorities online, and behavior change (to consider the possible effects of the environment on their own and their patients' health) were assessed using self-reported questionnaires on a Likert scale (1-5). Paired Student t tests and the McNemar χ 2 test were used to compare quantitative and qualitative variables, respectively, before and after the course., Results: A total of 74 GP residents completed the e-learning and answered the pre- and posttest questionnaires. The mean satisfaction score was 4.0 (SD 0.9) out of 5. Knowledge scores of EH risks increased significantly after the e-learning course, with a mean difference of 30% (P<.001) for all items. Behavioral scores improved significantly by 18% for the participant's health and by 26% for patients' health (P<.001). These improvements did not vary significantly according to participant characteristics (eg, sex, children, place of work)., Conclusions: The e-learning course improved knowledge and behavior related to EH. Further studies are needed to assess the impact of the PCEH course on clinical practice and potential benefits for patients. This course was designed to serve as a knowledge base that could be reused each year with a view toward sustainability. This course will integrate new modules and will be adapted to the evolution of EH status indicators and target population needs., (©Jean-Baptiste Tostain, Marina Mathieu, Agnès Oude Engberink, Bernard Clary, Michel Amouyal, Béatrice Lognos, Pascal Demoly, Isabella Annesi-Maesano, Grégory Ninot, Nicolas Molinari, Arnaud Richard, Maha Badreddine, Claire Duflos, Francois Carbonnel. Originally published in JMIR Formative Research (https://formative.jmir.org), 09.05.2024.)

Cell migration is controlled by the coordinated action of cell adhesion, cytoskeletal dynamics, contractility and cell extrinsic cues. Integrins are the main adhesion receptors to ligands of the extracellular matrix (ECM), linking the actin cytoskeleton to the ECM and enabling cells to sense matrix rigidity and mount a directional cell migration response to stiffness gradients. Most models studied show preferred migration of single cells or cell clusters towards increasing rigidity. This is referred to as durotaxis, and since its initial discovery in 2000, technical advances and elegant computational models have provided molecular level details of stiffness sensing in cell migration. However, modeling has long predicted that, depending on cell intrinsic factors, such as the balance of cell adhesion molecules (clutches) and the motor proteins pulling on them, cells might also prefer adhesion to intermediate rigidity. Recently, experimental evidence has supported this notion and demonstrated the ability of cells to migrate towards lower rigidity, in a process called negative durotaxis. In this Review, we discuss the significant conceptual advances that have been made in our appreciation of cell plasticity and context dependency in stiffness-guided directional cell migration., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Introduction: Return to Sport tests with functional hop tests are often used to decide when a person is ready to return to sport after an anterior cruciate ligament (ACL) injury. Poor movement quality, such as knee valgus, hip adduction and hip internal rotation is considered a risk factor for ACL injury. However, it is unclear whether existing tests adequately cover the aspect of movement quality. This study aims to investigate whether there is a relationship between the calculated limb symmetry index (LSI) of hop tests as an indication of performance and the total score of the "Quality First" assessment (movement quality). The second aim is to examine the reliability of the newly developed "Quality First" assessment for evaluating movement quality in hop tests., Methods: The cross-sectional study recruited 34 patients with an ACL reconstruction. The vertical hop, single-leg hop for distance, and side hop tests were performed and recorded. The video recordings were assessed using the "Quality First" assessment. The Spearman correlation coefficient was calculated using the LSI and the "Quality First" total score. Intraclass correlation coefficients (ICC) and standard error of measurements (SEM) were used to calculate intra- and interrater reliability. In addition, the minimal detectable change (MDC) was determined., Results: The correlation test between the LSI and the "Quality First" total score showed no correlation for all three jumps ( r  = -0.1-0.02/ p -value = 0.65-0.93). The interrater reliability of the "Quality First" assessment showed fair to good reliability (ICC 2 : 0.45-0.60), with SEM ranging from 1.46 to 1.73 and the MDC from 4.06 to 4.8. Intrarater reliability was good to excellent (ICC 3 : 0.73-0.85), with SEM values ranging from 0.89 to 1.09 and the MDC from 2.47 to 3.01., Conclusion: The quality of movement, measured with the "Quality First" assessment, indicated no correlation with the calculated LSI from jump performance, therefore movement quality should also be examined in Return to Sport tests. The "Quality First" assessment shows fair to good reliability when used by different raters. When used multiple times by the same rater, the assessment has good to excellent reliability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Weber, Müller, Mathieu-Kälin, Caminada, Häberli and Baur.)

