Simvastatin rises reactive oxygen species levels and induces senescence in human melanoma cells by activation of p53/p21 pathway

Recent studies demonstrated that simvastatin has antitumor properties in several types of cancer cells, mainly by inducing apoptosis and inhibiting growth. The arrest of proliferation is a feature of cellular senescence; however, the occurrence of senescence in melanoma cells upon simvastatin treatment has not been investigated until now. Our results demonstrated that exposure of human metastatic melanoma cells (WM9) to simvastatin induces a senescent phenotype, characterized by G1 arrest, positive staining for senescence-associated β-galactosidase assay, and morphological changes. Also, the main pathways leading to cell senescence were examined in simvastatin-treated human melanoma cells, and the expression levels of phospho-p53 and p21 were upregulated by simvastatin, suggesting that cell cycle regulators and DNA damage pathways are involved in the onset of senescence. Since simvastatin can act as a pro-oxidant agent, and oxidative stress may be related to senescence, we measured the intracellular ROS levels in WM9 cells upon simvastatin treatment. Interestingly, we found an increased amount of intracellular ROS in these cells, which was accompanied by elevated expression of catalase and peroxiredoxin-1. Collectively, our results demonstrated that simvastatin can induce senescence in human melanoma cells by activation of p53/p21 pathway, and that oxidative stress may be related to this process.     

DEFENSE TRAITS OF LARVAL DROSOPHILA MELANOGASTER EXHIBIT GENETICALLY BASED TRADE‐OFFS AGAINST DIFFERENT SPECIES OF PARASITOIDS

Populations of Drosophila melanogaster face significant mortality risks from parasitoid wasps that use species‐specific strategies to locate and survive in hosts. We tested the hypothesis that parasitoids with different strategies select for alternative host defense characteristics and in doing so contribute to the maintenance of fitness variation and produce trade‐offs among traits. We characterized defense traits of Drosophila when exposed to parasitoids with different host searching behaviors (Aphaereta sp. and Leptopilina boulardi). We used host larvae with different natural alleles of the gene Dopa decarboxylase (Ddc), a gene controlling the production of dopamine and known to influence the immune response against parasitoids. Previous population genetic analyses indicate that our focal alleles are maintained by balancing selection. Genotypes exhibited a trade‐off between the immune response against Aphaereta sp. and the ability to avoid parasitism by L. boulardi. We also identified a trade‐off between the ability to avoid parasitism by L. boulardi and larval competitive ability as indicated by differences in foraging and feeding behavior. Genotypes differed in dopamine levels potentially explaining variation in these traits. Our results highlight the potential role of parasitoid biodiversity on host fitness variation and implicate Ddc as an antagonistic pleiotropic locus influencing larval fitness traits.     

Stoichiometric modeling of oxidation of reduced inorganic sulfur compounds (Riscs) in Acidithiobacillus thiooxidans

The prokaryotic oxidation of reduced inorganic sulfur compounds (RISCs) is a topic of utmost importance from a biogeochemical and industrial perspective. Despite sulfur oxidizing bacterial activity is largely known, no quantitative approaches to biological RISCs oxidation have been made, gathering all the complex abiotic and enzymatic stoichiometry involved. Even though in the case of neutrophilic bacteria such as Paracoccus and Beggiatoa species the RISCs oxidation systems are well described, there is a lack of knowledge for acidophilic microorganisms. Here, we present the first experimentally validated stoichiometric model able to assess RISCs oxidation quantitatively in Acidithiobacillus thiooxidans (strain DSM 17318), the archetype of the sulfur oxidizing acidophilic chemolithoautotrophs. This model was built based on literature and genomic analysis, considering a widespread mix of formerly proposed RISCs oxidation models combined and evaluated experimentally. Thiosulfate partial oxidation by the Sox system (SoxABXYZ) was placed as central step of sulfur oxidation model, along with abiotic reactions. This model was coupled with a detailed stoichiometry of biomass production, providing accurate bacterial growth predictions. In silico deletion/inactivation highlights the role of sulfur dioxygenase as the main catalyzer and a moderate function of tetrathionate hydrolase in elemental sulfur catabolism, demonstrating that this model constitutes an advanced instrument for the optimization of At. thiooxidans biomass production with potential use in biohydrometallurgical and environmental applications. Biotechnol. Bioeng. 2013; 110: 2242–2251. © 2013 Wiley Periodicals, Inc.     

