Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS.

Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.

The p53-induced RNA-binding protein ZMAT3 is a splicing regulator that inhibits the splicing of oncogenic CD44 variants in colorectal carcinoma.

p53 is an intensely studied tumor-suppressive transcription factor. Recent studies suggest that the RNA-binding protein (RBP) ZMAT3 is important in mediating the tumor-suppressive effects of p53. Here, we globally identify ZMAT3-regulated RNAs and their binding sites at nucleotide resolution in intact colorectal cancer (CRC) cells. ZMAT3 binds to thousands of mRNA precursors, mainly at intronic uridine-rich sequences and affects their splicing. The strongest alternatively spliced ZMAT3 target was CD44, a cell adhesion gene and stem cell marker that controls tumorigenesis. Silencing ZMAT3 increased inclusion of CD44 variant exons, resulting in significant up-regulation of oncogenic CD44 isoforms (CD44v) and increased CRC cell growth that was rescued by concurrent knockdown of CD44v Silencing p53 phenocopied the loss of ZMAT3 with respect to CD44 alternative splicing, suggesting that ZMAT3-mediated regulation of CD44 splicing is vital for p53 function. Collectively, our findings uncover a p53-ZMAT3-CD44 axis in growth suppression in CRC cells.

Study protocol for a single-arm pilot trial investigating the feasibility of a multimodal digital technology for managing metabolic syndrome in patients with chronic obstructive pulmonary disease.

Individuals diagnosed with Chronic Obstructive Pulmonary Disease (COPD) are exposed to an increased risk of metabolic syndrome (MetS), which negatively affects their health outcomes and quality of life. Lifestyle interventions have shown promise in managing MetS. This study outlines the protocol for a web-based multimodal self-care program, Digital Metabolic Rehabilitation, for managing MetS in patients with COPD. The Digital Metabolic Rehabilitation is a single-arm pilot trial that integrates the Canadian Health Advanced by Nutrition and Graded Exercise (CHANGE) Program and a web-based wellness platform. The web-based wellness platform employed in this study is My Viva Plan (MVP)®, which integrates a holistic, multicomponent approach to promote wellness. The intervention will primarily focus on lifestyle changes for patients with COPD. Over 6 months, participants will use the web-based wellness platform and engage in weekly online support group sessions. Fifty patients diagnosed with stage I-II COPD and MetS will participate. Blood tests, anthropometrics, body composition, physical function, muscle strength, physical activity, energy metabolism, quality of life and mental health will be assessed at baseline, 3, and 6 months. The Digital Metabolic Rehabilitation program aims to explore whether a multimodal integrative intervention delivered through a web-based wellness platform can be implemented by patients with COPD with MetS. By combining the expertise of the CHANGE Program with the digital delivery format, the intervention seeks to enhance self-monitoring and foster better self-management practices. The protocol outlines a novel and potentially impactful intervention for managing MetS in patients with COPD.

Expanding chalcogen bonds in thiophenes to interactions with halogens.

Compounds containing the thiophene moiety find several applications in physics and chemistry, such as electrical conduction, which depends on specific conformations to properly exhibiting the desired properties. In turn, chalcogen bonding has found to modulate the conformation of some N-thiophen-2-ylfomamides. Since halogens participate in a kin interaction (halogen bonding) and are abundant in agrochemicals, pharmaceuticals, and materials, we have quantum-chemically explored the interaction between organic halogen and thiophene as a conformational modulator in some model compounds. Although such interaction indeed appears, as demonstrated by atoms in molecules and natural bond orbital analysis, it is inefficient to control the conformational equilibrium. An energy decomposition analysis scheme demonstrated that halomethane and thiophene tend to move away from one another due to a core component (Pauli repulsion and exchange), which is mainly due to a deformation term. Therefore, chalcogen bonds with halogens appear weaker than with other chalcogens.

Reference Values for Handgrip Strength, Five Times Sit-to-stand, and Gait Speed in Patients on Hemodialysis.

