Analysis of nucleic acid binding by a recombinant translin-trax complex

Translin is a highly conserved mammalian RNA and DNA-binding protein involved in DNA recombination and RNA trafficking. Crystal structures of mouse and human translin have been solved, but do not provide information about nucleic acid binding or recognition. Translin has a partner protein, translin-associated factor x (trax), which is believed to regulate translin’s subcellular locale and affinity for certain RNA and DNA sequences. Here we present a comparative study of recombinant translin and translin-trax complex binding to specific RNA and DNA sequences. It was observed that translin preferentially binds to G-rich RNA sequences whereas translin-trax preferentially binds G-rich DNA sequences. Translin can bind mRNA sequences with sub-micromolar K_d values, and the complex with trax can bind G-rich DNA with similar affinity. We conclude that trax acts to regulate translin’s RNA and DNA binding affinities as part of a cellular RNA trafficking mechanism.     

Grape seed procyanidins inhibit the expression of metallothione in genes in human HepG2 cells

Procyanidins are the most abundant polyphenols in red wine and are also found in cereals, fruits, chocolate and tea. They exert many beneficial health effects, especially on the cardiovascular system (Bagchi et al. in Mutat Res 523-524:87-97, 2003; Williams et al. in Free Radic Biol Med 36:838-849, 2004; Dell'Agli et al. in Cardiovasc Res 63(4):593-602, 2004; Del Bas et al. FASEB J 19:479-480, 2005). Here, we show that oral administration of a grape seed procyanidins extract (GSPE) to healthy rats results, 5 h after treatment, in a 70% inhibition of metallothionein (MT) gene expression in the liver, as determined by oligonucleotide microarray hybridization. Similarly, in cultured human hepatocytes HepG2, GSPE downregulate the expression of MT genes at the mRNA level, as evaluated by quantitative RTPCR. Thus, mRNA levels of six functional MT genes, MT1A, 1E, 1F, 1G, 1X and MT2A, are diminished between 50 and 80% when HepG2 cells are treated during 12 h with GSPE. Only the expression of two human MT genes, MT1G and MT1E, is transiently increased during the first 2 h of treatment. GSPE-induced inhibition of MT genes expression is dose dependent, at concentrations that are not toxic for the cells. Our findings demonstrate that metallothionein genes are direct targets of procyanidins action, both in vivo and in vitro, in hepatic cells. Thus, this study will help to elucidate the mechanisms by which procyanidin exert their beneficial actions.     

Vegetation and songbird response to land abandonment: from landscape to census plot

While intensification of human activities and its ecological effects in many natural areas have recently received much attention, land abandonment in marginal areas is still the largely ignored side of a process rooted in the same socioeconomic context. Decreasing human impact in marginal rural areas often triggers a recovery of seminatural vegetation. Over a period of 25 years, we studied the changes in landscape and vegetation structure that followed land abandonment in a traditional Mediterranean mosaic of crops, grasslands, shrublands and woodlands, and assessed their effects on songbird occurrence and distribution. We combined an analysis of vegetation changes based on aerial photo interpretation with an analysis of bird censuses from 1978, 1992 and 2003 at two spatial scales: landscape and census plot (respectively 2800 and 3 ha). The perceived temporal changes in the vegetation were scale dependent. At the landscape scale, open habitats tended to disappear and woodlands matured. The contrasts in vegetation structure that defined habitat patches at the onset of the study tended to disappear. There was an overall shift of the bird community in favour of woodland species. At the scale of the census plot, however, the colonization by woody vegetation of patches formerly characterized by a homogeneous grass cover increased the local diversity of the vegetation, at least temporarily. Of seven species dependent on open habitats, the occurrence rate of five species significantly decreased, whereas it increased for two species: woodlark (Lulula arborea) and melodious warbler (Hippolais polyglotta). This increase was linked to the transitional increase in local vegetation diversity. In patches originally dominated by woodlands, local vegetation diversity decreased as woody vegetation expanded into clearings. The occurrence rate significantly increased for seven species relying on closed woodlands, while it decreased for two woodland species. As most species of high conservation profile in the Mediterranean are tied to open or to heterogeneous transitional habitats, these trends raise questions concerning their persistence in the future.     

