Evaluation of the efficacy and safety of cannabidiol-rich cannabis extract in children with autism spectrum disorder: randomized, double-blind, and placebo-controlled clinical trial

Abstract Objective Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and social interaction and by restricted and repetitive patterns of behavior. Some studies have shown that substances derived from Cannabis sativa improve the quality of life of children with ASD without causing serious adverse effects, thus providing an alternative therapeutic option. The objective of this study was to evaluate the efficacy and safety of a cannabis extract rich in cannabidiol (CBD) in children with ASD. Methods In this randomized, double-blind, placebo-controlled clinical trial, 60 children, aged from 5 to 11 years, were selected and divided into two groups: the treatment group, which received the CBD-rich cannabis extract, and the control group, which received the placebo. They both used their respective products for a period of 12 weeks. Statistical analysis was done by two-factor mixed analysis of variance (two-way ANOVA). Results Significant results were found for social interaction (F1,116 = 14.13, p = 0.0002), anxiety (F1,116 = 5.99, p = 0.016), psychomotor agitation (F1,116 = 9.22, p = 0.003), number of meals a day (F1,116 = 4.11, p = 0.04), and concentration (F1,48 = 6.75, p = 0.01), the last of which was only significant in mild ASD cases. Regarding safety, it was found that only three children in the treatment group (9.7%) had adverse effects, namely dizziness, insomnia, colic, and weight gain. Conclusion CBD-rich cannabis extract was found to improve one of the diagnostic criteria for ASD (social interaction), as well as features that often co-exist with ASD, and to have few serious adverse effects.

Identifying biomarkers for tDCS treatment response in Alzheimer's disease patients: a machine learning approach using resting-state EEG classification.

Background: Transcranial direct current stimulation (tDCS) is a promising treatment for Alzheimer's Disease (AD). However, identifying objective biomarkers that can predict brain stimulation efficacy, remains a challenge. The primary aim of this investigation is to delineate the cerebral regions implicated in AD, taking into account the existing lacuna in comprehension of these regions. In pursuit of this objective, we have employed a supervised machine learning algorithm to prognosticate the neurophysiological outcomes resultant from the confluence of tDCS therapy plus cognitive intervention within both the cohort of responders and non-responders to antecedent tDCS treatment, stratified on the basis of antecedent cognitive outcomes. Methods: The data were obtained through an interventional trial. The study recorded high-resolution electroencephalography (EEG) in 70 AD patients and analyzed spectral power density during a 6 min resting period with eyes open focusing on a fixed point. The cognitive response was assessed using the AD Assessment Scale-Cognitive Subscale. The training process was carried out through a Random Forest classifier, and the dataset was partitioned into K equally-partitioned subsamples. The model was iterated k times using K-1 subsamples as the training bench and the remaining subsample as validation data for testing the model. Results: A clinical discriminating EEG biomarkers (features) was found. The ML model identified four brain regions that best predict the response to tDCS associated with cognitive intervention in AD patients. These regions included the channels: FC1, F8, CP5, Oz, and F7. Conclusion: These findings suggest that resting-state EEG features can provide valuable information on the likelihood of cognitive response to tDCS plus cognitive intervention in AD patients. The identified brain regions may serve as potential biomarkers for predicting treatment response and maybe guide a patient-centered strategy. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT02772185?term=NCT02772185&draw=2&rank=1, identifier ID: NCT02772185.

Facial morphometric differences across face databases: influence of ethnicities and sex.

The scientific need for standardized, high-quality facial stimuli has driven the creation of several face image databases in recent years. These stimuli are particularly important in facial asymmetry research. However, previous studies have reported facial anthropometric differences across a variety of ethnicities. This highlights the need to investigate whether these differences can also impact the use of face image databases, particularly in facial asymmetry research. In this study, we investigated facial asymmetry-based morphometric differences between the multi-ethnic Chicago Face Database (CFD) and the LACOP Face Database, which is composed of Brazilian subjects. We found reliable differences in facial asymmetry between the two databases, which were related to ethnic groups. Specifically, differences in eye and mouth asymmetry seem to drive these differences. The asymmetry-based morphometric differences among databases and ethnicities found in this study reinforce the necessity of creating multi-ethnic face databases.

