University of Paris-Sud

Natural products have a long history of providing probes into protein biosynthesis, with many of these compounds serving as therapeutics. The marine natural product girolline has been described as an inhibitor of protein synthesis. Its precise mechanism of action, however, has remained unknown. The data we present here suggests that girolline is a sequence-selective modulator of translation factor eIF5A. Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling where translational progress is impeded, including on AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in ribosome-associated quality control and in maintaining the efficiency of translational progress. Girolline helped to deepen our understanding of the interplay between protein production and quality control in a physiological setting and offers a potent chemical tool to selectively modulate gene expression.

The use of multiagent FOLFIRINOX chemotherapy for pancreatic adenocarcinoma in a neoadjuvant setting has been associated with an increased rate of complete pathological response (CPR) after surgery. This study investigated the long-term outcomes of patients with CPR in a multicenter setting to identify prognostic factors for overall survival (OS) and recurrence-free survival (RFS). This retrospective cohort study examined biopsy-proven pancreatic adenocarcinomas with CPR after neoadjuvant chemotherapy or chemoradiotherapy and surgery, between January 2006 and December 2023 across 22 French and 2 Belgian centers. Cox analyses were used to identify prognostic factors of OS and RFS. There were 101 patients with CPR after chemotherapy (n = 58, 57.4%) and chemoradiotherapy (n = 43, 42.6%) followed by surgery. Neoadjuvant FOLFIRINOX was used in 90% of patients. The median OS after surgery was 177 months (95% confidence interval (CI) 58.9–177 months) with 1-, 3-, 5-, and 10-year OS rates of 93%, 75%, 63%, and 51%, respectively. The median RFS was 67.8 months (95% CI:34.4–NR) with 1-, 3-, 5-, and 10-year RFS rates of 83%, 58%, 54%, and 49%, respectively. The multivariate Cox analysis of OS and RFS showed that preoperative radiotherapy was an independent negative prognostic factor for OS (hazard ratio (HR) 2.51; 95% CI 1.00–6.30; p = 0.03) and RFS (HR 2.62; 95% CI 1.27–5.41; p = 0.009). Complete pathologic response after neoadjuvant treatment is associated with remarkable long-term survival that is usually not seen after the resection of pancreatic adenocarcinomas. One-third of the patients still experienced disease recurrence, which was more common in those receiving preoperative chemoradiotherapy.

Background To reduce the number of deaths caused by exsanguination, the initial management of severe trauma aims to prevent, if not limit, the lethal triad, which consists of acidosis, coagulopathy, and hypothermia. Recently, several studies have suggested adding hypocalcemia to the lethal triad to form the lethal diamond, but the evidence supporting this change is limited. Therefore, the aim of this study was to compare the lethal triad and lethal diamond for their respective associations with 24-h mortality in severe trauma patients receiving transfusion. Methods We performed a multicenter retrospective analysis of patients in TraumaBase®, a French database (2011–2023). The patients included in this study were all trauma patients who had received transfusions of at least 1 unit of red blood cells (RBCs) within the first 6 h of hospital admission and for whom ionized calcium measurements were available. Hypocalcemia was defined as an ionized calcium level < 1.1 mmol/L. Results A total of 2141 severe trauma patients were included (median age: 39, interquartile range [IQR]: 26–57; median injury severity score: 27, IQR: 17–41). Patients primarily presented with blunt trauma (81.7%), and a 24-h mortality rate of 16.1% was observed. Receiver operating characteristic curve analysis revealed no significant difference in the association with 24-h mortality between the lethal diamond (area under the curve [AUC]: 0.71) and the lethal triad (AUC: 0.72) (p = 0.26). The strength of the association with 24-h mortality was similar between the lethal triad and the lethal diamond, with Cramer’s V values of 0.29 and 0.28, respectively. Conclusions This study revealed no significant difference between the lethal triad and the lethal diamond in terms of their respective associations with 24-h mortality in severe trauma patients requiring transfusion. These results raise questions about the independent role of hypocalcemia in early mortality.

