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The Arctic is projected to warm by 2 to 5 °C by the end of the century. Warming causes melting of glaciers, shrinking of the areas covered by sea ice, and increased terrestrial runoff from snowfields and permafrost thawing. Warming, decreasing coastal underwater irradiance, and lower salinity are potentially threatening polar marine organisms, including kelps, that are key species of hard-bottom shallow communities. The present study investigates the physiological responses of four kelp species (Alaria esculenta, Laminaria digitata, Saccharina latissima, and Hedophyllum nigripes) to these environmental changes through a perturbation experiment in ex situ mesocosms. Kelps were exposed for 6 weeks to four experimental treatments: an unmanipulated control; a warming condition under the CO2 emission scenario SSP5-8.5; and two multifactorial conditions combining warming, low salinity, and low irradiance reproducing the future coastal Arctic exposed to terrestrial runoff under two CO2 emission scenarios (SSP2-4.5 and SSP5-8.5). The physiological effects on A. esculenta, L. digitata, and S. latissima were investigated, and gene expression patterns of S. latissima and H. nigripes were analyzed. Across all species and experimental treatments, growth rates were similar, underlying the acclimation potential of these species to future Arctic conditions. Specimens of A. esculenta increased their chlorophyll a content when exposed to low irradiance conditions, suggesting that they may be resilient to an increase in glacier and river runoff with the potential to become more dominant at greater depths. S. latissima showed a lower carbon : nitrogen (C : N) ratio under the SSP5-8.5 multifactorial conditions' treatment, suggesting tolerance to coastal erosion and permafrost thawing. In contrast, L. digitata showed no response to the conditions tested on any of the investigated physiological parameters. The down-regulation of genes coding for heat-shock proteins in H. nigripes and S. latissima underscores their ability to acclimate to heat stress, which portrays temperature as a key influencing factor. Based on these results, it is expected that kelp communities will undergo changes in species composition that will vary at local scale as a function of the changes in environmental drivers.

Abstract The NEXT-White detector, a high-pressure gaseous xenon time projection chamber, demonstrated the excellence of this technology for future neutrinoless double beta decay searches using photomultiplier tubes (PMTs) to measure energy and silicon photomultipliers (SiPMs) to extract topology information. This analysis uses 83m Kr data from the NEXT-White detector to measure and understand the energy resolution that can be obtained with the SiPMs, rather than with PMTs. The energy resolution obtained of (10.9 ± 0.6)%, full-width half-maximum, is slightly larger than predicted based on the photon statistics resulting from very low light detection coverage of the SiPM plane in the NEXT-White detector. The difference in the predicted and measured resolution is attributed to poor corrections, which are expected to be improved with larger statistics. Furthermore, the noise of the SiPMs is shown to not be a dominant factor in the energy resolution and may be negligible when noise subtraction is applied appropriately, for high-energy events or larger SiPM coverage detectors. These results, which are extrapolated to estimate the response of large coverage SiPM planes, are promising for the development of future, SiPM-only, readout planes that can offer imaging and achieve similar energy resolution to that previously demonstrated with PMTs.

In this study, alternatively to the megathrust, we identify upper-plate normal faults orthogonal to the trench as a possible tsunami source along the Lesser Antilles subduction zone. The Morne Piton fault system is such a trench-perpendicular upper crustal fault at the latitude of Guadeloupe. By means of seismic reflection, high-resolution bathymetry, remotely operated vehicle (ROV) imaging and dating, we reassess the slip rate of the Morne Piton fault since 7 Ma, i.e., its inception, and quantify an average rate of 0.25 mm yr−1 since ca. 1.2 Ma. This result divides by two previous estimations, increases the earthquake time recurrence and lowers the associated hazard. The ROV dive revealed a metric scarp with striae at the toe of the Morne Piton fault system, suggesting a recent fault rupture. We estimate a fault rupture area of ∼ 450–675 km2 and then a magnitude range for a maximum seismic event around Mw 6.5 ± 0.5, making this fault potentially tsunamigenic as the nearby Les Saintes fault responsible for a tsunami following the 2004 Mw 6.3 earthquake. Consequently, we simulate a multi-segment tsunami model representative of a worst-case scenario if all the identified Morne Piton fault segments ruptured together. Our model provides clues for the potential impact of local tsunamis on the surrounding coastal area as well as for local bathymetric controls on tsunami propagation. We illustrate that (i) shallow-water plateaus act as secondary sources and are responsible for a wrapping of the tsunami waves around the island of Marie-Galante; (ii) canyons indenting the shallow-water plateau slope break focus and enhance the wave height in front of the most touristic and populated town of the island; and (iii) the resonance phenomenon is observed within the Les Saintes archipelago, showing that the waves' frequency content is able to perturb the sea level for many hours after the seismic rupture.

Abstract Background PARP inhibitors (PARPi) are used in the treatment of ovarian, breast, pancreatic, and prostate cancers. Pneumonitis has been identified as a potential side effect, with a higher meta-analysis-assessed risk for olaparib versus other PARPi. Olaparib-induced interstitial lung disease (O-ILD) was first described within the Japanese population, with few information available for Caucasian patients. Methods We performed a retrospective study by pooling data from the French and Belgian pharmacovigilance databases from 2018 to 2022. Patients with O-ILD were included following a central review by: 1) pharmacologists using the French drug causality assessment method; 2) senior pneumologists or radiologists, using the Fleischner Society’s recommendations. Results Five patients were identified and analysed. All were females, with ovarian or breast cancer. Median age at O-ILD diagnosis was 71 (38–72) years old, with no smoking history. Median delay between treatment initiation and symptom occurrence was 12 (6–33) weeks. Pneumonitis severity assessed using the Common Terminology Criteria for Adverse Events V5 was Grade 3 (n = 4) or 2 (n = 1). CT-scan review (n = 3) described hypersensitivity pneumonitis reaction as a common pattern. Bronchioalveolar lavage (n = 4) revealed lymphocytic alveolitis. Treatments relied on olaparib discontinuation (n = 5) and glucocorticoid intake (n = 4), with no fatal issue. Safe re-challenge with PARPi occurred in two patients. Forty additional O-ILD cases were identified in the WHO VigiBase database, including one fatal case. Conclusions PARPi-ILD is a rare but potentially life-threatening disease, presenting as a hypersensitivity pneumonitis pattern within 3 months of PARPi initiation. Treatment primarily relies on medication discontinuation. Re-challenging with another PARPi could be considered. Clinical trial number CEPRO #2023–010.

Abstract Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Abstract Background Septoria tritici blotch (STB), caused by the foliar fungus Zymoseptoria tritici, is one of the most damaging disease of wheat in Europe. Genetic resistance against this fungus relies on different types of resistance from non-host resistance (NHR) and host species specific resistance (HSSR) to host resistance mediated by quantitative trait loci (QTLs) or major resistance genes (Stb). Characterizing the diversity of theses resistances is of great importance for breeding wheat cultivars with efficient and durable resistance. While the functional mechanisms underlying these resistance types are not well understood, increasing piece of evidence suggest that fungus stomatal penetration and early establishment in the apoplast are both crucial for the outcome of some interactions between Z. tritici and plants. To validate and extend these previous observations, we conducted quantitative comparative phenotypical and cytological analyses of the infection process corresponding to 22 different interactions between plant species and Z. tritici isolates. These interactions included four major bread wheat Stb genes, four bread wheat accessions with contrasting quantitative resistance, two species resistant to Z. tritici isolates from bread wheat (HSSR) and four plant species resistant to all Z. tritici isolates (NHR). Results Infiltration of Z. tritici spores into plant leaves allowed the partial bypass of all bread wheat resistances and durum wheat resistance, but not resistances from other plants species. Quantitative comparative cytological analysis showed that in the non-grass plant Nicotiana benthamiana, Z. tritici was stopped before stomatal penetration. By contrast, in all resistant grass plants, Z. tritici was stopped, at least partly, during stomatal penetration. The intensity of this early plant control process varied depending on resistance types, quantitative resistances being the least effective. These analyses also demonstrated that Stb-mediated resistances, HSSR and NHR, but not quantitative resistances, relied on the strong growth inhibition of the few Z. tritici penetrating hyphae at their entry point in the sub-stomatal cavity. Conclusions In addition to furnishing a robust quantitative cytological assessment system, our study uncovered three stopping patterns of Z. tritici by plant resistances. Stomatal resistance was found important for most resistances to Z. tritici, independently of its type (Stb, HSSR, NHR). These results provided a basis for the functional analysis of wheat resistance to Z. tritici and its improvement.

