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Purpose There are increasing concerns about the intersection between NEET (not in education, employment, or training) status and youth mental ill-health and substance use. However, findings are inconsistent and differ across types of problems. This is the first systematic review and meta-analysis (PROSPERO-CRD42018087446) on the association between NEET status and youth mental health and substance use problems. Methods We searched Medline, EMBASE, Web of Science, ERIC, PsycINFO, and ProQuest Dissertations and Theses (1999–2020). Two reviewers extracted data and appraised study quality using a modified Newcastle–Ottawa Scale. We ran robust variance estimation random-effects models for associations between NEET and aggregate groups of mental ill-health and substance use measures; conventional random-effects models for associations with individual mental/substance use problems; and subgroup analyses to explore heterogeneity. Results We identified 24 studies from 6,120 references. NEET status was associated with aggregate groups of mental ill-health (OR 1.28, CI 1.06–1.54), substance use problems (OR 1.43, CI 1.08–1.89), and combined mental ill-health and substance use measures (OR 1.38, CI 1.15–1.64). Each disaggregated measure was associated with NEET status [mood (OR 1.43, CI 1.21–1.70), anxiety (OR 1.55, CI 1.07–2.24), behaviour problems (OR 1.49, CI 1.21–1.85), alcohol use (OR 1.28, CI 1.24–1.46), cannabis use (OR 1.62, CI 1.07–2.46), drug use (OR 1.99, CI 1.19–3.31), suicidality (OR 2.84, CI 2.04–3.95); and psychological distress (OR 1.10, CI 1.01–1.21)]. Longitudinal data indicated that aggregate measures of mental health problems and of mental health and substance use problems (combined) predicted being NEET later, while evidence for the inverse relationship was equivocal and sparse. Conclusion Our review provides evidence for meaningful, significant associations between youth mental health and substance use problems and being NEET. We, therefore, advocate for mental ill-health prevention and early intervention and integrating vocational supports in youth mental healthcare.

Cellular senescence is a heterogeneous process guided by genetic, epigenetic and environmental factors, characterizing many types of somatic cells. It has been suggested as an aging hallmark that is believed to contribute to aging and chronic diseases. Senescent cells (SC) exhibit a specific senescence-associated secretory phenotype (SASP), mainly characterized by the production of proinflammatory and matrix-degrading molecules. When SC accumulate, a chronic, systemic, low-grade inflammation, known as inflammaging, is induced. In turn, this chronic immune system activation results in reduced SC clearance thus establishing a vicious circle that fuels inflammaging. SC accumulation represents a causal factor for various age-related pathologies. Targeting of several aging hallmarks has been suggested as a strategy to ameliorate healthspan and possibly lifespan. Consequently, SC and SASP are viewed as potential therapeutic targets either through the selective killing of SC or the selective SASP blockage, through natural or synthetic compounds. These compounds are members of a family of agents called senotherapeutics divided into senolytics and senomorphics. Few of them are already in clinical trials, possibly representing a future treatment of age-related pathologies including diseases such as atherosclerosis, osteoarthritis, osteoporosis, cancer, diabetes, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, hepatic steatosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and age-related macular degeneration. In this review, we present the already identified senolytics and senomorphics focusing on their redox-sensitive properties. We describe the studies that revealed their effects on cellular senescence and enabled their nomination as novel anti-aging agents. We refer to the senolytics that are already in clinical trials and we present various adverse effects exhibited by senotherapeutics so far. Finally, we discuss aspects of the senotherapeutics that need improvement and we suggest the design of future senotherapeutics to target specific redox-regulated signaling pathways implicated either in the regulation of SASP or in the elimination of SC.

Background Coffee is one of the most consumed beverages worldwide due to its appreciated organoleptic characteristics and stimulant effects. It is known that coffee consumption can promote several health benefits. Neurodegenerative diseases are a well-known type of health conditions and a serious health problem, strongly related to the aging of world population. The effects of coffee and its compounds on these disorders have been extensively studied during last years, although there is still much to understand. Scope and approach Despite the great amount of research on this subject, review papers regarding the coffee beverage as a whole are limited. The aim of the present review is to assess the real impact of coffee intake on the onset, development and course of neurodegenerative disorders, through a literature review and a summary of the most relevant papers of the last 10 years. Key findings and conclusions Correlations have been found between coffee consumption and neuroprotective outcomes. Cognitive impairment, Parkinson's and Alzheimer's diseases are the most explored areas. Overall, the risk of developing such diseases seems to decrease with moderate to high coffee intake. The interactions between compounds, their relative amounts, and the changes during processing, demonstrated to influence the expected outcomes of neuroprotection. Recently, the step of storage has been investigated regarding modifications in composition, highlighting the importance of quality control within coffee industry and the need for further work. More investigation is still necessary, although coffee may be regarded at least as a complement in the treatment of neurodegenerative diseases.

Risk-benefit analysis of foods including a formal public health assessment followed by management and communication has been establishing itself as a scientific discipline during the past 15 years. Risk-Benefit Assessments (RBAs), integrating nutrition, toxicology and microbiology, have been increasingly conducted for a variety of foods and food components. Quantitative models in these assessments often use the Disability Adjusted Life Year (DALY) as a common health metric, as it allows for comparison of diverse health effects. Results are typically reported by population group to capture differences in health outcomes and target communication. Strengthening the links between a formal RBA, risk-benefit management decisions and dietary recommendations communicated to the public will improve transparency and potentially public health outcomes. In the coming years, sustainable food production and other factors in addition to public health might result in risk-benefit analysis becoming part of the broader food system analysis.

The objective of this survey was to estimate the prevalence, contamination level, and genetic diversity of Salmonella in selected raw, shelled tree nuts (Brazil nuts, cashews, hazelnuts, macadamia nuts, pecans, pine nuts, pistachios, and walnuts) at retail markets in the United States. A total of 3,374 samples of eight tree nuts were collected from different types of retail stores and markets nationwide between September 2015 and March 2017. These samples (375 g) were analyzed using a modified FDA's BAM Salmonella culture method. Of the 3,374 samples, 15 (0.44%) (95% confidence interval [CI] [0.25, 0.73]) were culturally confirmed as containing Salmonella; 17 isolates were obtained. Among these isolates, there were 11 serotypes. Salmonella was not detected in Brazil nuts (296), hazelnuts (487), pecans (510), pine nuts (500), and walnuts (498). Salmonella prevalence estimates in cashews (510), macadamia (278), and pistachios (295) were 0.20% (95% CI [

Purpose: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. Design: Case-control association analysis of metabolomics data. Participants: Five European cohorts consisting of 2267 AMD patients and 4266 control participants. Methods: Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. Metabolome–AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression. Main Outcome Measures: Metabolites associated with AMD. Results: We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high-density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. Conclusions: Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD.

Helping others is a key feature of human behavior. However, recent studies render this feature not uniquely human, and describe discoveries of prosocial behavior in non-human primates, other social mammals, and most recently in some bird species. Nevertheless, the cognitive underpinnings of this prosociality; i.e., whether animals take others’ need for help into account, often remain obscured. In this study, we take a first step in investigating prosociality in azure-winged magpies by presenting them with the opportunity to share highly desired food with their conspecifics i) in a situation in which these conspecifics had no such food, ii) in a situation in which they too had access to that highly desired food, and iii) in an open, base-line, situation where all had equal access to the same food and could move around freely. We find that azure-winged magpies regularly share high-value food items, preferably with, but not restricted to, members of the opposite sex. Most notably, we find that these birds, and specifically the females, seem to differentiate between whether others have food or do not have food, and subsequently cater to that lack. Begging calls by those without food seem to function as cues that elicit the food-sharing, but the response to that begging is condition-dependent. Moreover, analyses on a restricted dataset that excluded those events in which there was begging showed exactly the same patterns, raising the possibility that the azure-winged magpies might truly notice when others have access to fewer resources (even in the absence of vocal cues). This sharing behavior could indicate a high level of social awareness and prosociality that should be further investigated. Further studies are needed to establish the order of intentionality at play in this system, and whether azure-winged magpies might be able to attribute desire states to their conspecifics.