Position calibration in the deep sea is typically done by means of acoustic multilateration using three or more acoustic emitters installed at known positions. Rather than using hydrophones as receivers that are exposed to the ambient pressure, the sound signals can be coupled to piezo ceramics glued to the inside of existing containers for electronics or measuring instruments of a deep sea infrastructure. The ANTARES neutrino telescope operated from 2006 until 2022 in the Mediterranean Sea at a depth exceeding 2000 m. It comprised nearly 900 glass spheres with 432 mm diameter and 15 mm thickness, equipped with photomultiplier tubes to detect Cherenkov light from tracks of charged elementary particles. In an experimental setup within ANTARES, piezo sensors have been glued to the inside of such – otherwise empty – glass spheres. These sensors recorded signals from acoustic emitters with frequencies from 46545 to 60235 Hz. Two waves propagating through the glass sphere are found as a result of the excitation by the waves in the water. These can be qualitatively associated with symmetric and asymmetric Lamb-like waves of zeroth order: a fast (early) one with $\boldsymbol{v_e \approx 5\,{\textbf {mm}}/\mu \text {s}}$ and a slow (late) one with $\boldsymbol{v_\ell \approx \,2\,{\textbf {mm}}/\mu \text {s}}$. Taking these findings into account improves the accuracy of the position calibration. The results can be transferred to the KM3NeT neutrino telescope, currently under construction at multiple sites in the Mediterranean Sea, for which the concept of piezo sensors glued to the inside of glass spheres has been adapted for monitoring the positions of the photomultiplier tubes.

Aicardi–Goutières syndrome (AGS) is a rare monogenic type I interferonopathy. Janus kinase (JAK) inhibition has emerged as a potential treatment for AGS. RNU7‐1 is one of the most recently discovered genes for AGS, and the clinical effects of JAK inhibition in these patients have not been reported. Here, we describe the diagnosis and treatment of a South African infant with RNU7‐1 ‐related AGS. The patient presented with developmental delay at age 5 months and was diagnosed with cerebral palsy due to a suspected congenital infection. By 18 months of age, he had a vasculitic rash, prominent generalized dystonia, persistent transaminitis, recurrent stomatitis, moderate‐range global developmental delay, and difficulty sleeping. AGS was considered after finding neuroimaging features of the disease; the diagnosis was confirmed when genetic investigations revealed two likely pathogenic RNU7‐1 compound heterozygous variants in the patient. Elevated interferon gene expression was noted in the patient and his mother who was a carrier of one RNU7‐1 variant. Baricitinib treatment was started, leading to modest, transient improvements in some clinical manifestations and a reduction in interferon‐stimulated gene expression. Liver function, dystonia, and neurological function did not improve even after increasing the baricitinib dose. Baricitinib was discontinued due to persistent and worsening adverse effects.

Introduction Since 2017, women with absolute uterine infertility due to Mayer‐Rokitansky‐Küster‐Hauser (MRKH) syndrome have been eligible to participate in a uterine transplantation clinical trial conducted by Foch Hospital in France. The aim of this study is to assess the psychological state of potential candidates, including recipients, their partners, and their living‐related donors. Material and Methods Sixteen potential uterus transplant candidates, including recipients, partners, and living‐related donors, participated in the study. The psychological evaluation of these candidates was conducted using three validated questionnaires: the Dyadic Adjustment Scale (DAS‐16), the Hospital Anxiety and Depression Scale (HADS), and the Fertility Quality of Life (FertiQoL) questionnaire. Results No depression symptoms were observed in any participant according to the HADS. Most recipients did not exhibit signs of anxiety; however, three partners and three donors reported moderate to high anxiety levels. A positive correlation was found between the recipient's psychological distress related to infertility (FertiQoL) and the anxiety scores of their donors. The emotional aspect of infertility was identified as the most distressing factor for the recipients. Conclusions While the overall psychological state of the participants was generally good, anxiety was notably present among donors and partners. Therefore, providing psychological support throughout the uterine transplantation process is essential for not only the recipients but also their partners and donors.

