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Abstract Healthcare systems are major emitters of greenhouse gases that contribute to climate change. The resulting climate crisis harms human and planetary health and increasingly impacts lives on Earth. Because of their status as high emitters and their social role in society, healthcare systems have a clear obligation to decarbonise. This study investigates how healthcare systems worldwide can lower their greenhouse gas emissions and thereby contribute to global climate action. We performed a systematic literature review, searching PubMed, GreenFILE, Business Source Complete and CINAHL for relevant empirical studies, non-research papers and grey literature published between 1 January 2018 and 28 March 2023. The Greenhouse Gas Protocol applied to healthcare systems guided thematic and descriptive analyses to explore interventions targeted at scope 1, 2 and 3 emissions. The PRISMA guidelines were followed for reporting and synthesising the results. A total of 742 publications were initially identified, 230 of which were included in the systematic literature review, comprising 96 empirical studies, 132 non-research papers and two governmental reports. Numerous conventional and unique decarbonisation actions related to healthcare have been reported in the literature. Eight themes were identified: transportation, anaesthesia, energy, travel, supply chain, clinical practices, planetary health literacy and system changes. This study shows the abundant potential for healthcare decarbonisation while highlighting key uncertainties around decarbonisation in healthcare and providing ambitious recommendations to lower emissions globally. Decarbonisation actions are needed at the personal, organisational and system levels. The health workforce is vital in driving transformative change but needs to be adequately trained and educated about the importance of low-carbon solutions in healthcare. Countries worldwide must exchange knowledge about successful decarbonisation interventions and best practices to push global progress. Looking forward, action plans and audits at the local level combined with large-scale measures and policies are needed to influence the system as a whole.

Abstract Introduction Effective diabetes management relies mainly on an individual’s ability to perform self-care tasks. However, this process is influenced by a complex interplay of factors. This study explores the multifaceted influences on Diabetes Self-Management (DSM), examining both factors influencing and affecting DSM. Understanding these influences is crucial for developing targeted Digital Health Interventions that empower individuals with diabetes to achieve successful self-management. Objectives To identify problems faced by Type 2 Diabetes Mellitus (T2DM) individuals in self-managing diabetes and leveraging mHealth technology, with need-based solutions to Empower Self-Management in T2DM. Methodology In-depth semi-structured interviews were conducted among ten patients with T2DM visiting the outpatient department of a tertiary care hospital in coastal Karnataka. Additionally, six healthcare professionals (HCPs) working closely with T2DM patients were interviewed to understand their perspectives on using mHealth to manage T2DM effectively. The themes for the solutions described were analyzed using ATLAS-TI software. Results Our research examined certain factors that might have influenced effective diabetes self-management and investigated patient perspectives on using digital health solutions in diabetes self-management. This study found that technology skills, duration of diabetes, knowledge, and personal beliefs were all significant factors affecting self-management in participants with T2DM. Additionally, socioeconomic factors were also seen to influence effective diabetes self-management. The Google search engine was used by 50% of the participants interviewed to learn about T2DM. Diet management through Google searches was used by a minority (30%) of the patients. None of the participants had previously used any mobile health applications (mHealth apps) to manage T2DM. 20% of the participants expressed limited knowledge about using smartphones or wearables to track health parameters. The study also identified potential non-technological barriers to mHealth adoption. To address these concerns, researchers used an empathy map to develop solutions that promote mHealth use. Conclusion Several challenges and need-based mHealth solutions were identified to empower diabetes self-management education among T2DM patients. Implementing need-based mHealth solutions such as data tracking, personalized feedback, and access to educational resources can lead to better disease control and a higher quality of life for those with T2DM. Further research and development in mHealth interventions, and collaborative efforts among healthcare providers, patients, and technology developers, hold a promising future for the healthcare sector in providing efficient, effective, and accessible care.

Abstract Background and Aims The use of virtual reality (VR) therapy has grown considerably, as it is effective for reducing pain and anxiety in different clinical areas. However, it has not been well evaluated for coronary angiography and angioplasty. This study aimed to compare VR therapy with pharmacological sedation (Sedation) for reducing pain in patients undergoing a planned coronary angiography or coronary/peripheral angioplasty. Methods In this prospective randomized controlled trial, patients were randomly allocated to one of two groups before catheterization: a Sedation group (injection of midazolam and fentanyl) or a VR group (Deepsen VR headset). The primary outcome measure was the maximum pain during the procedure (visual analogue scale: 0–10). The secondary outcome measures were anxiety following the procedure (Spielberger State Anxiety Inventory: 20–80), the occurrence of arterial spasm, the haemodynamic profile and patient satisfaction. Results The VR group (n = 63) had a mean pain rating of 2.5; for the Sedation group (n = 59) this was 1.0. This did not meet the criterion for non‐inferiority. Anxiety was comparable between the two groups (VR: 25.4; Sedation: 24.7), as was the occurrence of arterial spasm (VR: 7.9%; Sedation: 8.5%; p = 0.91), but blood pressure was higher in the VR group (140.2/71.7 mmHg vs. 121.8/64.7 mmHg). There were no VR‐related adverse effects, and patient satisfaction was high for both groups. Conclusions Virtual reality therapy was not non‐inferior to pharmacological sedation for reducing pain during coronary angiography or angioplasty. However, it reduced anxiety to a comparable level. Virtual reality therapy represents an alternative to pharmacological sedation, which is well accepted by patients.

