The Alzheimer's disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons.

Bridging Integrator 1 (BIN1) is the second most important Alzheimer's disease (AD) risk gene, but its physiological roles in neurons and its contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role in the regulation of calcium homeostasis, electrical activity, and gene expression of glutamatergic neurons. Using single-cell RNA-sequencing on cerebral organoids generated from isogenic BIN1 wild type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), we show that BIN1 is mainly expressed by oligodendrocytes and glutamatergic neurons, like in the human brain. Both BIN1 HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1 cell-autonomously regulates gene expression in glutamatergic neurons by using a novel protocol to generate pure culture of hiPSC-derived induced neurons (hiNs). Using this system, we also show that BIN1 plays a key role in the regulation of neuronal calcium transients and electrical activity via its interaction with the L-type voltage-gated calcium channel Cav1.2. BIN1 KO hiNs show reduced activity-dependent internalization and higher Cav1.2 expression compared to WT hiNs. Pharmacological blocking of this channel with clinically relevant doses of nifedipine, a calcium channel blocker, partly rescues electrical and gene expression alterations in BIN1 KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1 KO hiNs that affect biological processes related to calcium homeostasis are also present in glutamatergic neurons of the human brain at late stages of AD pathology. Together, these findings suggest that BIN1-dependent alterations in neuronal properties could contribute to AD pathophysiology and that treatment with low doses of clinically approved calcium blockers should be considered as an option to slow disease-onset and progression.

Type I interferons and MAVS signaling are necessary for tissue resident memory CD8+ T cell responses to RSV infection.

Respiratory syncytial virus (RSV) can cause bronchiolitis and viral pneumonia in young children and the elderly. Lack of vaccines and recurrence of RSV infection indicate the difficulty in eliciting protective memory immune responses. Tissue resident memory T cells (TRM) can confer protection from pathogen re-infection and, in human experimental RSV infection, the presence of lung CD8+ TRM cells correlates with a better outcome. However, the requirements for generating and maintaining lung TRM cells during RSV infection are not fully understood. Here, we use mouse models to assess the impact of innate immune response determinants in the generation and subsequent expansion of the TRM cell pool during RSV infection. We show that CD8+ TRM cells expand independently from systemic CD8+ T cells after RSV re-infection. Re-infected MAVS and MyD88/TRIF deficient mice, lacking key components involved in innate immune recognition of RSV and induction of type I interferons (IFN-α/ß), display impaired expansion of CD8+ TRM cells and reduction in antigen specific production of granzyme B and IFN-γ. IFN-α treatment of MAVS deficient mice during primary RSV infection restored TRM cell expansion upon re-challenge but failed to recover TRM cell functionality. Our data reveal how innate immunity, including the axis controlling type I IFN induction, instructs and regulates CD8+ TRM cell responses to RSV infection, suggesting possible mechanisms for therapeutic intervention.

Airway-delivered short-chain fatty acid acetate boosts antiviral immunity during rhinovirus infection.

BACKGROUND: Microbiota are recognized to play a major role in regulation of immunity through release of immunomodulatory metabolites such as short-chain fatty acids (SCFAs). Rhinoviruses (RVs) induce upper respiratory tract illnesses and precipitate exacerbations of asthma and chronic obstructive pulmonary disease through poorly understood mechanisms. Local interactions between SCFAs and antiviral immune responses in the respiratory tract have not been previously investigated. OBJECTIVE: We sought to investigate whether pulmonary metabolite manipulation through lung-delivered administration of SCFAs can modulate antiviral immunity to RV infection. METHODS: We studied the effects of intranasal administration of the SCFAs acetate, butyrate, and propionate on basal expression of antiviral signatures, and of acetate in a mouse model of RV infection and in RV-infected lung epithelial cell lines. We additionally assessed the effects of acetate, butyrate, and propionate on RV infection in differentiated human primary bronchial epithelial cells. RESULTS: Intranasal acetate administration induced basal upregulation of IFN-ß, an effect not observed with other SCFAs. Butyrate induced RIG-I expression. Intranasal acetate treatment of mice increased interferon-stimulated gene and IFN-λ expression during RV infection and reduced lung virus loads at 8 hours postinfection. Acetate ameliorated virus-induced proinflammatory responses with attenuated pulmonary mucin and IL-6 expression observed at day 4 and 6 postinfection. This interferon-enhancing effect of acetate was confirmed in human bronchial and alveolar epithelial cell lines. In differentiated primary bronchial epithelial cells, butyrate treatment better modulated IFN-ß and IFN-λ gene expression during RV infection. CONCLUSIONS: SCFAs augment antiviral immunity and reduce virus load and proinflammatory responses during RV infection.