BACKGROUND AND HYPOTHESIS: Low levels of muscle strength and function predict adverse clinical outcomes in patients on hemodialysis; however, reference values remain lacking. We described reference values for handgrip strength, five times sit-to-stand (STS-5), and 4-m gait speed in a large-scale sample in patients on hemodialysis. METHODS: Baseline data from the SARCopenia trajectories and associations with adverse clinical outcomes in patients on HemoDialysis (SARC-HD) study were analyzed. Muscle strength was evaluated using handgrip strength and the STS-5, whereas physical performance was evaluated using usual 4-m gait speed before a midweek dialysis session. Sex- and age-specific smoothed reference curves for each test at the 3rd, 15th, 50th, 85th, and 97th percentiles were constructed using generalized additive models for location shape and scale. Comparisons between sex and age were also performed. RESULTS: Data from 1004 patients (39% female; 19 to 96 years; 49% ≥ 60 years) were analyzed. Declines in muscle strength and physical performance were observed with advancing age in both sexes. However, among males, muscle strength and performance were similar between 18 and 49 years of age. Males exhibited substantially greater performance in handgrip strength (10.3 kg, 95% confidence interval (CI) 9.1 to 11.4) and 4-m gait speed (-0.10 seconds, 95% CI: -0.14 to -0.05) compared to females. Older patients, independent of sex, exhibited poorer performance on most tests. Lower handgrip strength in the arm with arteriovenous fistula was observed in both sexes (males -2.3 kg, 95% CI: -2.8 to -1.7; and females -2.1 kg, 95% CI: -2.6 to -1.6). CONCLUSION: Reference values obtained in this study may be used in clinical and research settings to identify patients on hemodialysis with low physical function according to sex and age. Future studies should test these reference values as potential predictors of adverse clinical outcomes.

Are the physical activity habits of healthcare professionals associated with their physical activity promotion and counselling?: A systematic review.

OBJECTIVE: Healthcare professionals (HCPs) play an important role in conducting brief physical activity counselling during consultations, representing one of the population's most cost-effective interventions for its promotion. Despite this, their clinical practice often falls short in addressing physical activity with the necessary depth and frequency. This study aimed to synthesise the literature concerning the association between the physical activity habits of HCPs and their attitudes toward physical activity promotion and counselling. METHODS: The systematic review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Its protocol was registered in PROSPERO under ID: CRD42023408302. In March 2023, a comprehensive search was conducted using key terms related to physical activity levels and HCPs counselling practices across the Web of Science, Scopus, PubMed, SPORTDiscus, APA PsycInfo, and CINAHL databases. Registered HCPs classified under the International Standard Classification of Occupations (ISCO) were included. The Newcastle-Ottawa Scale was used for assessing articles quality. RESULTS: The search yielded 6618 articles, with 51 meeting the inclusion criteria after filtering and cross-referencing. Predominantly cross-sectional studies were included, mainly involving HCPs responding to questionnaires regarding their physical activity habits and promotion and counselling practices. Heterogeneous results were found. CONCLUSION: High-quality studies mainly concluded that higher physical activity levels among HCPs were associated with more physical activity promotion and counselling practices. These findings are an important contribution to the relevance of the physical activity practice by HCPs and highlighting the importance of promoting its counselling in clinical practice.

Sulforaphane Supplementation Did Not Modulate NRF2 and NF-kB mRNA Expressions in Hemodialysis Patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have reduced expression of erythroid nuclear factor-related factor 2 (NRF2) and increased nuclear factor κB (NF-κB). "Food as medicine" has been proposed as an adjuvant therapeutic alternative in modulating these factors. No studies have investigated the effects of sulforaphane (SFN) in cruciferous vegetables on the expression of these genes in patients with CKD. OBJECTIVE: The study aimed to evaluate the effects of SFN on the expression of NRF2 and NF-κB in patients on hemodialysis (HD). DESIGN AND METHODS: A randomized, double-blind, crossover study was performed on 30 patients on regular HD. Fourteen patients were randomly allocated to the intervention group (1 sachet/day of 2.5 g containing 1% SFN extract with 0.5% myrosinase) and 16 patients to the placebo group (1 sachet/day of 2.5 g containing corn starch colored with chlorophyll) for 2 months. After a washout period of 2 months, the groups were switched. NRF2 and NF-κB mRNA expression was evaluated by real-time quantitative polymerase chain reaction, and tumor necrosis factor alpha and interleukin-6 levels were quantified by enzyme-linked immunosorbent assay. Malondialdehyde was evaluated as a marker of lipid peroxidation. RESULTS: Twenty-five patients (17 women, 55 [interquartile range = 19] years and 55 [interquartile range = 74] months on HD) completed the study. There was no significant difference concerning the expression of mRNA NRF2 (P = .915) and mRNA NF-κB (P = .806) after supplementation with SFN. There was no difference in pro-inflammatory and oxidative stress biomarkers. CONCLUSION: 150 µmol of SFN for 2 months had no antioxidant and anti-inflammatory effect in patients with CKD undergoing HD.

