New parametrization method for dissipative particle dynamics

We introduce an improved method of parameterizing the Groot-Warren version of Dissipative Particle Dynamics (DPD) by exploiting a correspondence between DPD and Scatchard-Hildebrand regular solution theory. The new parameterization scheme widens the realm of applicability of DPD by first removing the restriction of equal repulsive interactions between like beads, and second, by relating all conservative interactions between beads directly to cohesive energy densities. We establish the correspondence by deriving an expression for the Helmoltz free energy of mixing obtaining a heat of mixing which is exactly the same form as that for a regular mixture (quadratic in the volume fraction) and an entropy of mixing which reduces to the ideal entropy of mixing for equal molar volumes. We equate the conservative interaction parameters in the DPD force law to the cohesive energy densities of the pure fluids providing an alternative method of calculating the self-interaction parameters as well as a route to the cross-interaction parameter. We validate the new parameterization by modelling the binary system: SnI4/SiCl4, which displays liquid-liquid coexistence below an upper critical solution temperature around 140°C. A series of DPD simulations were conducted at a set of temperatures ranging from 0°C to above the experimental upper critical solution temperature using conservative parameters based on extrapolated experimental data. These simulations can be regarded as being equivalent to a quench from a high temperature to a lower one at constant volume. Our simulations recover the expected phase behaviour ranging from solid-liquid coexistence to liquid-liquid co-existence and eventually leading to a homogeneous single phase system. The results yield a binodal curve in close agreement with one predicted using regular solution theory, but, significantly, in closer agreement with actual solubility measurements

A combined field, laboratory and numerical study of the forces applied to, and the potential for removal of, bar top vegetation in a braided river

Vegetation can have an important role in controlling channel planform, through its effects on channel roughness, and root-reinforcement of bank and bar materials. Along the Platte River in central Nebraska, USA, The Platte River Recovery Implementation Program (PRRIP) has been tasked with managing the planform of the river to benefit endangered species. To investigate the potential use of planned Short Duration High Flow events (SDHFs) to manage bar vegetation, this study combined several approaches to determine whether flows of up to 227 m3s-1 through the central Platte River, could remove cottonwood, Phragmites and reed canarygrass stands of various ages and densities from in-channel bars. First, fieldwork was carried out to measure the uprooting resistance, and resistance to bending for each species. Second, a set of flume experiments was carried out to measure the forces exerted on the three species of interest under different flow conditions. Finally, a numerical study compared drag forces (driving) measured in the flume study, with uprooting forces (resisting) measured in the field, was carried out for each species to determine the likelihood of plant removal by SDHFs. Results showed that plants with more than a year of root growth, likely cannot be removed through drag and local scour alone, even at the 100-year recurrence interval discharge. At most, a few cottonwood seedlings could be removed from bars through drag, scour and undercutting, where rooting depths are still small. The results presented here help us further understand the positive feedbacks that lead to the creation of permanent, vegetated bars rather than mobile braided channels. As such, the findings could help inform management decisions for other braided rivers, and the combined field, flume and modelling techniques used in this study could be applied to other fluvial systems where vegetation and planform dynamics are of interest

The ventral habenulae of zebrafish develop in prosomere 2 dependent on Tcf7l2 function

BACKGROUND: The conserved habenular neural circuit relays cognitive information from the forebrain into the ventral mid- and hindbrain. In zebrafish, the bilaterally formed habenulae in the dorsal diencephalon are made up of the asymmetric dorsal and symmetric ventral habenular nuclei, which are homologous to the medial and lateral nuclei respectively, in mammals. These structures have been implicated in various behaviors related to the serotonergic/dopaminergic neurotransmitter system. The dorsal habenulae develop adjacent to the medially positioned pineal complex. Their precursors differentiate into two main neuronal subpopulations which differ in size across brain hemispheres as signals from left-sided parapineal cells influence their differentiation program. Unlike the dorsal habenulae and despite their importance, the ventral habenulae have been poorly studied. It is not known which genetic programs underlie their development and why they are formed symmetrically, unlike the dorsal habenulae. A main reason for this lack of knowledge is that the vHb origin has remained elusive to date. RESULTS: To address these questions, we applied long-term 2-photon microscopy time-lapse analysis of habenular neural circuit development combined with depth color coding in a transgenic line, labeling all main components of the network. Additional laser ablations and cell tracking experiments using the photoconvertible PSmOrange system in GFP transgenic fish show that the ventral habenulae develop in prosomere 2, posterior and lateral to the dorsal habenulae in the dorsal thalamus. Mutant analysis demonstrates that the ventral habenular nuclei only develop in the presence of functional Tcf7l2, a downstream modulator of the Wnt signaling cascade. Consistently, photoconverted thalamic tcf7l2(exl/exl) mutant cells do not contribute to habenula formation. CONCLUSIONS: We show in vivo that dorsal and ventral habenulae develop in different regions of prosomere 2. In the process of ventral habenula formation, functional tcf7l2 gene activity is required and in its absence, ventral habenular neurons do not develop. Influenced by signals from parapineal cells, dorsal habenular neurons differentiate at a time at which ventral habenular cells are still on their way towards their final destination. Thus, our finding may provide a simple explanation as to why only neuronal populations of the dorsal habenulae differ in size across brain hemispheres