Dysregulated lipid metabolism contributes to neurodegenerative pathologies and neurological decline in lysosomal storage disorders as well as more common neurodegenerative diseases. Niemann-Pick type A (NPA) is a fatal neurodegenerative lysosomal storage disease characterized by abnormal sphingomyelin accumulation in the endolysosomal lumen. The ability to monitor abnormalities in lipid homeostasis intracranially could improve basic investigations and the development of effective treatment strategies. We investigated the carbon nanotube-based detection of intracranial lipid content. We found that the near-infrared emission of a carbon nanotube-based lipid sensor responds to lipid accumulation in neuronal and in vivo models of NPA. The nanosensor detected lipid accumulation intracranially in an acid sphingomyelinase knockout mouse via noninvasive near-infrared spectroscopy. This work indicates a tool to improve drug development processes in NPA, other lysosomal storage diseases, and neurodegenerative diseases.

Purpose: To determine the mechanisms involved in partial volume radiation therapy (RT)-induced tumor response., Methods and Materials: We investigated 67NR murine orthotopic breast tumors in Balb/c mice and Lewis lung carcinoma (LLC cells; WT, Crispr/Cas9 Sting KO, and Atm KO) injected in the flank of C57Bl/6, cGAS, or STING KO mice. RT was delivered to 50% or 100% of the tumor volume using a 2 × 2 cm collimator on a microirradiator allowing precise irradiation. Tumors and blood were collected at 6, 24, and 48 hours post-RT and assessed for cytokine measurements., Results: There is a significant activation of the cGAS/STING pathway in the hemi-irradiated tumors compared with control and to 100% exposed 67NR tumors. In the LLC model, we determined that an ATM-mediated noncanonical activation of STING is involved. We demonstrated that the partial exposure RT-mediated immune response is dependent on ATM activation in the tumor cells and on the STING activation in the host, and cGAS is dispensable. Our results also indicate that partial volume RT stimulates a proinflammatory cytokine response compared with the anti-inflammatory profile induced by 100% tumor volume exposure., Conclusions: Partial volume RT induces an antitumor response by activating STING, which stimulates a specific cytokine signature as part of the immune response. However, the mechanism of this STING activation, via the canonical cGAS/STING pathway or a noncanonical ATM-driven pathway, depends on the tumor type. Identifying the upstream pathways responsible for STING activation in the partial RT-mediated immune response in different tumor types would improve this therapy and its potential combination with immune checkpoint blockade and other antitumor therapies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Fibro-adipogenic progenitors (FAPs) are resident mesenchymal stromal cells (MSCs) of skeletal muscle. They play a crucial role in muscle homeostasis and regeneration through their paracrine activity. Recent technological advances in single-cell RNA sequencing have allowed the characterization of the heterogeneity within this cell population. In this article, we will present the different subpopulations of FAPs under basal, injury, or degenerative conditions, as well as their associated functions in mice and humans. We will then discuss the potential extramuscular origin of a post-injury FAP population. Indeed, our recent work demonstrates that MSCs from adipose tissue, infiltrating the muscle, could contribute to FAP heterogeneity., (© 2023 médecine/sciences – Inserm.)

