The mechanism of RNA base fraying: Molecular dynamics simulations analyzed with core-set Markov state models

The process of RNA base fraying (i.e., the transient opening of the termini of a helix) is involved in many aspects of RNA dynamics. We here use molecular dynamics simulations and Markov state models to characterize the kinetics of RNA fraying and its sequence and direction dependence. In particular, we first introduce a method for determining biomolecular dynamics employing core-set Markov state models constructed using an advanced clustering technique. The method is validated on previously reported simulations. We then use the method to analyze extensive trajectories for four different RNA model duplexes. Results obtained using D. E. Shaw research and AMBER force fields are compared and discussed in detail and show a non-trivial interplay between the stability of intermediate states and the overall fraying kinetics

The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies

Comparison and relative utility of inequality measurements: as applied to Scotland’s child dental health

This study compared and assessed the utility of tests of inequality on a series of very large population caries datasets. National cross-sectional caries datasets for Scotland’s 5-year-olds in 1993/94 (n = 5,078); 1995/96 (n = 6,240); 1997/98 (n = 6,584); 1999/00 (n = 6,781); 2002/03 (n = 9,747); 2003/04 (n = 10,956); 2005/06 (n = 10,945) and 2007/08 (n = 12,067) were obtained. Outcomes were based on the d3mft metric (i.e. the number of decayed, missing and filled teeth). An area-based deprivation category (DepCat) measured the subjects’ socioeconomic status (SES). Simple absolute and relative inequality, Odds Ratios and the Significant Caries Index (SIC) as advocated by the World Health Organization were calculated. The measures of complex inequality applied to data were: the Slope Index of Inequality (absolute) and a variety of relative inequality tests i.e. Gini coefficient; Relative Index of Inequality; concentration curve; Koolman and Doorslaer’s transformed Concentration Index; Receiver Operator Curve and Population Attributable Risk (PAR). Additional tests used were plots of SIC deciles (SIC10) and a Scottish Caries Inequality Metric (SCIM10). Over the period, mean d3mft improved from 3.1(95%CI 3.0–3.2) to 1.9(95%CI 1.8–1.9) and d3mft = 0% from 41.1(95%CI 39.8–42.3) to 58.3(95%CI 57.8–59.7). Absolute simple and complex inequality decreased. Relative simple and complex inequality remained comparatively stable. Our results support the use of the SII and RII to measure complex absolute and relative SES inequalities alongside additional tests of complex relative inequality such as PAR and Koolman and Doorslaer’s transformed CI. The latter two have clear interpretations which may influence policy makers. Specialised dental metrics (i.e. SIC, SIC10 and SCIM10) permit the exploration of other important inequalities not determined by SES, and could be applied to many other types of disease where ranking of morbidity is possible e.g. obesity. More generally, the approaches described may be applied to study patterns of health inequality affecting worldwide populations

GABAA receptor mapping in human using non-invasive electrophysiology

The non-invasive study of cortical oscillations provides a window onto neuronal processing. Temporal correlation of these oscillations between distinct anatomical regions is considered a marker of functional connectedness. As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) is thought to play a crucial role in shaping the frequency and amplitude of oscillations, which thereby suggests a role for GABA in shaping the topography of functional activity and connectivity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) through oral administration of the GABA transporter 1 (GAT1) blocker tiagabine (15 mg). We show that the spatial distribution of tiagabine-induced activity changes, across the brain, corresponds to group-average flumazenil PET maps of GABAA receptor distribution. In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy male individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo pill. Using leakage-corrected amplitude envelope correlations (AECs), we quantified the functional connectivity in discrete frequency bands across the whole brain, using the 90-region Automatic Anatomical Labelling atlas (AAL90), as well as quantifying the average oscillatory activity across the brain. Analysis of variance in connectivity using a drug-by-session (2×4) design revealed interaction effects, accompanied by main effects of drug and session. Post-hoc permutation testing of each post-drug recording against the respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, and across 1- 3- and 5- hour recordings following tiagabine, but not placebo. The same analysis applied to activity, across the brain, also revealed a significant interaction, with post-hoc permutation testing demonstrating significant increases in activity across frontal regions, coupled with reductions in activity in posterior regions, across the delta, theta, alpha and beta frequency bands. Crucially, we show that the spatial distribution of tiagabine-induced changes in oscillatory activity overlap significantly with group-averaged maps of the estimated distribution of GABAA receptors, derived from scaled flumazenil volume-of-distribution (FMZ-VT) PET, hence demonstrating a possible mechanistic link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. We therefore propose that electrophysiologically-derived maps of oscillatory connectivity and activity can be used as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging at the group level, providing direct measures of target engagement and pharmacodynamics

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Phase II Study of a Non-Platinum–Containing Doublet of Paclitaxel and Pemetrexed with Bevacizumab as Initial Therapy for Patients with Advanced Lung Adenocarcinomas

Many patients with lung cancers cannot receive platinum-containing regimens due to co-morbid medical conditions. We designed the PPB regimen of paclitaxel, pemetrexed, and bevacizumab to maintain or improve outcomes while averting the unique toxicities of platinum-based chemotherapies

Integration of decision support systems to improve decision support performance

Decision support system (DSS) is a well-established research and development area. Traditional isolated, stand-alone DSS has been recently facing new challenges. In order to improve the performance of DSS to meet the challenges, research has been actively carried out to develop integrated decision support systems (IDSS). This paper reviews the current research efforts with regard to the development of IDSS. The focus of the paper is on the integration aspect for IDSS through multiple perspectives, and the technologies that support this integration. More than 100 papers and software systems are discussed. Current research efforts and the development status of IDSS are explained, compared and classified. In addition, future trends and challenges in integration are outlined. The paper concludes that by addressing integration, better support will be provided to decision makers, with the expectation of both better decisions and improved decision making processes