The spatial grounding of politics.

In three studies, we advance the research on the association between abstract concepts and spatial dimensions by examining the spatial anchoring of political categories in three different paradigms (spatial placement, memory, and classification) and using non-linguistic stimuli (i.e., photos of politicians). The general hypothesis that politicians of a conservative or socialist party are grounded spatially was confirmed across the studies. In Study 1, photos of politicians were spontaneously placed to the left or right of an unanchored horizontal line depending on their socialist-conservative party affiliation. In Study 2, the political orientation of members of parliament systematically distorted the recall of the spatial positions in which they were originally presented. Finally, Study 3 revealed that classification was more accurate and faster when the politicians were presented in spatially congruent positions (e.g., socialist politician presented on the left side of the monitor) rather than incongruent ones (e.g., socialist on the right side). Additionally, we examined whether participants' political orientation and awareness moderated these effects and showed that spatial anchoring seems independent of political preference but increases with political awareness.

Gallic acid modulates purine metabolism and oxidative stress induced by ethanol exposure in zebrafish brain.

Gallic acid (GA) is a secondary metabolite found in plants. It has the ability to cross the blood-brain barrier and, through scavenging properties, has a protective effect in a brain insult model. Alcohol metabolism generates reactive oxygen species (ROS); thus, alcohol abuse has a deleterious effect on the brain. The zebrafish is a vertebrate often used for screening toxic substances and in acute ethanol exposure models. The aim of this study was to evaluate whether GA pretreatment (24 h) prevents the changes induced by acute ethanol exposure (1 h) in the purinergic signaling pathway in the zebrafish brain via degradation of extracellular nucleotides and oxidative stress. The nucleotide cascade promoted by the nucleoside triphosphate diphosphohydrolase (NTPDase) and 5'-nucleotidase was assessed by quantifying nucleotide metabolism. The effect of GA alone at 5 and 10 mg L-1 did not change the nucleotide levels. Pretreatment with 10 mg L-1 GA prevented an ethanol-induced increase in ATP and ADP levels. No significant difference was found between the AMP levels of the two pretreatment groups. Pretreatment with 10 mg L-1 GA prevented ethanol-enhanced lipid peroxidation and dichlorodihydrofluorescein (DCFH) levels. The higher GA concentration was also shown to positively modulate against ethanol-induced effects on superoxide dismutase (SOD), but not on catalase (CAT). This study demonstrated that GA prevents the inhibitory effect of ethanol on NTPDase activity and oxidative stress parameters, thus consequently modulating nucleotide levels that may contribute to the possible protective effects induced by alcohol and purinergic signaling.

Biocidal Activity of a Nanoemulsion Containing Essential Oil from Protium heptaphyllum Resin against Aedes aegypti (Diptera: Culicidae).

