Search

Abstract Understanding the architecture of the human deep brain is especially challenging because of the complex organization of the nuclei and fascicles that support most sensorimotor and behaviour controls. There are scant dedicated tools to explore and analyse this region. Here we took a transdisciplinary approach to build a new deep-brain MRI architecture atlas drawing on advanced clinical experience of MRI-based deep brain mapping. This new tool comprises a young-male-adult MRI template spatially normalized to the ICBM152, containing T1, inversion-recovery, and diffusion MRI datasets (in vivo acquisition), and an MRI atlas of 118 labelled deep brain structures. It is open-source and gives users high resolution image datasets to describe nuclear-based and axonal architecture, combining pioneering and recent knowledge. It is a useful addition to current 3D atlases and clinical tools.

Nutrient availability is a key determinant of tumor cell behavior. While nutrient‐rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non‐derepressible 2 (GCN2; also known as eIF‐2‐alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53‐mediated apoptosis in patient‐derived models of colon adenocarcinoma (COAD). In nutrient‐rich conditions, a cell‐autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl‐tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2–MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first‐line chemotherapy oxaliplatin, on patient‐derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co‐inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells.

Abstract Purpose Adding pembrolizumab to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) improves pathologic complete response (pCR) rates and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes is unknown. This study compares 90-day post-surgical complications (PSCs) and time to adjuvant treatment among patients undergoing NAC for TNBC with and without immunotherapy. Methods Patients treated with NAC alone or with immunotherapy (NAC-I) for stage I–III TNBC between 2018 and 2022 were retrospectively identified at a single academic institution. Kruskal–Wallis rank sum and Fisher's exact tests compared patient sociodemographic and clinical characteristics. Multivariable logistic regression determined odds ratios (OR) predicting PSCs. Results Of 54 patients, 29 received NAC alone and 25 received NAC-I. Compared to NAC patients, NAC-I patients had more advanced stage tumors (p = 0.038), and had slightly higher rates of mastectomy with reconstruction (p = 0.193). 72.0% of NAC-I patients experienced a pCR, compared with 44.8% of NAC patients (p = 0.193). There were 10 PSCs (34.5%) in NAC patients compared to 9 PSCs (36.0%) in NAC-I patients (p > 0.99). Regression analysis demonstrated no association of PSCs with NAC-I (OR 0.83, 95% CI 0.19–3.60). Time to adjuvant therapy was shorter for NAC-I patients (28 days vs 36 days, p = 0.013). Conclusions Patients with TNBC receiving NAC-I have higher pCR rates and do not appear to have added 90-day PSCs or delays to adjuvant therapy despite trending toward more extensive surgical procedures compared to NAC alone. Larger studies are needed to further evaluate the surgical safety of immunotherapy.

Abstract Skin healing is a complex and dynamic physiological process that follows mechanical alteration of the skin barrier. Under normal conditions, this complex process can be divided into at least three continuous and overlapping phases: an inflammatory reaction, a proliferative phase that leads to tissue reconstruction and a phase of tissue remodeling. Macrophages critically contribute to the physiological cascade for tissue repair. In fact, as the inflammatory phase progresses, macrophage gene expression gradually shifts from pro-inflammatory M1-like to pro-resolutive M2-like characteristics, which is critical for entry into the repair phase. A dysregulation in this macrophage’ shift phenotype leads to the persistence of the inflammatory phase. Mesenchymal stromal cells and specifically the MSC-derived from adipose tissue (ADSCs) are more and more use to treat inflammatory diseases and several studies have demonstrated that ADSCs promote the wound healing thanks to their neoangiogenic, immunomodulant and regenerative properties. In several studies, ADSCs and macrophages have been injected directly into the wound bed, but the delivery of exogenous cells directly to the wound raise the problem of cell engraftment and preservation of pro-resolutive phenotype and viability of the cells. Complementary approaches have therefore been explored, such as the use of biomaterials enriched with therapeutic cell to improve cell survival and function. This review will present a background of the current scaffold models, using adipose derived stromal-cells and macrophage as therapeutic cells for wound healing, through a discussion on the potential impact for future applications in skin regeneration. According to the PRISMA statement, we resumed data from investigations reporting the use ADSCs and bioscaffolds and data from macrophages behavior with functional biomaterials in wound healing models. In the era of tissue engineering, functional biomaterials, that can maintain cell delivery and cellular viability, have had a profound impact on the development of dressings for the treatment of chronic wounds. Promising results have been showed in pre-clinical reports using ADSCs- and macrophages-based scaffolds to accelerate and to improve the quality of the cutaneous healing.