cudaMap: a GPU accelerated program for gene expression connectivity mapping

BACKGROUND: Modern cancer research often involves large datasets and the use of sophisticated statistical techniques. Together these add a heavy computational load to the analysis, which is often coupled with issues surrounding data accessibility. Connectivity mapping is an advanced bioinformatic and computational technique dedicated to therapeutics discovery and drug re-purposing around differential gene expression analysis. On a normal desktop PC, it is common for the connectivity mapping task with a single gene signature to take > 2h to complete using sscMap, a popular Java application that runs on standard CPUs (Central Processing Units). Here, we describe new software, cudaMap, which has been implemented using CUDA C/C++ to harness the computational power of NVIDIA GPUs (Graphics Processing Units) to greatly reduce processing times for connectivity mapping. RESULTS: cudaMap can identify candidate therapeutics from the same signature in just over thirty seconds when using an NVIDIA Tesla C2050 GPU. Results from the analysis of multiple gene signatures, which would previously have taken several days, can now be obtained in as little as 10 minutes, greatly facilitating candidate therapeutics discovery with high throughput. We are able to demonstrate dramatic speed differentials between GPU assisted performance and CPU executions as the computational load increases for high accuracy evaluation of statistical significance. CONCLUSION: Emerging ‘omics’ technologies are constantly increasing the volume of data and information to be processed in all areas of biomedical research. Embracing the multicore functionality of GPUs represents a major avenue of local accelerated computing. cudaMap will make a strong contribution in the discovery of candidate therapeutics by enabling speedy execution of heavy duty connectivity mapping tasks, which are increasingly required in modern cancer research. cudaMap is open source and can be freely downloaded from http://purl.oclc.org/NET/cudaMap

B-type natriuretic peptide-guided treatment for heart failure

Background Heart failure is a condition in which the heart does not pump enough blood to meet all the needs of the body. Symptoms of heart failure include breathlessness, fatigue and fluid retention. Outcomes for patients with heart failure are highly variable; however on average, these patients have a poor prognosis. Prognosis can be improved with early diagnosis and appropriate use of medical treatment, use of devices and transplantation. Patients with heart failure are high users of healthcare resources, not only due to drug and device treatments, but due to high costs of hospitalisation care. B‐type natriuretic peptide levels are already used as biomarkers for diagnosis and prognosis of heart failure, but could offer to clinicians a possible tool to guide drug treatment. This could optimise drug management in heart failure patients whilst allaying concerns over potential side effects due to drug intolerance. Objectives To assess whether treatment guided by serial BNP or NT‐proBNP (collectively referred to as NP) monitoring improves outcomes compared with treatment guided by clinical assessment alone. Search methods Searches were conducted up to 15 March 2016 in the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (OVID), Embase (OVID), the Database of Abstracts of Reviews of Effects (DARE) and the NHS Economic Evaluation Database in the Cochrane Library. Searches were also conducted in the Science Citation Index Expanded, the Conference Proceedings Citation Index on Web of Science (Thomson Reuters), World Health Organization International Clinical Trials Registry and ClinicalTrials.gov. We applied no date or language restrictions. Selection criteria We included randomised controlled trials of NP‐guided treatment of heart failure versus treatment guided by clinical assessment alone with no restriction on follow‐up. Adults treated for heart failure, in both in‐hospital and out‐of‐hospital settings, and trials reporting a clinical outcome were included. Data collection and analysis Two review authors independently selected studies for inclusion, extracted data and evaluated risk of bias. Risk ratios (RR) were calculated for dichotomous data, and pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated for continuous data. We contacted trial authors to obtain missing data. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, we assessed the quality of the evidence and GRADE profiler (GRADEPRO) was used to import data from Review Manager to create a 'Summary of findings' table. Main results We included 18 randomised controlled trials with 3660 participants (range of mean age: 57 to 80 years) comparing NP‐guided treatment with clinical assessment alone. The evidence for all‐cause mortality using NP‐guided treatment showed uncertainty (RR 0.87, 95% CI 0.76 to 1.01; patients = 3169; studies = 15; low quality of the evidence), and for heart failure mortality (RR 0.84, 95% CI 0.54 to 1.30; patients = 853; studies = 6; low quality of evidence). The evidence suggested heart failure admission was reduced by NP‐guided treatment (38% versus 26%, RR 0.70, 95% CI 0.61 to 0.80; patients = 1928; studies = 10; low quality of evidence), but the evidence showed uncertainty for all‐cause admission (57% versus 53%, RR 0.93, 95% CI 0.84 to 1.03; patients = 1142; studies = 6; low quality of evidence). Six studies reported on adverse events, however the results could not be pooled (patients = 1144; low quality of evidence). Only four studies provided cost of treatment results, three of these studies reported a lower cost for NP‐guided treatment, whilst one reported a higher cost (results were not pooled; patients = 931, low quality of evidence). The evidence showed uncertainty for quality of life data (MD ‐0.03, 95% CI ‐1.18 to 1.13; patients = 1812; studies = 8; very low quality of evidence). We completed a 'Risk of bias' assessment for all studies. The impact of risk of bias from lack of blinding of outcome assessment and high attrition levels was examined by restricting analyses to only low 'Risk of bias' studies. Authors' conclusions In patients with heart failure low‐quality evidence showed a reduction in heart failure admission with NP‐guided treatment while low‐quality evidence showed uncertainty in the effect of NP‐guided treatment for all‐cause mortality, heart failure mortality, and all‐cause admission. Uncertainty in the effect was further shown by very low‐quality evidence for patient's quality of life. The evidence for adverse events and cost of treatment was low quality and we were unable to pool results.</p

