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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∗.

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 83mKr calibration electron captures (E∼45 keV), the position of origin of low-energy events is determined to 2 cm precision with bias

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.

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