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The precise localization of postsynaptic receptors opposite neurotransmitter release sites is essential for synaptic function. This alignment relies on adhesion molecules, intracellular scaffolds, and a growing class of extracellular scaffolding proteins. However, how these secreted proteins are retained at synapses remains unclear. We addressed this question using C. elegans neuromuscular junctions, where Punctin, a conserved extracellular synaptic organizer, positions postsynaptic receptors. We identified CLE-1, the ortholog of collagens XV/XVIII, as a key stabilizer of Punctin. Punctin and CLE-1B, the main isoform present at neuromuscular junctions, form a complex and rely on each other for synaptic localization. Punctin undergoes cleavage, and in the absence of CLE-1, specific fragments are lost, resulting in the mislocalization of cholinergic receptors to GABAergic synapses. Additionally, CLE-1 regulates receptor levels independently of Punctin. These findings highlight a crucial extracellular complex that maintains synapse identity.

Mouse embryos acquire global DNA methylation of their genome during implantation. However the exact roles of DNA methyltransferases (DNMTs) in embryos have not been studied comprehensively. Here we systematically analyze the consequences of genetic inactivation of Dnmt1 , Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos. We find a strict division of function between DNMT1, responsible for maintenance methylation, and DNMT3A/B, solely responsible for methylation acquisition in development. By analyzing severely hypomethylated embryos, we uncover multiple functions of DNA methylation that is used as a mechanism of repression for a panel of genes including not only imprinted and germline genes, but also lineage-committed genes and 2-cell genes. DNA methylation also suppresses multiple retrotransposons and illegitimate transcripts from cryptic promoters in transposons and gene bodies. Our work provides a thorough analysis of the roles of DNA methyltransferases and the importance of DNA methylation for transcriptome integrity in mammalian embryos. DNA methyltrasferases play important role during mouse embryo development. Here the authors reveal the consequences of genetic inactivation of Dnmt1, Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos genome-wide.

Background Cytosine DNA methylation is a heritable epigenetic mark present in most eukaryotic groups. While the patterns and functions of DNA methylation have been extensively studied in mouse and human, their conservation in other vertebrates remains poorly explored. In this study, we interrogated the distribution and function of DNA methylation in primary fibroblasts of seven vertebrate species including bio-medical models and livestock species (human, mouse, rabbit, dog, cow, pig, and chicken). Results Our data highlight both divergence and conservation of DNA methylation patterns and functions. We show that the chicken genome is hypomethylated compared to other vertebrates. Furthermore, compared to mouse, other species show a higher frequency of methylation of CpG-rich DNA. We reveal the conservation of large unmethylated valleys and patterns of DNA methylation associated with X-chromosome inactivation through vertebrate evolution and make predictions of conserved sets of imprinted genes across mammals. Finally, using chemical inhibition of DNA methylation, we show that the silencing of germline genes and endogenous retroviruses (ERVs) are conserved functions of DNA methylation in vertebrates. Conclusions Our data highlight conserved properties of DNA methylation in vertebrate genomes but at the same time point to differences between mouse and other vertebrate species.

In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development. DNA methylation targets CpG island promoters of germline genes to repress their expression in mouse somatic cells. Here the authors show that a transcription factor E2F6 is required to target CpG island DNA methylation and epigenetic silencing to germline genes during early mouse development.

Balance studies usually focus on quantities describing the global body motion. Assessing such quantities using classical marker-based approach can be tedious and modify the participant’s behaviour. The recent development of markerless motion capture methods could bypass the issues related to the use of markers. This work compared dynamic balance related quantities obtained with markers and videos. Sixteen young healthy participants performed four different motor tasks: walking at self-selected speed, balance loss, walking on a narrow beam and countermovement jumps. Their movements were recorded simultaneously by marker-based and markerless motion capture systems. Videos were processed using a commercial markerless pose estimation software, Theia3D. The centre of mass position (CoM) was computed, and the associated extrapolated centre of mass position (XCoM) and whole-body angular momentum (WBAM) were derived. Bland-Altman analysis was performed and root mean square difference (RMSD) and coefficient of correlation were computed to compare the results obtained with marker-based and markerless methods. Bias remained of the magnitude of a few mm for CoM and XCoM positions, and RMSD of CoM and XCoM was around 1 cm. RMSD of the WBAM was less than 10 % of the total amplitude in any direction, and bias was less than 1 %. Results suggest that outcomes of balance studies will be similar whether marker-based or markerless motion capture system are used. Nevertheless, one should be careful when assessing dynamic movements such as jumping, as they displayed the biggest differences (both bias and RMSD), although it is unclear whether these differences are due to errors in markerless or marker-based motion capture system.

