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Resveratrol and its glucoside, piceid, are the primary stilbenes present in wine. These compounds are well known for their pharmaceutical properties. However, these compounds can undergo chemical transformations in wines, such as polymerization in the presence of metallic reagents. This study investigates the oxidative coupling of resveratrol and piceid to form dimers, including δ-viniferin and δ-viniferin-diglucoside. These dimers were synthesized using silver acetate. The formation of these stilbenes was monitored in wine model solutions and red wines. The results indicated that resveratrol and piceid underwent transformation during heat treatment, forming their respective dimers. The polymerization of both compounds is temperature-dependent, with higher conversion rates at elevated temperatures. Notably, piceid was more reactive than resveratrol in wine. Finally, the anti-inflammatory effects of these compounds were evaluated on the RAW 264.7 macrophage cell line.

Background: Stilbenoid extracts, such as those originating from grapevine by-products (e.g. canes), are of interest for use as biopesticides in vineyard owing to their antimicrobial activities. However, stilbenoids are unstable in the environment, especially under light. This study aimed to chemically characterize the effect of UV light on stilbenoids present in a grapevine cane extract (CE), and to evaluate the antimicrobial activities against two major grapevine pathogens (Plasmopara viticola and Botrytis cinerea) of grapevine extracts exposed to UV., Results: Treatment with UV (365 nm) on a grapevine CE led to degradation of stilbenoids (up to 71% after 1 h). The stilbenoid stability depended on their chemical structure: only those possessing CC, as trans-resveratrol and trans-ε-viniferin, were affected with first their isomerization and secondly their oxidation/cyclization. As a consequence, UV-exposed extracts (UV-CEs) showed reduced antimicrobial activities against the two pathogens (mycelium and spores). For instance, regarding P. viticola, an UV-CE exposed during 4 h showed an almost total loss of its activity on oomycete development and a 2.4-fold inhibition of zoospore mobility in comparison to CE. For B. cinerea, the inhibition capacity of the same UV-CE was reduced by only 1.1-fold on mycelial development and by 3.2-fold on conidial germination compared to CE., Conclusion: UV light triggered modifications on the structure of bioactive stilbenoids, resulting in losses of their antimicrobial activities. Photoprotection of stilbenoids has to be considered in the perspective of using them in vineyards as biopesticides. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

For the purpose of enhancing the structural insights within the three-dimensional composition fields revealed by atom probe tomography, correlative microscopy approaches, combining (scanning) transmission electron microscopy with atom probe tomography, have emerged and demonstrated their relevance. To push the boundaries further and facilitate a more comprehensive analysis of nanoscale matter by coupling numerous two- or three-dimensional datasets, there is an increasing interest in combining transmission electron microscopy and atom probe tomography into a unified instrument. This study presents the tangible outcome of an instrumental endeavour aimed at integrating atom probe tomography into a commercial transmission electron microscope. The resulting instrument demonstrates the feasibility of combining in situ 3D reconstructions of composition fields with the detailed structural analysis afforded by transmission electron microscopy. This study shows a promising approach for converging these two important nanoscale microscopy techniques., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose : This study aimed to determine whether a better hemodynamic profile and a better sleep quality are associated with the duration of physical exercise in the water; secondly, it aims to determine whether better sleep quality is associated with a more favorable hemodynamic profile. Methods : 97 subjects (85 women, age 59.46 ± 10.62) were included in the study. Groups were divided into normotensive ( n  = 46) and hypertensive individuals, ( n  = 51) duration of water aerobics (1-6 ( n  = 18), 7-11 ( n  = 11), 12-35 ( n = 26), and > 36 months ( n  = 42), respectively), and sleep quality (Good, Poor, and Sleep Disordered). The peripheral (brachial), central (through applanation tonometry), and arterial blood pressure were assessed, and the Pittsburgh Sleep Quality Index questionnaire was collected. Results : We found that the groups practicing water-based exercise for a more extended period (>6 months) did not present improved pressure values and sleep quality. The best (though still weak) relationship between the water-based exercise time and the sleep quality values occurred between the group of 7-11 exercising for over 36 months ( r  = - 0.29 for both). When multivariate regression analysis was performed, there was interaction between AIx@75bpm and sleep quality score, as well as between AIx@75bpm and the age of subjects ( p = .006 and 0.003, respectively). Conclusion : The data from the present study reported that subjects who participated for a longer time in the water aerobics training protocol had no additional hemodynamic and sleep quality benefits compared to volunteers with shorter duration groups (<6 months).

Introduction: the need to correctly measure and follow body composition as a simple disease prevention metric is important, especially where the healthcare infrastructures are poor. The variety of inexpensive devices available for this purpose is large. However, it is imperative to validate them in relation to the gold standard method, dual-energy absorptiometry X-ray (DEXA). In low-income countries, DEXA measurements aren't available. Thus, easy-to-use, and accurate devices are indispensable. In Guinea-Bissau, two relatively inexpensive, bioelectrical impedance scales, simple to use, are available. However, their accuracy has not been assessed in this setting. The study compares the level of agreement in measurements between, the Tanita® BC-545 and the Omron Karada Scan BF511, in adult volunteers., Methods: volunteers grouped for athletic and sports modalities at stadiums and sports facilities in Bissau were included. All anthropometric measurements were done in both devices. For statistical analysis, we created Bland-Altman plots to assess their level of agreement., Results: the study included 274 participants, mean age 27.4 years, 214 (78%) males. For body fat, the median between the Omron and Tanita measures was 2.6 and the interquartile was 5.2. The Omron measured median body mass index, -0.3 kg/m 2 and 0.8 kg/m 2 of interquartile below that of the Tanita. For visceral fat, the Omron measured 1% of median and an interquartile of 2% above that of the Tanita. For skeletal muscle, the Omron median measured 11.3% and 11.4 % of interquartile below that of the Tanita. The intra-class correlation coefficient (ICC) for body fat (BF), body mass index (BMI) and skeletal muscle (SM) was 0.99 and for VF it was 1.00 on both devices., Conclusion: the results indicate a good level of agreement between the two devices. In resource-limited settings, the Omron is likely a reasonable substitute for more expensive body composition devices., Competing Interests: The authors declare no competing interests., (Copyright: Lilica Sanca et al.)

Patients who are edentulous experience challenges with their dentures, especially the mandibular ones. The primary concerns of these patients include reduced chewing efficiency, instability, and loss of retention. With the advancement of implants and prosthetic options, these concerns can be addressed by resorting to implant-supported fixed and removable prostheses. The impetuous use of dental implants to solve these issues leads to inadvertent failures in the treatment undertaken. Improper planning of cases leads to prosthesis breakage and implant failures leaving the patient dissatisfied. One such case of rehabilitation of a completely edentulous over-denture patient with ailing implants is described in this clinical report., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Akhtarkhavari et al.)

