Olomoucine II,but Not Purvalanol A,Is Transported by Breast Cancer Resistance Protein (ABCG2) and P-Glycoprotein (ABCB1)

Purine cyclin-dependent kinase inhibitors have been recognized as promising candidates for the treatment of various cancers; nevertheless, data regarding interaction of these substances with drug efflux transporters is still lacking. Recently, we have demonstrated inhibition of breast cancer resistance protein (ABCG2) by olomoucine II and purvalanol A and shown that these compounds are able to synergistically potentiate the antiproliferative effect of mitoxantrone, an ABCG2 substrate. In this follow up study, we investigated whether olomoucine II and purvalanol A are transported by ABCG2 and ABCB1 (P-glycoprotein). Using monolayers of MDCKII cells stably expressing human ABCB1 or ABCG2, we demonstrated that olomoucine II, but not purvalanol A, is a dual substrate of both ABCG2 and ABCB1. We, therefore, assume that pharmacokinetics of olomoucine II will be affected by both ABCB1 and ABCG2 transport proteins, which might potentially result in limited accumulation of the compound in tumor tissues or lead to drug-drug interactions. Pharmacokinetic behavior of purvalanol A, on the other hand, does not seem to be affected by either ABCG2 or ABCB1, theoretically favoring this drug in the potential treatment of efflux transporter-based multidrug resistant tumors. In addition, we observed intensive sulfatation of olomoucine II in MDCKII cell lines with subsequent active efflux of the metabolite out of the cells. Therefore, care should be taken when performing pharmacokinetic studies in MDCKII cells, especially if radiolabeled substrates are used; the generated sulfated conjugate may largely contaminate pharmacokinetic analysis and result in misleading interpretation. With regard to chemical structures of olomoucine II and purvalanol A, our data emphasize that even drugs with remarkable structure similarity may show different pharmacokinetic behavior such as interactions with ABC transporters or biotransformation enzymes.     

Environmental drivers interactively affect individual tree growth across temperate European forests

Forecasting the growth of tree species to future environmental changes requires a better understanding of its determinants. Tree growth is known to respond to global‐change drivers such as climate change or atmospheric deposition, as well as to local land‐use drivers such as forest management. Yet, large geographical scale studies examining interactive growth responses to multiple global‐change drivers are relatively scarce and rarely consider management effects. Here, we assessed the interactive effects of three global‐change drivers (temperature, precipitation and nitrogen deposition) on individual tree growth of three study species (Quercus robur/petraea, Fagus sylvatica and Fraxinus excelsior). We sampled trees along spatial environmental gradients across Europe and accounted for the effects of management for Quercus. We collected increment cores from 267 trees distributed over 151 plots in 19 forest regions and characterized their neighbouring environment to take into account potentially confounding factors such as tree size, competition, soil conditions and elevation. We demonstrate that growth responds interactively to global‐change drivers, with species‐specific sensitivities to the combined factors. Simultaneously high levels of precipitation and deposition benefited Fraxinus, but negatively affected Quercus’ growth, highlighting species‐specific interactive tree growth responses to combined drivers. For Fagus, a stronger growth response to higher temperatures was found when precipitation was also higher, illustrating the potential negative effects of drought stress under warming for this species. Furthermore, we show that past forest management can modulate the effects of changing temperatures on Quercus’ growth; individuals in plots with a coppicing history showed stronger growth responses to higher temperatures. Overall, our findings highlight how tree growth can be interactively determined by global‐change drivers, and how these growth responses might be modulated by past forest management. By showing future growth changes for scenarios of environmental change, we stress the importance of considering multiple drivers, including past management and their interactions, when predicting tree growth.     

A new rodent species of the genus Mus (Rodentia: Muridae) confirms the biogeographical uniqueness of the isolated forests of southern Ethiopia

Organisms Diversity & Evolution - The Ethiopian highlands represent the largest part of the Eastern Afromontane Biodiversity Hotspot (EAMBH). Their fauna and flora are largely unique....     

Drivers of temporal changes in temperate forest plant diversity vary across spatial scales

Global biodiversity is affected by numerous environmental drivers. Yet, the extent to which global environmental changes contribute to changes in local diversity is poorly understood. We investigated biodiversity changes in a meta‐analysis of 39 resurvey studies in European temperate forests (3988 vegetation records in total, 17–75 years between the two surveys) by assessing the importance of (i) coarse‐resolution (i.e., among sites) vs. fine‐resolution (i.e., within sites) environmental differences and (ii) changing environmental conditions between surveys. Our results clarify the mechanisms underlying the direction and magnitude of local‐scale biodiversity changes. While not detecting any net local diversity loss, we observed considerable among‐site variation, partly explained by temporal changes in light availability (a local driver) and density of large herbivores (a regional driver). Furthermore, strong evidence was found that presurvey levels of nitrogen deposition determined subsequent diversity changes. We conclude that models forecasting future biodiversity changes should consider coarse‐resolution environmental changes, account for differences in baseline environmental conditions and for local changes in fine‐resolution environmental conditions.     