Abstract The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK’s kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.

Abstract Background Like other countries in Europe and around the world, France was hit by the COVID-19 pandemic in 2020, although it had also experienced several social crises since 2017. This study assessed the evolution of self-reported health and activity limitations and explored the dynamics of their socio-territorial inequalities among the French population aged 18–75 years between 2017 and 2021. Methods Self-reported health (SRH) and global activity limitation indicator (GALI) were assessed in the same way in the four last editions of the French Health Barometer surveys conducted in the general population in 2017, 2019, 2020, and 2021, with between 9,200 and 24,500 subjects interviewed depending on the year. The prevalence of good or very good SRH and GALI (any limitation) and their evolution between 2017 and 2021 were studied according to sex, age, main socioeconomic positions (SEP), and regions. Poisson regression models were used to estimate adjusted prevalence ratios and potential modification effects of sociodemographic and geographic characteristics. Results Between 2017 and 2021, SRH and GALI deteriorated in adults in France in a continuous way. Very good or good SRH decreased from 75.2% (CI95% [74.5–75.9]) of subjects in 2017 to 68.5% (CI95% [67.7–69.3]) in 2021. In parallel, GALI increased from 21.5% (CI95% [21.0–22.2) in 2017 to 25.2% (CI95% [24.5–26.0]) in 2021.The deterioration of indicators affected both sexes, all age classes (except 65–75 years), especially younger age classes (18–24 and 25–34 years), all geographical regions, and all SEP variables, with groups with a higher SEP deteriorating more than others. Negative variations exceeding 20% (8–10 percentage points on the absolute scale of indicators) were observed in several population groups from 2019 onwards. Conclusion The previously observed deterioration of the SRH and GALI continued in France between 2017 and 2021, with narrowing socio-territorial gradients of inequalities. The impact of successive social and health crises on the poor evolution of self-reported health and activity limitations warrants further investigation over time and across locations using complementary and possibly more detailed indicators.

OBJECTIVES: Etiological factors of testicular germ cell tumors (TGCT) remain largely unknown, but a causal role of occupational exposures to solvents has been suggested. Previous studies analyzing these exposures reported discordant results, potentially related to exposure assessment methods. The aim of this study was to investigate the role of occupational exposure to solvents on the risk of developing TGCT among young men. METHODS: This study examined occupational exposures to solvents and TGCT risk based on the lifetime work histories of 454 cases and 670 controls, aged 18–45 years, of the French national TESTIS case–control study. Solvent exposure was estimated using: (i) exposure assignment by job-exposure matrix (JEM) and (ii) JEM combined with self-reported exposure data from specific questionnaires (SQ) and expert assessment (EA). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. RESULTS: Both approaches (JEM and JEM+SQ+EA) showed a consistent association between TGCT and trichloroethylene exposure (exposed versus not exposed; JEM=OR 1.80 [95% confidence interval (CI) 1.12–2.90] and JEM+SQ+EA= OR 2.59 (95% CI 1.42–4.72). Both approaches also observed positive associations with ketone esters and fuels & petroleum-based solvents. CONCLUSION: The results suggest that some organic solvents might be involved in the pathogenesis of TGCT among occupationally exposed men. The combined use of JEM+SQ+EA seemed to limit misclassification by considering individual exposure variability and is, therefore, an appealing approach to assess occupational exposures in epidemiological studies.

Abstract Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.

