Search

Abstract Selecting patients for phase I cancer trials is crucial to ensure a sufficient life expectancy. Frail patients, better suited for palliative care, should not be exposed to new drugs with minimal benefit. Enrolling patients at high risk of early death can jeopardize the study. Our analysis of two large precision medicine studies used tumor fraction from ctDNA to develop a predictive model, demonstrating notable predictive accuracy and aiding in patient selection.

Abstract Background Different responses in human coronary arteries (HCA) and human middle meningeal arteries (HMMA) were observed for some of the novel CGRP receptor antagonists, the gepants, for inhibiting CGRP-induced relaxation. These differences could be explained by the presence of different receptor populations in the two vascular beds. Here, we aim to elucidate which receptors are involved in the relaxation to calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) in HCA and HMMA. Methods RNA was isolated from homogenized human arteries (23 HCAs; 12 F, 11 M, age 50 ± 3 years and 26 HMMAs; 14 F, 12 M, age 51 ± 3 years) and qPCR was performed for different receptor subunits. Additionally, relaxation responses to CGRP, AM or AM2 of the human arteries were quantified using a Mulvany myograph system, in the presence or absence of the adrenomedullin 1 receptor antagonist AM22-52 and/or olcegepant. Results Calcitonin-like receptor (CLR) mRNA was expressed equally in both vascular beds, while calcitonin receptor (CTR) and receptor activity-modifying protein 3 (RAMP3) expression was low and could not be detected in all samples. RAMP1 expression was similar in HCA and HMMA, while RAMP2 expression was higher in HMMA. Moreover, receptor component protein (RCP) expression was higher in HMMA than in HCA. Functional experiments showed that olcegepant inhibits relaxation to all three agonists in both vascular beds. In HCA, antagonist AM22-52 did not inhibit relaxation to any of the agonists, while a trend for blocking relaxation to AM and AM2 could be observed in HMMA. Conclusion Based on the combined results from receptor subunit mRNA expression and the functional responses in both vascular tissues, relaxation of HCA is mainly mediated via the canonical CGRP receptor (CLR-RAMP1), while relaxation of HMMA can be mediated via both the canonical CGRP receptor and the adrenomedullin 1 receptor (CLR-RAMP2). Future research should investigate whether RAMP2 predominance over RAMP1 in the meningeal vasculature results in altered migraine susceptibility or in a different response to anti-migraine medication in these patients. Moreover, the exact role of RCP in CGRP receptor signalling should be elucidated in future research.

Endometrioid ovarian cancers (EOvC) are usually managed as serous tumors. In this study, we conducted a comprehensive molecular investigation to uncover the distinct biological characteristics of EOvC. This retrospective multicenter study involved patients from three European centers. We collected clinical data and formalin‐fixed paraffin‐embedded (FFPE) samples for analysis at the DNA level using panel‐based next‐generation sequencing and array‐comparative genomic hybridization. Additionally, we examined mRNA expression using NanoString nCounter® and protein expression through tissue microarray. We compared EOvC with other ovarian subtypes and uterine endometrioid tumors. Furthermore, we assessed the impact of molecular alterations on patient outcomes, including progression‐free survival (PFS) and overall survival (OS). Preliminary analysis of clinical data from 668 patients, including 86 (12.9%) EOvC, revealed more favorable prognosis for EOvC compared with serous ovarian carcinoma (5‐year OS of 60% versus 45%; P = 0.001) driven by diagnosis at an earlier stage. Immunohistochemistry and copy number alteration (CNA) profiles of 43 cases with clinical data and FFPE samples available indicated that EOvC protein expression and CNA profiles were more similar to endometrioid endometrial tumors than to serous ovarian carcinomas. EOvC exhibited specific alterations, such as lower rates of PTEN loss, mutations in DNA repair genes, and P53 abnormalities. Survival analysis showed that patients with tumors harboring loss of PTEN expression had worse outcomes (median PFS 19.6 months vs. not reached; P = 0.034). Gene expression profile analysis confirmed that EOvC differed from serous tumors. However, comparison to other rare subtypes of ovarian cancer suggested that the EOvC transcriptomic profile was close to that of ovarian clear cell carcinoma. Downregulation of genes involved in the PI3K pathway and DNA methylation was observed in EOvC. In conclusion, EOvC represents a distinct biological entity and should be regarded as such in the development of specific clinical approaches.

Abstract Background Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset autosomal dominant inherited neuromuscular disorder caused by mutations in the PAPBN1 gene. These mutations consist in short (1‐8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD. Methods In this study, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild‐type) and A17 (OPMD) mice underwent a 6‐week‐long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of gastrocnemius and soleus muscles was performed, inducing hypertrophy of the plantaris muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted. Results Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both tibialis anterior (+24%, **P = 0.0026) and gastrocnemius (+18%, ****P

Abstract Background Several fusion oncogenes showing a higher incidence in pediatric acute myeloid leukemia (AML) are associated with heterogeneous megakaryoblastic and other myeloid features. Here we addressed how developmental mechanisms influence human leukemogenesis by ETO2::GLIS2, associated with dismal prognosis. Methods We created novel ETO2::GLIS2 models of leukemogenesis through lentiviral transduction and CRISPR-Cas9 gene editing of human fetal and post-natal hematopoietic stem/progenitor cells (HSPCs), performed in-depth characterization of ETO2::GLIS2 transformed cells through multiple omics and compared them to patient samples. This led to a preclinical assay using patient-derived-xenograft models to test a combination of two clinically-relevant molecules. Results We showed that ETO2::GLIS2 expression in primary human fetal CD34+ hematopoietic cells led to more efficient in vivo leukemia development than expression in post-natal cells. Moreover, cord blood-derived leukemogenesis has a major dependency on the presence of human cytokines, including IL3 and SCF. Single cell transcriptomes revealed that this cytokine environment controlled two ETO2::GLIS2-transformed states that were also observed in primary patient cells. Importantly, this cytokine sensitivity may be therapeutically-exploited as combined MEK and BCL2 inhibition showed higher efficiency than individual molecules to reduce leukemia progression in vivo. Conclusions Our study uncovers an interplay between the cytokine milieu and transcriptional programs that extends a developmental window of permissiveness to transformation by the ETO2::GLIS2 AML fusion oncogene, controls the intratumoral cellular heterogeneity, and offers a ground-breaking therapeutical opportunity by a targeted combination strategy.