Emergence of polyphagous herbivorous insects entails significant adaptation to recognize, detoxify and digest a variety of host-plants. Despite of its biological and practical importance - since insects eat 20% of crops - no exhaustive analysis of gene repertoires required for adaptations in generalist insect herbivores has previously been performed. The noctuid moth Spodoptera frugiperda ranks as one of the world’s worst agricultural pests. This insect is polyphagous while the majority of other lepidopteran herbivores are specialist. It consists of two morphologically indistinguishable strains (“C” and “R”) that have different host plant ranges. To describe the evolutionary mechanisms that both enable the emergence of polyphagous herbivory and lead to the shift in the host preference, we analyzed whole genome sequences from laboratory and natural populations of both strains. We observed huge expansions of genes associated with chemosensation and detoxification compared with specialist Lepidoptera. These expansions are largely due to tandem duplication, a possible adaptation mechanism enabling polyphagy. Individuals from natural C and R populations show significant genomic differentiation. We found signatures of positive selection in genes involved in chemoreception, detoxification and digestion, and copy number variation in the two latter gene families, suggesting an adaptive role for structural variation.

Background Self-extubation is a common complication in intubated patients in the intensive care unit (ICU) and is associated with a high rate of reintubation. This study aimed to identify predictors of reintubation following self-extubation (SE) and assess the prognosis of these patients. Methods Data were extracted from the French ICU database, OutcomeRea™. The primary objective was to identify factors associated with reintubation within 48 h after self-extubation. Secondary objectives included evaluating the association between reintubation and mortality, ICU length of stay, and nosocomial pneumonia. Results Between November 1996 and May 2022, 12,917 patients were intubated in the ICU. Among them, 701 patients experienced SE without therapeutic limitations at the time, and 276 (39.4%) required reintubation. In adjusted analyses, the following factors were independently associated with reintubation: a higher non-neurological SOFA score on the day before SE (OR 1.16 [1.01; 1.34]; p = 0.03), duration of invasive mechanical ventilation > 7 days before SE (OR 1.79 [1.04; 3.26]; p = 0.04), enteral nutrition on the day of SE (OR 2.59 [1.75; 3.84]; p < 0.01) and the use of non-invasive ventilation (NIV) within 24 h after SE (OR 0.28 [0.16; 0.5];p < 0.01). Reintubation within 48 h after SE was independently associated with increased 28-day mortality (HR = 3.03 [1.79; 5.12]; p < 0.01) and 90-day mortality (HR = 2.86 [1.86; 4.4]; p < 0.01), a higher risk of nosocomial pneumonia (sdHR, 18.28 [7.70; 43.42]; p < 0.01), and a 13-day increase in ICU length of stay (p < 0.01). Conclusion Enteral nutrition on the day of SE, prolonged mechanical ventilation prior to SE, higher non-neurological SOFA scores, and use of NIV after SE were independently associated with the need for reintubation. Reintubation was also associated with increased mortality, a higher risk of nosocomial pneumonia, and prolonged ICU stay.

The increased use of legumes is viewed as a promising option to mitigate climate change, as they are a source of proteins and provide nitrogen to the soil. In this paper, we evaluate a strategy for the increased use of legumes in Europe until 2050 by integrating a large array of food and natural system processes into a consistent modeling framework. Three contrasting scenarios are studied: a supply-side scenario entailing a change in the animal feed mix, a demand-side scenario entailing a shift in human diet, and a combination of the shift in human diet with a reforestation in Europe. We find that mitigated emissions are much higher in the two diet shift scenarios (-231 and -259 MtCO2eq, respectively) than in the supply-side scenario (-10 MtCO2eq). Therefore, the main environmental benefit of legumes is to provide proteins as a substitute for animal products rather than enabling a lower consumption of synthetic fertilizer through increased leguminous nitrogen fixation. Diet shift scenarios require a lower use of lands that can then be used to either reduce intensification or reforest. In the former case, the reduction in emissions concerns almost exclusively non-CO2 emissions, mainly through enteric fermentation and manure management, and occurs largely outside Europe. In the latter case, the livestock sector still represents a substantial share of the emission reduction but is outpaced by CO2 emissions through carbon sequestration. An increase in legume production substantially reduces greenhouse gas emissions from the AFOLU sector only when combined with a change in diet, and its combination with reforestation allows the emission reduction to be relocated to Europe through carbon sequestration. Our study concludes that an increase in legume production accompanied by appropriate measures on both the supply and demand side can be effective in reducing emissions. These results can be used to design the European Commission’s “Farm to Fork” strategy for sustainable food and to support climate-friendly farming practices of the post-2020 European common agricultural policy.

