Université Paris-Sud 11

Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24 low /CD44 high ), we identified that pharmacological inhibition of the mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and thereby limits iron-mediated oxidative stress. Furthermore, integration of multi-omics data identified mitochondria as a key target of Sal action, leading to profound functional and structural alteration prevented by mTOR inhibition. On top of that, we found that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidence for the mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis pointing not only that metabolic reprogramming regulates ferroptosis, but also providing proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required in the development of an effective treatment.

The choice of medical specialization is influenced by various factors, including personal, educational, and interpersonal aspects. However, stereotypes and social representations (SRs) can also play a significant role in biasing the choice of a particular medical specialty. The aim of this study is to describe and understand the social representation (SR) of French Neurologist among medical peers, and factors explaining stereotypes about neurology. A nationwide web-based survey was sent to the French medical community (students, residents, and graduated physicians) to collect sociodemographic and professional data, status, experience, and acquaintance in Neurology as well as qualitative hierarchical evocation question to assess the SR of French Neurologists. Overall, 367 people participated in the survey, including 112 medical students, 170 residents, and 85 graduated physicians. Only 14.3% of students listed neurology among their top 5 specialty choices, and 63.8% disagreed with the statement “I could have chosen (or I will choose) neurology after the validation of my 6th year of medical studies.” Qualitative analysis revealed that the most frequently occurring words used to describe neurologists were “stroke”, “complicated”, “no treatment,” “clinical”, and “brain” and five themes corresponded to SRs of neurologist: his/her personal and professional traits (36.4% of the corpus), his/her daily practice (18.1%), the negative aspects of the neurological practice (15.3%), and the neurological pathology and daily skills (30.2%). The perception of neurologists by other physicians is nuanced. Neurologists are described as rigorous specialists, maybe excessively so but the cliché of a contemplative specialty with no effective treatment remains. The specialty and neurological patients suffer also from a reputation of complexity. Further interventions among medical students and better information are required to increase the attractiveness of our specialty.

Skin toxicities are very common in patients undergoing cancer treatment and have been found to occur with all types of cancer therapeutic interventions (cytotoxic chemotherapy, targeted therapies, immunotherapy, and radiotherapy). Further, skin toxicities can lead to interruption or even discontinuation of anticancer treatment in some patients, translating to suboptimal outcomes. Dermocosmetics (or cosmeceuticals)—defined as skincare solutions incorporating dermatologically active ingredients (beyond vehicle effects) that directly improve symptoms of various skin conditions—are increasingly being used in cancer care to prevent and manage skin toxicities. The active ingredients in these products have a measurable biological action in skin; they typically improve skin integrity (barrier function/hydration and other factors) while relieving skin symptoms. The Association Francophone des Soins Oncologiques de Support (AFSOS) and Multinational Association of Supportive Care in Cancer (MASCC) partnered to select a multidisciplinary group of healthcare professionals involved in the management of patients with cancer and skin toxicities. The group reviewed existing literature and created a summary of recommendations for managing these toxicities through online meetings and communication. In this publication, the group (1) reviews new skin toxicities seen with oncology drugs and (2) evaluates the role of dermocosmetics in improving patient outcomes and minimizing cancer treatment interruptions. We provide general recommendations for initiation and selection of skin care in all oncology patients as well as recommendations for what factors should be considered when using dermocosmetics in specific types of skin toxicities.

LipoParticles, core-shell assemblies consisting of a polymer core coated by a lipid membrane, are promising carriers for drug delivery applications with intracellular targets. This is of great interest since it is actually challenging to treat infections involving intracellular bacteria such as bone and joint infections where the bacteria are hidden in osteoblast cells. The present work reports for the first time to the best of our knowledge the proof of enhanced internalization of particles in osteoblast cells thanks to a lipid coating of particles (= LipoParticles). The ca. 300 nm-sized assemblies were elaborated by reorganization of liposomes (composed of DPPC/DPTAP 10/90 mol/mol) onto the surface of poly(lactic-co-glycolic acid) (PLGA) particles, and were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and zetametry. Optimization of these assemblies was also performed by adding poly(ethylene glycol) (PEG) chains on their surface (corresponding to a final formulation of DPPC/DPTAP/DPPE-PEG5000 8/90/2 mol/mol/mol). Interestingly, this provided them colloidal stability after their 20-fold dilution in PBS or cell culture medium, and made possible their freeze-drying without forming aggregates after their re-hydration. Their non-cytotoxicity towards a human osteoblast cell line (MG63) was also demonstrated. The enhanced internalization of LipoParticles in this MG63 cell line, in comparison with PLGA particles, was proven by observations with a confocal laser scanning microscope, as well as by flow cytometry assays. Finally, this efficient internalization of LipoParticles in MG63 cells was confirmed by TEM on ultrathin sections, which also revealed localization close to intracellular Staphylococcus aureus.

