Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic,Antidepressant and Antipsychotic Effects

Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4''-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors.     

Retinoic Acid Specifically Enhances Embryonic Stem Cell Metastate Marked by Zscan4

Pluripotency confers Embryonic Stem Cells (ESCs) the ability to differentiate in ectoderm, endoderm, and mesoderm derivatives, producing the majority of cell types. Although the majority of ESCs divide without losing pluripotency, it has become evident that ESCs culture consists of multiple cell populations with different degrees of potency that are spontaneously induced in regular ESC culture conditions. Zscan4, a key pluripotency factor, marks ESC subpopulation that is referred to as high-level of pluripotency metastate. Here, we report that in ESC cultures treated with retinoic acid (RA), Zscan4 ESCs metastate is strongly enhanced. In particular, we found that induction of Zscan4 metastate is mediated via RA receptors (RAR-alpha, RAR-beta, and RAR-gamma), and it is dependent on phosphoinositide-3-kinase (PI3K) signaling. Remarkably, Zscan4 metastate induced by RA lacks canonical pluripotency genes Oct3/4 and Nanog but retained both self-renewal and pluripotency capabilities. Finally we demonstrated that the conditional ablation of Zscan4 subpopulation is dispensable for both endoderm and mesoderm but is required for ectoderm lineage. In conclusion, our research provides new insights about the role of RA signaling during ESCs high pluripotency metastate fluctuation.     

Genomic Characterization of Phenylalanine Ammonia Lyase Gene in Buckwheat

Phenylalanine Ammonia Lyase (PAL) gene which plays a key role in bio-synthesis of medicinally important compounds, Rutin/quercetin was sequence characterized for its efficient genomics application. These compounds possessing anti-diabetic and anti-cancer properties and are predominantly produced by Fagopyrum spp. In the present study, PAL gene was sequenced from three Fagopyrum spp. (F. tataricum, F. esculentum and F. dibotrys) and showed the presence of three SNPs and four insertion/deletions at intra and inter specific level. Among them, the potential SNP (position 949^th bp G>C) with Parsimony Informative Site was selected and successfully utilised to individuate the zygosity/allelic variation of 16 F. tataricum varieties. Insertion mutations were identified in coding region, which resulted the change of a stretch of 39 amino acids on the putative protein. Our Study revealed that autogamous species (F. tataricum) has lower frequency of observed SNPs as compared to allogamous species (F. dibotrys and F. esculentum). The identified SNPs in F. tataricum didn’t result to amino acid change, while in other two species it caused both conservative and non-conservative variations. Consistent pattern of SNPs across the species revealed their phylogenetic importance. We found two groups of F. tataricum and one of them was closely related with F. dibotrys. Sequence characterization information of PAL gene reported in present investigation can be utilized in genetic improvement of buckwheat in reference to its medicinal value.     

Transgenic mice recapitulate the phenotypic heterogeneity of genetic prion diseases without developing prion infectivity: Role of intracellular PrP retention in neurotoxicity

Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport.     

Grapevine xylem response to fungi involved in trunk diseases

Grapevine trunk diseases (GTD), caused by a wide range of different fungi, are responsible for decline and productivity losses in vines at all growth stages. Grapevine responses to fungal attack include morphological and physiochemical defence mechanisms in the vascular system to reduce fungal infections. However, the extent to which these responses could control further spread by GTD‐fungi in the xylem vessels is poorly known. This study shows the formation of tyloses inside xylem vessels of diseased grapevines, as well as extracellular ligninolytic activities [lignin peroxidase, manganese peroxidase (MnP) and/or laccase] exhibited by some GTD‐fungi isolated here from symptomatic grapevines. In particular, Botryosphaeriaceae spp. and Phaeoacremonium minimum showed all three lignin‐degrading enzymatic activities. We also examined whether selected vine phenolic compounds, often located in the vascular system in response to fungal infection, could affect the lignin‐degrading activity from those GTD‐fungi as well as fungal colonisation. We found that phenolic compounds appeared to inhibit MnP activity, in addition to reducing fungal growth by causing anomalies in the hyphae morphology. Our results support that affected grapevines can initiate the tylosis formation in order to constrain fungi in the xylem vessels, while highlight the complementary action of the phenolic compounds to inhibit the fungi growth and colonisation. Phenolic compounds are therefore likely to have important role in alternative strategies for preventing trunk diseases.     

Salinity tolerance is related to cyanide‐resistant alternative respiration in Medicago truncatula under sudden severe stress

Salt respiration is defined as the increase of respiration under early salt stress. However, the response of respiration varies depending on the degree of salt tolerance and salt stress. It has been hypothesized that the activity of the alternative pathway may increase preventing over‐reduction of the ubiquinone pool in response to salinity, which in turn can increase respiration. Three genotypes of Medicago truncatula are reputed as differently responsive to salinity: TN1.11, A17 and TN6.18. We used the oxygen‐isotope fractionation technique to study the in vivo respiratory activities of the cytochrome oxidase pathway (COP) and the alternative oxidase pathway (AOP) in leaves and roots of these genotypes treated with severe salt stress (300 mM) during 1 and 3 days. In parallel, AOX capacity, gas exchange measurements, relative water content and metabolomics were determined in control and treated plants. Our study shows for first time that salt respiration is induced by the triggered AOP in response to salinity. Moreover, this phenomenon coincides with increased levels of metabolites such as amino and organic acids, and is shown to be related with higher photosynthetic rate and water content in TN6.18.     

Analysing freshwater fish biodiversity records and respective conservation areas in Spain

The number of threatened freshwater fish species in Spain is among the highest recorded in Europe and includes a high percentage of endemic taxa. Investigated were the distribution of Spanish freshwater fish to identify priority areas for conservation and assess the extent to which freshwater fish are included in the existing network of protected areas. Considered were those threatened species recorded in the Spanish National inventories. From these data, several biodiversity indices were calculated and analysed. The results reveal important discrepancies between the national and international assessments of conservation status, whereby the current Spanish national catalogue needs updating to reconcile these inconsistencies. Several important areas for the conservation of freshwater fish lie outside protected areas. The results encourage the establishment of protected areas specifically for freshwater environments. An extensive database of Spanish freshwater fish species is needed to redefine priority areas and to maintain freshwater biodiversity.     

Length–weight relationships of freshwater fishes of the Alto Madre de Dios River (Manu Biosphere Reserve,Peru)

The present work provides the estimates of morphometric relationships for 22 native freshwater fish species (11 Characidae, five Loricariidae, two Heptapteridae, one Astroblepidae, one Crenuchidae, one Curimatidae and one Erythrinidae) collected in the Alto Madre de Dios River (Cuzco and Madre de Dios, Peru) in June 2012 using a mobile backpack electrofishing unit. These are the first length–weight relationships reported for 24 species, mostly endemic to the Amazonian basin. Knowledge regarding these biometric relationships can be relevant in the management and conservation of the local fishes and fisheries.