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The search for bioactive compounds from enzymatic hydrolysates has increased in the last few decades. Fish by-products have been shown to be rich in these valuable molecules; for instance, herring milt is a complex matrix composed of lipids, nucleotides, minerals, and proteins. However, limited information is available on the potential health benefits of this by-product. In this context, three industrial products containing herring milt hydrolysate (HMH) were tested in both animal and cellular models to measure their effects on obesity-related metabolic disorders. Male C57Bl/6J mice were fed either a control chow diet or a high-fat high-sucrose (HFHS) diet for 8 weeks and received either the vehicle (water) or one of the three HMH products (HMH1, HMH2, and HMH3) at a dose of 208.8 mg/kg (representing 1 g/day for a human) by daily oral gavage. The impact of HMH treatments on insulin and glucose tolerance, lipid homeostasis, liver gene expression, and the gut microbiota profile was studied. In parallel, the effects of HMH on glucose uptake and inflammation were studied in L6 myocytes and J774 macrophages, respectively. In vivo, daily treatment with HMH2 and HMH3 improved early time point glycemia during the oral glucose tolerance test (OGTT) induced by the HFHS diet, without changes in weight gain and insulin secretion. Interestingly, we also observed that HMH2 consumption partially prevented a lower abundance of Lactobacillus species in the gut microbiota of HFHS diet-fed animals. In addition to this, modulations of gene expression in the liver, such as the upregulation of sucrose nonfermenting AMPK-related kinase (SNARK), were reported for the first time in mice treated with HMH products. While HMH2 and HMH3 inhibited inducible nitric oxide synthase (iNOS) induction in J774 macrophages, glucose uptake was not modified in L6 muscle cells. These results indicate that milt herring hydrolysates reduce some metabolic and inflammatory alterations in cellular and animal models, suggesting a possible novel marine ingredient to help fight against obesity-related immunometabolic disorders.

Over the past decade, growing evidence has established the gut microbiota as one of the most important determinants of metabolic disorders such as obesity and type 2 diabetes. Indeed, obesogenic diet can drastically alter bacterial populations (i.e., dysbiosis) leading to activation of pro-inflammatory mechanisms and metabolic endotoxemia, therefore promoting insulin resistance and cardiometabolic disorders. To counteract these deleterious effects, probiotic strains have been developed with the aim of reshaping the microbiome to improve gut health. In this review, we focus on benefits of widely used probiotics describing their potential mechanisms of action, especially their ability to decrease metabolic endotoxemia by restoring the disrupted intestinal mucosal barrier. We also discuss the perspective of using new bacterial strains such as butyrate-producing bacteria and the mucolytic Akkermansia muciniphila, as well as the use of prebiotics to enhance the functionality of probiotics. Finally, this review introduces the notion of genetically engineered bacterial strains specifically developed to deliver anti-inflammatory molecules to the gut.

Abstract Background Primaquine (PQ) has activity against mature P. falciparum gametocytes and proven transmission blocking efficacy (TBE) between humans and mosquitoes. WHO formerly recommended a single transmission blocking dose of 0.75 mg/kg but this was little used. Then in 2012, faced with the emergence of artemisinin-resistant P. falciparum (ARPf) in SE Asia, the WHO recommended a lower dose of 0.25 mg/kg to be added to artemisinin-based combination therapy in falciparum-infected patients in low transmission areas. This dose was considered safe in glucose-6-phosphate dehydrogenase deficiency (G6PDd) and not requiring G6PD testing. Subsequent single low-dose primaquine (SLDPQ) studies have demonstrated safety in different G6PD variants. Dosing remains challenging in children under the age of 5 because of the paucity of PQ pharmacokinetic (PK) data. We plan to assess the anti-infectivity efficacy of SLDPQ using an allometrically scaled, weight-based regimen, with a target dose of 0.25 mg/kg, in children with acute uncomplicated falciparum malaria. Methods This study is an open label, randomised 1:1, phase IIb study to assess TBE, tolerability, pharmacokinetics and acceptability of artesunate pyronaridine (ASPYR) administered alone or combined with SLDPQ in 56 Burkinabe children aged ≥ 6 months–

ContextRecent insights into type 2 inflammation have led to the development of monoclonal antibody therapies for severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Despite add-on therapy with a monoclonal antibody, some individuals remain uncontrolled in terms of upper and/or lower airway symptoms, prompting an exploration of the efficacy of combining biological therapies and their impact on inflammatory pathways.ObjectivesIn this article, we present a distinctive case of a patient with CRSwNP, severe eosinophilic asthma, and uncontrolled upper airway symptoms, who experienced substantial clinical and local inflammatory improvements through dual monoclonal antibody therapy.MethodsWe provide a detailed case description and analysis of the patient's nasal tissue and secretions to gain insights into the local nasal inflammation under this unique therapeutic approach.ResultsThe addition of an anti-IL-4Rα antibody led to an improvement in upper airway symptoms and a reduction in both eosinophilic and neutrophilic inflammation, despite prior anti-IL-5 therapy. These effects were consistently observed in both polyp tissue and nasal secretions.ConclusionOur patient, with CRSwNP, severe eosinophilic asthma, and uncontrolled upper airway symptoms, experienced substantial improvement with dual monoclonal antibody therapy, without major complications or side effects.