CHARACTERIZATION OF THE FUNGAL MICROBIOTA IN THE NOSTRILS AND RECTUM OF AMAZONIAN MANATEES (TRICHECHUS INUNGUIS) FROM A REHABILITATION PROGRAM IN BRAZIL.

The present study characterized the filamentous and yeast-like fungal microbiota of the nasal cavity and rectum of Amazonian manatees (Trichechus inunguis) undergoing rehabilitation at the Laboratory of Aquatic Mammals, National Institute of Amazonian Research, Manaus, Amazonas, and determined the antifungal susceptibility of these organisms. Nasal and rectal swabs were collected from 22 calves and three juveniles. The samples were seeded in Sabouraud agar supplemented with chloramphenicol 10%, incubated at 26°C, and observed daily for up to 7 d. The growth of different filamentous and yeast-like fungi was observed among the two anatomical sites. Filamentous fungi were categorized by macro- and microscopic characteristics of the colonies. Representatives of each group were selected for molecular identification based on the internal transcribed spacer region. Yeast identification was performed using MALDI-TOF MS and molecular analyses. Thirteen genera of filamentous fungi and six genera of yeasts were isolated and identified. The dominant filamentous species were Fusarium spp., Aspergillus spp., and Cochliobolus lunatus in the nostril samples and Aspergillus melleus in the rectal samples. Candida was the dominant genus among the identified yeasts at both anatomical sites. In the antifungal susceptibility test, 28 isolates showed resistance to fluconazole (78%), itraconazole (39%), and nystatin (42%). The knowledge of fungal microbiota composition of Amazonian manatees provides information that assists in monitoring the health status of individuals maintained in captivity, as these organisms can behave either as opportunists or as primary pathogens. Moreover, the composition and resistance of these organisms may vary among different rehabilitation institutions or different time frames of search, reinforcing the importance of constant in loco surveillance of these microorganisms. This study provides new perspectives on the fungal diversity in the microbiota of manatees and supports future studies concerning the clinical and epidemiological aspects and the impacts of these agents on the health of Amazonian manatees undergoing rehabilitation.

Interaction of pre- and postnatal nutrition on expression of leptin receptor variants and transporter molecules, leptin transport, and functional response to leptin in heifers†.

Perinatal nutrition modulates the hypothalamic neurocircuitries controlling GnRH release, thus programming pubertal maturation in female mammals. Objectives of experiments reported here were to test the hypotheses that prenatal nutrition during mid- to late gestation interacts with postnatal nutrition during the juvenile period in heifer offspring to alter expression of leptin receptor (LepR) variants (ObRa, ObRb, ObRc, ObRt), and lipoprotein transporter molecules (LRP1 and 2) in the choroid plexus, leptin transport across the blood-brain barrier, and hypothalamic-hypophyseal responsiveness to exogenous ovine leptin (oleptin) during fasting. Nutritional programming of heifers employed a 3 × 2 factorial design of maternal (high, H; low, L; and moderate, M) × postnatal (H and L) dietary treatments. Results (Expt. 1) demonstrated that prepubertal heifers born to L dams, regardless of postnatal diet, had reduced expression of the short isoform of ObRc compared to H and M dams, with sporadic effects of undernutrition (L or LL) on ObRb, ObRt, and LRP1. Intravenous administration of oleptin to a selected postpubertal group (HH, MH, LL) of ovariectomized, estradiol-implanted heifers fasted for 56 h (Expt. 2) did not create detectable increases in third ventricle cerebrospinal fluid but increased gonadotropin secretion in all nutritional groups tested. Previous work has shown that leptin enhances gonadotropin secretion during fasting via effects at both hypothalamic and anterior pituitary levels in cattle. Given the apparent lack of robust transfer of leptin across the blood-brain barrier in the current study, effects of leptin at the adenohypophyseal level may predominate in this experimental model.