This study aimed to explore the non-volatile metabolomic variability of a large panel of strains (44) belonging to the Saccharomyces cerevisiae and Saccharomyces uvarum species in the context of the wine alcoholic fermentation. For the S. cerevisiae strains flor, fruit and wine strains isolated from different anthropic niches were compared. This phenotypic survey was achieved with a special focus on acidity management by using natural grape juices showing opposite level of acidity. A 1 H NMR based metabolomics approach was developed for quantifying fifteen wine metabolites that showed important quantitative variability within the strains. Thanks to the robustness of the assay and the low amount of sample required, this tool is relevant for the analysis of the metabolomic profile of numerous wines. The S. cerevisiae and S. uvarum species displayed significant differences for malic, succinic, and pyruvic acids, as well as for glycerol and 2,3-butanediol production. As expected, S. uvarum showed weaker fermentation fitness but interesting acidifying properties. The three groups of S. cerevisiae strains showed different metabolic profiles mostly related to their production and consumption of organic acids. More specifically, flor yeast consumed more malic acid and produced more acetic acid than the other S. cerevisiae strains which was never reported before. These features might be linked to the ability of flor yeasts to shift their metabolism during wine oxidation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marullo Philippe reports financial support was provided by Biolaffort. Vion Charlotte reports financial support was provided by Biolaffort. Maitena Muro reports financial support was provided by Biolaffort. Margaux Bernard reports financial support was provided by Biolaffort., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The investigation of hydrogen in atom probe tomography appears as a relevant challenge due to its low mass, high diffusion coefficient, and presence as a residual gas in vacuum chambers, resulting in multiple complications for atom probe studies. Different solutions were proposed in the literature like ex situ charging coupled with cryotransfer or H charging at high temperature in a separate chamber. Nevertheless, these solutions often faced challenges due to the complex control of specimen temperature during hydrogen charging and subsequent analysis. In this paper, we propose an alternative route for in situ H charging in atom probe derived from a method developed in field ion microscopy. By applying negative voltage nanosecond pulse on the specimen in an atom probe chamber under a low pressure of H2, it is demonstrated that a high dose of H can be implanted in the range 2-20 nm beneath the specimen surface. An atom probe chamber was modified to enable direct negative pulse application with controlled gas pressure, pulse repetition rate, and pulse amplitude. Through electrodynamical simulations, we show that the implantation energy falls within the range 100-1,000 eV and a theoretical depth of implantation was predicted and compared to experiments., Competing Interests: Conflict of Interest. The authors declare that they have no competing interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes., Patients and Methods: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness., Results: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause., Conclusion: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.

Background: The etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown., Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3β and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype., Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or "healthy" microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders. Video Abstract., (© 2024. The Author(s).)

Preparations of black cohosh extract are sold as dietary supplements marketed to relieve the vasomotor symptoms of menopause, and some studies suggest it may protect against postmenopausal bone loss. Postmenopausal women are also frequently prescribed bisphosphonates, such as risedronate, to prevent osteoporotic bone loss. However, the pharmacodynamic interactions between these compounds when taken together is not known. To investigate possible interactions, 6-month-old, female Sprague-Dawley rats underwent bilateral ovariectomy or sham surgery and were treated for 24 weeks with either vehicle, ethinyl estradiol, risedronate, black cohosh extract or coadministration of risedronate and black cohosh extract, at low or high doses. Bone mineral density (BMD) of the femur, tibia, and lumbar vertebrae was then measured by dual-energy X-ray absorptiometry (DEXA) at weeks 0, 8, 16, and 24. A high dose of risedronate significantly increased BMD of the femur and vertebrae, while black cohosh extract had no significant effect on BMD individually and minimal effects upon coadministration with risedronate. Under these experimental conditions, black cohosh extract alone had no effect on BMD, nor did it negatively impact the BMD-enhancing properties of risedronate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Inselman, Masters, Moore, Agarwal, Gassman, Kuijpers, Beger, Delclos, Swift, Camacho, Vanlandingham, Sloper, Nakamura, Gamboa da Costa, Woodling, Bryant, Trbojevich, Wu, McLellen and Christner.)

Phthalates or phthalic acid esters (PAE) and bis(2-ethylhexyl)adipate (DEHA) are ubiquitous chemicals often used as plasticisers and additives in many industrial products and are classified as both persistent organic pollutants (POPs) and new emerging pollutants (NEPs). Exposure to these chemicals, especially through inhalation, is linked to a wide range of negative health effects, including endocrine disruption. Air particulate matter (PM) with an aerodynamic diameter ≤ 2.5 μm can be enriched with PAEs and DEHA and if inhaled can cause multi-system human toxicity. Therefore, proper monitoring of PAEs and DEHA in PM is required to assess human exposure to these pollutants. In this work, we developed and validated a new and sensitive gas-chromatography high-resolution mass spectrometry (GC-HRMS) method for targeted analysis of PAEs including dimethyl phthalate (DMP), diethyl phthalate (DEP), di- n -butyl phthalate (DBP), benzyl butyl phthalate (BBP), bis(2-ethylhexyl)adipate (DEHA), bis(2-ethylhexyl)phthalate (DEHP), di- n -octyl phthalate (DOP), in PM. Analytical aspects including sample preparation steps and GC-HRMS parameters, e.g. , quadrupole isolation window, to enhance method sensitivity have been assessed. The estimated limit of detection (LODs) of target PAEs and DEHA ranged from 5.5 to 17 pg μL -1 , allowing their trace-level detection in PM. Extraction efficiencies of 78-101% were obtained for the target compounds. Low DMP and DEP extraction efficiencies from the spiked filter substrates indicated that significant losses of higher volatility PAEs can occur during the sample collection when filter-based techniques are used. This work is the first targeted method based on GC-Orbitrap MS for PAEs and DEHA in environmental samples. The validated method was successfully applied for the targeted analysis of PAEs and DEHA in PM 2.5 samples from the eighth most populous city in Brazil, Curitiba. This work is the first to report DBP, DEHA, DEHP, and DOP in urban PM from Brazil. The observed concentrations of PAEs (up to 29 ng m -3 ) in PM 2.5 from Curitiba may not represent the extent of pollution by these toxic compounds since the analysed samples were collected during a COVID-19 restriction when anthropogenic activities were reduced.

Brazil has experienced one of the highest COVID-19 fatality rates globally. While numerous studies have explored the potential connection between air pollution, specifically fine particulate matter (PM 2.5 ), and the exacerbation of SARS-CoV-2 infection, the majority of this research has been conducted in foreign regions-Europe, the United States, and China-correlating generalized pollution levels with health-related scopes. In this study, our objective is to investigate the localized connection between exposure to air pollution exposure and its health implications within a specific Brazilian municipality, focusing on COVID-19 susceptibility. Our investigation involves assessing pollution levels through spatial interpolation of in situ PM 2.5 measurements. A network of affordable sensors collected data across 9 regions in Curitiba, as well as its metropolitan counterpart, Araucaria. Our findings distinctly reveal a significant positive correlation (with r-values reaching up to 0.36, p-value < 0.01) between regions characterized by higher levels of pollution, particularly during the winter months (with r-values peaking at 0.40, p-value < 0.05), with both COVID-19 mortality and incidence rates. This correlation gains added significance due to the intricate interplay between urban atmospheric pollution and regional human development indices. Notably, heightened pollution aligns with industrial hubs and intensified vehicular activity. The spatial analysis performed in this study assumes a pivotal role by identifying priority regions that require targeted action post-COVID. By comprehending the localized dynamics between air pollution and its health repercussions, tailored strategies can be implemented to alleviate these effects and ensure the well-being of the public., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The webinar series and workshop titled “Trust Your Gut: Establishing Confidence in Gastrointestinal Models – An Overview of the State of the Science and Contexts of Use” was co-organized by NICEATM, NIEHS, FDA, EPA, CPSC, DoD, and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) and hosted at the National Institutes of Health in Bethesda, MD, USA on October 11-12, 2023. New approach methods (NAMs) for assessing issues of gastrointestinal tract (GIT)- related toxicity offer promise in addressing some of the limitations associated with animal-based assessments. GIT NAMs vary in complexity, from two-dimensional monolayer cell line-based systems to sophisticated 3-dimensional organoid systems derived from human primary cells. Despite advances in GIT NAMs, challenges remain in fully replicating the complex interactions and pro­cesses occurring within the human GIT. Presentations and discussions addressed regulatory needs, challenges, and innovations in incorporating NAMs into risk assessment frameworks; explored the state of the science in using NAMs for evaluating systemic toxicity, understanding absorption and pharmacokinetics, evaluating GIT toxicity, and assessing potential allergenicity; and discussed strengths, limitations, and data gaps of GIT NAMs as well as steps needed to establish confidence in these models for use in the regulatory setting.