BACKGROUND AND AIMS OF THE STUDY: Congenital syphilis is a rare complication of syphilis in pregnant women. Vertical transmission may occur at any time during pregnancy. The incidence of congenital syphilis has been increasing worldwide. Congenital syphilis has been a notifiable disease for many years in Switzerland but reporting does not include maternal features associated with syphilis in pregnancy or infantʼs subsequent development. We described syphilis cases among pregnant women screened over a 10-year period in Switzerland and subsequent cases of congenital syphilis, in order to identify maternal risk profiles and to optimise prevention. Second, we compared the characteristics of pregnant women screened early (1st trimester) vs late in pregnancy (2nd or 3rd trimester). Finally, we assessed the risk factors for premature birth among these women with syphilis. METHODS: A multicentre retrospective study conducted in Swiss hospitals from 2012 to 2021, including pregnant women who screened positive for syphilis (Treponema pallidum haemagglutination assay [TPHA] / T. pallidum particle agglutination assay [TPPA ] ≥1:80) and newborns exposed to T. pallidum in utero and/or congenitally infected and with a positive syphilis serology at birth. Data were collected from medical records. RESULTS: A total of 147 syphilis-positive pregnant women and 102 infants were included. A history of treated syphilis was known for 44% (65/147) of the mothers corresponding to a serological scar and the remaining 56% (82/147) were newly identified syphilis cases. Syphilis screening was done during the first trimester in 54%, second trimester in 29% and third trimester in 13% of cases. Two babies were diagnosed with congenital syphilis (1.96%). Several potential factors that could contribute to women’s risk of syphilis during pregnancy were identified such as a foreign origin (93% of mothers), lack of healthcare insurance (25%), no employment status (37%), drug use (5%), co-infection with other sexually transmitted infections (24%) and a late first antenatal consultation (42%). The number of pregnant women without insurance was higher in women diagnosed in the second or third trimester than in those diagnosed in the first trimester (odds ratio 0.41; 95% CI 0.19–0.89; p = 0.024). Syphilis diagnosed in the second or third trimester was associated with a late first antenatal consultation (odds ratio 77.82; 95% CI 9.81–617.21; p

ABSTRACT Candida auris is a yeast pathogen causing nosocomial outbreaks of candidemia. Its ability to adhere to inert surfaces and to be transmitted from one patient to another via medical devices is of particular concern. Like other Candida spp., C. auris has the ability to transition from the yeast form to pseudohyphae and to build biofilms. Moreover, some isolates have a unique capacity to form aggregates. These morphogenetic changes may impact virulence. In this study, we demonstrated the role of the transcription factor Ume6 in C. auris morphogenesis. Genetic hyperactivation of Ume6 induced filamentation and aggregation. The Ume6-hyperactivated strain (UME6HA) also exhibited increased adhesion to inert surface and formed biofilms of higher biomass compared to the parental strain. Transcriptomic analyses of UME6HA revealed enrichment of genes encoding for adhesins, proteins involved in cell wall organization, sterol biosynthesis, and aspartic protease activities. The three most upregulated genes compared to wild-type were those encoding for the agglutin-like sequence adhesin Als4498, the C. auris-specific adhesin Scf1, and the hypha-specific G1 cyclin-related protein Hgc1. The deletion of these genes in the UME6HA background showed that Ume6 controls filamentation via Hgc1 and aggregation via Als4498 and Scf1. Adhesion to inert surface was essentially triggered by Scf1. However, Als4498 and Hgc1 were also crucial for biofilm formation. Our data show that Ume6 is a universal regulator of C. auris morphogenesis via distinct modulators.IMPORTANCEC. auris represents a public health threat because of its ability to cause difficult-to-treat infections and hospital outbreaks. The morphogenetic plasticity of C. auris, including its ability to filament, to form aggregates or biofilms on inert surfaces, is important to the fungus for interhuman transmission, skin or catheter colonization, tissue invasion, antifungal resistance, and escape of the host immune system. This work deciphered the importance of Ume6 in the control of distinct pathways involved in filamentation, aggregation, adhesion, and biofilm formation of C. auris. A better understanding of the mechanisms of C. auris morphogenesis may help identify novel antifungal targets.

Research Framework: Existing studies agree that the work involved in managing debts and their consequences is mostly undertaken by women. We know that this debt work involves more deprivation and sacrifice, but we do not know its effects on women’s wealth.Objectives : This article identifies processes explaining the link between debt work and the decline of women’s wealth.Methodology: This article is based on 44 semi-structured interviews conducted in Switzerland with overindebted couples with or without children as part of two debt-related research projects funded by the Swiss National Science Foundation (2016-2022).Results: We show that the predominance of women in debt work can be explained by the fact that it is not just financial and administrative work. It is experienced as parental and conjugal care work. Concern for and preservation of family members’ well-being, especially children, leads women to invest their own assets. Perceived as a means of doing gender in a situation of over-indebtedness by acting as a “good” mother and spouse, this work and the inequalities it produces are not called into question.Conclusion : The financialization of everyday life implies new forms of financial work, such as debt work, which reinforce wealth inequalities within the family, with men’s wealth and that of their children being preserved to the prejudice of women’s wealth. In this regard, the financial assets of each family members have different meanings, with women’s wealth becoming an adjustment variable in the event of economic difficulties, enabling family status and good family relations to be maintained.Contribution : By focusing on the financial burdens carried by women, this article offers a new approach to understanding the gendered processes involved in the constitution of wealth inequalities, which until now have focused mainly on gendered access to money and inheritance.