Abstract Volcanic eruptions necessitate precise monitoring of magma pressure and inflation for improved forecasting. Understanding deep magma storage is crucial for hazard assessment, yet imaging these systems is challenging due to complex heterogeneities that disrupt standard seismic migration techniques. Here we map the magmatic and hydrothermal system of the La Soufrière volcano in Guadeloupe by analyzing seismic noise data from a sparse geophone array under a matrix formalism. Seismic noise interferometry provides a reflection matrix containing the signature of echoes from deep heterogeneities. Using wave correlations resistant to disorder, matrix imaging successfully unscrambles wave distortions, revealing La Soufrière’s internal structure down to 10 km with 100 m resolution. This method surpasses the diffraction limit imposed by geophone array aperture, providing crucial data for modeling and high-resolution monitoring. We see matrix imaging as a revolutionary tool for understanding volcanic systems and enhancing observatories’ abilities to monitor dynamics and forecast eruptions.

Abstract Background Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Methods Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Results Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Conclusion Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.

Abstract Several studies have demonstrated the existence of a link between action observation (AO) and language. However, the optimizing parameters for this link have not been explored until now. To answer this question, the present study proposed two experiments for assessing the role of motor repertory and attentional focus. Sixty participants performed a priming task in which they had to decide if a verb was or was not an action verb after they saw a point-light display (PLD) representing an action. Only one difference distinguished the experiments. In experiment one, the PLD was either in accordance or not with the gender kinematics of the observer, whereas in the second experiment, the PLD either focused on or was unfocused on the main limbs implied in the action. The results show that motor repertory affects the link between action observation and action verb processing, whereas attentional focus does not. Implications of these results are highlighted in the discussion, notably to better understand the mechanisms that explain the link between action observation and action verb processing.

Abstract Background Dairy cattle breeds are populations of limited effective size, subject to recurrent outbreaks of recessive defects that are commonly studied using positional cloning. However, this strategy, based on the observation of animals with characteristic features, may overlook a number of conditions, such as immune or metabolic genetic disorders, which may be confused with pathologies of environmental etiology. Results We present a data mining framework specifically designed to detect recessive defects in livestock that have been previously missed due to a lack of specific signs, incomplete penetrance, or incomplete linkage disequilibrium. This approach leverages the massive data generated by genomic selection. Its basic principle is to compare the observed and expected numbers of homozygotes for sliding haplotypes in animals with different life histories. Within three cattle breeds, we report 33 new loci responsible for increased risk of juvenile mortality and present a series of validations based on large-scale genotyping, clinical examination, and functional studies for candidate variants affecting the NOA1, RFC5, and ITGB7 genes. In particular, we describe disorders associated with NOA1 and RFC5 mutations for the first time in vertebrates. Conclusions The discovery of these many new defects will help to characterize the genetic basis of inbreeding depression, while their management will improve animal welfare and reduce losses to the industry.

Abstract The bay scallop, Argopecten irradians, is a species of major commercial, cultural, and ecological importance. It is endemic to the eastern coast of the United States, but has also been introduced to China, where it supports a significant aquaculture industry. Here, we provide an annotated chromosome-level reference genome assembly for the bay scallop, assembled using PacBio and Hi-C data. The total genome size is 845.9 Mb, distributed over 1,503 scaffolds with a scaffold N50 of 44.3 Mb. The majority (92.9%) of the assembled genome is contained within the 16 largest scaffolds, corresponding to the 16 chromosomes confirmed by Hi-C analysis. The assembly also includes the complete mitochondrial genome. Approximately 36.2% of the genome consists of repetitive elements. The BUSCO analysis showed a completeness of 96.2%. We identified 33,772 protein-coding genes. This genome assembly will be a valuable resource for future research on evolutionary dynamics, adaptive mechanisms, and will support genome-assisted breeding, contributing to the conservation and management of this iconic species in the face of environmental and pathogenic challenges.

Abstract Biosensors are used to detect and quantify chemicals produced in industrial microbiology with high specificity, sensitivity, and portability. Most biosensors, however, are limited by the need for transcription factors engineered to recognize specific molecules. In this study, we overcome the limitations typically associated with traditional biosensors by engineering Pseudomonas putida for whole-cell sensing of a variety of chemicals. Our approach integrates fluorescent reporters with synthetic auxotrophies within central metabolism that can be complemented by target analytes in growth-coupled setups. This platform enables the detection of a wide array of structurally diverse chemicals under various conditions, including co-cultures of producer cell factories and sensor strains. We also demonstrate the applicability of this versatile biosensor platform for monitoring complex biochemical processes, including plastic degradation by either purified hydrolytic enzymes or engineered bacteria. This microbial system provides a rapid, sensitive, and readily adaptable tool for monitoring cell factory performance and for environmental analyzes.

Abstract Surfaces – by breaking bulk symmetries, introducing roughness, or hosting defects – can significantly influence magnetic order in magnetic materials. Determining their effect on the complex nanometer-scale phases present in certain non-centrosymmetric magnets is an outstanding problem requiring high-resolution magnetic microscopy. Here, we use scanning SQUID microscopy to image the surface of bulk Cu2OSeO3 at low temperature and in a magnetic field applied along $$\left\langle 100\right\rangle$$ 100 . Real-space maps measured as a function of applied field reveal the microscopic structure of the magnetic phases and their transitions. In low applied field, we observe a magnetic texture consistent with an in-plane stripe phase, pointing to the existence of a distinct surface state. In the low-temperature skyrmion phase, the surface is populated by clusters of disordered skyrmions, which emerge from rupturing domains of the tilted spiral phase. Furthermore, we displace individual skyrmions from their pinning sites by applying an electric potential to the scanning probe, thereby demonstrating local skyrmion control at the surface of a magnetoelectric insulator.