Objective: Frailty has been extensively studied in end-stage kidney disease (ESKD) and kidney transplant (KT) patients. The identification of frailty is useful to predict adverse outcomes among ESKD and KT patients. The recent concept of intrinsic capacity (IC) appears as a good and easy-to-understand tool to screen for and monitor frailty in older adults with ESKD. This study aims to assess the relationships between frailty and IC in older adults with ESKD awaiting KT. Design: Cross-sectional study Setting and participants: 236 patients from a day-care geriatric unit undergoing pre-KT geriatric assessment between 2017 and 2022 were included in the main sample, and 151 patients in an independent multicentric replication sample. Measurements: Frailty was evaluated using the physical frailty phenotype (PFP) and IC measures using the World Health Organization’s screening (step 1) and diagnostic (step 2) tools for five IC domains (vitality, locomotion, audition, cognition, psychology). Multivariate regressions were run to assess relationships between PFP and IC domains, adjusted for age, sex, and comorbidities. Analyses were replicated using another independent multicenter cohort including 151 patients with ESKD to confirm the results. Results: Impairments in the locomotion, psychology, and vitality IC domains according to WHO screening tools were associated with frailty (odds ratio 9.62 [95% CI 4.09−24.99], 3.19 [95% CI 1.11–8.88], and 3.11 [95% CI 1.32–7.29], respectively). When IC were measured linearly with z-scores, all IC domains except hearing were inversely associated with frailty. In the replication cohort, results were overall similar, with a greater association between psychology domain and frailty. Conclusion: This study highlights the relationship between frailty and IC in ESKD patients. We assume that IC may be assessed and monitored in ESKD patients, to predict and prevent future frailty, and post-KT adverse outcomes.

Abstract Phthalates constitute a family of anthropogenic chemicals developed to be used in the manufacture of plastics, solvents, and personal care products. Their dispersion and accumulation in many environments can occur at all stages of their use (from synthesis to recycling). However, many phthalates together with other accumulated engineered chemicals have been shown to interfere with hormone activities. These compounds are also in close contact with microorganisms that are free-living, in biofilms or in microbiota, within multicellular organisms. Herein, the activity of several phthalates and their substitutes were investigated on the opportunistic pathogen Legionella pneumophila, an aquatic microbe that can infect humans. Beside showing the toxicity of some phthalates, data suggested that Acetyl tributyl citrate (ATBC) and DBP (Di-n-butyl phthalate) at environmental doses (i.e. 10–6 M and 10–8 M) can modulate Legionella behavior in terms of motility, biofilm formation and response to antibiotics. A dose of 10–6 M mostly induced adverse effects for the bacteria, in contrast to a dose of 10–8 M. No perturbation of virulence towards Acanthamoeba castellanii was recorded. These behavioral alterations suggest that L. pneumophila is able to sense ATBC and DBP, in a cross-talk that either mimics the response to a native ligand, or dysregulates its physiology.

Calcium signalling in the endocardium is critical for heart valve development. Calcium ion pulses in the endocardium are generated in response to mechanical forces due to blood flow and can be visualised in the beating zebrafish heart using a genetically encoded calcium indicator such as GCaMP7a. Analysing these pulses is challenging because of the rapid movement of the heart during heartbeat. This protocol outlines an imaging analysis method used to phase-match the cardiac cycle in single z-slice movies of the beating heart, allowing easy measurement of the calcium signal.

Abstract Systemic sclerosis (SSc) is an autoimmune, inflammatory and fibrotic disease with limited treatment options. Developing new therapies is therefore crucial to address patient needs. To this end, we focused on galectin-3 (Gal-3), a lectin known to be associated with several pathological processes seen in SSc. Using RNA sequencing of whole-blood samples in a cross-sectional cohort of 249 patients with SSc, Gal-3 and its interactants defined a strong transcriptomic fingerprint associated with disease severity, pulmonary and cardiac malfunctions, neutrophilia and lymphopenia. We developed new Gal-3 neutralizing monoclonal antibodies (mAb), which were then evaluated in a mouse model of hypochlorous acid (HOCl)-induced SSc. We show that two of these antibodies, D11 and E07, reduced pathological skin thickening, lung and skin collagen deposition, pulmonary macrophage content, and plasma interleukin-5 and -6 levels. Moreover, E07 changed the transcriptional profiles of HOCl-treated mice, resulting in a gene expression pattern that resembled that of control mice. Similarly, pathological pathways engaged in patients with SSc were counteracted by E07 in mice. Collectively, these findings demonstrate the translational potential of Gal-3 blockade as a therapeutic option for SSc.

Abstract Mechanosensing is a ubiquitous process to translate external mechanical stimuli into biological responses. Piezo1 ion channels are directly gated by mechanical forces and play an essential role in cellular mechanotransduction. However, readouts of Piezo1 activity are mainly examined by invasive or indirect techniques, such as electrophysiological analyses and cytosolic calcium imaging. Here, we introduce GenEPi, a genetically-encoded fluorescent reporter for non-invasive optical monitoring of Piezo1-dependent activity. We demonstrate that GenEPi has high spatiotemporal resolution for Piezo1-dependent stimuli from the single-cell level to that of the entire organism. GenEPi reveals transient, local mechanical stimuli in the plasma membrane of single cells, resolves repetitive contraction-triggered stimulation of beating cardiomyocytes within microtissues, and allows for robust and reliable monitoring of Piezo1-dependent activity in vivo. GenEPi will enable non-invasive optical monitoring of Piezo1 activity in mechanochemical feedback loops during development, homeostatic regulation, and disease.

