Identification of a novel regulatory mechanism for the disease associated protein, uPAR

Expression quantitative trait loci (eQTLs), as determined through a series of statistical association studies collectively known as genome-wide association (GWA) studies, have provided us with a hypothesis free approach for the investigation into regulatory loci for disease and disease-associated proteins. This has led to the identification of multiple novel gene-disease interactions, especially in the field of respiratory medicine. This review describes the case study of a GWA approach in order to identify eQTLs for the soluble form of the urokinase plasminogen activator receptor (uPAR), a protein associated with obstructive respiratory disease. Molecular and cellular investigations based on the eQTLs identified for this GWA study has led to the identification of a novel regulatory mechanism with implications in the disease processes with which this protein is associated. This highlights the potential of eQTLs defined associations in the identification of novel mechanisms, with implications in disease.peer-reviewe

The Pion-Photon Transition Form Factor and New Physics in the Tau Sector

Recent measurement of the $\gamma\gamma^\ast$ form factor of the neutral pion in the high $Q^2$ region disagrees with {\em a priori} predictions of QCD-based calculations. We comment on existing explanations, and analyze a possibility that this discrepancy is not due to poorly understood QCD effects, but is a result of some new physics beyond the standard model (SM). We show that such physics would necessarily involve a new neutral light state with mass close to the mass of $\pi^0$, and with stronger than $\pi^0$ couplings to heavier SM flavors such as $c$, $\tau$, and $b$. It is found that only the coupling to the $\tau$ lepton can survive the existing constraints and lead to the observed rise of the pion form factor relative to $Q^{-2}$ at high $Q^2$. We perform numerical fits to data and determine the allowed range of masses and couplings for such new particles. This range of masses and couplings could also reduce or eliminate the tension between the $e^+e^-$ and $\tau$ decay determinations of the hadronic vacuum polarization. Dedicated experimental analysis of $\tau$ pair production in association with such new states should provide a conclusive test of the new physics hypothesis as an explanation to the pion form factor rise. We also comment on the calculations of the pion form factor in the chiral quark model, and point out a possible dynamical origin of the quark mass scale inferred from the form factor measurement.Comment: 13 pages, 6 figures, revtex4-1; v2: additional references, improved discussion of pion mixing case, published versio

Up and Down Quark Masses and Corrections to Dashen's Theorem from Lattice QCD and Quenched QED

In a previous letter (arXiv:1306.2287) we determined the isospin mass splittings of the baryon octet from a lattice calculation based on quenched QED and $N_f{=}2{+}1$ QCD simulations with 5 lattice spacings down to $0.054~\mathrm{fm}$, lattice sizes up to $6~\mathrm{fm}$ and average up-down quark masses all the way down to their physical value. Using the same data we determine here the corrections to Dashen's theorem and the individual up and down quark masses. For the parameter which quantifies violations to Dashens's theorem, we obtain $\epsilon=0.73(2)(5)(17)$, where the first error is statistical, the second is systematic, and the third is an estimate of the QED quenching error. For the light quark masses we obtain, $m_u=2.27(6)(5)(4)~\mathrm{MeV}$ and $m_d=4.67(6)(5)(4)~\mathrm{MeV}$ in the $\bar{\mathrm{MS}}$ scheme at $2~\mathrm{GeV}$ and the isospin breaking ratios $m_u/m_d=0.485(11)(8)(14)$, $R=38.2(1.1)(0.8)(1.4)$ and $Q=23.4(0.4)(0.3)(0.4)$. Our results exclude the $m_u=0$ solution to the strong CP problem by more than $24$ standard deviations

Targeting chemokines : new drugs for old diseases

Chemokine receptor antagonists are set to become novel important pharmacological tools within the current therapeutic repertoire available for the management of various inflammatory conditions.peer-reviewe

The Electromagnetic Self-Energy Contribution to M_p - M_n and the Isovector Nucleon Magnetic Polarizability