Neuroinflammation in Alzheimer's disease: potential beneficial effects of vitamin D.

Alzheimer's disease (AD) is the most common cause of dementia. In recent years, several studies have robustly shown that neuroinflammation plays a crucial role in the pathophysiology of this disease. The co-localization of amyloid-ß plaques near activated glial cells and the increased levels of inflammatory cytokines in AD patients indicate the involvement of the neuroinflammatory process in AD progression. Considering that pharmacological treatment remains a challenge for the management of this disease, compounds with anti-inflammatory and antioxidant properties are promising therapeutic strategies. In this context, vitamin D has gained attention in the last few years due to its neuroprotective property and the high prevalence of vitamin D deficiency in the population. Herein, in this narrative review we present the possible contribution of the antioxidant and anti-inflammatory properties of vitamin D for its neuroprotective effects, and the clinical and preclinical data dealing with the effects of vitamin D in AD, focusing mainly on the neuroinflammatory process.

The antidepressant-like effect elicited by vitamin D3 is associated with BDNF/TrkB-related synaptic protein synthesis.

Vitamin D3 (cholecalciferol) has been shown to exert antidepressant-like responses, but the role BDNF/TrkB-related synaptic plasticity in this effect remains to be established. Thus, this study investigated the time-course antidepressant-like response of vitamin D3 in female and male mice and the possible role of BDNF/TrkB signaling in this response. The repeated (7 and 21 days), but not acute (60 min), administration of vitamin D3 (2.5 µg/kg, p.o.) exerted an antidepressant-like effect in female and male mice subjected to the tail suspension test, without altering the basal locomotor activity in the open-field test. Notably, vitamin D3 caused a similar time-dependent antidepressant-like effect in male and female mice, suggesting that this behavioral response in the tail suspension test might not be affected by sex differences. Vitamin D3 administration for 21 days, but not for 7 days or 1 h, augmented BDNF levels in the hippocampus and prefrontal cortex of mice. No effects on phospho-CREB/CREB levels were detected in the hippocampus and prefrontal cortex after chronic vitamin D3 administration. Additionally, vitamin D3 increased TrkB, GluA1, and PSD-95 levels in the prefrontal cortex, but not in the hippocampus. Furthermore, an upregulation of synapsin level was observed in both brain regions after vitamin D3 administration. These findings reinforce and extend the notion that vitamin D3 is effective to produce antidepressant-like responses in male and female mice and provide novel evidence that this effect could be associated with BDNF/TrkB-related synaptic protein synthesis. Finally, vitamin D3 could be a feasible nutritional strategy for the management of depression.

Plasmodium vivax spleen-dependent genes encode antigens associated with cytoadhesion and clinical protection.

Plasmodium vivax, the most widely distributed human malaria parasite, causes severe clinical syndromes despite low peripheral blood parasitemia. This conundrum is further complicated as cytoadherence in the microvasculature is still a matter of investigations. Previous reports in Plasmodium knowlesi, another parasite species shown to infect humans, demonstrated that variant genes involved in cytoadherence were dependent on the spleen for their expression. Hence, using a global transcriptional analysis of parasites obtained from spleen-intact and splenectomized monkeys, we identified 67 P. vivax genes whose expression was spleen dependent. To determine their role in cytoadherence, two Plasmodium falciparum transgenic lines expressing two variant proteins pertaining to VIR and Pv-FAM-D multigene families were used. Cytoadherence assays demonstrated specific binding to human spleen but not lung fibroblasts of the transgenic line expressing the VIR14 protein. To gain more insights, we expressed five P. vivax spleen-dependent genes as recombinant proteins, including members of three different multigene families (VIR, Pv-FAM-A, Pv-FAM-D), one membrane transporter (SECY), and one hypothetical protein (HYP1), and determined their immunogenicity and association with clinical protection in a prospective study of 383 children in Papua New Guinea. Results demonstrated that spleen-dependent antigens are immunogenic in natural infections and that antibodies to HYP1 are associated with clinical protection. These results suggest that the spleen plays a major role in expression of parasite proteins involved in cytoadherence and can reveal antigens associated with clinical protection, thus prompting a paradigm shift in P. vivax biology toward deeper studies of the spleen during infections.