This book starts with the most elementary ideas of molecular orbital theory and leads the reader progressively to an understanding of the electronic structure, geometry and, in some cases, reactivity of transition metal complexes. The qualitative orbital approach, based on simple notions such as symmetry, overlap and electronegativity, is the focus of the presentation and a substantial part of the book is associated with the mechanics of the assembly of molecular orbital diagrams. The first chapter recalls the basis for electron counting in transition metal complexes. The main ligand fields (octahedral, square planar, tetrahedral, etc.) are studied in the second chapter and the structure of the "d block" is used to trace the relationships between the electronic structure and the geometry of the complexes. The third chapter studies the change in analysis when the ligands have pi-type interactions with the metal. All these ideas are then used in the fourth chapter to study a series of selected applications of varying complexity (e.g. structure and reactivity). The fifth chapter deals with the "isolobal analogy" which points out the resemblance between the molecular orbitals of inorganic and organic species and provides a bridge between these two subfields of chemistry. The last chapter is devoted to a presentation of basic Group Theory with applications to some of the complexes studied in the earlier chapters.

We develop a novel technique to exploit the extensive data sets provided by underwater neutrino telescopes to gain information on bioluminescence in the deep sea. The passive nature of the telescopes gives us the unique opportunity to infer information on bioluminescent organisms without actively interfering with them. We propose a statistical method that allows us to reconstruct the light emission of individual organisms, as well as their location and movement. A mathematical model is built to describe the measurement process of underwater neutrino telescopes and the signal generation of the biological organisms. The Metric Gaussian Variational Inference algorithm is used to reconstruct the model parameters using photon counts recorded by photomultiplier tubes. We apply this method to synthetic data sets and data collected by the ANTARES neutrino telescope. The telescope is located 40 km off the French coast and fixed to the sea floor at a depth of 2475 m. The runs with synthetic data reveal that we can model the emitted bioluminescent flashes of the organisms. Furthermore, we find that the spatial resolution of the localization of light sources highly depends on the configuration of the telescope. Precise measurements of the efficiencies of the detectors and the attenuation length of the water are crucial to reconstruct the light emission. Finally, the application to ANTARES data reveals the first localizations of bioluminescent organisms using neutrino telescope data.

Background Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. Materials and methods We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Results Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Conclusions Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

A complex pattern of preservation and deterioration in metacognition in aging is found, especially regarding predicting future memory retrieval (i.e., feeling-of-knowing, FOK). While semantic FOK (sFOK) is preserved with age, studies on episodic tasks (eFOK) produce equivocal findings. We present a meta-analysis of 20 studies on eFOK and sFOK, analyzing the difference in metacognitive sensitivity between 922 younger and 966 older adults, taking into account the difference in memory performance. The sFOK studies yielded no overall age effect (8 effects, g = −0.10 [−0.29, 0.10]). However, we found a reliable age-group difference on eFOK (22 effects, g = 0.53 [0.28, 0.78]), which was moderated when considering recognition performance. Moreover, using aggregated data of 134 young and 235 older adults from published and unpublished studies from our lab, we investigated memory performance as an explanation of the eFOK deficit. We show that older adults are less metacognitively sensitive than younger adults for eFOKs which is, at least partly, due to the age-related memory decline. We highlight two non-exclusive explanations: a recollection deficit at play in the first and second order tasks, and a confound between first order performance and the measure used to assess metacognitive sensitivity.

