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Mice irradiated and reconstituted with hematopoietic cells lacking manganese superoxide dismutase (SOD2) show a persistent hemolytic anemia similar to human sideroblastic anemia (SA), including characteristic intra-mitochondrial iron deposition. SA is primarily an acquired, clonal marrow disorder occurring in individuals over 60 years of age with uncertain etiology.To define early events in the pathogenesis of this murine model of SA, we compared erythroid differentiation of Sod2⁻/⁻ and normal bone marrow cells using flow cytometry and gene expression profiling of erythroblasts. The predominant transcriptional differences observed include widespread down-regulation of mitochondrial metabolic pathways and mitochondrial biogenesis. Multiple nuclear encoded subunits of complexes I-IV of the electron transport chain, ATP synthase (complex V), TCA cycle and mitochondrial ribosomal proteins were coordinately down-regulated in Sod2⁻/⁻ erythroblasts. Despite iron accumulation within mitochondria, we found increased expression of transferrin receptor, Tfrc, at both the transcript and protein level in SOD2 deficient cells, suggesting deregulation of iron delivery. Interestingly, there was decreased expression of ABCb7, the gene responsible for X-linked hereditary SA with ataxia, a component required for iron-sulfur cluster biogenesis.These results indicate that in erythroblasts, mitochondrial oxidative stress reduces expression of multiple nuclear genes encoding components of the respiratory chain, TCA cycle and mitochondrial protein synthesis. An additional target of particular relevance for SA is iron:sulfur cluster biosynthesis. By decreasing transcription of components of cluster synthesis machinery, both iron utilization and regulation of iron uptake are impacted, contributing to the sideroblastic phenotype.

La solidité bancaire traduit une situation dans laquelle le fonctionnement des différentes composantes du système bancaire et surtout leurs relations réciproques, sont assurées de manière saine et sans perturbations majeures. Cet article se propose d’analyser la solidité financière des banques commerciales en RDC. Les banques commerciales retenues dans le cadre de notre travail ont un ratio de liquidité conforme aux exigences de la BCC. La principale ressource des banques est constituée des dépôts à court terme.

Abstract The standard cosmological model, based on Cold Dark Matter and Dark Energy ( $$\varLambda $$ Λ CDM), faces several challenges. Among these is the need to adjust the scenario to account for the presence of vast voids in the large-scale structure of the universe, as well as the early formation of the first stars and galaxies. Additionally, the observed matter–antimatter asymmetry in the universe remains an unresolved issue. To address this latter question, Andrei Sakharov proposed a twin universe model in 1967. Building upon this idea and introducing interactions between these two universe sheets through a bimetric model, we propose an alternative interpretation of the large-scale structure of the universe, including its voids and the acceleration of cosmic expansion.

Abstract The brain constantly uses prior knowledge of the statistics of its environment to shape perception. These statistics are often implicit (not directly observable) and learned incrementally from observation, but they can also be explicitly communicated to the observer, especially in humans. Here, we show that priors are used differently in human perceptual inference depending on whether they are explicit or implicit in the environment. Bayesian modeling of learning and perception revealed that the weight of the sensory likelihood in perceptual decisions was highly correlated across participants between tasks with implicit and explicit priors, and slightly stronger in the implicit task. By contrast, the weight of priors was much less correlated across tasks, and it was markedly smaller for explicit priors. The model comparison also showed that different computations underpinned perceptual decisions depending on the origin of the priors. This dissociation may resolve previously conflicting results about the appropriate use of priors in human perception.

Abstract Domestication – the artificial selection of wild species to obtain variants with traits of human interest – was integral to the rise of complex societies. The oversupply of food was probably associated with the formalization of food preservation strategies through microbial fermentation. While considerable literature exists on the antiquity of fermented food, only few eukaryotic microbes have been studied so far for signs of domestication, less is known for bacteria. Here, we tested if cheese starter cultures harbour typical hallmarks of domestication by characterising over 100 community samples and over 100 individual strains isolated from historical and modern traditional Swiss cheese starter cultures. We find that cheese starter cultures have low genetic diversity both at the species and strain-level and maintained stable phenotypic traits. Molecular clock dating further suggests that the evolutionary origin of the bacteria approximately coincided with the first archaeological records of cheese making. Finally, we find evidence for ongoing genome decay and pseudogenization via transposon insertion related to a reduction of their niche breadth. Future work documenting the prevalence of these hallmarks across diverse fermented food systems and geographic regions will be key to unveiling the joint history of humanity with fermented food microbes.

