Cryptic diversity and unexpected evolutionary patterns in the meadow lizard,Darevskia praticola (Eversmann, 1834)

Darevskia praticola differs from the other species of the genus in having a large but disjunct distribution, covering the Balkan and the Caucasus regions. Furthermore, most Darevskia species occupy saxicolous habitats, whereas D. praticola inhabits meadows and forest environments. Here we determine the phylogeographic and phylogenetic relationships of Darevskia praticola sensu lato and evaluate the current, morphology-based taxonomy. We sequenced two mtDNA genes (Cyt-b and ND4) and two nuclear loci (MC1R and RELN) for samples collected across the species range. Because our sequences amplified with the Cyt-b primers appear to represent a nuclear pseudogene we excluded this marker from the final analysis. Our results support monophyly of D. praticola and show its division into three clades. The first divergence, dated to the Late Pliocene, is between the Balkans and the Caucasus. The Caucasus lineage is further subdivided in a western Greater Caucasus and a Transcaucasia clade, likely due to subsequent differentiation during the Pleistocene. Our findings do not support the current taxonomic arrangement within D. praticola. The main geographic divergence likely happened due to a vicariance event associated with Plio-Pleistocene climatic and vegetation oscillations.     

Modulation of the Endocannabinoids N-Arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) on Executive Functions in Humans

Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = −.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = −.17) or AEA (r = −.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.     

Maternal Malnutrition and Offspring Sex Determine Juvenile Obesity and Metabolic Disorders in a Swine Model of Leptin Resistance

The present study aimed to determine, in a swine model of leptin resistance, the effects of type and timing of maternal malnutrition on growth patterns, adiposity and metabolic features of the progeny when exposed to an obesogenic diet during their juvenile development and possible concomitant effects of the offspring sex. Thus, four groups were considered. A CONTROL group involved pigs born from sows fed with a diet fulfilling their daily maintenance requirements for pregnancy. The treated groups involved the progeny of females fed with the same diet but fulfilling either 160% or 50% of pregnancy requirements during the entire gestation (OVERFED and UNDERFED, respectively) or 100% of requirements until Day 35 of pregnancy and 50% of such amount from Day 36 onwards (LATE-UNDERFED). OVERFED and UNDERFED offspring were more prone to higher corpulence and fat deposition from early postnatal stages, during breast-feeding; adiposity increased significantly when exposed to obesogenic diets, especially in females. The effects of sex were even more remarkable in LATE-UNDERFED offspring, which had similar corpulence to CONTROL piglets; however, females showed a clear predisposition to obesity. Furthermore, the three groups of pigs with maternal malnutrition showed evidences of metabolic syndrome and, in the case of individuals born from OVERFED sows, even of insulin resistance and the prodrome of type-2 diabetes. These findings support the main role of early nutritional programming in the current rise of obesity and associated diseases in ethnics with leptin resistance.     

Insulin/IGF-I Signaling Pathways Enhances Tumor Cell Invasion through Bisecting GlcNAc N-glycans Modulation. An Interplay with E-Cadherin

Changes in glycosylation are considered a hallmark of cancer, and one of the key targets of glycosylation modifications is E-cadherin. We and others have previously demonstrated that E-cadherin has a role in the regulation of bisecting GlcNAc N-glycans expression, remaining to be determined the E-cadherin-dependent signaling pathway involved in this N-glycans expression regulation. In this study, we analysed the impact of E-cadherin expression in the activation profile of receptor tyrosine kinases such as insulin receptor (IR) and IGF-I receptor (IGF-IR). We demonstrated that exogenous E-cadherin expression inhibits IR, IGF-IR and ERK 1/2 phosphorylation. Stimulation with insulin and IGF-I in MDA-MD-435 cancer cells overexpressing E-cadherin induces a decrease of bisecting GlcNAc N-glycans that was accompanied with alterations on E-cadherin cellular localization. Concomitantly, IR/IGF-IR signaling activation induced a mesenchymal-like phenotype of cancer cells together with an increased tumor cell invasion capability. Altogether, these results demonstrate an interplay between E-cadherin and IR/IGF-IR signaling as major networking players in the regulation of bisecting N-glycans expression, with important effects in the modulation of epithelial characteristics and tumor cell invasion. Here we provide new insights into the role that Insulin/IGF-I signaling play during cancer progression through glycosylation modifications.     

Inhibition of Leishmania (Leishmania) amazonensis and Rat Arginases by Green Tea EGCG, (+)-Catechin and (?)-Epicatechin: A Comparative Structural Analysis of Enzyme-Inhibitor Interactions

Epigallocatechin-3-gallate (EGCG), a dietary polyphenol (flavanol) from green tea, possesses leishmanicidal and antitrypanosomal activity. Mitochondrial damage was observed in Leishmania treated with EGCG, and it contributed to the lethal effect. However, the molecular target has not been defined. In this study, EGCG, (+)-catechin and (−)-epicatechin were tested against recombinant arginase from Leishmania amazonensis (ARG-L) and rat liver arginase (ARG-1). The compounds inhibit ARG-L and ARG-1 but are more active against the parasite enzyme. Enzyme kinetics reveal that EGCG is a mixed inhibitor of the ARG-L while (+)-catechin and (−)-epicatechin are competitive inhibitors. The most potent arginase inhibitor is (+)-catechin (IC₅₀ = 0.8 µM) followed by (−)-epicatechin (IC₅₀ = 1.8 µM), gallic acid (IC₅₀ = 2.2 µM) and EGCG (IC₅₀ = 3.8 µM). Docking analyses showed different modes of interaction of the compounds with the active sites of ARG-L and ARG-1. Due to the low IC₅₀ values obtained for ARG-L, flavanols can be used as a supplement for leishmaniasis treatment.     

