Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

A “Candidate-Interactome” Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms

Droughts and broad-scale climate variability reflected by temperature-sensitive tree growth in the Qinling Mountains, central China

The relationship between temperature and drought was investigated using the temperature-sensitive growth of Larix chinensis Beissn in the Qinling Mountains, central China. Extremely high tree-ring width index values (TRWI) agreed well with dry conditions defined by the dryness-wetness index (DWI) obtained from data in Chinese historical documents and climate-related papers between 1814 and 1956 (before the short of instrumental measurements); the reverse applied to extremely low TRWI values. The main severe drought epochs occurred from the late 1850s to the 1870s, the 1920s to 1930s and in the 2000s, whereas wet spells occurred from 1817-1827 and 1881-1886. The droughts in the 2000s exhibited a similar pattern as the ones from the 1920s to 1930s, with obviously an increasing temperature. The variation of tree growth agreed well with other reconstructed temperature series from nearby and remote regions, suggesting that Larix chinensis could respond to broad-scale climate variability. The longest cold interval, 1817-1827, could be associated with the influence of the Tambora eruption in 1815.</p

Study of the rare B-s(0) and B-0 decays into the pi(+) pi(-) mu(+) mu(-) final state

A search for the rare decays B-s(0) -> pi(+) pi-mu(+) mu-and B-0 -> pi(+) pi-mu(+) mu-is performed in a data set corresponding to an integrated luminosity of 3.0 fb(-1) collected by the LHCb detector in proton-proton collisions at centre-of-mass energies of 7 and 8 TeV. Decay candidates with pion pairs that have invariant mass in the range 0.5-1.3GeV/c(2) and with muon pairs that do not originate from a resonance are considered. The first observation of the decay B-s(0) -> pi(+) pi-mu(+) mu- and the first evidence of the decay B-0 -> pi(+) pi-mu(+) mu-are obtained and the branching fractions, restricted to the dipion-mass range considered, are measured to be B(B-s(0) -> pi(+) pi-mu(+) mu(-)) =(8.6 +/- 1.5(stat) +/- 0.7(syst) +/- 0.7 (norm)) x 10(-8) and B(B-0 -> pi(+) pi-mu(+) mu(-)) =(2.11 +/- 0.51(stat) +/- 0.15(syst) +/- 0.16(norm)) x10(-8), where the third uncertainty is due to the branching fraction of the decay B-0. -> J/Psi(mu(+) mu(-)) K*(892)(0)(-> K+ pi(-)), used as a normalisation. (C) 2015 The Authors. Published by Elsevier B.V

Effective lifetime measurements in the B-s(0) -> K+K-, B-0 -> K+pi(-) and B-s(0) -> pi K-+(-) decays

Measurements of the effective lifetimes in the B-s(0) -> K+K-, B-0 -> K+pi(-) and B-s(0) -> pi K-+(-) decays are presented using 1.0 fb(-1)of pp collision data collected at a centre-of-mass energy of 7 TeV by the LHCb experiment. The analysis uses a data-driven approach to correct for the decay time acceptance. The measured effective lifetimes are tau(Bs0 -> K+K-) = 1.407 +/- 0.016 (stat) +/- 0.007 (syst) ps, tau(Bs0 -> K+pi-) = 1.524 +/- 0.011 (stat) +/- 0.004 (syst) ps, tau(Bs0 ->pi+K-) = 1.60 +/- 0.06 (stat) +/- 0.01 (syst) ps. This is the most precise determination to date of the effective lifetime in the B-s(0) -> K+K- decay and provides constraints on contributions from physics beyond the Standard Model to the B-s(0) mixing phase and the width difference Delta Gamma(s). (C) 2014 The Authors. Published by Elsevier B.V

Measurement of CP violation and constraints on the CKM angle gamma in B-+/- -> DK +/- with D -> K-s(0)pi(+)pi(-) decays

A model-dependent amplitude analysis of B-+/- -> DK +/- with D -> K-s(0)pi(+)pi(-) decays is performed using proton proton collision data, corresponding to an integrated luminosity of 1 fb(-1), recorded by LHCb at a centre-of-mass energy of 7 TeV in 2011. Values of the CP violation observables x +/- and y +/-, which are sensitive to the CKM angle gamma, are measured to be x- = +0.027 +/- 0.0441(-0.008)(+0.010) +/- 0.001, y- = +0.013 +/- 0.0481(-0.007)(+0.009) +/- 0.003, x+ = -0.084 +/- 0.045 +/- 0.009 +/- 0.005, y+ = -0.032 +/- 0.048(-0.009)(+0.010) +/- 0.008, where the first uncertainty is statistical, the second systematic and the third arises from the uncertainty of the D -> K-S(0)pi(+)pi(-) amplitude model. The value of gamma is determined to be (84(-42)(+49))degrees including all sources of uncertainty. Neutral D meson mixing is found to have negligible effect. (C) 2014 The Authors. Published by Elsevier B.V

Measurement of the Xi(-)(b) and Omega(-)(b) baryon lifetimes

Using a data sample of pp collisions corresponding to an integrated luminosity of 3 fb(-1), the Xi(-)(b) and Omega(-)(b) baryons are reconstructed in the Xi(-)(b) -> J/psi Xi(-) and Omega(-)(b) -> J/psi Omega(-) decay modes and their lifetimes measured to be tau(Xi(-)(b)) = 1.55(-0.09)(+0.10) (stat) +/- 0.03 (syst) ps, tau(Omega(-)(b)) = 1.54(-0.21)(+0.26) (stat) +/- 0.05 (syst) ps. These are the most precise determinations to date. Both measurements are in good agreement with previous experimental results and with theoretical predictions. (C) 2014 The Authors. Published by Elsevier B.V

Measurement of the CP-violating phase phi(s) in (B)over-bar(s)(0) -> J / psi pi(+)pi(-) decays

The mixing-induced CP-violating phase phi(s) in B-s(0) and (B) over bar (0)(s) decays is measured using the J / psi pi(+)pi(-) final state in data, taken from 3 fb(-1) of integrated luminosity, collected with the LHCb detector in 7 and 8 TeV centre-of-mass pp collisions at the LHC. A time-dependent flavour-tagged amplitude analysis, allowing for direct CP violation, yields a value for the phase phi(s) = 70 +/- 68 +/- 8 mrad. This result is consistent with the Standard Model expectation and previous measurements. (C) 2014 The Authors. Published by Elsevier B.V

Measurement of the charge asymmetry in B-+/- -> phi K +/- and search for B-+/- -> phi pi(+/-) decays

The CP-violating charge asymmetry in B-+/- -> phi K-+/- decays is measured in a sample of pp collisions at 7 TeV centre-of-mass energy, corresponding to an integrated luminosity of 1.0 fb-1 collected by the LHCb experiment. The result is A(CP)(B-+/- -> phi K-+/-) = 0.022 +/- 0.021 +/- 0.009, where the first uncertainty is statistical and the second systematic. In addition, a search for the B-+/- -> phi pi(+/-) decay mode is performed, using the B-+/- -> phi K-+/- decay rate for normalization. An upper limit on the branching fraction B(B-+/- -> phi pi(+/-)) < 1.5 x 10(-7) is set at 90% confidence level. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved