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Cell-free biocatalysis is gaining momentum in producing value-added chemicals, particularly in stepwise reaction cascades. However, the stability of enzyme cascades in industrial settings is often compromised when free enzymes are involved. In this study, we have developed a stable multifunctional heterogeneous biocatalyst coimmobilizing five enzymes on microparticles to transform 1,ω-diols into 1,ω-hydroxy acids. We improved the operational efficiency and stability of the heterogeneous biocatalyst by fine-tuning the enzyme loading and spatial organization. Stability issues are overcome through postimmobilization polymer coating. The general applicability of this heterogeneous biocatalyst is demonstrated by its scale-up in both batch and packed bed reactors, allowing a product yield of >80%. The continuous process is fed with H2O2 as the oxygen source, reaching a space-time yield (STY) of 0.76 g·L-1·h-1, maintained for the first 12 h. Finally, this flow system is telescoped with a second plug-flow reactor packed with a different heterogeneous biocatalyst integrating an additional transaminase. As a result, this 6-enzyme 2-reactor system sequentially transforms 1,ω-diols into 1,ω-amino acids while in situ recycling NAD+, depleting H2O2, and generating O2.

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We present an NLP web-based tool to help users understand consent forms (CFs) and clinical trial announcements (CTAs) in Spanish. For complex word identification, we collected: 1) a lexicon of technical terms and simplified synonyms (14 465 entries); and 2) a glossary (70 547 terms) with explanations from sources such as UMLS, the NCI dictionary, Orphadata or the FDA. For development, we extracted entities from 60 CTAs, 60 CFs and 60 patient information documents (PIDs). To prepare definitions for new terms, we used ChatGPT and experts validated them (28.99% needed to be fixed). We tested the system on 15 new CTAs, 15 CFs, and 15 PIDs, and we achieved an average F1 score of 82.91% (strict match) and of 94.65% (relaxed). The tool is available at: http://claramed.csic.es/demo.

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The objective assessment of habitual (poly)phenol-rich diets in nutritional epidemiology studies remains challenging. This study developed and evaluated the metabolic signature of a (poly)phenol-rich dietary score (PPS) using a targeted metabolomics method comprising 105 representative (poly)phenol metabolites, analyzed in 24 h of urine samples collected from healthy volunteers. The metabolites that were significantly associated with PPS after adjusting for energy intake were selected to establish a metabolic signature using a combination of linear regression followed by ridge regression to estimate penalized weights for each metabolite. A metabolic signature comprising 51 metabolites was significantly associated with adherence to PPS in 24 h urine samples, as well as with (poly)phenol intake estimated from food frequency questionnaires and diaries. Internal and external data sets were used for validation, and plasma, spot urine, and 24 h urine samples were compared. The metabolic signature proposed here has the potential to accurately reflect adherence to (poly)phenol-rich diets, and may be used as an objective tool for the assessment of (poly)phenol intake.

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Enzymes are natural catalysts which are gaining momentum in chemical synthesis due to their exquisiteselectivity and their biodegradability. However, the cost-efficiency and the sustainability of the overall biocatalytic process must be enhanced to unlock completely the potential of enzymes for industrial applications. To reach this goal, enzyme immobilization and the integration into continuous flow reactors have been the cornerstone of our research. We showed key examples of the advantages of those tools for the biosynthesis of antivirals, anticancer drugs, and valuable fragrance molecules. By combining new strategies to immobilize biocatalysts, innovative bioengineering approaches, and process development, the performance of the reactions could be boosted up to 100-fold.

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The mechanisms that underlie the regulation of enzymatic reactions by biomolecular condensates and how they scale with compartment size remain poorly understood. Here we use intrinsically disordered domains as building blocks to generate programmable enzymatic condensates of NADH-oxidase (NOX) with different sizes spanning from nanometers to microns. These disordered domains, derived from three distinct RNA-binding proteins, each possessing different net charge, result in the formation of condensates characterized by a comparable high local concentration of the enzyme yet within distinct environments. We show that only condensates with the highest recruitment of substrate and cofactor exhibit an increase in enzymatic activity. Notably, we observe an enhancement in enzymatic rate across a wide range of condensate sizes, from nanometers to microns, indicating that emergent properties of condensates can arise within assemblies as small as nanometers. Furthermore, we show a larger rate enhancement in smaller condensates. Our findings demonstrate the ability of condensates to modulate enzymatic reactions by creating distinct effective solvent environments compared to the surrounding solution, with implications for the design of protein-based heterogeneous biocatalysts.

