Control of cardiac contractions using Cre-lox and degron strategies in zebrafish.

Cardiac contractions and hemodynamic forces are essential for organ development and homeostasis. Control over cardiac contractions can be achieved pharmacologically or optogenetically. However, these approaches lack specificity or require direct access to the heart. Here, we compare two genetic approaches to control cardiac contractions by modulating the levels of the essential sarcomeric protein Tnnt2a in zebrafish. We first recombine a newly generated tnnt2a floxed allele using multiple lines expressing Cre under the control of cardiomyocyte-specific promoters, and show that it does not recapitulate the tnnt2a/silent heart mutant phenotype in embryos. We show that this lack of early cardiac contraction defects is due, at least in part, to the long half-life of tnnt2a mRNA, which masks the gene deletion effects until the early larval stages. We then generate an endogenous Tnnt2a-eGFP fusion line that we use together with the zGRAD system to efficiently degrade Tnnt2a in all cardiomyocytes. Using single-cell transcriptomics, we find that Tnnt2a depletion leads to cardiac phenotypes similar to those observed in tnnt2a mutants, with a loss of blood and pericardial flow-dependent cell types. Furthermore, we achieve conditional degradation of Tnnt2a-eGFP by splitting the zGRAD protein into two fragments that, when combined with the cpFRB2-FKBP system, can be reassembled upon rapamycin treatment. Thus, this Tnnt2a degradation line enables non-invasive control of cardiac contractions with high spatial and temporal specificity and will help further understand how they shape organ development and homeostasis.

Clinical Relevance of Lepidoglyphus destructor Sensitisation in Allergic Rhinitis: Nasal Provocation Test as in vivo Assessment.

BACKGROUND: Dust mites are the leading cause of respiratory allergic diseases worldwide. Allergy to storage mites (SMs) has mostly been related to occupational exposures. However, recent studies have shown that sensitisation to SM, such as Lepidoglyphus destructor (Lep d), is of considerable importance also in urban populations, with high prevalence in dust samples of domestic environments. Co-sensitisation between house dust mites (HDMs) and SM is now regarded as very frequent in some regions, and cross-reactivity between them seems to be narrow. Therefore, SM allergenic capacity is increasingly a subject of study. The nasal provocation test (NPT), as an in vivo technique, could be considered the gold standard for the clinical relevance assessment of an allergen, in polysensitised rhinitis patients. OBJECTIVE: The objective of this study was to analyse the clinical relevance of the SM Lep d, by assessing the relationship between in vivo sensitisation and expression of allergic respiratory disease in an urban setting. PATIENTS AND METHODS: In our study, we enrolled a total of 32 allergic patients with rhinitis (with or without asthma) with proven sensitisation by skin prick test (SPT) and specific IgE (sIgE) to HDMs and/or SM. Patients underwent NPT with Lep d using subjective (Lebel Symptom Score Scale) and objective measurements (peak nasal inspiratory flow [PNIF]) for assessment of nasal response. RESULTS: Most of the patients with positive SPT and sIgE to Lep d had a positive NPT (24/27; 89%). True Lep d allergy, assessed by a positive NPT, could be predicted by a SPT wheal size >9.7 mm and a sIgE >0.42 kUA/L, with 100%/95.7% sensitivity and 75.0%/83.3% specificity, respectively. Co-sensitisation between Lep d and Der p was high, 75.0%. Asthma was more frequent in the positive Lep d NPT group (54 vs. 12%, p < 0.05). Significantly more patients from this group reported physical exercise, nonspecific irritants, and respiratory infections as relevant triggers of respiratory symptoms (p < 0.01-p < 0.05). CONCLUSIONS: To our knowledge, this is the first study to show that sensitisation to Lep d may have clinical relevance in a non-occupational setting. In this group, there seems to be a relationship between allergy to Lep d and severity of respiratory disease, with more bronchial inflammation, when comparing with mite-allergic patients sensitised only to HDM. Therefore, the authors consider that sensitisation to Lep d should be considered when assessing and treating allergic respiratory disease in urban environments.

Maternal selenium dietary supplementation alters sociability and reinforcement learning deficits induced by in utero exposure to maternal immune activation in mice.