This work aimed to prepare a nanoemulsion containing the essential oil of the Protium heptaphyllum resin and evaluate its biocidal activities against the different stages of development of the Aedes aegypti mosquito. Ovicide, pupicide, adulticide and repellency assays were performed. The main constituents were p-cymene (27.70%) and α-pinene (22.31%). The developed nanoemulsion showed kinetic stability and monomodal distribution at a hydrophilic-lipophilic balance of 14 with a droplet size of 115.56 ± 1.68 nn and a zeta potential of -29.63 ± 3.46 mV. The nanoemulsion showed insecticidal action with LC50 0.404 µg·mL-1 for the ovicidal effect. In the pupicidal test, at the concentration of 160 µg·mL-1, 100% mortality was reached after 24 h. For adulticidal activity, a diagnostic concentration of 200 µg·mL-1 (120 min) was determined. In the repellency test, a concentration of 200 µg·mL-1 during the 180 min of the test showed a protection index of 77.67%. In conclusion, the nanobiotechnological product derived from the essential oil of P. heptaphyllum resin can be considered as a promising colloid that can be used to control infectious disease vectors through a wide range of possible modes of applications, probably as this bioactive delivery system may allow the optimal effect of the P. heptaphyllum terpenes in aqueous media and may also induce satisfactory delivery to air interfaces.

Chemical composition and biological activities of two chemotype-oils from Cinnamomum verum J. Presl growing in North Brazil.

Chemical composition and antioxidant and antifungal action of the oils from leaves and wood bark of two chemotypes of Cinnamomum verum J. Presl were evaluated. Plants were sampled in the cities of São Luís and Santa Inês, state of Maranhão, Brazil. GC-MS and GC-FID, DPPH radical scavenging, and in vitro test against the phytopathogenic fungus Colletotrichum musae were used to perform these analyses. Cinnamomum verum is worldwide known as Cinnamon, highlighted for its extensive use in the cooking of diverse cultures of the world, and as a medicinal plant to treat environmental viral diseases. In the leaf oil of São Luís chemotype, eugenol (93.6%) was the main constituent, while in Santa Inês chemotype, it was benzyl benzoate (95.3%). In the bark wood oil of São Luís chemotype, (E)-cinnamaldehyde (89.3%) was the main constituent, while in Santa Inês chemotype, they were benzyl benzoate (23.3%), linalool (14.0%), (E)-caryophyllene (9.1%), caryolan-8-ol (7.2%) and borneol (4.7%). Leaf oils from both chemotypes showed strong to moderate antifungal activity, reaching 100% efficacy in eugenol-containing oils and above 70% in benzyl benzoate oils. In the antioxidant evaluation, the chemotype with a high eugenol content presented an inhibitory concentration higher than 80%, compared to Trolox. The leaf oils of the two C. verum chemotypes showed significant antifungal and antioxidant potential, considering their economic use as a functional and nutraceutical food supplement.

Chemical Composition and In Vitro Antioxidant, Cytotoxic, Antimicrobial, and Larvicidal Activities of the Essential Oil of Mentha piperita L. (Lamiaceae).

The essential oil was obtained by hydrodistillation and the identification and quantification of components were achieved with the use of GC-MS analysis. The antioxidant activity was evaluated by the method of sequestration of DPPH. Essential oils were used for study the cytotoxic front larvae of Artemia salina. In the evaluation of the antimicrobial activity of essential oils, we employed the disk-diffusion method. The potential larvicide in mosquito larvae of the third stage of development of Aedes aegypti to different concentrations of essential oils was evaluated. The major compounds found in the essential oils of M. piperita were linalool (51.8%) and epoxyocimene (19.3%). The percentage of antioxidant activity was 79.9 ± 1.6%. The essential oil showed LC50 = 414.6 µg/mL front of A. saline and is considered highly toxic. It shows sensitivity and halos significant inhibition against E. coli. The essential possessed partial larvicidal efficiency against A. aegypti.

The adsorption of amino acids and cations onto goethite: a prebiotic chemistry experiment.

Few prebiotic chemistry experiments have assessed the adsorption of biomolecules by iron oxide-hydroxides. The present work investigated the effects of cations in artificial seawaters on the adsorption of Gly, α-Ala and ß-Ala onto goethite, and vice versa. Goethite served to concentrate K and Mg cations from solution; these effects could have played important roles in peptide nucleoside formation. Goethite showed low adsorption of Gly and α-Ala. On the other hand, ß-Ala (a non-protein amino acid) was highly adsorbed by goethite. Because Gly and α-Ala are the most common amino acids in living beings, and iron oxide-hydroxides are widespread on Earth, additional iron oxides should be studied. Increased ionic strength in artificial seawaters decreased the adsorption of amino acids by goethite. Because Na was highly abundant in the artificial seawater, it showed the highest effect on amino acid adsorption. ß-Ala increased the adsorption of K and Ca by goethite, this effect could have been important for peptide synthesis.