Occurrence of persistent and mobile chemicals and other contaminants of emerging concern in Spanish and Portuguese wastewater treatment plants, transnational river basins and coastal water.

This work investigated, during one year, the occurrence and fate of 52 contaminants of emerging concern (CECs) in transnational river basins and coastal areas of the North of Portugal and Galicia (NW Spain) and the wastewater treatment plants (WWTPs) discharging on these environments. The different CECs investigated included pharmaceuticals, personal care products, industrial chemicals, among others, of which ca. 90 % would fulfill the persistence, mobility and toxicity criteria proposed by the German Environmental Agency. The results showed the ubiquitous presence of these CECs and an incomplete removal of over 60 % of them with current conventional WWTPs. These findings highlight the requirement of a prominent and coordinated upgrade of WWTP treatments in order to meet the future European Union regulations on urban wastewater treatment and surface water quality. In fact, even some compounds exhibiting high removals, such as caffeine or xylene sulfonate, were frequently detected in river and estuarine waters at the high ng L-1 level. Thus, our preliminary risk assessment study concluded that 18 of the CECs presented a potential risk for the environment, being caffeine, sulpiride, perfluorooctanoic acid (PFOA), diclofenac, fipronil and perfluorobutanoic acid (PFBA) the most concerning ones. Yet, additional toxicity data as well as a more robust information on persistence and mobility of CECs are necessary for better estimating the magnitude of the problem and improve risk assessment. As an example, in the case of the antidiabetic metformin, recent research has revealed toxicity for model fish species at concentration levels below those found in 40 % of the river water samples analyzed in this work.

Are Fish Populations at Risk? Metformin Disrupts Zebrafish Development and Reproductive Processes at Chronic Environmentally Relevant Concentrations.

The antidiabetic drug Metformin (MET), one of the most prevalent pharmaceuticals in the environment, is currently detected in surface waters in the range of ng/L to low µg/L. As current knowledge regarding the long-term effects of environmentally relevant concentrations of MET in nontarget organisms is limited, the present study aimed at investigating the generational effects of MET, in concentrations ranging from 390 to 14 423 ng/L in the model organism Danio rerio (up to 9 mpf), including the effects on its nonexposed offspring (until 60 dpf). We integrate several apical end points, i.e., embryonic development, survival, growth, and reproduction, with qRT-PCR and RNA-seq analyses to provide additional insights into the mode of action of MET. Reproductive-related parameters in the first generation were particularly sensitive to MET. MET parental exposure impacted critical molecular processes involved in the metabolism of zebrafish males, which in turn affected steroid hormone biosynthesis and upregulated male vtg1 expression by 99.78- to 155.47-fold at 390 and 14 432 MET treatment, respectively, pointing to an estrogenic effect. These findings can potentially explain the significant decrease in the fertilization rate and the increase of unactivated eggs. Nonexposed offspring was also affected by parental MET exposure, impacting its survival and growth. Altogether, these results suggest that MET, at environmentally relevant concentrations, severely affects several biological processes in zebrafish, supporting the urgent need to revise the proposed Predicted No-Effect Concentration (PNEC) and the Environmental Quality Standard (EQS) for MET.

Effects on pain and cognition of transcranial direct current stimulation over the dorsolateral prefrontal cortex in women with chronic migraine.