Abstract Background The intricate three-dimensional anatomy of the inner ear presents significant challenges in diagnostic procedures and critical surgical interventions. Recent advancements in deep learning (DL), particularly convolutional neural networks (CNN), have shown promise for segmenting specific structures in medical imaging. This study aimed to train and externally validate an open-source U-net DL general model for automated segmentation of the inner ear from computed tomography (CT) scans, using quantitative and qualitative assessments. Methods In this multicenter study, we retrospectively collected a dataset of 271 CT scans to train an open-source U-net CNN model. An external set of 70 CT scans was used to evaluate the performance of the trained model. The model’s efficacy was quantitatively assessed using the Dice similarity coefficient (DSC) and qualitatively assessed using a 4-level Likert score. For comparative analysis, manual segmentation served as the reference standard, with assessments made on both training and validation datasets, as well as stratified analysis of normal and pathological subgroups. Results The optimized model yielded a mean DSC of 0.83 and achieved a Likert score of 1 in 42% of the cases, in conjunction with a significantly reduced processing time. Nevertheless, 27% of the patients received an indeterminate Likert score of 4. Overall, the mean DSCs were notably higher in the validation dataset than in the training dataset. Conclusion This study supports the external validation of an open-source U-net model for the automated segmentation of the inner ear from CT scans. Relevance statement This study optimized and assessed an open-source general deep learning model for automated segmentation of the inner ear using temporal CT scans, offering perspectives for application in clinical routine. The model weights, study datasets, and baseline model are worldwide accessible. Key Points A general open-source deep learning model was trained for CT automated inner ear segmentation. The Dice similarity coefficient was 0.83 and a Likert score of 1 was attributed to 42% of automated segmentations. The influence of scanning protocols on the model performances remains to be assessed. Graphical Abstract

Abstract Background The hard clam (Mercenaria mercenaria), a marine bivalve distributed along the U.S. eastern seaboard, supports a significant shellfish industry. Overharvest in the 1970s and 1980s led to a reduction in landings. While the transition of industry from wild harvest to aquaculture since that time has enhanced production, it has also exacerbated challenges such as disease outbreaks. In this study, we developed and validated a 66K SNP array designed to advance genetic studies and improve breeding programs in the hard clam, focusing particularly on the development of markers that could be useful in understanding disease resistance and environmental adaptability. Results Whole-genome resequencing of 84 individual clam samples and 277 pooled clam libraries yielded over 305 million SNPs, which were filtered down to a set of 370,456 SNPs that were used as input for the design of a 66K SNP array. This medium-density array features 66,543 probes targeting coding and non-coding regions, including 70 mitochondrial SNPs, to capture the extensive genetic diversity within the species. The SNPs were distributed evenly throughout the clam genome, with an average interval of 25,641 bp between SNPs. The array incorporates markers for detecting the clam pathogen Mucochytrium quahogii (formerly QPX), enhancing its utility in disease management. Performance evaluation on 1,904 samples demonstrated a 72.7% pass rate with stringent quality control. Concordance testing affirmed the array's repeatability, with an average agreement of allele calls of 99.64% across multiple tissue types, highlighting its reliability. The tissue-specific analysis demonstrated that some tissue types yield better genotyping results than others. Importantly, the array, including its embedded mitochondrial markers, effectively elucidated complex genetic relationships across different clam groups, both wild populations and aquacultured stocks, showcasing its utility for detailed population genetics studies. Conclusions The 66K SNP array is a powerful and robust genotyping tool that offers unprecedented insights into the species’ genomic architecture and population dynamics and that can greatly facilitate hard clam selective breeding. It represents an important resource that has the potential to transform clam aquaculture, thereby promoting industry sustainability and ecological and economic resilience.

Abstract Background Learning to interpret electrocardiograms (ECGs) is a crucial objective in medical education. Despite its importance, errors in ECGs interpretation are common, and the optimal teaching methods have not yet been clearly established. Objectives To evaluate students’ confidence in ECGs analysis and their opinion on current teaching methods, and to assess the effectiveness of a new ECG educational approach. Methods First, we conducted a survey on ECG learning among fourth to sixth-year medical students. Second, a 5-week multicenter comparative study was conducted with fourth-year medical students during their cardiology internship. Two different teaching methods were used, assigned by center. The first group participated in 5-minutes workshops 4 times a week using a “reversed classroom” method, supervised by a cardiologist, where students took turns selecting, presenting and discussing ECGs. The control group attended a single 2-hour face-to-face ECG course. All participants completed a 30-minute ECGs analysis test at baseline and after 5 weeks. Results Out of 401 survey respondents, the confidence levels in ECG interpretation were 3/5 (IQR 2–3) for routine situations and 2/5 (IQR 1–3) for emergency situations. Satisfaction with ECG teaching was low (2/5, IQR 1–3) and 96.3% of respondents favored more extensive ECG training. In the comparative study, 52 students from 3 medical schools were enrolled (control group: n = 27; workshop group: n = 25). Both groups showed significant improvement in exam scores from baseline to 5-week (33/100 ± 12/100 to 44/100 ± 12/100, p

Abstract Background Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce. Methods A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up. Results Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1–12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients. Conclusions Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.

Abstract Konzo is a neglected paralytic neurological disease associated with food (cassava) poisoning that affects the world’s poorest children and women of childbearing ages across regions of sub-Saharan Africa. Despite understanding the dietary factors that lead to konzo, the molecular markers and mechanisms that trigger this disease remain unknown. To identify potential protein biomarkers associated with a disease status, plasma was collected from two independent Congolese cohorts, a discovery cohort (n = 60) and validation cohort (n = 204), sampled 10 years apart and subjected to multiple high-throughput assays. We identified that Glutathione Peroxidase 3 (GPx3), a critical plasma-based antioxidant enzyme, was the sole protein examined that was both significantly and differentially abundant between affected and non-affected participants in both cohorts, with large reductions observed in those affected with konzo. Our findings raise the notion that reductions in key antioxidant mechanisms may be the biological risk factor for the development of konzo, particularly those mediated through pathways involving the glutathione peroxidase family.

Abstract The inhibitor of κB (IκB) kinase (IKK) is a central regulator of NF-κB signaling. All IKK complexes contain hetero- or homodimers of the catalytic IKKβ and/or IKKα subunits. Here, we identify a YDDΦxΦ motif, which is conserved in substrates of canonical (IκBα, IκBβ) and alternative (p100) NF-κB pathways, and which mediates docking to catalytic IKK dimers. We demonstrate a quantitative correlation between docking affinity and IKK activity related to IκBα phosphorylation/degradation. Furthermore, we show that phosphorylation of the motif’s conserved tyrosine, an event previously reported to promote IκBα accumulation and inhibition of NF-κB gene expression, suppresses the docking interaction. Results from integrated structural analyzes indicate that the motif binds to a groove at the IKK dimer interface. Consistently, suppression of IKK dimerization also abolishes IκBα substrate binding. Finally, we show that an optimized bivalent motif peptide inhibits NF-κB signaling. This work unveils a function for IKKα/β dimerization in substrate motif recognition.