ß-1,3/1,6-Glucan-supplemented diets antagonize immune inhibitory effects of hypoxia and enhance the immune response to a model vaccine.

The diets of farmed salmon are usually supplemented with immunostimulants to improve health status. Because ß-glucan is one of the most common immunostimulants used in diets, here we examined the effect of two ß-1,3/1,6-glucan-supplemented diets on the expression of immune response genes of Atlantic salmon. The relative abundances of IFN-α1, Mx, IFN-γ, IL-12, TGF-ß1, IL-10, and CD4 transcripts were evaluated in head kidney by qRT-PCR. We assessed the effects of the diets under normoxia and acute hypoxia, as salmon are especially sensitive to changes in the concentration of dissolved oxygen, which can also affect immunity. These effects were also tested on vaccinated fish, as we expected that ß-1,3/1,6-glucan-supplemented diets would enhance the adaptive immune response to the vaccine. We found that administration of the Bg diet (containing ß-1,3/1,6-glucan) under normoxia had no effects on the expression of the analyzed genes in the kidney of the diet-fed fish, but under hypoxia/re-oxygenation (90 min of acute hypoxia), the ßg diet affected the expression of the antiviral genes, IFN-α1 and Mx, preventing their decrease caused by hypoxia. The Bax diet, which in addition to ß-1,3/1,6-glucan, contained astaxanthin, increased IL-12 and IFN-γ in kidneys. With fish exposed to hypoxia/reoxygenation, the diet prevented the decrease of IFN-α1 and Mx levels observed after hypoxia. When fish were vaccinated, only the levels of IL-12 and CD4 transcripts increased, but interestingly if fish were also fed the Bax diet, the vaccination induced a significant increase in all the analyzed transcripts. Finally, when vaccinated fish were exposed to hypoxia, the effect of the Bax diet was greatly reduced for all genes tested and moreover, inducible effects completely disappeared for IL-12, IFN-α, and Mx. Altogether, these results showed that the tested ß-1,3/1,6-glucan diets increased the levels of transcripts of key genes involved in innate and adaptive immune response of salmon, potentiating the response to a model vaccine and also antagonizing the effects of hypoxia.

Effects of SARS-CoV-2 gestational exposure and risk factors on neurodevelopment until 12 months: A prospective cohort study in Brazil.

BACKGROUND: The effects of SARS-CoV-2 gestational exposure on child development remain inconclusive. AIMS: To analyze the effects of SARS-CoV-2 gestational exposure on neurodevelopment until 12 months. STUDY DESIGN: Prospective cohort study conducted in five municipalities in Southeast Brazil from August 2021 to September 2022. SUBJECTS: Infants were recruited from a serological survey performed during neonatal screening and followed up to 12 months old. We included 224 infants exposed to SARS-CoV-2 during pregnancy and 225 non-exposed, according to the serology results of the newborn as well as their mothers and the maternal antenatal RT-PCR results. OUTCOME MEASURES: Developmental assessments were performed at 6 and 12 months using the Survey of Wellbeing of Young Children-Brazilian Version (SWYC-BR). Children with suspected developmental delay (SDD) at 6 and 12 months were considered at high risk for developmental delay (HRDD). Additionally, risk factors associated with SDD were examined. RESULTS: There were 111 children identified with SDD and 52 with HRDD. SARS-CoV-2 gestational exposure was not associated with SDD. Exposure in the first gestational trimester increased SDD risk by 2.15 times compared to the third. Cesarean delivery predicted SDD (OR 1.56; 95%CI 1.01-2.42) and HRDD (OR 1.91; 95%CI 1.04-3.48). Additionally, suspected maternal depression predicted SDD (OR 1.76; 95%CI 1.01-3.10). CONCLUSION: SARS-CoV-2 gestational exposure did not increase the developmental delay risk. However, our findings suggest that the earlier the gestational exposure, the greater the developmental delay risk at 12 months. Cesarean delivery and suspected maternal depression increased the developmental delay risk, independent of virus exposure.