Blue Light Using Flavin (BLUF) domains are increasingly being adopted for use in optogenetic constructs. Despite this, much remains to be resolved on the mechanism of their activation. The advent of unnatural amino acid mutagenesis opens up a new toolbox for the study of protein structural dynamics. The tryptophan analogue, 7-aza-Trp (7AW) was incorporated in the BLUF domain of the Activation of Photopigment and pucA (AppA) photoreceptor in order to investigate the functional dynamics of the crucial W104 residue during photoactivation of the protein. The 7-aza modification to Trp makes selective excitation possible using 310 nm excitation and 380 nm emission, separating the signals of interest from other Trp and Tyr residues. We used Förster energy transfer (FRET) between 7AW and the flavin to estimate the distance between Trp and flavin in both the light- and dark-adapted states in solution. Nanosecond fluorescence anisotropy decay and picosecond fluorescence lifetime measurements for the flavin revealed a rather dynamic picture for the tryptophan residue. In the dark-adapted state, the major population of W104 is pointing away from the flavin and can move freely, in contrast to previous results reported in the literature. Upon blue-light excitation, the dominant tryptophan population is reorganized, moves closer to the flavin occupying a rigidly bound state participating in the hydrogen-bond network around the flavin molecule.

As the planarian research community expands, the need for an interoperable data organization framework for tool building has become increasingly apparent. Such software would streamline data annotation and enhance cross-platform and cross-species searchability. We created the Planarian Anatomy Ontology (PLANA), an extendable relational framework of defined Schmidtea mediterranea (Smed) anatomical terms used in the field. At publication, PLANA contains over 850 terms describing Smed anatomy from subcellular to system levels across all life cycle stages, in intact animals and regenerating body fragments. Terms from other anatomy ontologies were imported into PLANA to promote interoperability and comparative anatomy studies. To demonstrate the utility of PLANA as a tool for data curation, we created resources for planarian embryogenesis, including a staging series and molecular fate-mapping atlas, and the Planarian Anatomy Gene Expression database, which allows retrieval of a variety of published transcript/gene expression data associated with PLANA terms. As an open-source tool built using FAIR (findable, accessible, interoperable, reproducible) principles, our strategy for continued curation and versioning of PLANA also provides a platform for community-led growth and evolution of this resource., Summary: Description of the construction of an anatomy ontology tool for planaria with examples of its potential use to curate and mine data across multiple experimental platforms.

Introduction This study sought to characterize the initial presentation of hymenoptera venom allergic (HVA) patients and examine differences between patients with imported fire ant (IFA) and flying hymenoptera (FH) reactions. Methods A multi-year, observational, single-institution analysis of patients referred for evaluation of HVA was performed. Data was obtained via physician interview and chart review including baseline characteristics, comorbid conditions, medications, culprit stinging insect, reaction severity, treatments, emergency department (ED) interventions and specific IgE results. Results 175 patients were enrolled (mean age 28yrs ±14yrs; 44% males, 77/175). Of these, 21.7% (38/175) reacted to FH, 70.9% (124/175) to IFA and 7.4% (13/175) to both. There was no difference between FH and IFA patients when analyzing mean age, sex or likelihood to seek ED care. Asthma was similar in all groups and noted in 20.6% (36/175). The most common presentation was cutaneous plus another system and was similar in all groups; 114/175 (65%). ED treatments were similar in all groups and included epinephrine (32/150, 21%), antihistamines (141/155, 91%) and corticosteroids (67/148, 45.3%). Reaction severity correlated with likelihood of ED visit (p=0.0005), use of epinephrine (p=0.0002) and corticosteroid use (p=0.03). Patients presenting to the ED with anaphylaxis received epinephrine in 37% (27/73) of cases. Patients seen in ED whose venom allergy was confirmed was 68.3% (71/104), 91.5% of whom went on to initiate life-saving immunotherapy. Conclusions IFA and FH patients have many, now confirmed, similarities. The severity of HVA reactions correlated with ED visits, use of epinephrine and corticosteroids; however only 37% of patients with anaphylaxis received epinephrine.

The human commensal Staphylococcus aureus (SA) is a leading cause of skin/soft tissue and surgical-site infections, and bacteremia. Functional antibodies and T-cell-mediated immunity, particularly Th1/Th17 responses, are thought to mediate protection. Vaccine development may be hindered by modulation of vaccine-induced T cells by pathogen-activated immunoregulatory responses, e.g., via IL-10. We screened SA proteins for CD4+ T-cell-activating and IL-10/IL-17-inducing capacities using healthy donor-derived PBMCs. Responses were characterized (Th1/Th17/Th22/immunosuppressive IL-10-producing cells) using intracellular cytokine staining and flow cytometry. Phenotypic plasticity of Th1/Th17 cells was evaluated under pro- or anti-inflammatory conditions using modulatory cytokines. The impact of vaccination on SA-specific memory responses was assessed using samples from a clinical trial evaluating AS03-adjuvanted and non-adjuvanted multicomponent (CPS5/CPS8/α-toxin/ClfA) vaccines (NCT01160172). The donors exhibited SA-specific memory T-cell responses, indicative of pre-existing immunity to SA. We identified effective activators of Th1 responses (EbhA/IsaA/SdrE/MntC/Aaa/α-toxin), and Th17 and Th1/Th17 responses (EbhA/IsaA/SdrE and, to a lesser extent, α-toxin), but not of Th22 responses or IL-10 production. MRPII, IsdA, and ClfA were inefficient CD4+ T-cell activators in our assays. IL-10, likely produced by innate immune cells, influenced mainly Th1 cells by suppressing IFN-γ production. The memory CD4+ T-cells observed after long-term stimulation with α-toxin and ClfA indicated that vaccination with these proteins had induced expansion of pre-existing Th1 but not Th17 responses, without apparent adjuvant effect, confirming the trial data. The Th1/Th17-driving proteins (EbhA/IsaA/SdrE) shared low IL-10-promoting abilities and restricted phenotypic plasticity under pro- and anti-inflammatory conditions. Given the complex immunopathology and multiple virulence factors, identification of Th1/Th17-driving antigens, adjuvants and administration routes, and delineation of the role of memory responses, may advance vaccine development.

Electrical stimulation (ES) of the nervous system is a promising alternative for the treatment of refractory epilepsy. Based on the understanding that seizures are the expression of neural hypersynchronism, our group developed and tested a non-standard form of low-energy temporally unstructured ES termed NPS (Non-periodic stimulation), with pseudo-randomized inter-pulse intervals. Previous investigation demonstrated that NPS applied to the amygdala has a robust anticonvulsant effect against both acute and chronic seizures, and suggested that its therapeutic effect is based on direct desynchronization of ictogenic neural circuits. Further mechanistic investigation using functional magnetic resonance imaging has shown that NPS also activates nucleus accumbens (NAc) in seizure-free rats, raising the hypothesis of an alternative therapeutic mechanism: NPS-enhanced indirect inhibition / desynchronization of ictogenic circuits by NAc. In order to investigate this idea, here we evaluated behavior and cortical electrographic activity from animals submitted to pentylenetetrazole (PTZ) induced seizures, treated with NPS and with or without bilateral electrolytic lesion of NAc. NPS-treated animals with bilateral lesion of NAc expressed unexpected straub tail in addition to other stereotypical convulsive behavior, displayed increased susceptibility to PTZ (lower drug threshold), and had a much longer electrographic seizure, with a greater number of spikes, firing at a higher rate. Moreover, analysis of spike morphology showed an increase in amplitude and slope in these animals, suggesting that ablation of NAc results in disinhibition and/or increase of neural synchronism within ictogenic circuits. NPS had no therapeutic effect whatsoever in lesioned animals, while it displayed a mild anticonvulsant effect in those with intact brains. Results corroborate the notion that NAc has a key role in controlling aberrant epileptiform activity in ictogenic circuits through indirect polysynaptic connections that may enroll the ventral pallidum and ventral tegmental area. They also point to the possibility that NPS may enhance this effect, putatively by benefiting from the structure's property of detecting saliences.