Epidemiology of arthropods envenomation in Brazil: a public health issue.

Brazil is located between the Equator and Tropic of Capricorn, which allows diverse climates, reliefs, and habitats for arthropods, which sting represents a risk to human health and a public health issue. This manuscript updates the epidemiological data of cases of human envenoming by spiders, scorpions, and insects with medical relevance in Brazil from 2010 to 2021. Epidemiological data were taken using the Brazilian Notifiable Diseases Information System. Statistics of non-parametric data used the Kruskal-Wallis followed by the Nemenyi test. On average, more than 145,000 envenomation and 145 deaths are recorded annually, and more than 60% of deaths are caused by scorpion bites. When the number of deaths was pondered by the number of cases with each arthropod, bees kill the most. Most stings cause mild symptoms and affect men of working age. The incidence decreases during the colder months, which is better noticeable in regions with well-defined seasons. The distribution is distinct among the regions: Southeast, Northeast, and South have the highest rate of bites. The growing number of cases of envenomation reported annually is a serious public health concern, especially involving scorpions, and highlights the importance of studying arthropod venom and improving the therapies.

Yerba mate (Ilex paraguariensis A. St.-Hil.) for new therapeutic and nutraceutical interventions: A review of patents issued in the last 20 years (2000-2020).

It has been estimated that more than 70% of all drugs approved worldwide between 1981 and 2006 for human health are derived from or structurally similar to natural compounds. The identification of biological matrices containing bioactive compounds with therapeutic and nutraceutical potential is necessary to supply the global market demands. Researches have indicated that the consumption of dry and aqueous extracts of Ilex paraguariensis A. St.-Hil. is safe, providing that plant biomass does not be exposed to smoke over the drying process, avoiding contamination (e.g., ) with polycyclic aromatic hydrocarbon compounds, and can might help avoiding many diseases, with important potential applications in the pharma and nutraceutical industries. A survey was carried out covering the main therapeutic and nutraceutical studies performed on I. paraguariensis extracts and their relationship with the global patents granted in the last 20 years for the products using this specie in their composition. In the PubMed database, by searching for the term "Ilex paraguariensis," an output with 497 scientific publications was found. Each paper was analyzed individually and 26 publications encompassing exclusively therapeutical and nutraceutical approaches of that plant species were selected. For the patent screening regarding Ilex-derived products, the survey considered three patent databases: European Patent Office (EPO) (Espacenet), World Intellectual Property Organization, WIPO), and National Institute of Industrial Property (NIIP-Brazil). The criterion chosen to select the patents in the databases was the inclusion of the terms "Ilex paraguariensis" and "yerba mate" in the title and/or in the abstract, considering the patents issued from 2000 to 2020. Additionally, only patents with therapeutic and nutraceutical potential were considered on the survey. The screening and selection of the documents were performed independently by two researchers and the information cross-checked at the end. This review contributes to show the state of the art over the last 20 years on the knowledge about the therapeutical and nutraceutical usages of the yerba mate, associated to a certain number of issued patents. The patent survey afforded 62 relevant documents covering products based on Ilex paraguariensis biomass. Considering the number of patents issued, most of them are related to the pharmaceutical area (30), followed by food supplements and beverages (17), cosmetics (10) and, finally, nutraceuticals (5). A detailed analysis of the patents issued showed that most are related to pharmaceutical grade products, generally, marketed as oral and injectable compositions for treatments of obesity, insulin resistance, hyperlipemia and diabetes mellitus, arteriosclerosis, neurological diseases, and SARS-Cov-2, for example. In this work, a curious fact is that there are few patents for food, cosmetics, and nutraceuticals products containing yerba mate. Therefore, it seems to be relevant to take into account the potential of that species as source of bioactive compounds for the development of new products not only intended to the pharma sector. In this sense, 26 reports were identified showing possibilities and trendiness in developing new yerba mate based products, such as packaging, biopesticides, antiseptics, and food supply, expanding the possibilities of technological applications of this plant species.