The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson's Disease: a New Genetic State of the Art.

Parkinson's disease (PD) is a neurodegenerative disorder affecting 2-3% of those aged over 65, characterized by motor symptoms like slow movement, tremors, and muscle rigidity, along with non-motor symptoms such as anxiety and dementia. Lewy bodies, clumps of misfolded proteins, contribute to neuron loss in PD. Mutations in the GBA1 gene are considered the primary genetic risk factor of PD. GBA1 mutations result in decreased activity of the lysosomal enzyme glucocerebrosidase (GCase) resulting in α-synuclein accumulation. We know that α-synuclein aggregation, lysosomal dysfunction, and endoplasmic reticulum disturbance are recognized factors to PD susceptibility; however, the molecular mechanisms connecting GBA1 gene mutations to increased PD risk remain partly unknown. Thus, in this narrative review conducted according to a systematic review method, we aimed to present the main contributions arising from the molecular impact of the GBA1 gene to the pathogenesis of PD providing new insights into potential impacts for advances in the clinical care of people with PD, a neurological disorder that has contributed to the substantial increase in the global burden of disease accentuated by the aging population. In summary, this narrative review highlights the multifaceted impact of GBA1 mutations in PD, exploring their role in clinical manifestations, genetic predispositions, and molecular mechanisms. The review emphasizes the importance of GBA1 mutations in both motor and non-motor symptoms of PD, suggesting broader therapeutic and management strategies. It also discusses the potential of CRISPR/Cas9 technology in advancing PD treatment and the need for future research to integrate these diverse aspects for improved diagnostics and therapies.

Factors that Affect Performance of Clinical Breast Examination and Mammography Screening among Brazilian Women.

BACKGROUND: In the Brazilian health system, community health facilities consist of multidisciplinary teams that focus on family health, whereas health centers treat mainly illnesses of registered patients. In the present study we compared socio-economic factors and performance of mammography screening (MS) and clinical breast exam (CBE),  respectively, among women who used both types of public health service centers. METHODS: The present study included 180 women aged ≥40 years, who used different health service centers within the same municipal district. Of all 180 women, 110 (41.1%) and 70 (38.9%) used a health center and a community health facility. Logistic regression analysis was performed to calculate odds ratios (ORs) and confidence intervals (CIs) of variables. RESULTS: Regression modeling indicated that women who used the community health facility, performed annual MS 9.52 (OR= 0.105; 95%CI: 0.03- 0.36) times more often (p <0.001). In this model retirement and gynecological service use ≤ each second year, increased annual MS performance 8.16 (95%CI: 1.55- 54.32) and 7.78 (95%CI: 2.54- 23.79) times (p <0.001; p <0.001). Among 113 (62.8%) women who reported strong fear of MS, the chance of its performance was 35.71 (OR= 0.028; 95%CI: 0.02- 0.32) times decreased (p= 0.05). In a second model use of gynecological service ≤ each second year, increased chance of annual CBE performance 7.92 (95%CI: 3.25- 19.29) times (p <0.001). Women who used the community health facility performed annual and bi-annual CBE 2.90 (OR= 0.345; 95%CI: 0.14- 0.86) and 2.97 (OR= 0.337; 95%CI: 0.12- 0.92) times more often, compared to women who used the health center (p =0.030). CONCLUSIONS: Performance of MS and CBE varied both considerable among women who used different types of health service centers. Gynecological service use, fear and socioeconomic variables, additionally influenced regular performance of MS and CBE.

Cerium biosorption onto alginate/vermiculite-based particles functionalized with ionic imprinting: Kinetics, equilibrium, thermodynamic, and reuse studies.