PURPOSE: Genetic and epidemiologic studies have shown that lipid genes and High Density Lipoproteins (HDL) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relation to AMD in a large European dataset, and investigated whether this relationship is driven by certain sub fractions. DESIGN: (Pooled) analysis of cross-sectional data. PARTICIPANTS: 30,953 individuals aged 50+ participating in the E3 consortium; and 1530 individuals from the Rotterdam Study with lipid sub fraction data. METHODS: In E3, AMD features were graded per eye on fundus photographs using the Rotterdam Classification. Routine blood lipid measurements were available from each participant. Data on genetics, medication and confounders such as body mass index, were obtained from a common database. In a subgroup of the Rotterdam Study, lipid sub fractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random-effect were used to estimate the associations. MAIN OUTCOME MEASURES: early, late or any AMD, phenotypic features of early AMD, lipid measurements. RESULTS: HDL was associated with an increased risk of AMD, corrected for potential confounders (Odds Ratio (OR) 1.21 per 1mmol/L increase (95% confidence interval[CI] 1.14-1.29); while triglycerides were associated with a decreased risk (OR 0.94 per 1mmol/L increase [95%CI 0.91-0.97]). Both were associated with drusen size, higher HDL raises the odds of larger drusen while higher triglycerides decreases the odds. LDL-cholesterol only reached statistical significance in the association with early AMD (p=0.045). Regarding lipid sub fractions: the concentration of extra-large HDL particles showed the most prominent association with AMD (OR 1.24 [95%CI 1.10-1.40]). The CETP risk variant (rs17231506) for AMD was in line with increased-HDL levels (p=7.7x10-7); but LIPC risk variants (rs2043085, rs2070895) were associated in an opposite way (p=1.0x10-6 and 1.6x10-4). CONCLUSIONS: Our study suggests that HDL-cholesterol is associated with increased risk of AMD and triglycerides negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL sub fractions seem to be drivers in the relation with AMD, variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains a question to be answered.

BackgroundThere is general consensus that consumption of dietary fermentable fiber improves cardiometabolic health, in part by promoting mutualistic microbes and by increasing production of beneficial metabolites in the distal gut. However, human studies have reported variations in the observed benefits among individuals consuming the same fiber. Several factors likely contribute to this variation, including host genetic and gut microbial differences. We hypothesized that gut microbial metabolism of dietary fiber represents an important and differential factor that modulates how dietary fiber impacts the host.ResultsWe examined genetically identical gnotobiotic mice harboring two distinct complex gut microbial communities and exposed to four isocaloric diets, each containing different fibers: (i) cellulose, (ii) inulin, (iii) pectin, (iv) a mix of 5 fermentable fibers (assorted fiber). Gut microbiome analysis showed that each transplanted community preserved a core of common taxa across diets that differentiated it from the other community, but there were variations in richness and bacterial taxa abundance within each community among the different diet treatments. Host epigenetic, transcriptional, and metabolomic analyses revealed diet-directed differences between animals colonized with the two communities, including variation in amino acids and lipid pathways that were associated with divergent health outcomes.ConclusionThis study demonstrates that interindividual variation in the gut microbiome is causally linked to differential effects of dietary fiber on host metabolic phenotypes and suggests that a one-fits-all fiber supplementation approach to promote health is unlikely to elicit consistent effects across individuals. Overall, the presented results underscore the importance of microbe-diet interactions on host metabolism and suggest that gut microbes modulate dietary fiber efficacy.

Introduction Falls are the leading cause of injury-related death among older adults according to the Centers for Disease Control and Prevention (CDC). The Falls Efficacy Scale (FES) and Vulnerable Elder Survey (VES-13) are validated screening tools used to assess concern of falling, health deterioration and functional decline. We set out to determine if the FES or VES-13 could serve as a predictor of falls among older adults in the Emergency Department (ED) setting. Methods This prospective pilot cohort study was conducted at a Level 1 Trauma Center. ED patients aged ≥65 were eligible for the study if they had a mechanical fall risk defined by CDC criteria. After consent and enrollment, FES and the VES surveys were completed. Participants were followed by phone quarterly, and results of the one-year follow-up self-report of fall history described. Results There were 200 subjects enrolled and after excluding those that were withdrawn, deceased, or lost to follow-up, 184 were available for analysis of their follow-up visit at 12 months. A greater proportion of the participants were women (108 (58.7%) vs 76 (41.3%); P=0.88). The average age of the study participants was 74.2±7.3 years. There was no significant difference in age between men and women (median: 73 vs 73; p=0.47). At the follow-up visit, 33 (17.9%) had a reported fall. The mean age did not significantly differ when comparing those with versus without a fall (75.6 vs 73.9; p=0.24). There was no significant difference in the proportion with a VES-13 ≥ 3 when comparing those with and without a reported fall (45.5% vs 37.8%; p = 0.41). The median FES score did not differ among those with as compared to without a fall (11 vs 10; p=0.12). Conclusions Subjects who had a VES-13 score of ≥3 were statistically no more likely to have fallen than those with a score of

Overweight and obesity in childhood and adolescence represent major public health problems of our century, and account for increased morbidity and mortality in adult life. Irisin and Fibroblast Growth Factor 21 (FGF-21) have been proposed as prognostic and/or diagnostic biomarkers in subjects with obesity and metabolic syndrome, because they increase earlier than other traditional biomarkers. We determined the concentrations of Irisin and FGF-21 in children and adolescents with overweight and obesity before and after one year of a life-style intervention program of diet and physical exercise and explored the impact of body mass index (BMI) reduction on the concentrations of Irisin, FGF-21 and other cardiometabolic risk factors. Three hundred and ten (n = 310) children and adolescents (mean age ± SD: 10.5 ± 2.9 years) were studied prospectively. Following one year of the life-style intervention program, there was a significant decrease in BMI (p = 0.001), waist-to-hip ratio (p = 0.024), waist-to-height ratio (p = 0.024), and Irisin concentrations (p = 0.001), and an improvement in cardiometabolic risk factors. There was no alteration in FGF-21 concentrations. These findings indicate that Irisin concentrations decreased significantly as a result of BMI reduction in children and adolescents with overweight and obesity. Further studies are required to investigate the potential role of Irisin as a biomarker for monitoring the response to lifestyle interventions and for predicting the development of cardiometabolic risk factors.

Caffeic and dihydrocaffeic acid are relevant microbial catabolites, being described as products from the degradation of different phenolic compounds i.e., hydroxycinnamoyl derivatives, anthocyanins or flavonols. Furthermore, caffeic acid is found both in free and esterified forms in many fruits and in high concentrations in coffee. These phenolic acids may be responsible for a part of the bioactivity associated with the intake of phenolic compounds. With the aim of progressing in the knowledge of the health effects and mechanisms of action of dietary phenolics, the model nematode Caenorhabditis elegans has been used to evaluate the influence of caffeic and dihydrocaffeic acids on lifespan and the oxidative stress resistance. The involvement of different genes and transcription factors related to longevity and stress resistance in the response to these phenolic acids has also been explored. Caffeic acid (CA, 200 μM) and dihydrocaffeic acid (DHCA, 300 μM) induced an increase in the survival rate of C. elegans under thermal stress. Both compounds also increased the mean and maximum lifespan of the nematode, compared to untreated worms. In general, treatment with these acids led to a reduction in intracellular ROS concentrations, although not always significant. Results of gene expression studies conducted by RT-qPCR showed that the favorable effects of CA and DHCA on oxidative stress and longevity involve the activation of several genes related to insulin/IGF-1 pathway, such as daf-16, daf-18, hsf-1 and sod-3, as well as a sirtuin gene (sir-2.1).