The eriochrome black T dye belongs to the azo dye class and is often used as an indicator in complexometric titrations and as a fiber dye in industrial processes. It constitutes a direct threat to human health and the environment due to its toxic and carcinogenic nature. Separating this dye from wastewater is essential before its release into water bodies. In this work, the adsorption capacity of eriochrome black T in aqueous solution conferred on the chemically modified or unmodified coffee husk fibers was evaluated. Adsorption experiments were performed in triplicate and batch. The results obtained were adjusted and presented as adsorption isotherms using the Langmuir-Freundlich model. The mass value of adsorbed dye was 483.9 mg ± 17.35 mg and 547.2 mg ± 22.98 mg of eriochrome black T per gram of unmodified and chemically modified coffee husk, respectively, indicating great potential of coffee husk as an adsorbent for the removal of anionic azo dyes in aqueous solution.

Abstract is missing (Short communication)

Summary: Macrophages are major host cells for the protozoan Leishmania parasite. Depending on their activation state, they either contribute to the detection and elimination of Leishmania spp. or promote parasite resilience. Here, we report that the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages plays a pivotal role in the progression of Leishmania infantum infection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of the NOX2/reactive oxygen species (ROS) axis in early Nrf2 activation and, subsequently, prostaglandin E2 (PGE2)/EP2r signaling in the sustenance of Nrf2 activation upon infection. Moreover, we establish a ferroptosis-like process within macrophages as a cell death program of L. infantum and the protective effect of Nrf2 in macrophages against L. infantum death. Altogether, these results identify Nrf2 as a critical factor for the susceptibility of L. infantum infection, highlighting Nrf2 as a promising pharmacological target for the development of therapeutic approaches for the treatment of visceral leishmaniasis.

Abstract Background The objective of this study was to identify and qualify, by means of a three-dimensional kinematic analysis, the postures and movements of obstetricians during a simulated forceps birth, and then to study the association of the obstetricians’ experience with the technique adopted. Method Fifty-seven volunteer obstetricians, 20 from the Limoges and 37 from the Poitiers University hospitals, were included in this multi-centric study. They were classified into 3 groups: beginners, intermediates, and experts, beginners having performed fewer than 10 forceps deliveries in real conditions, intermediates between 10 and 100, and experts more than 100. The posture and movements of the obstetricians were recorded between December 2020 and March 2021 using an optoelectronic motion capture system during simulated forceps births. Joint angles qualifying these postures and movements were analysed between the three phases of the foetal traction. These phases were defined by the passage of a virtual point associated with the forceps blade through two anatomical planes: the mid-pelvis and the pelvic outlet. Then, a consolidated ascending hierarchical classification (AHC) was applied to these data in order to objectify the existence of groups of similar behaviours. Results The AHC distinguished four different postures adopted when crossing the first plane and three different traction techniques. 48% of the beginners adopted one of the two raised posture, 22% being raised without trunk flexion and 26% raised with trunk flexion. Conversely, 58% of the experts positioned themselves in a “chevalier servant” posture (going down on one knee) and 25% in a “squatting” posture before initiating traction. The results also show that the joint movement amplitude tends to reduce with the level of expertise. Conclusion Forceps delivery was performed in different ways, with the experienced obstetricians favouring postures that enabled observation at the level of the maternal perineum and techniques reducing movement amplitude. The first perspective of this work is to relate these different techniques to the traction force generated. The results of these studies have the potential to contribute to the training of obstetricians in forceps delivery, and to improve the safety of women and newborns.