Abstract Monitoring tumor evolution and predicting survival using non-invasive liquid biopsy is an unmet need for glioblastoma patients. The era of proteomics and metabolomics blood analyzes, may help in this context. A case–control study was conducted. Patients were included in the GLIOPLAK trial (ClinicalTrials.gov Identifier: NCT02617745), a prospective bicentric study conducted between November 2015 and December 2022. Patients underwent biopsy alone and received radiotherapy and temozolomide. Blood samples were collected at three different time points: before and after concomitant radiochemotherapy, and at the time of tumor progression. Plasma samples from patients and controls were analyzed using metabolomics and proteomics, generating 371 omics features. Descriptive, differential, and predictive analyses were performed to assess the relationship between plasma omics feature levels and patient outcome. Diagnostic performance and longitudinal variations were also analyzed. The study included 67 subjects (34 patients and 33 controls). A significant differential expression of metabolites and proteins between patients and controls was observed. Predictive models using omics features showed high accuracy in distinguishing patients from controls. Longitudinal analysis revealed temporal variations in a few omics features including CD22, CXCL13, EGF, IL6, GZMH, KLK4, and TNFRSP6B. Survival analysis identified 77 omics features significantly associated with OS, with ERBB2 and ITGAV consistently linked to OS at all timepoints. Pathway analysis revealed dynamic oncogenic pathways involved in glioblastoma progression. This study provides insights into the potential of plasma omics features as biomarkers for glioblastoma diagnosis, progression and overall survival. Clinical implication should now be explored in dedicated prospective trials.

Abstract The flexion relaxation phenomenon (FRP) is characterized by the reduction of paraspinal muscle activity at maximum trunk flexion. FRP is reported to be altered (persistence of spinal muscle activity) in more than half of nonspecific chronic low back pain (NSCLBP) patients. Little is known about how the multi-segmental spine affects FRP. The aim of this observational study was to investigate the relationship between FRP and kinematic parameters of the multi-segmental spine in NSCLBP patients. Forty NSCLBP patients and thirty-five asymptomatic participants performed a standing maximal trunk flexion task. Surface electromyography was recorded along the erector spinae longissimus. The kinematics of the spine were assessed using a 3D motion analysis system. The investigated spinal segments were upper thoracic, lower thoracic, thoracolumbar, upper lumbar, lower lumbar, and lumbopelvic. Upper lumbar ROM, anterior sagittal inclination of the upper lumbar relative to the lower lumbar in the upright position, and ROM of the upper lumbar relative to the lower lumbar during full trunk flexion were significantly correlated with the flexion relaxation ratio (Rho 0.42 to 0.58, p

Abstract Landscape fragmentation is statistically correlated with both increases and decreases in wildfire burned area (BA). These different directions-of-impact are not mechanistically understood. Here, road density, a land fragmentation proxy, is implemented in a CMIP6 coupled land-fire model, to represent fragmentation edge effects on fire-relevant environmental variables. Fragmentation caused modelled BA changes of over ±10% in 16% of [0.5°] grid-cells. On average, more fragmentation decreased net BA globally (−1.5%), as estimated empirically. However, in recently-deforested tropical areas, fragmentation drove observationally-consistent BA increases of over 20%. Globally, fragmentation-driven fire BA decreased with increasing population density, but was a hump-shaped function of it in forests. In some areas, fragmentation-driven decreases in BA occurred alongside higher-intensity fires, suggesting the decoupling of fire severity traits. This mechanistic model provides a starting point for quantifying policy-relevant fragmentation-fire impacts, whose results suggest future forest degradation may shift fragmentation from net global fire inhibitor to net fire driver.

Abstract Contagious diseases are a major threat to societies in which individuals live in close contact. Social insects have evolved collective defense behaviors, such as social care or isolation of infected workers, that prevent outbreaks of pathogens. It has thus been suggested that individual immunity is reduced in species with such ‘social immunity’. However, this hypothesis has not been tested functionally. Here, we characterize the immune response of the ant Lasius niger using a combination of genomic analysis, experimental infections, gene expression quantification, behavioural observations and pathogen quantifications. We uncover a striking specialization of immune responses towards different pathogens. Systemic individual immunity is effective against opportunistic bacterial infections, which are not covered by social immunity, but is not elicited upon fungal infections, which are effectively controlled by social immunity. This specialization suggests that immune layers have evolved complementary functions predicted to ensure the most cost-effective response against a wide range of pathogens.