This work aimed to evaluate the potential of chitosan/cellulose nanocrystals (CNC) films to be used as active pads for meat packages to prolong its shelf-life and preserve its properties over time. Several CNC concentrations (5, 10, 25, and 50wt%) were tested and the films were produced by solvent casting. The developed samples were characterized by ATR-FTIR, TGA, FESEM, and XRD. The transparency, antimicrobial, barrier and mechanical properties were also assessed. Finally, the films' ability to prolong food shelf-life was studied in real conditions using chicken meat. CNC incorporation improved the thermal stability and the oxygen barrier while the water vapor permeability was maintained. An enhancement of mechanical properties was also observed by the increase in tensile strength and Young's modulus in chitosan/CNC films. These films demonstrated bactericidal effect against Gram-positive and Gram-negative bacteria and fungicidal activity against Candida albicans. Lastly, chitosan-based films decreased the growth of Pseudomonas and Enterobacteriaceae bacteria in meat during the first days of storage compared to commercial membranes, while chitosan/CNC films reduced the total volatile basic nitrogen (TVB-N), indicating their efficiency in retarding meat's spoilage under refrigeration conditions. This work highlights the great potential of natural-based films to act as green alternatives for food preservation., The authors are thankful to project UID/CTM/00264/2019 of 2C2T - Centro de Ciencia e Tecnologia Textil, funded by National Founds through FCT/MCTES-Fundacao para a Ciencia e a Tecnologia. Sofia M. Costa is thankful to FCT PhD Scholarship (SFRH/BD/147517/2019). Diana Ferreira is thankful to CEECIND/02803/2017. The authors are also thankful for the financial support of the Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit and BioTecNorte operation (NORTE-010145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 -Programa Operacional Regional do Norte., info:eu-repo/semantics/publishedVersion

Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

SARS-CoV-2 is a novel virus with many unknowns. No vaccine or specific therapy is available yet to prevent and treat this deadly virus., SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as the primary receptor to enter host cells and initiate the infection. The critical binding region of ACE2 is an ∼30-amino-acid (aa)-long helix. Here, we report the design of four stapled peptides based on the ACE2 helix, which is expected to bind to SARS-CoV-2 and prevent the binding of the virus to the ACE2 receptor and disrupt the infection. All stapled peptides showed high helical contents (50 to 94% helicity). In contrast, the linear control peptide NYBSP-C showed no helicity (19%). We have evaluated the peptides in a pseudovirus-based single-cycle assay in HT1080/ACE2 cells and human lung cell line A549/ACE2, overexpressing ACE2. Three of the four stapled peptides showed potent antiviral activity in HT1080/ACE2 (50% inhibitory concentration [IC50]: 1.9 to 4.1 μM) and A549/ACE2 (IC50: 2.2 to 2.8 μM) cells. The linear peptide NYBSP-C and the double-stapled peptide StRIP16, used as controls, showed no antiviral activity. Most significantly, none of the stapled peptides show any cytotoxicity at the highest dose tested. We also evaluated the antiviral activity of the peptides by infecting Vero E6 cells with the replication-competent authentic SARS-CoV-2 (US_WA-1/2020). NYBSP-1 was the most efficient, preventing the complete formation of cytopathic effects (CPEs) at an IC100 of 17.2 μM. NYBSP-2 and NYBSP-4 also prevented the formation of the virus-induced CPE with an IC100 of about 33 μM. We determined the proteolytic stability of one of the most active stapled peptides, NYBSP-4, in human plasma, which showed a half-life (T1/2) of >289 min.

Significance Transposable elements (TEs) represent the largest component of the genomes of higher eukaryotes. Among this component are some TEs that have attained very high copy numbers, with hundreds, even thousands, of elements. By documenting the spread of mPing elements throughout the genomes of a rice population, we demonstrate that such bursts of amplification generate functionally relevant genomic variations upon which selection can act. Specifically, continued mPing amplification increases the number of tightly linked elements that, in turn, increases the frequency of structural variations that appear to be derived from aberrant transposition events. The significance of this finding is that it provides a TE-mediated mechanism that may generate much of the structural variation represented by pan-genomes in plants and other organisms., Genomes of all characterized higher eukaryotes harbor examples of transposable element (TE) bursts—the rapid amplification of TE copies throughout a genome. Despite their prevalence, understanding how bursts diversify genomes requires the characterization of actively transposing TEs before insertion sites and structural rearrangements have been obscured by selection acting over evolutionary time. In this study, rice recombinant inbred lines (RILs), generated by crossing a bursting accession and the reference Nipponbare accession, were exploited to characterize the spread of the very active Ping/mPing family through a small population and the resulting impact on genome diversity. Comparative sequence analysis of 272 individuals led to the identification of over 14,000 new insertions of the mPing miniature inverted-repeat transposable element (MITE), with no evidence for silencing of the transposase-encoding Ping element. In addition to new insertions, Ping-encoded transposase was found to preferentially catalyze the excision of mPing loci tightly linked to a second mPing insertion. Similarly, structural variations, including deletion of rice exons or regulatory regions, were enriched for those with break points at one or both ends of linked mPing elements. Taken together, these results indicate that structural variations are generated during a TE burst as transposase catalyzes both the high copy numbers needed to distribute linked elements throughout the genome and the DNA cuts at the TE ends known to dramatically increase the frequency of recombination.

The Expanded Program for Immunization Consortium – Human Immunology Project Consortium study aims to employ systems biology to identify and characterize vaccine-induced biomarkers that predict immunogenicity in newborns. Key to this effort is the establishment of the Data Management Core (DMC) to provide reliable data and bioinformatic infrastructure for centralized curation, storage, and analysis of multiple de-identified “omic” datasets. The DMC established a cloud-based architecture using Amazon Web Services to track, store, and share data according to National Institutes of Health standards. The DMC tracks biological samples during collection, shipping, and processing while capturing sample metadata and associated clinical data. Multi-omic datasets are stored in access-controlled Amazon Simple Storage Service (S3) for data security and file version control. All data undergo quality control processes at the generating site followed by DMC validation for quality assurance. The DMC maintains a controlled computing environment for data analysis and integration. Upon publication, the DMC deposits finalized datasets to public repositories. The DMC architecture provides resources and scientific expertise to accelerate translational discovery. Robust operations allow rapid sharing of results across the project team. Maintenance of data quality standards and public data deposition will further benefit the scientific community.

Contains fulltext : 245098.pdf (Publisher’s version ) (Closed access) PURPOSE: Current prediction models for advanced age-related macular degeneration (AMD) are based on a restrictive set of risk factors. The objective of this study was to develop a comprehensive prediction model applying a machine learning algorithm allowing selection of the most predictive risk factors automatically. DESIGN: Two population-based cohort studies. PARTICIPANTS: The Rotterdam Study I (RS-I; training set) included 3838 participants 55 years of age or older, with a median follow-up period of 10.8 years, and 108 incident cases of advanced AMD. The Antioxydants, Lipids Essentiels, Nutrition et Maladies Oculaires (ALIENOR) study (test set) included 362 participants 73 years of age or older, with a median follow-up period of 6.5 years, and 33 incident cases of advanced AMD. METHODS: The prediction model used the bootstrap least absolute shrinkage and selection operator (LASSO) method for survival analysis to select the best predictors of incident advanced AMD in the training set. Predictive performance of the model was assessed using the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Incident advanced AMD (atrophic, neovascular, or both), based on standardized interpretation of retinal photographs. RESULTS: The prediction model retained (1) age, (2) a combination of phenotypic predictors (based on the presence of intermediate drusen, hyperpigmentation in one or both eyes, and Age-Related Eye Disease Study simplified score), (3) a summary genetic risk score based on 49 single nucleotide polymorphisms, (4) smoking, (5) diet quality, (6) education, and (7) pulse pressure. The cross-validated AUC estimation in RS-I was 0.92 (95% confidence interval [CI], 0.88-0.97) at 5 years, 0.92 (95% CI, 0.90-0.95) at 10 years, and 0.91 (95% CI, 0.88-0.94) at 15 years. In ALIENOR, the AUC reached 0.92 at 5 years (95% CI, 0.87-0.98). In terms of calibration, the model tended to underestimate the cumulative incidence of advanced AMD for the high-risk groups, especially in ALIENOR. CONCLUSIONS: This prediction model reached high discrimination abilities, paving the way toward making precision medicine for AMD patients a reality in the near future.