Cerium is an essential element for several applications in industry, therefore, recovering it from secondary sources is a promising strategy from an economic and environmental perspective. For this purpose, biosorption is a low-cost and effective alternative. The present work evaluated the recovery of Ce3+ from aqueous solutions using alginate/vermiculite-based particles (ALEV) functionalized by ionic imprinting. From the kinetic assays, it was verified that the uptake of Ce3+ followed the pseudo-second-order model and was mainly controlled by external diffusion. The Langmuir model better described the equilibrium data, and a maximum biosorption capacity of 0.671 mmol/g at 45 °C was attained. The evaluation of the thermodynamic quantities revealed that the process occurs spontaneously and endothermically. The particles reuse and Ce3+ recovery were achieved using 0.1 mol/L HCl or 1.0 mol/L CaCl2 solutions for up to four cycles of biosorption/desorption. The biosorbent was characterized before and posted Ce3+ biosorption to investigate the morphology, textural properties, crystallinity, thermal resistance, composition, and functional groups of the biosorbent.

Amyloid-Beta Peptides Trigger Premature Functional and Gene Expression Alterations in Human-Induced Neurons.

Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aß) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aß peptides is the causative agent of AD pathology, but we still lack comprehensive understanding of the molecular mechanisms connecting Aß peptides to neuronal dysfunctions in AD. In this work, we investigate the early effects of Aß peptide accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). We show that hiNs acutely exposed to low concentrations of both cell-secreted Aß peptides or synthetic Aß1-42 exhibit alterations in the frequency of calcium transients suggestive of increased neuronal excitability. Using single-cell RNA sequencing, we also show that cell-secreted Aß up-regulates the expression of several synapse-related genes and down-regulates the expression of genes associated with metabolic stress mainly in glutamatergic neurons and, to a lesser degree, in GABAergic neurons and astrocytes. These neuronal alterations correlate with activation of the SEMA5, EPHA and NECTIN signaling pathways, which are important regulators of synaptic plasticity. Altogether, our findings indicate that slight elevations in Aß concentrations are sufficient to elicit transcriptional changes in human neurons, which can contribute to early alterations in neural network activity.

Derivative of 7-hydroxycoumarin has antifungal potential against Candida species and low cytotoxicity against human cells: In silico studies and biological evaluation.

This study investigates the antifungal and cytotoxic properties of 7-(pentyloxy)-2H-chromen-2-one. Through molecular docking and dynamics simulations, we explored the compound's interactions with fungal cell protein targets. Notably, it exhibited strong affinities for 1,3ß-glucan synthase, squalene epoxidase, δ-14-sterol reductase, 14-α-demethylase, and thymidylate synthase, with binding energies ranging from -100.39 to -73.15 kcal/mol. Molecular dynamics simulations confirmed its stable binding at active targets. The MIC and MFC values ranged from 67.16 µM (15.6 µg/mL) to 537.28 µM (125.0 µg/mL). The compound displayed promising antifungal effects, inhibiting fungal growth for at least 24 hours. Fungal plasma membrane function alteration likely contributed to these antifungal mechanisms. Additionally, the combination of the compound with nystatin, fluconazole, and caspofungin showed indifferent effects on antifungal activity. Cytotoxicity assessment in human keratinocyte cells (HaCaT) revealed an IC50 of 100 µM, which was approximately 1.5 times higher than the MIC for C. krusei. Thus, the compound exhibited strongly in silico and in vitro antifungal activity with low cytotoxicity in HaCaT cells. These findings support its potential as a candidate for further development as an antifungal compound.

Proximal and fatty acid analysis in Ostrea chilensis, Crassostrea gigas and Mytilus chilensis (Bivalvia: Mollusca) from southern Chile.

Oysters and blue mussels are important hydrobiological resources for aquaculture. In Chile, they are farming on the Chiloé island, where around 18% of the world's mussels are produced, however, their nutritional dynamics are largely unknown. For this reason, the objective of this study was to determine the proximal biochemical composition and the fatty acid profile in the Chilean oyster (Ostrea chilensis), the Pacific oyster (Crassostrea gigas) and the Chilean mussel (Mytilus chilensis), to perform an intra and interspecific comparison. Shellfish sampled in winter were characterized by a high protein content, followed by medium values for lipid content and a low carbohydrate content compared to similar species in Europe. Also, oysters and mussels were found to be rich in omega-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), so they can be considered excellent functional food option for a healthy human diet. Their high contribution of n-3 LC-PUFA ranged between 5.2-12.9 µg FA mg-1 dry weight with high n-3/n-6 ratios, which depends on both the species and the on-growing location. Both taxa can be considered a plausible option to promote a healthy diet of marine origin in future generations. Also, these results could benefit the projection and development of aquaculture of these mollusks.

