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.

High Throughput Experimentation (HTE) is a rapidly expanding field. However, the productivity gains obtained via the synthesis or parallel testing of catalysts may be lost due to poor data management (numerous manual inputs, information difficult to access, etc.). A global framework has then been developed. It includes the HTE pilot plants in the global information system. It produces dedicated computer tools offering spectacular time savings in the operation of HTE units, information storage and rapid extraction of relevant information. To optimize the productivity of engineers, Excel has been included in the system by adding specific features in order to treat it as an industrial tool (development of additional modules, update of modules, etc.). The success obtained by setting up the information system is largely due to the chosen development method. An Agile method (Agile Alliance (2012) http://www.agilealliance.org/the-alliancel)[1] was chosen since close collaboration between the computer specialists and the chemist engineers is essential. Rather than a global and precise description of the framework which might be boring and tedious, the global framework is presented through 3 examples: scheduling experiments applied to zeolite synthesis; data management (storage and access); real application to pilot plant: dedicated interfaces to pilot and supervise HTE pilot plants, comparison of tests runs coming from several pilot plants. L’Expérimentation Haut Débit (EHD) est un domaine en plein essor. Cependant, les gains de productivité obtenus via la synthèse ou le test parallélisé de catalyseurs peuvent être annihilés par une mauvaise gestion de données (nombreuses saisies manuelles, difficulté d’accès à l’information, etc.). Dans ce document, une nouvelle architecture permettant d’intégrer les unités EHD dans un système d’information global est présentée. Des outils informatiques dédiés ont été développés. Ils permettent des gains de temps spectaculaires dans la conduite des unités EHD, le stockage des données et l’extraction rapide des informations pertinentes. L’approche retenue a été guidée par une approche Agile (Agile Alliance (2012) http://www. agilealliance.org/the-alliance/) [1] basée sur une très forte collaboration entre les chimistes et les informaticiens. Excel, l’outil principal des chimistes, a été positionné au coeur du système d’information avec des liens bidirectionnels (entrée/sortie) avec les bases de données et les différentes unités pilotes. Plutôt qu’une description globale du système d’information qui serait longue et fastidieuse, le framework est présenté via 3 exemples principaux : planification de données en utilisant des outils de gestion de production; gestion optimisée des données (stockage, requêtes), analyse de données; exemples d’application sur des unités pilotes : développements d’interfaces dédiées pour la conduite, le monitoring des unités et l’exploitation multi runs et multi unités pilotes.

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.