Abstract Strains of the Bacillus cereus (Bc) group are sporulating bacteria commonly associated with foodborne outbreaks. Spores are dormant cells highly resistant to extreme conditions. Nevertheless, the pathological processes associated with the ingestion of either vegetative cells or spores remain poorly understood. Here, we demonstrate that while ingestion of vegetative bacteria leads to their rapid elimination from the intestine of Drosophila melanogaster, a single ingestion of spores leads to the persistence of bacteria for at least 10 days. We show that spores do not germinate in the anterior part of the intestine which bears the innate immune defenses. Consequently, spores reach the posterior intestine where they germinate and activate both the Imd and Toll immune pathways. Unexpectedly, this leads to the induction of amidases, which are negative regulators of the immune response, but not to antimicrobial peptides. Thereby, the local germination of spores in the posterior intestine dampens the immune signaling that in turn fosters the persistence of Bc bacteria. This study provides evidence for how Bc spores hijack the intestinal immune defenses allowing the localized birth of vegetative bacteria responsible for the digestive symptoms associated with foodborne illness outbreaks.

Abstract Background A train-the-trainer approach can effectively support the integration of new practice standards for health and social services professionals. This study describes the effects of an enhanced train-the-trainer program to support registered nurses and social workers working in primary care clinics in their understanding of the fundamental principles of primary care. Methods We implemented an enhanced train-the-trainer program for registered nurses and social workers in six primary care clinics. We conducted a pre-post study using quantitative and qualitative data to assess trainers’ and trainees’ intention, commitment, and confidence in applying acquired knowledge. Results We trained 11 trainers and 33 trainees. All the trainers and trainees were satisfied with the program. Trainers were less confident in their abilities as trainers following the training, especially regarding tailored coaching (p = 0.03). Trainees’ commitment to becoming familiar with the functioning of their clinic (p = 0.05) and becoming part of the team increased significantly (p = 0.01); however, their intention to use their knowledge decreased (p = 0.02). Trainers and trainees identified organizational and professional barriers that may explain the observed decrease. Conclusion An enhanced train-the-trainer program positively impacted registered nurses’ and social workers’ assimilation of the fundamental principles of primary care. Further research is needed to understand the long-term effects of train-the-trainer programs on primary care trainees and how these effects translate into patient care.

Abstract Background Over the past three decades, our understanding of sleep apnea in women has advanced, revealing disparities in pathophysiology, diagnosis, and treatment compared to men. However, no real-life study to date has explored the relationship between mask-related side effects (MRSEs) and gender in the context of long-term CPAP. Methods The InterfaceVent-CPAP study is a prospective real-life cross-sectional study conducted in an apneic adult cohort undergoing at least 3 months of CPAP with unrestricted mask-access (34 different masks, no gender specific mask series). MRSE were assessed by the patient using visual analog scales (VAS). CPAP-non-adherence was defined as a mean CPAP-usage of less than 4 h per day. The primary objective of this ancillary study was to investigate the impact of gender on the prevalence of MRSEs reported by the patient. Secondary analyses assessed the impact of MRSEs on CPAP-usage and CPAP-non-adherence depending on the gender. Results A total of 1484 patients treated for a median duration of 4.4 years (IQ25–75: 2.0–9.7) were included in the cohort, with women accounting for 27.8%. The prevalence of patient-reported mask injury, defined as a VAS score ≥ 5 (p = 0.021), was higher in women than in men (9.6% versus 5.3%). For nasal pillow masks, the median MRSE VAS score for dry mouth was higher in women (p = 0.039). For oronasal masks, the median MRSE VAS score for runny nose was higher in men (p = 0.039). Multivariable regression analyses revealed that, for both women and men, dry mouth was independently and negatively associated with CPAP-usage, and positively associated with CPAP-non-adherence. Conclusion In real-life patients treated with long-term CPAP, there are gender differences in patient reported MRSEs. In the context of personalized medicine, these results suggest that the design of future masks should consider these gender differences if masks specifically for women are developed. However, only dry mouth, a side effect not related to mask design, impacts CPAP-usage and non-adherence. Trial Registration: InterfaceVent is registered with ClinicalTrials.gov (NCT03013283).First registration date is 2016–12-23.

Abstract Purpose The aim of the study was to identify settings associated with SARS-CoV-2 transmission throughout the COVID-19 pandemic in France. Methods Cases with recent SARS-CoV-2 infection were matched with controls (4:1 ratio) on age, sex, region, population size, and calendar week. Odds ratios for SARS-CoV-2 infection were estimated for nine periods in models adjusting for socio-demographic characteristics, health status, COVID-19 vaccine, and past infection. Results Between October 27, 2020 and October 2, 2022, 175,688 cases were matched with 43,922 controls. An increased risk of infection was documented throughout the study for open-space offices compared to offices without open space (OR range across the nine periods: 1.12 to 1.57) and long-distance trains (1.25 to 1.88), and during most of the study for convenience stores (OR range in the periods with increased risk: 1.15 to 1.44), take-away delivery (1.07 to 1.28), car-pooling with relatives (1.09 to 1.68), taxis (1.08 to 1.89), airplanes (1.20 to 1.78), concerts (1.31 to 2.09) and night-clubs (1.45 to 2.95). No increase in transmission was associated with short-distance shared transport, car-pooling booked over platforms, markets, supermarkets and malls, hairdressers, museums, movie theatres, outdoor sports, and swimming pools. The increased risk of infection in bars and restaurants was no longer present in restaurants after reopening in June 2021. It persisted in bars only among those aged under 40 years. Conclusion Closed settings in which people are less likely to wear masks were most affected by SARS-CoV-2 transmission and should be the focus of air quality improvement. ClinicalTrials.gov (03/09/2022) NCT04607941.