Melatonin Pretreatment Protects Against Status epilepticus, Glutamate Transport, and Oxidative Stress Induced by Kainic Acid in Zebrafish.

Status epilepticus (SE) develops from abnormal electrical discharges, resulting in neuronal damage. Current treatments include antiepileptic drugs. However, the most common drugs used to treat seizures may sometimes be ineffective and have many side effects. Melatonin is an endogenous physiological hormone that is considered an alternative treatment for neurological disorders because of its free radical scavenging property. Thus, this study aimed to determine the effects of melatonin pretreatment on SE by inducing glutamatergic hyperstimulation in zebrafish. Seizures were induced in zebrafish using kainic acid (KA), a glutamate analog, and the seizure intensity was recorded for 60 min. Melatonin treatment for 7 days showed a decrease in seizure intensity (28%), latency to reach score 5 (14 min), and duration of SE (29%). In addition, melatonin treatment attenuated glutamate transporter levels, which significantly decreased in the zebrafish brain after 12 h of KA-induced seizures. Melatonin treatment reduced the increase in oxidative stress by reactive oxygen species formation through thiobarbituric acid reactive substances and 2',7'-dichiorofluorescin, induced by KA-seizure. An imbalance of antioxidant enzyme activities such as superoxide dismutase and catalase was influenced by melatonin and KA-induced seizures. Our study indicates that melatonin promotes a neuroprotective response against the epileptic profile in zebrafish. These effects could be related to the modulation of glutamatergic neurotransmission, recovery of glutamate uptake, and oxidative stress parameters in the zebrafish brain.

Effects of PAHs on meiofauna from three estuaries with different levels of urbanization in the South Atlantic.

Estuarine environments are suggested to be the final receivers of human pollution and are impacted by surrounding urbanization and compounds carried by the river waters that flow from the continent. Polycyclic aromatic hydrocarbons (PAHs) are among the contaminants that can reach estuaries and can directly affect marine conservation, being considered highly deleterious to organisms living in these environments. This research investigated the meiofauna of three estuaries exposed to different levels of urbanization and consequently different levels of PAH concentrations, in order to assess how these compounds and environmental factors affect the distribution, structure and diversity of these interstitial invertebrates. A total of 15 major meiofauna groups were identified, with Nematoda being the dominant taxon (74.64%), followed by Copepoda (9.55%) and Polychaeta (8.56%). It was possible to observe significant differences in all diversity indices studied in the estuaries. With the exception of average density, the diversity indices (richness, Shannon index and evenness) were higher in the reference estuary, Goiana estuarine system (GES). On the other hand, the Timbó estuarine system (TES) had the lowest Shannon index value and richness, while the Capibaribe estuarine system (CES) had the lowest evenness value. The latter two estuaries (TES and CES) presented intermediate and high levels of urbanization, respectively. The ecological quality assessment (EcoQ) in the studied estuaries was classified from Poor to Moderate and the estuary with the lowest demographic density in its surroundings, GES, showed a better ecological quality (Moderate EcoQ). A significant distance-based multivariate linear modelling regression (DistLM) was observed between the environmental variables and the density of the meiobenthic community, where PAHs and pH were the main contributors to organism variation. The sediments were characterized by predominance of very fine sand and silt-clay in the most polluted environments, while the control site environment (GES) was dominated by medium grains. The highest concentrations of PAHs were found in the most urbanized estuaries, and directly affected the structure of the interstitial benthic community. The metrics used in the present study proved to be adequate for assessing the environmental quality of the investigated estuaries.

The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects.

The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer's disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.