The impact generated by public and charity-funded research in the UK: A systematic literature review

Objective: To identify, synthesize and critically assess the empirical evidence of the impact generated by public and charity funded health research in the United Kingdom. Methods: We conducted a systematic literature review of the empirical evidence published in English in peer-reviewed journals between 2006 and 2017. Studies meeting the inclusion criteria were selected and their findings were analysed using the Payback Framework into five main categories: knowledge, benefits to future research and research use, benefits from informing policy and product development, health and health sector benefits and broader economic benefits. We assessed the studies for risk of selection, reporting and funding bias. Results: Thirteen studies met the inclusion criteria. The majority of the studies (10 out of 13) assessed impact at multiple domains including the main 5 key themes of the Payback Framework. All of them showed a positive impact of funded research on outcomes. Of those studies, one presented low risk of bias (8%), 6 studies were classified as presenting moderate risk of bias (46%) and 6 studies presented high risk of bias (46%). Conclusions: Empirical evidence on the impact of public and charity funded research is still limited and subject to funding and selection bias. More work is needed to establish the causal effects of funded research on academic outcomes, policy, practice and the broader economy

Delay in referral of oropharyngeal squamous cell carcinoma to secondary care correlates with a more advanced stage at presentation, and is associated with poorer survival

Squamous carcinoma of the oropharynx presents with symptoms common to many benign diseases, and this can cause delay in referral to secondary care. We investigate delay in referral, defining this as the time from symptom-onset to date of general practitioners referral letter to secondary care, and the effect of that delay, using a retrospective case notes based study of patients presenting at our institution with oropharyngeal squamous carcinoma between 1995 and 2005. Using correlation analysis and ordinal regression, we examined the relationship between increased referral delay from primary care, clinical stage at presentation, and survival. Increasing time from symptom onset to referral to secondary care was positively correlated with more advanced disease stage at presentation (rs=+0.346, P=0.004). This was confirmed with ordinal regression modelling (delay estimate=0.045, P=0.042). Patients with delay of less than 6 weeks had significantly improved survival compared to those with a delay of greater than 6 weeks (P=0.032). For every 1 week of delay in referral, we estimate that the stage of presentation will progress by 0.045 of ‘a stage'

A novel workflow for three-dimensional analysis of tumour cell migration

The limitations of two-dimensional analysis in three-dimensional (3D) cellular imaging impair the accuracy of research findings in biological studies. Here, we report a novel 3D approach to acquisition, analysis and interpretation of tumour spheroid images. Our research interest in mesenchymal–amoeboid transition led to the development of a workflow incorporating the generation and analysis of 3D data with instant structured illumination microscopy and a new ImageJ plugin

G+C content dominates intrinsic nucleosome occupancy

<p>Abstract</p> <p>Background</p> <p>The relative preference of nucleosomes to form on individual DNA sequences plays a major role in genome packaging. A wide variety of DNA sequence features are believed to influence nucleosome formation, including periodic dinucleotide signals, poly-A stretches and other short motifs, and sequence properties that influence DNA structure, including base content. It was recently shown by Kaplan et al. that a probabilistic model using composition of all 5-mers within a nucleosome-sized tiling window accurately predicts intrinsic nucleosome occupancy across an entire genome <it>in vitro</it>. However, the model is complicated, and it is not clear which specific DNA sequence properties are most important for intrinsic nucleosome-forming preferences.</p> <p>Results</p> <p>We find that a simple linear combination of only 14 simple DNA sequence attributes (G+C content, two transformations of dinucleotide composition, and the frequency of eleven 4-bp sequences) explains nucleosome occupancy <it>in vitro </it>and <it>in vivo </it>in a manner comparable to the Kaplan model. G+C content and frequency of AAAA are the most important features. G+C content is dominant, alone explaining ~50% of the variation in nucleosome occupancy <it>in vitro</it>.</p> <p>Conclusions</p> <p>Our findings provide a dramatically simplified means to predict and understand intrinsic nucleosome occupancy. G+C content may dominate because it both reduces frequency of poly-A-like stretches and correlates with many other DNA structural characteristics. Since G+C content is enriched or depleted at many types of features in diverse eukaryotic genomes, our results suggest that variation in nucleotide composition may have a widespread and direct influence on chromatin structure.</p

Genomic Organization of H2Av Containing Nucleosomes in Drosophila Heterochromatin

H2Av is a versatile histone variant that plays both positive and negative roles in transcription, DNA repair, and chromatin structure in Drosophila. H2Av, and its broader homolog H2A.Z, tend to be enriched toward 5′ ends of genes, and exist in both euchromatin and heterochromatin. Its organization around euchromatin genes and other features have been described in many eukaryotic model organisms. However, less is known about H2Av nucleosome organization in heterochromatin. Here we report the properties and organization of individual H2Av nucleosomes around genes and transposable elements located in Drosophila heterochromatic regions. We compare the similarity and differences with that found in euchromatic regions. Our analyses suggest that nucleosomes are intrinsically positioned on inverted repeats of DNA transposable elements such as those related to the “1360” element, but are not intrinsically positioned on retrotransposon-related elements

