A Multi-Parametric Imaging Investigation of the Response of C6 Glioma Xenografts to MLN0518 (Tandutinib) Treatment.

Angiogenesis, the development of new blood vessels, is essential for tumour growth; this process is stimulated by the secretion of numerous growth factors including platelet derived growth factor (PDGF). PDGF signalling, through its receptor platelet derived growth factor receptor (PDGFR), is involved in vessel maturation, stimulation of angiogenesis and upregulation of other angiogenic factors, including vascular endothelial growth factor (VEGF). PDGFR is a promising target for anti-cancer therapy because it is expressed on both tumour cells and stromal cells associated with the vasculature. MLN0518 (tandutinib) is a potent inhibitor of type III receptor tyrosine kinases that demonstrates activity against PDGFRα/β, FLT3 and c-KIT. In this study a multi-parametric MRI and histopathological approach was used to interrogate changes in vascular haemodynamics, structural response and hypoxia in C6 glioma xenografts in response to treatment with MLN0518. The doubling time of tumours in mice treated with MLN0518 was significantly longer than tumours in vehicle treated mice. The perfused vessel area, number of alpha smooth muscle actin positive vessels and hypoxic area in MLN0518 treated tumours were also significantly lower after 10 days treatment. These changes were not accompanied by alterations in vessel calibre or fractional blood volume as assessed using susceptibility contrast MRI. Histological assessment of vessel size and total perfused area did not demonstrate any change with treatment. Intrinsic susceptibility MRI did not reveal any difference in baseline R2* or carbogen-induced change in R2*. Dynamic contrast-enhanced MRI revealed anti-vascular effects of MLN0518 following 3 days treatment. Hypoxia confers chemo- and radio-resistance, and alongside PDGF, is implicated in evasive resistance to agents targeted against VEGF signalling. PDGFR antagonists may improve potency and efficacy of other therapeutics in combination. This study highlights the challenges of identifying appropriate quantitative imaging response biomarkers in heterogeneous models, particularly considering the multifaceted roles of angiogenic growth factors

Nitrogen addition alters composition, diversity, and functioning of microbial communities in mangrove soils : an incubation experiment

Mangrove ecosystems are important for carbon storage due to their high productivity and low decomposition rates. Waterways have experienced increased nutrient loads as a result of anthropogenic activities and it is unclear how this may affect carbon and nutrient cycles in downstream mangroves that receive these nutrient-rich waters. Using a laboratory-based incubation experiment, this study aimed to assess the effects of nutrient addition on the diversity and structure of mangrove soil bacterial communities, as well as biomass and activity of the soil microbial community, under different oxygen conditions. Bacterial community diversity and composition was characterised using 16S rRNA gene sequencing and microbial activity was examined through the measurement of microbial respiration and the activities of enzymes associated with organic matter decomposition. Nitrogen addition caused clear shifts in bacterial community composition, with decreases in bacterial diversity and the abundance of sulfate-reducing bacteria. Microbial biomass also decreased with nitrogen addition under reduced oxygen incubations. Changes in bacterial community structure were accompanied by changes in the activity of some enzymes involved in carbon, nitrogen and phosphorus cycling. Under reduced oxygen conditions, nitrogen addition resulted in a significant increase in the microbial metabolic quotient but no accompanying change in microbial respiration, which was explained by a decrease in microbial biomass. The findings of this study indicate that nitrogen loading has potential implications for microbial communities and carbon and nutrient cycling in mangrove environments that warrant further investigation under field conditions

Testing and recommending methods for fitting size spectra to data

The size spectrum of an ecological community characterizes how a property, such as abundance or biomass, varies with body size. Size spectra are often used as ecosystem indicators of marine systems. They have been fitted to data from various sources, including groundfish trawl surveys, visual surveys of fish in kelp forests and coral reefs, sediment samples of benthic invertebrates and satellite remote sensing of chlorophyll.Over the past decades, several methods have been used to fit size spectra to data. We document eight such methods, demonstrating their commonalities and differences. Seven methods use linear regression (of which six require binning of data), while the eighth uses maximum likelihood estimation. We test the accuracy of the methods on simulated data.We demonstrate that estimated size-spectrum slopes are not always comparable between the seven regression-based methods because such methods are not estimating the same parameter. We find that four of the eight tested methods can sometimes give reasonably accurate estimates of the exponent of the individual size distribution (which is related to the slope of the size spectrum). However, sensitivity analyses find that maximum likelihood estimation is the only method that is consistently accurate, and the only one that yields reliable confidence intervals for the exponent.We therefore recommend the use of maximum likelihood estimation when fitting size spectra. To facilitate this, we provide documented R code for fitting and plotting results. This should provide consistency in future studies and improve the quality of any resulting advice to ecosystem managers. In particular, the calculation of reliable confidence intervals will allow proper consideration of uncertainty when making management decisions