We evaluated associations of smoking heaviness markers and the effects of smoking cessation on the intestinal microbiota and cardiovascular disease risk factors in current smokers undertaking a quit attempt. Participants were current smokers enrolled in a prospective randomized clinical trial of smoking cessation therapies with visits at baseline, 2, and 12 weeks. Genomic DNA was extracted from fecal samples followed by 16S rRNA gene sequencing and analysis using the QIIME2 software workflow. Relative abundances of bacterial taxa and alpha- and beta-diversity measures were used for comparisons. The 36 smokers were (mean (standard deviation)) 51.5 (11.1) years old (42% male) and smoked 15.1 (6.4) cigarettes per day for 22.7 (11.9) pack-years. Relative abundances of the phylum Actinobacteria correlated with pack-years (rho = &minus, 0.44, p = 0.008) and Cyanobacteria correlated with CO levels (rho = 0.39, p = 0.021). After 12 weeks, relative abundances of the phylum Bacteroidetes increased (pANCOVA = 0.048) and Firmicutes decreased (pANCOVA = 0.036) among abstainers compared to continuing smokers. Increases in alpha-diversity were associated with heart rates (rho = &minus, 0.59, p = 0.037), systolic blood pressures (rho = &minus, 0.58, p = 0.043), and C-reactive protein (rho = &minus, 0.60, p = 0.034). Smoking cessation led to minor changes in the intestinal microbiota. It is unclear if the proven health benefits of smoking cessation lead to salutary changes in the intestinal microbiota.

Combination antiretroviral therapy (cART) is successful in maintaining undetectable levels of HIV in the blood, however, the persistence of latent HIV reservoirs has become the major barrier for a HIV cure. Substantial efforts are underway in finding the best latency-reversing agents (LRAs) to purge the latent viruses from the reservoirs. We hypothesize that identifying the right combination of LRAs will be the key to accomplishing that goal. In this study, we evaluated the effect of combinations of three protein kinase C activators (prostratin, (-)-indolactam V, and TPPB) with four histone deacetylase inhibitors (AR-42, PCI-24781, givinostat, and belinostat) on reversing HIV latency in different cell lines including in a primary CD4+ T-cell model. Combinations including indolactam and TPPB with AR-42 and PCI produced a strong synergistic effect in reactivating latent virus as indicated by higher p24 production and envelope gp120 expression. Furthermore, treatment with TPPB and indolactam greatly downregulated the cellular receptor CD4. Indolactam/AR-42 combination emerged from this study as the best combination that showed a strong synergistic effect in reactivating latent virus. Although AR-42 alone did not downregulate CD4 expression, indolactam/AR-42 showed the most efficient downregulation. Our results suggest that indolactam/AR-42 is the most effective combination, showing a strong synergistic effect in reversing HIV latency combined with the most efficient CD4 downregulation.

SUMMARYLoss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause Neuronal Ceroid Lipofuscinosis type 1 (CLN1), a devastating neurodegenerative disease. Here, we provide a resource identifying PPT1 substrates. We utilized Acyl Resin-Assisted Capture and mass spectrometry to identify proteins with increased in vivo palmitoylation in PPT1 knockout mouse brains. We then validated putative substrates through direct depalmitoylation with recombinant PPT1. This stringent screen elucidated >100 novel PPT1 substrates at the synapse, including channels and transporters, G-protein-associated molecules, endo/exocytic components, synaptic adhesion molecules, and mitochondrial proteins. Cysteine depalmitoylation sites in transmembrane PPT1 substrates frequently participate in disulfide bonds in the mature protein. We confirmed that depalmitoylation regulates disulfide bond formation in a tertiary screen analyzing post-translational modifications. Collectively, the diverse PPT1 substrates highlight the role of PPT1 in mediating synapse functions, implicate molecular pathways in the etiology of CLN1, and advance our basic understanding of the purpose of depalmitoylation.Highlights∼10% of palmitoylated proteins are palmitoyl protein thioesterase 1 (PPT1) substratesUnbiased proteomic approaches identify 9 distinct classes of PPT1 substrates, including synaptic adhesion molecules and endocytic proteinsProtein degradation does not require depalmitoylation by PPT1Depalmitoylation mediates disulfide bond formation in transmembrane PPT1 substrates

BACKGROUND: Change in bowel habit as a sole alarm symptom for colorectal cancer is disputed. OBJECTIVE: We investigated the diagnostic value of change in bowel habit for colorectal cancer, particularly as a single symptom and within different age groups. METHODS: This retrospective cohort study examined colorectal cancer fast track referrals and outcomes across four Swedish hospitals (April 2016–May 2017). Entry criteria constituted one or more of three alarm features: anaemia, visible rectal bleeding, or change in bowel habit for more than 4 weeks in patients over 40 years of age. Patients were grouped as having only change in bowel habit, change in bowel habit plus anaemia/bleeding or anaemia/bleeding only. RESULTS: Of 628 patients, 22% were diagnosed with colorectal cancer. There were no cases of colorectal cancer in the only change in bowel habit group under 55 years, while this was 6% for 55–64 years, 8% for 65–74 years and 14% for 75 years and older. Among subjects under 55 years, 2% with anaemia/bleeding had colorectal cancer, this increased to 34% for 55 years and older (P

Phylogenomic approaches have the potential to improve confidence about the inter-relationships of species in the order Mucorales within the fungal tree of life. Rhizopus species are especially important as plant and animal pathogens and bioindustrial fermenters for food and metabolite production. A dataset of 192 orthologous genes was used to construct a phylogenetic tree of 21 Rhizopus strains, classified into four species isolated from habitats of industrial, medical and environmental importance. The phylogeny indicates that the genus Rhizopus consists of three major clades, with R. microsporus as the basal species and the sister lineage to R. stolonifer and two closely related species R. arrhizus and R. delemar. A comparative analysis of the mating type locus across Rhizopus reveals that its structure is flexible even between different species in the same genus, but shows similarities between Rhizopus and other mucoralean fungi. The topology of single-gene phylogenies built for two genes involved in mating is similar to the phylogenomic tree. Comparison of the total length of the genome assemblies showed that genome size varies by as much as threefold within a species and is driven by changes in transposable element copy numbers and genome duplications.

Leucocyte telomere length (LTL) is a robust marker of biological aging and is associated with obesity and cardiometabolic risk factors in childhood and adolescence. We investigated the effect of a structured, comprehensive, multidisciplinary, personalized, lifestyle intervention program of healthy diet and physical exercise on LTL in 508 children and adolescents (239 males, 269 females, 282 prepubertal, 226 pubertal), aged 10.14 ± 0.13 years. Participants were classified as obese (n = 267, 52.6%), overweight (n = 174, 34.2%), or of normal BMI (n = 67, 13.2%) according to the International Obesity Task Force (IOTF) cutoff points and were studied prospectively for one year. We demonstrated that LTL increased significantly after 1 year of the lifestyle interventions, irrespective of gender, pubertal status, or body mass index (BMI). Waist circumference was the best negative predictor of LTL at initial assessment. The implementation of the lifestyle interventions also resulted in a significant improvement in clinical (BMI, BMI z-score and waist to height ratio) and body composition indices of obesity, inflammatory markers, hepatic enzymes, glycated hemoglobin (HbA1C), quantitative insulin sensitivity check index (QUICKI), and lipid profile in all participants. These findings indicate that the increased LTL may be associated with a more favorable metabolic profile and decreased morbidity later in life.

Leafcutter ants propagate co-evolving fungi for food. The nearly 50 species of leafcutter ants (Atta, Acromyrmex) range from Argentina to the United States, with the greatest species diversity in southern South America. We elucidate the biogeography of fungi cultivated by leafcutter ants using DNA sequence and microsatellite-marker analyses of 474 cultivars collected across the leafcutter range. Fungal cultivars belong to two clades (Clade-A and Clade-B). The dominant and widespread Clade-A cultivars form three genotype clusters, with their relative prevalence corresponding to southern South America, northern South America, Central and North America. Admixture between Clade-A populations supports genetic exchange within a single species, Leucocoprinus gongylophorus. Some leafcutter species that cut grass as fungicultural substrate are specialized to cultivate Clade-B fungi, whereas leafcutters preferring dicot plants appear specialized on Clade-A fungi. Cultivar sharing between sympatric leafcutter species occurs frequently such that cultivars of Atta are not distinct from those of Acromyrmex. Leafcutters specialized on Clade-B fungi occur only in South America. Diversity of Clade-A fungi is greatest in South America, but minimal in Central and North America. Maximum cultivar diversity in South America is predicted by the Kusnezov-Fowler hypothesis that leafcutter ants originated in subtropical South America and only dicot-specialized leafcutter ants migrated out of South America, but the cultivar diversity becomes also compatible with a recently proposed hypothesis of a Central American origin by postulating that leafcutter ants acquired novel cultivars many times from other nonleafcutter fungus-growing ants during their migrations from Central America across South America. We evaluate these biogeographic hypotheses in the light of estimated dates for the origins of leafcutter ants and their cultivars.