Importance: The food industry has always used many strains of microorganisms including fungi in their production processes. These strains have been widely characterized for their biotechnological value, but we still know very little about their interaction capacities with the host at a time when the intestinal microbiota is at the center of many pathologies. In this study, we characterized five yeast strains from food production which allowed us to identify two new strains with high probiotic potential and beneficial effects in a model of intestinal inflammation., Competing Interests: The authors declare no conflict of interest.

This study explored the intracellular metabolic variations between 17 strains of Saccharomyces cerevisiae belonging to two different genetic populations: flor and wine yeasts, in the context of alcoholic fermentation. These two populations are closely related as they share the same ecological niche but display distinct genetic characteristics. A protocol was developed for intracellular metabolites extraction and 1 H-NMR analysis. This methodology allowed us to identify and quantify 21 intracellular metabolites at two different fermentation steps: the exponential and stationary phases. This work provided evidence of significant differences in the abundance of intracellular metabolites, which are strain- and time-dependent, thus revealing complex interactions. Moreover, the differences in abundance appeared to be correlated with life-history traits such as average cell size and specific glycolytic flux, which revealed unsuspected phenotypic correlations between metabolite load and fermentation activity., Competing Interests: CV, PM and MB were employed by the Biolaffort. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vion, Brambati, Da Costa, Richard and Marullo.)

Introduction: Antibiotic effects on gut bacteria have been widely studied, but very little is known about the consequences of such treatments on the mycobiota, the fungal part of the microbiota and how the length of administration influences both microbiota. Here, we examined the effect of antibiotics (ATB) on the composition of bacterial and fungal microbiota and how the administration of Saccharomyces boulardii CNCM I-745 influences both microbiota., Methods: In order to get closer to the human microbiota, the mice used in this study were subjected to fecal microbiota transfer (FMT) using human feces and subsequently called human microbiotaassociated (HMA) mice. These mice were then treated with amoxicillinclavulanate antibiotics and supplemented with S. boulardii during and after ATB treatment to understand the effect of the yeast probiotic on both bacterial and fungal microbiota. Bacterial and fungal microbiota analyses were done using 16S and ITS2 rRNA amplicon-based sequencing., Results: We showed that the administration of S. boulardii during ATB treatment had very limited effect on the fungal populations on the long term, once the yeast probiotic has been cleared from the gut. Concerning bacterial microbiota, S. boulardii administration allowed a better recovery of bacterial populations after the end of the ATB treatment period. Additionally, 16S and ITS2 rRNA sequence analysis revealed that 7 additional days of S. boulardii administration (17 days in total) enhanced the return of the initial bacterial equilibrium., Discussion: In this study, we provide a comprehensive analysis of how probiotic yeast administration can influence the fungal and bacterial microbiota in a model of broad-spectrum antibiotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The original study design was initially discussed between the research group and Biocodex. The decision to submit the data for publication was approved by Biocodex., (Copyright © 2023 Spatz, Wang, Lapiere, Da Costa, Michaudel, Danne, Michel, Langella, Sokol and Richard.)

Global warming poses serious implications to animal physiology and a gradual increase in ambient temperature affects all living organisms, particularly fast-growing selected species. We recorded ventilation (V̇ E ), body temperature (T B ), oxygen consumption (V̇O 2 ) and respiratory equivalent (V̇ E /V̇O 2 ) of 14-day-old (14d) male and female chicks at room air conditions, hypercapnia and hypoxia at heat stress (HS, 32 °C). These chicks had previously been exposed to control (CI, 37.5 °C) and high (HI, 39 °C) temperatures during the first 5 days of incubation. Under resting conditions, acute HS increased V̇ E in HI females but not in HI males. Hypercapnia combined with heat promoted a potentiation of CO 2 -hyperventilatory response in HI females when compared with thermoneutral condition, whereas in HI incubated males a hypoventilation under hypercapnia and heat stress was observed compared to the CI group. Hypoxia associated with heat stress increased V̇ E only in HI females. Our data indicates that females are more sensitive to thermal manipulation during incubation and it seems that the thermal embryonic manipulation, at least during the first days of development, does not improve the adaptive response of chicks to heat stress., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare and have no relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Absolute quantification of individual metabolites in complex biological samples is crucial in targeted metabolomic profiling., Objectives: An inter-laboratory test was performed to evaluate the impact of the NMR software, peak-area determination method (integration vs. deconvolution) and operator on quantification trueness and precision., Methods: A synthetic urine containing 32 compounds was prepared. One site prepared the urine and calibration samples, and performed NMR acquisition. NMR spectra were acquired with two pulse sequences including water suppression used in routine analyses. The pre-processed spectra were sent to the other sites where each operator quantified the metabolites using internal referencing or external calibration, and his/her favourite in-house, open-access or commercial NMR tool., Results: For 1D NMR measurements with solvent presaturation during the recovery delay (zgpr), 20 metabolites were successfully quantified by all processing strategies. Some metabolites could not be quantified by some methods. For internal referencing with TSP, only one half of the metabolites were quantified with a trueness below 5%. With peak integration and external calibration, about 90% of the metabolites were quantified with a trueness below 5%. The NMRProcFlow integration module allowed the quantification of several additional metabolites. The number of quantified metabolites and quantification trueness improved for some metabolites with deconvolution tools. Trueness and precision were not significantly different between zgpr- and NOESYpr-based spectra for about 70% of the variables., Conclusion: External calibration performed better than TSP internal referencing. Inter-laboratory tests are useful when choosing to better rationalize the choice of quantification tools for NMR-based metabolomic profiling and confirm the value of spectra deconvolution tools., (© 2023. The Author(s).)

Objective: The extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway., Design: Targeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition., Results: In mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models., Conclusion: Our study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4 + T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT., Competing Interests: Competing interests: HS report lecture fee, board membership, or consultancy from Carenity, AbbVie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, BiomX, Biose, Novartis,Takeda, Biocodex and is cofounder of Exeliom Biosciences., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Atom probe tomography (APT) is a powerful three-dimensional nanoanalyzing microscopy technique considered key in modern materials science. However, progress in the spatial reconstruction of APT data has been rather limited since the first implementation of the protocol proposed by Bas et al. in 1995. This paper proposes a simple semianalytical approach to reconstruct multilayered structures, i.e., two or more different compounds stacked perpendicular to the analysis direction. Using a field evaporation model, the general dynamic evolution of parameters involved in the reconstruction of this type of structure is estimated. Some experimental reconstructions of different structures through the implementation of this method that dynamically accommodates variations in the tomographic reconstruction parameters are presented. It is shown both experimentally and theoretically that the depth accuracy of reconstructed APT images is improved using this method. The method requires few parameters in order to be easily usable and substantially improves atom probe tomographic reconstructions of multilayered structures., Competing Interests: Conflict of Interest The authors declare that they have no competing interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Microscopy Society of America.)