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BACKGROUND: A large group of psychiatric patients suffer from auditory hallucinations (AH) despite relevant treatment regimens. In mental health populations, AH tend to be verbal (AVH) and the content critical or abusive. Trials employing immersive virtual reality (VR) to treat mental health disorders are emerging. OBJECTIVE: The aim of this scoping review is to provide an overview of clinical trials utilizing VR in the treatment of AH and to document knowledge gaps in the literature. METHODS: PubMed, Cochrane Library, and Embase were searched for studies reporting on the use of VR to target AH. RESULTS: 16 papers were included in this PRISMA scoping review (ScR). In most studies VR therapy (VRT) was employed to ameliorate treatment resistant AVH in schizophrenia spectrum disorders. Only two studies included patients with a diagnosis of affective disorders. The VRT was carried out with the use of an avatar to represent the patient's most dominant voice. DISCUSSION: The research field employing VR to treat AH is promising but still in its infancy. Results from larger randomized clinical trials are needed to establish substantial evidence of therapy effectiveness. Additionally, the knowledge base would benefit from more profound qualitative data exploring views of patients and therapists.

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(Poly)phenols are plant secondary metabolites widely abundant in plant foods and beverages comprising a very large number of compounds with diverse structure and biological activities. Accumulating evidence indicates that these compounds exert beneficial effects against cardiometabolic diseases, and this review will provide a summary of current knowledge in this area. Epidemiological and clinical data collectively suggest that intake of flavonoids reduces the risk of cardiovascular disease (CVD), with the evidence being particularly strong for the flavan-3-ol subclass. However, to provide adequate dietary recommendations, a better understanding of their estimated content in foods and intake among the general public is needed. Regarding mechanisms of action, we now know that it is unlikely that (poly)phenols act as direct antioxidants in vivo, as it was hypothesised for decades with the popularity of in vitro antioxidant capacity assays. One of the reasons is that upon ingestion, (poly)phenols are extensively metabolised into a wide array of circulating metabolites with different bioactivities than their precursors. Well-conducted in vitro and in vivo studies and human nutrigenomic analysis have revealed new molecular targets that may be underlying the health benefits of (poly)phenols, such as the nitric oxide pathway. Recently, a bi-directional relationship was established between (poly)phenols and the gut microbiota, suggesting that individual gut microbial metabolising capacity may be a key factor explaining the variability in the cardiometabolic response to (poly)phenols. Future research is needed to elucidate which are the key factors affecting such capacity, and whether it can be modulated, along with the mechanisms of action.

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Gut microbiota is an important modulator of human health and contributes to high inter-individual variation in response to food and pharmaceutical ingredients. The clinical outcomes of interventions with prebiotics, probiotics, and synbiotics have been mixed and often unpredictable, arguing for novel approaches for developing microbiome-targeted therapeutics. Here, we review how the gut microbiota determines the fate of and individual responses to dietary and xenobiotic compounds via its immense metabolic potential. We highlight that microbial metabolites play a crucial role as targetable mediators in the microbiota-host health relationship. With this in mind, we expand the concept of synbiotics beyond prebiotics' role in facilitating growth and engraftment of probiotics, by focusing on microbial metabolism as a vital mode of action thereof. Consequently, we discuss synbiotic compositions that enable the guided metabolism of dietary or co-formulated ingredients by specific microbes leading to target molecules with beneficial functions. A workflow to develop novel synbiotics is presented, including the selection of promising target metabolites (e.g. equol, urolithin A, spermidine, indole-3 derivatives), identification of suitable substrates and producer strains applying bioinformatic tools, gut models, and eventually human trials.In conclusion, we propose that discovering and enabling specific substrate-microbe interactions is a valuable strategy to rationally design synbiotics that could establish a new category of hybrid nutra-/pharmaceuticals.

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Dietary (poly)phenols have received great interest due to their potential role in the prevention and management of non-communicable diseases. In recent years, a high inter-individual variability in the biological response to (poly)phenols has been demonstrated, which could be related to the high variability in (poly)phenol gut microbial metabolism existing within individuals. An interplay between (poly)phenols and the gut microbiota exists, with (poly)phenols being metabolised by the gut microbiota and their metabolites modulating gut microbiota diversity and composition. A number of (poly)phenol metabolising phenotypes or metabotypes have been proposed, however, potential metabotypes for most (poly)phenols have not been investigated, and the relationship between metabotypes and human health remains ambiguous. This review presents updated knowledge on the reciprocal interaction between (poly)phenols and the gut microbiome, associated gut metabotypes, and subsequent impact on human health.

