Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D.

Mendelian randomization (MR) studies use genetic variants mimicking the influence of a modifiable exposure to assess and quantify a causal association with an outcome, with an aim to avoid problems with confounding and reverse causality affecting other types of observational studies

Evolving solitons in bubbly flows

At the end of the sixties, it was shown that pressure waves in a bubbly liquid obey the KdV equation, the nonlinear term coming from convective acceleration and the dispersive term from volume oscillations of the bubbles.\ud For a variableu, proportional to –p, wherep denotes pressure, the appropriate KdV equation can be casted in the formu t –6uu x +u xxx =0. The theory of this equation predicts that, under certain conditions, solitons evolve from an initial profileu(x,0). In particular, it can be shown that the numberN of those solitons can be found from solving the eigenvalue problem xx–u(x,0)=0, with(0)=1 and(0)=0.N is found from counting the zeros of the solution of this equation betweenx=0 andx=Q, say,Q being determined by the shape ofu(x,0). We took as an initial pressure profile a Shockwave, followed by an expansion wave. This can be realised in the laboratory and the problem, formulated above, can be solved exactly.\ud In this contribution the solution is outlined and it is shown from the experimental results that from the said initial disturbance, indeed solitons evolve in the predicated quantity.\u

Cyprideis torosa (Jones, 1850) in its type area and stratigraphical context: potential for mapping the freshwater/estuarine boundaries of the Thames-Medway river system in the MIS 9 and MIS 11 interglacials

GB’s contribution was supported by a Queen Mary University of London PhD studentship

Analytical method for perturbed frozen orbit around an Asteroid in highly inhomogeneous gravitational fields : A first approach

This article provides a method for nding initial conditions for perturbed frozen orbits around inhomogeneous fast rotating asteroids. These orbits can be used as reference trajectories in missions that require close inspection of any rigid body. The generalized perturbative procedure followed exploits the analytical methods of relegation of the argument of node and Delaunay normalisation to arbitrary order. These analytical methods are extremely powerful but highly computational. The gravitational potential of the heterogeneous body is rstly stated, in polar-nodal coordinates, which takes into account the coecients of the spherical harmonics up to an arbitrary order. Through the relegation of the argument of node and the Delaunay normalization, a series of canonical transformations of coordinates is found, which reduces the Hamiltonian describing the system to a integrable, two degrees of freedom Hamiltonian plus a truncated reminder of higher order. Setting eccentricity, argument of pericenter and inclination of the orbit of the truncated system to be constant, initial conditions are found, which evolve into frozen orbits for the truncated system. Using the same initial conditions yields perturbed frozen orbits for the full system, whose perturbation decreases with the consideration of arbitrary homologic equations in the relegation and normalization procedures. Such procedure can be automated for the first homologic equation up to the consideration of any arbitrary number of spherical harmonics coefficients. The project has been developed in collaboration with the European Space Agency (ESA)

A Study of Brain Networks Associated with Swallowing Using Graph-Theoretical Approaches

Functional connectivity between brain regions during swallowing tasks is still not well understood. Understanding these complex interactions is of great interest from both a scientific and a clinical perspective. In this study, functional magnetic resonance imaging (fMRI) was utilized to study brain functional networks during voluntary saliva swallowing in twenty-two adult healthy subjects (all females, 23.1±1.52 years of age). To construct these functional connections, we computed mean partial correlation matrices over ninety brain regions for each participant. Two regions were determined to be functionally connected if their correlation was above a certain threshold. These correlation matrices were then analyzed using graph-theoretical approaches. In particular, we considered several network measures for the whole brain and for swallowing-related brain regions. The results have shown that significant pairwise functional connections were, mostly, either local and intra-hemispheric or symmetrically inter-hemispheric. Furthermore, we showed that all human brain functional network, although varying in some degree, had typical small-world properties as compared to regular networks and random networks. These properties allow information transfer within the network at a relatively high efficiency. Swallowing-related brain regions also had higher values for some of the network measures in comparison to when these measures were calculated for the whole brain. The current results warrant further investigation of graph-theoretical approaches as a potential tool for understanding the neural basis of dysphagia. © 2013 Luan et al

How informative is a negative finding in a small pharmacogenetic study?