Objectives: Inflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 ( Card9 ), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown., Design: We used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real-time bioenergetic profile analysis (Seahorse)., Results: Lymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction increases mitochondrial reactive oxygen species production leading to the premature death of neutrophilsthrough apoptosis, especially in oxidative environment. The decreased functional neutrophils in tissues might explain the impaired containment of fungi and increased susceptibility to intestinal inflammation., Conclusion: These results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: This study aimed to perform a systematic review and meta-analysis to assess the scientific evidence of the relationship between vulnerability to access to safe drinking water, sanitation, and hygiene (WASH) practices on stunting in children aged <5 years in developing countries., Study Design: This is a systematic review and meta-analysis article to assess the relationship between under-five stunting and WASH vulnerability in developing countries., Methods: The systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol methodology. The following databases were used: LILACS, MEDLINE (via PubMed), SciELO, Web of Science, ScienceDirect, SCOPUS, and Embase. All original studies identified that related WASH vulnerability to stunting in children aged <5 years in developing countries was included. Three authors performed independently the selection and extraction of data from the articles. The statistical software STATA version 11 was used. Cochran's Q test and Chi-square test (I 2 ) with 95% significance were used to assess the heterogeneity of the studies., Results: The search resulted in the initial identification of 2047 articles; after reading the abstracts, followed by the full articles, 14 articles were included in the systematic review and eight articles were included in the meta-analysis. The studies selected for the systematic review were published between the years 1992 and 2021 and conducted in eight countries, namely, Ethiopia, India, Indonesia, Bangladesh, Tanzania, Peru, China, and Lesotho. The studies assessed vulnerability to access to WASH on the growth of children aged <5 years. There was a significant difference when relating WASH vulnerability to children's height. The meta-analysis of this study showed that the impact of WASH on child stunting is significant when it comes to lack of sanitation in 72% of the studies., Conclusions: The study found that WASH vulnerability contributes to stunting in children aged <5 years in developing countries. Based on our findings, we recommend incorporating WASH strategies, especially sanitation, into the formulation of interventions integrating with health promotion policies for healthy early childhood development., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Introduction: S taphylococcus epidermidis is a commensal bacterium ubiquitously present on human skin. This species is considered as a key member of the healthy skin microbiota, involved in the defense against pathogens, modulating the immune system, and involved in wound repair. Simultaneously, S. epidermidis is the second cause of nosocomial infections and an overgrowth of S. epidermidis has been described in skin disorders such as atopic dermatitis. Diverse isolates of S. epidermidis co-exist on the skin. Elucidating the genetic and phenotypic specificities of these species in skin health and disease is key to better understand their role in various skin conditions. Additionally, the exact mechanisms by which commensals interact with host cells is partially understood. We hypothesized that S. epidermidis isolates identified from different skin origins could play distinct roles on skin differentiation and that these effects could be mediated by the aryl hydrocarbon receptor (AhR) pathway., Methods: For this purpose, a library of 12 strains originated from healthy skin (non-hyperseborrheic (NH) and hyperseborrheic (H) skin types) and disease skin (atopic (AD) skin type) was characterized at the genomic and phenotypic levels., Results and Discussion: Here we showed that strains from atopic lesional skin alter the epidermis structure of a 3D reconstructed skin model whereas strains from NH healthy skin do not. All strains from NH healthy skin induced AhR/OVOL1 path and produced high quantities of indole metabolites in co-culture with NHEK; especially indole-3-aldehyde (IAld) and indole-3-lactic acid (ILA); while AD strains did not induce AhR/OVOL1 path but its inhibitor STAT6 and produced the lowest levels of indoles as compared to the other strains. As a consequence, strains from AD skin altered the differentiation markers FLG and DSG1. The results presented here, on a library of 12 strains, showed that S. epidermidis originated from NH healthy skin and atopic skin have opposite effects on the epidermal cohesion and structure and that these differences could be linked to their capacity to produce metabolites, which in turn could activate AHR pathway. Our results on a specific library of strains provide new insights into how S. epidermidis may interact with the skin to promote health or disease., Competing Interests: Authors LL, CC, CF, SM, AG, DB and LA were employed by the company L’Oréal Research and Innovation, Aulnay-sous-Bois. JV was employed by iMEAN, Toulouse, France. L’Oréal Research and Innovation, as funder, has been involved in the decision to submit the study for publication., (Copyright © 2023 Landemaine, Da Costa, Fissier, Francis, Morand, Verbeke, Michel, Briandet, Sokol, Gueniche, Bernard, Chatel, Aguilar, Langella, Clavaud and Richard.)

Background: Effects of antibiotics on gut bacteria have been widely studied, but very little is known about the consequences of such treatments on the fungal microbiota (mycobiota). It is commonly believed that fungal load increases in the gastrointestinal tract following antibiotic treatment, but better characterization is clearly needed of how antibiotics directly or indirectly affect the mycobiota and thus the entire microbiota., Design: We used samples from humans (infant cohort) and mice (conventional and human microbiota-associated mice) to study the consequences of antibiotic treatment (amoxicillin-clavulanic acid) on the intestinal microbiota. Bacterial and fungal communities were subjected to qPCR or 16S and ITS2 amplicon-based sequencing for microbiota analysis. In vitro assays further characterized bacterial-fungal interactions, with mixed cultures between specific bacteria and fungi., Results: Amoxicillin-clavulanic acid treatment triggered a decrease in the total fungal population in mouse feces, while other antibiotics had opposite effects on the fungal load. This decrease is accompanied by a total remodelling of the fungal population with the enrichment in Aspergillus, Cladosporium, and Valsa genera. In the presence of amoxicillin-clavulanic acid, microbiota analysis showed a remodeling of bacterial microbiota with an increase in specific bacteria belonging to the Enterobacteriaceae. Using in vitro assays, we isolated different Enterobacteriaceae species and explored their effect on different fungal strains. We showed that Enterobacter hormaechei was able to reduce the fungal population in vitro and in vivo through yet unknown mechanisms., Conclusions: Bacteria and fungi have strong interactions within the microbiota; hence, the perturbation initiated by an antibiotic treatment targeting the bacterial community can have complex consequences and can induce opposite alterations of the mycobiota. Interestingly, amoxicillin-clavulanic acid treatment has a deleterious effect on the fungal community, which may have been partially due to the overgrowth of specific bacterial strains with inhibiting or competing effects on fungi. This study provides new insights into the interactions between fungi and bacteria of the intestinal microbiota and might offer new strategies to modulate gut microbiota equilibrium. Video Abstract., (© 2023. The Author(s).)