Abstract Background Trypanosomes are protozoan parasites of vertebrates that are of medical and veterinary concern. A variety of blood-feeding invertebrates have been identified as vectors, but the role of ticks in trypanosome transmission remains unclear. Methods In this study, we undertook extensive molecular screening for the presence and genetic diversity of trypanosomes in field ticks. Results Examination of 1089 specimens belonging to 28 tick species from Europe and South America led to the identification of two new trypanosome strains. The prevalence may be as high as 4% in tick species such as the castor bean tick Ixodes ricinus, but we found no evidence of transovarial transmission. Further phylogenetic analyses based on 18S rRNA, EF1-α, hsp60 and hsp85 gene sequences revealed that different tick species, originating from different continents, often harbour phylogenetically related trypanosome strains and species. Most tick-associated trypanosomes cluster in a monophyletic clade, the Trypanosoma pestanai clade, distinct from clades of trypanosomes associated with transmission by other blood-feeding invertebrates. Conclusions These observations suggest that ticks may be specific arthropod hosts for trypanosomes of the T. pestanai clade. Phylogenetic analyses provide further evidence that ticks may transmit these trypanosomes to a diversity of mammal species (including placental and marsupial species) on most continents. Graphical Abstract

Summary: Cognitive functioning requires coordination between brain areas. Between visual areas, feedforward gamma synchronization improves behavioral performance. Here, we investigate whether similar principles hold across brain regions and frequency bands, using simultaneous electrocorticographic recordings from 15 areas of two macaque monkeys during performance of a selective attention task. Short behavioral reaction times (RTs), suggesting efficient interareal communication, occurred when occipital areas V1, V2, V4, and DP showed gamma synchronization, and fronto-central areas S1, 5, F1, F2, and F4 showed beta synchronization. For both area clusters and corresponding frequency bands, deviations from the typically observed phase relations increased RTs. Across clusters and frequency bands, good phase relations occurred in a correlated manner specifically when they processed the behaviorally relevant stimulus. Furthermore, the fronto-central cluster exerted a beta-band influence onto the occipital cluster whose strength predicted short RTs. These results suggest that local gamma and beta synchronization and their inter-regional coordination jointly improve behavioral performance.

Bacterial communication is a fundamental process used to synchronize gene expression and collective behavior among the bacterial population. The most studied bacterial communication system is quorum sensing, a cell density system, in which the concentration of inductors increases to a threshold level allowing detection by specific receptors. As a result, bacteria can change their behavior in a coordinated way. While in Pseudomonas quorum sensing based on the synthesis of N-acyl homoserine lactone molecules is well studied, volatile organic compounds, although considered to be communication signals in the rhizosphere, are understudied. The Pseudomonas fluorescens MFE01 strain has a very active type six secretion system that can kill some competitive bacteria. Furthermore, MFE01 emits numerous volatile organic compounds, including 1-undecene, which contributes to the aerial inhibition of Legionella pneumophila growth. Finally, MFE01 appears to be deprived of N-acyl homoserine lactone synthase. The main objective of this study was to explore the role of 1-undecene in the communication of MFE01. We constructed a mutant affected in undA gene encoding the enzyme responsible for 1-undecene synthesis to provide further insight into the role of 1-undecene in MFE01. First, we studied the impacts of this mutation both on volatile organic compounds emission, using headspace solid-phase microextraction combined with gas chromatography-mass spectrometry and on L. pneumophila long-range inhibition. Then, we analyzed influence of 1-undecene on MFE01 coordinated phenotypes, including type six secretion system activity and biofilm formation. Next, to test the ability of MFE01 to synthesize N-acyl homoserine lactones in our conditions, we investigated in silico the presence of corresponding genes across the MFE01 genome and we exposed its biofilms to an N-acyl homoserine lactone-degrading enzyme. Finally, we examined the effects of 1-undecene emission on MFE01 biofilm maturation and aerial communication using an original experimental set-up. This study demonstrated that the ΔundA mutant is impaired in biofilm maturation. An exposure of the ΔundA mutant to the volatile compounds emitted by MFE01 during the biofilm development restored the biofilm maturation process. These findings indicate that P. fluorescens MFE01 uses 1-undecene emission for aerial communication, reporting for the first time this volatile organic compound as bacterial intraspecific communication signal.

Objectives: We performed exhaled breath (EB) and nasopharyngeal (NP) quantitative polymerase chain reaction (qPCR) and NP rapid antigen testing (NP RAT) of SARS-CoV-2 infections with different variants. Methods: We included immuno-naïve alpha-infected (n = 11) and partly boosted omicron-infected patients (n = 8) as high-risk contacts. We compared peak NP and EB qPCR cycle time (ct) values between cohorts (Wilcoxon-Mann-Whitney test). Test positivity was compared for three infection phases using Cochran Q test. Results: Peak median NP ct was 11.5 (interquartile range [IQR] 10.1-12.1) for alpha and 12.2 (IQR 11.1-15.3) for omicron infections. Peak median EB ct was 25.2 (IQR 24.5-26.9) and 28.3 (IQR 26.4-30.8) for alpha and omicron infections, respectively. Distributions did not differ between cohorts for NP (P = 0.19) or EB (P = 0.09). SARS-CoV-2 shedding peaked on day 1 in EB (confidence interval [CI] 0.0 - 4.5) and day 3 in NP (CI 1.5 - 6.0). EB qPCR positivity equaled NP qPCR positivity on D0-D1 (P = 0.44) and D2-D6 (P = 1.0). It superseded NP RAT positivity on D0-D1 (P = 0.003) and D2-D6 (P = 0.008). It was inferior to both on D7-D10 (P < 0.001). Conclusion: Peak EB and nasopharynx shedding were comparable across variants. EB qPCR positivity matched NP qPCR and superseded NP RAT in the first week of infection.

Summary: Expansion microscopy of millimeter-large mechanically heterogeneous tissues, such as whole vertebrate embryos, has been limited, particularly when combined with post-expansion immunofluorescence. Here, we present a protocol to perform ultrastructure expansion microscopy of whole vertebrate embryos, optimized to perform post-expansion labeling. We describe steps for embedding and denaturing zebrafish larvae or mouse embryos. We then detail procedures for hydrogel handling and mounting. This protocol is particularly well suited for super-resolution imaging of macromolecular protein complexes in situ but does not preserve lipids.For complete details on the use and execution of this protocol, please refer to Steib et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

The ComFC protein is essential for natural transformation, a process that plays a major role in the spread of antibiotic resistance genes. Here the authors show that ComFC is a membrane-associated protein that participates in the transport of DNA through the cell membrane and the handling of the single-stranded DNA once delivered into the cytoplasm.