Abstract Candida parapsilosis is an opportunistic fungal pathogen commonly isolated from the environment and associated with nosocomial infection outbreaks worldwide. We describe here the construction of a large collection of gene disruptions, greatly increasing the molecular tools available for probing gene function in C. parapsilosis. We use these to identify transcription factors associated with multiple metabolic pathways, and in particular to dissect the network regulating the assimilation of sulphur. We find that, unlike in other yeasts and filamentous fungi, the transcription factor Met4 is not the main regulator of methionine synthesis. In C. parapsilosis, assimilation of inorganic sulphur (sulphate) and synthesis of cysteine and methionine is regulated by Met28, a paralog of Met4, whereas Met4 regulates expression of a wide array of transporters and enzymes involved in the assimilation of organosulfur compounds. Analysis of transcription factor binding sites suggests that Met4 is recruited by the DNA-binding protein Met32, and Met28 is recruited by Cbf1. Despite having different target genes, Met4 and Met28 have partial functional overlap, possibly because Met4 can contribute to assimilation of inorganic sulphur in the absence of Met28.

Kodamaea ohmeri is an emerging and opportunistic yeast associated with a high mortality rate in humans. As it is commonly found in the environment, it is possible that environmental conditions and agricultural practices contribute to the adaptation of this yeast and the selection of antifungal resistance. During a multicentric study in Brazil, conducted under a One Health perspective, 14 isolates of K. ohmeri were identified from different sources: three from blood cultures, three from animals (swine and poultry), and eight from animal environments (swine and poultry). Yeasts were isolated using CHROmagar® Candida medium and identified by MALDI-TOF MS and ITS rDNA barcoding. Minimum inhibitory concentration (MIC) was determined using the broth microdilution method for clinical (azoles, echinocandins, pyrimidine analogs, and polyenes), and environmental antifungals (tebuconazole, pyraclostrobin, carbendazim, and mancozeb), and hospital disinfectants (quaternary ammonium compounds). Of note, color variations of K. ohmeri were noted on CHROmagar® depending on the incubation time, which is likely to complicate its identification. Following polyphasic identification and taxonomic confirmation, all isolates demonstrated low MIC values for clinical antifungals, disinfectants, and tebuconazole. However, all isolates were able to grow in the presence of carbendazim, mancozeb, and pyraclostrobin. Together, these findings highlight the risks associated with the use of environmental azoles, such as tebuconazole, as they may impact non-target fungi of medical importance, but other fungicides do not present the same risk. This is the first study to demonstrate that K. ohmeri, an important emerging yeast in human medicine, can be isolated from various sources, including patients. Although the isolates exhibited low MIC values for clinical antifungals, it is crucial to monitor changes in sensitivity patterns over time in emerging microorganisms to prevent the development of multidrug resistance, which may originate in the environment.

Abstract Multiple myeloma (MM) is a chronic hematologic malignancy that remains incurable, because most patients eventually relapse or become refractory to current treatments. MM is a major health problem, with a globally increasing incidence. While, increase in the choice of MM treatment, including new immunotherapies (bispecific monoclonal antibodies and chimeric antigen receptor (CAR)-T cell therapy), may allow to further improve MM patients’ outcomes, some non-therapy-related key issues may represent a pre-requisite towards improving MM outcomes in the next few years. This includes, the necessity of real-world evidence data, of a better definition of frailty, of a dynamic disease risk assessment, of a better definition of high-risk disease, broader accessibility to novel drugs, and to ensure diversity and representation of underrepresented groups. These key issues will be discussed in the current perspective review.

Intestinal microsporidiosis caused by Enterocytozoon bieneusi is an opportunistic infection that especially affects solid organ transplant (SOT) recipients. Management revolves around tapering the immunosuppressive regimen and/or using a specific anti-microsporidia treatment, but only fumagillin has demonstrated efficacy for treatment of this infection. Since fumagillin has been commercially discontinued, nitazoxanide is increasingly being used in this indication. We aimed to describe therapeutic management of E. bieneusi infections in this context. We conducted a French nationwide observational retrospective study on reported cases of E. bieneusi infections in SOT recipients. We identified 154 cases: 64 (41.6%) were managed by simply modifying the immunosuppressive regimen, 54 (35.1%) were given fumagillin, and 36 (23.4%) were given nitazoxanide. Clinical remission rate ranged from 77.8% to 90.7% and was not significantly different between therapeutic strategies but tended to be lower with nitazoxanide. Stool negativization rate was highest with fumagillin (91.7%) and lowest with nitazoxanide (28.6%). Relapses occurred in 6.9% of cases and were more frequent with nitazoxanide (14.3%). This study shows that tapering immunosuppression can result in a satisfactory remission rate but is sometimes accompanied by relapses. Nitazoxanide had limited effectiveness, whereas fumagillin had good results that provide a solid rationale for bringing fumagillin back to market.Trial Registration NumberClinicalTrials.gov ID: NCT05417815.