Abstract In acute ischemic stroke, even when successful recanalization is obtained, downstream microcirculation may still be obstructed by microvascular thrombosis, which is associated with compromised brain reperfusion and cognitive decline. Identifying these microthrombi through non-invasive methods remains challenging. We developed the PHySIOMIC (Polydopamine Hybridized Self-assembled Iron Oxide Mussel Inspired Clusters), a MRI-based contrast agent that unmasks these microthrombi. In a mouse model of thromboembolic ischemic stroke, our findings demonstrate that the PHySIOMIC generate a distinct hypointense signal on T2*-weighted MRI in the presence of microthrombi, that correlates with the lesion areas observed 24 hours post-stroke. Our microfluidic studies reveal the role of fibrinogen in the protein corona for the thrombosis targeting properties. Finally, we observe the biodegradation and biocompatibility of these particles. This work demonstrates that the PHySIOMIC particles offer an innovative and valuable tool for non-invasive in vivo diagnosis and monitoring of microthrombi, using MRI during ischemic stroke.

Abstract Metastatic cancer remains incurable as patients eventually loose sensitivity to targeted therapies and chemotherapies, further leading to poor clinical outcome. Thus, there is a clear medical gap and urgent need to develop efficient and improved targeted therapies for cancer patients. In this study, we investigated the role of DYRK1A kinase in regulating cancer progression and evaluated the therapeutic potential of DYRK1A inhibition in invasive solid tumors, including colon and triple-negative breast cancers. We uncovered new roles played by the DYRK1A kinase. We found that blocking DYRK1A gene expression or pharmacological inhibition of its kinase activity via harmine efficiently blocked primary tumor formation and the metastatic tumor spread in preclinical models of breast and colon cancers. Further assessing the underlying molecular mechanisms, we found that DYRK1A inhibition resulted in increased expression of the G1/S cell cycle regulators while decreasing expression of the G2/M regulators. Combined, these effects release cancer cells from quiescence, leading to their accumulation in G1/S and further delaying/preventing their progression toward G2/M, ultimately leading to growth arrest and tumor growth inhibition. Furthermore, we show that accumulation of cancer cells in G1/S upon DYRK1A inhibition led to significant potentiation of G1/S targeting chemotherapy drug responses in vitro and in vivo. This study underscores the potential for developing novel DYRK1A-targeting therapies in colon and breast cancers and, at the same time, further defines DYRK1A pharmacological inhibition as a viable and powerful combinatorial treatment approach for improving G1/S targeting chemotherapy drugs treatments in solid tumors.

Abstract Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGFβ3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGFβ3 treatment can overcome this. This study defines TGFβ3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGFβ3 to propose a new combinatorial treatment for TNBC.

Abstract Biochar is the product of intentional pyrolysis of organic feedstocks. It is made under controlled conditions in order to achieve desired physico‐chemical characteristics. These characteristics ultimately affect biochar properties as a soil amendment. When biochar is used for carbon storage, an important property is its persistence in soil, often described by the proportion of biochar carbon remaining in soil after a 100 years (Fperm). We analyzed published data on 1230 biochars to re‐evaluate the effect of pyrolysis parameters on biochar characteristics and the possibility to predict Fperm from the maximum temperature reached during pyrolysis (HTT). We showed that biochar ash and nitrogen (N) contents were mostly affected by feedstock type. The oxygen to carbon (O:C) and hydrogen to carbon (H:C) ratios were mostly affected by the extent of pyrolysis (a combination of HTT and pyrolysis duration), except for non (ligno)cellulosic feedstocks (plastic waste, sewage sludge). The volatile matter (VM) content was affected by both feedstock type and the extent of pyrolysis. We demonstrated that HTT is the main driver of H:C ‐‐ an indicator of persistence ‐‐ but that it is not measured accurately enough to precisely predict H:C, let alone persistence. We examined the equations to estimate Fperm available in the literature and showed that Fperm calculated from HTT presented little agreement with Fperm calculated from H:C. The sign and magnitude of the bias depended on the equation used to calculate Fperm and the dispersion was usually large. This could lead to improper compensation of carbon emissions and wrong reporting of carbon sinks in national carbon accounting schemes. We recommend not to use HTT as a predictor for persistence and stress the importance to rapidly develop more accurate proxies of biochar C persistence in soil.

Abstract Fjord systems in the Norwegian Arctic are experiencing an increasing frequency and magnitude of marine heatwaves. These episodic heat stress events can have varying degrees of acute impacts on primary production and nutrient uptake of mixed kelp communities, as well as modifying the biogeochemical cycling in nearshore systems where vast areas of kelp create structural habitat. To assess the impact of future marine heatwaves on kelp communities, we conducted a 23 day mesocosm experiment exposing mixed kelp communities to warming and heatwave scenarios projected for the year 2100. Three treatments were considered: a constant warming (+1.8°C from the control), a medium magnitude and long duration heatwave event (+2.8°C from the control for 13 days), and two short‐term, more intense, heatwaves(5 day long scenarios with temperature peaks at +3.9°C from the control). The results show that both marine heatwave treatments reduced net community production, whereas the constant warm temperature treatment displayed no difference from the control. The long marine heatwave scenario resulted in reduced accumulated net community production, indicating that prolonged exposure had a greater severity than two high magnitude, short‐term heatwave events. We estimated an 11°C temperature threshold at which negative effects to primary production appeared present. We highlight that marine heatwaves can induce sublethal effects on kelp communities by depressing net community production. These results are placed in the context of potential physiological resilience of kelp communities and implications of reduced net community production to future Arctic fjord environmental conditions.

Varicella-zoster virus (VZV) encephalitis and meningitis are potential central nervous system (CNS) complications following primary VZV infection or reactivation. With Type-I interferon (IFN) signalling being an important first line cellular defence mechanism against VZV infection by the peripheral tissues, we here investigated the triggering of innate immune responses in a human neural-like environment. For this, we established and characterised 5-month matured hiPSC-derived neurospheroids (NSPHs) containing neurons and astrocytes. Subsequently, NSPHs were infected with reporter strains of VZV (VZVeGFP-ORF23) or Sendai virus (SeVeGFP), with the latter serving as an immune-activating positive control. Live cell and immunocytochemical analyses demonstrated VZVeGFP-ORF23 infection throughout the NSPHs, while SeVeGFP infection was limited to the outer NSPH border. Next, NanoString digital transcriptomics revealed that SeVeGFP-infected NSPHs activated a clear Type-I IFN response, while this was not the case in VZVeGFP-ORF23-infected NSPHs. Moreover, the latter displayed a strong suppression of genes related to IFN signalling and antigen presentation, as further demonstrated by suppression of IL-6 and CXCL10 production, failure to upregulate Type-I IFN activated anti-viral proteins (Mx1, IFIT2 and ISG15), as well as reduced expression of CD74, a key-protein in the MHC class II antigen presentation pathway. Finally, even though VZVeGFP-ORF23-infection seems to be immunologically ignored in NSPHs, its presence does result in the formation of stress granules upon long-term infection, as well as disruption of cellular integrity within the infected NSPHs. Concluding, in this study we demonstrate that 5-month matured hiPSC-derived NSPHs display functional innate immune reactivity towards SeV infection, and have the capacity to recapitulate the strong immune evasive behaviour towards VZV.