Staphylococcus aureus is a skin commensal microorganism commonly colonizing healthy humans. Nevertheless, S. aureus can also be responsible for cutaneous infections and contribute to flare-up of inflammatory skin diseases such as atopic dermatitis (AD), which is characterized by dysbiosis of the skin microbiota with S. aureus as the predominant species. However, the role of major virulence factors of this pathogen such as phenol-soluble modulin (PSM) toxins in epidermal inflammation remains poorly understood. Stimulation of primary human keratinocytes with sublytic concentrations of synthetic and purified PSM α3 resulted in upregulation of a large panel of pro-inflammatory chemokine and cytokine gene expression, including CXCL1, CXCL2, CXCL3, CXCL5, CXCL8, CCL20, IL-1α, IL-1β, IL-6, IL-36γ and TNF-α, while inducing the release of CXCL8, CCL20, TNF-α and IL-6. In addition, using S. aureus culture supernatant from mutants deleted from genes encoding either α-type PSMs or all PSM production, PSMs were shown to be the main factors of S. aureus secretome responsible for pro-inflammatory mediator induction in human keratinocytes. On the other hand, α-type PSM-containing supernatant triggered an intense induction of pro-inflammatory mediator expression and secretion during both topical and basal layer stimulation of an ex vivo model of human skin explants, a physiologically relevant model of pluristratified epidermis. Taken together, the results of this study show that PSMs and more specifically α-type PSMs are major virulence factors of S. aureus inducing a potent inflammatory response during infection of the human epidermis and could thereby contribute to AD flare-up through exacerbation of skin inflammation.

Myasthenia Gravis (MG) is a neurological autoimmune disease characterized by disabling muscle weaknesses due to anti-acetylcholine receptor (AChR) autoantibodies. To gain insight into immune dysregulation underlying early-onset AChR+ MG, we performed an in-depth analysis of peripheral mononuclear blood cells (PBMCs) using mass cytometry. PBMCs from 24 AChR+ MG patients without thymoma and 16 controls were stained with a panel of 37 antibodies. Using both unsupervised and supervised approaches, we observed a decrease in monocytes, for all subpopulations: classical, intermediate, and non-classical monocytes. In contrast, an increase in innate lymphoid cells 2 (ILC2s) and CD27- γδ T cells was observed. We further investigated the dysregulations affecting monocytes and γδ T cells in MG. We analyzed CD27- γδ T cells in PBMCs and thymic cells from AChR+ MG patients. We detected the increase in CD27- γδ T cells in thymic cells of MG patients suggesting that the inflammatory thymic environment might affect γδ T cell differentiation. To better understand changes that might affect monocytes, we analyzed RNA sequencing data from CD14+ PBMCs and showed a global decrease activity of monocytes in MG patients. Next, by flow cytometry, we especially confirmed the decrease affecting non-classical monocytes. In MG, as for other B-cell mediated autoimmune diseases, dysregulations are well known for adaptive immune cells, such as B and T cells. Here, using single-cell mass cytometry, we unraveled unexpected dysregulations for innate immune cells. If these cells are known to be crucial for host defense, our results demonstrated that they could also be involved in autoimmunity.

Introduction A variety of mobile health (mHealth) applications are available to monitor an individual’s health or lifestyle to make it convenient to access healthcare facilities at home. The usability of mHealth applications in controlling HbA1c (estimated average blood glucose) levels is unclear despite their increasing use. The burden of type 2 diabetes mellitus (T2DM) is high in low and middle-income countries (LMICs), with the highest burden in the Indian population. Our objective is to identify the effectiveness of mHealth applications in managing blood glucose levels of individuals with T2DM and to assess the impact of using mHealth applications in managing T2DM concerning health-promoting behaviour among the LMICs in the context of India.Methods and analysis The electronic databases included for search are PubMed, Ovid Medline, EBSCO, CINAHL, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials; additional sources of the search will be grey literature available on diabetes management websites and reference lists of included studies. Studies published in the English language in indexed and peer-reviewed sources will be considered. Studies reporting the effectiveness of mobile applications in the management of T2D in LMICs will be eligible for inclusion. The Population-Intervention-Comparison-Outcomes framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement 2021 will be used for reporting. Data analysis will be carried out using narrative synthesis, and a meta-analysis may be conducted if we come across homogenous data for the outcome.Ethics and dissemination As this study is a systematic review, we will not be recruiting any participants for the study and hence will not require ethical approval. The study summary will be disseminated at a conference.PROSPERO registration number CRD42021245517.

Abstract We previously showed that the physiological concentration of 17β-estradiol in the vaginal environment is sufficient to affect the membrane dynamics and adhesion phenotype of the Lactobacillus crispatus strain CIP104459. However, L. crispatus is a heterogeneous species. Here, we investigated the effect of 17β-estradiol on the recently isolated L. crispatus vaginal strain V4, related to a cluster distant from CIP104459 and at the limit of being a different subspecies. Grown in the same medium, the two strains expressed a highly similar pool of proteins. However, in contrast to CIP104459, L. crispatus V4 showed high aggregation potential and 17β-estradiol promoted this phenotype. This effect was associated with large changes in cell-surface polarity and Lewis acid/base properties. In addition, we observed no effect on the membrane dynamics, contrary to CIP104459. These results can be explained by differences in the properties and organization of the S layer between the two strains. However, as for CIP104459, 17β-estradiol increased biosurfactant production of L. crispatus V4 and their adhesion to vaginal cells. This suggests that 17β-estradiol agonists would be valuable tools to favor a stable re-implantation of L. crispatus in the vaginal mucosa.

