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Background: Several studies have described a potential anti-tumour effect of cannabinoids (CNB). CNB receptor 2 (CB2) is mostly present in hematopoietic stem cells (HSC). The present study evaluates the anti-leukaemic effect of CNB. Methods: Cell lines and primary cells from acute myeloid leukaemia (AML) patients were used and the effect of the CNB derivative WIN-55 was evaluated in vitro, ex vivo and in vivo. Results: We demonstrate a potent antileukemic effect of WIN-55 which is abolished with CB antagonists. WIN-treated mice, xenografted with AML cells, had better survival as compared to vehicle or cytarabine. DNA damage-related genes were affected upon exposure to WIN. Co-incubation with the PARP inhibitor Olaparib prevented WIN-induced cell death, suggesting PARP-mediated apoptosis which was further confirmed with the translocation of AIF to the nucleus observed in WIN-treated cells. Nicotinamide prevented WIN-related apoptosis, indicating NAD+ depletion. Finally, WIN altered glycolytic enzymes levels as well as the activity of G6PDH. These effects are reversed through PARP1 inhibition. Conclusions: WIN-55 exerts an antileukemic effect through Parthanatos, leading to translocation of AIF to the nucleus and depletion of NAD+, which are reversed through PARP1 inhibition. It also induces metabolic disruptions. These effects are not observed in normal HSC. [ABSTRACT FROM AUTHOR]

As a first step in determining the identity and relative importance of the evolutionary forces promoting the speciation process in two closely related European taxa of Aquilegia, we investigated the levels of morphological variation in floral and vegetative characters over the narrow region where their ranges enter into contact, and evaluate the relative importance of both types of traits in their differentiation. A total of 12 floral and ten vegetative characters were measured on 375 plants belonging to seven A. vulgaris populations and six A. pyrenaica subsp. cazorlensis populations located in southeastern Spain. Floral and vegetative morphological differentiation occur between taxa and among populations within taxa, but only vegetative characters (particularly plant height and leaf petiolule length) contribute significantly to the discrimination between taxa. Differentiation among populations within taxa is mostly explained by variation in floral traits. Consequently, morphological divergence between the two taxa cannot be interpreted as an extension of among-population differences occurring within taxa. Multivariate vegetative, but not floral, similarity between populations could be predicted from geographical distance. Moreover, the key role of certain vegetative traits in the differentiation of A. vulgaris and A. p. cazorlensis could possibly be attributable to the contrasting habitat requirements and stress tolerance strategies of the two taxa. These preliminary findings seem to disagree with the currently established view of the radiation process in the genus Aquilegia in North America, where the differentiation of floral traits seems to have played a more important role. [ABSTRACT FROM AUTHOR]

Although in gynodioecious populations male steriles require a fecundity advantage to compensate for their gametic disadvantage, southern Spanish populations of the long-lived shrub Daphne laureola do not show any fecundity advantage over hermaphrodites in terms of seed production and early seedling establishment. By using allozyme markers, we assess the mating system of this species in five populations differing in sex ratio, and infer levels of inbreeding depression over the whole life cycle by comparing the inbreeding coefficients at the seed and adult plant stages. Extremely low outcrossing rates (0.001

In hermaphrodite plants, variations in structural gender (defined as the ratio between male and female gametes) may occur at different levels (among flowers, plants, and populations). In this study, we investigated variation in four traits influencing structural gender (number of carpels, ovules per carpel, stamens, and pollen grains per stamen) within and among six distant populations of the hermaphrodite perennial herb Helleborus foetidus (Ranunculaceae) in the Iberian Peninsula. Our results show that the four traits investigated varied significantly at all levels considered. Traits influencing the female sexual component (number of carpels and ovules per carpel) showed greater variation at the lowermost levels (within flower and plant) than traits influencing the male component, which in turn varied more markedly among populations. Number of carpels per flower and number of pollen grains per anther were the most important traits affecting between-plant variation in structural gender. There was no evidence of significant plant-level trade-offs or correlations between the various male and female traits, which covaried differently across populations. The observed between-population variation in structural gender of Helleborus foetidus can be explained as a consequence of differences in self-pollination levels related to a flower’s “mating environment”. [ABSTRACT FROM AUTHOR]

Familial Alzheimer's disease (AD[MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112?cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138?cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.Molecular Psychiatry (2004) 9, 1042-1051. doi:10.1038/sj.mp.4001538 Published online 6 July 2004 [ABSTRACT FROM AUTHOR]