Since 1998, the state of Rio de Janeiro, Brazil, has become a public health problem regarding sporotrichosis, a disease caused by Sporothrix spp. involving contact with infected cats. Efforts to isolate these species from environmental sources are not always successful. In our study, soil from residences situated in cities of Rio de Janeiro where cats with sporotrichosis live was collected and cultured an attempt to isolate Sporothrix spp. but it was not successful. However, other saprophytic fungal species were isolated from soil and identified and among them Purpureocillium lilacinum was the most frequent. From there, we decided to study the in vitro interaction of this species with S. brasiliensis , the principal agent that causes sporotrichosis in this state. The results showed that ten isolates of P. lilacinum inhibited the radial mycelial growth of S. brasiliensis with different percentage of inhibition. The interaction between them revealed the pattern described as overgrowth by antagonist. In conclusion, our data suggest that fungal species with very fast growth and capable of producing metabolites could hinder the growth of Sporothrix spp., it also opens the way for the identification of secondary metabolites with biological activity that could be tested against pathogenic fungi., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lara da Costa, Escórcio Ferreira, Corrêa-Moreira, Marinho, Benedito de Almeida, Antônio Pereira, Moraes Borba and Marques Evangelista Oliveira.)

Stilbene metabolites are attracting great interest because many of them exhibit similar or even stronger biological effects than their parent compounds. Furthermore, the metabolized forms are predominant in biological fluids; therefore, their study is highly relevant. After hemisynthesis production, isolation, and structural elucidation, three glucuronide metabolites for oxyresveratrol (ORV) were formed: trans -ORV-4'- O -glucuronide, trans -ORV-3- O -glucuronide, and trans -ORV-2'- O -glucuronide. In addition, two glucuronide metabolites were obtained for gnetol (GN): trans -GN-2'- O -glucuronide and trans -GN-3- O -glucuronide. When the metabolism of ORV and GN is studied in vitro by human and rat hepatic enzymes, four of the five hemisynthesized compounds were identified and quantified. Human enzymes glucuronidated preferably at the C-2' position, whereas rat enzymes do so at the C-3 position. In view of these kinetic findings, rat enzymes have a stronger metabolic capacity than human enzymes. Finally, ORV, GN, and their glucuronide metabolites (mainly at the C-3 position) decreased nitric oxide, reactive oxygen species, interleukin 1β, and tumor necrosis factor α production in lipopolysaccharide-stimulated macrophages.

Food processes use different microorganisms, from bacteria to fungi. Yeast strains have been extensively studied, especially Saccharomyces cerevisiae. However, to date, very little is known about the potential beneficial effects of molds on gut health as part of gut microbiota. We undertook a comprehensive characterization of five mold strains, Penicillium camemberti, P. nalgiovense, P. roqueforti, Fusarium domesticum, and Geotrichum candidum used in food processes, on their ability to trigger or protect intestinal inflammation using in vitro human cell models and in vivo susceptibility to sodium dextran sulfate-induced colitis. Comparison of spore adhesion to epithelial cells showed a very wide disparity in results, with F. domesticum and P. roqueforti being the two extremes, with almost no adhesion and 20% adhesion, respectively. Interaction with human immune cells showed mild pro-inflammatory properties of all Penicillium strains and no effect of the others. However, the potential anti-inflammatory abilities detected for G. candidum in vitro were not confirmed in vivo after oral gavage to mice before and during induced colitis. According to the different series of experiments carried out in this study, the impact of the spores of these molds used in food production is limited, with no specific beneficial or harmful effect on the gut.

Introduction: In Brazil, the Unified Health System (Sistema Único de Saúde, or SUS) provides health care, and an aging population overwhelms the system due to the greater vulnerability of the elderly. In the Federal District, two models of primary care coexist-the traditional primary care and the family health strategy. The present study aimed to analyze the factors associated with mortality of the elderly due to conditions sensitive to ambulatory care in the Federal District, Brazil., Materials and Methods: This cross-sectional study investigated all deaths that occurred in people over 60 years old between 2008 and 2018. The variables studied were age at death, sex, marital status, education, race/color, death by condition sensitive to ambulatory care, and population coverage of primary care services. The Urban Well-Being Index (UWBI) was used, which includes the dimensions: mobility, environmental and housing conditions, infrastructure, and collective services, to analyze issues related to the place where the senior citizen resides., Results: The deaths 70,503 senior citizens were recorded during the study period. The factors associated with mortality in the elderly due to ambulatory care sensitive conditions were male, lower income, and less education. Residing in a place with poor UWBI presented a response gradient with higher mortality. Increased ambulatory care coverage was also associated with lower mortality., Conclusions: The study evidenced an association between male gender, age, income, and education, and UWBI with lower mortality due to ambulatory care sensitive conditions, and these associations presented a response gradient. The study also found that increased coverage of the elderly population was associated with lower mortality from sensitive conditions., Competing Interests: The authors have declared that no competing interests exist.

Brominated vegetable oil (BVO) has been approved by the US Food and Drug Administration on an interim basis as a food additive. Past studies have raised concerns about potential toxicities from consuming BVO. To investigate further these toxicities, we conducted a 90-day dietary exposure study in Sprague Dawley rats and analyzed tissue distribution of the main metabolites. Six-week-old male and female rats were fed diets containing 0 (control), 0.002%, 0.02%, 0.1%, or 0.5% BVO by weight. Statistically significant increases were observed in the serum bromide in the high-dose group of both sexes and in the incidence of thyroid follicular cell hypertrophy in the two highest dose groups of males and the high-dose group of females. An increase in serum TSH was observed in the high-dose group for both sexes, as well as a decrease in serum T4 in the high-dose males. A clear dose-response was observed in di- and tetra-bromostearic acid levels in the heart, liver, and inguinal fat. These data expand upon previous observations in rats and pigs that oral exposure to BVO is associated with increased tissue levels of inorganic and organic bromine, and that the thyroid is a potential target organ of toxicity., (Published by Elsevier Ltd.)

Purpureocillium lilacinum is a filamentous and hyaline fungus cosmopolitan, saprophytic, largely used in the biological control of plant-parasitic nematodes and insects, also considered an emerging and opportunistic human pathogen. The standard treatment for hyalohyphomycosis caused by P. lilacinum is not yet defined, since this fungus is resistant to different antifungals, in vitro and in vivo. The aim of this study was to evaluate and compare in vitro antifungal activity against environmental and clinical P. lilacinum isolates and our results demonstrated that these isolates can be resistant to newer generation triazoles, such as voriconazole, and to caspofungin, a drug of the echinocandin class. In summary, we highlight the importance of knowing the different susceptibility profiles of P. lilacinum isolates, and besides that, the emergence of uncommon human and animal opportunistic fungi, such P. lilacinum, especially during COVID-19, highlight the need for antifungal susceptibility testing of isolates since empirical therapy with different treatment schedules failed in great number of patients., (© 2022 The Society for Applied Microbiology.)

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in the Comprehensive in vitro Proarrhythmia Assay (CiPA). The notable difference of the electrophysiological (EP) responses of hiPSC-CMs in serum and serum-free media (SFM) is puzzling and may impact regulatory decision-making on the cardiac safety of candidate drugs in inducing QT prolongation and torsade de pointes (TdP). In this study, we compared the EP responses of hiPSC-CMs to 10 CiPA compounds and moxifloxacin in serum and SFM; explained the potential reason behind the different EP responses-abiotic compound loss to plastic tubes/plates of hydrophobic compounds prepared in SFM; and investigated the impact of compound preparation methods on drug bioavailability in exposure media, which affects the TdP risk prediction of drugs tested in serum-containing and SFM. For assays to be conducted in SFM, awareness of abiotic compound loss of hydrophobic compounds in serum-free preparations is critical for delay repolarization evaluation and data extrapolation from in vitro to in vivo., (Published by Oxford University Press on behalf of the Society of Toxicology 2022. This work is written by US Government employees and is in the public domain in the US.)