Abstract A novel methylation class, “neuroepithelial tumor, with PLAGL1 fusion” (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as “mixed subependymomas-ependymomas” with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Here we present a detailed description of different geomorphic features to complement the Maps of Geohazard Features of the Ionian Calabrian Margin produced by the Magic project (Marine Geohazard along Italian Coasts). Some of the most striking features we imaged are sources of widespread and recurrent geohazards. These include multiple coastal landslides, failure scars along open slopes, shelf-indenting retrogressive canyon headwalls and active fluid venting structures, that we investigated by integrating regional high-resolution multibeam sonar and sub-bottom profiling data. The main triggers and predisposing factors for the marine geohazards that we identify in our study area include frequent seismic activity, the rapid uplift of the margin since 1 Ma and the presence of Messinian evaporites at depth. Large-scale gravity-driven movements and the incipient retrogressive canyon headwalls are of particular concern, as they are located just a few hundred meters from the coast, where critical infrastructures and densely populated urban centers are situated, and also where high-resolution geophysical data are often lacking. Overall, our study provides a key reference for more detailed follow-up studies to foster a better understanding of marine geohazard occurrences. The insights provided are critical for planning monitoring programs and for the protection of coastal settlements and marine infrastructures along the Calabrian Ionian margin.

ABSTRACTWe present the characterization of geohazard-related features of the Ligurian Sea with the map of its physiographic domains (1:250,000 scale) and five maps (1:100,000 scale) of the morphological and morpho-bathymetric elements. These were realized in the framework of the MaGIC (Marine Geohazard along Italian Coasts) project, promoted by the Italian Civil Protection Department. The characterization of submarine geohazards along continental margins, together with mapping of marine geological features are critical for the management of coastal risks. Multibeam bathymetric data combined with high-resolution 2D reflection seismic data, allowed to identify and map the main tectono-sedimentary features related to mass movements along the Ligurian continental margin. A dense grid of seismic profiles allowed to improve the comprehension of the margin structure as well as its recent tectonic activity providing new insights concerning mass wasting processes and active tectonics relationships to plan further, focalized investigations in areas of maximum risk.

Collagens are the most abundant proteins in the body and among the most biosynthetically complex. A molecular ensemble of over 20 endoplasmic reticulum resident proteins participates in collagen biosynthesis and contributes to heterogeneous post-translational modifications. Pathogenic variants in genes encoding collagens cause connective tissue disorders, including osteogenesis imperfecta, Ehlers-Danlos syndrome, and Gould syndrome (caused by mutations in COL4A1 and COL4A2), and pathogenic variants in genes encoding proteins required for collagen biosynthesis can cause similar but overlapping clinical phenotypes. Notably, pathogenic variants in lysyl hydroxylase 3 (LH3) cause a multisystem connective tissue disorder that exhibits pathophysiological features of collagen-related disorders. LH3 is a multifunctional collagen-modifying enzyme; however, its precise role(s) and substrate specificity during collagen biosynthesis has not been defined. To address this critical gap in knowledge, we generated LH3 KO cells and performed detailed quantitative and molecular analyses of collagen substrates. We found that LH3 deficiency severely impaired secretion of collagen α1α1α2(IV) but not collagens α1α1α2(I) or α1α1α1(III). Amino acid analysis revealed that LH3 is a selective LH for collagen α1α1α2(IV) but a general glucosyltransferase for collagens α1α1α2(IV), α1α1α2(I), and α1α1α1(III). Importantly, we identified rare variants that are predicted to be pathogenic in the gene encoding LH3 in two of 113 fetuses with intracranial hemorrhage-a cardinal feature of Gould syndrome. Collectively, our findings highlight a critical role of LH3 in α1α1α2(IV) biosynthesis and suggest that LH3 pathogenic variants might contribute to Gould syndrome.