Maternal immune activation (MIA) during pregnancy increases the risk for the unborn foetus to develop neurodevelopmental conditions such as autism spectrum disorder and schizophrenia later in life. MIA mouse models recapitulate behavioural and biological phenotypes relevant to both conditions, and are valuable models to test novel treatment approaches. Selenium (Se) has potent anti-inflammatory properties suggesting it may be an effective prophylactic treatment against MIA. The aim of this study was to determine if Se supplementation during pregnancy can prevent adverse effects of MIA on offspring brain and behaviour in a mouse model. Selenium was administered via drinking water (1.5 ppm) to pregnant dams from gestational day (GD) 9 to birth, and MIA was induced at GD17 using polyinosinic:polycytidylic acid (poly-I:C, 20 mg/kg via intraperitoneal injection). Foetal placenta and brain cytokine levels were assessed using a Luminex assay and brain elemental nutrients assessed using inductively coupled plasma- mass spectrometry. Adult offspring were behaviourally assessed using a reinforcement learning paradigm, the three-chamber sociability test and the open field test. MIA elevated placental IL-1ß and IL-17, and Se supplementation successfully prevented this elevation. MIA caused an increase in foetal brain calcium, which was prevented by Se supplement. MIA caused in offspring a female-specific reduction in sociability, which was recovered by Se, and a male-specific reduction in social memory, which was not recovered by Se. Exposure to poly-I:C or selenium, but not both, reduced performance in the reinforcement learning task. Computational modelling indicated that this was predominantly due to increased exploratory behaviour, rather than reduced rate of learning the location of the food reward. This study demonstrates that while Se may be beneficial in ameliorating sociability deficits caused by MIA, it may have negative effects in other behavioural domains. Caution in the use of Se supplementation during pregnancy is therefore warranted.

Salt-loading promotes extracellular ATP release mediated by glial cells in the hypothalamic paraventricular nucleus of rats.

Previously, we have shown that purinergic signalling is involved in the control of hyperosmotic-induced sympathoexcitation at the level of the PVN, via activation of P2X receptors. However, the source(s) of ATP that drives osmotically-induced increases in sympathetic outflow remained undetermined. Here, we tested the two competing hypotheses that either (1) higher extracellular ATP in PVN during salt loading (SL) is a result of a failure of ectonucleotidases to metabolize ATP; and/or (2) SL can stimulate PVN astrocytes to release ATP. Rats were salt loaded with a 2 % NaCl solution replacing drinking water up to 4 days, an experimental model known to cause a gradual increase in blood pressure and plasma osmolarity. Immunohistochemical assessment of glial-fibrillary acidic protein (GFAP) revealed increased glial cell reactivity in the PVN of rats after 4 days of high salt exposure. ATP and adenosine release measurements via biosensors in hypothalamic slices showed that baseline ATP release was increased 17-fold in the PVN while adenosine remained unchanged. Disruption of Ca2+-dependent vesicular release mechanisms in PVN astrocytes by virally-driven expression of a dominant-negative SNARE protein decreased the release of ATP. The activity of ectonucleotidases quantified in vitro by production of adenosine from ATP was increased in SL group. Our results showed that SL stimulates the release of ATP in the PVN, at least in part, from glial cells by a vesicle-mediated route and likely contributes to the neural control of circulation during osmotic challenges.

Ergonomic intervention program for office workers: a case study about its effect in computer vision syndrome and musculoskeletal discomfort.

This study aims to develop and implement an ergonomic intervention program at the workplace of knowledge workers, and to evaluate its impact on the reduction of Computer Vision Syndrome (CVS) and musculoskeletal symptoms. 84 workers were part of the study (mean age 43.2 ± 9.7 years). The intervention included training, delivery of a packaging of artificial tears, and adjustments in workstations. It was conducted intensively along 6 weeks. Data was collected on-site, with questionnaires administered pre-intervention, 2 months after, and 4 months after. Participants exhibited behavioural changes, especially in workplace adjustments and visual rest. By the intervention's end, over 90% had correctly adjusted screens and adopted appropriate postures, while 42.7% adhered to the 20x20x20 rule. CVS severity and prevalence decreased, but not significantly across the three time points. Significant improvements were observed in upper back and neck musculoskeletal symptoms at the end of workdays. Findings suggest that an ergonomic intervention program can benefit employees by reducing visual and musculoskeletal symptoms.