Background: Innate immunity genes have been reported to affect susceptibility to inflammatory bowel diseases (IBDs) and colitis in mice. Dectin-1, a receptor for fungal cell wall β-glucans, has been clearly implicated in gut microbiota modulation and modification of the susceptibility to gut inflammation. Here, we explored the role of Dectin-1 and Dectin-2 (another receptor for fungal cell wall molecules) deficiency in intestinal inflammation., Design: Susceptibility to dextran sodium sulfate (DSS)-induced colitis was assessed in wild-type, Dectin-1 knockout (KO), Dectin-2KO, and double Dectin-1KO and Dectin-2KO (D-1/2KO) mice. Inflammation severity, as well as bacterial and fungal microbiota compositions, was monitored., Results: While deletion of Dectin-1 or Dectin-2 did not have a strong effect on DSS-induced colitis, double deletion of Dectin-1 and Dectin-2 significantly protected the mice from colitis. The protection was largely mediated by the gut microbiota, as demonstrated by fecal transfer experiments. Treatment of D-1/2KO mice with opportunistic fungal pathogens or antifungal agents did not affect the protection against gut inflammation, suggesting that the fungal microbiota had no role in the protective phenotype. Amplicon-based microbiota analysis of the fecal bacterial and fungal microbiota of D-1/2KO mice confirmed the absence of changes in the mycobiota but strong modification of the bacterial microbiota. We showed that bacteria from the Lachnospiraceae family were at least partly involved in this protection and that treatment with Blautia hansenii was enough to recapitulate the protection., Conclusions: Deletion of both the Dectin-1 and Dectin-2 receptors triggered a global shift in the microbial gut environment, affecting, surprisingly, mainly the bacterial population and driving protective effects in colitis. Members of the Lachnospiraceae family seem to play a central role in this protection. These findings provide new insights into the role of the Dectin receptors, which have been described to date as affecting only the fungal population, in intestinal physiopathology and in IBD. Video Abstract., (© 2022. The Author(s).)

Polyethylene glycol (PEG) is present in a variety of products. Little is known regarding the accumulation of high-molecular-weight PEGs or the long-term effects resulting from PEG accumulation in certain tissues, especially the choroid plexus. We evaluated the toxicity of high-molecular-weight PEGs administered to Sprague Dawley rats. Groups of 12 rats per sex were administered subcutaneous injections of 20, 40, or 60 kDa PEG or intravenous injections of 60 kDa PEG at 100 mg PEG/kg body weight/injection once a week for 24 weeks. A significant decrease in triglycerides occurred in the 60 kDa PEG groups. PEG treatment led to a molecular-weight-related increase in PEG in plasma and a low level of PEG in cerebrospinal fluid. PEG was excreted in urine and feces, with a molecular-weight-related decrease in the urinary excretion. A higher prevalence of anti-PEG IgM was observed in PEG groups; anti-PEG IgG was not detected. PEG treatment produced a molecular-weight-related increase in vacuolation in the spleen, lymph nodes, lungs, and ovaries/testes, without an inflammatory response. Mast cell infiltration at the application site was noted in all PEG-treated groups. These data indicate that subcutaneous and intravenous exposure to high-molecular-weight PEGs produces anti-PEG IgM antibody responses and tissue vacuolation without inflammation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The chemical composition of wine is known to be influenced by multiple factors including some viticulture practices and winemaking processes. 1 H-NMR metabolomics has been successfully applied to the study of wine authenticity. In the present study, 1 H-NMR metabolomics in combination with multivariate analysis was applied to investigate the effects of grape maturity and enzyme and fining treatments on Cabernet Sauvignon wines. A total of forty wine metabolites were quantified. Three different stages of maturity were studied (under-maturity, maturity and over-maturity). Enzyme treatments were carried out using two pectolytic enzymes (E1 and E2). Finally, two proteinaceous fining treatments were compared (vegetable protein, fining F1; pea protein and PVPP, fining F2). The results show a clear difference between the three stages of maturity, with an impact on different classes of metabolites including amino acids, organic acids, sugars, phenolic compounds, alcohols and esters. A clear separation between enzymes E1 and E2 was observed. Both fining agents had a significant effect on metabolite concentrations. The results demonstrate that 1 H-NMR metabolomics provides a fast and robust approach to study the effect of winemaking processes on wine metabolites. These results support the interest to pursue the development of 1 H-NMR metabolomics to investigate the effects of winemaking on wine quality.

A position and energy-sensitive detector has been developed for atom probe tomography (APT) instruments in order to deal with some mass peak overlap issues encountered in APT experiments. Through this new type of detector, quantitative and qualitative improvements could be considered for critical materials with mass peak overlaps, such as nitrogen and silicon in TiSiN systems, or titanium and carbon in cemented carbide materials. This new detector is based on a thin carbon foil positioned on the front panel of a conventional MCP-DLD detector. According to several studies, it has been demonstrated that the impact of ions on thin carbon foils has the effect of generating a number of transmitted and reflected secondary electrons. The number generated mainly depends on both the kinetic energy and the mass of incident particles. Despite the fact that this phenomenon is well known and has been widely discussed for decades, no studies have been performed to date for using it as a means to discriminate particles energy. Therefore, this study introduces the first experiments on a potential new generation of APT detectors that would be able to resolve mass peak overlaps through the energy-sensitivity of thin carbon foils.

Gut interleukin-17A (IL-17)-producing γδ T cells are tissue-resident cells that are involved in both host defense and regulation of intestinal inflammation. However, factors that regulate their functions are poorly understood. In this study, we find that the gut microbiota represses IL-17 production by cecal γδ T cells. Treatment with vancomycin, a Gram-positive bacterium-targeting antibiotic, leads to decreased production of short-chain fatty acids (SCFAs) by the gut microbiota. Our data reveal that these microbiota-derived metabolites, particularly propionate, reduce IL-17 and IL-22 production by intestinal γδ T cells. Propionate acts directly on γδ T cells to inhibit their production of IL-17 in a histone deacetylase-dependent manner. Moreover, the production of IL-17 by human IL-17-producing γδ T cells from patients with inflammatory bowel disease (IBD) is regulated by propionate. These data contribute to a better understanding of the mechanisms regulating gut γδ T cell functions and offer therapeutic perspectives of these cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Neutron-star mergers were recently confirmed as sites of rapid-neutron-capture (r-process) nucleosynthesis 1-3 . However, in Galactic chemical evolution models, neutron-star mergers alone cannot reproduce the observed element abundance patterns of extremely metal-poor stars, which indicates the existence of other sites of r-process nucleosynthesis 4-6 . These sites may be investigated by studying the element abundance patterns of chemically primitive stars in the halo of the Milky Way, because these objects retain the nucleosynthetic signatures of the earliest generation of stars 7-13 . Here we report the element abundance pattern of the extremely metal-poor star SMSS J200322.54-114203.3. We observe a large enhancement in r-process elements, with very low overall metallicity. The element abundance pattern is well matched by the yields of a single 25-solar-mass magnetorotational hypernova. Such a hypernova could produce not only the r-process elements, but also light elements during stellar evolution, and iron-peak elements during explosive nuclear burning. Hypernovae are often associated with long-duration γ-ray bursts in the nearby Universe 8 . This connection indicates that similar explosions of fast-spinning strongly magnetized stars occurred during the earliest epochs of star formation in our Galaxy.