In the current context of increasing globalisation, innovation and investment in R&D become crucial. Furthermore, European Lisbon strategy gave disappointing results in terms of R&D expenditures and patents. In this context, our paper deals with some OECD characteristics concerning their connection to global markets of knowledge and technology trade. Statistical results show that the USA are great performers in terms of R&D expenditures and patents, with large openness to foreign collaboration, Japan is successful in innovative activities while quite isolated from global research network. The European Union seems to be in the opposite situation. Nevertheless contrasted situations are observed, depending on the European countries. For instance Sweden, Finland and Denmark register quite good results in terms of R&D. Concerning technological trade, Technology Balance of Payments (TBP) statistics give some additional results. While the EU15 used to exhibiting a TBP deficit, the situation has changed since 2006 and the EU15 registers a surplus. This performance relies on Germany, Sweden and Austria, which are the main exporters of technology among European countries. Thanks to this first statistical analysis, it seems that technological profiles of OECD countries impact on technological trade flows. Except some specific countries’ characteristics, leaders in R&D are quite active in terms of technological exports and also imports. For instance, the European leaders in R&D export their technologies but seem also active by importing technologies from abroad.

The head and neck is an extremely common location for tumors of cutaneous origin. This is primarily the result of chronic UV exposure inducing DNA damage in epidermal and (less so) dermal cells, and the year-round exposure of this anatomic site. Most neoplasms will require histopathologic evaluation for accurate diagnosis, and often staging information, as well as margin assessment. Some tumors will require ancillary testing in order to make an accurate diagnosis. Although an extremely wide range of diagnostic entities occur on the head and neck, this chapter covers the most commonly encountered and critically important cutaneous tumors and the diagnostic approach to them.

Leprosy is a chronic disease of the skin and peripheral nerves caused by Mycobacterium leprae. A major public health and clinical problem are leprosy reactions, which are inflammatory episodes that often contribute to nerve damage and disability. Type I reversal reactions (T1R) can occur after microbiological cure of leprosy and affect up to 50% of leprosy patients. Early intervention to prevent T1R and, hence, nerve damage, is a major focus of current leprosy control efforts. In a prospective study, we enrolled and collected samples from 32 leprosy patients before the onset of T1R. Whole blood aliquots were challenged with M. leprae sonicate or media and total RNA was extracted. After a three-year follow-up, the transcriptomic response was compared between cells from 22 patients who remained T1R-free and 10 patients who developed T1R during that period. Our analysis focused on differential transcript (i.e. isoform) expression and usage. Results showed that, at baseline, cells from T1R-destined and T1R-free subjects had no main difference in their transcripts expression and usage. However, the cells of T1R patients displayed a transcriptomic immune response to M. leprae antigens that was significantly different from the one of cells from leprosy patients who remained T1R-free. Transcripts with significantly higher upregulation in the T1R-destined group, compared to the cells from T1R-free patients, were enriched for pathways and GO terms involved in response to intracellular pathogens, apoptosis regulation and inflammatory processes. Similarly, transcript usage analysis pinpointed different transcript proportions in response to the in-vitro challenge of cells from T1R-destined patients. Hence, transcript usage in concert with transcript expression suggested a dysregulated inflammatory response including increased apoptosis regulation in the peripheral blood cells of T1R-destined patients before the onset of T1R symptoms. Combined, these results provided detailed insight into the pathogenesis of T1R.

During meiosis, programmed DNA double-strand breaks (DSBs) are formed by the topoisomerase-like enzyme, Spo11, activating the DNA damage response (DDR) kinase Mec1ATR via the checkpoint clamp loader, Rad24RAD17. At single loci, loss of Mec1 and Rad24 activity alters DSB formation and recombination outcome, but their genome-wide roles have not been examined in detail. Here, we utilise two strategies—deletion of the mismatch repair protein, Msh2, and control of meiotic prophase length via regulation of the Ndt80 transcription factor—to help characterise the roles Mec1 and Rad24 play in meiotic recombination by enabling genome-wide mapping of meiotic progeny. In line with previous studies, we observe severely impacted spore viability and a reduction in the frequency of recombination upon deletion of RAD24—driven by a shortened prophase. By contrast, loss of Mec1 function increases recombination frequency, consistent with its role in DSB trans-interference, and has less effect on spore viability. Despite these differences, complex multi-chromatid events initiated by closely spaced DSBs—rare in wild-type cells—occur more frequently in the absence of either Rad24 or Mec1, suggesting a loss of spatial regulation at the level of DSB formation in both. Mec1 and Rad24 also have important roles in the spatial regulation of crossovers (COs). Upon loss of either Mec1 or Rad24, CO distributions become more random—suggesting reductions in the global manifestation of interference. Such effects are similar to, but less extreme than, the phenotype of ‘ZMM’ mutants such as zip3Δ, and may be driven by reductions in the proportion of interfering COs. Collectively, in addition to shared roles in CO regulation, our results highlight separable roles for Rad24 as a pro-CO factor, and for Mec1 as a regulator of recombination frequency, the loss of which helps to suppress any broader defects in CO regulation caused by abrogation of the DDR.