Practitioner summary: This study addresses CVS and MSDs, commonly experienced by individuals working with display screen equipment. It was emphasised the significance of ergonomic interventions in reducing musculoskeletal discomfort. The major finding was the positive behavioural changes, such as improved workplace adjustments and visual rest practices.

The role of fingernail selenium in the association between arsenic, lead and mercury and child development in rural Vietnam: a cross-sectional analysis.

As, Pb and Hg are common environmental contaminants in low- and middle-income countries. We investigated the association between child toxicant exposure and growth and development and determined if this association was mitigated by Se concentration. Toxicant concentrations in fingernail samples, anthropometry and Bayley's Scales of Infant Development, 3rd edition domains were assessed in 36-month-old children whose mothers had been part of a randomised controlled trial in rural Vietnam. Multivariable regression analyses were performed to estimate the effect of toxicant exposure on clinical outcomes with adjustments for potential confounders and interaction with fingernail Se concentration. We analysed 658 children who had data for at least one physical or developmental outcome, and at least one toxicant measurement, and each of the covariates. Fingernail As concentration was negatively associated with language (estimate per 10 % increase in As: -0·19, 95 % CI: (-0·32, -0·05)). Pb was negatively associated with cognition (estimate per 10 % increase in Pb: -0·08 (-0·15, -0·02)), language (estimate per 10 % increase in Pb: -0·18 (-0·28, -0·10)) and motor skills (estimate per 10 % increase in Pb: -0·12 (-0·24, 0·00)). Hg was negatively associated with cognition (estimate per 10 % increase in Hg: -0·48, (-0·72, -0·23)) and language (estimate per 10 % increase in Hg -0·51, (-0·88, -0·13)) when Se concentration was set at zero in the model. As Se concentration increased, the negative associations between Hg and both cognition and language scores were attenuated. There was no association between toxicant concentration and growth. As, Pb and Hg concentrations in fingernails of 3-year-old children were associated with lower child development scores. The negative association between Hg and neurological development was reduced in magnitude with increasing Se concentration. Se status should be considered when assessing heavy metal toxicants in children and their impact on neurodevelopmental outcomes.

Association between ultra-processed food consumption and cognitive performance in US older adults: a cross-sectional analysis of the NHANES 2011-2014.

PURPOSE: This study evaluated the association between ultra-processed food (UPF) consumption and cognitive performance among older US adults. METHODS: This cross-sectional study assessed 3632 participants aged 60+ years from the National Health and Nutrition Examination Survey (NHANES) 2011-14. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Word Learning test, Animal Fluency test, and the Digit Symbol Substitution test (DSST). Dietary intake was assessed using two 24-h diet recalls. Food items were classified according to the NOVA system, a classification based on the nature, extent, and purpose of industrial food processing. Linear regression models were used to evaluate the association of dietary share of UPF (% of daily energy intake) (categorized as tertiles) and cognitive test scores, adjusting for socio-demographic variables, physical activity, smoking status, and chronic diseases (cardiovascular diseases, diabetes, and depression). Models excluding participants with pre-existing diseases were carried out to address potential reverse causality. RESULTS: On average, UPF accounted for 53% of total energy intake, ranging from 33 to 70% across extreme tertiles. Inverted U-shape association between UPF consumption and Animal fluency and DSST was observed. No significant associations were observed between the UPF intake tertiles and the cognitive test results. Nonetheless, UPF consumption was significantly associated with worse performance in Animal Fluency in older adults without pre-existing diseases (P < 0.05). CONCLUSION: UPF consumption was associated with worse performance in Animal Fluency among older people without pre-existing diseases. Decreasing UPF consumption may be a way to improve impaired cognition among older adults.

Career decision-making in unemployed Portuguese adults: Test of the social cognitive model of career self-management.

Most research applications of the social cognitive model of career self-management (CSM; Lent & Brown, 2013) to career exploration and decision-making have involved U.S. college students. To extend research on the model, we tested its fit to the data in a sample of 345 unemployed adult workers in Portugal. Participants completed measures of career decision self-efficacy, outcome expectations, social support, conscientiousness, neuroticism, exploration goals, decisional stress, and career choice certainty. The model test yielded good overall fit to the data and accounted for significant variance in goals, stress, and choice certainty. When compared with prior findings, the results suggest that the CSM model may offer explanatory utility relative to the making of initial as well as subsequent career decisions and across national boundaries. Implications of the findings for the social cognitive model as well as for future research and practice are considered. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Reducing l-lactate release from hippocampal astrocytes by intracellular oxidation increases novelty induced activity in mice.