The validity of the Weak Equivalence Principle (WEP) as predicted by General Relativity has been tested up to astounding precision using ordinary matter. The lack hitherto of a stable source of a probe being at the same time electrically neutral, cold and stable enough to be measured has prevented highaccuracy testing of the WEP on anti-matter. The AEg̅IS (Antimatter Experiment: Gravity, Interferometry, Spectroscopy) experiment located at CERN's AD (Antiproton Decelerator) facility aims at producing such a probe in the form of a pulsed beam of cold anti-hydrogen, and at measuring by means of a moiré deflectometer the gravitational force that Earth's mass exerts on it. Low temperature and abundance of the H̅ are paramount to attain a high precision measurement. A technique employing a charge-exchange reaction between antiprotons coming from the AD and excited positronium atoms is being developed at AEg̅IS and will be presented hereafter, alongside an overview of the experimental apparatus and the current status of the experiment

The AEgIS (Antimatter Experiment: Gravity, Interferometry, Spectroscopy) is a CERN based experiment with the central aim to measure directly the gravitational acceleration of antihydrogen. Antihydrogen atoms will be produced via charge exchange reactions which will consist of Rydberg-excited positronium atoms sent to cooled antiprotons within an electromagnetic trap. The resulting Rydberg antihydrogen atoms will then be horizontally accelerated by an electric field gradient (Stark effect), they will then pass through a moiré deflectometer. The vertical deflection caused by the Earth's gravitational field will test for the first time the Weak Equivalence Principle for antimatter. Detection will be undertaken via a position sensitive detector. Around 103 antihydrogen atoms are needed for the gravitational measurement to be completed. The present status, current achievements and results will be presented, with special attention toward the laser excitation of positronium (Ps) to the n=3 state and the production of Ps atoms in the transmission geometry.

Abstract Noble element time projection chambers are a leading technology for rare event detection in physics, such as for dark matter and neutrinoless double beta decay searches. Time projection chambers typically assign event position in the drift direction using the relative timing of prompt scintillation and delayed charge collection signals, allowing for reconstruction of an absolute position in the drift direction. In this paper, alternate methods for assigning event drift distance via quantification of electron diffusion in a pure high pressure xenon gas time projection chamber are explored. Data from the NEXT-White detector demonstrate the ability to achieve good position assignment accuracy for both high- and low-energy events. Using point-like energy deposits from $$^{83\textrm{m}}$$ 83 m Kr calibration electron captures ( $$E\sim 45$$ E ∼ 45 keV), the position of origin of low-energy events is determined to 2 cm precision with bias $$< 1~$$ < 1 mm. A convolutional neural network approach is then used to quantify diffusion for longer tracks ( $$E\ge ~1.5$$ E ≥ 1.5 MeV), from radiogenic electrons, yielding a precision of 3 cm on the event barycenter. The precision achieved with these methods indicates the feasibility energy calibrations of better than 1% FWHM at Q $$_{\beta \beta }$$ β β in pure xenon, as well as the potential for event fiducialization in large future detectors using an alternate method that does not rely on primary scintillation.

Abstract Introduction Over the past few years, anti-CD20 therapies like rituximab, ocrelizumab or ofatumumab have seen an increase in interest in the treatment of neurological autoimmune disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or resistant forms of generalized myasthenia gravis (MG). They are generally well-tolerated, but recent reports have highlighted severe dental disorders in patients undergoing anti-CD20 therapies. The aim was to describe a series of cases and to compare with the available scientific literature. Methods We reviewed 6 patient cases with dental disorders during anti-CD20 therapy that were reported to the pharmacovigilance center. A disproportionality analysis was also conducted on Vigibase® for each anti-CD20 and each adverse effect described in the cases. Results Six cases of dental and gingival conditions in relatively young patients were reported (median age: 40.5 years old [min: 34; max: 79]). Oral conditions were developed in four patients with MS treated with ocrelizumab and in two patients receiving rituximab (one patient with MG and one with NMOSD). The onset of oral conditions ranged from 10 days to 2 years after treatment initiation. Notably, all patients treated with ocrelizumab experienced gingival recession. Various dental pathologies were observed, including tooth loss, dental pain, caries, brittle teeth, dental fractures, dental abscesses, and periodontitis. Analysis of Vigibase® revealed 284 worldwide cases of dental and gingival conditions under ocrelizumab, 386 cases under rituximab, and 80 under ofatumumab. Significant associations were found between these therapies and dental pathologies, particularly tooth abscesses and infections. Conclusion To our knowledge, this is the first case series reporting dental conditions developed in patients long-term treated with anti-CD20 treatments. This issue, literature data, and Vigilyze® analysis might be considered a safety signal that necessitates being confirmed with more robust data, such as a retrospective study with a control group. Meanwhile, proactive measures are essential like frequent dental checkups and dental hygienic measures to prevent oral health problems associated with anti-CD20 therapies.

Abstract Background The fruity aromatic bouquet of coffee has attracted recent interest to differentiate high value market produce as specialty coffee. Although the volatile compounds present in green and roasted coffee beans have been extensively described, no study has yet linked varietal molecular differences to the greater abundance of specific substances and support the aroma specificity of specialty coffees. Results This study compared four Arabica genotypes including one, Geisha Especial, suggested to generate specialty coffee. Formal sensory evaluations of coffee beverages stressed the importance of coffee genotype in aroma perception and that Geisha Especial-made coffee stood out by having fine fruity, and floral, aromas and a more balanced acidity. Comparative SPME–GC–MS analyses of green and roasted bean volatile compounds indicated that those of Geisha Especial differed by having greater amounts of limonene and 3-methylbutanoic acid in agreement with the coffee cup aroma perception. A search for gene ontology differences of ripening beans transcriptomes of the four varieties revealed that they differed by metabolic processes linked to terpene biosynthesis due to the greater gene expression of prenyl-pyrophosphate biosynthetic genes and terpene synthases. Only one terpene synthase (CaTPS10-like) had an expression pattern that paralleled limonene loss during the final stage of berry ripening and limonene content in the studied four varieties beans. Its functional expression in tobacco leaves confirmed its functioning as a limonene synthase. Conclusions Taken together, these data indicate that coffee variety genotypic specificities may influence ripe berry chemotype and final coffee aroma unicity. For the specialty coffee variety Geisha Especial, greater expression of terpene biosynthetic genes including CaTPS10-like, a limonene synthase, resulted in the greater abundance of limonene in green beans, roasted beans and a unique citrus note of the coffee drink.