Objective: The aim of this study was to describe different causes and consequences of fever during pregnancy in Western French Guiana and along the Maroni River., Study Design: A retrospective single-center study including all patients with a history of documented fever ≥ 38°C during pregnancy at the West French Guiana Hospital for 9 years. Postpartum fever and nosocomial infections were excluded. We focused on medical history and on clinical and biological findings. Causes were characterized as confirmed or uncertain and then classified as preventable or non-preventable., Results: A total of 940 pregnant women who experienced at least one episode of fever were included and compared to 23,811 deliveries who occurred during the same period without documented fever. Among them, 43.7% (411/940) were in labor. About 3.7% (35/940) of febrile pregnant women had at least two episodes of fever, while 0.3% (3/940) had a coinfection at the time of diagnosis, resulting in a total of 978 febrile episodes. Among them, causes remained unknown or uncertain in 7.6% (75/978) and 0.9% (9/978) of cases, respectively. Among confirmed causes of fever throughout pregnancy (n = 483), the most common known cause was arbovirus infection (146/483, 30.2%), followed by urinary tract infection (134/483, 27.7%), chickenpox (27/483, 5.6%), and gastrointestinal (14/483, 2.9%) and pulmonary infections (10/483, 2%). Mothers with fever had a higher risk of cesarean section (19.8% vs 15.5%, aOR 1.3 [95% CI 1.14-1.6], stillbirth (5.5% versus 1.9%, aOR 2.7 [95% CI 2-3.7]), and preterm delivery < 34 weeks of gestation (7.2% vs 4.7%, aOR 1.5 [95% CI 1.2-2]., Conclusions: In the Amazon region, causes of fever are diverse and often associated with epidemic waves, notably arboviruses. This must be considered when exploring possible causes of fever during pregnancy in these localities, including fetal anomalies and/or fetal loss. Physicians should consider the epidemiological context and avoid generalizations. Given the impact of emergent agents such as arboviruses on pregnancy, particular attention must be paid to the epidemiological context. This study can also help clinicians when managing fever in pregnant travelers or in their partner after having visited exposed areas. In this context, fetal abnormalities and adverse obstetric outcomes should be explored accordingly., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hcini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Atrial fibrillation (AF) is the most common sustained heart arrhythmia in adults. Holter monitoring, a long-term 2-lead electrocardiogram (ECG), is a key tool available to cardiologists for AF diagnosis. Machine learning (ML) and deep learning (DL) models have shown great capacity to automatically detect AF in ECG and their use as medical decision support tool is growing. Training these models rely on a few open and annotated databases. We present a new Holter monitoring database from patients with paroxysmal AF with 167 records from 152 patients, acquired from an outpatient cardiology clinic from 2006 to 2017 in Belgium. AF episodes were manually annotated and reviewed by an expert cardiologist and a specialist cardiac nurse. Records last from 19 hours up to 95 hours, divided into 24-hour files. In total, it represents 24 million seconds of annotated Holter monitoring, sampled at 200 Hz. This dataset aims at expanding the available options for researchers and offers a valuable resource for advancing ML and DL use in the field of cardiac arrhythmia diagnosis., (© 2023. Springer Nature Limited.)

In clinical research and care, information notices are too often reduced to complicated and hard-to-understand mandatory documents. However, every person has the right to transparent and truthful information. These considerations prompted the creation of a multidisciplinary working group in the fall of 2020, headed by the College des relecteurs de l'Inserm. This group associates the different actors involved in the development, evaluation and use of information notices: Health and research professionals, representatives of patient associations or research foundations, ethicists, jurists, scientific educators and communicators. This group has created a set of texts, pictograms and illustrations, adapted to the people concerned and accepted by all actors. These contents will be easily used by professionals through the app Notice infobox© . A pilot phase was conducted to generate the notices of the France Genomic Medicine Plan 2025, used for genetic examinations. This app Notice infobox© is a response to society's request to be an actor in its own healthcare and to adopt more ethical and responsible research., (© 2023 médecine/sciences – Inserm.)