Astrocytes are in control of metabolic homeostasis in the brain and support and modulate neuronal function in various ways. Astrocyte-derived l-lactate (lactate) is thought to play a dual role as a metabolic and a signaling molecule in inter-cellular communication. The biological significance of lactate release from astrocytes is poorly understood, largely because the tools to manipulate lactate levels in vivo are limited. We therefore developed new viral vectors for astrocyte-specific expression of a mammalianized version of lactate oxidase (LOx) from Aerococcus viridans. LOx expression in astrocytes in vitro reduced their intracellular lactate levels as well as the release of lactate to the extracellular space. Selective expression of LOx in astrocytes of the dorsal hippocampus in mice resulted in increased locomotor activity in response to novel stimuli. Our findings suggest that a localized decreased intracellular lactate pool in hippocampal astrocytes could contribute to greater responsiveness to environmental novelty. We expect that use of this molecular tool to chronically limit astrocytic lactate release will significantly facilitate future studies into the roles and mechanisms of intercellular lactate communication in the brain.

Intake of Nuts and Seeds Is Associated with a Lower Prevalence of Nonalcoholic Fatty Liver Disease in US Adults: Findings from 2005-2018 NHANES.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Nuts and seeds, due to their unique nutrient composition, may provide health benefits for the prevention of NAFLD. To date, no research has investigated the association between nut and seed intake and NAFLD prevalence in a non-Mediterranean Western population. OBJECTIVES: This study aimed to explore the association between nut and seed intake with NAFLD and metabolic biomarkers in a US representative sample. METHODS: This cross-sectional study used data from 25,360 adults involved in the 2005-2018 NHANES, including adults (aged ≥18 y) with negative serology for hepatitis B and C and nonexcessive alcohol consumption. NAFLD was assessed using the fatty liver index (FLI); metabolic biomarkers were also assessed; nut and seed intake was evaluated from two 24-h dietary recalls. ANOVA and Poisson regression were used to establish the relation between nut and seed intake categories and NAFLD prevalence. RESULTS: Nut and seed consumption was associated with a reduced prevalence of NAFLD. In females, in the fully adjusted model, this was significant across all nut and seed consumption categories but was most prominent in the moderate consumption group (7%, 15%, and 14% risk reduction in low, moderate, and adequate consumption categories, respectively, compared with nonconsumers). In males, moderate intake of nuts and seeds demonstrated a significantly lower prevalence of NAFLD (9%) compared with nonconsumers. CONCLUSIONS: Daily consumption for nuts and seeds was associated with a lower prevalence of NAFLD in non-Mediterranean, US adults, although the benefits seem to be greater in females across all categories of nut and seed consumption groups compared with nonconsumers. Both males and females presented with lower prevalence of NAFLD with intakes of 15-30 g/d.

Sex-dependent association between selenium status and cognitive performance in older adults.

PURPOSE: Selenium (Se) is an essential nutrient required for maintaining brain health across lifespan, and adequate nutritional Se status has been positively associated with sustained cognitive performance in older adults. However, critical physiological sex differences in Se metabolism have not been specifically assessed in human studies. Therefore, we aimed to investigate sex differences in the association between Se concentration in whole blood and cognitive performance in US older adults. METHODS: This cross-sectional study included 2016 participants (984 male and 1032 female) ≥ 60 years from the 2011 to 2014 National Health and Nutrition Survey (NHANES). All participants were assessed for whole blood Se concentration and completed the following battery of cognitive tests: Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning Test, Animal Fluency test, and Digit Symbol Substitution Test (DSST). RESULTS: In this cohort, all participants presented with adequate Se status (mean 196.7 µg/L; 95% CI 193.5, 200.0), and cohort-wide scores were equivalent to a cognitively healthy population. A sex effect on CERAD recall (P = 0.005) and animal fluency (P = 0.018) was observed in models adjusted for age, diabetes, history of cardiovascular disease, physical activity and body mass index. Se concentration was positively associated with CERAD recall (ß: 0.015, 95% CI 0.007, 0.022) and animal fluency (ß: 0.017, 95% CI 0.003, 0.030) performance in males only, while no associations were observed for females. CONCLUSION: This study provides the first evidence for sex differences in the association between Se status and cognitive performance in older adults.