Associations between Level and Change in Physical Function and Brain Volumes

Background

Higher levels of fitness or physical function are positively associated with cognitive outcomes but the potential underlying mechanisms via brain structure are still to be elucidated in detail. We examined associations between brain structure and physical function (contemporaneous and change over the previous three years) in community-dwelling older adults.

Methodology/Principal Findings

Participants from the Lothian Birth Cohort 1936 (N=694) underwent brain MRI at age 73 years to assess intracranial volume, and the volumes of total brain tissue, ventricles, grey matter, normal-appearing white matter, and white matter lesions. At ages 70 and 73, physical function was assessed by 6-meter walk, grip strength, and forced expiratory volume. A summary ‘physical function factor’ was derived from the individual measures using principal components analysis. Performance on each individual physical function measure declined across the three year interval (p<0.001). Higher level of physical function at ages 70 and 73 was associated with larger total brain tissue and white matter volumes, and smaller ventricular and white matter lesion volumes (standardized β ranged in magnitude from 0.07 to 0.17, p<0.001 to 0.034). Decline in physical function from age 70 to 73 was associated with smaller white matter volume (0.08, p<0.01, though not after correction for multiple testing), but not with any other brain volumetric measurements.

Conclusions/Significance

Physical function was related to brain volumes in community-dwelling older adults: declining physical function was associated with less white matter tissue. Further study is required to explore the detailed mechanisms through which physical function might influence brain structure, and vice versa.     

RKIP Inhibition in Cervical Cancer Is Associated with Higher Tumor Aggressive Behavior and Resistance to Cisplatin Therapy

Cervical cancer is one of the most common cancers in women worldwide, being high-risk group the HPV infected, the leading etiological factor. The raf kinase inhibitory protein (RKIP) has been associated with tumor progression and metastasis in several human neoplasms, however its role on cervical cancer is unclear. In the present study, 259 uterine cervix tissues, including cervicitis, cervical intraepithelial lesions and carcinomas, were analyzed for RKIP expression by immunohistochemistry. We found that RKIP expression was significantly decreased during malignant progression, being highly expressed in non-neoplastic tissues (54% of the samples; 73/135), and expressed at low levels in the cervix invasive carcinomas (∼15% (19/124). Following in vitro downregulation of RKIP, we observed a viability and proliferative advantage of RKIP-inhibited cells over time, which was associated with an altered cell cycle distribution and higher colony number in a colony formation assay. An in vitro wound healing assay showed that RKIP abrogation is associated with increased migratory capability. RKIP downregulation was also associated with an increased vascularization of the tumors in vivo using a CAM assay. Furthermore, RKIP inhibition induced cervical cancer cells apoptotic resistance to cisplatin treatment. In conclusion, we described that RKIP protein is significantly depleted during the malignant progression of cervical tumors. Despite the lack of association with patient clinical outcome, we demonstrate, in vitro and in vivo, that loss of RKIP expression can be one of the factors that are behind the aggressiveness, malignant progression and chemotherapy resistance of cervical cancer.     

Millennial-Scale Temperature Change Velocity in the Continental Northern Neotropics

Climate has been inherently linked to global diversity patterns, and yet no empirical data are available to put modern climate change into a millennial-scale context. High tropical species diversity has been linked to slow rates of climate change during the Quaternary, an assumption that lacks an empirical foundation. Thus, there is the need for quantifying the velocity at which the bioclimatic space changed during the Quaternary in the tropics. Here we present rates of climate change for the late Pleistocene and Holocene from Mexico and Guatemala. An extensive modern pollen survey and fossil pollen data from two long sedimentary records (30,000 and 86,000 years for highlands and lowlands, respectively) were used to estimate past temperatures. Derived temperature profiles show a parallel long-term trend and a similar cooling during the Last Glacial Maximum in the Guatemalan lowlands and the Mexican highlands. Temperature estimates and digital elevation models were used to calculate the velocity of isotherm displacement (temperature change velocity) for the time period contained in each record. Our analyses showed that temperature change velocities in Mesoamerica during the late Quaternary were at least four times slower than values reported for the last 50 years, but also at least twice as fast as those obtained from recent models. Our data demonstrate that, given extremely high temperature change velocities, species survival must have relied on either microrefugial populations or persistence of suppressed individuals. Contrary to the usual expectation of stable climates being associated with high diversity, our results suggest that Quaternary tropical diversity was probably maintained by centennial-scale oscillatory climatic variability that forestalled competitive exclusion. As humans have simplified modern landscapes, thereby removing potential microrefugia, and climate change is occurring monotonically at a very high velocity, extinction risk for tropical species is higher than at any time in the last 86,000 years.     

Using Information Interaction to Discover Epistatic Effects in Complex Diseases

It is widely agreed that complex diseases are typically caused by the joint effects of multiple instead of a single genetic variation. These genetic variations may show stronger effects when considered together than when considered individually, a phenomenon known as epistasis or multilocus interaction. In this work, we explore the applicability of information interaction to discover pairwise epistatic effects related with complex diseases. We start by showing that traditional approaches such as classification methods or greedy feature selection methods (such as the Fleuret method) do not perform well on this problem. We then compare our information interaction method with BEAM and SNPHarvester in artificial datasets simulating epistatic interactions and show that our method is more powerful to detect pairwise epistatic interactions than its competitors. We show results of the application of information interaction method to the WTCCC breast cancer dataset. Our results are validated using permutation tests. We were able to find 89 statistically significant pairwise interactions with a p-value lower than . Even though many recent algorithms have been designed to find epistasis with low marginals, we observed that all (except one) of the SNPs involved in statistically significant interactions have moderate or high marginals. We also report that the interactions found in this work were not present in gene-gene interaction network STRING.