Prediction of self-assembly of adenosine analogues in solution: a computational approach validated by isothermal titration calorimetry.

The recent discovery of the role of adenosine-analogues as neuroprotectants and cognitive enhancers has sparked interest in these molecules as new therapeutic drugs. Understanding the behavior of these molecules in solution and predicting their ability to self-assemble will accelerate new discoveries. We propose a computational approach based on density functional theory, a polarizable continuum solvation description of the aqueous environment, and an efficient search procedure to probe the potential energy surface, to determine the structure and thermodynamic stability of molecular clusters of adenosine analogues in solution, using caffeine as a model. The method was validated as a tool for the prediction of the impact of small structural variations on self-assembly using paraxanthine. The computational results were supported by isothermal titration calorimetry experiments. The thermodynamic parameters enabled the quantification of the actual percentage of dimer present in solution as a function of concentration. The data suggest that both caffeine and paraxanthine are present at concentrations comparable to the ones found in biological samples

Establishing a generalized polyepigenetic biomarker for tobacco smoking

Large-scale epigenome-wide association meta-analyses have identified multiple 'signatures'' of smoking. Drawing on these findings, we describe the construction of a polyepigenetic DNA methylation score that indexes smoking behavior and that can be utilized for multiple purposes in population health research. To validate the score, we use data from two birth cohort studies: The Dunedin Longitudinal Study, followed to age-38 years, and the Environmental Risk Study, followed to age-18 years. Longitudinal data show that changes in DNA methylation accumulate with increased exposure to tobacco smoking and attenuate with quitting. Data from twins discordant for smoking behavior show that smoking influences DNA methylation independently of genetic and environmental risk factors. Physiological data show that changes in DNA methylation track smoking-related changes in lung function and gum health over time. Moreover, DNA methylation changes predict corresponding changes in gene expression in pathways related to inflammation, immune response, and cellular trafficking. Finally, we present prospective data about the link between adverse childhood experiences (ACEs) and epigenetic modifications; these findings document the importance of controlling for smoking-related DNA methylation changes when studying biological embedding of stress in life-course research. We introduce the polyepigenetic DNA methylation score as a tool both for discovery and theory-guided research in epigenetic epidemiology.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.The Dunedin Longitudinal Study is funded by the New Zealand Health Research Council, the New Zealand Ministry of Business, Innovation, and Employment, the National Institute on Aging (AG032282), and the Medical Research Council (MR/P005918/1). The E-Risk Study is funded by the Medical Research Council (G1002190) and the National Institute of Child Health and Human Development (HD077482). Additional support was provided by a Distinguished Investigator Award from the American Asthma Foundation to Dr. Mill, and by the Jacobs Foundation and the Avielle Foundation. Dr. Arseneault is the Mental Health Leadership Fellow for the U.K. Economic and Social Research Council. Dr. Belsky is a Jacobs Foundation Fellow. This work used a high-performance computing facility partially supported by grant 2016-IDG-1013 (“HARDAC + : Reproducible HPC for Next-generation Genomics”) from the North Carolina Biotechnology Center. Illumina DNA methylation data are accessible from the Gene Expression Omnibus (accession code: GSE105018).pre-print, post-print, publisher's PD

Metabolic characterization of Palatinate German white wines according to sensory attributes, varieties, and vintages using NMR spectroscopy and multivariate data analyses

1H NMR (nuclear magnetic resonance spectroscopy) has been used for metabolomic analysis of ‘Riesling’ and ‘Mueller-Thurgau’ white wines from the German Palatinate region. Diverse two-dimensional NMR techniques have been applied for the identification of metabolites, including phenolics. It is shown that sensory analysis correlates with NMR-based metabolic profiles of wine. 1H NMR data in combination with multivariate data analysis methods, like principal component analysis (PCA), partial least squares projections to latent structures (PLS), and bidirectional orthogonal projections to latent structures (O2PLS) analysis, were employed in an attempt to identify the metabolites responsible for the taste of wine, using a non-targeted approach. The high quality wines were characterized by elevated levels of compounds like proline, 2,3-butanediol, malate, quercetin, and catechin. Characterization of wine based on type and vintage was also done using orthogonal projections to latent structures (OPLS) analysis. ‘Riesling’ wines were characterized by higher levels of catechin, caftarate, valine, proline, malate, and citrate whereas compounds like quercetin, resveratrol, gallate, leucine, threonine, succinate, and lactate, were found discriminating for ‘Mueller-Thurgau’. The wines from 2006 vintage were dominated by leucine, phenylalanine, citrate, malate, and phenolics, while valine, proline, alanine, and succinate were predominantly present in the 2007 vintage. Based on these results, it can be postulated the NMR-based metabolomics offers an easy and comprehensive analysis of wine and in combination with multivariate data analyses can be used to investigate the source of the wines and to predict certain sensory aspects of wine