Over the course of a six-year trial, we investigated the physiological response of the Swiss white cultivar Vitis vinifera Petite Arvine, rich in varietal thiols, to the following canopy removal treatments from the cluster area, i.e. from the shoot base to the sixth leaf of each shoot: A) lateral shoots only, B) lateral shoots + 50 % main leaves, C) lateral shoots + 100 % main leaves or D) main leaves only. All leaf removal (LR) treatments were performed at the pre-flowering stage. Intensive pre-flowering removal of both lateral shoots + 100 % main leaves from the cluster area (C) strongly reduced yield potential (‒47 % on average) and tended to reduce the concentration of 3-mercaptohexanol precursors (Cys-3MH) in the must (‒21 %; p-value < 0.10). The effect of LR on berry set and must composition was modulated by removing fewer main leaves (‒24 % in yield potential and ‒6 % in Cys-3MH concentration). Climate conditions primarily influenced yield and grape composition. Main leaves and lateral shoots played different physiological roles: removal of main leaves only (D) resulted in a larger leaf area (+15 %) due to the development of lateral shoots in the cluster area and a lower yield potential (‒12 %) due to fewer berries per cluster when compared one-to-one with removal of lateral shoots only (A). In the must at harvest, treatment D had higher concentrations of malic acid (+12 %), yeast-assimilable nitrogen (+10 %) and glutathione (+8 %), but there were no significant trends for TSS, pH, Cys-3MH or Folin index. The overall effects of pre-flowering LR on wine composition were negligible in the context of this trial. The study highlighted the different physiological roles of the main leaves and lateral shoots, suggesting that pre-flowering leaf removal should be used cautiously, taking into account the plant’s resilience to environmental conditions. This research is part of a broader project on grapevine canopy management in temperate climates in Switzerland.

This article aims to reposition Nietzsche's thought within contemporary fields of research through the prism of its reception by Pierre Klossowski. Our analysis makes use of Klossowski's unpublished manuscripts, allowing us to better articulate and situate Nietzsche's thought within Klossowski's thought, which is nourished by a dialogue that goes beyond his work devoted to Nietzsche and develops an analysis that is particularly amenable to updating. In developing a Nietzsche-informed general economy of subjectivation, Klossowskian theory tends toward various aspects of theoretical explorations present in media thought and the posthumanities. In doing so, we show that Nietzsche's thought, as approached by Klossowski, allows for unprecedented connections that shed light on the genealogy of the posthumanities, conceptually enrich research in Media archaeology and Science and Technology Studies, and anticipate the crucial role of affect and information in contemporary processes of subjectivation.

Abstract There is considerable interest in the use of doxycycline post exposure prophylaxis (PEP) to reduce the incidence of bacterial sexually transmitted infections (STIs). An important concern is that this could select for tetracycline resistance in these STIs and other species. We searched PubMed and Google Scholar, (1948–2023) for randomized controlled trials comparing tetracycline PEP with non-tetracycline controls. The primary outcome was antimicrobial resistance (AMR) to tetracyclines in all bacterial species with available data. Our search yielded 140 studies, of which three met the inclusion criteria. Tetracycline PEP was associated with an increasedprevalence of tetracycline resistance in Neisseria gonorrhoeae, but this effect was not statistically significant (Pooled OR 2.3, 95% CI 0.9-3.4). PEP had a marked effect on the N. gonorrhoeae tetracycline MIC distribution in the one study where this was assessed. Prophylactic efficacy was 100% at low MICs and 0% at high MICs. In the one study where this was assessed, PEP resulted in a significant increase in tetracycline resistance in commensal Neisseria species compared to the control group (OR 2.9, 95% CI 1.5-5.5) but no significant effect on the prevalence of tetracycline resistance in Staphylococcus aureus. The available evidence suggests that PEP with tetracyclines could be associated with selecting tetracycline resistance in N. gonorrhoeae and commensal Neisseria species.

The effectiveness of an application of foliar nitrogen at veraison depends on the initial level of vine nitrogen deficiency, an Agroscope study has shown. The threshold levels of assimilable nitrogen deficiency in the grape must are validated for Chardonnay but still need to be confirmed for Sauvignon Blanc.