Abstract Lactobacilli and estrogens play essential roles in vaginal homeostasis. We investigated the potential direct effect of 17β-estradiol on a vaginal strain of Lactobacillus crispatus, the major bacterial species of the vaginal microbiota. 17β-estradiol (10–6 to 10–10 M) had no effect on L. crispatus growth, but markedly affected the membrane dynamics of this bacterium. This effect appeared consistent with a signal transduction process. The surface polarity and aggregation potential of the bacterium were unaffected by exposure to 17β-estradiol, but its mean size was significantly reduced. 17β-estradiol also promoted biosurfactant production by L. crispatus and adhesion to vaginal VK2/E6E7 cells, but had little effect on bacterial biofilm formation activity. Bioinformatic analysis of L. crispatus identified a membrane lipid raft–associated stomatin/prohibitin/flotillin/HflK domain containing protein as a potential 17β-estradiol binding site. Overall, our results reveal direct effects of 17β-estradiol on L. crispatus. These effects are of potential importance in the physiology of the vaginal environment, through the promotion of lactobacillus adhesion to the mucosa and protection against pathogens.

La gestion des ressources en eau nécessite l’utilisation de données hydrométriques provenant principalement de stations in situ. Malgré les efforts déployés pour la mise en place et le maintien d’un réseau de stations (hydrométriques ou météorologiques), les gestionnaires de ressources en eau font face à de nombreux problèmes (dégradation des équipements lors des crues, vandalisme, inaccessibilité, moyens financiers pour la maintenance …). Les données satellitaires peuvent enrichir le suivi des ressources en eau, quels que soient les objectifs de ce suivi (gestion stratégique des ressources en eau, gestion des ouvrages, prévision des crues et étiages …). Ces données présentent l’avantage de couvrir à pas-de-temps régulier le monde entier, y compris des territoires difficiles d’accès. A travers plusieurs projets, différents partenaires scientifiques et industriels (IRD, CNES, CLS, CNRS, CENEAU …) ont contribué à évaluer et à valoriser l’usage des données satellitaires pour la gestion des ressources en eau à l’échelle d’un bassin-versant (e.g. l’Amazone) ou d’un territoire (l’Ouganda). L’objectif est de délivrer des indicateurs hydrologiques issus de l’association de modèles hydrologiques, de données in-situ et de données satellitaires. Cet article présente les possibilités et les limites actuelles de l’utilisation des données satellitaires afin d’optimiser le suivi des ressources en eau.

Graphical Abstract

Embryonic heart development is a mechanosensitive process, where specific fluid forces are needed for the correct development, and abnormal mechanical stimuli can lead to malformations. It is thus important to understand the nature of embryonic heart fluid forces. However, the fluid dynamical behaviour close to the embryonic endocardial surface is very sensitive to the geometry and motion dynamics of fine-scale cardiac trabecular surface structures. Here, we conducted image-based computational fluid dynamics (CFD) simulations to quantify the fluid mechanics associated with the zebrafish embryonic heart trabeculae. To capture trabecular geometric and motion details, we used a fish line that expresses fluorescence at the endocardial cell membrane, and high resolution 3D confocal microscopy. Our endocardial wall shear stress (WSS) results were found to exceed those reported in existing literature, which were estimated using myocardial rather than endocardial boundaries. By conducting simulations of single intra-trabecular spaces under varied scenarios, where the translational or deformational motions (caused by contraction) were removed, we found that a squeeze flow effect was responsible for most of the WSS magnitude in the intra-trabecular spaces, rather than the shear interaction with the flow in the main ventricular chamber. We found that trabecular structures were responsible for the high spatial variability of the magnitude and oscillatory nature of WSS, and for reducing the endocardial deformational burden. We further found cells attached to the endocardium within the intra-trabecular spaces, which were likely embryonic hemogenic cells, whose presence increased endocardial WSS. Overall, our results suggested that a complex multi-component consideration of both anatomic features and motion dynamics were needed to quantify the trabeculated embryonic heart fluid mechanics.

Abstract Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality‐of‐life of patients. Circadian‐rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold‐standard 6‐methyl‐1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.

Mutation of the TET2 DNA-hydroxymethylase has been associated with a number of immune pathologies. The disparity in phenotype and clinical presentation among these pathologies leads to questions regarding the role of TET2 mutation in promoting disease evolution in different immune cell types. Here we show that, in primary mast cells, Tet2 expression is induced in response to chronic and acute activation signals. In TET2-deficient mast cells, chronic activation via the oncogenic KITD816V allele associated with mastocytosis, selects for a specific epigenetic signature characterized by hypermethylated DNA regions (HMR) at immune response genes. H3K27ac and transcription factor binding is consistent with priming or more open chromatin at both HMR and non-HMR in proximity to immune genes in these cells, and this signature coincides with increased pathological inflammation signals. HMR are also associated with a subset of immune genes that are direct targets of TET2 and repressed in TET2-deficient cells. Repression of these genes results in immune tolerance to acute stimulation that can be rescued with vitamin C treatment or reiterated with a Tet inhibitor. Overall, our data support a model where TET2 plays a direct role in preventing immune tolerance in chronically activated mast cells, supporting TET2 as a viable target to reprogram the innate immune response for innovative therapies.

Heterodox economics may study rent from various angles. The first one is that of the source of income; the second is that of its macroeconomic impacts; the third is that of income distribution. This introduction highlights the contributions of the papers published in this issue from these three different angles. As far as it is concerned, Régulation Theory has developed a comprehensive reading of what it called the “rentier accumulation regime”, including it in the analysis of the variety of capitalism and allowing for a dialogue with development economics. In particular, it shows that institutional hierarchies co-evolve with the fluctuations of rent. The notion of rentier accumulation regime enables us to understand how some developing countries have resilient institutions despite structural weaknesses.