This article presents a fast and highly efficient algorithm developed to reconstruct a three-dimensional (3D) volume with a high spatial precision from a set of field ion microscopy (FIM) images, and specific tools developed to characterize crystallographic lattice and defects. A set of FIM digital images and image processing algorithms allow the construction of a 3D reconstruction of the sample at the atomic scale. The capability of the 3D FIM to resolve the crystallographic lattice and the finest defects in metals opens a new way to analyze materials. This spatial precision was quantified on tungsten, analyzed at different analyzing conditions. A specific data mining tool, based on Fourier transforms, was also developed to characterize lattice distortions in the reconstructed volumes. This tool has been used in simulated and experimental volumes to successfully locate and characterize defects such as dislocations and grain boundaries.

Ultrafast control of matter by a strong electromagnetic field on the atomic scale is essential for future investigations and manipulations of ionization dynamics and excitation in solids. Coupling picosecond duration terahertz pulses to metallic nanostructures allows the generation of extremely localized and intense electric fields. Here, using single-cycle terahertz pulses, we demonstrate control over field ion emission from metallic nanotips. The terahertz near field is shown to induce an athermal ultrafast evaporation of surface atoms as ions on the subpicosecond time scale, with the tip acting as a field amplifier. The ultrafast terahertz-ion interaction offers unprecedented control over ultrashort free-ion pulses for imaging, analyzing, and manipulating matter at atomic scales. Here, we demonstrate terahertz atom probe microscopy as a new platform for microscopy with atomic spatial resolution and ultimate chemical resolution., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

In 2007, dietary exposure to "scrap melamine' resulted in the death of a large number of cats and dogs, which was attributed to the formation of melamine cyanurate crystals in their kidneys. In this study, we investigated if changes in urinary pH could diminish the renal toxicity associated with exposure to combinations of melamine and cyanuric acid. Female Sprague-Dawley rats were treated for three days with suspensions of melamine and cyanuric acid at doses that were expected to induce renal toxicity. Dosing was then discontinued and the rats were treated for seven days with drinking water solutions ( i.e. , ammonium chloride and sodium bicarbonate) that would alter urinary pH. The urinary pH of rats administered ammonium chloride drinking water decreased from pH 6.0-6.2 to pH 5.1-5.2. This was accompanied by a decrease in the incidence of melamine cyanurate crystals in the kidneys and a decrease in the incidence of renal lesions. These data suggest that acidification of urine may help overcome the renal toxicities associated with the formation of melamine cyanurate crystals in the kidney.

Dissociation processes involving phosphorus cations were investigated during laser-assisted atom probe tomography of crystalline indium phosphide (InP). This technique not only allows the formation of medium-sized phosphorus cations by means of femtosecond laser pulses under ultrahigh vacuum and high electric field conditions but also allows one to study the time-resolved dissociation dynamics. Data reveal the formation of cations up to P 23 2+ and their subsequent dissociation into two smaller P k + cations ( k > 2). The use of a time- and position-sensitive detector combined with numerical calculations provided information related to the molecule orientation, decay time, and kinetic energy release during dissociation phenomena. Results suggest that the dissociation processes are most likely due to the emission of P k 2+ cations in excited states and their subsequent decay in low field regions during their flight toward the detector. This study provides operative guidelines to obtain information on dissociation processes using a tomographic atom probe as a reaction microscope and indicates the current capabilities and limitations of such an approach.

The analysis of the fatty acid profile of triglycerides has long played a central role in the evaluation and classification of edible vegetable oils. However, the range of analytical procedures available to evaluate these profiles remains limited and are typically based on transesterification of the triglyceride fatty acid residues to methyl esters, followed by capillary gas-liquid chromatography (GC) coupled with flame ionization or mass spectrometry detection. Although robust and long-proven, these analytical methods tend to entail long chromatographic runs and are relatively insensitive. In order to expand the range of available techniques for the analysis of the fatty acid profile of triglycerides in vegetable oils, we report herein a novel method based upon a rapid and straightforward transesterification of the triglycerides with dimethylaminoethanol under alkaline conditions, followed by a "dilute-and-shoot" analysis by ultra-performance liquid chromatography coupled with electrospray tandem mass spectrometry. The chromatographic analysis is accomplished in 1.5 min, affording a high throughput of samples compared to techniques based upon GC approaches. The method performance was assessed intra- and inter-day with 10 representative saturated and unsaturated fatty acids ranging from C 8 to C 18 and afforded fatty acid profile accuracies of 93-108% and imprecisions of only 0.3-2.0%. The limit of quantification of the method, estimated as the minimum amount of derivatized oil sample capable of affording less than 20% accuracy and precision error was determined to be approximately 0.5 pg on-column, making this new method potentially valuable for fields where high sensitivity, precision, and accuracy may be required, such as in toxicology studies, forensics, archeology, or art analysis., (Published by Elsevier B.V.)

Acrylamide is a suspected human carcinogen formed during high-temperature cooking of starch-rich foods. It is metabolised by cytochrome P450 2E1 to its reactive metabolite glycidamide, which forms pre-mutagenic DNA adducts. Using the human TP53 knock-in (Hupki) mouse embryo fibroblasts (HUFs) immortalisation assay (HIMA), acrylamide- and glycidamide-induced mutagenesis was studied in the tumour suppressor gene TP53. Selected immortalised HUF clones were also subjected to next-generation sequencing to determine mutations across the whole genome. The TP53-mutant frequency after glycidamide exposure (1.1 mM for 24 h, n = 198) was 9% compared with 0% in cultures treated with acrylamide [1.5 (n = 24) or 3 mM (n = 6) for 48 h] and untreated vehicle (water) controls (n = 36). Most glycidamide-induced mutations occurred at adenines with A > T/T > A and A > G/T > C mutations being the most common types. Mutations induced by glycidamide occurred at specific TP53 codons that have also been found to be mutated in human tumours (i.e., breast, ovary, colorectal, and lung) previously associated with acrylamide exposure. The spectrum of TP53 mutations was further reflected by the mutations detected by whole-genome sequencing (WGS) and a distinct WGS mutational signature was found in HUF clones treated with glycidamide that was again characterised by A > G/T > C and A > T/T > A mutations. The WGS mutational signature showed similarities with COSMIC mutational signatures SBS3 and 25 previously found in human tumours (e.g., breast and ovary), while the adenine component was similar to COSMIC SBS4 found mostly in smokers' lung cancer. In contrast, in acrylamide-treated HUF clones, only culture-related background WGS mutational signatures were observed. In summary, the results of the present study suggest that glycidamide may be involved in the development of breast, ovarian, and lung cancer.