Convalescent plasma for COVID-19 in hospitalised patients: an open-label, randomised clinical trial.

BACKGROUND: The effects of convalescent plasma (CP) therapy in hospitalised patients with coronavirus disease 2019 (COVID-19) remain uncertain. This study investigates the effect of CP on clinical improvement in these patients. METHODS: This is an investigator-initiated, randomised, parallel arm, open-label, superiority clinical trial. Patients were randomly (1:1) assigned to two infusions of CP plus standard of care (SOC) or SOC alone. The primary outcome was the proportion of patients with clinical improvement 28 days after enrolment. RESULTS: A total of 160 (80 in each arm) patients (66.3% critically ill, 33.7% severely ill) completed the trial. The median (interquartile range (IQR)) age was 60.5 (48-68) years; 58.1% were male and the median (IQR) time from symptom onset to randomisation was 10 (8-12) days. Neutralising antibody titres >1:80 were present in 133 (83.1%) patients at baseline. The proportion of patients with clinical improvement on day 28 was 61.3% in the CP+SOC group and 65.0% in the SOC group (difference -3.7%, 95% CI -18.8-11.3%). The results were similar in the severe and critically ill subgroups. There was no significant difference between CP+SOC and SOC groups in pre-specified secondary outcomes, including 28-day mortality, days alive and free of respiratory support and duration of invasive ventilatory support. Inflammatory and other laboratory marker values on days 3, 7 and 14 were similar between groups. CONCLUSIONS: CP+SOC did not result in a higher proportion of clinical improvement on day 28 in hospitalised patients with COVID-19 compared to SOC alone.

Functional Connectivity Hypersynchronization in Relatives of Alzheimer's Disease Patients: An Early E/I Balance Dysfunction?

Alzheimer's disease (AD) studies on animal models, and humans showed a tendency of the brain tissue to become hyperexcitable and hypersynchronized, causing neurodegeneration. However, we know little about either the onset of this phenomenon or its early effects on functional brain networks. We studied functional connectivity (FC) on 127 participants (92 middle-age relatives of AD patients and 35 age-matched nonrelatives) using magnetoencephalography. FC was estimated in the alpha band in areas known both for early amyloid accumulation and disrupted FC in MCI converters to AD. We found a frontoparietal network (anterior cingulate cortex, dorsal frontal, and precuneus) where relatives of AD patients showed hypersynchronization in high alpha (not modulated by APOE-ε4 genotype) in comparison to age-matched nonrelatives. These results represent the first evidence of neurophysiological events causing early network disruption in humans, opening a new perspective for intervention on the excitation/inhibition unbalance.

Acoustic identification and classification of four dolphin species in the Brazilian marine area affected by the largest tailings dam failure disaster.

Passive acoustic monitoring (PAM) is an increasingly used technique to access the occurrence, distribution, and abundance of cetaceans that may be visually unavailable most of the time. The largest tailings dam failure disaster occurred on 5 November 2015, when the Fundão dam collapsed, releasing over 50 million cubic meters of tailings into the Doce River basin; 14 days later, the tailings plume reached the Atlantic Ocean. PAM was implemented in the concerned area and cetacean species were acoustically identified. Whistles and clicks of visual and acoustic matches were used to predict and classify exclusive acoustic records through random forest models. The identified species were Guiana, rough-toothed, and bottlenose dolphins. Additionally, the franciscana, the most threatened cetacean in the western South Atlantic Ocean, was also acoustically identified. The whistle classifier had 86.9% accuracy with final frequency, duration, and maximum frequency ranked as the most important parameters. The clicks classifier had 86.7% accuracy with peak frequency and 3 dB bandwidth as the most important parameters for classifying species. Considering the potential effect of the increase in turbidity on sound transmission, such as attenuation, the presented classifier should be continuously improved with novel data collected from long-term acoustic monitoring.