Objectives: Antimicrobial resistance poses a considerable threat in high-antimicrobial-consumption populations, such as men who have sex with men (MSM) taking HIV pre-exposure prophylaxis. While the ResistAZM trial found no increase in macrolide resistance genes in MSM with gonorrhea after azithromycin treatment, the MORDOR trial observed an increase in these genes after mass azithromycin distribution. We hypothesized that this could be due to saturation of the resistome. To test this hypothesis, we compared the abundance of macrolide resistance determinants in anorectal samples between the baselines of the two trials. Methods: Shotgun metagenome reads from the anorectal baseline samples from the ResistAZM (n = 42) and MORDOR (n = 30) trials were analyzed using AMRPlusPlus. Nonhost reads were mapped to the MEGARes database to detect antibiotic resistance genes (ARG). Antimicrobial resistance (AMR) was normalized using cumulative sum scaling, and ARG abundance was estimated. Results: Macrolide, lincosamides, and streptogramins determinants were approximately 10-fold more abundant in the ResistAZM than the MORDOR samples (P ≤ 0.001). Conclusion: The findings are compatible with our hypothesis. Thus, in populations with high-antimicrobial use, the relationship between antimicrobial consumption and AMR may be diminished due to saturation. These findings are vital for future studies investigating the resistogencity of novel interventions, such as doxycycline post-exposure prophylaxis, in populations with high preceding consumption of antimicrobials.

Formation of mineral scale, particularly calcium carbonate, has long been a concern in domestic appliances such as boilers, steamers and washing machines. In this work, the formation of inorganic deposits was studied on solid surfaces and in the bulk solution as a result of evaporation of potable water. Scale precipitation was evaluated on metallic samples for various bulk temperatures, surface roughness and surface material as a function of time. The morphology of scale crystals from both surface and solution was evaluated. The microstructure and morphology of deposits on the surface were analyzed using Scanning Electron Microscopy and X-ray diffraction. The present work has demonstrated that deposition rates increase as the evaporation process proceeds as expected. The nature of the material and the surface roughness both affect surface deposition kinetics. The complex relationship between the saturation ratio (as the bulk solution shows precipitation) and the kinetics of bulk and surface precipitation/deposition is demonstrated. The prevailing crystalline form of calcium carbonate is aragonite. However, the polymorphic composition of surface deposition and the bulk precipitate is influenced by temperature. [ABSTRACT FROM AUTHOR]

Embedded Operating Systems (OSs) are often developed in the C programming language. Developers justify this choice by the performance that can be achieved, the low memory footprint, and the ease of mapping hardware to software, as well as the strong adoption by industry of this programming language. The downside is that C is prone to security vulnerabilities unknowingly introduced by the software developer. Examples of such vulnerabilities are use-after-free, and buffer overflows. Like C, Rust is a compiled programming language that guarantees memory safety at compile time by adhering to a set of rules. There already exist a few OSs and frameworks that are entirely written in Rust, targeting sensor nodes. In this work, we give an overview of these OSs and frameworks and compare them on the basis of the features they provide, such as application isolation, scheduling, inter-process communication, and networking. Furthermore, we compare the OSs on the basis of the performance they provide, such as cycles and memory usage.

IntroductionImmune checkpoint inhibitors (ICIs) are used in several advanced malignancies and may cause various immune-related adverse events (irAEs). Among them, hematological irAEs are less described. Acquired amegakaryocytic thrombocytopenia (AAT) is a rare immune hematologic disorder characterized by severe thrombocytopenia and complete absence of megakaryocytes in bone marrow.Case presentationHerein, we present the case of a patient in their 40s with metastatic melanoma who developed an AAT after 12 cycles of nivolumab (anti-PD1). His platelet count decreased by ≤5 × 109/l without other cytopenia. Bone marrow biopsy showed normal cellularity with a complete absence of megakaryocyte and T-CD8+ lymphocyte infiltration. Given the failure of systemic steroids, eltrombopag was started, an oral thrombopoietin receptor agonist (TPO-RA), and his platelet count subsequently increased with complete response.DiscussionFour other cases are described on literature with the same features than non-ICI-related AAT. All cases occurred after anti-PD/PD-L1 treatment with a median onset of 5 weeks. The presentation of our case is quite different with delayed cytopenia. Both ciclosporin and TPO-RA seem to be efficient therapies.ConclusionTPO-RA could be preferred in oncologic patients, but safety data are still missing to define clear guidelines for immune-related AAT management.

Abstract Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A + NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A + NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.

We deploy artificial neural networks to unfold neutron spectra from measured energy-integrated quantities. These neutron spectra represent an important parameter allowing to compute the absorbed dose and the kerma to serve radiation protection in addition to nuclear safety. The built architectures are inspired from convolutional neural networks. The first architecture is made up of residual transposed convolution's blocks while the second is a modified version of the U-net architecture. A large and balanced dataset is simulated following “realistic” physical constraints to train the architectures in an efficient way. Results show a high accuracy prediction of neutron spectra ranging from thermal up to fast spectrum. The dataset processing, the attention paid to performances' metrics and the hyper-optimization are behind the architectures' robustness.