Since 2001, the Moderate Resolution Imaging Spectroradiometer (MODIS) sensor on board the Aqua and Terra platforms has made great strides in providing information on global burned areas (BA). However, the MODIS mission is nearing its end. The Visible Infrared Imaging Radiometer Suite (VIIRS) sensors, presented as the MODIS Aqua heritage, could be an excellent alternative to ensure the temporal continuity of this information at a moderate resolution. This paper describes and evaluates the effectiveness of our developed hybrid algorithm, which utilizes VIIRS reflectance and active fire products on the Google Earth Engine platform, in producing efficient information about BA. The study investigates the algorithm's performance in sub-Saharan Africa as the region of interest in 2019, using biweekly outputs and a spatial resolution of 250 m. The algorithm encompasses several steps, including pre-processing individual scenes, creating cloud-free composites, generating binary reference data for burned and non-burned areas, conducting a supervised classification using random forest, and performing region shaping. The VIIRS-BA final product, which includes three confidence levels (low, moderate, and high) known as the uncertainty layer, is compared to four other burned area products. The validation is conducted against 27 reference sampling units from the Sentinel-2 Burned Area Reference Database dataset, allowing for a comprehensive uncertainty assessment across five various biomes. The VIIRS-BA product identified 5.1 million km2 of BA, which was significantly larger than other global coarse resolution BA products such as FireCCI51, FireCCIS310, and MCD64A1 and close to the fine resolution FireCCISFD20 with a difference of 7.3%. The differences were less significant in biomes such as “Tropical Savannas” and “Temperate Grasslands” which are characterized by persistent biomass burning. Based on a stratified random sampling, the validation results demonstrate varying levels of accuracy for the VIIRS-BA product across different confidence levels. The commission error (CE) ranges from 7.8% to 23.4%, while the omission error (OE) falls between 29.4% and 58.8%. Notably, there is a significant reduction in OE (ranging from 40.7% to 50.5%) compared to global BA products like FireCCI51, FireCCIS310, and MCD64A1. When compared to VIIRS-BA, the FireCCISFD20 regional product has a 37% better OE performance. While VIIRS-BA shows great potential in detecting fires that global products miss, the VIIRS-BA with low confidence level tends to overestimate BA in regions with high fire activity. To address this, future versions of the algorithm will integrate the updated VIIRS reflectance data alongside VIIRS active fire from the National Oceanic and Atmospheric Administration to reduce CE and improve understanding spatial patterns.

Although brought to the forefront in the 1980s with the AIDS pandemic, microsporidia infecting humans are still little known. Enterocytozoon bieneusi, by far the most frequent microsporidia species causing diseases in humans, is responsible for intestinal illness in both non- and immunocompromised patients. This species presents an astonishing genetic diversity with more than 500 genotypes described, some of which have a strong zoonotic potential. Indeed, E. bieneusi infects a broad array of hosts, from wild to domestic animals. This emerging eukaryotic pathogen has thus been associated with foodborne/waterborne outbreaks. Several molecular assays have been developed to enhance its diagnosis or for epidemiological purposes, providing valuable new data. Here, we propose an overview of the current knowledge on this major species among the microsporidia, so far rather neglected in human medicine.

Various stakeholders, such as modelers, policy makers, farmers, and environmental regulators need reliable soil bulk density and coarse fragment content data. These two soil parameters are necessary to calculate soil carbon and nutrients stocks, to estimate water availability for plants, or to assess soil compaction. However, measuring these two parameters is labor intensive and time consuming. Therefore, many agricultural and environmental studies often miss these two soil parameters. Here, we provide four datasets, one with bulk density and coarse fragment contents of topsoil and subsoil, measured in two campaigns of the French Soil Quality Monitoring Network (RMQS for its acronym in French), a second one with the average values for bulk density and coarse fragments of the two campaigns at 0–30 cm and 30–50 cm. The third and the fourth ones are the raw data needed to calculate the two first datasets divided by campaign. In addition, the R script for calculating the depth-weighted values per soil layer is provided