Associations between nut intake, cognitive function and non-alcoholic fatty liver disease (NAFLD) in older adults in the United States: NHANES 2011-14.

BACKGROUND: Nuts are nutrient-rich and reported to provide some cognitive and cardiometabolic health benefits, but limited studies have focused on older adults. This study investigated the cross-sectional relationship between habitual nut intake, dietary pattern and quality, cognition and non-alcoholic fatty liver disease (NAFLD) in older adults. METHODS: Older adults (≥ 60 years) from the NHANES 2011-12 and 2013-14 cohorts, who had complete data on cognitive function (as CERAD total, delayed recall, animal fluency and digit-symbol substitution test) and variables to calculate the Fatty Liver Index (FLI), an indicator of NAFLD, were included (n = 1848). Nut intake and diet quality (Healthy Eating Index 2015) were determined using two 24-hour diet recalls. Participants were categorised into one of four groups based on their habitual nut intake: non-consumers (0 g/d), low intake (0.1-15.0 g/d), moderate intake (15.1-30.0 g/d) or met recommendation (> 30 g/d), with all outcomes compared between these nut intake groups. RESULTS: Cognitive scores of older adults were the lowest in non-consumers and significantly highest in the moderate intake group, with no further increase in those who consumed nuts more than 30 g/d (p < 0.007). FLI was the lowest among older adults with moderate nut intake but the associations disappeared after adjusting for covariates (p = 0.329). Moderate nut intake was also associated with better immediate and delayed memory in older adults with high risk of NAFLD (FLI ≥ 60) (B = 1.84 and 1.11, p < 0.05 respectively). Higher nutrient intake and better diet quality (p < 0.001) were seen with higher nut intake but did not influence energy from saturated fat intake. Factor analysis revealed 'Nuts and oils' as one of the four major dietary patterns associated with better cognition and lower FLI scores. CONCLUSIONS: Moderate nut intake (15.1-30.0 g/d) may be sufficient for better cognitive performance, but not NAFLD risk of older adults in the US.

Determination of the Phytochemical Composition and Antioxidant Potential of Eugenia copacabanensis and Myrciaria tenella Leaves (Myrtaceae) Using a Saccharomyces cerevisiae Model.

Eugenia copacabanensis and Myrciaria tenella are present in restingas of the Atlantic Forest, but little information is available about their chemical and biological potential. In this context, the hexane, dichloromethane, ethyl acetate and butanol fractions from the leaves of methanolic extract were analyzed by GC/MS and HPLC-DAD and the antioxidant potential was determined by DPPH and ABTS assays and using a Saccharomyces cerevisiae model. Dereplication allowed the identification of 68 compounds, 42 and 41 of which, respectively, are first reported here for E. copacabanensis and M. tenella. In vivo results revealed that the ethyl acetate and butanol fractions showed expressive antioxidant protection in the BY4741 and Δgsh1 strains, with greater impact on glutathione-deficient cells. With a high diversity of phenolic compounds, these polar fractions of E. copacabanensis and M. tenella leaves are potential protectors against intracellular oxidative stress.

Comparative testis structure and function in three representative mice strains.

Mice are widely used as experimental models due to several positive characteristics and in particular their suitability for studies involving molecular biology and transgenesis. Despite the large number of mice strains currently available, the literature regarding their basic reproductive biology is still relatively scarce. Herein, we comparatively evaluated several important and correlated parameters related to testis structure and function in sexually mature male mice of inbred (C57BL/6, n = 19; BALB/c, n = 17) and outbred (Swiss, n = 17) strains, frequently utilized in research. Swiss mice presented significant variation for many parameters evaluated, including higher sperm production, mainly when compared to the C57BL/6 strain. However, some key parameters such as the duration of spermatogenesis, the Sertoli cell number per testis, and the spermatogenic efficiency were similar among the different strains. Although presenting significantly higher Leydig cell (LC) proportion and numbers per testis gram and per testis, the anogenital index was smaller in Swiss mice. Estradiol levels were lower in C57BL/6, whereas testosterone levels and 3ß-HSD expression were similar among strains. Regarding the LC/macrophages relationship, in comparison to the literature, we reported a much higher contribution of macrophages to the mouse intertubule. Thus, we estimated that there are around 1.6 macrophages per LC in BALB/c mice and this intriguing finding could be relevant to testis function in overall and spermatogonial biology in particular. Taken together, our results highlight the importance of knowing more accurately the testis structure and function in the different mice strains available for research, particularly when a specific testis parameter is being investigated.