The study of microbiomes across organisms and environments has become a prominent focus in molecular ecology. This perspective article explores methodological advancements, common challenges and future directions in the field. Key research areas include understanding the drivers of microbiome community assembly, linking microbiome composition to host genetics, exploring microbial functions, transience, and spatial partitioning, and disentangling non-bacterial components of the microbiome. Methodological advancements, such as quantifying absolute abundances, sequencing complete genomes, and utilizing novel statistical approaches, are also useful tools for understanding complex microbial diversity patterns. Our aims are to encourage robust practices in microbiome studies and inspire researchers to explore the next frontier of this rapidly changing field.

Recent studies have found that avian bill and tarsus morphology may have evolved in response to climatic conditions, and these organs play important roles in thermoregulation and water retention in extreme environments. Here, we examined whether bill surface area and tarsus length were associated with climatic conditions in the plain laughingthrush, Garrulax davidi , which mainly occurs in north China and occupies several climatic zones from east to west. We measured bill surface area and tarsus length in 321 adults from 11 populations, almost encompassing all habitat types of the species. We analyzed the relationships among these morphological traits and local climatic factors. Bill surface area was positively correlated with maximum temperature, indicating that bill surface area tended to be larger in hotter environments. Furthermore, we found a negative relationship among bill surface area and winter precipitation, indicating that bill surface area tended to be larger in arid areas. However, we did not find any relationships between tarsus length and climatic factors. These results suggest that local climates may shape the evolution of bill morphology divergence, and summer seems to be the critical season for thermoregulation in this temperate zone passerine.

ESA’s Jupiter Icy Moons Explorer (JUICE) will provide a detailed investigation of the Jovian system in the 2030s, combining a suite of state-of-the-art instruments with an orbital tour tailored to maximise observing opportunities. We review the Jupiter science enabled by the JUICE mission, building on the legacy of discoveries from the Galileo, Cassini, and Juno missions, alongside ground- and space-based observatories. We focus on remote sensing of the climate, meteorology, and chemistry of the atmosphere and auroras from the cloud-forming weather layer, through the upper troposphere, into the stratosphere and ionosphere. The Jupiter orbital tour provides a wealth of opportunities for atmospheric and auroral science: global perspectives with its near-equatorial and inclined phases, sampling all phase angles from dayside to nightside, and investigating phenomena evolving on timescales from minutes to months. The remote sensing payload spans far-UV spectroscopy (50-210 nm), visible imaging (340-1080 nm), visible/near-infrared spectroscopy (0.49-5.56 μm), and sub-millimetre sounding (near 530-625 GHz and 1067-1275 GHz). This is coupled to radio, stellar, and solar occultation opportunities to explore the atmosphere at high vertical resolution; and radio and plasma wave measurements of electric discharges in the Jovian atmosphere and auroras. Cross-disciplinary scientific investigations enable JUICE to explore coupling processes in giant planet atmospheres, to show how the atmosphere is connected to (i) the deep circulation and composition of the hydrogen-dominated interior; and (ii) to the currents and charged particle environments of the external magnetosphere. JUICE will provide a comprehensive characterisation of the atmosphere and auroras of this archetypal giant planet.