Spintronic terahertz emitters (STEs), based on optical excitation of nanometer thick ferromagnetic/heavy metal (FM/HM) heterojunctions, have become important sources for the generation of terahertz (THz) pulses. However, the efficiency of the optical-to-THz conversion remains limited. Although optical techniques have been developed to enhance the optical absorption, no investigations have studied the application of THz cavities. Here, to enhance the THz efficiency of STEs in a selected THz spectral range, FM/HM structures are realized on ultra-thin sapphire layers with metallic mirrors to create λ/4 THz resonant cavities. THz emission time domain spectroscopy of these STE/sapphire/mirror heterostructures, with sapphire thicknesses ranging from 110 µm to 25 µm, shows enhancement of the emitted THz field that fits the λ/4 cavity resonance with up to a doubling of the field in the spectrum, and in agreement with temporal simulations of the emitted THz pulse. By taking advantage of birefringent materials, we further show the potential of control of the polarization state of the emitted THz pulse. This work shows the potential of enhancing and engineering THz emission from STEs using THz cavities that can be controlled over a broad spectral range, which can be easily combined with optical cavities.

Abstract Viral neuroinfections represent a major health burden for which the development of antivirals is needed. Antiviral compounds that target the consequences of a brain infection (symptomatic treatment) rather than the cause (direct-acting antivirals) constitute a promising mitigation strategy that requires to be investigated in relevant models. However, physiological surrogates mimicking an adult human cortex are lacking, limiting our understanding of the mechanisms associated with viro-induced neurological disorders. Here, we optimized the Organotypic culture of Post-mortem Adult human cortical Brain explants (OPAB) as a preclinical platform for Artificial Intelligence (AI)-driven antiviral studies. OPAB shows robust viability over weeks, well-preserved 3D cytoarchitecture, viral permissiveness, and spontaneous local field potential (LFP). Using LFP as a surrogate for neurohealth, we developed a machine learning framework to predict with high confidence the infection status of OPAB. As a proof-of-concept, we showed that antiviral-treated OPAB could partially restore LFP-based electrical activity of infected OPAB in a donor-dependent manner. Together, we propose OPAB as a physiologically relevant and versatile model to study neuroinfections and beyond, providing a platform for preclinical drug discovery.

Abstract Objective The radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS). Increasing evidence suggests that the central vein sign (CVS) enhances lesion specificity, allowing for greater MS diagnostic accuracy. This study evaluated the diagnostic performance of the CVS in RIS. Methods Patients were prospectively recruited in a single tertiary center for MS care. Participants with RIS were included and compared to a control group of sex and age‐matched subjects. All participants underwent 3 Tesla magnetic resonance imaging, including postcontrast susceptibility‐based sequences, and the presence of CVS was analyzed. Sensitivity and specificity were assessed for different CVS lesion criteria, defined by proportions of lesions positive for CVS (CVS+) or by the absolute number of CVS+ lesions. Results 180 participants (45 RIS, 45 MS, 90 non‐MS) were included, representing 5285 white matter lesions. Among them, 4608 were eligible for the CVS assessment (970 in RIS, 1378 in MS, and 2260 in non‐MS). According to independent ROC comparisons, the proportion of CVS+ lesions performed similarly in diagnosing RIS from non‐MS than MS from non‐MS (p = 0.837). When a 6‐lesion CVS+ threshold was applied, RIS lesions could be diagnosed with an accuracy of 87%. MS could be diagnosed with a sensitivity of 98% and a specificity of 83%. Adding OCBs or Kappa index to CVS biomarker increased the specificity to 100% for RIS diagnosis. Interpretation This study shows evidence that CVS is an effective imaging biomarker in differentiating RIS from non‐MS, with similar performances to those in MS.

Background Anorexia nervosa (AN) is a severe psychiatric disorder associated with frequent relapses and variability in treatment responses. Previous literature suggested that such variability is influenced by premorbid vulnerabilities such as abnormalities of the reward system. Several factors may indicate these vulnerabilities, such as neurocognitive markers (tendency to favour delayed reward, poor cognitive flexibility, abnormal decision process), genetic and epigenetic markers, biological and hormonal markers, and physiological markers.The present study will aim to identify markers that can predict body mass index (BMI) stability 6 months after discharge. The secondary aim of this study will be focused on characterising the biological, genetic, epigenetic and neurocognitive markers of remission in AN.Methods and analysis One hundred and twenty-five (n=125) female adult inpatients diagnosed with AN will be recruited and evaluated at three different times: at the beginning of hospitalisation, when discharged and 6 months later. Depending on the BMI at the third visit, patients will be split into two groups: stable remission (BMI≥18.5 kg/m²) or unstable remission (BMI

The chemistry of chitosan is a promising way to afford biobased and biodegradable complex materials using highly reactive compounds such as anhydrides. However, the potential applications are limited due to the absence of control over the acylation and the lack of precise characterization. After a model study on glucosamine, a selective acylation method of amines or alcohols of chitosan oligomers using anhydrides has been developed. The N-acylation of chitooligosaccharides has been achieved using several anhydrides and the O-acylation has been achieved in three steps: (1) Amine protection using p-anisaldehyde (2) O-acylation (with four anhydrides), and (3) Amine deprotection by removing the protective anisyl groups. Functionalized chitooligosaccharides have been characterized by a precise quantification method using 13C nuclear magnetic resonance spectroscopy. The resulting degrees of substitution show in most of the cases a stochiometric reaction between anhydrides and amines of chitooligosaccharides, and around 70 % of efficiency for O-acylation, proving the promising potential of such modifications. To the best of our knowledge, we describe here the first example of selective acylation of chitooligosaccharides using anhydrides, and most of all the first example of 13C quantitative NMR spectroscopy performed on chitooligosaccharides and its derivatives. These innovative structures are the gateway to the creation of new biosourced and/or biodegradable surfactants.

IntroductionCraniopharyngiomas (CPs) are benign brain tumors accounting for 5 - 11% of intracranial tumors in children. These tumors often recur and can cause severe morbidity. Postoperative radiotherapy efficiently controls and prevents progression and recurrence. Despite advancements in neurosurgery, endocrinological, visual, and neuropsychological complications are common and significantly lower the quality of life of patients.MethodsWe performed a retrospective study, including all patients younger than sixteen diagnosed with CP between July 1989 and August 2022 and followed up in Hôpital Universitaire de Bruxelles.ResultsNineteen children with CP were included, with median age of 7 years at first symptoms and 7.5 at diagnosis. Common symptoms at diagnosis were increased intracranial pressure (63%), visual impairment (47%), growth failure (26%), polyuria/polydipsia (16%), and weight gain (10.5%). As clinical signs at diagnosis, growth failure was observed in 11/18 patients, starting with a median lag of 1 year and 4 months before diagnosis. On ophthalmological examination, 27% of patients had papillary edema and 79% had visual impairment. When visual disturbances were found, the average preoperative volume was higher (p=0.039). Only 6/19 patients had gross total surgical resection. After the first neurosurgery, 83% experienced tumor recurrence or progression at a median time of 22 months. Eleven patients (73%) underwent postsurgical radiotherapy. At diagnosis, growth hormone deficiency (GHD) was the most frequent endocrine deficit (8/17) and one year post surgery, AVP deficiency was the most frequent deficit (14/17). Obesity was present in 13% of patients at diagnosis, and in 40% six months after surgery. There was no significant change in body mass index over time (p=0.273) after the first six months post-surgery.ConclusionCP is a challenging brain tumor that requires multimodal therapy and lifelong multidisciplinary follow-up including hormonal substitution therapy. Early recognition of symptoms is crucial for prompt surgical management. The management of long-term sequelae and morbidity are crucial parts of the clinical path of the patients. The results of this study highlight the fundamental importance of carrying out a complete assessment (ophthalmological, endocrinological, neurocognitive) at the time of diagnosis and during follow-up so that patients can benefit from the best possible care.