Rate of polymyxin resistance among Acinetobacter baumannii recovered from hospitalized patients: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to determine the rate of polymyxin resistance among Acinetobacter baumannii isolates causing infection in hospitalized patients around the world during the period of 2010-2019. The systematic review was performed on September 1, 2019, using PubMed/MEDLINE, Scopus, and Web of Science; studies published after January 1, 2010, were selected. The data were summarized in tables, critically analyzed, and treated statistically using the RStudio® Software with Meta package and Metaprop Command. After applying exclusion factors, 41 relevant studies were selected from 969 articles identified on literature search. The overall rate of polymyxin-resistant A. baumannii (PRAB) related to hospitalized patients was estimated to be 13% (95% CI, 0.06-0.27), where a higher rate was observed in America (29%; 95% CI, 0.12-0.55), followed by Europe (13%; 95% CI, 0.02-0.52), and Asia (10%; 95% CI, 0.02-0.32). The extensive use of polymyxins on veterinary to control bacterial infection and growth promotion, as well as the resurgence in prescription and use of polymyxins in the clinics against carbapenem-resistant gram-negative bacteria, may have contributed to the increased incidence of PRAB. The findings of this meta-analysis revealed that the rate of PRAB recovered from hospitalized patients is distinctively high. Thus, action needs to be taken to develop strategies to combat the clinical incidence of PRAB-induced hospital infections.

Evaluation of the effect of cafeteria diet on the kidney Na,K-ATPase activity, and oxidative stress.

In this study, renal tissue, subdivided into the cortex and medulla of Wistar rats subjected to a cafeteria diet (CAF) for 24 days or to normal diet, was used to analyze whether the renal enzyme Na,K-ATPase activity was modified by CAF diet, as well as to analyze the α1 subunit of renal Na,K-ATPase expression levels. The lipid profile of the renal plasma membrane and oxidative stress were verified. In the Na,K-ATPase activity evaluation, no alteration was found, but a significant decrease of 30% in the cortex was detected in the α1 subunit expression of the enzyme. There was a 24% decrease in phospholipids in the cortex of rats submitted to CAF, a 17% increase in cholesterol levels in the cortex, and a 23% decrease in the medulla. Lipid peroxidation was significantly increased in the groups submitted to CAF, both in the cortical region, 29%, and in the medulla, 35%. Also, a reduction of 45% in the glutathione levels was observed in the cortex and medulla with CAF. CAF showed a nearly two-fold increase in glutathione peroxidase (GPX) activity in relation to the control group in the cortex and a 59% increase in the GPx activity in the medulla. In conclusion, although the diet was administered for a short period of time, important results were found, especially those related to the lipid profile and oxidative stress, which may directly affect renal function.

Glio- and neuro-protection by prosaposin is mediated by orphan G-protein coupled receptors GPR37L1 and GPR37.

Discovery of neuroprotective pathways is one of the major priorities for neuroscience. Astrocytes are natural neuroprotectors and it is likely that brain resilience can be enhanced by mobilizing their protective potential. Among G-protein coupled receptors expressed by astrocytes, two highly related receptors, GPR37L1 and GPR37, are of particular interest. Previous studies suggested that these receptors are activated by a peptide Saposin C and its neuroactive fragments (prosaptide TX14(A)), which were demonstrated to be neuroprotective in various animal models by several groups. However, pairing of Saposin C or prosaptides with GPR37L1/GPR37 has been challenged and presently GPR37L1/GPR37 have regained their orphan status. Here, we demonstrate that in their natural habitat, astrocytes, these receptors mediate a range of effects of TX14(A), including protection from oxidative stress. The Saposin C/GPR37L1/GPR37 pathway is also involved in the neuroprotective effect of astrocytes on neurons subjected to oxidative stress. The action of TX14(A) is at least partially mediated by Gi-proteins and the cAMP-PKA axis. On the other hand, when recombinant GPR37L1 or GPR37 are expressed in HEK293 cells, they are not functional and do not respond to TX14(A), which explains unsuccessful attempts to confirm the ligand-receptor pairing. Therefore, this study identifies GPR37L1/GPR37 as the receptors for TX14(A), and, by extension of Saposin C, and paves the way for the development of neuroprotective therapeutics acting via these receptors.