We compared the effects of one versus two daily sessions of anodal transcranial direct current stimulation (a-tDCS) delivered to the left dorsolateral prefrontal cortex (DLPFC) for 10 days in a cohort of 30 women (mean age 28.0±6.92) with chronic migraine (CM, disease duration: 37.8±48.41 month). Participants were randomly allocated to three groups: a-tDCS 1-s Group received one daily a-tDCS session; a-tDCS 2-s Group received two daily a-tDCS sessions; Group SHAM received one daily session with a simulated (placebo) current. All participants were assessed before, after and one month after treatment, using the Migraine Disability Assessment, Montreal Cognitive Assessment, d2 Test of Attention, Trail Making Test (part B), Sequence of Letters and Numbers of the Wechsler Adult Intelligence Scale - III, and Nine Hole Peg Test. We found no difference between groups in the cognitive measures and motor dexterity. However, after treatment, a significant decrease in migraine-related disability was found for the a-tDCS 1-s Group. For all variables, no cumulative effects were observed in a-tDCS 2-s compared to the a-tDCS 1-s Group. The study findings provide preliminary results for future clinical trials designed to compare different intervals between tDCS sessions in CM.

Metformin disrupts Danio rerio metabolism at environmentally relevant concentrations: A full life-cycle study.

Metformin (MET), an anti-diabetic pharmaceutical of large-scale consumption, is increasingly detected in surface waters. However, current knowledge on the long-term effects of MET on non-target organisms is limited. The present study aimed to investigate the effects of MET in the model freshwater teleost Danio rerio, following a full life-cycle exposure to environmentally relevant concentrations (390 to 14 423 ng/L). Considering that the mode of action (MoA) of MET on non-target organisms remains underexplored and that MET may act through similar human pathways, i.e., lipid and energy metabolisms, biochemical markers were used to determine cholesterol and triglycerides levels, as well as mitochondrial complex I activity in zebrafish liver. Also, the hepatosomatic index as an indication of metabolic disruption, and the expression levels of genes involved in MET's putative MoA, i.e. acaca, acadm, cox5aa, idh3a, hmgcra, prkaa1, were determined, the last by qRT-PCR. A screening of mRNA transcripts, associated with lipid and energy metabolisms, and other signaling pathways potentially involved in MET-induced toxicity were also assessed using an exploratory RNA-seq analysis. The findings here reported indicate that MET significantly disrupted critical biochemical and molecular processes involved in zebrafish metabolism, such as cholesterol and fatty acid biosynthesis, mitochondrial electron transport chain and tricarboxylic acid cycle, concomitantly to changes on the hepatosomatic index. Likewise, MET impacted other relevant pathways mainly associated with cell cycle, DNA repair and steroid hormone biosynthesis, here reported for the first time in a non-target aquatic organism. Non-monotonic dose response curves were frequently detected in biochemical and qRT-PCR data, with higher effects observed at 390 and 2 929 ng/L MET treatments. Collectively, the results suggest that environmentally relevant concentrations of MET severely disrupt D. rerio metabolism and other important biological processes, supporting the need to revise the proposed environmental quality standard (EQS) and predicted no-effect concentration (PNEC) for MET.

Screening of Contaminants of Emerging Concern in Surface Water and Wastewater Effluents, Assisted by the Persistency-Mobility-Toxicity Criteria.

Contaminants of emerging concern (CECs) are compounds of diverse origins that have not been deeply studied in the past which are now accruing growing environmental interest. The NOR-Water project aimed to identify the main CECs and their sources in the water environment of Northern Portugal-Galicia (located in northwest Spain) transnational region. To achieve these goals, a suspect screening analytical methodology based on the use of liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) was applied to 29 sampling sites in two campaigns. These sampling sites included river and sea water, as well as treated wastewater. The screening was driven by a library of over 3500 compounds, which included 604 compounds prioritized from different relevant lists on the basis of the persistency, mobility, and toxicity criteria. Thus, a total of 343 chemicals could be tentatively identified in the analyzed samples. This list of 343 identified chemicals was submitted to the classification workflow used for prioritization and resulted in 153 chemicals tentatively classified as persistent, mobile, and toxic (PMT) and 23 as very persistent and very mobile (vMvP), pinpointing the relevance of these types of chemicals in the aqueous environment. Pharmaceuticals, such as the antidepressant venlafaxine or the antipsychotic sulpiride, and industrial chemicals, especially high production volume chemicals (HPVC) such as ε-caprolactam, were the groups of compounds that were detected at the highest frequencies.