Mathematically Gifted Adolescents Have Deficiencies in Social Valuation and Mentalization

Many mathematically gifted adolescents are characterized as being indolent, underachieving and unsuccessful despite their high cognitive ability. This is often due to difficulties with social and emotional development. However, research on social and emotional interactions in gifted adolescents has been limited. The purpose of this study was to observe differences in complex social strategic behaviors between gifted and average adolescents of the same age using the repeated Ultimatum Game. Twenty-two gifted adolescents and 24 average adolescents participated in the Ultimatum Game. Two adolescents participate in the game, one as a proposer and the other as a responder. Because of its simplicity, the Ultimatum Game is an apt tool for investigating complex human emotional and cognitive decision-making in an empirical setting. We observed strategic but socially impaired offers from gifted proposers and lower acceptance rates from gifted responders, resulting in lower total earnings in the Ultimatum Game. Thus, our results indicate that mathematically gifted adolescents have deficiencies in social valuation and mentalization

Evidence-based practice educational intervention studies: A systematic review of what is taught and how it is measured

Abstract Background Despite the established interest in evidence-based practice (EBP) as a core competence for clinicians, evidence for how best to teach and evaluate EBP remains weak. We sought to systematically assess coverage of the five EBP steps, review the outcome domains measured, and assess the properties of the instruments used in studies evaluating EBP educational interventions. Methods We conducted a systematic review of controlled studies (i.e. studies with a separate control group) which had investigated the effect of EBP educational interventions. We used citation analysis technique and tracked the forward and backward citations of the index articles (i.e. the systematic reviews and primary studies included in an overview of the effect of EBP teaching) using Web of Science until May 2017. We extracted information on intervention content (grouped into the five EBP steps), and the outcome domains assessed. We also searched the literature for published reliability and validity data of the EBP instruments used. Results Of 1831 records identified, 302 full-text articles were screened, and 85 included. Of these, 46 (54%) studies were randomised trials, 51 (60%) included postgraduate level participants, and 63 (75%) taught medical professionals. EBP Step 3 (critical appraisal) was the most frequently taught step (63 studies; 74%). Only 10 (12%) of the studies taught content which addressed all five EBP steps. Of the 85 studies, 52 (61%) evaluated EBP skills, 39 (46%) knowledge, 35 (41%) attitudes, 19 (22%) behaviours, 15 (18%) self-efficacy, and 7 (8%) measured reactions to EBP teaching delivery. Of the 24 instruments used in the included studies, 6 were high-quality (achieved ≥3 types of established validity evidence) and these were used in 14 (29%) of the 52 studies that measured EBP skills; 14 (41%) of the 39 studies that measured EBP knowledge; and 8 (26%) of the 35 studies that measured EBP attitude. Conclusions Most EBP educational interventions which have been evaluated in controlled studies focus on teaching only some of the EBP steps (predominantly critically appraisal of evidence) and did not use high-quality instruments to measure outcomes. Educational packages and instruments which address all EBP steps are needed to improve EBP teaching

Facilitating return to work through early specialist health-based interventions (FRESH): protocol for a feasibility randomised controlled trial

Background Over one million people sustain traumatic brain injury each year in the UK and more than 10 % of these are moderate or severe injuries, resulting in cognitive and psychological problems that affect the ability to work. Returning to work is a primary rehabilitation goal but fewer than half of traumatic brain injury survivors achieve this. Work is a recognised health service outcome, yet UK service provision varies widely and there is little robust evidence to inform rehabilitation practice. A single-centre cohort comparison suggested better work outcomes may be achieved through early occupational therapy targeted at job retention. This study aims to determine whether this intervention can be delivered in three new trauma centres and to conduct a feasibility, randomised controlled trial to determine whether its effects and cost effectiveness can be measured to inform a definitive trial. Methods/design Mixed methods study, including feasibility randomised controlled trial, embedded qualitative studies and feasibility economic evaluation will recruit 102 people with traumatic brain injury and their nominated carers from three English UK National Health Service (NHS) trauma centres. Participants will be randomised to receive either usual NHS rehabilitation or usual rehabilitation plus early specialist traumatic brain injury vocational rehabilitation delivered by an occupational therapist. The primary objective is to assess the feasibility of conducting a definitive trial; secondary objectives include measurement of protocol integrity (inclusion/exclusion criteria, intervention adherence, reasons for non-adherence) recruitment rate, the proportion of eligible patients recruited, reasons for non-recruitment, spectrum of TBI severity, proportion of and reasons for loss to follow-up, completeness of data collection, gains in face-to-face Vs postal data collection and the most appropriate methods of measuring primary outcomes (return to work, retention) to determine the sample size for a larger trial. Discussion To our knowledge, this is the first feasibility randomised controlled trial of a vocational rehabilitation health intervention specific to traumatic brain injury. The results will inform the design of a definitive trial

