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Abstract: Terrestrial groundwater travels through subterranean estuaries before reaching the sea. Groundwater‐derived nutrients drive coastal water quality, primary production, and eutrophication. We determined how dissolved inorganic nitrogen (DIN), dissolved inorganic phosphorus (DIP), and dissolved organic nitrogen (DON) are transformed within subterranean estuaries and estimated submarine groundwater discharge (SGD) nutrient loads compiling > 10,000 groundwater samples from 216 sites worldwide. Nutrients exhibited complex, nonconservative behavior in subterranean estuaries. Fresh groundwater DIN and DIP are usually produced, and DON is consumed during transport. Median total SGD (saline and fresh) fluxes globally were 5.4, 2.6, and 0.18 Tmol yr−1 for DIN, DON, and DIP, respectively. Despite large natural variability, total SGD fluxes likely exceed global riverine nutrient export. Fresh SGD is a small source of new nutrients, but saline SGD is an important source of mostly recycled nutrients. Nutrients exported via SGD via subterranean estuaries are critical to coastal biogeochemistry and a significant nutrient source to the oceans.

Abstract The development of synthetic bone substitutes that equal or exceed the efficacy of autologous graft remains challenging. In this study, a rat calvarial defect model was used as a reference to investigate the influence of composition and architecture of 3D-printed cement, with or without bioactives, on tissue regeneration. Printable cement pastes were formulated by combining hyaluronic acid and cement precursors. Cementitious scaffolds were printed with 3 different patterns. After 7 weeks of implantation with or without bone marrow, multiparametric qualitative and quantitative assessments were performed using µCT, SEM, and histology. None of the set-up strategies was as efficient as autologous cancellous bone graft to repair calvarial defects. Nonetheless, the presence of scaffold improved the skull vault closure, particularly when the scaffold was soaked in total bone marrow before implantation. No significant effect of scaffold macro-architecture was observed on tissue mineralization. Magnesium phosphate-based scaffolds (MgP) seemed to induce higher bone formation than their calcium-phosphate-based counterparts. They also displayed a quicker biodegradation and sparse remaining material was found after 7 weeks of implantation. Although further improvements are required to reach clinical settings, this study demonstrated the potential of organo-mineral cements for bone regeneration and highlighted the peculiar properties of MgP-based cements.

Abstract During meiosis, nucleoprotein filaments of the strand exchange proteins RAD51 and DMC1 are crucial for repairing SPO11-generated DNA double-strand breaks (DSBs) by homologous recombination (HR). A balanced activity of positive and negative RAD51/DMC1 regulators ensures proper recombination. Fidgetin-like 1 (FIGNL1) was previously shown to negatively regulate RAD51 in human cells. However, FIGNL1’s role during meiotic recombination in mammals remains unknown. Here, we decipher the meiotic functions of FIGNL1 and FIGNL1 Interacting Regulator of Recombination and Mitosis (FIRRM) using male germline-specific conditional knock-out (cKO) mouse models. Both FIGNL1 and FIRRM are required for completing meiotic prophase in mouse spermatocytes. Despite efficient recruitment of DMC1 on ssDNA at meiotic DSB hotspots, the formation of late recombination intermediates is defective in Firrm cKO and Fignl1 cKO spermatocytes. Moreover, the FIGNL1-FIRRM complex limits RAD51 and DMC1 accumulation on intact chromatin, independently from the formation of SPO11-catalyzed DSBs. Purified human FIGNL1ΔN alters the RAD51/DMC1 nucleoprotein filament structure and inhibits strand invasion in vitro. Thus, this complex might regulate RAD51 and DMC1 association at sites of meiotic DSBs to promote proficient strand invasion and processing of recombination intermediates.

Abstract Background Severe chronic obstructive pulmonary disease (COPD) often results in hyperinflation and flattening of the diaphragm. An automated computed tomography (CT)-based tool for quantifying diaphragm configuration, a biomarker for COPD, was developed in-house and tested in a large cohort of COPD patients. Methods We used the LungQ platform to extract the lung-diaphragm intersection, as direct diaphragm segmentation is challenging. The tool computed the diaphragm index (surface area/projected surface area) as a measure of diaphragm configuration on inspiratory scans in a COPDGene subcohort. Visual inspection of 250 randomly selected segmentations served as a quality check. Associations between the diaphragm index, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, forced expiratory volume in 1 s (FEV1) % predicted, and CT-derived emphysema scores were explored using analysis of variance and Pearson correlation. Results The tool yielded incomplete segmentation in 9.2% (2.4% major defect, 6.8% minor defect) of 250 randomly selected cases. In 8431 COPDGene subjects (4240 healthy; 4191 COPD), the diaphragm index was increasingly lower with higher GOLD stages (never-smoked 1.83 ± 0.16; GOLD-0 1.79 ± 0.18; GOLD-1 1.71 ± 0.15; GOLD-2: 1.67 ± 0.16; GOLD-3 1.58 ± 0.14; GOLD-4 1.54 ± 0.11) (p