We update the determination of the isovector nucleon electromagnetic self-energy, valid to leading order in QED. A technical oversight in the literature concerning the elastic contribution to Cottingham's formula is corrected and modern knowledge of the structure functions is used to precisely determine the inelastic contribution. We find \delta M_{p-n}^\gamma = 1.30(03)(47) MeV. The largest uncertainty arises from a subtraction term required in the dispersive analysis, which can be related to the isovector magnetic polarizability. With plausible model assumptions, we can combine our calculation with additional input from lattice QCD to constrain this polarizability as: \beta_{p-n} = -0.87(85) x 10^{-4} fm^3.Comment: 5 pages, version accepted for publication in PR

Isospin breaking in the nucleon mass and the sensitivity of β decays to new physics

We discuss the consequences of the approximate conservation of the vector and axial currents for the hadronic matrix elements appearing in β decay if nonstandard interactions are present. In particular, the isovector (pseudo)scalar charge gS(P) of the nucleon can be related to the difference (sum) of the nucleon masses in the absence of electromagnetic effects. Using recent determinations of these quantities from phenomenological and lattice QCD studies we obtain the accurate values gS=1.02(11) and gP=349(9) in the modified minimal subtraction scheme at μ=2  GeV. The consequences for searches of nonstandard scalar interactions in nuclear β decays are studied, finding for the corresponding Wilson coefficient εS=0.0012(24) at 90% C.L., which is significantly more stringent than current LHC bounds and previous low-energy bounds using less precise gS values. We argue that our results could be rapidly improved with updated computations and the direct calculation of certain ratios in lattice QCD. Finally, we discuss the pion-pole enhancement of gP, which makes β decays much more sensitive to nonstandard pseudoscalar interactions than previously thought

Genetic risk factors for the development of allergic disease identified by genome-wide association

An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non-disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities

Full QED+QCD Low-Energy Constants through Reweighting

The effect of sea quark electromagnetic charge on meson masses is investigated, and first results for full QED+QCD low-energy constants are presented. The electromagnetic charge for sea quarks is incorporated in quenched QED+full QCD lattice simulations by a reweighting method. The reweighting factor, which connects quenched and unquenched QED, is estimated using a stochastic method on 2+1 flavor dynamical domain-wall quark ensembles.Comment: 5 pages, 9 figures, REVTeX 4.1, v2: published versio

Isospin splittings in the light-baryon octet from lattice QCD and QED

While electromagnetic and up-down quark mass difference effects on octet baryon masses are very small, they have important consequences. The stability of the hydrogen atom against beta decay is a prominent example. Here we include these effects by adding them to valence quarks in a lattice QCD calculation based on $N_f=2+1$ simulations with 5 lattice spacings down to 0.054 fm, lattice sizes up to 6 fm and average up-down quark masses all the way down to their physical value. This allows us to gain control over all systematic errors, except for the one associated with neglecting electromagnetism in the sea. We compute the octet baryon isomultiplet mass splittings, as well as the individual contributions from electromagnetism and the up-down quark mass difference. Our results for the total splittings are in good agreement with experiment.Comment: 5 pages, 3 figures. Version accepted for publication by Phys. Rev. Let

Canonical Generations and the British Left: The Narrative Construction of the Miners’ Strike 1984–85

‘Generations’ have been invoked to describe a variety of social and cultural relationships, and to understand the development of self-conscious group identity. Equally, the term can be an applied label and politically useful construct; generations can be retrospectively produced. Drawing on the concept of ‘canonical generations’ – those whose experiences come to epitomise an event of historic and symbolic importance – this article examines the narrative creation and functions of ‘generations’ as collective memory shapes and re-shapes the desire for social change. Building a case study of the canonical role of the miners’ strike of 1984–85 in the narrative history of the British left, it examines the selective appropriation and transmission of the past in the development of political consciousness. It foregrounds the autobiographical narratives of activists who, in examining and legitimising their own actions and prospects, (re)produce a ‘generation’ in order to create a relatable and useful historical understanding