Two recently published randomized trials of doxycycline post exposure prophylaxis (PEP) have concluded that this intervention is highly effective at reducing the incidence of bacterial sexually transmitted infections (STIs) and has little or no risk of promoting the spread of antimicrobial resistance (AMR). In this perspective piece, we review four types of evidence that suggest that the risk of promoting AMR has been inadequately assessed in these studies. 1) The studies have all used proportion resistant as the outcome measure. This is a less sensitive measure of resistogenicity than MIC distribution. 2) These RCTs have not considered population-level pathways of AMR selection. 3) In populations with very high antimicrobial consumption such as PrEP cohorts, the relationship between antimicrobial consumption and resistance may be saturated. 4) Genetic linkage of AMR means that increased tetracycline use may select for AMR to not only tetracyclines but also other antimicrobials in STIs and other bacterial species. We recommend novel study designs to more adequately assess the AMR-inducing risk of doxycycline PEP.

In this paper, we examine a new set of hybrid ludic practices utilizing cross-media narration that emerged with the rise of the Internet commonly called Alternate Reality Games. However, we propose to coin the term Alternate Virtuality Games (or AVG) as a way to distinguish these digital practices from their real-life counterpart. Viral online AVGs like This House Has People in It (Resnick, 2016) or Ben Drowned (Jadusable, 2010) are emblematic of a horizontal relationship between work and spectator, as well as performance outside of art institutions. The immersiveness of AVGs is unbound by the space and time of a specific happening, and is rather experienced by a multitude of agents at different times and places. This characteristic of being an extra-individual experience as well as being independent from institutions also places AVGs within liminal experiences such as studied by anthropologist Victor Turner. As such, we analyze these hybrid games as a mean for the 21st century spectator to overturn societal status quo through newfound agency. These performing agents get into a subjective state where they can experience and criticize our relationship to digital devices in a society of information and control, without being subjected to it.

Grapevine leaf removal (LR) in the cluster area is a common practice in temperate and cool climates, usually done between berry-set and cluster closure to create a less favourable microclimate for fungal diseases and to improve grape ripening. When applied before flowering, LR affects berry-set and is, therefore, an effective yield-control tool, reducing time-consuming manual cluster thinning; it also improves berry structure and composition (i.e., total soluble sugars [TSS], titratable acidity [TA] and polyphenols) (VanderWeide et al., 2021). The present five-year trial follows a previous study about pre-flowering LR under identical environmental conditions (Verdenal et al., 2019); it validates the sustainability of moderate pre-flowering LR and its possible mechanisation under Swiss climatic conditions, using low-pressure double airflow.

The authors report how the cold and heat sensing properties of the pain receptor TRPA1 are separately modulated by the C-terminal intracellular domain, and in concert with either the S1–S4 or the S5–S6 transmembrane domain.

BackgroundFour randomized controlled trials have now established that doxycycline post exposure (sex) prophylaxis (PEP) can reduce the incidence of chlamydia and syphilis in men who have sex with men. These studies have concluded that the risk of selecting for antimicrobial resistance is low. We evaluated this risk in vitro and in vivo using a Galleria mellonella infection model.MethodsWe evaluated how long it took for doxycycline resistance to emerge during passage on doxycycline containing agar plates in 4 species – Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae and Neisseria subflava. We then assessed if K. pneumoniae could acquire resistance to doxycycline (and cross resistance to other antimicrobials) during intermittent exposure to doxycycline in a Galleria mellonella model of doxycycline PEP.ResultsIn our passage experiments, we found that resistance first emerged in K. pneumoniae. By day 7 the K. pneumoniae MIC had increased from 2 mg/L to a median of 96 mg/L (IQR 64–96). Under various simulations of doxycycline PEP in the G. mellonella model, the doxycycline MIC of K. pneumoniae increased from 2 mg/L to 48 mg/L (IQR 48–84). Ceftriaxone and ciprofloxacin MICs increased over ten-fold. Whole genome sequencing revealed acquired mutations in ramR which regulates the expression of the AcrAB-TolC efflux pump.ConclusionDoxycycline PEP can select for doxycycline, ceftriaxone and ciprofloxacin resistance in K. pneumoniae in a G. mellonella model. The emergent ramR mutations were similar to those seen in circulating strains of K. pneumoniae. These findings suggest that we need to assess the effect of doxycycline PEP on resistance induction on a broader range of bacterial species than has hitherto been the case.