Molecular docking study and antireabsorptive activity of a semi-synthetic coumarin derivative from Platymiscium floribundum in the ligature-induced periodontitis in rats: the involvement of heme oxygenase-1.

OBJETIVE: This study aimed to evaluate the anti-resorptive activity of a semi-synthetic coumarin derivative from Platymiscium floribundum, named 6,7-dimethoxy-3-nitrocoumarin. MATERIAL AND METHODS: Molecular docking studies were performed to test the binding performance of the derivative against targets associated with alveolar bone loss (TNF-α, IL-1ß, and catalase) and a target considered an antioxidant defense (HO-1) during periodontitis. Periodontitis was induced by placing a nylon ligature around the second molars. The rats received for 11 days 6,7-dimethoxy-3-nitrocoumarin (0.01, 0.1, or 1 mg/kg) or vehicle. We investigated by RT-qPCR analysis (TNF-α, IL-1ß, and HO-1 mRNA expression levels) and by colorimetric assay (catalase activity) the mechanism of action mediated by 6,7-dimethoxy-3-nitrocoumarin. The in vivo toxicity of 6,7-dimethoxy-3-nitrocoumarin was evaluated. RESULTS: 6,7-Dimethoxy-3-nitrocoumarin (0.1 or 1 mg/kg) reduced alveolar bone loss (1.05 ± 0.24), when compared to vehicle-treated group (3.05 ± 0.30). The interactions of 6,7-dimethoxy-3-nitrocoumarin and the four targets (TNF-α, IL-1ß, catalase, and HO-1) showed firm bonds above 6.0 kcal/mol. 6,7-dimethoxy-3-nitrocoumarin (1 mg/kg) lowered mRNA expression levels of TNF-α (2.33 ± 0.56) and IL-1ß (19.87 ± 2.9), while it increased both the mRNA expression levels of HO-1 (43.40 ± 1.05) and the catalase activity (46.42 ± 4.59), when compared to vehicle-treated group (46.29 ± 8.43; 37.83 ± 4.38; 1.58 ± 0.11; 8.93 ± 1.86, respectively). The animals did not show any signs of toxicity. CONCLUSION: 6,7-Dimethoxy-3-nitrocoumarin decreased inflammatory bone loss in the ligature-induced periodontitis in rats, and the activation of the HO-1 pathway may contribute, at least partially, to its protective effects by reducing TNF-α and IL-1ß mRNA levels and increasing catalase activity. CLINICAL RELEVANCE: 6,7-Dimethoxy-3-nitrocumarin could be used as an adjunct to subgingival instrumentation during active and supportive periodontal treatment.

NLRP3 Inflammasome: From Pathophysiology to Therapeutic Target in Major Depressive Disorder.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, whose pathophysiology has been linked to the neuroinflammatory process. The increased activity of the Nod-like receptor pyrin containing protein 3 (NLRP3) inflammasome, an intracellular multiprotein complex, is intrinsically implicated in neuroinflammation by promoting the maturation and release of proinflammatory cytokines such as interleukin (IL)-1ß and IL-18. Interestingly, individuals suffering from MDD have higher expression of NLRP3 inflammasome components and proinflammatory cytokines when compared to healthy individuals. In part, intense activation of the inflammasome may be related to autophagic impairment. Noteworthy, some conventional antidepressants induce autophagy, resulting in less activation of the NLRP3 inflammasome. In addition, the fast-acting antidepressant ketamine, some bioactive compounds and physical exercise have also been shown to have anti-inflammatory properties via inflammasome inhibition. Therefore, it is suggested that modulation of inflammasome-driven pathways may have an antidepressant effect. Here, we review the role of the NLRP3 inflammasome in the pathogenesis of MDD, highlighting that pathways related to its priming and activation are potential therapeutic targets for the treatment of MDD.

Molecular Basis Underlying the Therapeutic Potential of Vitamin D for the Treatment of Depression and Anxiety.

Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium-phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.