Background: Although there have been several studies describing risk factors for complications after outpatient total hip arthroplasty (THA), data describing the timing of such complications is lacking. Methods: Patients who underwent outpatient or inpatient primary THA were identified in the 2012-2019 National Surgical Quality Improvement Program database. For 9 different 30-day complications, the median postoperative day of diagnosis was determined. Multivariable regressions were used to compare the risk of each complication between outpatient vs inpatient groups. Multivariable Cox proportional hazards modeling was used to evaluate the differences in the timing of each adverse event between the groups. Results: After outpatient THA, the median day of diagnosis for readmission was 12.5 (interquartile range 5-22), surgical site infection 15 (2-21), urinary tract infection 13.5 (6-19.5), deep vein thrombosis 13 (8-21), myocardial infarction 4.5 (1-7), pulmonary embolism 15 (8-25), sepsis 16 (9-26), stroke 2 (0-7), and pneumonia 6.5 (3-10). On multivariable regressions, outpatients had a lower relative risk (RR) of readmission (RR = 0.73), surgical site infection (RR = 0.72), and pneumonia (RR = 0.1), all P < .05. On multivariable cox proportional hazards modeling, there were no statistically significant differences in the timing of each complication between outpatient vs inpatient procedures (P > .05). Conclusions: The timing of complications after outpatient THA was similar to inpatient procedures. Consideration should be given to lowering thresholds for diagnostic testing after outpatient THA for each complication during the at-risk time periods identified here. Although extremely rare, this is especially important for catastrophic adverse events, which tend to occur early after discharge.

This study aimed to investigate the volatile organic compounds (VOCs) variations during the spoilage of palm wine stored at ambient temperature and identify potential shelf-life markers. Palm wine collected from local tappers and resellers were stored at ambient temperature (28-30°C) for 96 h. At an interval of 24 h, VOCs variations were investigated using Solid phase Microextraction-Gas Chromatography-Mass Spectroscopy (SPME-GC/MS) method. Changes in sensory quality and potential flavour contributors were also explored. The sensory rejection time was found at 24 h and 48 h of storage for palm wines collected from the tappers and resellers, respectively. The first attribute to be spoiled was taste followed by odour and appearance. A total of 23 VOCs distributed in six chemical families were identified. Alteration of palm wine sample is characterised by an increase in concentration of alcohol (isoamyl alcohol, isobutanol and 1-octanol), aceti acid and acetoin, and a decrease in ester concentration (ethyl acetate and ethyl hexanoate). In the view to fight against the short shelf-life and develop new preservation methods, these compounds can be used as markers of spoiled palm wine.

Abstract The emergence of exceptional points (EPs) in the parameter space of a non-hermitian (2D) eigenvalue problem has long been interest in mathematical physics, however, only in the last decade entered the scope of experiments. In coupled systems, EPs give rise to unique physical phenomena, and enable the development of highly sensitive sensors. Here, we demonstrate at room temperature the emergence of EPs in coupled spintronic nanoscale oscillators and exploit the system’s non-hermiticity. We observe amplitude death of self-oscillations and other complex dynamics, and develop a linearized non-hermitian model of the coupled spintronic system, which describes the main experimental features. The room temperature operation, and CMOS compatibility of our spintronic nanoscale oscillators means that they are ready to be employed in a variety of applications, such as field, current or rotation sensors, radiofrequeny and wireless devices, and in dedicated neuromorphic computing hardware. Furthermore, their unique and versatile properties, notably their large nonlinear behavior, open up unprecedented perspectives in experiments as well as in theory on the physics of exceptional points expanding to strongly nonlinear systems.

Abstract Magnonic nano-devices exploit magnons - quanta of spin waves - to transmit and process information within a single integrated platform that has the potential to outperform traditional semiconductor-based electronics. The main missing cornerstone of this information nanotechnology is an efficient scheme for the amplification of propagating spin waves. The recent discovery of spin-orbit torque provided an elegant mechanism for propagation losses compensation. While partial compensation of the spin-wave losses has been achieved, true amplification – the exponential increase in the spin-wave intensity during propagation – has so far remained elusive. Here we evidence the operating conditions to achieve unambiguous amplification using clocked nanoseconds-long spin-orbit torque pulses in magnonic nano-waveguides, where the effective magnetization has been engineered to be close to zero to suppress the detrimental magnon scattering. We achieve an exponential increase in the intensity of propagating spin waves up to 500% at a propagation distance of several micrometers.

Abstract Oocyte maturation is a key process during which the female germ cell undergoes resumption of meiosis and completes its preparation for embryonic development including cytoplasmic and epigenetic maturation. The cumulus cells directly surrounding the oocyte are involved in this process by transferring essential metabolites, such as pyruvate, to the oocyte. This process is controlled by cyclic adenosine monophosphate (cAMP)-dependent mechanisms recruited downstream of follicle-stimulating hormone (FSH) signaling in cumulus cells. As mitochondria have a critical but poorly understood contribution to this process, we defined the effects of FSH and high cAMP concentrations on mitochondrial dynamics and function in porcine cumulus cells. During in vitro maturation (IVM) of cumulus-oocyte complexes (COCs), we observed an FSH-dependent mitochondrial elongation shortly after stimulation that led to mitochondrial fragmentation 24 h later. Importantly, mitochondrial elongation was accompanied by decreased mitochondrial activity and a switch to glycolysis. During a pre-IVM culture step increasing intracellular cAMP, mitochondrial fragmentation was prevented. Altogether, the results demonstrate that FSH triggers rapid changes in mitochondrial structure and function in COCs involving cAMP.

Background: Cortical Blindness is most commonly caused by stroke or traumatic brain injury. The case study has the unique function of outlining the story of a young patient who incurred multiple gunshot wounds in an incident that ultimately transpired into a complete and permanent cortical blindness.Case presentation: The present subject exhibits cortical blindness in the absence of either etiology. The proposed etiology is that of perioperative hypoxic seizures. Neuroanatomical and pathophysiological framework is established to elucidate the conditions surrounding the outcome.Discussion: It is known that acute neuronal ischemia presents as drastically urgent to the tune of a five-minute intervention window, and it is learned that the prognosis of recovery from cortical blindness is statistically confined to an interval of around six months. Statistical context paves the way for a practical perspective on rehabilitation for patients with vision loss.

The rapid environmental changes in aquatic systems as a result of anthropogenic forcings are creating a multitude of challenging conditions for organisms and communities. The need to better understand the interaction of environmental stressors now, and in the future, is fundamental to determining the response of ecosystems to these perturbations. This work describes an automated ex situ mesocosm perturbation system that can manipulate several variables of aquatic media in a controlled setting. This perturbation system was deployed in Kongsfjorden (Svalbard); within this system, ambient water from the fjord was heated and mixed with freshwater in a multifactorial design to investigate the response of mixed-kelp communities in mesocosms to projected future Arctic conditions. The system employed an automated dynamic offset scenario in which a nominal temperature increase was programmed as a set value above real-time ambient conditions in order to simulate future warming. A freshening component was applied in a similar manner: a decrease in salinity was coupled to track the temperature offset based on a temperature–salinity relationship in the fjord. The system functioned as an automated mixing manifold that adjusted flow rates of warmed and chilled ambient seawater, with unmanipulated ambient seawater and freshwater delivered as a single source of mixed media to individual mesocosms. These conditions were maintained via continuously measured temperature and salinity in 12 mesocosms (1 control and 3 treatments, all in triplicate) for 54 d. System regulation was robust, as median deviations from nominal conditions were < 0.15 for both temperature (∘C) and salinity across the three replicates per treatment. Regulation further improved during a second deployment that mimicked three marine heat wave scenarios in which a dynamic temperature regulation held median deviations to < 0.036 ∘C from the nominal value for all treatment conditions and replicates. This perturbation system has the potential to be implemented across a wide range of conditions to test single or multi-stressor drivers (e.g., increased temperature, freshening, and high CO2) while maintaining natural variability. The automated and independent control for each experimental unit (if desired) provides a large breadth of versatility with respect to experimental design.