Introduction: Current approaches fail to adequately identify sport readiness after anterior cruciate ligament (ACL) rehabilitation. Altered landing biomechanics after ACL reconstruction are associated with increased risk of a noncontact ACL reinjury. There is a lack of objective factors to screen for deficient movement patterns. Therefore, the aim of this study was to investigate content validity, interpretability, and internal consistency for the newly developed "Quality First" assessment to evaluate movement quality during hop tests in patients after ACL rehabilitation., Method: Participants in this cross-sectional study were recruited in collaboration with the Altius Swiss Sportmed Center in Rheinfelden, Switzerland. After a successful ACL reconstruction, the movement quality of 50 hop test batteries was evaluated between 6 and 24 months postoperatively with the "Quality First" assessment. Content validity was assessed from the perspective of professionals. To check the interpretability, classical test theory was employed. Cronbach's α was calculated to evaluate internal consistency., Results: Content validity resulted in the inclusion of three different hop tests (single-leg hop for distance, vertical hop, and side hop). The "Quality First" assessment is enabled to evaluate movement quality in the sagittal, vertical, and the transversal plane. After the exclusion process, the "Quality First" assessment was free from floor and ceiling effects and obtained a sufficient Cronbach's α . The final version consists of 15 items, rated on a 4-point scale., Discussion: By means of further validations, the "Quality First" assessment could offer a possibility to evaluate movement quality after ACL rehabilitation during hop tests., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Mathieu-Kälin, Müller, Weber, Caminada, Häberli and Baur.)

Multi-specific antibodies (msAbs) are being developed as next generation antibody-based therapeutics. Knowledge of the three-dimensional structures, in the full antibody context, of their fragment antigen-binding (Fab) moieties with or without bound antigens is key to elucidating their therapeutic efficiency and stability. However, the flexibility of msAbs, a feature essential for their multi specificity, has hindered efforts in this direction. Cross-Over Dual Variable immunoglobulin (CODV Ig ) is a promising bispecific antibody format, designed to simultaneously target the interleukins IL4 and IL13. In this work we present the biophysical and structural characterisation of a CODV Fab :IL13 complex in the full antibody context, using cryo-electron microscopy at an overall resolution of 4.2 Å. Unlike the 1:2 stoichiometry previously observed for CODV Ig :IL4, CODV Ig :IL13 shows a 1:1 stoichiometry. As well as providing details of the IL13-CODV binding interface, including the residues involved in the epitope-paratope region, the structure of CODV Fab :IL13 also validates the use of labelling antibody as a new strategy for the single particle cryo-EM study of msAbs in complex with one, or more, antigens. This strategy reduced the inherent flexibility of the IL13 binding domain of CODV without inducing either structural changes at the epitope level or steric hindrance between the IL4 and IL13 binding regions of CODV Ig . The work presented here thus also contributes to the development of methodology for the structural study of msAbs, a promising platform for cancer immunotherapy., (© 2023. The Author(s).)

Objective: Cartilage, as the majority of adult mammalian tissues, has limited regeneration capacity. Cartilage degradation consecutive to joint injury or aging then leads to irreversible joint damage and diseases. In contrast, several vertebrate species such as the zebrafish have the remarkable capacity to spontaneously regenerate skeletal structures after severe injuries. The objective of our study was to test the regenerative capacity of Meckel's cartilage (MC) upon mechanical injury in zebrafish and to identify the mechanisms underlying this process. Methods and Results: Cartilage regenerative capacity in zebrafish larvae was investigated after mechanical injuries of the lower jaw MC in TgBAC(col2a1a:mCherry) , to visualize the loss and recovery of cartilage. Confocal analysis revealed the formation of new chondrocytes and complete regeneration of MC at 14 days post-injury (dpi) via chondrocyte cell cycle re-entry and proliferation of pre-existing MC chondrocytes near the wound. Through expression analyses, we showed an increase of nrg1 expression in the regenerating lower jaw, which also expresses Nrg1 receptors, ErbB3 and ErbB2. Pharmacological inhibition of the ErbB pathway and specific knockdown of Nrg1 affected MC regeneration indicating the pivotal role of this pathway for cartilage regeneration. Finally, addition of exogenous NRG1 in an in vitro model of osteoarthritic (OA)-like chondrocytes induced by IL1β suggests that Nrg1/ErbB pathway is functional in mammalian chondrocytes and alleviates the increased expression of catabolic markers characteristic of OA-like chondrocytes. Conclusion: Our results show that the Nrg1/ErbB pathway is required for spontaneous cartilage regeneration in zebrafish and is of interest to design new therapeutic approaches to promote cartilage regeneration in mammals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sapède, Bahraoui, Abou Nassif, Barthelaix, Mathieu, Jorgensen and Djouad.)