Melatonin induces mechanisms of brain resilience against neurodegeneration.

Melatonin is an endogenous pleiotropic molecule which orchestrates regulatory functions and protective capacity against age-related ailments. The increase in circulating levels of melatonin through dietary supplements intensifies its health benefits. Investigations in animal models have shown that melatonin protects against Alzheimer's disease (AD)-like pathology, although clinical studies have not been conclusive. We hypothesized that melatonin induces changes in the brain that prevent or attenuate AD by increasing resilience. Therefore, we treated healthy nontransgenic (NoTg) and AD transgenic (3xTg-AD) 6-month-old mice with a daily dose of 10 mg/kg of melatonin until 12 months of age. As expected, melatonin reversed cognitive impairment and dementia-associated behaviors of anxiety and apathy and reduced amyloid and tau burden in 3xTg-AD mice. Remarkably, melatonin induced cognitive enhancement and higher wellness level-related behavior in NoTg mice. At the mechanism level, NF-κB and proinflammatory cytokine expressions were decreased in both NoTg and 3xTg-AD mice. The SIRT1 pathway of longevity and neuroprotection was also activated in both mouse strains after melatonin dosing. Furthermore, we explored new mechanisms and pathways not previously associated with melatonin treatment such as the ubiquitin-proteasome proteolytic system and the recently proposed neuroprotective Gas6/TAM pathway. The upregulation of proteasome activity and the modulation of Gas6 and its receptors by melatonin were similarly displayed by both NoTg and 3xTg-AD mice. Therefore, these results confirm the potential of melatonin treatment against AD pathology, by way of opening new pathways in its mechanisms of action, and demonstrating that melatonin induces cognitive enhancement and brain resilience against neurodegenerative processes.

Prevalence, virulence factors and antifungal susceptibility of Candida spp. isolated from bloodstream infections in a tertiary care hospital in Brazil.

Candida spp. are responsible for 80% of all systemic fungal infections and are associated with high mortality rates. This study characterised 79 bloodstream isolates of C. albicans, C. glabrata, C. orthopsilosis, C. parapsilosis and C. tropicalis from patients in a Brazilian hospital. The susceptibility to amphotericin B, caspofungin, fluconazole and voriconazole was determined; virulence factor production was assessed based on haemolysin, phospholipase and proteinase activities, and the patients' clinical characteristics were analysed. C. albicans was the predominant species (44%), followed by C. glabrata (19%), C. tropicalis (19%), C. parapsilosis (14%) and C. orthopsilosis (4%). The candidemia incidence was 1.52 per 1000 admissions, and the crude mortality rate was 52%. One C. albicans isolate was resistant to fluconazole and voriconazole. Moreover, 20.2%, 2.5% and 3.8% of the isolates exhibited dose-dependent susceptibility to fluconazole, voriconazole and caspofungin, respectively. In conclusion, although the C. glabrata incidence was higher than that usually described in Brazil, its increase was previously observed in studies conducted worldwide. Furthermore, the azole resistance of the C. albicans isolate could be due to previous exposure to these antifungals. These results highlight the importance of epidemiological studies and will facilitate an improved understanding of candidemia in the studied hospital.

Wastewater Chlorination for Reuse, an Alternative for Small Communities.

Reuse of wastewater is a practice that has been employed all over the world, mainly in agriculture, where the main aim is to reduce the demand for water and provide nutrients. However, these waters for reuse often have excessive amounts of pathogenic microorganisms, requiring a specific disinfection step even after being subjected to a purification process. Thus, this research aimed to evaluate the potential use of calcium hypochlorite and sodium hypochlorite as disinfectant agents for the sanitary effluent of the treatment system based on constructed wetlands for later reuse. Disinfection tests were carried out in batch, using three dosages of hypochlorite (5, 10 and 15 mg.L-1) and different contact. In all disinfection tests, inactivation of indicator microorganisms (total coliforms and E. coli) was considered effective for the two disinfectant agents adopted, satisfying the criteria for reuse according to the World Health Organization (WHO). There was no formation of trihalomethanes after disinfection tests.