Abstract Klebsiella pneumoniae has been classified into two types, classical K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP). cKP isolates are highly diverse and important causes of nosocomial infections; they include globally disseminated antibiotic-resistant clones. hvKP isolates are sensitive to most antibiotics but are highly virulent, causing community-acquired infections in healthy individuals. The virulence phenotype of hvKP is associated with pathogenicity loci responsible for siderophore and hypermucoid capsule production. Recently, convergent strains of K. pneumoniae, which possess features of both cKP and hvKP, have emerged and are cause of much concern. Here, we screen the genomes of 2,608 multidrug-resistant K. pneumoniae isolates from the United States and identify 47 convergent isolates. We perform phenotypic and genomic characterization of 12 representative isolates. These 12 convergent isolates contain a variety of antimicrobial resistance plasmids and virulence plasmids. Most convergent isolates contain aerobactin biosynthesis genes and produce more siderophores than cKP isolates but not more capsule. Unexpectedly, only 1 of the 12 tested convergent isolates has a level of virulence consistent with hvKP isolates in a murine pneumonia model. These findings suggest that additional studies should be performed to clarify whether convergent strains are indeed more virulent than cKP in mouse and human infections.

Objectives: The aim was to evaluate the clinical, ultrasound (US) and, when indicated, the cytological and histological characteristics of autonomously functioning thyroid nodules (AFTN) in consecutive patients. Methods: A prospective, single-centre study was conducted between March 2018 and September 2021. In total, 901 consecutive patients were referred for thyroid workup and of 67 AFTN were evaluated. All enrolled patients underwent 99mTcO4− scintigraphy, additional 123I scintigraphy only in case of normal serum TSH, evaluation of thyroid function, US examination using European Thyroid Imaging and Reporting Data System (EU-TIRADS), and US-guided fine needle aspiration (FNA) cytology when indicated. All indeterminate FNA samples were subjected to DNA sequencing analysis. Results: More than half of the evaluated patients with AFTN were euthyroid; median serum TSH was 0.41 (IQR: 0.03–0.97) mU/L. The median AFTN size measured by US was 27.0 (IQR: 21.1–35.0) mm. 28.4% of AFTN were classified as E U-TIRADS score 3 and 71.6% as EU-TIRADS score 4, indicating that the majority of AFTN had intermediate risk for malignancy according to US. Out of the 47 AFTN subjected to cytological evaluation, 24 (51%) yielded indeterminate FNA results. DNA sequencing revealed pathogenic TSHR and GNAS mutations in 60% of cases. No malignancy was detected at final histology in surgically excised AFTN (n = 12). Conclusions: Of the 67 AFTN evaluated in this study, 50% presented with normal serum TSH, 70% displayed ultrasound features suggesting an intermediate malignancy risk and 50% of the AFTN submitted to cytology yielded indeterminate results. No malignant AFTN was detected.

Body temperature is primarily regulated by the hypothalamus, ensuring proper metabolic function. Envenomation by Phoneutria nigriventer can cause symptoms such as hypothermia, hyperthermia, sweating, and shivering, all related to thermoregulation. This study aims to analyze and identify components of the venom that affect thermoregulation and to evaluate possible mechanisms. Rats were used for thermoregulation analysis, venom fractionation by gel filtration and reverse-phase chromatography (C18), and sequencing by Edman degradation. The venom exhibited hypothermic effects in rats, while its fractions demonstrated both hypothermic (pool II) and hyperthermic (pool III) effects. Further separations of the pools with C18 identified specific peaks responsible for these effects. However, as the peaks were further purified, their effects became less significant. Tests on U87 human glioblastoma cells showed no toxicity. Sequencing of the most active peaks revealed masses similar to those of the Tachykinin and Ctenotoxin families, both known to act on the nervous system. The study concludes that molecules derived from venom can act synergistically or antagonistically. Additionally, toxins that affect thermoregulation are poorly studied and require further characterization. These toxins could potentially serve as sources for the development of new thermoregulatory drugs.

The weak equivalence principle states that the motion of a body in a gravitational field is independent of its structure or composition. This postulate of general relativity has been tested to very high precision with ordinary matter, but no relevant experimental verification with antimatter has ever been carried out. The AEGIS experiment will measure the gravitational acceleration of antihydrogen to ultimately 1% precision. For this purpose, a pulsed horizontal antihydrogen beam with a velocity of several 100 m s−1 will be produced. Its vertical deflection due to gravity will be detected by a setup consisting of material gratings coupled with a position-sensitive detector, operating as a moiré deflectometer or an atom interferometer. The AEGIS experiment is installed at CERN’s Antiproton Decelerator, currently the only facility in the world which produces copious amounts of low-energy antiprotons. The construction of the setup has been going on since 2010 and is nearing completion. A proof-of-principle experiment with antiprotons has demonstrated that the deflection of antiparticles by a few μm due to an external force can be detected. Technological and scientific development pertaining to specific challenges of the experiment, such as antihydrogen formation by positronium charge exchange or the position-sensitive detection of antihydrogen annihilations, is ongoing.

Introduction Anorexia nervosa (AN) is a severe and chronic psychiatric disorder, resulting from a voluntary food restriction, vomiting, use of laxatives and excessive exercises, leading in dramatic weight loss and high mortality. AN is a multifactorial disease involving genetic and epigenetic factors supporting that AN is a metabo-psychiatric disorder. The molecular mechanisms involved in the etiology of AN remain unclear. One work reported gene expression by RNA sequencing in peripheral blood before and after weight restoration in 6 AN patients (Kim 2013), and one RNA sequencing in human iiPSC-derived neurons from 4 patients and 4 controls (Negraes 2017). To date, the profile of expression of genes and proteins in AN is undetermined. Objectives In this study, our goal is to identify specific gene expression signatures from circulating blood nuclear cells to decipher the pathophysiology of AN and characterize biomarkers that can be used for diagnostic or prognostic of AN. Methods All consented participants are recruited at Sainte-Anne Hospital, Paris, France, using DSM5 criteria. They had a blood draw in Paxgene tube for the collection of RNAs. Total RNA was extracted from peripheral blood mononuclear cells of 15 patients suffering of AN and 15 healthy controls. All messenger RNAs are sequenced on a Novaseq plateform. Reads are aligned to the human genome 19 and statistical analyses on the read counts for differentially expressed genes are computed with DESeq2. Results The total RNA sequencing allows us to identify 673 dysregulates genes (p adjusted value 1,5). Among them, 248 are down-regulated and 425 are up-regulated genes in AN patients compared to controls. From them, 151 transcripts are annotated as pseudogene and 45 are referenced as antisense RNA. Of the 522 remaining transcripts, 424 correspond to a transcript or protein annotated by HGNC and ENSEMBL and 93 are known pseudogenes. A large number of proteins resulting from the expression of deregulated genes interact with each other and form a statistically enriched network impacting biological processes. They are mainly increased and acting in the cellular machinery allowing protein synthesis (biological process: transcription, ribosome, spliceosome and mitochondria). In contrast, down-regulated genes present an enrichment in genes involved in immunity pathways. Finally, several genes are also expressed in the brain. We observed a significant enrichment of genes expressed in the blood and brain tissues. Conclusions We identify specific profiles of gene expression in AN. Several genes are both blood and brain tissue expression. Some genes are good candidates for biomarker of the diagnostic in AN that need to be investigated in a longitudinal study to evaluate their useful as prognostic biomarker of AN. This work is supported by Fondation de France & Fédération Recherche sur le Cerveau. Disclosure of Interest None Declared