A quantitative risk assessment was conducted to assess the risk of human salmonellosis acquired from consumption of pecans in the United States. The model considered the potential for Salmonella survival, growth, and recontamination of pecans from the sheller to the consumer, including steps such as immersion in water, drying, conditioning, cracking, partitioning, and storage. Five theoretical microbial reduction treatment levels (1 to 5 log CFU) were modeled. Data from the 2010 to 2013 surveys by the National Pecan Shellers Association were used for initial prevalence and contamination levels. The impacts of atypical situations in the pecan production system were also evaluated. Higher initial contamination levels, recontamination during processing, and a delay in drying postconditioning were the modeled atypical situations. The baseline model predicted a mean risk of salmonellosis in the United States from consumption of in-shell and shelled pecans processed by cold conditioning with no microbial reduction treatment and no further home cooking as 1 case per 775,193 servings (95% confidence interval [CI]: 1 case per 1,915,709 to 178,253 servings). This predicted risk per serving was estimated as a mean of 529 cases of salmonellosis per year (95% CI: 213 to 2,295 cases). Hot conditioning for shelled pecans and microbial reduction treatment of both shelled and in-shell pecans had a significant impact on the predicted mean risk of illness. Assuming 77% of the shelled pecans sold at retail (i.e., 80% of the retail supply) received hot conditioning, the mean estimated salmonellosis cases per year from consumption of in-shell and shelled pecans uncooked at home was 203 (95% CI: 81 to 882 cases) if no additional microbial reduction treatment were applied. The predicted risk of illness per serving was higher for all atypical situations modeled compared with the baseline model, and delay in drying had the greatest impact on risk.

In this work a novel bioprocess for hydrogenation of CO2 to formate was developed, using whole cell catalysis by a sulfate-reducing bacterium. Three Desulfovibrio species were tested (D. vulgaris Hildenborough, D. alaskensis G20, and D. desulfuricans ATCC 27774), of which D. desulfuricans showed the highest activity, producing 12mM of formate in batch, with a production rate of 0.09mMh-1. Gene expression analysis indicated that among the three formate dehydrogenases and five hydrogenases, the cytoplasmic FdhAB and the periplasmic [FeFe] HydAB are the main enzymes expressed in D. desulfuricans in these conditions. The new bioprocess for continuous formate production by D. desulfuricans had a maximum specific formate production rate of 14mMgdcw-1h-1, and more than 45mM of formate were obtained with a production rate of 0.40mMh-1. This is the first report of a continuous process for biocatalytic formate production.

© The Author 2017. Background: The ventral subiculum is known to be activated by the presentation of novel stressors. It has been hypothesized that neuronal ensembles at the ventral aspect of the hippocampal formation are involved in context-dependent processing and can guide the learning of appropriate action selections in response to threatening contexts. Artificial activation of the ventral subiculum can excite medium spiny neurons of the nucleus accumbens and can increase the excitability of mesolimbic dopamine neurons via a polysynaptic pathway through the basal ganglia. However, it remains unknown whether this circuit can be activated by aversive experience, and if so, whether ventral subiculum engages nucleus accumbens monosynaptically. Methods: To address this, the retrograde tracer fluorogold was used in rats to label neurons projecting to the caudomedial nucleus accumbens. One to 2 weeks later, the same rats were exposed to psychogenic stress (i.e., acute restraint in a novel test room) or served as nonhandled controls, followed by dual immunocytochemical localization of retrogradely transported tracer and nuclear Fos. Results: Compared with controls, rats exposed to psychogenic stress displayed more fluorogold-positive ventral subiculum neurons that were double-labeled for Fos. Conclusion: This study establishes that the direct pathway from ventral subiculum to the caudomedial nucleus accumbens is activated by stressful experience.

Regeneration has long fascinated humanity, and its documentation has progressed from simple descriptive observations to the intense molecular and cellular investigations of today. The overarching goal of this work is to make the key methods and tools being used in modern regeneration and stem cell biology research accessible to docents and students in the classroom. We have designed a series of experimental activities with accompanying protocols using four inexpensive, commercially available planarian species indigenous to North America: Girardia sp., Dugesia dorotocephala, Phagocata morgani, and Phagocata gracilis. These planarians are fast and robust regenerators, and can easily be maintained in the classroom. The activities presented here can be used to guide students through hypothesis-driven experiments, and range from simple manipulations aimed at high school students (e.g., planarian husbandry, feeding, and cutting experiments) to gene expression and protein function analyses suitable for college students. Regeneration time courses, the more complex whole worm in situ hybridizations, and RNA interference for gene knock-down experiments are described for each of the four species. Cumulatively, the suggested methods and experiments will facilitate the exploration of animal regeneration biology and promote curiosity-driven, hands-on application of the scientific method.

Nuts have been identified as a vector for salmonellosis. The objective of this project was to estimate the prevalence and contamination level of Salmonella in raw tree nuts (cashews, pecans, hazelnuts, macadamia nuts, pine nuts, and walnuts) at retail markets in the United States. A total of 3,656 samples of six types of tree nuts were collected from different types of retail stores and markets nationwide between October 2014 and October 2015. These samples were analyzed using a modified version of the Salmonella culture method from the U.S. Food and Drug Administration's Bacteriological Analytical Manual. Of the 3,656 samples collected and tested, 32 were culturally confirmed as containing Salmonella. These isolates represented 25 serotypes. Salmonella was not detected in pecans and in-shell hazelnuts. Salmonella prevalence estimates (and 95% confidence intervals) in cashews, shelled hazelnuts, pine nuts, walnuts, and macadamia nuts were 0.55% [0.15, 1.40], 0.35% [0.04, 1.20], 0.48% [0.10, 1.40], 1.20% [0.53, 2.40], and 4.20% [2.40, 6.90], respectively. The rates of Salmonella isolation from major or big chain supermarkets, small chain supermarkets, discount, variety, or drug stores, and online were 0.64% [0.38, 1.00], 1.60% [0.80, 2.90], 0.00% [0.00, 2.40], and 13.64% [2.90, 35.00], respectively (Cochran-Mantel-Haenszel test: P = 0.02). The rates of Salmonella isolation for conventional and organic nuts were not significantly different. Of the samples containing Salmonella, 60.7% had levels less than 0.003 most probable number (MPN)/g. The highest contamination level observed was 0.092 MPN/g. The prevalence and levels of Salmonella in these tree nut samples were comparable to those previously reported for similar foods.

© 2020 by the authors., Cancer is one of the highest prevalent diseases in humans. The chances of surviving cancer and its prognosis are very dependent on the affected tissue, body location, and stage at which the disease is diagnosed. Researchers and pharmaceutical companies worldwide are pursuing many attempts to look for compounds to treat this malignancy. Most of the current strategies to fight cancer implicate the use of compounds acting on DNA damage checkpoints, non-receptor tyrosine kinases activities, regulators of the hedgehog signaling pathways, and metabolic adaptations placed in cancer. In the last decade, the finding of a lipid peroxidation increase linked to 15-lipoxygenases isoform 1 (15-LOX-1) activity stimulation has been found in specific successful treatments against cancer. This discovery contrasts with the production of other lipid oxidation signatures generated by stimulation of other lipoxygenases such as 5-LOX and 12-LOX, and cyclooxygenase (COX-2) activities, which have been suggested as cancer biomarkers and which inhibitors present anti-tumoral and antiproliferative activities. These findings support the previously proposed role of lipid hydroperoxides and their metabolites as cancer cell mediators. Depletion or promotion of lipid peroxidation is generally related to a specific production source associated with a cancer stage or tissue in which cancer originates. This review highlights the potential therapeutical use of chemical derivatives to stimulate or block specific cellular routes to generate lipid hydroperoxides to treat this disease., This research was funded by Ministerio de Ciencia e Innovación grant number RTI2018-093864-B-I00 and the European Union’s Horizon 2020 Research and Innovation Programme MSCA GA 721236-TREATMENT.