High temperature increases energy demand in ectotherms, limiting their physiological capability to cope with hypoxic events. The present study aimed to assess the metabolic tolerance of juvenile Nodipecten subnodosus scallops to acute hyperthermia combined with moderate hypoxia. A previous study showed that juveniles exhibited a high upper temperature limit (32 °C), but the responses of juveniles to combined hyperthermia and low dissolved oxygen are unknown. Scallops were exposed to control conditions (treatment C: 22 °C, ∼7.1 mg O 2 L -1 or PO 2 156.9 mmHg), acute hyperthermia under normoxia (treatment T: 30 °C, ∼6.0 mg O 2 L -1 or PO 2 150.9 mmHg) or acute hyperthermia plus hypoxia (treatment TH: 30 °C, ∼2.5 mg O 2 L -1 or PO 2 62.5 mmHg) for 18 h. In T, juveniles exhibited an enhanced oxygen consumption, together with a decrease in adenylate energy charge (AEC) and arginine phosphate (ArgP), and with no changes in metabolic enzyme activity in the muscle. In TH, scallops maintained similar AEC and ArgP levels in muscle as those observed in T treatment. This response occurred along with the accumulation of inosine monophosphate and hypoxanthine. Besides, reduced citrate synthase and pyruvate kinase activities, enhanced hexokinase activity, and a higher octopine dehydrogenase/lactate dehydrogenase ratio in the mantle indicated the onset of anaerobiosis in TH. These responses indicate that juvenile scallops showed tissue-specific compensatory responses regarding their energy balance under moderate hypoxia at high temperatures. Our results give an insight into the tolerance limit of this species to combined hyperthermia and hypoxia in its northern limit of distribution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We aimed to describe the epidemiology of intrauterine fetal deaths in multiethnic western French Guiana and to assess its main causes and risk factors., Study Design: A retrospective descriptive study was conducted based on data from January 2016 to December 2021. All information on stillbirth with a gestational age ≥20 weeks in the Western French Guiana Hospital Center was extracted. Terminations of pregnancy were excluded. We focused on medical history, clinical investigation, biological findings, placental histology, and autopsy examination to elucidate the cause of death. We used the Initial Cause of Fetal Death (INCODE) classification system for assessment. Univariable and multivariable logistic regression analyses were performed., Results: Overall, 331 fetuses in 318 stillbirth deliveries were reviewed and compared to live births that occurred during the same period. The rate of fetal death varied between 1.3 % and 2.1 %, with an average of 1.8 % over the 6-year period. Poor antenatal care (104/318, 32.7 %), obesity ≥30 kg/m 2 (88/318, 31.7 %), and preeclampsia (59/318, 18.5 %) were the main risk factors associated with fetal death in this group. Four hypertensive crises were reported. According to the INCODE classification, the main causes of fetal death were obstetric complications (112/331, 33.8 %), particularly intrapartum fetal death with labor-associated asphyxia under 26 weeks (64/112, 57.1 %), and placental abruption (29/112, 25.9 %). Maternal-fetal infections were common, particularly mosquito-borne diseases (e.g., Zika virus, dengue, and malaria), re-emerging infectious agents such as syphilis, and severe maternal infections (8/331, 2.4 %). 19.3 % of fetal deaths (64/331) remained unexplained., Conclusion: Change in lifestyle as well as social deprivation and isolation adversely affect pregnancy in western French Guiana, in the context of a poor health care system that is similar to what is found in the Amazonian basin. Particular attention must be paid to emerging infectious agents in pregnant women and travelers returning from the Amazon region., Competing Interests: The authors report no declarations of interest., (© 2023 The Authors.)