The Trillat procedure, initially described by Albert Trillat, is historically one of the first techniques for addressing recurrent anterior shoulder instability, incorporating fascinating biomechanical mechanisms. After lowering, medializing, and fixing the coracoid process to the glenoid neck, the subcoracoid space is reduced, the subscapularis lowered, and its line of pull changed, accentuating the function of the subscapularis as a humeral head depressor centering the glenohumeral joint. Furthermore, the conjoint tendon creates a ‘seatbelt’ effect, preventing anteroinferior humeral head dislocation. Even though contemporary preferences lean towards arthroscopic Bankart repair with optional remplissage, bone augmentation, and the Latarjet procedure, enduring surgical indications remain valid for the Trillat procedure, which offers joint preservation and superior outcomes in two distinct scenarios: (i) older patients with massive irreparable cuff tears and anterior recurrent instability with an intact subscapularis tendon regardless of the extent of glenoid bone loss; (ii) younger patients with instability associated shoulder joint capsule hyperlaxity without concomitant injuries (glenoid bone loss, large Hill–Sachs lesion). Complications associated with the Trillat procedure include recurrent anterior instability, potential overtightening of the coracoid, leading to pain and a significant reduction in range of motion, risk of subcoracoid impingement, and restriction of external rotation by up to 10°, a limitation that is generally well-tolerated. The Trillat procedure may be an effective alternative technique for specific indications and should remain part of the surgical armamentarium for addressing anterior shoulder instability.

The formation of defects, due to drying, in robocasted ceramic objects is an important issue arising from non-uniform shrinkage of the material during this step in the process. Common methods for shrinkage measurement are not well suited to the small size of robocasted cords or the complexity of robocasted objects. Innovative methods for shrinkage measurement were developed using non-destructive optical vision techniques with computer-controlled data acquisition, allowing measurement on millimetric cords and on specific zones of a product. The study of a single porcelain cord revealed an anisometric shrinkage related to the orientation of grains during extrusion. A differential shrinkage at the macroscopic scale was also measured on a robocasted object, indicating a moisture content gradient in the material. The methods presented in this paper are of particular relevance to real-time control of the drying process for robocasted objects.

Abstract Due to their high resolution, anonymized CT scans can be reidentified using face recognition tools. However, little is known regarding PET deanonymization because of its lower resolution. In this study, we analysed PET/CT scans of 853 patients from a TCIA-restricted dataset (AutoPET). First, we built denoised 2D morphological reconstructions of both PET and CT scans, and then we determined how frequently a PET reconstruction could be matched to the correct CT reconstruction with no other metadata. Using the CT morphological reconstructions as ground truth allows us to frame the problem as a face recognition problem and to quantify our performance using traditional metrics (top k accuracies) without any use of patient pictures. Using our denoised PET 2D reconstructions, we achieved 72% top 10 accuracy after the realignment of all CTs in the same reference frame, and 71% top 10 accuracy after realignment and mixing within a larger face dataset of 10, 168 pictures. This highlights the need to consider face identification issues when dealing with PET imaging data.

Abstract The Cluster mission will always be the first ever multi-spacecraft mission mapping the Earth magnetosphere in three dimensions. Launched in 2000 and originally planned to operate for two years, it has been orbiting Earth for more than two solar cycles. Over the course of its lifetime, its data have enabled the scientific community to conduct pioneer science. Recent scientific highlights will be presented first, followed by the latest scientific objectives that have guided the Cluster mission operations from 2021 until 2024. Early September 2024, one spacecraft of this veteran constellation will re-enter in a controlled manner the Earth’s atmosphere, followed by its companions in 2025 and 2026. As we will see, this will be a unique opportunity to improve the ESA space debris re-entry models. Lastly, preparation of its legacy phase will be presented. Graphical Abstract

Abstract Working life is associated with lifestyle, screening uptake, and occupational health risks that may explain differences in cancer onset. To better understand the association between working life and cancer risk, we need to account for the entire employment history. We investigated whether lifetime employment trajectories are associated with cancer risk. We used data from 6809 women and 5716 men, average age 70 years, from the Survey of Health, Ageing, and Retirement in Europe. Employment history from age 16 to 65 was collected retrospectively using a life calendar and trajectories were constructed using sequence analysis. Associations between employment trajectories and self-reported cancer were assessed using logistic regression. We identified eight employment trajectories for women and two for men. Among women, the risk of cancer was higher in the trajectories “Mainly full-time to home/family”, “Full-time or home/family to part-time”, “Mainly full-time”, and “Other” compared with the “Mainly home/family” trajectory. Among men, the risk of cancer was lower in the “Mainly self-employment” trajectory compared with “Mainly full-time”. We could show how employment trajectories were associated with cancer risk, underlining the potential of sequence analysis for life course epidemiology. More research is needed to understand these associations and determine if causal relationships exist.

Abstract Across the stable density stratification of the abyssal ocean, deep dense water is slowly propelled upward by sustained, though irregular, turbulent mixing. The resulting mean upwelling determines large-scale oceanic circulation properties like heat and carbon transport. In the ocean interior, this turbulent mixing is caused mainly by breaking internal waves: generated predominantly by winds and tides, these waves interact nonlinearly, transferring energy downscale, and finally become unstable, break and mix the water column. This paradigm, long parameterized heuristically, still lacks full theoretical explanation. Here, we close this gap using wave-wave interaction theory with input from both localized and global observations. We find near-ubiquitous agreement between first-principle predictions and observed mixing patterns in the global ocean interior. Our findings lay the foundations for a wave-driven mixing parameterization for ocean general circulation models that is entirely physics-based, which is key to reliably represent future climate states that could differ substantially from today’s.

Abstract Background Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance. Methods We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research. Results We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations. Conclusions The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients.

Abstract Background Post-intensive care syndrome could be responsible for inability to receive proper cancer treatment after ICU stay in patients with solid tumors (ST). Our purpose was to determine the factors associated with cancer treatment resumption and the impact of cancer treatment on the outcome of patients with ST after ICU stay. Methods We conducted a retrospective study including all patients with ST admitted to the ICU between 2014 and 2019 in a French University-affiliated Hospital. Results A total of 219 patients were included. Median SAPS II at ICU admission was 44.0 [IQR 32.8, 66.3]. Among the 136 patients who survived the ICU stay, 81 (59.6%) received cancer treatment after ICU discharge. There was an important increase in patients with poor performance status (PS) of 3 or 4 after ICU stay (16.2% at admission vs. 44.5% of patients who survived), with significant PS decline following the ICU stay (median difference − 1.5, 95% confidence interval [-1.5-1.0], p