Background Depression is associated with an increased risk of type 2 diabetes. This study aimed to determine whether the association between depression and incident type 2 diabetes differs by measure of depression. Methods Data sources included MEDLINE, EMBASE, PsycINFO, CINAHL, ProQuest Dissertations & Theses Global, Web of Science Emerging Sources Citation Index and Conference Proceedings Citation Index, Cochrane Library, the University of York Center for Reviews and Dissemination, abstracts from the PsychoSocial Aspects of Diabetes conference. Inclusion criteria: comparison of participants with and without depression, depression measured at age 18 or older, longitudinal follow-up with an outcome of type 2 diabetes, effect estimate adjusted for important confounders, full-text available in English or French, and study at overall low or moderate risk of bias. Two reviewers extracted data and assessed study quality. Results Twenty-one studies reporting twenty-five effect estimates were included. Depressive symptom scales, clinical interviews, physician diagnoses, and use of antidepressants were all associated with an increased risk of incident type 2 diabetes. When all measures of depression were combined, the meta-analyzed risk ratio for type 2 diabetes was 1.18 (95% CI 1.12–1.24, I2=45.4%). Results did not provide conclusive evidence that the association between depression and incident diabetes differs by measure of depression. Limitations Results showed heterogeneity and evidence of publication bias. Conclusions Results suggest that various measures of depression may be used to identify individuals at higher risk of type 2 diabetes.

Locked volar plating is the most common surgical procedure to address distal radius fractures. The extended flexor carpi radialis approach continues to be an excellent method for visualizing distal radius fractures and applying a volar plate. A new understanding of the anatomy allows for better visualization and reduction of the many different distal radius fracture patterns surgeons commonly see. Within the extended flexor carpi radialis approach, we describe the radial septum in further detail including the anatomy which comprises the radial septum triangle. Knowledge of this area allows for better visualization, more anatomic reductions, and fewer complications.

Purpose: To investigate associations of adherence to the Mediterranean diet (MeDi) with incidence of advanced age-related macular degeneration (AMD; the symptomatic form of AMD) in 2 European population-based prospective cohorts. Design: Prospective cohort study of the Rotterdam Study I (RS-I) and the Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires (Alienor) Study populations. Participants: Four thousand four hundred forty-six participants 55 years of age or older from the RS-I (The Netherlands) and 550 French adults 73 years of age or older from the Alienor Study with complete ophthalmologic and dietary data were included in the present study. Methods: Examinations were performed approximately every 5 years over a 21-year period (1990–2011) in RS-I and every 2 years over a 4-year period (2006–2012) in the Alienor Study. Adherence to the MeDi was evaluated using a 9-component score based on intake of vegetables, fruits, legumes, cereals, fish, meat, dairy products, alcohol, and the monounsaturated-to-saturated fatty acids ratio. Associations of incidence of AMD with MeDi were estimated using multivariate Cox proportional hazard models. Main Outcomes Measures: Incidence of advanced AMD based on retinal fundus photographs. Results: Among the 4996 included participants, 155 demonstrated advanced incident AMD (117 from the RS-I and 38 from the Alienor Study). The mean follow-up time was 9.9 years (range, 0.6–21.7 years) in the RS-I and 4.1 years (range, 2.5–5.0 years) in the Alienor Study. Pooling data for both the RS-I and Alienor Study, participants with a high (range, 6–9) MeDi score showed a significantly reduced risk for incident advanced AMD compared with participants with a low (range, 0–3) MeDi score in the fully adjusted Cox model (hazard ratio, 0.59; 95% confidence interval, 0.37–0.95; P = 0.04 for trend). Conclusions: Pooling data from the RS-I and Alienor Study, higher adherence to the MeDi was associated with a 41% reduced risk of incident advanced AMD. These findings support the role of a diet rich in healthful nutrient-rich foods such as fruits, vegetables, legumes, and fish in the prevention of AMD.

Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is a phenolic acid present in plants as a secondary metabolite and is also produced in the human organism as a metabolite from the degradation of polyphenols by the intestinal microbiota, particularly of flavonoids. However, PCA, like most polyphenols, is biotransformed in the human body to different conjugates as sulfates, which are found circulating in blood and could be involved in the bioactivity of the original compound. This paper describes a simple process for the preparation of PCA monosulfates with satisfactory yields. Two compounds were obtained that were identified as PCA-3-sulfate and PCA-4-sulfate by mass spectrometry and 1H and 13C nuclear magnetic resonance using one- and two-dimensional techniques (heteronuclear single-quantum coherence and heteronuclear multiple-bond correlation). Differential MS fragmentation behavior and UV spectra were observed for each compound, which could be used for their identification in samples of unknown composition. The described procedure can be used for the preparation of these polyphenol metabolites in view of their use in in vivo and in vitro studies, as well as standards for their analysis in biological fluids, to contribute to the elucidation of biological effects of dietary polyphenols.

Contains fulltext : 205500.pdf (Publisher’s version ) (Open Access) Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology.

We assessed the risk of human salmonellosis from consumption of shelled walnuts in the United States and the impact of 0- to 5-log reduction treatments for Salmonella during processing. We established a baseline model with Salmonella contamination data from 2010 to 2013 surveys of walnuts from California operations to estimate baseline prevalence and levels of Salmonella during preshelling storage and typical walnut processing stages, considered U.S. consumption data, and applied an adapted dose-response model from the Food and Agriculture Organization and the World Health Organization to evaluate risk of illness per serving and per year. Our baseline model predicted 1 case of salmonellosis per 100 million servings (95% confidence interval [CI], 1 case per 3 million to 1 case per 2 billion servings) of walnuts untreated during processing and uncooked by consumers, resulting in an estimated 6 cases of salmonellosis per year (95% CI,1 to 278 cases) in the United States. A minimum 3-log reduction treatment for Salmonella during processing of walnuts eaten alone or as an uncooked ingredient resulted in a mean risk of1 case per year. We modeled the impact on risk per serving of three atypical situations in which the Salmonella levels were increased by 0.5 to 1.5 log CFU per unit pretreatment during processing at the float tank or during preshelling storage or posttreatment during partitioning into consumer packages. No change in risk was associated with the small increase in levels of Salmonella at the float tank, whereas an increase in risk was estimated for each of the other two atypical events. In a fourth scenario, we estimated the risk per serving associated with consumption of walnuts with Salmonella prevalence and levels from a 2014 to 2015 U.S. retail survey. Risk per serving estimates were two orders of magnitude larger than those of the baseline model without treatment. Further research is needed to determine whether this finding reflects variability in Salmonella contamination across the supply or a rare event affecting a portion of the supply.

Several studies have demonstrated that administration of doxorubicin (DOXO) results in cardiotoxicity, which eventually progresses to dilated cardiomyopathy. The present work aimed to evaluate the early myocardial changes of DOXO-induced cardiotoxicity. Male New Zealand White rabbits were injected intravenously with DOXO twice weekly for 8 wk [DOXO-induced heart failure (DOXO-HF)] or with an equivolumetric dose of saline (control). Echocardiographic evaluation was performed, and myocardial samples were collected to evaluate myocardial cellular and molecular modifications. The DOXO-HF group presented cardiac hypertrophy and higher left ventricular cavity diameters, showing a dilated phenotype but preserved ejection fraction. Concerning cardiomyocyte function, the DOXO-HF group presented a trend toward increased active tension without significant differences in passive tension. The myocardial GSSG-to-GSH ratio and interstitial fibrosis were increased and Bax-to- Bcl-2 ratio presented a trend toward an increase, suggesting the activation of apoptosis signaling pathways. The macromolecule titin shifted toward the more compliant isoform (N2BA), whereas the stiffer one (N2B) was shown to be hypophosphorylated. Differential protein analysis from the aggregate-enriched fraction through gel liquid chromatography-tandem mass spectrometry revealed an increase in the histidine-rich glycoprotein fragment in DOXO-HF animals. This work describes novel and early myocardial effects of DOXO-induced cardiotoxicity. Thus, tracking these changes appears to be of extreme relevance for the early detection of cardiac damage (as soon as ventricular dilation becomes evident) before irreversible cardiac function deterioration occurs (reduced ejection fraction). Moreover, it allows for the adjustment of the therapeutic approach and thus the prevention of cardiomyopathy progression.NEW & NOTEWORTHY Identification of early myocardial effects of doxorubicin in the heart is essential to hinder the development of cardiac complications and adjust the therapeutic approach. This study describes doxorubicin-induced cellular and molecular modifications before the onset of dilated cardiomyopathy. Myocardial samples from doxorubicin-treated rabbits showed a tendency for higher cardiomyocyte active tension, titin isoform shift from N2B to N2BA, hypophosphorylation of N2B, increased apoptotic genes, left ventricular interstitial fibrosis, and increased aggregation of histidine-rich glycoprotein.