In the clinic, most cases of congenital heart valve defects are thought to arise through errors that occur after the endothelial-mesenchymal transition (EndoMT) stage of valve development. Although mechanical forces caused by heartbeat are essential modulators of cardiovascular development, their role in these later developmental events is poorly understood. To address this question, we used the zebrafish superior atrioventricular valve (AV) as a model. We found that cellularized cushions of the superior atrioventricular canal (AVC) morph into valve leaflets via mesenchymal-endothelial transition (MEndoT) and tissue sheet delamination. Defects in delamination result in thickened, hyperplastic valves, and reduced heart function. Mechanical, chemical, and genetic perturbation of cardiac forces showed that mechanical stimuli are important regulators of valve delamination. Mechanistically, we show that forces modulate Nfatc activity to control delamination. Together, our results establish the cellular and molecular signature of cardiac valve delamination in vivo and demonstrate the continuous regulatory role of mechanical forces and blood flow during valve formation.

Mediterranean hurricanes, or medicanes, are tropical-like cyclones forming once or twice per year over the waters of the Mediterranean Sea. These mesocyclones pose a serious threat to coastal infrastructure and lives because of their strong winds and intense rainfall. Infrasound technology has already been employed to investigate the acoustic signatures of severe weather events, and this study aims at characterizing, for the first time, the infrasound detections that can be related to medicanes. This work also contributes to infrasound source discrimination efforts in the context of the Comprehensive Nuclear-Test-Ban Treaty. We use data from the infrasound station IS48 of the International Monitoring System in Tunisia to investigate the infrasound signatures of mesocyclones using a multi-channel correlation algorithm. We discuss the detections using meteorological fields to assess the presence of stratospheric waveguides favoring propagation. We corroborate the detections by considering other datasets, such as satellite observations, a surface lightning detection network, and products mapping the simulated intensity of the swell. High- and low-frequency detections are evidenced for three medicanes at distances ranging between 250 and 1100 km from the station. Several cases of non-detection are also discussed. While deep convective systems, and mostly lightning within them, seem to be the main source of detections above 1 Hz, hotspots of swell (microbarom) related to the medicanes are evidenced between 0.1 and 0.5 Hz. In the latter case, simulations of microbarom detections are consistent with the observations. Multi-source situations are highlighted, stressing the need for more resilient detection-estimation algorithms. Cloud-to-ground lightning seems not to explain all high-frequency detections, suggesting that additional sources of electrical or dynamical origin may be at play that are related to deep convective systems.

ABSTRACT Legionella pneumophila, the causative agent of Legionnaires’ disease, is mostly found in man-made water systems and is one of the most closely monitored waterborne pathogens. With the aim of finding natural ways to control waterborne pathogens and thus further reduce the impact of disinfection by-products on human health, some studies have demonstrated the ability of bacteria to kill Legionella through the production of secondary metabolites or antimicrobial compounds. Here, we describe an unexpected growth inhibition of L. pneumophila when exposed to a physically separated strain of Pseudomonas fluorescens, designated as MFE01. Most of the members of the Legionellaceae family are sensitive to the volatile substances emitted by MFE01, unlike other bacteria tested. Using headspace solid-phase microextraction GC-MS strategy, a volatilome comparison revealed that emission of 1-undecene, 2-undecanone, and 2-tridecanone were mainly reduced in a Tn5-transposon mutant unable to inhibit at distance the growth of L. pneumophila strain Lens. We showed that 1-undecene was mainly responsible for the inhibition at distance in vitro, and led to cell lysis in small amounts, as determined by gas chromatography-mass spectrometry (GC-MS). Collectively, our results provide new insights into the mode of action of bacterial volatiles and highlight them as potent anti-Legionella agents to focus research on novel strategies to fight legionellosis. IMPORTANCE Microbial volatile compounds are molecules whose activities are increasingly attracting the attention of researchers. Indeed, they can act as key compounds in long-distance intrakingdom and interkingdom communication, but also as antimicrobials in competition and predation. In fact, most studies to date have focused on their antifungal activities and only a few have reported on their antibacterial properties. Here, we describe that 1-undecene, naturally produced by P. fluorescens, is a volatile with potent activity against bacteria of the genus Legionella. In small amounts, it is capable of inducing cell lysis even when the producing strain is physically separated from the target. This is the first time that such activity is described. This molecule could therefore constitute an efficient compound to counter bacterial pathogens whose treatment may fail, particularly in pulmonary diseases. Indeed, inhalation of these volatiles should be considered as a possible route of therapy in addition to antibiotic treatment.

Macrophages play a key role in the inflammatory phase of wound repair and foreign body reactions—two important processes in the Masquelet-induced membrane technique for extremity reconstruction. The macrophage response depends largely on the nature of the biomaterials implanted. However, little is known about the influence of the macrophage microenvironment on the osteogenic properties of the induced membrane or subsequent bone regeneration. We used metakaolin, an immunogenic material, as an alternative spacer to standard polymethylmethacrylate (PMMA) in a Masquelet model in rats. Four weeks after implantation, the PMMA- and metakaolin-induced membranes were harvested, and their osteogenic properties and macrophage microenvironments were investigated by histology, immunohistochemistry, mass spectroscopy and gene expression analysis. The metakaolin spacer induced membranes with higher levels of two potent pro-osteogenic factors, transforming growth factor-β (TGF-β) and bone morphogenic protein-2 (BMP-2). These alternative membranes thus had greater osteogenic activity, which was accompanied by a significant expansion of the total macrophage population, including both the M1-like and M2-like subtypes. Microcomputed tomographic analysis showed that metakaolin-induced membranes supported bone regeneration more effectively than PMMA-induced membranes through better callus properties (+58%), although this difference was not significant. This study provides the first evidence of the influence of the immune microenvironment on the osteogenic properties of the induced membranes.