Summary: Background: Mucormycosis is a deadly invasive fungal infection recently included in the WHO priority pathogen list. Here we sought to describe epidemiological trends of mucormycosis in France, and to evaluate factors associated with mortality. Methods: From 2012 to 2022, we implemented a nationwide prospective surveillance programme for mucormycosis in France, focusing on epidemiology, species, seasonal variations. Factors associated with 3-month mortality were studied by univariable and multivariable logistic regression. Findings: Among 550 cases of mucormycosis, the main underlying conditions were haematological malignancy (HM, 65.1%, 358/550), trauma (8%, 44/550), diabetes (7.5%, 41/550) and solid-organ transplants (6.5%, 36/550). Site of infection was pulmonary in 52.4% (288/550), rhinocerebral in 14.5% (80/550), and cutaneo-articular in 17.1% (94/550). Main species identified were Rhizopus arrhizus (21%, 67/316), Rhizopus microsporus (13.6%, 43/316), Lichtheimia corymbifera and Mucor circinelloides (13.3%, 42/316 each), Rhizomucor pusillus (12%, 38/316), and Lichtheimia ramosa (10.8%, 34/316). We found associations between underlying condition, site of infection, and infecting species, including a previously undescribed triad of trauma, cutaneo-articular localisations, and L. ramosa/M. circinelloides. Diagnostic contribution of Polymerase Chain Reaction (PCR) increased from 16% (4/25) in 2012 to 91% (61/67) in 2022, with more than 50% of diagnoses relying solely on PCR in 2022. We also found seasonal variations with relatively more cases in autumn. Ninety-day mortality was 55.8% (276/495). Independent prognostic factors were age, diagnosis in Intensive Care Unit (ICU), and HM while diagnosis after 2015 (i.e. large implementation of PCR) and surgery were associated with reduced mortality. Interpretation: This study reveals major mucormycosis epidemiological changes in France, with a large predominance of HM patients, and a parallel between PCR multicentre implementation and improved prognosis. We also evidence new associations between species, localisations and risk factors, as well as seasonal variations. Funding: Recurrent financial support from Santé Publique France and Institut Pasteur.

Societal Impact Statement Vanilla is one of the most valuable spices in the world. In Madagascar and La Réunion, the world's leading producers, vanilla is of great economic and cultural importance. Like all orchids, vanilla plants associate with mycorrhizal fungi in their roots forming mutualistic associations that allow them to grow and thrive. Understanding the diversity of mycorrhizal fungi adapted to vanilla cultivation, particularly in the Indian Ocean islands where they have never previously been studied, is becoming a necessity for maintaining vanilla crops in these regions in the face of climate change and the emergence of new pathogens. Summary The vanilla orchid (Vanilla spp.) is one of the most valuable cultivated plants worldwide. As with all orchids, vanillas form mycorrhizal associations with fungi in their roots, but their fungal partners have not been investigated outside their native geographic range in Central America. We investigated the whole fungal and mycorrhizal associations in cultivated vanilla (Vanilla planifolia) by sequencing the fungal ITS‐2 marker in the terrestrial and aerial roots using a metabarcoding approach. We selected plants cultivated in three conditions (i.e., cultivation under shade house, in openfield, or in the understory) in one locality of La Réunion island (Indian Ocean) and tested for a possible effect of cultivation practices on fungal communities. Cultivated vanillas in La Réunion mainly associate with Tulasnellaceae (75 OTUs) and Ceratobasidiaceae (8 OTUs). Among the seven most abundant Tulasnellaceae, six are similar to fungi detected in the roots of cultivated vanillas in Central America or in the roots of native orchids in La Réunion. Cultivation practices impacted both total fungal and mycorrhizal community compositions with no clear effect on fungal richness. Notably, Tulasnellaceae and Ceratobasidiaceae were scarce in aerial roots, except in the traditional cultivation in the forest understory. These results shed light on the geographical origins of mycorrhizal fungi of cultivated vanillas in La Réunion and show that they form a pool of both locally and globally distributed fungal partners. These mycorrhizal communities vary according to cultivation practices, and their potential roles in plant nutrition and resistance against pathogens await further attention.