Measuring Biomass and Carbon Stock in Resprouting Woody Plants

Resprouting multi-stemmed woody plants form an important component of the woody vegetation in many ecosystems, but a clear methodology for reliable measurement of their size and quick, non-destructive estimation of their woody biomass and carbon stock is lacking. Our goal was to find a minimum number of sprouts, i.e., the most easily obtainable, and sprout parameters that should be measured for accurate sprout biomass and carbon stock estimates. Using data for 5 common temperate woody species, we modelled carbon stock and sprout biomass as a function of an increasing number of sprouts in an interaction with different sprout parameters. The mean basal diameter of only two to five of the thickest sprouts and the basal diameter and DBH of the thickest sprouts per stump proved to be accurate estimators for the total sprout biomass of the individual resprouters and the populations of resprouters, respectively. Carbon stock estimates were strongly correlated with biomass estimates, but relative carbon content varied among species. Our study demonstrated that the size of the resprouters can be easily measured, and their biomass and carbon stock estimated; therefore, resprouters can be simply incorporated into studies of woody vegetation.     

Repeated intraspecific divergence in life span and aging of African annual fishes along an aridity gradient

Life span and aging are substantially modified by natural selection. Across species, higher extrinsic (environmentally related) mortality (and hence shorter life expectancy) selects for the evolution of more rapid aging. However, among populations within species, high extrinsic mortality can lead to extended life span and slower aging as a consequence of condition‐dependent survival. Using within‐species contrasts of eight natural populations of Nothobranchius fishes in common garden experiments, we demonstrate that populations originating from dry regions (with short life expectancy) had shorter intrinsic life spans and a greater increase in mortality with age, more pronounced cellular and physiological deterioration (oxidative damage, tumor load), and a faster decline in fertility than populations from wetter regions. This parallel intraspecific divergence in life span and aging was not associated with divergence in early life history (rapid growth, maturation) or pace‐of‐life syndrome (high metabolic rates, active behavior). Variability across four study species suggests that a combination of different aging and life‐history traits conformed with or contradicted the predictions for each species. These findings demonstrate that variation in life span and functional decline among natural populations are linked, genetically underpinned, and can evolve relatively rapidly.     

Micronucleus frequency and content in healthy relatives of cancer patients

Objective: To compare chromosomal damage in lymphocytes of individuals who did or did not report first-degree relatives with cancer.

Materials and methods: Cases and controls (68 each) were matched for sex, age and radon exposure. Chromosomal damage was quantified as frequency of micronucleus-containing cells and proportion of centromere-free micronuclei.

Results: Individuals not reporting cancer in their families showed lower values of both the frequency of micronucleus-containing cells (n.s.) and the proportion of centromere-free micronuclei (p?<?0.05) in some subgroups, but not in all.

Conclusion: The chromosomal damage observed may be due to inheritable genomic instability, but environmental influences cannot be excluded.     

Proteomic Identification of a Candidate Sequence of Wheat Cytokinin-Binding Protein 1

Our knowledge on the principle mechanisms of cytokinin action has been significantly deepened over the last years, but several weakly explored areas still remain on the map of cytokinin cellular physiology. Cytokinin-binding proteins could also be included in this pending field of cytokinin research. Probably, the best explored representative of this group is the wheat cytokinin-binding protein 1 (CBP-1). The role of this germ-allocated protein as a presumable regulator of free aromatic cytokinin levels during grain germination has been discussed intensively. To dig deeper into this interesting protein, this study was aimed at the identification of the CBP-1 amino acid sequence. A combination of in silico BLAST search, classical biochemical CBP-1 purification based on isoelectric point precipitation and ion-exchange chromatography, and proteomic analysis of the isolated protein by ultra-high resolution tandem mass spectrometry allowed us to uncover and validate two CBP-1 subunit candidate sequences with molecular masses of 56.2 and 55.0 kDa, respectively. Interestingly, we found the latter sequence alternated in two amino acids in the putative cytokinin-binding motive in comparison to the composition of this domain reported in the original studies. A BLAST search for the amino acid sequence of the binding region among plant proteomes revealed several highly related protein sequences, all originating from the Poaceae family. This piece of information could give support to the elucidation of the role of CBP-1 in physiological processes mediated by aromatic cytokinins.