Phthalates are used in a variety of applications—for example, as plasticizers in polyvinylchloride products to improve their flexibility—and can be easily released into the environment. In addition to being major persistent organic environmental pollutants, some phthalates are responsible for the carcinogenicity, teratogenicity, and endocrine disruption that are notably affecting steroidogenesis in mammals. Numerous studies have thus focused on deciphering their effects on mammals and eukaryotic cells. While multicellular organisms such as humans are known to display various microbiota, including all of the microorganisms that may be commensal, symbiotic, or pathogenic, few studies have aimed at investigating the relationships between phthalates and bacteria, notably regarding their effects on opportunistic pathogens and the severity of the associated pathologies. Herein, the effects of phthalates and their substitutes were investigated on the human pathogen, Pseudomonas aeruginosa, in terms of physiology, virulence, susceptibility to antibiotics, and ability to form biofilms. We show in particular that most of these compounds increased biofilm formation, while some of them enhanced the bacterial membrane fluidity and altered the bacterial morphology.

Hierarchy is a major organizational principle of the cortex and underscores modern computational theories of cortical function. The local microcircuit amplifies long-distance inter-areal input, which show distance-dependent changes in their laminar profiles. Statistical modeling of these changes in laminar profiles demonstrates that inputs from multiple hierarchical levels to their target areas show remarkable consistency, allowing the construction of a cortical hierarchy based on a principle of hierarchical distance. The statistical modeling that is applied to structure can also be applied to laminar differences in the oscillatory coherence between areas thereby determining a functional hierarchy of the cortex. Close examination of the anatomy of inter-areal connectivity reveals a dual counterstream architecture with well-defined distance-dependent feedback and feedforward pathways in both the supra- and infragranular layers, suggesting a multiplicity of feedback pathways with well-defined functional properties. These findings are consistent with feedback connections providing a generative network involved in a wide range of cognitive functions. A dynamical model constrained by connectivity data sheds insight into the experimentally observed signatures of frequency-dependent Granger causality for feedforward versus feedback signaling. Concerted experiments capitalizing on recent technical advances and combining tract-tracing, high-resolution fMRI, optogenetics and mathematical modeling hold the promise of a much improved understanding of lamina-constrained mechanisms of neural computation and cognition. However, because inter-areal interactions involve cortical layers that have been the target of important evolutionary changes in the primate lineage, these investigations will need to include human and non-human primate comparisons.

The endothelium is the cell monolayer that lines the interior of the blood vessels separating the vessel lumen where blood circulates, from the surrounding tissues. During embryonic development, endothelial cells (ECs) must ensure that a tight barrier function is maintained whilst dynamically adapting to the growing vascular tree that is being formed and remodeled. Blood circulation generates mechanical forces, such as shear stress and circumferential stretch that are directly acting on the endothelium. ECs actively respond to flow-derived mechanical cues by becoming polarized, migrating and changing neighbors, undergoing shape changes, proliferating or even leaving the tissue and changing identity. It is now accepted that coordinated changes at the single cell level drive fundamental processes governing vascular network morphogenesis such as angiogenic sprouting, network pruning, lumen formation, regulation of vessel caliber and stability or cell fate transitions. Here we summarize the cell biology and mechanics of ECs in response to flow-derived forces, discuss the latest advances made at the single cell level with particular emphasis on in vivo studies and highlight potential implications for vascular pathologies.

The thymus is involved in autoimmune Myasthenia gravis (MG) associated with anti-acetylcholine (AChR) antibodies. In MG, thymic regulatory T cells (Treg) are not efficiently suppressive, and conventional T cells (Tconv) are resistant to suppression. To better understand the specific role of the thymus in MG, we compared the phenotype and function of peripheral and thymic Treg and Tconv from controls and MG patients. Suppression assays with thymic or peripheral CD4 + T cells showed that the functional impairment in MG was more pronounced in the thymus than in the periphery. Phenotypic analysis of Treg showed a significant reduction of resting and effector Treg in the thymus but not in the periphery of MG patients. CD31, a marker lost with excessive immunoreactivity, was significantly reduced in thymic but not blood resting Treg. These results suggest that an altered thymic environment may explain Treg differences between MG patients and controls. Since thymic epithelial cells (TECs) play a major role in the generation of Treg, we co-cultured healthy thymic CD4 + T cells with control or MG TECs and tested their suppressive function. Co-culture with MG TECs consistently hampers regulatory activity, as compared with control TECs, suggesting that MG TECs contribute to the immune regulation defects of MG CD4 + T cells. MG TECs produced significantly higher thymic stromal lymphopoietin (TSLP) than control TECs, and a neutralizing anti-TSLP antibody partially restored the suppressive capacity of Treg derived from co-cultures with MG TECs, suggesting that TSLP contributed to the defect of thymic Treg in MG patients. Finally, a co-culture of MG CD4 + T cells with control TECs restored numbers and function of MG Treg, demonstrating that a favorable environment could correct the immune regulation defects of T cells in MG. Altogether, our data suggest that the severe defect of thymic Treg is at least partially due to MG TECs that overproduce TSLP. The Treg defects could be corrected by replacing dysfunctional TECs by healthy TECs. These findings highlight the role of the tissue environment on the immune regulation.

The Autophagy Lysosomal Pathway is one of the most important mechanisms for removing dysfunctional cellular components. Increasing evidence suggests that alterations in this pathway play a pathogenic role in Parkinson’s disease, making it a point of particular vulnerability. Numerous studies have proposed nanotechnologies as a promising approach for delivering active substances within the central nervous system to treat and diagnose neurodegenerative diseases. In this context, the aim was to propose the development of a new pharmaceutical technology for the treatment of neurodegenerative diseases. We designed a trehalose-based nanosystem by combining both a small natural autophagy enhancer molecule named trehalose and an amphiphilic nucleolipid conjugate. To improve nucleolipid protection and cellular uptake, these conjugates were formulated by rapid mixing in either solid lipid nanoparticles (Ø = 120.4 ± 1.4 nm) or incorporated into poly(lactic-co-glycolic acid) nanoparticles (Ø = 167.2 ± 2.4 nm). In vitro biological assays demonstrated a safe and an efficient cellular uptake associated with autophagy induction. Overall, these nucleolipid-based formulations represent a promising new pharmaceutical tool to deliver trehalose and restore the autophagy impaired function.