Abstract Terrestrial groundwater travels through subterranean estuaries before reaching the sea. Groundwater‐derived nutrients drive coastal water quality, primary production, and eutrophication. We determined how dissolved inorganic nitrogen (DIN), dissolved inorganic phosphorus (DIP), and dissolved organic nitrogen (DON) are transformed within subterranean estuaries and estimated submarine groundwater discharge (SGD) nutrient loads compiling > 10,000 groundwater samples from 216 sites worldwide. Nutrients exhibited complex, nonconservative behavior in subterranean estuaries. Fresh groundwater DIN and DIP are usually produced, and DON is consumed during transport. Median total SGD (saline and fresh) fluxes globally were 5.4, 2.6, and 0.18 Tmol yr−1 for DIN, DON, and DIP, respectively. Despite large natural variability, total SGD fluxes likely exceed global riverine nutrient export. Fresh SGD is a small source of new nutrients, but saline SGD is an important source of mostly recycled nutrients. Nutrients exported via SGD via subterranean estuaries are critical to coastal biogeochemistry and a significant nutrient source to the oceans.

Abstract The biology of extinct animals is usually reconstructed from external morphological characters and comparison with present-day analogues. Internal soft organs are very rarely preserved in fossils and require high-tech approaches for visualization. Here, we report the internal anatomy of a female and male of the ~ 162 Myr-old lobster Eryma ventrosum from the Jurassic La Voulte-sur-Rhône Konservat-Lagerstätte in France using X-ray synchrotron tomography. The Erymidae is an extinct, species-rich, widespread and ecologically important Mesozoic family of decapod crustaceans. Our investigation revealed the anatomy of the locomotory, respiratory, circulatory, excretory, digestive, nervous and sensory, and reproductive systems at a resolution resembling low-magnification histology. Particularly notable is the detailed preservation of the small brain and the fragile hepatopancreas, the main metabolic organ of decapods that decays rapidly post-mortem. The remarkable preservation shows that the internal anatomy of Eryma ventrosum is closer to that of Nephropidae (clawed lobsters) than Astacidae (freshwater crayfish), their closest living relatives based on skeletal morphology. The microanatomy of the gonads and hepatopancreas indicates that the two specimens investigated were a young, well-nourished female and male prior to sexual maturity. The analysis of the soft anatomy reveals remarkable conservatism over 160 Myr and offers new insights into feeding, reproduction, life history and lifestyle of an important component of the macrozoobenthos of Middle Jurassic seas.

Victoire Menseau,1 Jeanne Charbonnier,1 Angélique Franchi,2 Sihem Ouar,2 Karim Hamiche,2 Jean Pujo,1,3 Hatem Kallel,3,4 Mathieu Nacher,3,5 Alexis Fremery1,3 1Emergency Department, Cayenne General Hospital, French Guiana, France; 2Forensic Medicine Department, Cayenne General Hospital, French Guiana, France; 3Faculty of Medicine, French Guiana University, French Guiana, France; 4Intensive Care Unit, Cayenne General Hospital, French Guiana, France; 5CIC INSERM1424, Cayenne General Hospital, French Guiana, FranceCorrespondence: Alexis Fremery, Email alexis.fremery@gmail.comIntroduction: Sexual violence is a major public health issue, including in French Guiana. The feeling of insecurity is significant in this part of France. Sexual violence is an important reason for consultation in forensic and emergency medicine. The challenge is to provide care within the first 72 hours, particularly in medicolegal terms and for infectious disease management. The objectives of our study were, firstly, to establish the epidemiology of sexual assaults at Cayenne General Hospital (CGH), and secondly, to evaluate the management of these victims.Materials and Methods: From January 1st, 2019 to December 31st, 2020, we conducted a single-center retrospective descriptive study including patients who were consulted for sexual assaults in the Forensic medicine and the Emergency departments of CGH.Results: Over this period, 400 sexual assault victims were consulted. Most of them, were women (87%) with a median age of 13 years-old [8; 17.5]. The aggressor was mostly male (99%) frequently known by the victim (87%) and from her family (39%). Suspected assaults represented 19% of consultations. The most frequent assault on women was penile-vaginal penetration (82%) and penile-anal penetration (77%) on men. The delay of consultation was superior to 72 hours in 60% of the cases. A psychological follow-up was recommended for 62% of these victims.Conclusion: This work allowed to identify a young and female population at risk, most often assaulted by a male known to her. Most of the patients consulted more than 72 hours after the assault. Our study highlights the need for prevention actions in French Guiana focusing on this population at risk.Keywords: sexual assaults, emergency, management, epidemiology, child abuse

