How much of the variation in the mutation rate along the human genome can be explained?

It has been claimed recently that it may be possible to predict the rate of de novo mutation of each site in the human genome with a high degree of accuracy [Michaelson et al. (2012), Cell 151: 143121442]. We show that this claim is unwarranted. By considering the correlation between the rate of de novo mutation and the predictions from the model of Michaelson et al., we show there could be substantial unexplained variance in the mutation rate. We investigate whether the model of Michaelson et al. captures variation at the single nucleotide level that is not due to simple context. We show that the model captures a substantial fraction of this variation at CpG dinucleotides but fails to explain much of the variation at non-CpG sites

Evidence that both G + C rich and G + C poor isochores are replicated early and late in the cell cycle

Since the G + C content of a gene is correlated to that of the isochore in which it resides, and early replicating isochores are thought to be relatively G + C rich, early replicating genes should also be rich in G + C. This hypothesis is tested on a sample of 44 mammalian genes for which replication time data and sequence information are available. Early replicating genes do not appear to be more G + C rich than late replicating genes, instead there is considerable variation in the G + C content of genes replicated during both halves of S phase. These results show that both G + C rich and poor fractions of the genome are replicated early and late in the cell cycle, and suggest that isochores are not maintained by the replication of DNA sequences in compositionally biased free nucleotide pools

Locating the orbits delineated by tidal streams

We describe a technique that finds orbits through the Galaxy that are consistent with measurements of a tidal stream, taking into account the extent that tidal streams do not precisely delineate orbits. We show that if accurate line-of-sight velocities are measured along a well defined stream, the technique recovers the underlying orbit through the Galaxy and predicts the distances and proper motions along the stream to high precision. As the error bars on the location and velocities of the stream grow, the technique is able to find more and more orbits that are consistent with the data and the uncertainties in the predicted distances and proper motions increase. With radial-velocity data along a stream ~40deg long and <0.3deg wide on the sky accurate to ~1 km/s the precisions of the distances and tangential velocities along the stream are 4 percent and 5 km/s, respectively. The technique can be used to diagnose the Galactic potential: if circular-speed curve is actually flat, both a Keplerian potential and Phi(r) proportional to r are readily excluded. Given the correct radial density profile for the dark halo, the halo's mass can be determined to a precision of 5 percent.Comment: 13 pages, 16 figures, submitted to MNRA

Energy policy in transition: evidence from energy supply and demand in the UK

Whilst much of Europe is turning to supplier obligations in order to compel energy companies to deliver energy efficiency improvements, the UK, after 18 years of using such schemes, will from 2013 have a financing scheme as the central delivery mechanism, relying fully on the market rather than government intervention. The remaining supplier obligation will focus on the areas that financing is not expected to fully support: more expensive insulation and help for those with no access to finance. In addition, the publicly funded fuel poverty policy is to be terminated: for the first time since 1978, there will be no taxpayer funded energy efficiency programme for the most vulnerable. These changes represent the biggest shift in the history of energy efficiency policy in the UK since the first and second oil crisis. Yet, despite appeals from many stakeholders, no period of transition will exist between the end of the current and the start of the new policies. The impact is likely to be stark: the expectation is for a dramatic reduction in the delivery of cost-effective energy efficiency measures leading to a big fall in employment and carbon reduction.Plans for the supply-side are equally profound. In order to create a market with greater capacity and to encourage nuclear investment, the Government has unveiled plans for electricity market reform (EMR). For renewable generators, EMR will mark a change in policy support, from a quantity-based green certificate mechanism (the Renewables Obligation) to a price-based feed-in-tariff approach. In contrast to the approach on the demand-side, Government is allowing a three year transition between these schemes. The paper outlines the reasons for the different approaches to policy continuity across the demand and supply side. It highlights what we see as key considerations for policy makers when planning a transition from a supplier obligation to a finance mechanism. We assess the implications of this shift in terms of carbon reduction effort, the industry and fuel poverty

Change management - practising what we teach: successfully engaging international students in the teaching, learning & assessment process

In this article we review processes of change in a module whose subject matter is change management. The module attracts mainly international students, and has suffered from uneven student engagement and performance. We will recount how a Teaching Enhancement and Student Success (TESS) project was used to inform our attempts to improve engagement and performance. Bearing in mind the origins of action research as part of Kurt Lewin‟s approach to planned change, we will use the four different elements of Lewin‟s work to reflect on the challenges we have been grappling with. The article will highlight different approaches to action research, which are linked to different aspirations as to the scope of change

Work relations for a system governed by Tsallis statistics

We derive analogues of the Jarzynski equality and Crooks relation to characterise the nonequilibrium work associated with changes in the spring constant of an overdamped oscillator in a quadratically varying spatial temperature profile. The stationary state of such an oscillator is described by Tsallis statistics, and the work relations for certain processes may be expressed in terms of q-exponentials. We suggest that these identities might be a feature of nonequilibrium processes in circumstances where Tsallis distributions are found

What can a participatory approach to evaluation contribute to the field of integrated care?

© 2017 BMJ Publishing Group. All rights reserved. Better integration of care within the health sector and between health and social care is seen in many countries as an essential way of addressing the enduring problems of dwindling resources, changing demographics and unacceptable variation in quality of care. Current research evidence about the effectiveness of integration efforts supports neither the enthusiasm of those promoting and designing integrated care programmes nor the growing efforts of practitioners attempting to integrate care on the ground. In this paper we present a methodological approach, based on the principles of participatory research, that attempts to address this challenge. Participatory approaches are characterised by a desire to use social science methods to solve practical problems and a commitment on the part of researchers to substantive and sustained collaboration with relevant stakeholders. We describe how we applied an emerging practical model of participatory research, the researcher-in-residence model, to evaluate a large-scale integrated care programme in the UK. We propose that the approach added value to the programme in a number of ways: by engaging stakeholders in using established evidence and with the benefits of rigorously evaluating their work, by providing insights for local stakeholders that they were either not familiar with or had not fully considered in relation to the development and implementation of the programme and by challenging established mindsets and norms. While there is still much to learn about the benefits and challenges of applying participatory approaches in the health sector, we demonstrate how using such approaches have the potential to help practitioners integrate care more effectively in their daily practice and help progress the academic study of integrated care

Cryptic Variation in the Human Mutation Rate

The mutation rate is known to vary between adjacent sites within the human genome as a consequence of context, the most well-studied example being the influence of CpG dinucelotides. We investigated whether there is additional variation by testing whether there is an excess of sites at which both humans and chimpanzees have a single-nucleotide polymorphism ( SNP). We found a highly significant excess of such sites, and we demonstrated that this excess is not due to neighbouring nucleotide effects, ancestral polymorphism, or natural selection. We therefore infer that there is cryptic variation in the mutation rate. However, although this variation in the mutation rate is not associated with the adjacent nucleotides, we show that there are highly nonrandom patterns of nucleotides that extend similar to 80 base pairs on either side of sites with coincident SNPs, suggesting that there are extensive and complex context effects. Finally, we estimate the level of variation needed to produce the excess of coincident SNPs and show that there is a similar, or higher, level of variation in the mutation rate associated with this cryptic process than there is associated with adjacent nucleotides, including the CpG effect. We conclude that there is substantial variation in the mutation that has, until now, been hidden from view