Many pharmacogenetic studies fail to yield any statistically significant associations. Such negative findings may be due to the absence of, or inadequate statistical power to test for, an effect at the genetic variants tested. In many instances, sample sizes are small, making it unclear how to interpret the absence of statistically significant findings. We demonstrate that the amount of information that can be drawn from a negative study is improved by incorporating statistical power and the added context of well-validated pharmacogenetic effects into the interpretation process. This approach permits clearer inferences to be made about the possible range of genetic effects that may be present in, or are likely absent from, small drug studies

Fregene: Simulation of realistic sequence-level data in populations and ascertained samples

Background: FREGENE simulates sequence-level data over large genomic regions in large populations. Because, unlike coalescent simulators, it works forwards through time, it allows complex scenarios of selection, demography, and recombination to be modelled simultaneously. Detailed tracking of sites under selection is implemented in FREGENE and provides the opportunity to test theoretical predictions and gain new insights into mechanisms of selection. We describe here main functionalities of both FREGENE and SAMPLE, a companion program that can replicate association study datasets.Results: We report detailed analyses of six large simulated datasets that we have made publicly available. Three demographic scenarios are modelled: one panmictic, one substructured with migration, and one complex scenario that mimics the principle features of genetic variation in major worldwide human populations. For each scenario there is one neutral simulation, and one with a complex pattern of selection.Conclusion: FREGENE and the simulated datasets will be valuable for assessing the validity of models for selection, demography and population genetic parameters, as well as the efficacy of association studies. Its principle advantages are modelling flexibility and computational efficiency. It is open source and object-oriented. As such, it can be customised and the range of models extended

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Platypus globin genes and flanking loci suggest a new insertional model for beta-globin evolution in birds and mammals

Background: Vertebrate alpha (α)- and beta (β)-globin gene families exemplify the way in which genomes evolve to produce functional complexity. From tandem duplication of a single globin locus, the α- and β-globin clusters expanded, and then were separated onto different chromosomes. The previous finding of a fossil β-globin gene (ω) in the marsupial α-cluster, however, suggested that duplication of the α-β cluster onto two chromosomes, followed by lineage-specific gene loss and duplication, produced paralogous α- and β-globin clusters in birds and mammals. Here we analyse genomic data from an egg-laying monotreme mammal, the platypus (Ornithorhynchus anatinus), to explore haemoglobin evolution at the stem of the mammalian radiation. Results: The platypus α-globin cluster (chromosome 21) contains embryonic and adult α- globin genes, a β-like ω-globin gene, and the GBY globin gene with homology to cytoglobin, arranged as 5'-ζ-ζ'-αD-α3-α2-α1-ω-GBY-3'. The platypus β-globin cluster (chromosome 2) contains single embryonic and adult globin genes arranged as 5'-ε-β-3'. Surprisingly, all of these globin genes were expressed in some adult tissues. Comparison of flanking sequences revealed that all jawed vertebrate α-globin clusters are flanked by MPG-C16orf35 and LUC7L, whereas all bird and mammal β-globin clusters are embedded in olfactory genes. Thus, the mammalian α- and β-globin clusters are orthologous to the bird α- and β-globin clusters respectively. Conclusion: We propose that α- and β-globin clusters evolved from an ancient MPG-C16orf35-α-β-GBY-LUC7L arrangement 410 million years ago. A copy of the original β (represented by ω in marsupials and monotremes) was inserted into an array of olfactory genes before the amniote radiation (>315 million years ago), then duplicated and diverged to form orthologous clusters of β-globin genes with different expression profiles in different lineages.Vidushi S. Patel, Steven J.B. Cooper, Janine E. Deakin, Bob Fulton, Tina Graves, Wesley C. Warren, Richard K. Wilson and Jennifer A.M. Grave