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Significance: Hydroxycinnamic acids (HCAs) are the main phenolic acids in the western diet. Harmonizing the available information on the absorption, distribution, metabolism, and excretion (ADME) of HCAs is fundamental to unraveling the compounds responsible for their health effects. This work systematically assessed pharmacokinetics, including urinary recovery, and bioavailability of HCAs and their metabolites, based on literature reports. Recent Advances: Forty-seven intervention studies with coffee, berries, herbs, cereals, tomato, orange, grape products, and pure compounds, as well as other sources yielding HCA metabolites, were included. Up to 105 HCA metabolites were collected, mainly acyl-quinic and C6-C3 cinnamic acids. C6-C3 cinnamic acids, such as caffeic and ferulic acid, reached the highest blood concentrations (maximum plasma concentration [Cmax] = 423 nM), with time to reach Cmax (Tmax) values ranging from 2.7 to 4.2 h. These compounds were excreted in urine in higher amounts than their phenylpropanoic acid derivatives (4% and 1% of intake, respectively), but both in a lower percentage than hydroxybenzene catabolites (11%). Data accounted for 16 and 18 main urinary and blood HCA metabolites, which were moderately bioavailable in humans (collectively 25%). Critical Issues: A relevant variability emerged. It was not possible to unequivocally assess the bioavailability of HCAs from each ingested source, and data from some plant based-foods were absent or inconsistent. Future Directions: A comprehensive study investigating the ADME of HCAs derived from their most important dietary sources is urgently required. Eight key metabolites were identified and reached interesting plasma Cmax concentrations and urinary recoveries, opening up new perspectives to evaluate their bioactivity at physiological concentrations. Antioxid. Redox Signal. 40, 510-541.

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Antecedentes y objetivos: La artritis reumatoide (AR) cursa generalmente con una afectación mayor en el miembro superior, pudiendo ocasionar dificultades en el desempeño de actividades en el día a día. El objetivo principal de este estudio fue establecer la relación entre la autoeficacia, la intensidad del dolor y la duración de los síntomas en pacientes con AR, y analizar cómo y en qué medida cada uno de ellos influye en la discapacidad funcional, así como, conocer el valor predictivo de la autoeficacia sobre las demás variables. Métodos: Estudio transversal con una muestra de 117 mujeres con AR. Las variables de evaluación empleadas fueron la escala visual analógica (EVA), el cuestionario QuickDASH y la escala española de autoeficacia en enfermedades reumáticas. Resultados: Los resultados muestran que el modelo más significativo para la función (R2=0,35) incluye la variable función y dolor, por lo que, sí hay relación existente entre la autoeficacia, la intensidad del dolor y la funcionalidad del miembro superior, así como la asociación de las puntuaciones obtenidas en la EVA, QuickDASH y la escala española de autoeficacia en enfermedades reumáticas para su evaluación. Discusión y conclusiones: Nuestros resultados, concuerdan con estudios previos donde se establece la posible relación entre la autoeficacia y la discapacidad funcional, así como la autoeficacia y su relación con funciones físicas, demostrando que un bajo nivel de autoeficacia implica una disminución de la funcionalidad, pero sin que ninguna variable sea más predictora que otra.(AU)

Background and objectives: Rheumatoid arthritis (RA) primarily affects the upper limbs and can cause disturbances in the performance of daily activities. The main objective of this study was to establish the relationship between self-efficacy, pain intensity, and duration of symptoms in patients with RA and analyse how each influences functional disability, and to determine the predictive value of self-efficacy over the other variables. Methods: Cross-sectional study with a sample of 117 women diagnosed with RA. The endpoints were the visual analogue scale (VAS), Quick-DASH questionnaire and the Spanish scale of self-efficacy in rheumatic diseases. Results: The most significant model for function (R2=0.35) includes function and pain, therefore, there is a relationship between self-efficacy, pain intensity, and upper limb functionality. Discussion and conclusions: Our results agree with previous studies where a relationship between self-efficacy and functional disability is established, as well as self-efficacy and its relationship with physical functions, demonstrating that a low level of self-efficacy implies a decrease in functionality; however, no variable is more predictive than another.(AU)