Background: Given the increasing accessibility of Internet access, it is critical to ensure that the informational material available online for patient education is both accurate and readable to promote a greater degree of health literacy. This study sought to investigate the quality and readability of the most popular online resources for ankle fractures. Methods: After conducting a Google search using 6 terms related to ankle fractures, we collected the first 20 nonsponsored results for each term. Readability was evaluated using the Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), and Gunning Fog Index (GFI) instruments. Quality was evaluated using custom created Ankle Fracture Index (AFI). Results: A total of 46 of 120 articles met the inclusion criteria. The mean FKGL, FRE, and GFI scores were 8.4 ± 0.5, 57.5 ± 3.2, and 10.5 ± 0.5, respectively. The average AFI score was 15.4 ± 1.4, corresponding to an “acceptable” quality rating. Almost 70% of articles (n = 32) were written at or below the recommended eighth-grade reading level. Most articles discussed the need for imaging in diagnosis and treatment planning while neglecting to discuss the risks of surgery or potential future operations. Conclusion: We found that online patient-facing materials on ankle fractures demonstrated an eighth-grade average reading grade level and an acceptable quality on content analysis. Further work should surround increasing information regarding risk factors, complications for surgery, and long-term recovery while ensuring that readability levels remain below at least the eighth-grade level.

Summary: Background: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. Methods: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. Findings: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951). Interpretation: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. Funding: Paul Gougis was supported by the academic program: “Contrats ED: Programme blanc Institut Curie PSL” for the conduct of his PhD. Baptiste Abbar was supported by “the Fondation ARC Pour le Rechercher Sur le Cancer”. The RT2L research group (Institut Curie) was supported by the academic program “SHS INCa”, Sanofi iTech award, and by Monoprix∗.

Background: Femoral neck anteversion has traditionally been measured by the angle between the distal femur posterior condylar axis (PCA) and a line drawn through the center of the femoral head and neck. While less common, the transepicondylar axis (TEA) has also been used to reference femoral neck anteversion. The purpose of this study was to compare femoral neck version of the PCA vs the TEA using computerized tomography (CT). Methods: A total of 1507 femoral CTs were included. Precise bony landmarks were established: lateral epicondyle, medial epicondyle, posteromedial condyle, posterolateral condyle, center of the femoral neck, and center of the femoral head. Femoral version was calculated between the head and neck axis and either the PCA or TEA. Differences between sex and ethnicity were evaluated. Results: The mean femoral anteversion was 12.7° ± 9.1° based on the PCA and 11.5° ± 7.9° based on the TEA (mean difference 1.2° ± 1.9°, P < .001). Males were less anteverted than females (9.8° ± 7.6° vs 13.5° ± 7.8°, P < .001). African Americans had less anteversion than other groups (8.1° ± 9.2° vs 11.5° ± 7.8°, P = .04), while Asians were more anteverted than other groups (12.1° ± 9.0° vs 11.2° ± 7.3°, P = .04). These values were referenced on the TEA. Conclusions: In this series of over 1500 femoral CT scans, the mean difference between anteversion measurements referencing the PCA and TEA was 1.2°. Native femoral version varied widely between gender and ethnic groups. Extreme femoral version, defined as 30°, was present in 11.8% of patients referencing the PCA.

The MONITOOL project (2017–2023) was carried out to describe the relationships between total dissolved and labile metal concentrations measured in spot water samples and in concurrently deployed Diffusive Gradients in Thin-films (DGTs) passive samplers, respectively. The ultimate aim was to adapt existing marine metal Environmental Quality Standards (EQS marine water) for DGTs, enabling their use in the context of the European Directives (the Water Framework Directive (WFD) and the Marine Strategy Framework Directive (MSFD)). Time-integrated metal concentrations provided by DGTs, representing several days, are an advantage compared to conventional spot sampling, especially in highly dynamic systems, such as transitional waters. Hence, the MONITOOL project aimed to provide a robust database of dissolved and labile metal concentrations in transitional and coastal waters, based upon co-deployments of DGTs and collection of spot water samples at several sampling sites (England, France, Ireland, Italy, Northern Ireland, Portugal, Scotland and Spain), followed subsequently by DGT and water metal analysis. Samplings were carried out in 2018 and 2022, following agreed protocols developed in the framework of the project.The MONITOOL dataset includes metal concentrations from DGTs, measured with Inductively Coupled Plasma Mass Spectrometry (ICP-MS: Cd, Co, Cu, Fe, Mn, Ni, Pb, Zn) and in concurrently collected spot water samples by ICP-MS (Al, Cd, Co, Cu, Mn, Ni, Pb, Zn) and Anodic/Cathodic Stripping Voltammetry (ASV/CSV: Cd, Pb, Ni). Moreover, data on seawater physical-chemical parameters (salinity, temperature, dissolved oxygen, pH, turbidity, total suspended solids, dissolved organic carbon, and total organic carbon) is provided.This database presents the results obtained using, concurrently, different forms of sampling and analytical techniques, enabling the comparison of the results obtained by these strategies and allowing the adaptation of EQS in marine water (EQS marine water) to DGTs (EQS DGT), in the context of the WFD. Moreover, due to the large number of sampling sites, it could also be used for other types of research, such as those dealing with metal speciation or the determination of baseline levels.

At a time when the term proximity is facing an inflation of more or less well-defined usages, this article proposes some elements of clarification. To this end, I believe it would be useful to apply the resource/asset binomial, proposed 30 years ago by G. Colletis and B. Pecqueur, to the study of proximities. This distinction between potential and activation is based on the same logic as the motility/mobility binomial proposed by V. Kaufmann at the dawn of the 2000s. This will enable us to return to what makes proximity a resource, so that it can be invoked wisely. We can see that mobility takes up too much space in our understanding of the value of proximity. However, at a time when environmental transitions are more than necessary, a maximized and reasoned use of proximity seems necessary. The search for what I call a hyperproxible society must therefore be an accepted objective.

Abstract Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.

Abstract Antarctic sea ice is mostly seasonal. While changes in sea ice seasonality have been observed in recent decades, the lack of process understanding remains a key challenge to interpret these changes. To address this knowledge gap, we investigate the processes driving the ice season onset, known as sea ice advance, using remote sensing and in situ observations. Here, we find that seawater freezing predominantly drives advance in the inner seasonal ice zone. By contrast, in an outer band a few degrees wide, advance is due to the import of drifting ice into warmer waters. We show that advance dates are strongly related to the heat stored in the summer ocean mixed layer. This heat is controlled by the timing of sea ice retreat, explaining the tight link between retreat and advance dates. Such a thermodynamic linkage strongly constrains the climatology and interannual variations, albeit with less influence on the latter.

Abstract The NEXT experiment aims at the sensitive search of the neutrinoless double beta decay in 136Xe, using high-pressure gas electroluminescent time projection chambers. The NEXT-White detector is the first radiopure demonstrator of this technology, operated in the Laboratorio Subterráneo de Canfranc. Achieving an energy resolution of 1% FWHM at 2.6 MeV and further background rejection by means of the topology of the reconstructed tracks, NEXT-White has been exploited beyond its original goals in order to perform a neu- trinoless double beta decay search. The analysis considers the combination of 271.6 days of 136Xe-enriched data and 208.9 days of 136Xe-depleted data. A detailed background modeling and measurement has been developed, ensuring the time stability of the radiogenic and cosmogenic contributions across both data samples. Limits to the neutrinoless mode are obtained in two alternative analyses: a background-model-dependent approach and a novel direct background-subtraction technique, offering results with small dependence on the background model assumptions. With a fiducial mass of only 3.50 ± 0.01 kg of 136Xe-enriched xenon, 90% C.L. lower limits to the neutrinoless double beta decay are found in the T 1 / 2 0 ν $$ {T}_{1/2}^{0\nu } $$ > 5.5 × 1023 − 1.3 × 1024 yr range, depending on the method. The presented techniques stand as a proof-of-concept for the searches to be implemented with larger NEXT detectors.