BackgroundThe objective of this study was to evaluate the ability of endothelial biomarkers to early predict clinical deterioration of patients admitted to the emergency department (ED) with a suspected sepsis. This was a prospective, multicentre, international study conducted in EDs. Adult patients with suspected acute bacterial infection and sepsis were enrolled but only those with confirmed infection were analysed. The kinetics of biomarkers and organ dysfunction were collected at T0, T6 and T24 hours after ED admission to assess prognostic performances of sVEGFR2, suPAR and procalcitonin (PCT). The primary outcome was the deterioration within 72 h and was defined as a composite of relevant outcomes such as death, intensive care unit admission and/or SOFA score increase validated by an independent adjudication committee.ResultsAfter adjudication of 602 patients, 462 were analysed including 124 who deteriorated (27%). On admission, those who deteriorated were significantly older (73 [60–82] vs 63 [45–78] y-o, p < 0.001) and presented significantly higher SOFA scores (2.15 ± 1.61 vs 1.56 ± 1.40, p = 0.003). At T0, sVEGFR2 (5794 [5026–6788] vs 6681 [5516–8059], p < 0.0001), suPAR (6.04 [4.42–8.85] vs 4.68 [3.50–6.43], p < 0.0001) and PCT (7.8 ± 25.0 vs 5.4 ± 17.9 ng/mL, p = 0.001) were associated with clinical deterioration. In multivariate analysis, low sVEGFR2 expression and high suPAR and PCT levels were significantly associated with early deterioration, independently of confounding parameters (sVEGFR2, OR = 1.53 [1.07–2.23], p < 0.001; suPAR, OR = 1.57 [1.21–2.07], p = 0.003; PCT, OR = 1.10 [1.04–1.17], p = 0.0019). Combination of sVEGFR2 and suPAR had the best prognostic performance (AUC = 0.7 [0.65–0.75]) compared to clinical or biological variables.ConclusionssVEGFR2, either alone or combined with suPAR, seems of interest to predict deterioration of patients with suspected bacterial acute infection upon ED admission and could help front-line physicians in the triage process.

Background The primary aim of this study was to assess the outcome of elderly intensive care unit (ICU) patients treated during the spring and autumn COVID-19 surges in Europe. Methods This was a prospective European observational study (the COVIP study) in ICU patients aged 70 years and older admitted with COVID-19 disease from March to December 2020 to 159 ICUs in 14 European countries. An electronic database was used to register a number of parameters including: SOFA score, Clinical Frailty Scale, co-morbidities, usual ICU procedures and survival at 90 days. The study was registered at ClinicalTrials.gov (NCT04321265). Results In total, 2625 patients were included, 1327 from the first and 1298 from the second surge. Median age was 74 and 75 years in surge 1 and 2, respectively. SOFA score was higher in the first surge (median 6 versus 5, p  < 0.0001). The PaO 2 /FiO 2 ratio at admission was higher during surge 1, and more patients received invasive mechanical ventilation (78% versus 68%, p  < 0.0001). During the first 15 days of treatment, survival was similar during the first and the second surge. Survival was lower in the second surge after day 15 and differed after 30 days (57% vs 50%) as well as after 90 days (51% vs 40%). Conclusion An unexpected, but significant, decrease in 30-day and 90-day survival was observed during the second surge in our cohort of elderly ICU patients. The reason for this is unclear. Our main concern is whether the widespread changes in practice and treatment of COVID-19 between the two surges have contributed to this increased mortality in elderly patients. Further studies are urgently warranted to provide more evidence for current practice in elderly patients. Trial registration number NCT04321265 , registered March 19th, 2020.