Abstract In nature, parasite species often coinfect the same host. Yet, it is not clear what drives the natural dynamics of coinfection prevalence. The prevalence of coinfections might be affected by interactions among coinfecting species, or simply derive from parasite diversity. Identifying the relative impact of these parameters is crucial for understanding patterns of coinfections. We studied the occurrence and likelihood of coinfections in natural populations of water fleas (Daphnia magna). Coinfection prevalence was within the bounds expected by chance and parasite diversity had a strong positive effect on the likelihood of coinfections. Additionally, coinfection prevalence increased over the season and became as common as a single infection. Our results demonstrate how patterns of coinfection, and particularly their temporal variation, are affected by overlapping epidemics of different parasites. We suggest that monitoring parasite diversity can help predict where and when coinfection prevalence will be high, potentially leading to increased health risks to their hosts.

Abstract Background High ovarian cancer mortality rates motivate the development of effective and patient-friendly diagnostics. Here, we explored the potential of molecular testing in patient-friendly samples for ovarian cancer detection. Methods Home-collected urine, cervicovaginal self-samples, and clinician-taken cervical scrapes were prospectively collected from 54 patients diagnosed with a highly suspicious ovarian mass (benign n = 25, malignant n = 29). All samples were tested for nine methylation markers, using quantitative methylation-specific PCRs that were verified on ovarian tissue samples, and compared to non-paired patient-friendly samples of 110 age-matched healthy controls. Copy number analysis was performed on a subset of urine samples of ovarian cancer patients by shallow whole-genome sequencing. Results Three methylation markers are significantly elevated in full void urine of ovarian cancer patients as compared to healthy controls (C2CD4D, P = 0.008; CDO1, P = 0.022; MAL, P = 0.008), of which two are also discriminatory in cervical scrapes (C2CD4D, P = 0.001; CDO1, P = 0.004). When comparing benign and malignant ovarian masses, GHSR shows significantly elevated methylation levels in the urine sediment of ovarian cancer patients (P = 0.024). Other methylation markers demonstrate comparably high methylation levels in benign and malignant ovarian masses. Cervicovaginal self-samples show no elevated methylation levels in patients with ovarian masses as compared to healthy controls. Copy number changes are identified in 4 out of 23 urine samples of ovarian cancer patients. Conclusions Our study reveals increased methylation levels of ovarian cancer-associated genes and copy number aberrations in the urine of ovarian cancer patients. Our findings support continued research into urine biomarkers for ovarian cancer detection and highlight the importance of including benign ovarian masses in future studies to develop a clinically useful test.

Abstract The prevalence of diabetes steadily increases worldwide mirroring the prevalence of obesity. Endoplasmic reticulum (ER) stress is activated in diabetes and contributes to β-cell dysfunction and apoptosis through the activation of a terminal unfolded protein response (UPR). Our results uncover a new role for Bax Inhibitor-One (BI-1), a negative regulator of inositol-requiring enzyme 1 (IRE1α) in preserving β-cell health against terminal UPR-induced apoptosis and pyroptosis in the context of supraphysiological loads of insulin production. BI-1-deficient mice experience a decline in endocrine pancreatic function in physiological and pathophysiological conditions, namely obesity induced by high-fat diet (HFD). We observed early-onset diabetes characterized by hyperglycemia, reduced serum insulin levels, β-cell loss, increased pancreatic lipases and pro-inflammatory cytokines, and the progression of metabolic dysfunction. Pancreatic section analysis revealed that BI-1 deletion overburdens unfolded proinsulin in the ER of β-cells, confirmed by ultrastructural signs of ER stress with overwhelmed IRE1α endoribonuclease (RNase) activity in freshly isolated islets. ER stress led to β-cell dysfunction and islet loss, due to an increase in immature proinsulin granules and defects in insulin crystallization with the presence of Rod-like granules. These results correlated with the induction of autophagy, ER phagy, and crinophagy quality control mechanisms, likely to alleviate the atypical accumulation of misfolded proinsulin in the ER. In fine, BI-1 in β-cells limited IRE1α RNase activity from triggering programmed β-cell death through apoptosis and pyroptosis (caspase-1, IL-1β) via NLRP3 inflammasome activation and metabolic dysfunction. Pharmaceutical IRE1α inhibition with STF-083010 reversed β-cell failure and normalized the metabolic phenotype. These results uncover a new protective role for BI-1 in pancreatic β-cell physiology as a stress integrator to modulate the UPR triggered by accumulating unfolded proinsulin in the ER, as well as autophagy and programmed cell death, with consequences on β-cell function and insulin secretion. In pancreatic β-cells, BI-1 –/– deficiency perturbs proteostasis with proinsulin misfolding, ER stress, terminal UPR with overwhelmed IRE1α/XBP1s/CHOP activation, inflammation, β-cell programmed cell death, and diabetes.