Compound Evolutionary History of the Rhesus Macaque Mhc Class I B Region Revealed by Microsatellite Analysis and Localization of Retroviral Sequences

In humans, the single polymorphic B locus of the major histocompatibility complex is linked to the microsatellite MIB. In rhesus macaques, however, haplotypes are characterized by the presence of unique combinations of multiple B genes, which may display different levels of polymorphism. The aim of the study was to shed light on the evolutionary history of this highly complex region. First, the robustness of the microsatellite MIB-linked to almost half of the B genes in rhesus macaques (Mamu-B)–for accurate B haplotyping was studied. Based on the physical map of an established haplotype comprising 7 MIB loci, each located next to a certain Mamu-B gene, two MIB loci, MIB1 and MIB6, were investigated in a panel of MHC homozygous monkeys. MIB1 revealed a complex genotyping pattern, whereas MIB6 analysis resulted in the detection of one or no amplicon. Both patterns are specific for a given B haplotype, show Mendelian segregation, and even allow a more precise haplotype definition than do traditional typing methods. Second, a search was performed for retroelements that may have played a role in duplication processes as observed in the macaque B region. This resulted in the description of two types of duplicons. One basic unit comprises an expressed Mamu-B gene, adjacent to an HERV16 copy closely linked to MIB. The second type of duplicon comprises a Mamu-B (pseudo)gene, linked to a truncated HERV16 structure lacking its MIB segment. Such truncation seems to coincide with the loss of B gene transcription. Subsequent to the duplication processes, recombination between MIB and Mamu-B loci appears to have occurred, resulting in a hyperplastic B region. Thus, analysis of MIB in addition to B loci allows deciphering of the compound evolutionary history of the class I B region in Old World monkeys

Structural and functional insights into DNA-end processing by the archaeal HerA helicase-NurA nuclease complex

Helicase-nuclease systems dedicated to DNA end resection in preparation for homologous recombination (HR) are present in all kingdoms of life. In thermophilic archaea, the HerA helicase and NurA nuclease cooperate with the highly conserved Mre11 and Rad50 proteins during HR-dependent DNA repair. Here we show that HerA and NurA must interact in a complex with specific subunit stoichiometry to process DNA ends efficiently. We determine crystallographically that NurA folds in a toroidal dimer of intertwined RNaseH-like domains. The central channel of the NurA dimer is too narrow for double-stranded DNA but appears well suited to accommodate one or two strands of an unwound duplex. We map a critical interface of the complex to an exposed hydrophobic epitope of NurA abutting the active site. Based upon the presented evidence, we propose alternative mechanisms of DNA end processing by the HerA-NurA complex.Research in the N.P.R. laboratory is funded by the Medical Research Council [Career Development Award (G0701443)]. Research in L.P. laboratory is funded by a Wellcome Trust Senior Fellowship Award in Basic Biomedical Sciences (08279/Z/07/Z). Funding for open access charge: the Medical Research (G0701443 to N.P.R.) and the Wellcome Trust (08279/Z/07/Z to L.P.) and the Department of Biochemistry, University of Cambridge

Audio Cartography: Visual Encoding of Acoustic Parameters

Our sonic environment is the matter of subject in multiple domains which developed individual means of its description. As a result, it lacks an established visual language through which knowledge can be connected and insights shared. We provide a visual communication framework for the systematic and coherent documentation of sound in large-scale environments. This consists of visual encodings and mappings of acoustic parameters into distinct graphic variables that present plausible solutions for the visualization of sound. These candidate encodings are assembled into an application-independent, multifunctional, and extensible design guide. We apply the guidelines and show example maps that acts as a basis for the exploration of audio cartography