Introduction The prevalence of chronic knee pain is increasing. Osteoarthritis (OA) and persistent postsurgical pain (PPSP) are two important causes of knee pain. Chronic knee pain is primarily treated with medications, physiotherapy, life-style changes and intra-articular infiltrations. A radiofrequency treatment (RF) of the genicular nerves is a therapeutical option for refractory knee pain. This study investigates the effectiveness and cost-effectiveness of conventional and cooled RF in patients suffering from chronic, therapy resistant, moderate to severe knee pain due to OA and PPSP.Methods and analysis The COGENIUS trial is a double-blinded, randomised controlled trial with 2-year follow-up. Patients and outcome assessors are blinded. Patients will be recruited and treated in Belgium and the Netherlands. All PPSP after a total knee prothesis and OA patients (grades 2–4) will undergo a run-in period of 1–3 months where conservative treatment will be optimised. After the run-in period, 200 patient per group will be randomised to conventional RF, cooled RF or a sham procedure following a 2:2:1 ratio. The analysis will include a comparison of the effectiveness of each RF treatment with the sham procedure and secondarily between conventional and cooled RF. All comparisons will be made for each indication separately. The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis Index score at 6 months. Other outcomes include knee pain, physical functionality, health-related quality of life, emotional health, medication use, healthcare and societal cost and adverse events up to 24 months postintervention.Ethics and dissemination Ethics approval was obtained from the Ethics Committee of the University of Antwerp (Number Project ID 3069-Edge 002190-BUN B3002022000025), the Ethics committee of Maastricht University (Number NL80503.068.22-METC22-023) and the Ethics committee of all participating hospitals. Results of the study will be published in international peer-reviewed journals.Trial registration number NCT05407610.

Knowledge of the nitrogen nutrition status of the vine is essential for long-term management of its nutrition with the aim of producing high-quality grapes. Measurement of the chlorophyll index is a fast, non-destructive and relatively inexpensive method that provides a good approximation of the nitrogen nutrition status of the vine during the growing season. Several chlorophyll meters are available on the market, each using its own measurement unit. With the aim of popularizing the use of chlorophyll meters, the interpretation thresholds of the SPAD index, measured on the vine at the veraison stage, have been established from correlation with the N-tester index, for which the thresholds are already known.

Background: In antibiotic naïve populations, there is a strong association between the use of an antimicrobial and resistance to this antimicrobial. Less evidence is available as to whether this relationship is weakened in populations highly exposed to antimicrobials. Individuals taking HIV preexposure prophylaxis (PrEP) have a high intake of antimicrobials. We previously found that there was no difference in the prevalence of pheno- and genotypic antimicrobial resistance between two groups of PrEP clients who had, and had not, taken antimicrobials in the prior 6 months. Both groups did, however, have a higher prevalence of resistance than a sample of the general population. Methods: In the current study, we used zero-inflated negative binomial regression models to evaluate if there was an individual level association between the consumption of antimicrobials and 1. the minimum inhibitory susceptibilities of oral Neisseria subflava and 2. the abundance of antimicrobial resistance genes in the oropharynges of these individuals. Results: We found no evidence of an association between the consumption of antimicrobials and the minimum inhibitory susceptibilities of oral Neisseria subflava or the abundance of antimicrobial resistance genes in these individuals. Conclusions: We conclude that in high-antimicrobial-consumption populations, the association between antimicrobial consumption and resistance may be attenuated. This conclusion would not apply to lower-consumption populations.

The Internet of Things (IoT) facilitates the integration of diverse devices, leading to the formation of networks such as Low-power Wireless Personal Area Networks (LoWPANs). These networks have inherent constraints that make header and payload compression an attractive solution to optimise communication. In this work, we evaluate the performance of Generic Header Compression (6LoWPAN-GHC), defined in RFC 7400, for IEEE 802.15.4-based networks running the IPv6 Routing Protocol for Low-Power and Lossy Networks (RPL). Through simulation and real-device experiments, we study the impact of 6LoWPAN-GHC on energy consumption and delays and investigate for which scenarios 6LoWPAN-GHC is beneficial. We show that all RPL control packets are compressible by 6LoWPAN-GHC, which reduces their transmission delay and as such their vulnerability to interference. However, for the devices under study transmitting at 250 kbit/s, the energy gain obtained from sending a compressed packet is outweighed by the energy needed to compress it. The use of 6LoWPAN-GHC causes an energy increase of between 2% and 26%, depending on the RPL packet type. When the range is more important than the bandwidth and a sub-GHz band is used at 10 kbit/s, an energy gain of 11% to 29% can be obtained, depending on the type of RPL control packet.

Abstract Background Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system. Methods Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo. Results We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors. Conclusions Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy.