Featuring ACE2 binding SARS-CoV and SARS-CoV-2 through a conserved evolutionary pattern of amino acid residues.

Spike (S) glycoproteins mediate the coronavirus entry into the host cell. The S1 subunit of S-proteins contains the receptor-binding domain (RBD) that is able to recognize different host receptors, highlighting its remarkable capacity to adapt to their hosts along the viral evolution. While RBD in spike proteins is determinant for the virus-receptor interaction, the active residues lie at the receptor-binding motif (RBM), a region located in RBD that plays a fundamental role binding the outer surface of their receptors. Here, we address the hypothesis that SARS-CoV and SARS-CoV-2 strains able to use angiotensin-converting enzyme 2 (ACE2) proteins have adapted their RBM along the viral evolution to explore specific conformational topology driven by the residues YGF to infect host cells. We also speculate that this YGF-based mechanism can act as a protein signature located at the RBM to distinguish coronaviruses able to use ACE2 as a cell entry receptor.Communicated by Ramaswamy H. Sarma.

A genome assembly of the Atlantic chub mackerel (Scomber colias): a valuable teleost fishing resource.

The Atlantic chub mackerel, Scomber colias (Gmelin, 1789), is a medium-sized pelagic fish with substantial importance in the fisheries of the Atlantic Ocean and the Mediterranean Sea. Over the past decade, this species has gained special relevance, being one of the main targets of pelagic fisheries in the NE Atlantic. Here, we sequenced and annotated the first high-quality draft genome assembly of S. colias, produced with PacBio HiFi long reads and Illumina paired-end short reads. The estimated genome size is 814 Mbp, distributed into 2,028 scaffolds and 2,093 contigs with an N50 length of 4.19 and 3.34 Mbp, respectively. We annotated 27,675 protein-coding genes and the BUSCO analyses indicated high completeness, with 97.3% of the single-copy orthologs in the Actinopterygii library profile. The present genome assembly represents a valuable resource to address the biology and management of this relevant fishery. Finally, this genome assembly ranks fourth in high-quality genome assemblies within the order Scombriformes and first in the genus Scomber.

The high stability of the three-helix bundle UBA domain of p62 protein as revealed by molecular dynamics simulations.

The ubiquitin-associated (UBA) domain is an important motif in the modulation of many molecular functionalities. It has been mainly associated with ubiquitin-mediated proteolysis, a multistep mechanism in which undesirable proteins are tagged with polyubiquitin chains for degradation in the proteasome complex. Comparison among UBA domains reveals a quite small structural variability, displaying an overall fold with a tightly packed three-helix bundle, and a common conserved hydrophobic patch on their surface that is important for ubiquitin binding. Mutations in the UBA domain, mainly in the highly conserved hydrophobic patch, induce conformational instabilities, which can be related to weak affinity for ubiquitin. This raises the question whether such hydrophobic patch presents conserved structural arrangement for selective recognition and protein binding. A concern that led us to investigate the stability of the p62-UBA domain as a case study regarding its structural arrangement as a function of temperature and two NaCl concentrations. Our results reveal that the temperature range and ionic strengths considered in this work produced a negligible effect on the three-helix bundle fold of p62-UBA domain.

The anti-lipidemic drug simvastatin modifies epigenetic biomarkers in the amphipod Gammarus locusta.

