Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

Effectiveness and cost-effectiveness of an educational intervention for practice teams to deliver problem focused therapy for insomnia: rationale and design of a pilot cluster randomised trial

Background: Sleep problems are common, affecting over a third of adults in the United Kingdom and leading to reduced productivity and impaired health-related quality of life. Many of those whose lives are affected seek medical help from primary care. Drug treatment is ineffective long term. Psychological methods for managing sleep problems, including cognitive behavioural therapy for insomnia (CBTi) have been shown to be effective and cost effective but have not been widely implemented or evaluated in a general practice setting where they are most likely to be needed and most appropriately delivered. This paper outlines the protocol for a pilot study designed to evaluate the effectiveness and cost-effectiveness of an educational intervention for general practitioners, primary care nurses and other members of the primary care team to deliver problem focused therapy to adult patients presenting with sleep problems due to lifestyle causes, pain or mild to moderate depression or anxiety. Methods and design: This will be a pilot cluster randomised controlled trial of a complex intervention. General practices will be randomised to an educational intervention for problem focused therapy which includes a consultation approach comprising careful assessment (using assessment of secondary causes, sleep diaries and severity) and use of modified CBTi for insomnia in the consultation compared with usual care (general advice on sleep hygiene and pharmacotherapy with hypnotic drugs). Clinicians randomised to the intervention will receive an educational intervention (2 × 2 hours) to implement a complex intervention of problem focused therapy. Clinicians randomised to the control group will receive reinforcement of usual care with sleep hygiene advice. Outcomes will be assessed via self-completion questionnaires and telephone interviews of patients and staff as well as clinical records for interventions and prescribing. Discussion: Previous studies in adults have shown that psychological treatments for insomnia administered by specialist nurses to groups of patients can be effective within a primary care setting. This will be a pilot study to determine whether an educational intervention aimed at primary care teams to deliver problem focused therapy for insomnia can improve sleep management and outcomes for individual adult patients presenting to general practice. The study will also test procedures and collect information in preparation for a larger definitive cluster-randomised trial. The study is funded by The Health Foundation

Quantum dynamics of atomic bright solitons under splitting and re-collision, and implications for interferometry

We numerically study the classical and quantum dynamics of an atomic bright soliton in a highly-elongated one-dimensional harmonic trap with a Gaussian barrier. In the regime of the recent experiment by Dyke {\it et al.}, the system realizes a coherent nonlinear soliton beam-splitter and interferometer whose accuracy we analyze. In the case of tighter radial trap confinement and enhanced quantum fluctuations, a split soliton can represent a spin-squeezed, or alternatively, a fragmented condensate with reduced phase-coherence that can be measured by interfering the split soliton by the barrier. We also find large quantum mechanical uncertainties in the soliton's position and momentum due to nonlinear interaction with the barrier.Comment: 30 pages, 9 figures. Modified in response to referees' comments, and with additional simulation result

Men, Mental Health and Elite Sport: a Narrative Review

Mental health in elite sport is receiving more publicity due to an increase in male athletes sharing their personal experiences. Sports injury is recognised as the major risk factor for psychological distress amongst male athletes, although anecdotally this may be that athletes are more likely to discuss their emotional wellbeing when related to the injury they are experiencing. Stress can be amplified within elite sport and the pressure they experience in relation to competition and performance can be exacerbated by adverse life events. This ongoing stress does not end when their sporting career does, it can follow them into retirement. The physical and psychological demands placed upon them by the sporting environment may predispose athletes to developing depression. As an athlete's symptoms of mental illness intensify, their performance can be negatively affected leaving them vulnerable and exposed to further symptoms of common mental disorders. The pressure of performance can also expose male athletes to overtraining syndrome which can be difficult to distinguish from depression. Male athletes are more vulnerable to eating disorders compared with males in the general population and they do have anxieties, particularly around their bodies, but find it difficult to disclose their concerns. In addition to this, male athletes are more likely to use substances, including opioids to improve both sport and non-sport performance.Despite the prevalence of common mental disorders in male athletes, stigma still exists, and although some athletes discuss their issues publicly after their career has ended, the majority of athletes prefer to remain silent. There remains a view that athletes who seek help for psychological problems may be seen as weak. Although there is an improvement in help-seeking attitudes within elite sport, further research and education is needed to encourage men to talk about their mental health, share their experiences and to enjoy a greater sense of emotional wellbeing

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Effects of an H3R Antagonist on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data

A theoretical model for template-free synthesis of long DNA sequence

This theoretical scheme is intended to formulate a potential method for high fidelity synthesis of Nucleic Acid molecules towards a few thousand bases using an enzyme system. Terminal Deoxyribonucleotidyl Transferase, which adds a nucleotide to the 3′OH end of a Nucleic Acid molecule, may be used in combination with a controlled method for nucleotide addition and degradation, to synthesize a predefined Nucleic Acid sequence. A pH control system is suggested to regulate the sequential activity switching of different enzymes in the synthetic scheme. Current practice of synthetic biology is cumbersome, expensive and often error prone owing to the dependence on the ligation of short oligonucleotides to fabricate functional genetic parts. The projected scheme is likely to render synthetic genomics appreciably convenient and economic by providing longer DNA molecules to start with