Single and Synergistic Effects of Cannabidiol and Δ-9-Tetrahydrocannabinol on Zebrafish Models of Neuro-Hyperactivity

In this study, we aimed to investigate the effect of the two main active cannabinoids extracted from cannabis: Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on two distinct behavioral models of induced neuro-hyperactivity. We have taken advantage of two previously developed zebrafish models of neuro-hyperactivity: a chemically induced pentylenetetrazole model and a genetic model caused by loss-of-function mutations in the GABA receptor subunit alpha 1 (GABRA1−/−). Both CBD and THC have a significant effect on the behavioral changes induced by both models. Importantly, we have also shown that when applied together at different ratios of THC to CBD (1:1, 1:5, and 1:10), there was a synergistic effect at a ratio of 1:1. This was particularly important for the genetically induced neuro-hyperactivity as it brought the concentrations of THC and CBD required to oppose the induced behavioral changes to levels that had much less of an effect on baseline larval behavior. The results of this study help to validate the ability of THC and CBD to oppose neuro-hyperactivity linked to seizure modalities. Additionally, it appears that individually, each cannabinoid may be more effective against the chemically induced model than against the GABRA1−/− transgenic model. However, when applied together, the concentration of each compound required to oppose the GABRA1−/− light-induced activity was lowered. This is of particular interest since the use of cannabinoids as therapeutics can be dampened by their side-effect profile. Reducing the level of each cannabinoid required may help to prevent off target effects that lead to side effects. Additionally, this study provides a validation of the complimentary nature of the two zebrafish models and sets a platform for future work with cannabinoids, particularly in the context of neuro-hyperactivity disorders such as epilepsy

Global patterns and environmental drivers of forest functional composition

To determine the relationships between the functional trait composition of forest communities and environmental gradients across scales and biomes and the role of species relative abundances in these relationships. We integrated species abundance records from worldwide forest inventories and associated functional traits (wood density, specific leaf area and seed mass) to obtain a data set of 99,953 to 149,285 plots (depending on the trait) spanning all forested continents. We computed community-weighted and unweighted means of trait values for each plot and related them to three broad environmental gradients and their interactions (energy availability, precipitation and soil properties) at two scales (global and biomes). Our models explained up to 60% of the variance in trait distribution. At global scale, the energy gradient had the strongest influence on traits. However, withinbiome models revealed different relationships among biomes. Notably, the functional composition of tropical forests was more influenced by precipitation and soil properties than energy availability, whereas temperate forests showed the opposite pattern. Depending on the trait studied, response to gradients was more variable and proportionally weaker in boreal forests. Community unweighted means were better predicted than weighted means for almost all models. Worldwide, trees require a large amount of energy (following latitude) to produce dense wood and seeds, while leaves with large surface to weight ratios are concentrated in temperate forests. However, patterns of functional composition within-biome differ from global patterns due to biome specificities such as the presence of conifers or unique combinations of climatic and soil properties. We recommend assessing the sensitivity of tree functional traits to environmental changes in their geographic context. Furthermore, at a given site, the distribution of tree functional traits appears to be driven more by species presence than species abundance.Fil: Bouchard, Elise. Université du Québec a Montreal; CanadáFil: Searle, Eric B.. Université du Québec a Montreal; CanadáFil: Drapeau, Pierre. Université du Québec a Montreal; CanadáFil: Liang, Jingjing. Purdue University; Estados UnidosFil: Gamarra, Javier G. P.. Food and Agriculture Organization of the United Nations; ItaliaFil: Abegg, Meinrad. No especifíca;Fil: Alberti, Giorgio. No especifíca;Fil: Zambrano, Angelica Almeyda. No especifíca;Fil: Alvarez Davila, Esteban. No especifíca;Fil: Alves, Luciana F.. No especifíca;Fil: Avitabile, Valerio. No especifíca;Fil: Aymard, Gerardo. No especifíca;Fil: Bastin, Jean François. No especifíca;Fil: Birnbaum, Philippe. No especifíca;Fil: Bongers, Frans. No especifíca;Fil: Bouriaud, Olivier. No especifíca;Fil: Brancalion, Pedro. No especifíca;Fil: Broadbent, Eben. No especifíca;Fil: Bussotti, Filippo. No especifíca;Fil: Gatti, Roberto Cazzolla. No especifíca;Fil: Češljar, Goran. No especifíca;Fil: Chisholm, Chelsea. No especifíca;Fil: Cienciala, Emil. No especifíca;Fil: Clark, Connie J.. No especifíca;Fil: Peri, Pablo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Santa Cruz. Universidad Tecnológica Nacional. Facultad Regional Santa Cruz. Centro de Investigaciones y Transferencia de Santa Cruz. Universidad Nacional de la Patagonia Austral. Centro de Investigaciones y Transferencia de Santa Cruz; ArgentinaFil: Zawiła Niedźwiecki, Tomasz. No especifíca;Fil: Zhou, Mo. No especifíca;Fil: Zhu, Zhi Xin. No especifíca;Fil: Zo Bi, Irié C.. No especifíca;Fil: Paquette, Alain. Université du Québec a Montreal; Canad