The present trial follows a previous study about pre-flowering leaf removal (LR) (Verdenal et al., 2019) and validates the sustainability of mechanical pre-flowering LR under local Swiss vineyard conditions, using a low-pressure double airflow, to reduce the cost of laborious bunch thinning. In previous studies, pre-flowering LR has shown additional benefits over post-berry-set LR in terms of yield regulation and grape and wine compositions. This trial had two objectives: 1) to test the technical feasibility of mechanical pre-flowering LR, using a low-pressure double airflow and 2) to observe the impact of this practice over five years on yield parameters, grape composition at harvest and wine quality over five years. For this purpose, a trial was conducted on the two cultivars, Doral (white) and Gamay (red), to compare four LR treatments, that is, A) mechanical post-berry-set LR, B) manual pre-flowering LR, C) mechanical pre-flowering LR, and D) double mechanical pre-flowering + post-berry-set LR. More broadly, this work provides practical insights into the consequences of pre-flowering LR on the grapevine, pointing out the advantages and the limits of intensity, timing and mechanisation of this practice. In comparison with the mechanical post-berry-set LR, mechanical pre-flowering LR induced a 7 % loss in bud fruitfulness, a 30 % yield loss and a 3 % gain in total soluble solids (TSS) accumulation in grapes in both cultivars, although the improvement in grape maturity was small and uneven through the years; Gamay anthocyanin concentration remained stable. Pre-flowering LR had no overall impact on the quality of Doral and Gamay wines. Damage was observed on the inflorescences due to the intensity of mechanical pre-flowering LR, which resulted in fewer berries per cluster and a lower yield than with manual LR by the same date. A second LR after berry set was also tested to limit the growth of laterals and clean the clusters from the remaining flower caps to prevent the development of fungal diseases, but it did not show any benefit over a single pre-flowering LR. In conclusion of this trial, a single, moderate mechanical pre-flowering LR is an effective and sustainable practice under temperate climatic conditions, to reduce the costs of laborious manual pre-flowering LR.

Background: The presentation of mpox clade IIb during the 2022 outbreak overlaps with a range of other diseases. Understanding the factors associated with mpox is important for clinical decision making. Methods: We described the characteristics of mpox patients who sought care at Belgian sexual health clinic. Furthermore we compared their characteristics to those of patients with a clinical suspicion of mpox but who tested negative on polymerase chain reaction. Results: Between May 23 and September 20, 2022, 155 patients were diagnosed with mpox, and 51 patients with suspected symptoms tested negative. All mpox patients self-identified as men and 148/155 (95.5%) as gay or bisexual MSM. Systemic symptoms were present in 116/155 (74.8%) patients. All but 10 patients (145/155, 93.5%) presented with skin lesions. Other manifestations were lymphadenopathy (72/155, 46.5%), proctitis (50/155, 32.3%), urethritis (12/155, 7.7%), tonsillitis (2/155, 1.3%). Complications involved bacterial skin infection (13/155, 8.4%) and penile oedema with or without paraphimosis (4/155, 2.6%). In multivariable logistic regression models, the presence of lymphadenopathy (OR 3.79 95% CI 1.44–11.49), skin lesions (OR 4.35 95% CI 1.15–17.57) and proctitis (OR 9.41 95% CI 2.72–47.07) were associated with the diagnosis of mpox. There were no associations with age, HIV status, childhood smallpox vaccination, number of sexual partners and international travel. Conclusions: The presence of proctitis, lymphadenopathies and skin lesions should increase clinical suspicion of mpox in patients with compatible symptoms.

Abstract Background The broodstock diet, and in particular the lipid and fatty acid composition of the diet, is known to play a key role in reproductive efficiency and survival of the progeny in fish. A major problem when replacing both fish meal and fish oil by plant sources is the lack of n-3 long chain polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). To address this problem, we studied the effect of the plant-based diet supplemented with Schizochytrium sp. microalgae, source of DHA, compared to a conventional commercial diet rich in fish meal and fish oil on reproductive performance and egg quality and the consequences on progeny, in female rainbow trout broodstock. Results The results demonstrated that DHA-rich microalgae supplementation in a plant-based diet allowed for the maintenance of reproductive performance and egg quality comparable to a conventional commercial feed rich in fish meal and fish oil and led to an increased significant fry survival after resorption. Moreover, when females were fed a plant-based diet supplemented with micro-algae, the 4-month-old progenies showed a significant higher growth when they were challenged with a similar diet as broodstock during 1 month. We provide evidence for metabolic programming in which the maternal dietary induced significant protracted effects on lipid metabolism of progeny. Conclusions The present study demonstrates that supplementation of a plant-based diet with DHA-rich microalgae can be an effective alternative to fish meal and fish oil in rainbow trout broodstock aquafeed.

Driven by the increased consciousness in data ownership and privacy, zero-knowledge proofs (ZKPs) have become a popular tool to convince a third party of the truthfulness of a statement without disclosing any further information. As ZKPs are rather complex to design, frameworks that transform high-level languages into ZKPs have been proposed. We propose Circuitree, a Datalog reasoner in zero-knowledge. Datalog is a high-level declarative logic language that is generally used for querying. Furthermore, as a logic language, it can also be used to solve logic problems. An application using Circuitree can efficiently generate ZKPs, based on Datalog rules and encrypted data, to prove that a certain conclusion follows from a Datalog ruleset and encrypted input data. Compared to existing frameworks, which generally use their own limited imperative languages, Circuitree uses an existing high-level declarative language. We point out several applications for Circuitree, including EU Digital COVID Certificates and privacy-preserving access control for peer-to-peer (p2p) networks. Circuitree’s performance is evaluated for access control in a p2p network. First results show that our approach allows for fast proofs and proof verification for this application.