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Metabolic syndrome (MetS) is a growing global health problem. Evidence suggests that diets rich in phytochemical-containing herbs and spices can contribute to reducing the risk of chronic diseases. This review assesses the scope of evidence supporting the use of herbs and spices in the diet for the prevention or treatment of MetS and its associated health conditions. A search of the PubMed, Scopus and Google Scholar databases was carried out to assess the available clinical evidence for culinary doses of commonly used herbs and spices. Trials that were measuring health factors related to metabolic disorders in healthy individuals, or the health of individuals with MetS or associated diseases, were included. Out of a total of 1738 papers identified, there were 142 relevant studies on black pepper, chilli, cardamom, cinnamon, coriander, cumin, fennel, fenugreek, garlic, ginger, nigella seed, rosemary, sage and turmeric. No relevant research was found for cloves, mint, oregano, parsley or thyme. Cinnamon, fenugreek and ginger were the herbs/spices with the most published trials on them and that showed promise for glycaemic control. Cardamom appears to have potential to reduce inflammatory markers, and cinnamon, ginger and turmeric to reduce blood lipids. Patients with type 2 diabetes were the population most likely to be included in studies, but the preventative benefits of herbs/spices in healthy populations were also investigated, particularly for chilli, ginger and cinnamon. There is evidence for the beneficial effect of culinary doses of many common herbs/spices in the prevention and treatment of MetS and associated disorders.

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AIM: To investigate differences between gut microbiota diversity and composition of healthy pregnant women and women with pre-eclampsia (PE). METHODS AND RESULTS: This is a systematic review and meta-analysis of the literature, in which the terms "pre-eclampsia", "gastrointestinal microbiome" and "pregnant women" were used to search MEDLINE (PubMed), BVS (LILACS and others), Embase (Elsevier) and Cochrane Library, including observational studies and case-control that investigated changes in the gut microbiota during pregnancy. Six studies were included, with 479 pregnant women. A significantly lower gut microbiota alpha diversity measured as the Shannon index was found in pregnant women with PE in comparison with healthy controls (SMD: -0.47; 95 %IC: -0.77 to -0.18; P = 0.02; I2 = 0 %; three studies, 179 participants), while no significant differences were found in the relative abundance of Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria, despite significant differences reported in the individual studies. CONCLUSION: Pregnant women with PE have lower gut microbiome diversity, however, there is insufficient evidence to determine whether there are changes in gut microbiota composition. SIGNIFICANCE AND IMPACT OF THE STUDY: The gut microbiota can be a new treatment target to try to prevent changes in maternal bacterial proportions, aiming to reduce complications during pregnancy.

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Three years have passed since the outbreak of Coronavirus Disease 2019 (COVID-19) brought the world to standstill. In most countries, the restrictions have ended, and the immunity of the population has increased; however, the possibility of new dangerous variants emerging remains. Therefore, it is crucial to develop tools to study and forecast the dynamics of future pandemics. In this study, a generalized additive model (GAM) was developed to evaluate the impact of meteorological and environmental variables, along with pandemic-related restrictions, on the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Córdoba, Argentina. The results revealed that mean temperature and vegetation cover were the most significant predictors affecting SARS-CoV-2 cases, followed by government restriction phases, days of the week, and hours of sunlight. Although fine particulate matter (PM2.5) and NO2 were less related, they improved the model's predictive power, and a 1-day lag enhanced accuracy metrics. The models exhibited strong adjusted coefficients of determination (R2adj) but did not perform as well in terms of root-mean-square error (RMSE). This suggests that the number of cases may not be the primary variable for controlling the spread of the disease. Furthermore, the increase in positive cases related to policy interventions may indicate the presence of lockdown fatigue. This study highlights the potential of data science as a management tool for identifying crucial variables that influence epidemiological patterns and can be monitored to prevent an overload in the healthcare system.

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Background: Estimating (poly)phenol intake is challenging due to inadequate dietary assessment tools and limited food content data. Currently, a priori diet scores to characterise (poly)phenol-rich diets are lacking. This study aimed to develop a novel (poly)phenol-rich diet score (PPS) and explore its relationship with circulating (poly)phenol metabolites. Methods: A total of 543 healthy free-living participants aged 18-80 years completed a food frequency questionnaire (FFQ) (EPIC-Norfolk) and provided 24 h urine samples. The PPS was developed based on the relative intake (quintiles) of 20 selected (poly)phenol-rich food items abundant in the UK diet, including tea, coffee, red wine, whole grains, chocolate and cocoa products, berries, apples and juice, pears, grapes, plums, citrus fruits and juice, potatoes and carrots, onions, peppers, garlic, green vegetables, pulses, soy and soy products, nuts, and olive oil. Foods included in the PPS were chosen based on their (poly)phenol content, main sources of (poly)phenols, and consumption frequencies in the UK population. Associations between the PPS and urinary phenolic metabolites were investigated using linear models adjusting energy intake and multiple testing (FDR adjusted p < 0.05). Result: The total PPS ranged from 25 to 88, with a mean score of 54. A total of 51 individual urinary metabolites were significantly associated with the PPS, including 39 phenolic acids, 5 flavonoids, 3 lignans, 2 resveratrol and 2 other (poly)phenol metabolites. The total (poly)phenol intake derived from FFQs also showed a positive association with PPS (stdBeta 0.32, 95% CI (0.24, 0.40), p < 0.01). Significant positive associations were observed in 24 of 27 classes and subclasses of estimated (poly)phenol intake and PPS, with stdBeta values ranging from 0.12 (0.04, 0.20) for theaflavins/thearubigins to 0.43 (0.34, 0.51) for flavonols (p < 0.01). Conclusion: High adherence to the PPS diet is associated with (poly)phenol intake and urinary biomarkers, indicating the utility of the PPS to characterise diets rich in (poly)phenols at a population level.