Background: Non-muscle invasive bladder cancer (NMIBC) patients are affected by a high risk of recurrence. The topography of collagen fibers represents a hallmark of the neoplastic extracellular microenvironment. Objective: Assess the topographic change associated with different stages of bladder cancer (from neoplastic lesions to bona fide tumor) and whether those changes favour the development of NMIBC. Design, Setting, and Participants: Seventy-one clinical samples of urothelial carcinoma at different stages were used. Topographic changes preceding tumor onset and progression were evaluated in the rat bladder cancer model induced by nitrosamine (BBN), a bladder-specific carcinogen. The preclinical model of actinic cystitis was also used in combination with BBN. Validated hematoxylin-eosin sections were used to assess the topography of collagen fibrils associated with pre-tumoral steps, NMIBC, and MIBC. Findings: Linearization of collagen fibers was higher in Cis and Ta vs. dysplastic urothelium, further increased in T1 and greatest in T2 tumors. In the BBN preclinical model, an increase in the linearization of collagen fibers was established since the beginning of inflammation, such as the onset of atypia of a non-univocal nature and dysplasia, and further increased in the presence of the tumor. Linearization of collagen fibers in the model of actinic cystitis was associated with earlier onset of BBN-induced tumor. Conclusions: The topographic modification of the extracellular microenvironment occurs during the inflammatory processes preceding and favoring the onset of bladder cancer. The topographic reconfiguration of the stroma could represent a marker for identifying and treating the non-neoplastic tissue susceptible to tumor recurrence.

Abstract Climate change is projected to increase the frequency and intensity of extreme heat events, and may increase humidity levels, leading to coupled thermal and hydric stress. However, how humidity modulates the impacts of heat stress on species and their interactions is currently unknown. Using an insect host‐parasitoid interaction: the Indian meal moth, Plodia interpunctella, and its endoparasitoid wasp, Venturia canescens, we investigated how humidity interacted with heat stress duration, applied at different host developmental stages, to affect life history traits. Hosts parasitized as 4th instar larvae and unparasitized hosts were maintained in high‐ (60.8% RH) or low‐humidity (32.5% RH) at constant 28°C. They were then exposed to a 38°C thermal stress with a duration of 0 (no heat stress), 6 or 72 h in either the 4th or 5th host instar. Neither humidity nor heat stress duration affected emergence of unparasitized hosts, but increasing heat stress duration during the 4th instar decreased parasitoid emergence irrespective of humidity. When applied during the 5th instar, increasing heat duration decreased parasitoid emergence under low humidity, but no effect of heat stress was found under high humidity. Moreover, experiencing longer heat stress in the 4th instar increased host larval development time and decreased body size under high humidity, but this effect differed under low humidity; increasing heat duration in the 5th instar decreased parasitoid body sizes only under low humidity. Larval stage and heat stress duration directly affected parasitized host survival time, with a concomitant indirect reduction of parasitoid sizes. We show that humidity modifies key life history responses of hosts and parasitoids to heat stress in species‐specific ways, highlighting the potential importance of humidity in regulating host‐parasitoid interactions and their population dynamics. Finally, we emphasize that interactions between environmental stressors need to be considered in climate change research.

Summary: Background: Nomegestrol acetate (NOMAC) is a synthetic potent progestogen. This study aimed to assess the risk of intracranial meningioma associated with the prolonged use of NOMAC. Methods: Observational cohort study using SNDS data (France). Women included had ≥ one dispensing of NOMAC between 2007 and 2017 (no dispensing in 2006). Exposure was defined as a cumulative dose >150 mg NOMAC within six months after first dispensing. A control group of women (cumulative dose ≤150 mg) was assembled. The outcome was surgery (resection or decompression) or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma. Findings: In total, 1,060,779 women were included in the cohort (535,115 in the exposed group and 525,664 in the control group). The incidence of meningioma in the two groups was 19.3 and 7.0 per 100,000 person-years, respectively (age-adjusted RRa = 2.9 [2.4–3.7]). The RRa for a cumulative dose of more than 6 g NOMAC was 12.0 [9.9–16.0]. In the event of treatment discontinuation for at least one year, the risk of meningioma was identical to that in the control group (RRa = 1.0 [0.8–1.3]). The location of meningiomas in the anterior and middle part of the skull base was more frequent with exposure to NOMAC. Interpretation: We observed a strong dose-dependent association between prolonged use of NOMAC and the risk of intracranial meningiomas. These results are comparable to those obtained for cyproterone acetate, although the magnitude of the risk is lower. It is now recommended to stop using NOMAC if a meningioma is diagnosed. Funding: The French National Health Insurance Fund (Cnam) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group EPI-PHARE.

IntroductionWithin adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in-vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties.MethodsStroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate.ResultsThis innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow–derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of in-vivo AT resident macrophages.DiscussionOur study describes a 3D in-vitro system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.