Abstract More than half of the world’s rivers dry up periodically, but our understanding of the biological communities in dry riverbeds remains limited. Specifically, the roles of dispersal, environmental filtering and biotic interactions in driving biodiversity in dry rivers are poorly understood. Here, we conduct a large-scale coordinated survey of patterns and drivers of biodiversity in dry riverbeds. We focus on eight major taxa, including microorganisms, invertebrates and plants: Algae, Archaea, Bacteria, Fungi, Protozoa, Arthropods, Nematodes and Streptophyta. We use environmental DNA metabarcoding to assess biodiversity in dry sediments collected over a 1-year period from 84 non-perennial rivers across 19 countries on four continents. Both direct factors, such as nutrient and carbon availability, and indirect factors such as climate influence the local biodiversity of most taxa. Limited resource availability and prolonged dry phases favor oligotrophic microbial taxa. Co-variation among taxa, particularly Bacteria, Fungi, Algae and Protozoa, explain more spatial variation in community composition than dispersal or environmental gradients. This finding suggests that biotic interactions or unmeasured ecological and evolutionary factors may strongly influence communities during dry phases, altering biodiversity responses to global changes.

Abstract Quantum spin liquids (QSLs) have become a key area of research in magnetism due to their remarkable properties, such as long-range entanglement, fractional excitations, and topologically protected phenomena. Recently, the search for QSLs has expanded into the three-dimensional world, despite the suppression of quantum fluctuations due to high dimensionality. A new candidate material, K2Ni2(SO4)3, belongs to the langbeinite family and consists of two interconnected trillium lattices. Although magnetically ordered, it exhibits a highly dynamical and correlated state. In this work, we combine inelastic neutron scattering measurements with density functional theory (DFT), pseudo-fermion functional renormalization group (PFFRG), and classical Monte Carlo (cMC) calculations to study the magnetic properties of K2Ni2(SO4)3, revealing a high level of agreement between experiment and theory. We further reveal the origin of the dynamical state in K2Ni2(SO4)3 to be centred around a magnetic network composed of tetrahedra on a trillium lattice.

Abstract Background Nitric oxide (NO) is a strong vasodilator, selectively directed on pulmonary circulation through inhaled administration. In adult intensive care units (ICU), it is mainly used for refractory hypoxemia in mechanically ventilated patients. Several medical delivery devices have been developed to deliver inhaled nitric oxide (iNO). The main purpose of those devices is to guarantee an accurate inspiratory NO concentration, whatever the ventilator used, with NO2 concentrations lower than 0.3 ppm. We hypothesized that the performances of the different available iNO delivery systems could depend on their working principle and could be influenced by the ventilator settings. The objective of this study was to assess the accuracy of seven different iNO-devices combined with different ICU ventilators’ flow-by to reach inspiratory NO concentration targets and to evaluate their potential risk of toxicity. Methods We tested seven iNO-devices on a test-lung connected to distinct ICU ventilators offering four different levels of flow-by. We measured the flow in the inspiratory limb of the patient circuit and the airway pressure. The nitric oxide/nitrogen (NO/N2) flow was measured on the administration line of the iNO-devices. NO and NO2 concentrations were measured in the test-lung using an electrochemical analyzer. Results We identified three iNO-device generations based on the way they deliver NO flow: “Continuous”, “Sequential to inspiratory phase” (I-Sequential) and “Proportional to inspiratory and expiratory ventilator flow” (Proportional). Median accuracy of iNO concentration measured in the test lung was 2% (interquartile range, IQR -19; 36), -23% (IQR -29; -17) and 0% (IQR -2; 0) with Continuous, I-Sequential and Proportional devices, respectively. Increased ventilator flow-by resulted in decreased iNO concentration in the test-lung with Continuous and I-Sequential devices, but not with Proportional ones. NO2 formation measured to assess potential risks of toxicity never exceeded the predefined safety target of 0.5 ppm. However, NO2 concentrations higher than or equal to 0.3 ppm, a concentration that can cause bronchoconstriction, were observed in 19% of the different configurations. Conclusion We identified three different generations of iNO-devices, based on their gas administration modalities, that were associated with highly variable iNO concentrations’ accuracy. Ventilator’s flow by significantly impacted iNO concentration. Only the Proportional devices permitted to accurately deliver iNO whatever the conditions and the ventilators tested.

A new spider species, Selenogyrus foordi sp. nov. (♂♀), is described from Mount Nimba, Guinea. Consequently, we provide the first in vivo photographs of a selenogyrine in the scientific literature and the first record of Selenogyrinae Smith, 1990 from Guinea. We also record S. aureus Pocock, 1897, described from Sierra Leone, from Massif du Ziama Biosphere Reserve, Guinea, representing the second known species for this country.

Abstract Musculoskeletal disorders (MDs) represent a global health issue, which can lead to disability. Physical activity (PA) reduces pain and increases physical function among patients with MDs. To promote behavioural changes, it seems important to focus on modifiable factors, such as motivation. Thus, this review aims to assess effects of interventions targeting PA on motivation towards PA. Searches used terms referring to “physical activity”, “motivation” and “chronic musculoskeletal disorders” on the databases PubMed, PsychINFO, MEDLINE, EMBASE, PEDro and Web of Science. All types of intervention—including but not limited to RCTs—were eligible for inclusion. Risk of bias was assessed with the Quality Assessment Tool for Studies with Diverse Designs (QATSDD). Among 6 489 abstracts identified, there were 387 eligible studies and 19 were included, reporting in total 34 effect sizes. The meta-analysis concerned 1 869 patients and indicated a small effect of interventions on change in motivation towards PA (d = 0.34; 95% CI [0.15; 0.54]; p

Purpose: This review aims to discuss the psychological aspects of Graves’ ophthalmopathy (GO), estimate the prevalence of depression and anxiety disorders in GO, examine whether these psychiatric disorders are more prevalent in GO than in Graves’ disease (GD) without eye disease, and evaluate the main contributors for depression and anxiety in GO. Methods: A review of the literature. Results: Both depression and anxiety are associated with GO. The prevalence of depression and anxiety disorders specifically in GO patients was estimated at 18–33% and 26–41%, respectively. The reported prevalence in GD patients ranged from 9% to 70% for depression and from 18% to 88% for anxiety disorders. Significantly higher levels of depression and anxiety were found in GD patients compared with patients with non-autoimmune hyperthyroidism. Conflicting results have been reported regarding the association of antithyroid autoantibodies with depression and anxiety disorders. Serum thyroid hormone levels do not correlate with the severity of depression and anxiety. An improvement of psychiatric symptoms is observed in hyperthyroid patients after treatment of thyrotoxicosis. Moreover, depression and anxiety are significantly related to impaired quality of life (QoL) in GO. Exophthalmos and diplopia were not associated with depression nor anxiety, but orbital decompression and strabismus surgery do seem to improve QoL in GO patients. Conclusions: The results of this review suggest that altered thyroid hormone levels and autoimmunity are prognostic factors for depression and anxiety in GO. With regard to the visual and disfiguring aspects of GO as contributing factors for depression and anxiety, no decisive conclusions can be made.