Alzheimer disease's (AD) is a neurodegenerative disease induced by amyloid-β (Aβ) aggregation and accumulation of neurotoxic metals in the brain. Fraxinus angustifolia Vahl. (Oleaceae) is a Mediterranean plant traditionally used to treat several human problems as nervous system problems. This study aimed to evaluate the neuroprotective effects of F. angustifolia Vahl. bark extract (FAB) in vitro and in vivo against Aβ-aggregation and aluminium induced-neurotoxicity in mice. FAB was characterized by colorimetric methods and its individual compounds were identified and quantified by LC-MS. First, the neuroprotective effect of FAB was evaluated against Aβ 25-35 -aggregation where it was directly incubated with Aβ 25-35 and the kinetic of aggregation was measured by spectrophotometer at 200 nm. Then, the extract was tested against Aβ 25-35 -induced cytotoxicity on PC12 cells and the cells viability was determined by MTT test. On the other hand, FAB (0.01-0.5 mg/mL) was tested against aluminium-activated lipid peroxidation in mice synaptosomal membranes, and in vivo against aluminium-caused neurotoxicity in male N.M.R.I. (Naval Medical Research Institute) mice; this test consisted of daily co-administration of the extract with Al for 60 days. At the end of the treatment, behavioral and memory tests (locomotor activity, black and white and Morris water maze tests) and histological analysis were realized. The identification and quantification of FAB phenolics revealed the presence of different phenolic classes with high concentration of phenylethanoids and hydroxycoumarins. FAB showed a high Aβ 25-35 anti-aggregative effect and a dose dependent protective effect on PC12 cells. The extract also demonstrated a significant inhibition of lipid peroxidation and was found to prevent the Al harmful effects where it significantly increased the locomotor activity, decreased the anxiety, improved memory and reduced histological alterations. In conclusion, FAB is rich of bioactive compounds that gave it the ability to inhibit Aβ-aggregation and Al-caused neurotoxicity in mice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the courses of studies on ellagitannin changes during oak wood toasting, two C-glycosidic ellagitannins were isolated from the french oak wood for the first time. These two compounds exhibited [M-H] - ion peak at m / z 1055.0631 (compound A) and at m / z 1011.0756 (compound B). A compound is named Castacrenin E and is produced by Castacrenin D oxidation. Castacrenin D is a vescalagin with an additional aromating ring to the C-1 through a C-C bond. These compounds are not only found under laboratory conditions but also in commercial oak wood representing different toasting methods and sizes. Their levels are conditioned by oak wood dimensions and toasting degree. The wood pieces with the smallest size present almost two times more compounds A and B. Moreover, the compound B is the only compound to be present in medium toasting temperatures of the smallest wood pieces. Both of them can influence either astringency sensation or bitterness taste.

Background: Mental ill-health is the leading cause of disability worldwide. Moreover, 75% of mental health conditions emerge between the ages of 12 and 25 years. Unfortunately, due to lack of resources and limited engagement with services, a majority of young people affected by mental ill-health do not access evidence-based support. To address this gap, our team has developed a multimodal, scalable digital mental health service (Enhanced Moderated Online Social Therapy [MOST+]) merging real-time, clinician-delivered web chat counseling; interactive user-directed online therapy; expert and peer moderation; and peer-to-peer social networking., Objective: The primary aim of this study is to ascertain the feasibility, acceptability, and safety of MOST+. The secondary aims are to assess pre-post changes in clinical, psychosocial, and well-being outcomes and to explore the correlations between system use, perceived helpfulness, and secondary outcome variables., Methods: Overall, 157 young people seeking help from a national youth e-mental health service were recruited over 5 weeks. MOST+ was active for 9 weeks. All participants had access to interactive online therapy and integrated web chat counseling. Additional access to peer-to-peer social networking was granted to 73 participants (46.5%) for whom it was deemed safe. The intervention was evaluated via an uncontrolled single-group study., Results: Overall, 93 participants completed the follow-up assessment. Most participants had moderate (52/157, 33%) to severe (96/157, 61%) mental health conditions. All a priori feasibility, acceptability, and safety criteria were met. Participants provided mean scores of ≥3.5 (out of 5) on ease of use (mean 3.7, SD 1.1), relevancy (mean 3.9, SD 1.0), helpfulness (mean 3.5, SD 0.9), and overall experience (mean 3.9, SD 0.8). Moreover, 98% (91/93) of participants reported a positive experience using MOST+, 82% (70/93) reported that using MOST+ helped them feel better, 86% (76/93) felt more socially connected using it, and 92% (86/93) said they would recommend it to others. No serious adverse events or inappropriate use were detected, and 97% (90/93) of participants reported feeling safe. There were statistically significant improvements in 8 of the 11 secondary outcomes assessed: psychological distress (d=-0.39; P<.001), perceived stress (d=-0.44; P<.001), psychological well-being (d=0.51; P<.001), depression (d=-0.29; P<.001), loneliness (d=-0.23; P=.04), social support (d=0.30; P<.001), autonomy (d=0.36; P=.001), and self-competence (d=0.30; P<.001). There were significant correlations between system use, perceived helpfulness, and a number of secondary outcome variables., Conclusions: MOST+ is a feasible, acceptable, and safe online clinical service for young people with mental ill-health. The high level of perceived helpfulness, the significant improvements in secondary outcomes, and the correlations between indicators of system use and secondary outcome variables provide initial support for the therapeutic potential of MOST+. MOST+ is a promising and scalable platform to deliver standalone e-mental health services as well as enhance the growing international network of face-to-face youth mental health services., (©Mario Alvarez-Jimenez, Simon Rice, Simon D'Alfonso, Steven Leicester, Sarah Bendall, Ingrid Pryor, Penni Russon, Carla McEnery, Olga Santesteban-Echarri, Gustavo Da Costa, Tamsyn Gilbertson, Lee Valentine, Laia Solves, Aswin Ratheesh, Patrick D McGorry, John Gleeson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 13.08.2020.)

The oral squamous cell carcinoma (OSCC) stands out as a public health problem due to its high incidence and low survival rate, despite advances in diagnosis and treatment. Moreover, the most commonly chemotherapeutic agents for OSCC, such as carboplatin and cisplatin, generate important side effects, evidencing the urgency in developing new drugs. Naphthoquinones are an important class of natural products or synthetic compounds with cytotoxic effect demonstrated on different cancer types. In the present study, thirty-five 1,4-naphthoquinones tethered to 1,2,3-1H-triazoles were synthesized and the antitumor activity and molecular mechanisms were evaluated in several assays including in vitro and in vivo models of OSCC and normal oral human cells. Compounds 16a, 16b and 16 g were able to induce cytotoxicity in three different tumor cell lines of human OSCC (SCC4, SCC9 and SCC25) and were more toxic and selective to tumor cells (Selective Index, SI > 2) than classical and chemically similar controls (Carboplatin and Lapachol). Compound 16 g showed the higher SI value. Besides, compounds 16a, 16b and 16 g significantly reduced colony formation of SCC9 cells in the tested concentrations. Hemolytic assay using compounds 16a, 16b and 16 g at high concentrations showed no compound exhibited hemolysis higher than 5%, similar to controls. In vivo acute toxicity study showed that 16 g was the only one, among the three compounds, with no apparent limiting toxic effects on mice in the tested concentrations. Thus, the investigation of cell death mechanisms was conducted with this compound. 16 g does not trigger ROS production nor binds to DNA. On the other hand, compound 16 g induced microtubule disorganization, and molecular modeling studies suggests a potential mechanism of action related to inhibition of topoisomerases and/or hPKM2 activities. Cell morphology, pyknotic nuclei presence, cleaved caspase-3 staining and viability assays using caspase-3 inhibitors demonstrate compound 16 g induced cell death through apoptosis. Among the 35 synthesized triazole naphthoquinones, compound 16 g was the most effective compound against OSCC cells, presenting high cytotoxicity (~35 µM), selectivity (SI ~ 6) and low acute toxicity on animals, and therefore might be considered for future cancer therapy., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)