Abstract The outcome of CRISPR-Cas-mediated genome modifications is dependent on DNA double-strand break (DSB) processing and repair pathway choice. Homology-directed repair (HDR) of protein-blocked DSBs requires DNA end resection that is initiated by the endonuclease activity of the MRE11 complex. Using reconstituted reactions, we show that Cas9 breaks are unexpectedly not directly resectable by the MRE11 complex. In contrast, breaks catalyzed by Cas12a are readily processed. Cas9, unlike Cas12a, bridges the broken ends, preventing DSB detection and processing by MRE11. We demonstrate that Cas9 must be dislocated after DNA cleavage to allow DNA end resection and repair. Using single molecule and bulk biochemical assays, we next find that the HLTF translocase directly removes Cas9 from broken ends, which allows DSB processing by DNA end resection or non-homologous end-joining machineries. Mechanistically, the activity of HLTF requires its HIRAN domain and the release of the 3′-end generated by the cleavage of the non-target DNA strand by the Cas9 RuvC domain. Consequently, HLTF removes the H840A but not the D10A Cas9 nickase. The removal of Cas9 H840A by HLTF explains the different cellular impact of the two Cas9 nickase variants in human cells, with potential implications for gene editing.

Abstract Background Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that commonly results from a high-calorie diet and sedentary lifestyle, leading to insulin resistance and glucose homeostasis perturbation. Physical activity is recommended as one first-line treatment in T2DM, but it leads to contrasted results. We hypothesized that, instead of applying standard exercise protocols, the prescription of personalized exercise programs specifically designed to reverse the potential metabolic alterations in skeletal muscle could result in better results. Methods To test this hypothesis, we drew the metabolic signature of the fast-twitch quadriceps muscle, based on a combined unbiased NMR spectroscopy and RT-qPCR study, in several T2DM mouse models of different genetic background (129S1/SvImJ, C57Bl/6J), sex and aetiology (high-fat diet (HFD) or HFD/Streptozotocin (STZ) induction or transgenic MKR (FVB-Tg Ckm-IGF1R*K1003R)1Dlr/J) mice. Three selected mouse models with unique muscular metabolic signatures were submitted to three different swimming-based programs, designed to address each metabolic specificity. Results We found that depending on the genetic background, the sex, and the mode of T2DM induction, specific muscular adaptations occurred, including depressed glycolysis associated with elevated PDK4 expression, shift to β-oxidation, or deregulation of amino-acid homeostasis. Interestingly, dedicated swimming-based exercises designed to restore specific metabolic alterations in muscle were found optimal in improving systemic T2DM hallmarks, including a significant reduction in insulin resistance, the improvement of glucose homeostasis, and a delay in sensorimotor function alterations. Conclusion The muscle metabolism constitutes an important clue for the design of precision exercises with potential clinical implications for T2DM patients.

Abstract Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.

Abstract Adolescence is a strategic developmental stage in terms of preventing later difficulties and ensuring good mental health. Prophylactic interventions, which are conducted before the onset, prolongation, or worsening of difficulties, and aim to prevent or reduce symptoms or to promote wellbeing, therefore appear particularly appropriate for adolescents. However, existing prophylactic interventions conducted with adolescents have several weaknesses, including sparse theoretical frameworks, ambivalent evidence of their efficacy, and implementation and dissemination difficulties. In addition, no data are currently available on the effectiveness of such interventions in France. To fill this gap, a four-arm randomized controlled trial will be performed to assess the effectiveness of three prophylactic interventions targeting reactive, proactive and interpersonal adaptation in fourth-grade middle-school students, together with participants’ experience and perception of the interventions. Based on existing knowledge about adolescents, their learning mechanisms, and field constraints, these three interventions have been designed to promote their learning and receptiveness to interventions. Compared with baseline (i.e., before the intervention), we expect to observe a significant decrease in the level of distress (anxiety and depressive symptoms, functional impairment, and psychosocial difficulties) and a significant increase in the level of wellbeing after the intervention, across the three intervention groups, but not in the control group. In addition, we expect to observe post-intervention improvements in the processes targeted by the reactive adaptation intervention (operationalized as coping strategy use and flexibility), those targeted by the proactive adaptation intervention (operationalized as the tendency to engage in committed actions and general self-efficacy), and those targeted by the interpersonal adaptation intervention (operationalized as assertiveness in interactions), but only in the corresponding groups, with no change in any of these processes in the control group. The results of this research will not only enrich our knowledge of the processes involved in adolescents’ distress and wellbeing, but also provide clues as to the best targets for intervention. Moreover, the material for these interventions will be freely available in French on request to the corresponding author, providing access to innovative and fully assessed interventions aimed at promoting adolescents’ mental health in France. This clinical trial is currently being registered under no. 2023-A01973-42 on https://ansm.sante.fr/ . This is the first version of the protocol.