The adverse effects of certain environmental chemicals have been recently associated with the modulation of the epigenome. Although changes in the epigenetic signature have yet to be integrated into hazard and risk assessment, they are interesting candidates to link environmental exposures and altered phenotypes, since these changes may be passed across multiple non-exposed generations. Here, we addressed the effects of simvastatin (SIM), one of the most prescribed pharmaceuticals in the world, on epigenetic regulation using the amphipod Gammarus locusta as a proxy, to support its integration into hazard and environmental risk assessment. SIM is a known modulator of the epigenome in mammalian cell lines and has been reported to impact G. locusta ecological endpoints at environmentally relevant levels. G. locusta juveniles were exposed to three SIM environmentally relevant concentrations (0.32, 1.6 and 8 µg L-1) for 15 days. Gene transcription levels of selected epigenetic regulators, i.e., dnmt1, dmap1, usp7, kat5 and uhrf1 were assessed, along with the quantification of DNA methylation levels and evaluation of key ecological endpoints: survival and growth. Exposure to 0.32 and 8 µg L-1 SIM induced significant downregulation of DNA methyltransferase 1 (dnmt1), concomitant with global DNA hypomethylation and growth impacts. Overall, this work is the first to validate the basal expression of key epigenetic regulators in a keystone marine crustacean, supporting the integration of epigenetic biomarkers into hazard assessment frameworks.

Functional, biochemical and molecular impact of sediment plumes from deep-sea mining on Mytilus galloprovincialis under hyperbaric conditions.

The deep-sea is the biggest ecosystem in the world and despite the extreme conditions that characterize it, is highly biodiverse and complex. Deep-sea mining has been foreseen as a potential and concerning new stressor, and among the deep-sea mining associated stressors, sediment plumes, likely to be released into the water column as a side effect of mining, can reach habitats within a radius of more than a hundred kilometers. The present study examined the effects of suspended sediments of different grain sizes (63-125 µm, 125-250 µm and 250-500 µm) in the model species Mytilus galloprovincialis, at 4 bar, as a proxy to address the potential effects of sediment plumes, in the water column, with different grain sizes under high pressure conditions. Functional (filtration rate - FR), biochemical (catalase - CAT, glutathione s-transferase - GST, lipid peroxidation - LPO) and molecular (gene expression of [actin (ACTN), glutathione S-transferase alpha (GSTA), superoxide dismutase 2 (SOD2), catalase (CAT), heat shock protein 60 (HSP60), cytochrome c oxidase (COI) and DNA mismatch repair protein (MSH6)]) endpoints were studied in juvenile organisms. The FR decreased significantly for all tested grain size ranges, with a more severe effect for the particles with a diameter between 63 and 125 µm. In addition to the FR, significant changes were also observed for all tested biomarkers. Gene expression was significantly downregulated for CAT and ACTN. Overall, this study demonstrated that the smaller sized particles are the ones leading to more severe effects. Given their high dispersion potential and longer suspension periods under mining operation scenarios, particular attention should be given to the release of sediment plumes that may affect deep-sea environments and the water column. It is, therefore, vital to create standards and guidelines for sustainable mining practices.

Personalidade de insensibilidade e afetividade restrita em crianças vítimas de bullying / Callous-unemotional personality in children bullying victims / Personalidad de la insensibilidad y afectividad restringida en niños víctimas de bullying

A personalidade com insensibilidade e afetividade restrita (Callous-Unemotional personality) é bem investigada nos agressores de bullying, porém pouco se sabe sobre essa característica nas vítimas. O presente estudo objetivou avaliar a personalidade de insensibilidade e afetividade restrita em crianças que vivenciaram situações de bullying. Participaram da pesquisa 60 crianças do 6.º ano escolar divididas em grupos de agressores (n=15), vítimas (n=15), vítimas-agressores (n=15), e grupo controle (n=15). Foram aplicadas escalas de personalidade e de comportamento. Os resultados apontaram que as vítimas demonstraram um nível mais baixo de personalidade com insensibilidade e afetividade restrita se comparado aos outros grupos, apresentando também maior nível de comportamento pró-social. Torna-se, então, necessário investigar se níveis mais baixos deste traço de personalidade estão associados a maior passividade nas vítimas e, consequentemente, a uma maior probabilidade de serem alvo de bullying.