Abstract Background Despite recent advancements, limitations in the treatment and control of hepatitis C virus (HCV) infection reprioritized the studies for invention of an efficient HCV vaccine to elicit strong neutralizing antibodies (NAbs) and cellular responses. Methods Herein, we report molecular construction of a BacMam virus-based surface display for a subtype-1a HCV gpE2 (Bac-CMV-E2-gp64; Bac) that both expressed and displayed gpE2 in mammalian cells and bacouloviral envelope, respectively. Results Assessments by western blotting, Immunofluorescence and Immunogold-electron microscopy indicated the proper expression and incorporation in insect cell and baculovirus envelope, respectively. Mice immunized in three different prime-boost immunization groups of: Bac/Bac, Bac/Pro (bacoulovirus-derived gpE2) and Bac/DNA (plasmid DNA (pCDNA)-encoding gpE2) developed high levels of IgG and IFN-γ (highest for Bac/Bac group) indicating the induction of both humeral and cellular immune responses. Calculation of the IgG2a/IgG1 and IFN-γ/IL-4 ratios indicated a Th1 polarization of immune responses in the Bac/Bac and Bac/DNA groups but a balanced Th1-Th2 phenotype in the Bac/Pro group. Sera of the mice in the Bac/Bac group provided the highest percentage of cross-NAbs against a subtype-2a HCVcc (JFH1) compared to Bac/Pro and Bac/DNA groups (62% versus 41% and 6%). Conclusions Results indicated that BacMam virus-based surface display for gpE2 might act as both subunit and DNA vaccine and offers a promising strategy for development of HCV vaccine for concurrent induction of strong humoral and cellular immune responses.

The Madeira archipelago has a unique underwater landscape that is characterised by narrow shelves, steep slopes and a large submarine tributary system that boosts primary productivity in oligotrophic waters and thus offers a potential for hotspots of biodiversity. Despite this, there have been limited deep-water exploration activities with less than five expeditions since the 1960s. Here, we investigated the seabed on the southern side of the Madeira-Desertas Ridge using a manned submersible along a 3.8 km long transect starting at 366 m depth up the ridge shelf until its top at 73 m. Benthic habitats and community composition were documented with video along a depth gradient from mesophotic to deep sea. Six distinct biotopes were recognised (three deeper, and three shallower than 115 m depth). Our results showed a rich biodiversity with deep biotopes characterised by sponges and non-reef-building corals (e.g., Pachastrella monilifera, Viminella flagellum, Eunicella verrucosa) and shallow biotopes comprising macroalgae and the gorgonian Paramuricea cf. grayi. The pronounced benthic zonation reflects the steep environmental gradient that includes high topographic variation, heterogeneous substrates, and bidirectional regular wave-motion at the shallow mesophotic part. Together with biotic factors, such as low density of sea urchins and presence of predatory fish, this environment with unusual deep light penetration, a mesoscale cyclonic eddy, and deep wave-motion, has allowed the establishment of a mature deep-water kelp population of Laminaria ochroleuca in the plateau (max. >100 individuals p/100 m2). At the same time, a conspicuous coral fauna was observed on a wide range of soft to hard bottoms with several species taking advantage of the favourable hydrodynamic regime and seawater properties together with substratum availability to create coral gardens. These habitats were previously not known from Madeira, and their newfound discovery in the archipelago merit further investigation and protection.

Hepatitis E virus (HEV) infection is the most common cause of acute viral hepatitis worldwide. Hepatitis E is usually asymptomatic and self-limiting but it can become chronic in immunocompromised patients and is associated with increased fulminant hepatic failure and mortality rates in pregnant women. HEV genome encodes three proteins including the ORF2 protein that is the viral capsid protein. Interestingly, HEV produces 3 isoforms of the ORF2 capsid protein which are partitioned in different subcellular compartments and perform distinct functions in the HEV lifecycle. Notably, the infectious ORF2 (ORF2i) protein is the structural component of virions, whereas the genome-free secreted and glycosylated ORF2 proteins likely act as a humoral immune decoy. Here, by using a series of ORF2 capsid protein mutants expressed in the infectious genotype 3 p6 HEV strain as well as chimeras between ORF2 and the CD4 glycoprotein, we demonstrated how an Arginine-Rich Motif (ARM) located in the ORF2 N-terminal region controls the fate and functions of ORF2 isoforms. We showed that the ARM controls ORF2 nuclear translocation likely to promote regulation of host antiviral responses. This motif also regulates the dual topology and functionality of ORF2 signal peptide, leading to the production of either cytosolic infectious ORF2i or reticular non-infectious glycosylated ORF2 forms. It serves as maturation site of glycosylated ORF2 by furin, and promotes ORF2-host cell membrane interactions. The identification of ORF2 ARM as a unique central regulator of the HEV lifecycle uncovers how viruses settle strategies to condense their genetic information and hijack cellular processes.