Abstract Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer’s disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies. Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer’s disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits. In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer’s disease.

Abstract Background Multiple RNA samples are frequently processed together and often mixed before multiplex sequencing in the same sequencing run. While different samples can be separated post sequencing using sample barcodes, the possibility of cross contamination between biological samples from different species that have been processed or sequenced in parallel has the potential to be extremely deleterious for downstream analyses. Results We present CroCo, a software package for identifying and removing such cross contaminants from assembled transcriptomes. Using multiple, recently published sequence datasets, we show that cross contamination is consistently present at varying levels in real data. Using real and simulated data, we demonstrate that CroCo detects contaminants efficiently and correctly. Using a real example from a molecular phylogenetic dataset, we show that contaminants, if not eliminated, can have a decisive, deleterious impact on downstream comparative analyses. Conclusions Cross contamination is pervasive in new and published datasets and, if undetected, can have serious deleterious effects on downstream analyses. CroCo is a database-independent, multi-platform tool, designed for ease of use, that efficiently and accurately detects and removes cross contamination in assembled transcriptomes to avoid these problems. We suggest that the use of CroCo should become a standard cleaning step when processing multiple samples for transcriptome sequencing.

Crescentic rapidly progressive glomerulonephritis is a severe form of glomerula disease characterized by podocyte proliferation and migration. Here Henique et al. demonstrate that inhibition of miRNA-92a prevents kidney failure by promoting the expression of CDK inhibitor p57Kip2 that regulates podocyte cell cycle.

Plants live in association with complex populations of microorganisms, including Plant Growth-Promoting Rhizobacteria (PGPR) that confer to plants an improved growth and enhanced stress tolerance. This large and diverse group includes endophytic bacteria that are able to colonize the internal tissues of plants. In the present study, we have isolated a nonrhizobial species from surface sterilized root nodules of Retama monosperma, a perennial leguminous species growing in poor and high salinity soils. Sequencing of its genome reveals this endophytic bacterium is a Bacillus megaterium strain (RmBm31) that possesses a wide range of genomic features linked to plant growth promotion. Furthermore, we show that RmBm31 is able to increase the biomass and positively modify the root architecture of seedlings of the model plant species Arabidopsis thaliana both in physical contact with its roots and via the production of volatile organic compounds. Lastly, we investigated the molecular mechanisms implicated in RmBm31 plant beneficial effects by carrying out a transcriptional analysis on a comprehensive set of phytohormone-responsive marker genes. Altogether, our results demonstrate that RmBm31 displays plant growth-promoting traits of potential interest for agricultural applications.

Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are important factors modulating these pathways. In addition, live reporters reveal that Piezo controls Klf2 and Notch activity in the endothelium and Yap1 localization in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

Aging is one of the strongest risk factor for Alzheimer's disease (AD). However, several data suggest that dyslipidemia can either contribute or serve as co-factors in AD appearance. AD could be examined as a metabolic disorder mediated by peripheral insulin resistance. Insulin resistance is associated with dyslipidemia, which results in increased hepatic ceramide generation. Hepatic steatosis induces pro-inflammatory cytokine activation which is mediated by the increased ceramides production. Ceramides levels increased in cells due to perturbation in sphingolipid metabolism and upregulated expression of enzymes involved in ceramide synthesis. Cytotoxic ceramides and related molecules generated in liver promote insulin resistance, traffic through the circulation due to injury or cell death caused by local liver inflammation, and because of their hydrophobic nature, they can cross the blood-brain barrier and thereby exert neurotoxic responses as reducing insulin signaling and increasing pro-inflammatory cytokines. These abnormalities propagate a cascade of neurodegeneration associated with oxidative stress and ceramide generation, which potentiate brain insulin resistance, apoptosis, myelin degeneration, and neuro-inflammation. Therefore, excess of toxic lipids generated in liver can cause neurodegeneration. Elevated homocysteine level is also a risk factor for AD pathology and is narrowly associated with metabolic diseases and non-alcoholic fatty liver disease. The existence of a homocysteine/ceramides signaling pathway suggests that homocysteine toxicity could be partly mediated by intracellular ceramide accumulation due to stimulation of ceramide synthase. In this article, we briefly examined the role of homocysteine and ceramide metabolism linking metabolic diseases and non-alcoholic fatty liver disease to AD. We therefore analyzed the expression of mainly enzymes implicated in ceramide and sphingolipid metabolism and demonstrated deregulation of de novo ceramide biosynthesis and S1P metabolism in liver and brain of hyperhomocysteinemic mice.

Lower vertebrate and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through the reprogramming of pre-existing cardiomyocytes. However, how cardiac injury initiates signaling pathways controlling this regenerative reprogramming remains to be defined. Here, we utilize in vivo biophysical and genetic fate mapping zebrafish studies to reveal that altered hemodynamic forces due to cardiac injury activate a sequential endocardial-myocardial signaling cascade to direct cardiomyocyte reprogramming and heart regeneration. Specifically, these altered forces are sensed by the endocardium through the mechanosensitive channel Trpv4 to control Klf2a transcription factor expression. Consequently, Klf2a then activates endocardial Notch signaling which results in the non-cell autonomous initiation of myocardial Erbb2 and BMP signaling to promote cardiomyocyte reprogramming and heart regeneration. Overall, these findings not only reveal how the heart senses and adaptively responds to environmental changes due to cardiac injury, but also provide insight into how flow-mediated mechanisms may regulate cardiomyocyte reprogramming and heart regeneration.