Abstract While de novo variants (DNV) are overall at low risk of recurrence in subsequent pregnancies, a subset is at high risk due to parental mosaicism. Accurately identifying cases of parental mosaicism is therefore important for genetic counseling in clinical care. Some studies have investigated the rate of parental mosaics, but most were either limited by the sensitivity of the techniques (i.e. exome or genome sequencing), or focused on specific types of disease such as epileptic syndromes. This study aimed to determine the proportion of parental mosaicism among the DNV causing neurodevelopmental disorders (NDDs) in a series not enriched in epilepsy syndromes. We collected 189 patients with NDD-associated DNV. We applied a smMIP enrichment method and sequenced parental blood DNA samples to an average depth of 7000x. Power simulation indicated that mosaicism with an allelic fraction of 0.5% would have been detected for 87% of positions with 90% power. We observed seven parental mosaic variants (3.7% of families), of which four (2.1% of families) had an allelic fraction of less than 1%. In total, our study identifies a relatively low proportion of parental mosaicism in NDD-associated DNVs and raises the question of a biological mechanism behind the higher rates of parental mosaicism detected in other studies, particularly those focusing on epileptic syndromes.

El artículo analiza la huelga de albañiles de 1895 en Montevideo, centrada en la reducción de la jornada laboral, reflejando las duras condiciones de trabajo de la época. Montevideo experimentaba un rápido crecimiento urbano y económico, con una clase trabajadora diversa enfrentando largas jornadas, bajos salarios y falta de protección social. Los trabajadores, organizados en “sociedades de resistencia”, buscaron mejorar sus condiciones a través de acciones colectivas. La Sociedad de albañiles lideró la huelga como ejemplo de estas luchas. El artículo explora los métodos de trabajo, las relaciones laborales y las estrategias de organización de los albañiles, destacando la limitada atención historiográfica sobre su historia en el siglo XIX. Se basa en una revisión exhaustiva de la prensa y diversas fuentes para iluminar este período.

The present corrigendum rectifies several issues with repository numbers of the specimens studied in Laville et al. (2024).

Purpose: Transducer positioning for liver ablation by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is challenging due to the presence of air-filled organs or bones on the beam path. This paper presents a software tool developed to optimize the positioning of a HIFU transducer dedicated to abdominal thermal therapy, to maximize the treatment's efficiency while minimizing the near-field risk. Methods: A software tool was developed to determine the theoretical optimal position (TOP) of the transducer based on the minimization of a cost function using the particle swarm optimization (PSO). After an initialization phase and a manual segmentation of the abdomen of 5 pigs, the program randomly generates particles with 2 degrees of freedom and iteratively minimizes the cost function of the particles considering 3 parameters weighted according to their criticality. New particles are generated around the best position obtained at the previous step and the process is repeated until the optimal position of the transducer is reached. MR imaging data from in vivo HIFU ablation in pig livers was used for ground truth comparison between the TOP and the experimental position (EP). Results: As compared to the manual EP, the rotation difference with the TOP was on average −3.1 ± 7.1° and the distance difference was on average −7.1 ± 5.4 mm. The computational time to suggest the TOP was 20s. The software tool is modulable and demonstrated consistency and robustness when repeating the calculation and changing the initial position of the transducer.

Abstract The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II–IV and III–IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III–IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II–IV; 16% for aGVHD III–IV) than with BM (28% for aGVHD II–IV; 8% for aGVHD III–IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III–IV remained higher with PB than with BM graft (HR = 2.0; range [1.17–3.43], p = 0.012).

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.