Structural and dynamical properties of KTS‐disintegrins: A comparison between Obtustatin and Lebestatin

Obtustatin and Lebestatin are lysine‐threonine‐serine (KTS)‐disintegrins, which are a family of low molecular weight polypeptides present in many viperidae venoms and are potent and specific inhibitors of collagen‐binding integrins. The integrin binding loop, harboring the ²¹KTS²³ motif, and the C‐terminal tail are known to be responsible for the selective binding to the α1β1 integrin. Despite a very high sequence homology (only two mutations are present in Lebestatin relative to Obtustatin, namely R24L and S38L), Lebestatin exhibits a higher inhibitory effect than Obtustatin on cell adhesion and cell migration to collagens I and IV. Here we show, by means of molecular dynamics simulations of the two polypeptides in aqueous solution, that Lebestatin possesses a higher flexibility of the C‐terminal tail and a greater solvent accessibility of the integrin binding loop than Obtustatin. It may be hypothesized that these properties may contribute to the higher binding‐affinity of Lebestatin to its biological partner. © 2012 Wiley Periodicals, Inc.     

Bitrophic toxicity of Cry1Ac to Cycloneda sanguinea,a predator in Brazilian cotton

Insect predators are exposed to the Cry1Ac toxin in Bt cotton fields through several pathways. In this study, we investigated the effects of activated Cry1Ac added to a diet on Cycloneda sanguinea (L.) (Coleoptera: Coccinellidae), which is one of the main predators of non‐target pests in Brazilian cotton. Direct bitrophic exposure of C. sanguinea to Cry1Ac was done by feeding beetles with Aphis gossypii (Glover) (Hemiptera: Aphidae) sprayed with 500 μg per ml Cry1Ac solution. Larval and pupal survival, development time, aphid consumption, and adult longevity were recorded daily. Couples within the same experimental treatment were paired and numbers of eggs laid and hatched per female were recorded daily. Net replacement rate was calculated for each female. During development, a C. sanguinea larva consumed on average 1.8 μg of activated Cry1Ac. No significant differences due to Cry1Ac were observed for any of the response variables, except aphid consumption. Larvae receiving Cry1Ac consumed more aphids than larvae receiving distilled water alone. Additional statistical analyses were conducted to evaluate independence of responses, and for the independent responses, a simple meta‐analysis was conducted to test the null hypothesis that all responses were zero. Nearly all of the response variables were statistically independent. Two pairs of responses were not independent, but the associated multivariate tests were not significant. The meta‐analysis suggested that all effects were not different from random variation around zero and no cumulative effects could be detected. Our results indicated that bitrophic exposure to activated Cry1Ac is likely to have little or no adverse ecological effect on C. sanguinea.     

On the origins,rapid expansion and genetic diversity of native Americans from hunting‐gatherers to agriculturalists

Given the importance of Y‐chromosome haplogroup Q to better understand the source populations of contemporary Native Americans, we studied 8 biallelic and 17 microsatellite polymorphisms on the background of 128 Q Y‐chromosomes from geographically targeted populations. The populations examined in this study include three from the Tuva Republic in Central Asia (Bai‐Tai, Kungurtug, and Toora‐Hem, n = 146), two from the northeastern tip of Siberia (New Chaplino and Chukchi, n = 32), and two from Mesoamerica (Mayans from Yucatan, Mexico n = 72, and Mayans from the Guatemalan Highlands, n = 43). We also see evidence of a dramatic Mesoamerican post‐migration population growth in the ubiquitous and diverse Y‐STR profiles of the Mayan and other Mesoamerican populations. In the case of the Mayans, this demographic growth was most likely fueled by the agricultural‐ and trade‐based subsistence adopted during the Pre‐Classic, Classic and Post‐Classic periods of their empire. The limited diversity levels observed in the Altaian and Tuvinian regions of Central Asia, the lowest of all populations examined, may be the consequence of bottleneck events fostered by the spatial isolation and low effective population size characteristic of a nomadic lifestyle. Furthermore, our data illustrate how a sociocultural characteristic such as mode of subsistence may be of impact on the genetic structure of populations. We analyzed our genetic data using Multidimensional Scaling Analysis of populations, Principal Component Analysis of individuals, Median‐joining networks of M242, M346, L54, and M3 individuals, age estimations based on microsatellite variation utilizing genealogical and evolutionary mutation rates/generation times and estimation of Y‐ STR average gene diversity indices. Am J Phys Anthropol, 2013. © 2013 Wiley Periodicals, Inc.