Purpose This study aims to identify a combination of clinical, demographic, and patient competence determinants of patients’ communication with doctors and nurses in an international sample of cancer patients. Methods For our cross-sectional study, cancer patients assessed their communication with their doctors or nurses at the start of their treatment. Patients completed EORTC communication questionnaire QLQ-COMU26 to assess ten areas of communication with their doctor or nurses plus another item to assess how competent they felt when communicating with professionals. Bivariable analyses and multivariable linear regression models were performed separately for each QLQ-COMU26 area. Results Included in the study were 988 patients from 15 centres in 13 countries (five cultural areas). Higher age was related to higher level of communication in eight QLQ-COMU26 areas. Males reported higher level of communication in three areas. Lower levels of studies and higher level of perceived competence when communicating with professionals were related to higher level of communication in the ten QLQ-COMU26 areas. Communication was of a higher level with nurses than with doctors in four areas. Having received previous treatment with the same doctor or group of nurses was related to higher communication levels in seven areas. Lack of comorbidity was related to higher communication levels in two areas. Various differences in determinants were found among tumour sites. Conclusion Our regression model has shown several relationships between communication and the demographic and clinical variables that may help identify patients at risk of poor communication. Future studies could focus on communication at diagnosis and in follow-up, and on areas such as assessing the particularities of communication between patient and professionals in relation to cancer type.

Cold piezoelectric plasma (CPP) is a novel approach in cancer therapy, enabling the development of portable treatment devices capable of triggering cancer cell death. While its effectiveness remains underexplored, this research focuses on its application against cholangiocarcinoma (CCA), an aggressive cancer of the biliary tract. A CPP device is utilized to generate either a corona discharge (Pz-CD) or a dielectric barrier discharge (Pz-DBD) for in vitro experiments. Notably, Pz-CD can deliver more power than Pz-DBD, although both sources produce significant levels of reactive species in plasma and liquid phases. This work shows that CPP causes a gradient increase in medium temperature from the center towards the edges of the culture well, especially for longer treatment times. Although Pz-CD heats more significantly, it cools quickly after plasma extinction. When applied to human CCA cells, CPP shows immediate and long-term effects, more localized for Pz-CD, while more uniform for Pz-DBD. Immediate effects result also in actin cytoskeleton remodeling without alteration of the cell membrane permeability. Long-term effects of CPP, although the antioxidant system is engaged, include activation of the DNA damage response pathway leading to cell death. In conclusion, CPP should be recognized as a promising antitumor therapy. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-81664-9.