Background Progressive familial intrahepatic cholestasis (PFIC) is a group of rare cholestatic liver diseases characterised by intractable pruritus, elevated serum bile acids (sBAs), and progressive liver damage. NAPPED (NAtural course and Prognosis of PFIC and Effect of biliary Diversion) is a large retrospective database investigating the natural history of PFIC. Odevixibat, an ileal bile acid transporter inhibitor, reduced sBAs and pruritus in patients with PFIC in the phase 3 PEDFIC 1 and PEDFIC 2 studies. We compared clinical outcomes of surgical biliary diversion (SBD), liver transplantation (LT), and death in patients from NAPPED (not treated with odevixibat) with odevixibat-treated patients from the PEDFIC studies. Methods The analysis population comprised odevixibat-naive patients from NAPPED and odevixibat-treated patients from PEDFIC 1 and/or PEDFIC 2. Patients with bile salt export pump subtype 3 (BSEP3) mutations were excluded. Eligibility criteria were aligned across cohorts and included genetically proven diagnosis of PFIC1 or PFIC2, sBAs ≥100 µmol/L, alanine aminotransaminase and total bilirubin ≤10× the upper limit of normal, and no prior SBD or LT. Propensity scores, inverse probability of treatment weighting, and matching methods were used to identify and balance baseline covariates, including PFIC1, PFIC2-BSEP1, or PFIC2-BSEP2. The primary endpoint was event-free survival (EFS; time to first event of SBD, LT, or death); secondary endpoints included native liver survival (NLS), SBD-free survival (DFS), and overall survival (OS). Survival outcomes were measured from study day 1; treatment differences were evaluated by weighted log-rank tests and Cox regression. Results A cohort of 80 NAPPED patients (controls) was compared with 69 odevixibat-treated patients. Median study duration in the odevixibat cohort was 22.6 months (range: 1.9–39.2 months). Follow-up duration in the NAPPED cohort was truncated accordingly. Odevixibat-treated patients showed significantly higher EFS and DFS than controls (hazard ratio [HR] [95% CI]: 0.20 [0.09−0.45] and 0.13 [0.04−0.39], respectively); numerical improvements in NLS and OS were also observed. Results were consistent when different sensitivity analyses were performed. Additional subgroup analyses indicated that EFS was higher in odevixibat-treated patients with PFIC1 (HR [95% CI]: 0.10 [0.02−0.55]) and PFIC2 (HR [95% CI]: 0.34 [0.12−1.00]) vs controls. Conclusions Odevixibat treatment is associated with higher EFS in patients with PFIC without prior SBD upon comparison with matched non-odevixibat-treated patients from the NAPPED registry.

Isomeric states were observed in nuclei produced in an experiment at the RIKEN Nishina Center Radioactive Isotope Beam Factory following the in-flight fission of a 345 MeV/nucleon \(^{238}\)U beam. Isomers reported in nuclei spanning a predicted prolate-oblate shape change boundary, \(^{111}\)Zr (\(E=283.1~\)keV; \(\tau =0.326(63)\) \(\upmu \)s), \(^{112}\)Nb (\(E=44.2\) keV; \(\tau =0.094(26)\) \(\upmu \)s), \(^{113}\)Nb (\(E=135.4\) keV; \(\tau =0.846(80)\) \(\upmu \)s), and \(^{115}\)Mo (\(E=198.6\) keV; \(\tau =63(4)\) \(\upmu \)s), are compared to potential-energy surface calculations which gave a selection of low-lying configurations for each nucleus. Tentative assignments of ground and excited states were made based on energy similarities to the calculations, reduced transition probabilities of the decays, and constraints of transition multipolarities from \(\gamma \)-ray coincidence measurements. These assignments are suggestive of significant deformation being persistent for \(N>70\) in this region. In addition, isomers in \(^{108}\)Nb, \(^{109}\)Nb, \(^{113}\)Tc, \(^{117}\)Ru, \(^{119}\)Ru, \(^{120}\)Rh, and \(^{122}\)Rh, not spanning the prolate-oblate transition discussed, are presented.

In this short note, I present a very quick review of the peculiarities of dimension four in geometric topology. I consider, in particular, the role of geometric simple connectivity (which means handle decomposition without handles of index one) for both closed manifolds and open manifolds and for finitely presented groups, together with some of recent developments in geometric group theory.

Social networks have become important objects of study in recent years. Social media marketing has, for example, greatly benefited from the vast literature developed in the past two decades. The study of social networks has taken advantage of recent advances in machine learning to process these immense amounts of data. Automatic emotional labeling of content on social media has, for example, been made possible by the recent progress in natural language processing. In this work, we are interested in the influence maximization problem, which consists of finding the most influential nodes in the social network. The problem is classically carried out using classical performance metrics such as accuracy or recall, which is not the end goal of the influence maximization problem. Our work presents an end-to-end learning model, SGREEDYNN, for the selection of the most influential nodes in a social network, given a history of information diffusion. In addition, this work proposes data visualization techniques to interpret the augmenting performances of our method compared to classical training. The results of this method are confirmed by visualizing the final influence of the selected nodes on network instances with edge bundling techniques. Edge bundling is a visual aggregation technique that makes patterns emerge. It has been shown to be an interesting asset for decision-making. By using edge bundling, we observe that our method chooses more diverse and high-degree nodes compared to the classical training.