Fibro-adipogenic progenitors (FAPs) play a crucial role in skeletal muscle regeneration, as they generate a favorable niche that allows satellite cells to perform efficient muscle regeneration. After muscle injury, FAP content increases rapidly within the injured muscle, the origin of which has been attributed to their proliferation within the muscle itself. However, recent single-cell RNAseq approaches have revealed phenotype and functional heterogeneity in FAPs, raising the question of how this differentiation of regenerative subtypes occurs. Here we report that FAP-like cells residing in subcutaneous adipose tissue (ScAT), the adipose stromal cells (ASCs), are rapidly released from ScAT in response to muscle injury. Additionally, we find that released ASCs infiltrate the damaged muscle, via a platelet-dependent mechanism and thus contribute to the FAP heterogeneity. Moreover, we show that either blocking ASCs infiltration or removing ASCs tissue source impair muscle regeneration. Collectively, our data reveal that ScAT is an unsuspected physiological reservoir of regenerative cells that support skeletal muscle regeneration, underlining a beneficial relationship between muscle and fat., (© 2023. The Author(s).)

The physiological dependence of animals on dietary intake of vitamins, amino acids, and fatty acids is ubiquitous. Sharp differences in the availability of these vital dietary biomolecules among different resources mean that consumers must adopt a range of strategies to meet their physiological needs. We review the emerging work on omega-3 long-chain polyunsaturated fatty acids, focusing predominantly on predator-prey interactions, to illustrate that trade-off between capacities to consume resources rich in vital biomolecules and internal synthesis capacity drives differences in phenotype and fitness of consumers. This can then feedback to impact ecosystem functioning. We outline how focus on vital dietary biomolecules in eco-eco-devo dynamics can improve our understanding of anthropogenic changes across multiple levels of biological organization., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Fishponds, despite being globally abundant, have mainly been considered as food production sites and have received little scientific attention in terms of their ecological contributions to the surrounding terrestrial environment. Emergent insects from fishponds may be important contributors of lipids and essential fatty acids to terrestrial ecosystems. In this field study, we investigated nine eutrophic fishponds in Austria from June to September 2020 to examine how Chlorophyll- a concentrations affect the biomass of emergent insect taxa (i.e., quantity of dietary subsidies; n  = 108) and their total lipid and long-chain polyunsaturated fatty acid content (LC-PUFA, i.e., quality of dietary subsidies; n  = 94). Chironomidae and Chaoboridae were the most abundant emergent insect taxa, followed by Trichoptera, Ephemeroptera, and Odonata. A total of 1068 kg of emergent insect dry mass were exported from these ponds (65.3 hectares). Chironomidae alone exported 103 kg of total lipids and 9.4 kg of omega-3 PUFA. Increasing Chl- a concentrations were associated with decreasing biomass export and a decrease in total lipid and LC-PUFA export via emergent Chironomidae. The PUFA composition of emergent insect taxa differed significantly from dietary algae, suggesting selective PUFA retention by insects. The export of insect biomass from these eutrophic carp ponds was higher than that previously reported from oligotrophic lakes. However, lower biomass and diversity are exported from the fishponds compared to managed ponds. Nonetheless, our data suggest that fishponds provide crucial ecosystem services to terrestrial consumers by contributing essential dietary nutrients to consumer diets via emergent insects., Supplementary Information: The online version contains supplementary material available at 10.1007/s10750-022-05040-2., Competing Interests: Conflict of interestThe authors have no potential conflict of interest., (© The Author(s) 2022.)