Determining the date of diagnosis – is it a simple matter? The impact of different approaches to dating diagnosis on estimates of delayed care for ovarian cancer in UK primary care

Background Studies of cancer incidence and early management will increasingly draw on routine electronic patient records. However, data may be incomplete or inaccurate. We developed a generalisable strategy for investigating presenting symptoms and delays in diagnosis using ovarian cancer as an example. Methods The General Practice Research Database was used to investigate the time between first report of symptom and diagnosis of 344 women diagnosed with ovarian cancer between 01/06/2002 and 31/05/2008. Effects of possible inaccuracies in dating of diagnosis on the frequencies and timing of the most commonly reported symptoms were investigated using four increasingly inclusive definitions of first diagnosis/suspicion: 1. "Definite diagnosis" 2. "Ambiguous diagnosis" 3. "First treatment or complication suggesting pre-existing diagnosis", 4 "First relevant test or referral". Results The most commonly coded symptoms before a definite diagnosis of ovarian cancer, were abdominal pain (41%), urogenital problems(25%), abdominal distension (24%), constipation/change in bowel habits (23%) with 70% of cases reporting at least one of these. The median time between first reporting each of these symptoms and diagnosis was 13, 21, 9.5 and 8.5 weeks respectively. 19% had a code for definitions 2 or 3 prior to definite diagnosis and 73% a code for 4. However, the proportion with symptoms and the delays were similar for all four definitions except 4, where the median delay was 8, 8, 3, 10 and 0 weeks respectively. Conclusion Symptoms recorded in the General Practice Research Database are similar to those reported in the literature, although their frequency is lower than in studies based on self-report. Generalisable strategies for exploring the impact of recording practice on date of diagnosis in electronic patient records are recommended, and studies which date diagnoses in GP records need to present sensitivity analyses based on investigation, referral and diagnosis data. Free text information may be essential in obtaining accurate estimates of incidence, and for accurate dating of diagnoses

A cultural, scientific and technical study of the Durham lead cloth seal assemblage.

This thesis is an integrated and interdisciplinary study of 275 lead cloth seals dated from the mid-fourteenth to the early-nineteenth centuries. These recently discovered objects, recovered from a single submerged river-bed site located in the North-East of England, were once linked to the trade, industrial regulation and taxation of commercially produced cloth. They are presented here, catalogued and illustrated. These objects represent the largest assemblage of such material outside London and are of crucial significance for understanding the cloth trade in the late- and post-medieval period. Due to the unusual deposition conditions from which the objects were recovered, rare scraps of textiles have survived in many of the cloth seals. A range of scientific and analytical analyses was undertaken on three cloth seals containing textiles revealing important information. For the first time in the UK, ultra-high performance liquid chromatography (performed at The Centre for Textile Conservation and Technical Art History, Glasgow University) was successfully used to extract colourants related to dyes from textile fragments preserved in lead cloth seals. This significant new information provides new insights into textile availability, trade and the consumption of cloth, mordants and dyestuffs in the late-sixteenth to early-nineteenth century. Evidence from the cloth seals is combined with other documentary, cartographic and archaeological sources of evidence to produce a synthesis providing new understanding of the cloth trade in Durham in the late- and post-medieval periods. The research generated by this thesis has demonstrated not just the scale and extent of textile production in the City of Durham, but has also revealed evidence of hitherto unknown English and European trade routes

Cloning of a Rare Chronic Wasting Disease Prion Allele from Mule Deer

The prion protein is thought to be the causative agent for Chronic Wasting Disease in mule deer (Odocoileus hemionus). Prion protein polymorphisms at amino acid 225 cause three different allele product combinations: homozygous 225 serine/serine, heterozygous 225 serine/phenylalanine, and homozygous 225 phenylalanine/phenylalanine. The most common combination of allele products in clinically progressed CWD in O. hemionus is serine/serine at 225. The phenylalanine substitution is underrepresented in diseased animals. The goal of this project was to clone the very rare phenylalanine encoding prion allele for future study. The polymerase chain reaction (PCR) was used to amplify the prion protein structural gene but not the pseudogene that is present in deer. Positional cloning was used to insert this amplified product into a DNA vector. Successful cloning of the phenylalanine allele was confirmed by restriction enzyme analysis and DNA sequencing. In the future, the cloned gene can be used to generate a recombinant virus that will be used to express this rare protein for in vitro study