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Consumption of animal-sourced food is an important factor in broadening the diet of early hominins, promoting brain and body growth, and increasing behavioural complexity. However, whether early hominins obtained animal food by scavenging or hunting large mammals remains debated. Sabre-toothed felids have been proposed to facilitate the expansion of early Homo out of Africa into Europe 1.4-0.8 Ma by creating a niche for scavengers in Eurasia as the carcasses abandoned by these felids still contained abundant edible resources. In contrast, it has been argued that the niche for a large scavenger was already occupied in Eurasia by the giant hyena, preventing hominins from utilising this resource. This study shows that sabre-toothed felids generated carcasses rich in edible resources and that hominins were capable of competing with giant hyenas for this resource. The simulation experiments showed that maintaining an optimum group size is essential for the success of the hominin scavenging strategy. Early hominins could outcompete giant hyenas only if they could successfully dispute carcasses with them. Thus, in the presence of a strong competitor, passive scavenging is essentially the same as confrontational scavenging.

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Increasing evidence suggests that dietary (poly)phenols and methylxanthines have neuroprotective effects; however, little is known about whether they can cross the blood-brain barrier (BBB) and exert direct effects on the brain. We investigated the presence of (poly)phenol and methylxanthine metabolites in plasma and cerebrospinal fluid (CSF) from 90 individuals at risk of dementia using liquid chromatography-mass spectrometry and predicted their mechanism of transport across the BBB using in silico modelling techniques. A total of 123 and 127 metabolites were detected in CSF and plasma, respectively. In silico analysis suggests that 5 of the 20 metabolites quantified in CSF can cross the BBB by passive diffusion, while at least 9 metabolites require the aid of cell transporters to cross the BBB. Our results showed that (poly)phenols and methylxanthines are bioavailable, can cross the BBB via passive diffusion or transport carriers, and can reach brain tissues to exert neuroprotective effects.

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The human body has evolved to remove xenobiotics through a multistep clearance process. Non-endogenous metabolites are converted through a series of phase I and different phase II enzymes into compounds with higher hydrophilicity. These compounds are important for diverse research fields such as toxicology, nutrition, biomarker discovery, doping control, and microbiome metabolism. One of the challenges in these research fields has been the investigation of the two major phase II modifications, sulfation and glucuronidation, and the corresponding unconjugated aglycon independently. We have now developed a new methodology utilizing an immobilized arylsulfatase and an immobilized ß-glucuronidase to magnetic beads for treatment of human urine samples. The enzyme activities remained the same compared to the enzyme in solution. The separate mass spectrometric investigation of each metabolite class in a single sample was successfully applied to obtain the dietary glucuronidation and sulfation profile of 116 compounds. Our new chemical biology strategy provides a new tool for the investigation of metabolites in biological samples with the potential for broad-scale application in metabolomics, nutrition, and microbiome studies.

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Berries are rich in (poly)phenols, and these compounds may be beneficial to human health. Estimating berry consumption through self-reported questionnaires has been challenging due to compliance issues and a lack of precision. Estimation via food-derived biomarkers in biofluids was proposed as a complementary alternative. We aimed to review and update the existing evidence on biomarkers of intake for six different types of berries. A systematic literature search was performed to update a previous systematic review on PubMed, Web of Science, and Scopus from January 2020 until December 2022. Out of 42 papers, only 18 studies were eligible. A multimetabolite panel is suggested for blueberry and cranberry intake. Proposed biomarkers for blueberries include hippuric acid and malvidin glycosides. For cranberries, suggested biomarkers are glycosides of peonidin and cyanidin together with sulfate and glucuronide conjugates of phenyl-γ-valerolactone derivatives. No new metabolite candidates have been found for raspberries, strawberries, blackcurrants, and blackberries. Further studies are encouraged to validate these multimetabolite panels for improving the estimation of berry consumption.

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