The Callous-Unemotional personality it is well examined among bullying aggressors, however little is known regarding this characteristic in victims. The present study aimed to investigate the insensibility and coldness in children living under bullying circumstances. Sixty children of the 6° school grade took part in the study, divided in groups of aggressors (n=15), victims (n=15), bully-victims (n=15), and a control group (n=15). Personality and behavior assessment scales were applied. Results revealed that victims showed a lower level of Callous-Unemotional personality compared to other groups, and also presented a higher level of pro-social behavior. It turns necessary to investigate if lower levels of those personality traits are associated to a higher passivity in victims and, consequently, to a greater probability of being target of bullying.

La personalidad con insensibilidad y afectividad restringida (Callous-Unemotional Personality) está bien investigada en agresores de bullying, pero poco se sabe sobre este rasgo en las víctimas. El presente estudio tuvo como objetivo evaluar la personalidad de insensibilidad y afectividad restringida en niños que experimentaron situaciones de bullying. Participaran de la investigación 60 niños del 6º año escolar divididos en grupos de agresores (n = 15), víctimas (n = 15), víctimas-agresores (n = 15) y grupo controle (n = 15). Se aplicaron escalas de personalidad y conducta. Los resultados mostraron que las víctimas mostraron un menor nivel de personalidad con insensibilidad y afectividad restringida en comparación con los otros grupos, además de presentar un mayor nivel de conducta prosocial. Entonces se hace necesario investigar si los niveles más bajos de este rasgo de personalidad están asociados con una mayor pasividad en las víctimas y, en consecuencia, a una mayor probabilidad de ser acosado.

Transcriptomic data on the transgenerational exposure of the keystone amphipod Gammarus locusta to simvastatin.

The use of transcriptomics data brings new insights and works as a powerful tool to explore the molecular mode of action (MoA) of transgenerational inheritance effects of contaminants of emerging concern. Therefore, in this dataset, we present the transcriptomic data of the transgenerational effects of environmentally relevant simvastatin levels, one of the most prescribed human pharmaceuticals, in the keystone amphipod species Gammarus locusta. In summary, G. locusta juveniles were maintained under simvastatin exposure up to adulthood (exposed group - F0E) and the offspring of F0E were transferred to control water for the three subsequent generations (transgenerational group - F1T, F2T and F3T). To gain insights into the biological functions and canonical pathways transgenerationally disrupted by simvastatin, a G. locusta de novo transcriptome assembly was produced and the transcriptomic profiles of three individual G. locusta females, per group, over the four generations (F0 to F3) - solvent control groups (F0.C, F1.C, F2.C and F3.C), F0 320 ng/L simvastatin exposed group (F0.320E) and F1 to F3 320 transgenerational group (F1.320T; F2.320T and F3.320T) - were analyzed. Briefly, Illumina HiSeq™ 2500 platform was used to perform RNA sequencing, and due to the unavailability of G. locusta genome, the RNA-seq datasets were assembled de novo using Trinity and annotated with Trinotate software. After assembly and post-processing steps, 106093 transcripts with N50 of 2371 bp and mean sequence length of 1343.98 bp was produced. BUSCO analyses showed a transcriptome with gene completeness of 97.5 % Arthropoda library profile. The Bowtie2, RSEM and edgeR tools were used for the differential gene expression (DEGs) analyses that allowed the identification of a high quantity of genes differentially expressed in all generations. Finally, to identify the main metabolic pathways affected by the transgenerational effects of SIM across all generations, the DGEs genes were blasted onto KEGG pathways database using the KAAS webserver. The data furnished in this article allows a better molecular understanding of the transgenerational effects produced by simvastatin in the keystone amphipod G. locusta and has major implications for hazard and risk assessment of pharmaceuticals and other emerging contaminants. This article is related to the research article entitled "Transgenerational inheritance of chemical-induced signature: a case study with simvastatin [1].

Facial Emotion Recognition and Executive Functions in Insomnia Disorder: An Exploratory Study.