Invasive aspergillosis (IA) represents a common form of fungal infection caused by various species of Aspergillus that most frequently affect immunocompromised patients. Typically, this disease occurs preferentially in high-risk groups including patients infected with the human immunodeficiency virus (HIV), patients with leukemia, patients with autoimmune diseases, and organ transplant patients undergoing medical immunosuppression. Considered the second most common cause of opportunistic fungal infection in humans after Candida albicans, this pathogen predominantly affects the lungs, but it may also spread by a hematogenous route to various organs and have a heterogeneous presentation. Owing to its high iodine levels, high perfusion, and enclosed capsule, the thyroid gland is considered to have a lower susceptibility to microbial invasion, and it is fairly uncommon to find associated infectious nodules. In metabolic imaging, 18F-FDG-PET/CT has become increasingly useful for detecting a wide range of infectious and inflammatory diseases and is already the gold standard for certain indications. According to the literature, no studies of hypermetabolic nodular thyroid aspergillosis on 18F-FDG-PET/CT confirmed on histology have yet been reported. Here, we report the first case of a patient with a heterogeneous presentation of IA and the presence of a hypermetabolic nodule in the thyroid with a surprising result.

Animal venoms are intricate and teem with potential for groundbreaking medical advancements. Although traditional methods for purifying venom proteins are effective, they usually require complicated, multi-step processes that lead to lower yields. Our study introduces an efficient, one-step technique for extracting venom-derived proteins through reverse-phase high-performance liquid chromatography (RP-HPLC). We carefully optimized the RP-HPLC process, focusing on the gradient elution conditions and the strategic use of our columns’ stationary phase characteristics, to enhance the effectiveness of our separations. This enabled us to efficiently isolate six venom proteins: melittin (2.846 kDa) from Apis mellifera with a yield of 4.5% and homogeneity of 99%; α-cobratoxin (7.821 kDa) from Naja kaouthia with a yield of 15% and homogeneity of 99%; α-bungarotoxin (7.983 kDa) from Bungarus multicinctus with a yield of 7% and purity of 99%; calciseptine (7.035 kDa) from Dendroaspis polylepis with a yield of 6% and homogeneity of 95%; notexin (13.593 kDa) from Notechis scutatus with a yield of 10% and homogeneity of 95%; and CVFm (150 kDa) from Naja melanoleuca with a yield of 0.8% and homogeneity of 94%. These were all accomplished in one step. This breakthrough simplifies the purification of venom peptides and proteins, making the process more feasible and economical. It paves the way for developing new drugs and promising treatments that are both more effective and precisely targeted.

Over the past few decades, the worldwide incidence of cutaneous melanoma, a malignant neoplasm arising from melanocytes, has been increasing markedly, leading to the highest rate of skin cancer-related deaths. While localized tumors are easily removed by excision surgery, late-stage metastatic melanomas are refractory to treatment and exhibit a poor prognosis. Consequently, unraveling the molecular mechanisms underlying melanoma tumorigenesis and metastasis is crucial for developing novel targeted therapies. We found that the multiple endocrine neoplasia type 1 (MEN1) gene product Menin is required for the transforming growth factor beta (TGFβ) signaling pathway to induce cell growth arrest and apoptosis in vitro and prevent tumorigenesis in vivo in preclinical xenograft models of melanoma. We further identified point mutations in two MEN1 family members affected by melanoma that led to proteasomal degradation of the MEN1 gene product and to a loss of TGFβ signaling. Interestingly, blocking the proteasome degradation pathway using an FDA-approved drug and RNAi targeting could efficiently restore MEN1 expression and TGFβ transcriptional responses. Together, these results provide new potential therapeutic strategies and patient stratification for the treatment of cutaneous melanoma.

Abstract The Pandora Software Development Kit and algorithm libraries provide pattern-recognition logic essential to the reconstruction of particle interactions in liquid argon time projection chamber detectors. Pandora is the primary event reconstruction software used at ProtoDUNE-SP, a prototype for the Deep Underground Neutrino Experiment far detector. ProtoDUNE-SP, located at CERN, is exposed to a charged-particle test beam. This paper gives an overview of the Pandora reconstruction algorithms and how they have been tailored for use at ProtoDUNE-SP. In complex events with numerous cosmic-ray and beam background particles, the simulated reconstruction and identification efficiency for triggered test-beam particles is above 80% for the majority of particle type and beam momentum combinations. Specifically, simulated 1 GeV/c charged pions and protons are correctly reconstructed and identified with efficiencies of 86.1 $$\pm 0.6$$ ± 0.6 % and 84.1 $$\pm 0.6$$ ± 0.6 %, respectively. The efficiencies measured for test-beam data are shown to be within 5% of those predicted by the simulation.

IntroductionDesulfovibrio vulgaris Hildenborough is a gram-negative anaerobic bacterium belonging to the sulfate-reducing bacteria that exhibits highly versatile metabolism. By switching from one energy mode to another depending on nutrients availability in the environments„ it plays a central role in shaping ecosystems. Despite intensive efforts to study D. vulgaris energy metabolism at the genomic, biochemical and ecological level, bioenergetics in this microorganism remain far from being fully understood. Alternatively, metabolic modeling is a powerful tool to understand bioenergetics. However, all the current models for D. vulgaris appeared to be not easily adaptable to various environmental conditions.MethodsTo lift off these limitations, here we constructed a novel transparent and robust metabolic model to explain D. vulgaris bioenergetics by combining whole-cell proteomic analysis with modeling approaches (Flux Balance Analysis).ResultsThe iDvu71 model showed over 0.95 correlation with experimental data. Further simulations allowed a detailed description of D. vulgaris metabolism in various conditions of growth. Altogether, the simulations run in this study highlighted the sulfate-to-lactate consumption ratio as a pivotal factor in D. vulgaris energy metabolism.DiscussionIn particular, the impact on the hydrogen/formate balance and biomass synthesis is discussed. Overall, this study provides a novel insight into D. vulgaris metabolic flexibility.

Online questionnaires that use crowdsourcing platforms to recruit participants have become commonplace, due to their ease of use and low costs. Artificial intelligence (AI)-based large language models (LLMs) have made it easy for bad actors to automatically fill in online forms, including generating meaningful text for open-ended tasks. These technological advances threaten the data quality for studies that use online questionnaires. This study tested whether text generated by an AI for the purpose of an online study can be detected by both humans and automatic AI detection systems. While humans were able to correctly identify the authorship of such text above chance level (76% accuracy), their performance was still below what would be required to ensure satisfactory data quality. Researchers currently have to rely on a lack of interest among bad actors to successfully use open-ended responses as a useful tool for ensuring data quality. Automatic AI detection systems are currently completely unusable. If AI submissions of responses become too prevalent, then the costs associated with detecting fraudulent submissions will outweigh the benefits of online questionnaires. Individual attention checks will no longer be a sufficient tool to ensure good data quality. This problem can only be systematically addressed by crowdsourcing platforms. They cannot rely on automatic AI detection systems and it is unclear how they can ensure data quality for their paying clients.