Building health research systems to achieve better health

Health research systems can link knowledge generation with practical concerns to improve health and health equity. Interest in health research, and in how health research systems should best be organised, is moving up the agenda of bodies such as the World Health Organisation. Pioneering health research systems, for example those in Canada and the UK, show that progress is possible. However, radical steps are required to achieve this. Such steps should be based on evidence not anecdotes. Health Research Policy and Systems (HARPS) provides a vehicle for the publication of research, and informed opinion, on a range of topics related to the organisation of health research systems and the enormous benefits that can be achieved. Following the Mexico ministerial summit on health research, WHO has been identifying ways in which it could itself improve the use of research evidence. The results from this activity are soon to be published as a series of articles in HARPS. This editorial provides an account of some of these recent key developments in health research systems but places them in the context of a distinguished tradition of debate about the role of science in society. It also identifies some of the main issues on which 'research on health research' has already been conducted and published, in some cases in HARPS. Finding and retaining adequate financial and human resources to conduct health research is a major problem, especially in low and middle income countries where the need is often greatest. Research ethics and agenda-setting that responds to the demands of the public are issues of growing concern. Innovative and collaborative ways are being found to organise the conduct and utilisation of research so as to inform policy, and improve health and health equity. This is crucial, not least to achieve the health-related Millennium Development Goals. But much more progress is needed. The editorial ends by listing a wide range of topics related to the above priorities on which we hope to feature further articles in HARPS and thus contribute to an informed debate on how best to achieve such progress

Predicting Human Nucleosome Occupancy from Primary Sequence

Nucleosomes are the fundamental repeating unit of chromatin and comprise the structural building blocks of the living eukaryotic genome. Micrococcal nuclease (MNase) has long been used to delineate nucleosomal organization. Microarray-based nucleosome mapping experiments in yeast chromatin have revealed regularly-spaced translational phasing of nucleosomes. These data have been used to train computational models of sequence-directed nuclesosome positioning, which have identified ubiquitous strong intrinsic nucleosome positioning signals. Here, we successfully apply this approach to nucleosome positioning experiments from human chromatin. The predictions made by the human-trained and yeast-trained models are strongly correlated, suggesting a shared mechanism for sequence-based determination of nucleosome occupancy. In addition, we observed striking complementarity between classifiers trained on experimental data from weakly versus heavily digested MNase samples. In the former case, the resulting model accurately identifies nucleosome-forming sequences; in the latter, the classifier excels at identifying nucleosome-free regions. Using this model we are able to identify several characteristics of nucleosome-forming and nucleosome-disfavoring sequences. First, by combining results from each classifier applied de novo across the human ENCODE regions, the classifier reveals distinct sequence composition and periodicity features of nucleosome-forming and nucleosome-disfavoring sequences. Short runs of dinucleotide repeat appear as a hallmark of nucleosome-disfavoring sequences, while nucleosome-forming sequences contain short periodic runs of GC base pairs. Second, we show that nucleosome phasing is most frequently predicted flanking nucleosome-free regions. The results suggest that the major mechanism of nucleosome positioning in vivo is boundary-event-driven and affirm the classical statistical positioning theory of nucleosome organization

Oligonucleotide Sequence Motifs as Nucleosome Positioning Signals

To gain a better understanding of the sequence patterns that characterize positioned nucleosomes, we first performed an analysis of the periodicities of the 256 tetranucleotides in a yeast genome-wide library of nucleosomal DNA sequences that was prepared by in vitro reconstitution. The approach entailed the identification and analysis of 24 unique tetranucleotides that were defined by 8 consensus sequences. These consensus sequences were shown to be responsible for most if not all of the tetranucleotide and dinucleotide periodicities displayed by the entire library, demonstrating that the periodicities of dinucleotides that characterize the yeast genome are, in actuality, due primarily to the 8 consensus sequences. A novel combination of experimental and bioinformatic approaches was then used to show that these tetranucleotides are important for preferred formation of nucleosomes at specific sites along DNA in vitro. These results were then compared to tetranucleotide patterns in genome-wide in vivo libraries from yeast and C. elegans in order to assess the contributions of DNA sequence in the control of nucleosome residency in the cell. These comparisons revealed striking similarities in the tetranucleotide occurrence profiles that are likely to be involved in nucleosome positioning in both in vitro and in vivo libraries, suggesting that DNA sequence is an important factor in the control of nucleosome placement in vivo. However, the strengths of the tetranucleotide periodicities were 3–4 fold higher in the in vitro as compared to the in vivo libraries, which implies that DNA sequence plays less of a role in dictating nucleosome positions in vivo. The results of this study have important implications for models of sequence-dependent positioning since they suggest that a defined subset of tetranucleotides is involved in preferred nucleosome occupancy and that these tetranucleotides are the major source of the dinucleotide periodicities that are characteristic of positioned nucleosomes

Contribution of histone sequence preferences to nucleosome organization: proposed definitions and methodology

We propose definitions and procedures for comparing nucleosome maps and discuss current agreement and disagreement on the effect of histone sequence preferences on nucleosome organization in vivo