BACKGROUND: Clinical and experimental findings suggest that insomnia is associated with changes in emotional processing and impairments in cognitive functioning. In the present study, we investigate the relationship between facial emotion recognition and executive functioning among individuals with insomnia as well as healthy controls. METHOD: A total of 11 individuals (mean age 31.3 ± 9.4) diagnosed with insomnia disorder and 15 control participants (mean age 24.8 ± 4.6) took part in the study. Participants responded to a facial emotion recognition task which presented them with static and dynamic stimuli, and were evaluated with regard to cognition, sleep, and mood. RESULTS: Compared to controls, we found that participants with insomnia performed worse in the recognition of the facial emotion of fear (p = 0.001; η p 2 = 0.549; ß = 0.999) and had lower scores in tests of verbal comprehension and perceptual organization (104.00 vs. 115.00, U = 135.5; p = 0.004; Cohen's, 2013 d = 1.281). We also found a relationship between facial emotion recognition and performance in cognitive tests, such as those related to perceptual organization, cognitive flexibility, and working memory. CONCLUSION: Results suggest that participants with insomnia may present some impairment in executive functions as well as in the recognition of facial emotions with negative valences (fear and sadness).

Chronic exposure to environmentally relevant levels of simvastatin disrupts zebrafish brain gene signaling involved in energy metabolism.

Simvastatin (SIM), a hypocholesterolaemic drug belonging to the statins group, is a widely prescribed pharmaceutical for prevention of cardiovascular diseases. Several studies showed that lipophilic statins, as SIM, cross the blood-brain barrier and interfere with the energy metabolism of the central nervous system in humans and mammalian models. In fish and other aquatic organisms, the effects of SIM on the brain energy metabolism are unknown, particularly following exposure to low environmentally relevant concentrations. Therefore, the present study aimed at investigating the influence of SIM on gene signaling pathways involved in brain energy metabolism of adult zebrafish (Danio rerio) following chronic exposure (90 days) to environmentally relevant SIM concentrations ranging from 8 ng/L to 1000 ng/L. Real-time PCR was used to determine the transcript levels of several genes involved in different pathways of the brain energy metabolism (glut1b, gapdh, acadm, accα, fasn, idh3a, cox4i1, and cox5aa). The findings here reported integrated well with ecological and biochemical responses obtained in a parallel study. Data demonstrated that SIM modulates transcription of key genes involved in the mitochondrial electron transport chain, in glucose transport and metabolism, in fatty acid synthesis and ß-oxidation. Further, SIM exposure led to a sex-dependent transcription profile for some of the studied genes. Overall, the present study demonstrated, for the first time, that SIM modulates gene regulation of key pathways involved in the energy metabolism in fish brain at environmentally relevant concentrations.

Occurrence of Biased Conformations as Precursors of Assembly States in Fibril Elongation of Amyloid-ß Fibril Variants: An In Silico Study.

We investigate the prevalence, and so the role in the amyloidogenesis, of biased conformations in large ensembles of monomeric forms for Aß42 and Aß40 that can trigger the formation and growth of fibrils described by a dock-lock mechanism. We model such biased conformations as the structural monomeric units that constitute the Protein Data Bank fibrils 2beg, 2mxu, and 2lmn. These units were employed as templates to search for similar structures in statistical conformational ensembles of Aß peptides generated by molecular dynamics with an accurate force field in explicit solvation, whose high quality is revealed by comparison with residual dipolar coupling (RDC) experiments. The conformational ensembles generated by these intrinsically disordered peptides do not contain conformations highly similar to the amyloidogenic templates. This is a consequence of the low thermodynamic stability exhibited by the template-like conformations. A further constant-pH Monte Carlo study has revealed that this stability can be increased by suitable pH conditions, which helps to trigger the fibril elongation. Moreover, our analyses on the free energy landscapes, hydrogen bond prevalences, and principal component analysis distributions emphasize the relevance of many-body long-range cooperative interactions, likely acting over the infrequent preexisting structurally biased conformations, to explain the fibrils' emergence.