The original article was published on 02 March 2018 in Nature Communications; International audience; The originally published version of this article contained an error in the subheading ‘Heme is required for CO-dependent channel activation’, which was incorrectly given as ‘Hame is required for CO-dependent channel activation’. This has now been corrected in both the PDF and HTML versions of the Article

Members of the pepsin-like family (A1) of aspartic proteases (APs) are widely distributed in plants. A large number of genes encoding putative A1 APs are found in different plant genomes, the vast majority of which exhibit distinct features when compared with the so-called typical APs (and, therefore, grouped as atypical and nucellin-like APs). These features include the absence of the plant-specific insert; an unusually high number of cysteine residues; the nature of the amino acids preceding the first catalytic aspartate; and unexpected localizations. The over-representation of atypical and nucellin-like APs in plants is suggestive of greater diversification of protein functions and a more regulatory role for these APs, as compared with the housekeeping function generally attributed to typical APs. New functions have been uncovered for non-typical APs, with proposed roles in biotic and abiotic stress responses, chloroplast metabolism, and reproductive development, clearly suggesting functional specialization and tight regulation of activity. Furthermore, unusual enzymatic properties have also been documented for some of these proteases. Here, we give an overview of the current knowledge on the distinctive features and functions of both atypical and nucellin-like APs, and discuss this emerging pattern of functional complexity and specialization among plant pepsin-like proteases.

In the eukaryotic model yeast Saccharomyces cerevisiae, arsenic (As) detoxification is regulated by two transcriptional factors, Yap8 and Yap1. Yap8 specifically controls As extrusion from the cell, whether Yap1 avoids arsenic-induced oxidative damages. Accordingly, cells lacking both Yap1 and Yap8 are more sensitive to arsenate than cells lacking each regulator individually. Strikingly enough, the same sensitivity pattern was observed under anoxia, suggesting that Yap1 role in As detoxification might not be restricted to the regulation of the oxidative stress response. This finding prompted us to study the transcriptomic profile of wild-type and yap1 mutant cells exposed to arsenate. Interestingly, we found that, under such conditions, several genes involved in the biogenesis of FeS proteins were upregulated in a Yap1-dependent way. In line with this observation, arsenate treatment decreases the activity of the mitochondrial aconitase, Aco1, an FeS cluster-containing enzyme, this effect being even more pronounced in the yap1 mutant. Reinforcing the relevance of FeS cluster biogenesis in arsenate detoxification, the overexpression of several ISC and CIA machinery genes alleviates the deleterious effect of arsenate caused by the absence of Yap1 and Yap8. Altogether our data suggest that the upregulation of FeS biogenesis genes regulated by Yap1 might work as a cellular shield against arsenate toxicity.

Ready-to-eat foods based on dried partially sprouted seeds have been associated with foodborne salmonellosis. Whereas research has focused on the potential for Salmonella initially present in or on seeds to grow and survive during fresh sprout production, little is known about the potential for growth and survival of Salmonella associated with seeds that have been partially sprouted and dried. The goal of this study was to determine the growth of Salmonella during soaking for partial germination of pumpkin, sunflower, and chia seeds and subsequent survival during drying and storage. Pumpkin, sunflower, and chia seeds were inoculated with a four-serotype Salmonella cocktail by the dry transfer method and were soaked in sterile water at 25 or 37°C for 24 h. During the soaking period, Salmonella exhibited growth rates of 0.37 ± 0.26, 0.27 ± 0.12, and 0.45 ± 0.19 log CFU/h at 25°C and 0.94 ± 0.44, 1.04 ± 0.84, and 0.73 ± 0.36 log CFU/h at 37°C for chia, pumpkin, and sunflower seeds, respectively. Soaked seeds were drained and dried at 25, 51, and 60°C. Drying resulted in >5 log CFU/g loss at both 51 and 60°C and ∼3 log CFU/g loss at 25°C on partially sprouted pumpkin and sunflower seeds. There was no decrease in Salmonella during drying of chia seeds at 25°C, and only drying at 60°C provided losses >5 log CFU/g. Dried seeds were stored at 37 and 45°C at 15 and 76% relative humidity (RH) levels. The combination of temperature and RH exerted a stronger effect than either factor alone, such that rates at which Salmonella decreased generally followed this order: 37°C at 15% RH < 45°C at 15% RH < 37°C at 76% RH < 45°C at 76% RH for all seeds tested. Rates differed based on seed type, with chia seeds and chia seed powder having the smallest rate of Salmonella decrease, followed by sunflower and pumpkin seeds. Drying at higher temperatures (50 and 61°C) or storing at elevated temperature and humidity (45°C and 76% RH) resulted in significantly different rates of Salmonella decrease.

In the present work a family of novel secnidazole-derived Schiff base compounds and their copper(II) complexes were synthesized. The antimicrobial activities of the compounds were evaluated against clinically important anaerobic bacterial strains. The compounds exhibited in vitro antibacterial activity against Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides ovatus, Parabacteroides distasonis and Fusubacterium nucleatum pathogenic anaerobic bacteria. Upon coordination to copper(II) the antibacterial activity significantly increased in several cases. Some derivatives were even more active than the antimicrobial drugs secnidazole and metronidazole. Therefore, the compounds under study are suitable for in vivo evaluation and the microorganisms should be classified as susceptible to them. Electrochemical studies on the reduction of the nitro group revealed that the compounds show comparable reduction potentials, which are in the same range of the bio-reducible drugs secnidazole and benznidazole. The nitro group reduction potential is more favorable for the copper(II) complexes than for the starting ligands. Hence, the antimicrobial activities of the compounds under study might in part be related to intracellular bio-reduction activation. Considering the increasing resistance rates of anaerobic bacteria against a wide range of antimicrobial drugs, the present work constitutes an important contribution to the development of new antibacterial drug candidates.

The sea lamprey (Petromyzon marinus) serves as a comparative model for reconstructing vertebrate evolution. To enable more informed analyses, we developed a new assembly of the lamprey germline genome that integrates several complementary data sets. Analysis of this highly contiguous (chromosome-scale) assembly shows that both chromosomal and whole-genome duplications have played significant roles in the evolution of ancestral vertebrate and lamprey genomes, including chromosomes that carry the six lamprey HOX clusters. The assembly also contains several hundred genes that are reproducibly eliminated from somatic cells during early development in lamprey. Comparative analyses show that gnathostome (mouse) homologs of these genes are frequently marked by polycomb repressive complexes (PRCs) in embryonic stem cells, suggesting overlaps in the regulatory logic of somatic DNA elimination and bivalent states that are regulated by early embryonic PRCs. This new assembly will enhance diverse studies that are informed by lampreys’ unique biology and evolutionary/comparative perspective.

There is considerable variation in glucocorticoid (GC) baseline status and stress responses of individuals, yet the cause and consequence of this variation remains ambiguous. Attempts to relate GC levels to fitness and life-history trade-offs have yielded variable results. In this study, we evaluated whether baseline and poststressor GC hormone concentrations predicted migration strategy (i.e., resident or migrant) and successful seaward migration in a partially migrating population of juvenile brown trout (Salmo trutta Linnaeus, 1758). Baseline (N = 99) or poststressor (N = 102) plasma cortisol concentrations were obtained from brown trout and they were tagged with passive integrated transponder (PIT) and released in a natural Danish stream. Subsequently, fish were tracked with PIT reader systems and the stream was resampled for resident individuals. GC levels were not found to be associated with recapture of resident individuals or migration propensity to our first tracking station (S1), but increased baseline (and not poststressor) GC levels were associated with increased passage from S1 to our second tracking station, which anecdotally was an area of high predation or challenge. Our study found no evidence to suggest that cortisol regulates the migration life history in juvenile brown trout, but intermediate increases in baseline GC (and not poststressor GC) levels may favor migration performance.