Abstract Globe-LFMC 2.0, an updated version of Globe-LFMC, is a comprehensive dataset of over 280,000 Live Fuel Moisture Content (LFMC) measurements. These measurements were gathered through field campaigns conducted in 15 countries spanning 47 years. In contrast to its prior version, Globe-LFMC 2.0 incorporates over 120,000 additional data entries, introduces more than 800 new sampling sites, and comprises LFMC values obtained from samples collected until the calendar year 2023. Each entry within the dataset provides essential information, including date, geographical coordinates, plant species, functional type, and, where available, topographical details. Moreover, the dataset encompasses insights into the sampling and weighing procedures, as well as information about land cover type and meteorological conditions at the time and location of each sampling event. Globe-LFMC 2.0 can facilitate advanced LFMC research, supporting studies on wildfire behaviour, physiological traits, ecological dynamics, and land surface modelling, whether remote sensing-based or otherwise. This dataset represents a valuable resource for researchers exploring the diverse LFMC aspects, contributing to the broader field of environmental and ecological research.

Abstract We assembled the first gridded burned area (BA) database of national wildfire data (ONFIRE), a comprehensive and integrated resource for researchers, non-government organisations, and government agencies analysing wildfires in various regions of the Earth. We extracted and harmonised records from different regions and sources using open and reproducible methods, providing data in a common framework for the whole period available (starting from 1950 in Australia, 1959 in Canada, 1985 in Chile, 1980 in Europe, and 1984 in the United States) up to 2021 on a common 1° × 1° grid. The data originate from national agencies (often, ground mapping), thus representing the best local expert knowledge. Key opportunities and limits in using this dataset are discussed as well as possible future expansions of this open-source approach that should be explored. This dataset complements existing gridded BA data based on remote sensing and offers a valuable opportunity to better understand and assess fire regime changes, and their drivers, in these regions. The ONFIRE database can be freely accessed at https://zenodo.org/record/8289245 .

Summary: Blood contains multiple analytes that can be used as liquid biopsy to analyze cancer. Mutations have been detected in DNA associated with small extracellular vesicles (sEVs). The genome-wide composition and structure of sEV DNA remains poorly characterized, and whether sEVs are enriched in tumor signal compared to cell-free DNA (cfDNA) is unclear. Here, using whole-genome sequencing from lung cancer patients we determined that the tumor fraction and heterogeneity are comparable between DNA associated with sEV (1000 bp fragments poor in tumor signal. The structural patterns of sEV DNA are related to plasma cfDNA. Mitochondrial DNA is relatively enriched in the sEV fractions. Our results suggest that DNA associated to sEV (including exosomes) is not preferentially enriched in tumor signal and is less abundant than cfDNA.

Summary: Treatments for cancer patients are becoming increasingly complex, and there is a growing desire from clinicians and patients for biomarkers that can account for this complexity to support informed decisions about clinical care. To achieve precision medicine, the new generation of biomarkers must reflect the spatial and temporal heterogeneity of cancer biology both between patients and within an individual patient. Mining the different layers of 'omics in a multi-modal way from a minimally invasive, easily repeatable, liquid biopsy has increasing potential in a range of clinical applications, and for improving our understanding of treatment response and resistance. Here, we detail the recent developments and methods allowing exploration of genomic, epigenomic, transcriptomic, and fragmentomic layers of 'omics from liquid biopsy, and their integration in a range of applications. We also consider the specific challenges that are posed by the clinical implementation of multi-omic liquid biopsies.

Abstract The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.

Abstract Archaeologists commonly use airborne LIDAR technology to produce 3D models of structures, even when obscured by a forest canopy. However, this technology has a high cost, both from the plane itself and from the processing of the LIDAR point cloud. Furthermore, this technique can only be used over limited regions. This paper proposes a technique that uses SAR satellite imagery to identify man-made structures hidden by a forest canopy. To do so, we exploit the Ascending and Descending passes of Sentinel-1 so that we obtain two images of the candidate site but from different sight directions. Because of cardinal effects, a large enough building will sign differently from the comparatively isotropic forest canopy it is obscured by. Practically, the technique is based on the ratio of backscattered intensity from these two illumination angles and is well adapted for large areas. The advantages and shortcomings are discussed for the specific case of Sentinel-1 SAR images over two Maya archaeological sites in Central America. Our analysis shows that SAR satellite imagery might provide a free, global-scale way of preselecting sites with large or tall structures to complement LIDAR technology.