Nitrogen (N) is an essential element for vine development and yield; it is also involved in the winemaking process and significantly affects wine composition. It is therefore essential to control and optimise plant N use to ensure an adequate N composition of the grapes at harvest. An improved understanding of the impact of cultivation practices on plant N metabolism would allow a better orientation of technical choices with the objective of quality and sustainability (i.e., fewer inputs, more efficiency). Our trial focused on the impacts of fertilisation and crop thinning on grape N composition. A wide crop load gradient was set up in a homogeneous plot of Chasselas (Vitis vinifera L.) in an experimental vineyard in Switzerland. Foliar urea was applied at veraison in order to compare it with an unfertilised control. Vine development and grape composition were evaluated over two years, with particular attention to the carryover effects of both fertilisation and crop thinning. Foliar N fertilisation effectively increased the amount of N in grapes at harvest in the same year, but had no impact on grape ripeness or carryover effect on year n + 1. Conversely, crop thinning improved grape maturity by reducing fruit N and C demand. Interestingly, amino N proportions could be distinguished according to crop load, while the global grape N concentration at harvest remained unchanged. Some amino acids were more affected by crop thinning than others. The concentrations of alanine, γ-aminobutyric acid (GABA), serine and threonine were reduced by crop thinning. Crop thinning had a strong carryover effect on year n + 1. The carryover impact of crop thinning on grapes in terms of both maturation index and N composition could be observed at the onset of grape ripening on year n + 1. This experiment highlighted the influence of the previous year’s agricultural practices on grape C and N accumulation before and during the ripening phase. Consequently, the modulation of grape composition at harvest should be considered over two consecutive years. These results will contribute to the improvement of predictive models and sustainable agronomic practices in perennial crops.

Background & Aims: Infection with hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, there is no approved therapeutic targeting this potentially druggable biomarker. Methods: The anti-HCV activity of a fusion protein consisting of Avaren lectin and the fragment crystallizable (Fc) region of a human immunoglobulin G1 antibody, Avaren-Fc (AvFc) was evaluated through the use of in vitro neutralization assays as well as an in vivo challenge in a chimeric human liver (PXB) mouse model. Drug toxicity was assessed by histopathology, serum alanine aminotransferase, and mouse body weights. Results: AvFc was capable of neutralizing cell culture–derived HCV in a genotype-independent manner, with 50% inhibitory concentration values in the low nanomolar range. Systemic administration of AvFc in a histidine-based buffer was well tolerated; after 11 doses every other day at 25 mg/kg there were no significant changes in body or liver weights or in blood human albumin or serum alanine aminotransferase activity. Gross necropsy and liver pathology confirmed the lack of toxicity. This regimen successfully prevented genotype 1a HCV infection in all animals, although an AvFc mutant lacking HMG binding activity failed. Conclusions: These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection, and AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients.

Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to its favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients.

Under the global warming scenario, water scarcity is expected to intensify in most grape-growing regions. The use of drought-tolerant rootstocks is considered a useful tool to mitigate the negative effects of soil water deficit on vine functioning. Differences in leaf gas exchange, plant water status, specific hydraulic conductivity in petioles (Kpetiole), xylem vessel size and vegetative vigour of field-grown Pinot noir grafted onto five rootstocks (3309C, 101-14 MGt, Kober 5BB, Riparia Gloire de Montpellier, 41B MGt) were investigated during one season under water deficit in Switzerland. The water deficit was imposed by installing waterproof and non-reflecting plastic sheets on the soil from March to harvest (September) to avoid rainfall infiltration. Rootstocks had stronger effects on vine water status than on gas exchanges. During the grape ripening stage, vines grafted onto 41B MGt and 101-14 MGt were characterised by more severe water stress as shown by the lowest values of pre-dawn leaf (Ψpd), stem water potential (Ψstem) and water stress integral (SΨ), whereas 3309C and Kober 5BB rootstocks induced milder effects. Significant differences in photosynthesis (A), stomatal conductance (gs) and transpiration (E) were only observed between vines grafted onto 41B MGt and 3309C at later stages of ripening. Changes induced by rootstocks in shoot vigour, Kpetiole and the number and size of xylem vessels in petioles and stems were correlated to differential responses of Pinot noir to water deficit. The increased vegetative vigour induced by 3309C and Kober 5BB was associated with the highest Kpetiole, xylem vessel size and a good plant water status of Pinot noir under low soil water availability. Kober 5BB induced the highest yield, probably due to the better vine water status, whereas vines grafted onto 41B MGt showed the lowest malic acid content and yeast assimilable nitrogen in berries.