Delineating the precise regions on an antigen that are targeted by antibodies has become a key step for the development of antibody therapeutics. X-ray crystallography and cryogenic electron microscopy are considered the gold standard for providing precise information about these binding sites at atomic resolution. However, they are labor-intensive and a successful outcome is not guaranteed. We used deep mutational scanning (DMS) of the human LAMP-1 antigen displayed on yeast surface and leveraged next-generation sequencing to observe the effect of individual mutants on the binding of two LAMP-1 antibodies and to determine their functional epitopes on LAMP-1. Fine-tuned epitope mapping by DMS approaches is augmented by knowledge of experimental antigen structure. As human LAMP-1 structure has not yet been solved, we used the AlphaFold predicted structure of the full-length protein to combine with DMS data and ultimately finely map antibody epitopes. The accuracy of this method was confirmed by comparing the results to the co-crystal structure of one of the two antibodies with a LAMP-1 luminal domain. Finally, we used AlphaFold models of non-human LAMP-1 to understand the lack of mAb cross-reactivity. While both epitopes in the murine form exhibit multiple mutations in comparison to human LAMP-1, only one and two mutations in the Macaca form suffice to hinder the recognition by mAb B and A, respectively. Altogether, this study promotes a new application of AlphaFold to speed up precision mapping of antibody-antigen interactions and consequently accelerate antibody engineering for optimization.

In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Cervicofacial cellulitis is mainly due to neglected oral/pharyngeal diseases. Untreated or incorrectly treated, they can be complicated by thoraco-cervical necrosis, which has a gloomy prognosis and is difficult to manage, especially in an under-medicalized environment. The aim of this work was to report the difficulties of management in precarious context by underlining the interest of primary prevention., Patients and Method: This was a descriptive cross-sectional retrospective study from January 2018 to March., Results: Fifty cases of thoracic-cervical necrosis were collected during this period. The man/woman sex ratio was 3.55. Dental etiology was found in 96% of cases. The main complications were: pneumopathy (n = 10), mediastinitis (n = 10), pleurisy (n = 3) and polyseritis (n = 2). The management combined medical and surgical treatment under local or general anesthesia. The mortality rate was 12.8%. The functional results were satisfactory in surviving cases., Conclusion: The management of thoracic-cervical necrosis remains a challenge in precarious conditions. Primary must play a major role in these conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest in relation to this article., (Copyright © 2022. Published by Elsevier Masson SAS.)

How cells sense tissue stiffness to guide cell migration is a fundamental question in development, fibrosis and cancer. Although durotaxis-cell migration towards increasing substrate stiffness-is well established, it remains unknown whether individual cells can migrate towards softer environments. Here, using microfabricated stiffness gradients, we describe the directed migration of U-251MG glioma cells towards less stiff regions. This 'negative durotaxis' does not coincide with changes in canonical mechanosensitive signalling or actomyosin contractility. Instead, as predicted by the motor-clutch-based model, migration occurs towards areas of 'optimal stiffness', where cells can generate maximal traction. In agreement with this model, negative durotaxis is selectively disrupted and even reversed by the partial inhibition of actomyosin contractility. Conversely, positive durotaxis can be switched to negative by lowering the optimal stiffness by the downregulation of talin-a key clutch component. Our results identify the molecular mechanism driving context-dependent positive or negative durotaxis, determined by a cell's contractile and adhesive machinery., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Membrane proteins, including ion channels, receptors and transporters, are often composed of multiple subunits and can form large complexes. Their specific composition in native tissues is difficult to determine and remains largely unknown. In this study, we developed a method for determining the subunit composition of endogenous cell surface protein complexes from isolated native tissues. Our method relies on nanobody-based sensors, which enable proximity detection between subunits in time-resolved Förster resonance energy transfer (FRET) measurements. Additionally, given conformation-specific nanobodies, the activation of these complexes can be recorded in native brain tissue. Applied to the metabotropic glutamate receptors in different brain regions, this approach revealed the clear existence of functional metabotropic glutamate (mGlu)2-mGlu4 heterodimers in addition to mGlu2 and mGlu4 homodimers. Strikingly, the mGlu4 subunits appear to be mainly heterodimers in the brain. Overall, these versatile biosensors can determine the presence and activity of endogenous membrane proteins in native tissues with high fidelity and convenience., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)