Abstract Background Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR −/− ) to examine the evolution of pancreatic disease through gestation. Methods Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. Results Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR −/− pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR −/− animals at 80- and 120-days gestation, as are stellate cells at term. Conclusion The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.

The discovery of novel therapeutic targets, defined as proteins which drugs can interact with to induce therapeutic benefits, typically represent the first and most important step of drug discovery. One solution for target discovery is target repositioning, a strategy which relies on the repurposing of known targets for new diseases, leading to new treatments, less side effects and potential drug synergies. Biological networks have emerged as powerful tools for integrating heterogeneous data and facilitating the prediction of biological or therapeutic properties. Consequently, they are widely employed to predict new therapeutic targets by characterizing potential candidates, often based on their interactions within a Protein-Protein Interaction (PPI) network, and their proximity to genes associated with the disease. However, over-reliance on PPI networks and the assumption that potential targets are necessarily near known genes can introduce biases that may limit the effectiveness of these methods. This study addresses these limitations in two ways. First, by exploiting a multi-layer network which incorporates additional information such as gene regulation, metabolite interactions, metabolic pathways, and several disease signatures such as Differentially Expressed Genes, mutated genes, Copy Number Alteration, and structural variants. Second, by extracting relevant features from the network using several approaches including proximity to disease-associated genes, but also unbiased approaches such as propagation-based methods, topological metrics, and module detection algorithms. Using prostate cancer as a case study, the best features were identified and utilized to train machine learning algorithms to predict 5 novel promising therapeutic targets for prostate cancer: IGF2R, C5AR, RAB7, SETD2 and NPBWR1.

Seminal vesicle cystadenomas (SVC) are exceedingly rare benign tumors, with only 22 cases reported in the literature up to 2018. Here, we present the case of a 40-year-old man who presented with acute urinary retention secondary to a giant pelvic mass. Radiological imaging diagnosed a retrovesical well-delimited multicystic tumor, initially suspected to arise from the left lobe of the prostate but ultimately confirmed to originate from left seminal vesicle. Despite inconclusive biopsy results and normal tumor markers, surgical removal was recommended to confirm diagnosis. The patient initially opted for conservative management but eventually underwent open surgery due to the tumor's significant enlargement on the follow-up imagery. The procedure, though challenging due to the mass's size and proximity to adjacent structures, was successfully completed with minimal blood loss and uncomplicated postoperative phase. Histopathological evaluation confirmed the diagnosis of SVC, marking the largest reported case of its kind and the first to be discovered upon investigation of an acute urinary retention. This case highlights importance of considering SVC in the differential diagnosis of pelvic masses and underscores the role of imagery and surgery together for definitive diagnosis.

Preterm infants are prone to NeuroDevelopmental Impairment (NDI). Some previous works have identified clinical variables that can be potential predictors of NDI. However, machine learning (ML)-based models still present low predictive capabilities when addressing this problem. This work attempts to evaluate the application of ML techniques to predict NDI using clinical data from a cohort of very preterm infants recruited at birth and assessed at 2 years of age. Six different classification models were assessed, using all features, clinician-selected features, and mutual information feature selection. The best results were obtained by ML models trained using mutual information-selected features and employing oversampling, for cognitive and motor impairment prediction, while for language impairment prediction the best setting was clinician-selected features. Although the performance indicators in this local cohort are consistent with similar previous works and still rather poor. This is a clear indication that, in order to obtain better performance rates, further analysis and methods should be considered, and other types of data should be taken into account together with the clinical variables.

Este artículo cruza la Historia política de las elites y del poder con la Historia de las profesiones para analizar en una perspectiva comparada (España, Francia y Reino Unido) la cuestión del estatus social de los médicos en la Europa liberal decimonónica. Se trata de demostrar que el prestigio social alcanzado por los médicos les valía una consideración suficiente para estar contado dentro de las elites de las sociedades liberales. Pero esta condición de elite era marginal, esencialmente local y muy por debajo de lo que el conjunto de la profesión esperaba. Mientras los regímenes liberales fueron censitarios, con una participación política fundada en la propiedad o la condición de funcionario, los únicos médicos que obtuvieron títulos nobiliarios u otras recompensas honorificas fueron médicos integrados a la administración pública o médicos de Corte.

Abstract Background Specific microglia responses are thought to contribute to the development and progression of neurodegenerative diseases, including Parkinson’s disease (PD). However, the phenotypic acquisition of microglial cells and their role during the underlying neuroinflammatory processes remain largely elusive. Here, according to the multiple-hit hypothesis, which stipulates that PD etiology is determined by a combination of genetics and various environmental risk factors, we investigate microglial transcriptional programs and morphological adaptations under PARK7/DJ-1 deficiency, a genetic cause of PD, during lipopolysaccharide (LPS)-induced inflammation. Methods Using a combination of single-cell RNA-sequencing, bulk RNA-sequencing, multicolor flow cytometry and immunofluorescence analyses, we comprehensively compared microglial cell phenotypic characteristics in PARK7/DJ-1 knock-out (KO) with wildtype littermate mice following 6- or 24-h intraperitoneal injection with LPS. For translational perspectives, we conducted corresponding analyses in human PARK7/DJ-1 mutant induced pluripotent stem cell (iPSC)-derived microglia and murine bone marrow-derived macrophages (BMDMs). Results By excluding the contribution of other immune brain resident and peripheral cells, we show that microglia acutely isolated from PARK7/DJ-1 KO mice display a distinct phenotype, specially related to type II interferon and DNA damage response signaling, when compared with wildtype microglia, in response to LPS. We also detected discrete signatures in human PARK7/DJ-1 mutant iPSC-derived microglia and BMDMs from PARK7/DJ-1 KO mice. These specific transcriptional signatures were reflected at the morphological level, with microglia in LPS-treated PARK7/DJ-1 KO mice showing a less amoeboid cell shape compared to wildtype mice, both at 6 and 24 h after acute inflammation, as also observed in BMDMs. Conclusions Taken together, our results show that, under inflammatory conditions, PARK7/DJ-1 deficiency skews microglia towards a distinct phenotype characterized by downregulation of genes involved in type II interferon signaling and a less prominent amoeboid morphology compared to wildtype microglia. These findings suggest that the underlying oxidative stress associated with the lack of PARK7/DJ-1 affects microglia neuroinflammatory responses, which may play a causative role in PD onset and progression.