Hepatoblastoma is the most common primary liver malignancy in children, with metabolic reprogramming playing a critical role in its progression due to the liver’s intrinsic metabolic functions. Enhanced glycolysis, glutaminolysis, and fatty acid synthesis have been implicated in hepatoblastoma cell proliferation and survival. In this study, we screened for altered overexpression of metabolic enzymes in hepatoblastoma tumors at tissue and single-cell levels, establishing and validating a hepatoblastoma tumor expression metabolic score using machine learning. Starting from the Mammalian Metabolic Enzyme Database, bulk RNA sequencing data from GSE104766 and GSE131329 datasets were analyzed using supervised methods to compare tumors versus adjacent liver tissue. Differential expression analysis identified 287 significantly regulated enzymes, 59 of which were overexpressed in tumors. Functional enrichment in the KEGG metabolic database highlighted a network enriched in amino acid metabolism, as well as carbohydrate, steroid, one-carbon, purine, and glycosaminoglycan metabolism pathways. A metabolic score based on these enzymes was validated in an independent cohort (GSE131329) and applied to single-cell transcriptomic data (GSE180665), predicting tumor cell status with an AUC of 0.98 (sensitivity 0.93, specificity 0.94). Elasticnet model tuning on individual marker expression revealed top tumor predictive markers, including FKBP10, ATP1A2, NT5DC2, UGT3A2, PYCR1, CKB, GPX7, DNMT3B, GSTP1, and OXCT1. These findings indicate that an activated metabolic transcriptional program, potentially influencing epigenetic functions, is observed in hepatoblastoma tumors and confirmed at the single-cell level.

We explored the pressure-induced structural phase transitions and elastic properties of Au M Te 2 ( M = Ga, In) using the full-potential linearized augmented plane wave method within the framework of density functional theory, applying both generalized gradient and local density approximations. Thermodynamic properties were further assessed through the quasi-harmonic model. We determined the transition pressures for the phase shift from the chalcopyrite structure to the NaCl rock-salt phase in both AuGaTe 2 and AuInTe 2 . Additionally, we calculated and analyzed mechanical properties, such as bulk modulus, shear modulus, Young's modulus, Poisson's ratio, elastic anisotropy, ductility versus brittleness, and hardness for the polycrystalline forms of Au M Te 2 ( M = Ga, In). The study also examined how temperature and pressure affect the Debye temperature, heat capacities, thermal expansion, entropy, bulk modulus, Grüneisen parameter, and hardness, utilizing the quasi-harmonic Debye model.

The $^{246}$Cm(n,$\gamma$) and $^{248}$Cm(n,$\gamma$) cross-sections have been measured at the Experimental Area 2 (EAR2) of the n_TOF facility at CERN with three C$_6$D$_6$ detectors. This measurement is part of a collective effort to improve the capture cross-section data for Minor Actinides (MAs), which are required to estimate the production and transmutation rates of these isotopes in light water reactors and innovative reactor systems. In particular, the neutron capture in $^{246}$Cm and $^{248}$Cm open the path for the formation of other Cm isotopes and heavier elements such as Bk and Cf and the knowledge of (n,$\gamma$) cross-sections of these Cm isotopes plays an important role in the transport, transmutation and storage of the spent nuclear fuel. The reactions $^{246}$Cm(n,$\gamma$) and $^{248}$Cm(n,$\gamma$) have been the two first capture measurements analyzed at n_TOF EAR2. Until this experiment and two recent measurements performed at J-PARC, there was only one set of data of the capture cross-sections of $^{246}$Cm and $^{248}$Cm, that was obtained in 1969 in an underground nuclear explosion experiment. In the measurement at n_TOF a total of 13 resonances of $^{246}$Cm between 4 and 400 eV and 5 of $^{248}$Cm between 7 and 100 eV have been identified and fitted. The radiative kernels obtained for $^{246}$Cm are compatible with JENDL-5, but some of them are not with JENDL-4, which has been adopted by JEFF-3.3 and ENDF/B-VIII.0. The radiative kernels obtained for the first three $^{248}$Cm resonances are compatible with JENDL-5, however, the other two are not compatible with any other evaluation and are 20 and 60% larger than JENDL-5.

Animals use dietary lipids to sustain their growth and survival. Insects can synthesize fatty acids (FAs) and are autotroph for a number of lipids, but auxotroph for specific lipids classes (e.g. sterols, polyunsaturated FAs). Once ingested, lipids are hydrolysed in the intestinal lumen and taken up into intestinal cells within specific regions of the insect digestive tract. These lipids can be either stored in the intestinal cells or exported through the haemolymph circulation to specific organs. In this chapter, we describe the various lipids provided by insect diets, their extracellular hydrolysis in the gut lumen and their intake and metabolic fate in the intestinal cells. This chapter emphasizes the critical role of the digestive tract and its regionalization in processing dietary lipids prior to their transfer to the requiring tissues.