In vitro leishmanicidal activity of monomeric and dimeric naphthoquinones

A series of monomeric and dimeric naphthoquinones with potential for treatment of Leishmania infections was identified in vitro using both a direct cytotoxicity assay against extracellular promastigotes of Leishmania donovani, L. infantum, L. enriettii, and L. major and a test against intracellular amastigote L. donovani residing within murine macrophages. Several naphthoquinones proved to be active at concentrations in the microgram range (EC(50) 0.9-17.0 microg/ml). When tested against a panel of human cancer cell lines (KB, SKMel, A549, MDA) and murine bone marrow culture-derived macrophages (BMMPhi) as mammalian host cell controls, compounds with anti-Leishmania-activity showed moderate (EC(50)>25 microg/ml) to pronounced (EC(50)<10 microg/ml) toxic effects.     

Prestimulus influences on auditory perception from sensory representations and decision processes

The qualities of perception depend not only on the sensory inputs but also on the brain state before stimulus presentation. Although the collective evidence from neuroimaging studies for a relation between prestimulus state and perception is strong, the interpretation in the context of sensory computations or decision processes has remained difficult. In the auditory system, for example, previous studies have reported a wide range of effects in terms of the perceptually relevant frequency bands and state parameters (phase/power). To dissociate influences of state on earlier sensory representations and higher-level decision processes, we collected behavioral and EEG data in human participants performing two auditory discrimination tasks relying on distinct acoustic features. Using single-trial decoding, we quantified the relation between prestimulus activity, relevant sensory evidence, and choice in different task-relevant EEG components. Within auditory networks, we found that phase had no direct influence on choice, whereas power in task-specific frequency bands affected the encoding of sensory evidence. Within later-activated frontoparietal regions, theta and alpha phase had a direct influence on choice, without involving sensory evidence. These results delineate two consistent mechanisms by which prestimulus activity shapes perception. However, the timescales of the relevant neural activity depend on the specific brain regions engaged by the respective task.Sensory percepts depend not only on the environmental inputs but also on the internal brain state before stimulus presentation (1). Many studies have shown that the accuracy and speed of sensory performance change with the power and timing (phase) of rhythmic activity during a prestimulus period (2, 3). Studies in the auditory system, for example, have demonstrated that performance in detecting sounds and gaps in noise, or the discrimination of lexical stimuli, varies with the power and phase of rhythmic activity between about 1 and 12 Hz (4–9).Although the collective evidence makes a strong case that prestimulus state shapes the processing and perceptual consequences of sensory inputs, the functional interpretation of these findings in the context of specific sensory computations or higher cognitive processes has remained difficult (7, 10, 11). Electrophysiological studies in animals have described the state dependency of firing rates relative to cortical oscillations (12–15). Hence, it is tempting to interpret the reported prestimulus effects in neuroimaging studies as direct evidence for a link between the neural gain of early sensory cortices and perception. However, this is difficult for two reasons. First, previous studies have used different behavioral protocols (detection and discrimination) and stimuli (tones in silence or noise, gaps in noise, or speech), and each has implied different frequency bands and state parameters as relevant (from 1 to 12 Hz, reporting effects for phase, power, or both). Second, given the coarse spatial resolution of neuroimaging, it has often been difficult to localize the observed correlation of prestimulus state with perception to a specific neural process or brain region. Hence, it remains unclear whether previously reported prestimulus influences indeed originate from auditory cortices, possibly reflecting changes in sensory gain, or result from other high-level regions that are involved in general decision making.To disambiguate these two possibilities, we collected behavioral and EEG data during two auditory discrimination tasks relying on distinct acoustic features in the same participants. To dissect different stages of the sensory–perceptual cascade, we used single-trial decoding to separate earlier auditory from later decision-related activity (16–18). We then used linear modeling to quantify the relation between prestimulus activity, task-relevant sensory evidence, and perceptual choice within each of these components. This allowed us to directly quantify whether putative correlations of prestimulus activity with perceptual choice are mediated by an impact of prestimulus state on early auditory evidence, or arise from higher cognitive processes activated subsequent to early sensory representations.     

Endophytic fungi harbored in Cannabis sativa L.: diversity and potential as biocontrol agents against host plant-specific phytopathogens

The objective of the present work was isolation, phylogenetic characterization, and assessment of biocontrol potential of endophytic fungi harbored in various tissues (leaves, twigs, and apical and lateral buds) of the medicinal plant, Cannabis sativa L. A total of 30 different fungal endophytes were isolated from all the plant tissues which were authenticated by molecular identification based on rDNA ITS sequence analysis (ITS1, 5.8S and ITS2 regions). The Menhinick’s index revealed that the buds were immensely rich in fungal species, and Camargo’s index showed the highest tissue-specific fungal dominance for the twigs. The most dominant species was Penicillium copticola that could be isolated from the twigs, leaves, and apical and lateral buds. A detailed calculation of Fisher’s log series index, Shannon diversity index, Simpson’s index, Simpson’s diversity index, and Margalef’s richness revealed moderate overall biodiversity of C. sativa endophytes distributed among its tissues. The fungal endophytes were challenged by two host phytopathogens, Botrytis cinerea and Trichothecium roseum, devising a dual culture antagonistic assay on five different media. We observed 11 distinct types of pathogen inhibition encompassing a variable degree of antagonism (%) on changing the media. This revealed the potential chemodiversity of the isolated fungal endophytes not only as promising resources of biocontrol agents against the known and emerging phytopathogens of Cannabis plants, but also as sustainable resources of biologically active and defensive secondary metabolites.     

Antileishmanial activities of aphidicolin and its semisynthetic derivatives

Aphidicolin and a series of semisynthetic aphidicolan derivatives have been identified in in vitro tests as novel drugs with antiparasitic potential. All compounds have been tested against extracellular promastigotes of Leishmania donovani, L. infantum, L. enriettii, and L. major and against intracellular amastigotes of L. donovani in murine macrophages. The compounds showed antileishmanial activity at concentrations in the microgram range (50% effective concentration [EC(50)] = 0.02 to 1.83 microg/ml). The most active derivative (aphidicolin-17-glycinate hydrochloride) had EC(50)s of 0. 2 microg/ml against extracellular and 0.02 microg/ml against intracellular L. donovani parasites. To validate the pharmacological potential of tested drugs, pharmacological safety was determined by testing all compounds against two neoplastic cell lines (squamous carcinoma [KB] and melanoma [SK-Mel]) and against murine bone marrow-derived macrophages as host cells. With minor exceptions only for macrophages, tested aphidicolans did not show significant cytotoxicity (EC(50) > 25.0 microg/ml). Structure-activity relationships of these aphidicolan derivatives are discussed.     

Signatures of Positive Selection in Genes Associated with Human Skin Pigmentation as Revealed from Analyses of Single Nucleotide Polymorphisms

Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level. A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour, but only limited genetic evidence for positive selection has been presented. To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset, studying single nucleotide polymorphisms (SNPs), and analyzed 55 genes in detail. We identified eight genes that are associated with the melanin pathway ( SLC45A2, OCA2, TYRP1, DCT, KITLG, EGFR, DRD2 and PPARD ) and presented significant differences in genetic variation between Europeans, Africans and Asians. In six of these genes we detected, by means of the EHH test, variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( OCA2, TYRP1 and KITLG ) and in Asians ( OCA2, DCT, KITLG, EGFR and DRD2 ), whereas signals were scarce in Africans ( DCT, EGFR and DRD2 ). Furthermore, a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed. Overall, our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians, whereas dark skin color seems of unique origin, reflecting the ancestral state in humans.