Abstract Background Inference of Gene Regulatory Networks (GRNs) is a difficult and long-standing question in Systems Biology. Numerous approaches have been proposed with the latest methods exploring the richness of single-cell data. One of the current difficulties lies in the fact that many methods of GRN inference do not result in one proposed GRN but in a collection of plausible networks that need to be further refined. In this work, we present a Design of Experiment strategy to use as a second stage after the inference process. It is specifically fitted for identifying the next most informative experiment to perform for deciding between multiple network topologies, in the case where proposed GRNs are executable models. This strategy first performs a topological analysis to reduce the number of perturbations that need to be tested, then predicts the outcome of the retained perturbations by simulation of the GRNs and finally compares predictions with novel experimental data. Results We apply this method to the results of our divide-and-conquer algorithm called WASABI, adapt its gene expression model to produce perturbations and compare our predictions with experimental results. We show that our networks were able to produce in silico predictions on the outcome of a gene knock-out, which were qualitatively validated for 48 out of 49 genes. Finally, we eliminate as many as two thirds of the candidate networks for which we could identify an incorrect topology, thus greatly improving the accuracy of our predictions. Conclusion These results both confirm the inference accuracy of WASABI and show how executable gene expression models can be leveraged to further refine the topology of inferred GRNs. We hope this strategy will help systems biologists further explore their data and encourage the development of more executable GRN models.

Abstract Phospholipid Hydroperoxide Gluthatione Peroxidase also called Glutathione Peroxidase 4 is one of the 25 described human selenoproteins. It plays an essential role in eliminating toxic lipid hydroxy peroxides, thus inhibiting ferroptosis and favoring cell survival. GPX4 is differentially expressed according to myeloid differentiation stage, exhibiting lower expression in hematopoietic stem cells and polymorphonuclear leucocytes, while harboring higher level of expression in common myeloid progenitors and monocytes. In addition, GPX4 is highly expressed in most of acute myeloid leukemia (AML) subtypes compared to normal hematopoietic stem cells. High GPX4 expression is consistently correlated to poor prognosis in patients suffering AML. However, the role of GPX4 in the development of the myeloid lineage and in the initiation and progression of myeloid leukemia remains poorly explored. Given its essential role in the detoxification of lipid hydroperoxides, and its overexpression in most of myeloid malignancies, GPX4 inhibition has emerged as a promising therapeutic strategy to specifically trigger ferroptosis and eradicate myeloid leukemia cells. In this review, we describe the most recent advances concerning the role of GPX4 and, more generally ferroptosis in the myeloid lineage and in the emergence of AML. We also discuss the therapeutic interest and limitations of GPX4 inhibition alone or in combination with other drugs as innovative therapies to treat AML patients.

Abstract Over the past decade, several strategies have revolutionized the clinical management of patients with cutaneous melanoma (CM), including immunotherapy and targeted tyrosine kinase inhibitor (TKI)-based therapies. Indeed, immune checkpoint inhibitors (ICIs), alone or in combination, represent the standard of care for patients with advanced disease without an actionable mutation. Notably BRAF combined with MEK inhibitors represent the therapeutic standard for disease disclosing BRAF mutation. At the same time, FDG PET/CT has become part of the routine staging and evaluation of patients with cutaneous melanoma. There is growing interest in using FDG PET/CT measurements to predict response to ICI therapy and/or target therapy. While semiquantitative values such as standardized uptake value (SUV) are limited for predicting outcome, new measures including tumor metabolic volume, total lesion glycolysis and radiomics seem promising as potential imaging biomarkers for nuclear medicine. The aim of this review, prepared by an interdisciplinary group of experts, is to take stock of the current literature on radiomics approaches that could improve outcomes in CM.

Abstract Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite extensive research into new treatments. One factor contributing to its poor prognosis is the tumor's immunosuppressive microenvironment, in which the kynurenine pathway (KP) plays a significant role. This study aimed to explore how KP impacts the survival of newly diagnosed GBM patients. We examined tissue samples from 108 GBM patients to assess the expression levels of key KP markers—tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase (IDO1/2), and the aryl hydrocarbon receptor (AhR). Using immunohistochemistry and QuPath software, three tumor cores were analyzed per patient to evaluate KP marker expression. Kaplan–Meier survival analysis and stepwise multivariate Cox regression were used to determine the effect of these markers on patient survival. Results showed that patients with high expression of TDO2, IDO1/2, and AhR had significantly shorter survival times. This finding held true even when controlling for other known prognostic variables, with a hazard ratio of 3.393 for IDO1, 2.775 for IDO2, 1.891 for TDO2, and 1.902 for AhR. We suggest that KP markers could serve as useful tools for patient stratification, potentially guiding future immunomodulating trials and personalized treatment approaches for GBM patients.

Abstract B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+ T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH[MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5- T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner.

In recent years, the rapid growth of on-demand delivery services, especially in food deliveries, has spurred the exploration of innovative mobility solutions. In this context, lightweight autonomous vehicles have emerged as a potential alternative. However, their fleet-level behavior remains largely unexplored. To address this gap, we have developed an agent-based model and an environmental impact study assessing the fleet performance of lightweight autonomous food delivery vehicles. This model explores critical factors such as fleet sizing, service level, operational strategies, and environmental impacts. We have applied this model to a case study in Cambridge, MA, USA, where results indicate that there could be significant environmental benefits in replacing traditional car-based deliveries with shared lightweight autonomous vehicle fleets. Lastly, we introduce an interactive platform that offers a user-friendly means of comprehending the model’s performance and potential trade-offs, which can help inform decision-makers in the evolving landscape of food delivery innovation.