White adipose tissue reference network: a knowledge resource for exploring health-relevant relations

Optimal health is maintained by interaction of multiple intrinsic and environmental factors at different levels of complexity—from molecular, to physiological, to social. Understanding and quantification of these interactions will aid design of successful health interventions. We introduce the reference network concept as a platform for multi-level exploration of biological relations relevant for metabolic health, by integration and mining of biological interactions derived from public resources and context-specific experimental data. A White Adipose Tissue Health Reference Network (WATRefNet) was constructed as a resource for discovery and prioritization of mechanism-based biomarkers for white adipose tissue (WAT) health status and the effect of food and drug compounds on WAT health status. The WATRefNet (6,797 nodes and 32,171 edges) is based on (1) experimental data obtained from 10 studies addressing different adiposity states, (2) seven public knowledge bases of molecular interactions, (3) expert’s definitions of five physiologically relevant processes key to WAT health, namely WAT expandability, Oxidative capacity, Metabolic state, Oxidative stress and Tissue inflammation, and (4) a collection of relevant biomarkers of these processes identified by BIOCLAIMS (http://bioclaims.uib.es). The WATRefNet comprehends multiple layers of biological complexity as it contains various types of nodes and edges that represent different biological levels and interactions. We have validated the reference network by showing overrepresentation with anti-obesity drug targets, pathology-associated genes and differentially expressed genes from an external disease model dataset. The resulting network has been used to extract subnetworks specific to the above-mentioned expert-defined physiological processes. Each of these process-specific signatures represents a mechanistically supported composite biomarker for assessing and quantifying the effect of interventions on a physiological aspect that determines WAT health status. Following this principle, five anti-diabetic drug interventions and one diet intervention were scored for the match of their expression signature to the five biomarker signatures derived from the WATRefNet. This confirmed previous observations of successful intervention by dietary lifestyle and revealed WAT-specific effects of drug interventions. The WATRefNet represents a sustainable knowledge resource for extraction of relevant relationships such as mechanisms of action, nutrient intervention targets and biomarkers and for assessment of health effects for support of health claims made on food products.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-014-0439-x) contains supplementary material, which is available to authorized users.     

A multitrophic model to quantify the effects of marine viruses on microbial food webs and ecosystem processes

Viral lysis of microbial hosts releases organic matter that can then be assimilated by nontargeted microorganisms. Quantitative estimates of virus-mediated recycling of carbon in marine waters, first established in the late 1990s, were originally extrapolated from marine host and virus densities, host carbon content and inferred viral lysis rates. Yet, these estimates did not explicitly incorporate the cascade of complex feedbacks associated with virus-mediated lysis. To evaluate the role of viruses in shaping community structure and ecosystem functioning, we extend dynamic multitrophic ecosystem models to include a virus component, specifically parameterized for processes taking place in the ocean euphotic zone. Crucially, we are able to solve this model analytically, facilitating evaluation of model behavior under many alternative parameterizations. Analyses reveal that the addition of a virus component promotes the emergence of complex communities. In addition, biomass partitioning of the emergent multitrophic community is consistent with well-established empirical norms in the surface oceans. At steady state, ecosystem fluxes can be probed to characterize the effects that viruses have when compared with putative marine surface ecosystems without viruses. The model suggests that ecosystems with viruses will have (1) increased organic matter recycling, (2) reduced transfer to higher trophic levels and (3) increased net primary productivity. These model findings support hypotheses that viruses can have significant stimulatory effects across whole-ecosystem scales. We suggest that existing efforts to predict carbon and nutrient cycling without considering virus effects are likely to miss essential features of marine food webs that regulate global biogeochemical cycles.     

Biventricular / left ventricular pacing in hypertrophic obstructive cardiomyopathy: an overview

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction. In an important proportion of patients with HCM, the site and extent of cardiac hypertrophy results in severe obstruction to LV outflow tract (LVOT), contributing to disabling symptoms and increasing the risk of sudden cardiac death (SCD). In patients with progressive and/or refractory symptoms despite optimal pharmacological treatment, invasive therapies that diminish or abolish LVOT obstruction relieve heart failure-related symptoms, improve quality of life and could be associated with long-term survival similar to that observed in the general population. The gold standard in this respect is surgical septal myectomy, which might be supplementary associated with a reduction in SCD. Percutaneous techniques, particularly alcohol septal ablation (ASA) and more recently radiofrequency (RF) septal ablation, can achieve LVOT gradient reduction and symptomatic benefit in a large proportion of HOCM patients at the cost of a supposedly limited septal myocardial necrosis and a 10-20% risk of chronic atrioventricular block. After an initial period of enthusiasm, standard DDD pacing failed to show in randomized trials significant LVOT gradient reductions and objective improvement in exercise capacity. However, case reports and recent small pilot studies suggested that atrial synchronous LV or biventricular (biV) pacing significantly reduce LVOT obstruction and improve symptoms (acutely as well as long-term) in a large proportion of severely symptomatic HOCM patients not suitable to other gradient reduction therapies. Moreover, biV/LV pacing in HOCM seems to be associated with significant LV reverse remodelling.     

Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer

Peroxisome proliferator-activated receptor gamma (PPARgamma) might not be permissive to ligand activation in prostate cancer cells. Association of PPARgamma with repressing factors or posttranslational modifications in PPARgamma protein could explain the lack of effect of PPARgamma ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPARgamma agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPARgamma agonists, defining a new class of PPARgamma target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.