Abstract Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.

This study compares the mobility behaviour, in a H2O2 environment, of three different geometries of hybrid particle made of silica core functionalized by gold (nanoparticles or layer). It is known that the decomposition of H2O2 on gold surfaces drives mobility; however, the link between mobility orientation and the organization of gold on silica surfaces is still questionable. While conventional wisdom posits that asymmetric designs are crucial for generating phoretic forces or localized bubble propulsion, recent research suggests that symmetrical particles may also exhibit motility. To address this debate, we developed a robust workflow for synthesizing gold grafted silica nanoparticles with precise control over size and shape, enabling the direct comparison of their motile behaviour by dynamic light scattering and particle tracking velocimetry. Our results indicate, first, that a combination of techniques is necessary to overcome their intrinsic limitation and, second, that the inherent asymmetry generated by isotropic gold nanoparticle deposition onto silica surfaces may enable particle motility.

This study was carried out to determine the phytochemical and mineral composition of Piptadeniastrum africanum (Hook.f.) Brenan and Ipomoea involucrata P. Beauv., two plants presumed anti-fertilizers, were cited during an ethnobotanical survey carried out in 2018 among indigenous women in Mbandaka and the surrounding area. Micrography was carried out, followed by determination of mineral composition by ICP-AES and SAA, and the TLC for a highlight of the various phytochemical compounds making up these two plants. The study determined the relative structure of the multiple cells and tissues making up these plant drugs, including numerous raphids characteristic of Ipomoea involucrata and calcium oxalate crystals characteristic of Piptadeniastrum africanum. Among the chemical compounds, those directly linked to female anti-fertility have been highlighted. These include flavonoids, tannins, phenolic compounds, and terpenoids. Elemental analysis revealed mineral salts and trace elements directly influencing reproduction, such as iron, zinc, calcium, sodium, and arsenic. Even if these data make it possible to justify the activity of these two plants in reproductive health, it is, however, necessary for an in-depth study on the in vitro evaluation to determine the clear anti-fertilizing activity of these plants used, raw, by indigenous women.

Abstract Cell‐free DNA (cfDNA) can be isolated and sequenced from blood and/or urine of cancer patients. Conventional short‐read sequencing lacks deployability and speed and can be biased for short cfDNA fragments. Here, we demonstrate that with Oxford Nanopore Technologies (ONT) sequencing we can achieve delivery of genomic and fragmentomic data from liquid biopsies. Copy number aberrations and cfDNA fragmentation patterns can be determined in less than 24 h from sample collection. The tumor‐derived cfDNA fraction calculated from plasma of lung cancer patients and urine of bladder cancer patients was highly correlated (R = 0.98) with the tumor fraction calculated from short‐read sequencing of the same samples. cfDNA size profile, fragmentation patterns, fragment‐end composition, and nucleosome profiling near transcription start sites in plasma and urine exhibited the typical cfDNA features. Additionally, a high proportion of long tumor‐derived cfDNA fragments (> 300 bp) are recovered in plasma and urine using ONT sequencing. ONT sequencing is a cost‐effective, fast, and deployable approach for obtaining genomic and fragmentomic results from liquid biopsies, allowing the analysis of previously understudied cfDNA populations.

Abstract Background Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and in particular mitochondrial DNA (mtDNA) has been understudied. We hypothesize that an increase in mtDNA in plasma could reflect the presence of cancer, and that leveraging cell-free mtDNA could enhance cancer detection. Results We survey 203 healthy and 664 cancer plasma samples from three collection centers covering 12 cancer types with whole genome sequencing to catalogue the plasma mtDNA fraction. The mtDNA fraction is increased in individuals with cholangiocarcinoma, colorectal, liver, pancreatic, or prostate cancer, in comparison to that in healthy individuals. We detect almost no increase of mtDNA fraction in individuals with other cancer types. The mtDNA fraction in plasma correlates with the cfDNA tumor fraction as determined by somatic mutations and/or copy number aberrations. However, the mtDNA fraction is also elevated in a fraction of patients without an apparent increase in tumor-derived cfDNA. A predictive model integrating mtDNA and copy number analysis increases the area under the curve (AUC) from 0.73 when using copy number alterations alone to an AUC of 0.81. Conclusions The mtDNA signal retrieved by whole genome sequencing has the potential to boost the detection of cancer when combined with other tumor-derived signals in liquid biopsies.