Mutant TDP-43 and FUS Cause Age-Dependent Paralysis and Neurodegeneration in C. elegans

Mutations in the DNA/RNA binding proteins TDP-43 and FUS are associated with Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. Intracellular accumulations of wild type TDP-43 and FUS are observed in a growing number of late-onset diseases suggesting that TDP-43 and FUS proteinopathies may contribute to multiple neurodegenerative diseases. To better understand the mechanisms of TDP-43 and FUS toxicity we have created transgenic Caenorhabditis elegans strains that express full-length, untagged human TDP-43 and FUS in the worm's GABAergic motor neurons. Transgenic worms expressing mutant TDP-43 and FUS display adult-onset, age-dependent loss of motility, progressive paralysis and neuronal degeneration that is distinct from wild type alleles. Additionally, mutant TDP-43 and FUS proteins are highly insoluble while wild type proteins remain soluble suggesting that protein misfolding may contribute to toxicity. Populations of mutant TDP-43 and FUS transgenics grown on solid media become paralyzed over 7 to 12 days. We have developed a liquid culture assay where the paralysis phenotype evolves over several hours. We introduce C. elegans transgenics for mutant TDP-43 and FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening

Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord

Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is still lacking. Here, we describe the first mutation in the human AP1S1 gene, encoding the small subunit σ1A of the AP-1 complex. This founder splice mutation, which leads to a premature stop codon, was found in four families with a unique syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). To validate the pathogenic effect of the mutation, we knocked down Ap1s1 expression in zebrafish using selective antisens morpholino oligonucleotides (AMO). The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development. Both neural and skin defects were rescued by co-injection of AMO with wild-type (WT) human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, consistent with a loss-of-function effect of this mutation. Together, these results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in development of the skin and spinal cord

Perceived discrimination based on the symptoms of covid-19, mental health, and emotional responses–the international online COVISTRESS survey

Background Despite the potential detrimental consequences for individuals’ health and discrimination from covid-19 symptoms, the outcomes have received little attention. This study examines the relationships between having personally experienced discrimination based on the symptoms of covid-19 (during the first wave of the pandemic), mental health, and emotional responses (anger and sadness). It was predicted that covid-19 discrimination would be positively related to poor mental health and that this relationship would be mediated by the emotions of anger and sadness. Methods The study was conducted using an online questionnaire from January to June 2020 (the Covistress network; including 44 countries). Participants were extracted from the COVISTRESS database (Ntotal = 280) with about a half declaring having been discriminated due to covid-19 symptoms (N = 135). Discriminated participants were compared to non-discriminated participants using ANOVA. A mediation analysis was conducted to examine the indirect effect of emotional responses and the relationships between perceived discrimination and self-reported mental health. Results The results indicated that individuals who experienced discrimination based on the symptoms of covid-19 had poorer mental health and experienced more anger and sadness. The relationship between covid-19 personal discrimination and mental health disappeared when the emotions of anger and sadness were statistically controlled for. The indirect effects for both anger and sadness were statistically significant. Discussion This study suggests that the covid-19 pandemic may have generated discriminatory behaviors toward those suspected of having symptoms and that this is related to poorer mental health via anger and sadness.publishedVersio

FUS and TARDBP but Not SOD1 Interact in Genetic Models of Amyotrophic Lateral Sclerosis

Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS–related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS–related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1

Recherche des virus dans les eaux de distribution grâce à une nouvelle technique - premier rapport

RÉSUMÉ La technique de concentration des virus a connu un développement important ces dernières années. Un grand nombre de chercheurs ont proposé différentes techniques et essayé d'en expliquer les facteurs susceptibles de les influencer. Ces méthodes sont plus ou moins incomplètes et leur application pratique reste encore limitée. Dans le cadre de la présente étude, on essaie d'explorer la filtration sur membrane et de trouver une membrance capable de retenir les virus, de permettre simultanément de filtrer de grands volumes et d'extraire avec une efficacité élevée les virus adsorbés. On cherche aussi à étudier l'influence de pH et des produits chimiques, ajoutés dans la suspension des virus à filtrer, sur le comportement des membranes. CONTENU Méthodes expérimentales -- Description et caractéristiques de l'équipement -- Mode opératoire -- Résultats -- Systèmes de préfiltres