Bioactive non-coloured polyphenols content of grapes, wines and vinification by-products: Evaluation of the antioxidant activities of their extracts

The comparative quantization of main non-coloured polyphenols, the assessment of total polyphenolic content (TPC) and the detailed evaluation of the antioxidant activities of various grape-based products - from the harvest stage up to the production of the corresponding wines - are presented. The material studied consisted of grape tissues (berries, seeds and skins) of native Greek Vitis vinifera cultivars, which provided polyphenol-rich extracts via an optimized ultrasound extraction procedure, while the respective wine samples were condensed by a novel extraction procedure using XAD-4 adsorption resin column. The extraction methods accuracies were thoroughly validated and the polyphenolic content of extracts was assessed by HPLC-DAD and photometric methods. Their antioxidant properties were evaluated by following assays, modified to fit into a high throughput approach: DPPHradical dot radical scavenging, FRAP, inhibition of CuSO4-induced LDL oxidation and the reduction of intracellular reactive oxygen species (ROS) in smooth muscle cell cultures. Seed samples exhibited the highest TPC values, which are well correlated with their significant antioxidant properties in all assays performed. Of special interest is the significant capability of the tested extracts to prevent the LDL oxidation at very low concentrations. Furthermore, the good correlation between the antioxidant activities assessed for the LDL oxidation inhibition and the intracellular ROS assays is indicative of the possible in vivo antioxidant properties of the extracts. Results herein reveal the considerable antioxidant potential of the Greek grapevine production and exploits their vinification by-products as a potential inexpensive source of high added value antioxidants. © 2009 Elsevier Ltd. All rights reserved

Grape stem extracts: Polyphenolic content and assessment of their in vitro antioxidant properties

Grape stems constitute a scarcely investigated class of vinification byproducts with limited reports on their bioactive polyphenol content and/or industrial applications. Herein we present the outcome of our investigation on various grape stems extracts from native Greek grape varieties, concerning the assessment of their total polyphenolic content (TPC), the quantification of the individual bioactive polyphenols and the detailed evaluation of their antioxidant properties. Results obtained indicate that grape stems are particularly rich in flavonoids and stilbenes, with trans-resveratrol and e{open}-viniferin present in considerably high concentrations. They also exhibit significant antioxidant properties, which were determined by DPPH • radical scavenging and FRAP assays (modified to fit into a high throughput approach). Additional experiments concerning the inhibition of CuSO 4-induced LDL oxidation and the reduction of intracellular reactive oxygen species (ROS) indicated that most extracts tested display an extreme capability to prevent the oxidation of LDL-lipoprotein at very low concentrations and to reduce the intracellular ROS levels, exhibiting IC 75 values between 10.4 μg and 49.1 μg per gram of extract. Results herein reveal that grape stems represent a rich source of high added value natural antioxidants, particularly stilbenes such as trans-resveratrol, which may be used by pharmaceutical, food and cosmetic industries. © 2012 Elsevier Ltd

Targeted therapy and novel agents for the treatment of gastric cancer: A view toward the future

Multimodal treatment of resectable gastric cancer has been standardized including R0–D2 gastrectomy and adjuvant treatment. For advanced gastric cancer, several molecular agents have been evaluated in well–conducted randomized studies. The most important is represented by trastuzumab, a monoclonal antibody, which has shown significant antitumor activity against human epidermal growth factor receptor (Her)–2–positive advanced gastric cancer. Recently it has been established that the HER2 positive subgroup disease benefits from targeted therapy with trastuzumab. However, a substantial fraction of these patients who account for 25 % of all patients develop recurrence while for the remaining 75 % no targeted therapy exists. Therefore, there is now the crucial need for the development of more effective drugs and for the identification of predictive and prognostic biomarkers to select in an appropriate way those patients who will benefit from specific therapies. Nowadays, an alternative is offered by the single agent trastuzumab–emtansine (T–DM1). T–DMI provides increased therapeutic efficacy in HER2 positive breast cancer setting and we hope that similar results are achieved in HER2 positive gastric cancer. Clinical next generation sequencing (NGS) analyses provides the opportunity for understanding therapeutic resistance mechanism and developing next generation biomarkers and drugs

An Uncommon, Life-Threatening, Traumatic Hematoma in the Neck Area

It is well known that blunt neck trauma, when compared to a penetrating injury in the same anatomical area, is very rare. We report a case of an 81-year-old Caucasian woman with a blunt life-threatening neck trauma due to a bully goat. Although rare, direct evaluation should always be done in these cases because any misinterpretation may result in unfavorable outcomes. We have to highlight that close medical attention and prompt surgical treatment should be always considered in order to avoid dramatic consequences