Tarefa de compatibilidade espacial afetiva como modelo de estudo do comportamento emocional / Affective spatial compatibility task as a model for the study of emotional behavior / Tarea de compatibilidad espacial afectiva como modelo para el estudio del comportamiento emocional

Além dos aspectos emocionais, o comportamento humano pode ser afetado por outros fatores, tal como a localização espacial dos estímulos, que favorecem a ocorrência de respostas motoras mais rápidas para o mesmo lado de sua apresentação em uma tarefa clássica de compatibilidade estímulo-resposta. O presente artigo consiste em uma revisão narrativa de estudos que utilizaram a Tarefa de Compatibilidade Espacial Afetiva (TCEA) para avaliar a influência da valência afetiva do estímulo sobre os padrões de compatibilidade espacial. De modo geral, os estudos analisados indicam que figuras, imagens e palavras com valência emocional são capazes de influenciar o comportamento do voluntário. Portanto, a TCEA é uma ferramenta com potencial aplicação ao estudo da interação entre emoção e cognição na avaliação neuropsicológica.

Besides emotional aspects, human behavior can be affected by other factors, such as the spatial location of stimuli, which tend to facilitate the occurrence of faster motor responses to stimulus at the same side in a classic stimulus-response compatibility task. This article consists of a narrative review of studies that used the Affective Spatial Compatibility Task (TCEA) to assess the influence of the stimulus' affective valence on spatial compatibility patterns. In general, studies analyzed indicate that figures, images and words with emotional valence are capable of influencing the subject's behavior. Thus, we conclude that TCEA is a tool with potential application to the study of the interaction between emotion and cognition in the neuropsychological evaluation.

Además de los aspectos emocionales, el comportamiento humano puede verse afectado por otros factores, como la ubicación espacial de los estímulos, que favorecen la aparición de respuestas motoras más rápidas al estímulo en el mismo lado en una tarea de compatibilidad estímulo-respuesta. Este artículo consiste en una revisión narrativa de estudios que utilizaron la Tarea compatibilidad espacial afectiva (TCEA) para evaluar la influencia de la valencia afectiva del estímulo en los patrones de compatibilidad espacial. En general, los estudios analizados indican que las figuras, imágenes y palabras con valencia emocional son capaces de influir en el comportamiento del sujeto. TCEA es una herramienta con potencial aplicación para el estudio de la interacción entre emoción y cognición en la evaluación neuropsicológica.

Synergistic long-range effects of mutations underlie aggregation propensities of amylin analogues.

The USFDA has approved pramlintide, commercially named Symlin (sIAPP), as adjunctive therapy for type 2 diabetes (T2D). This analogue of the human amylin peptide (hIAPP) has triple proline substitutions typical of the rat isoform (rIAPP). Recently, it was proposed that pramlintide solubility and aggregation resistance might be improved by incorporating further mutations, as S20R, screened from the wild-type porcine isoform (pIAPP), which leads to the variant named sIAPP+. To better elucidate how such properties might be systematically induced in rationally designed analogues, we performed comparative assessments of rIAPP, sIAPP, and sIAPP+ using replica-exchange molecular dynamics (REMD) with an accurate combination of force field Charmm22* and explicit aqueous solvation TIP4P/Ew. Our thermo-structural analyses show that sIAPP exhibits a thermal conversion channel of helices[Formula: see text]-sheets resembling hIAPP. This channel is depleted in rIAPP and is absent in sIAPP+. As a consequence, sIAPP+ presents an overall decrease of ß-like secondary structures and an overstabilization of α-helices. Additionally, we observed in rIAPP and sIAPP+ an increase in the backbone RMSF of molecular terminals and the exposed area of key residues. These structural features of sIAPP+ suggest a nonamyloidogenic character, which is corroborated by our judicious estimate of the electrostatic component of the solvation free energy using a generalized Born model, and so it may constitute an alternative strategy to sIAPP as a peptide analogue of hIAPP. Furthermore, our findings confirm that different aggregation propensities of amylin and its analogues are synergistically modulated by long-range effects of key mutations. Graphical Abstract S20R-Pramlintide.