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

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

An embedding technique to determine ττ backgrounds in proton-proton collision data

An embedding technique is presented to estimate standard model tau tau backgrounds from data with minimal simulation input. In the data, the muons are removed from reconstructed mu mu events and replaced with simulated tau leptons with the same kinematic properties. In this way, a set of hybrid events is obtained that does not rely on simulation except for the decay of the tau leptons. The challenges in describing the underlying event or the production of associated jets in the simulation are avoided. The technique described in this paper was developed for CMS. Its validation and the inherent uncertainties are also discussed. The demonstration of the performance of the technique is based on a sample of proton-proton collisions collected by CMS in 2017 at root s = 13 TeV corresponding to an integrated luminosity of 41.5 fb(-1).Peer reviewe

Performance of missing transverse momentum reconstruction in proton-proton collisions at root s=13 TeV using the CMS detector

The performance of missing transverse momentum ((p) over right arrow (miss)(T)) reconstruction algorithms for the CMS experiment is presented, using proton-proton collisions at a center-of-mass energy of 13 TeV, collected at the CERN LHC in 2016. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The results include measurements of the scale and resolution of (p) over right arrow (miss)(T), and detailed studies of events identified with anomalous (p) over right arrow (miss)(T). The performance is presented of a (p) over right arrow (miss)(T) reconstruction algorithm that mitigates the effects of multiple proton-proton interactions, using the "pileup per particle identification" method. The performance is shown of an algorithm used to estimate the compatibility of the reconstructed (p) over right arrow (miss)(T) with the hypothesis that it originates from resolution effects.Peer reviewe

Measurement of the ratio B(t -> Wb)/B(t -> Wq) in pp collisions at root s=8 TeV

The ratio of the top-quark branching fractions R = B(t --> Wb)/B(t --> Wq), where the denominator includes the sum over all down-type quarks (q = b, s, d), is measured in the t (t) over bar dilepton final state with proton-proton collision data at root s = 8 TeV from an integrated luminosity of 19.7 fb(-1), collected with the CMS detector. In order to quantify the purity of the signal sample, the cross section is measured by fitting the observed jet multiplicity, thereby constraining the signal and background contributions. By counting the number of b jets per event, an unconstrained value of R = 1.014 +/- 0.003 (stat.) +/- 0.032 (syst.) is measured, in a good agreement with current precision measurements in electroweak and flavour sectors. A lower limit R > 0.955 at the 95% confidence level is obtained after requiring R 0.975 is set at 95% confidence level. The result is combined with a previous CMS measurement of the t-channel single-top-quark cross section to determine the top-quark total decay width, Gamma(t) = 1.36 +/- 0.02 (stat.)(-0.11)(+0.14) (syst.) GeV

Search for excited quarks in the gamma plus jet final state in proton-proton collisions at root s=8 TeV

A search for excited quarks decaying into the gamma + jet final state is presented. The analysis is based on data corresponding to an integrated luminosity of 19.7 fb(-1) collected by the CMS experiment in proton-proton collisions at root s = 8 TeV at the LHC. Events with photons and jets with high transverse momenta are selected and the gamma + jet invariant mass distribution is studied to search for a resonance peak. The 95% confidence level upper limits on the product of cross section and branching fraction are evaluated as a function of the excited quark mass. Limits on excited quarks are presented as a function of their mass and coupling strength; masses below 3.5 TeV are excluded at 95% confidence level for unit couplings to their standard model partners

Koulutusluokitus : Koulutuskoodimuutokset vuonna 1989, Liite 3

A measurement of inclusive ZZ production cross section and constraints on anomalous triple gauge couplings in proton-proton collisions at $\sqrt{s}$ = 8 TeV are presented. A data sample, corresponding to an integrated luminosity of 19.6 inverse-femtobarns was collected with the CMS experiment at the LHC. The measurements are performed in the leptonic decay modes $ZZ \to lll'l'$, where $l = e, \mu$ and $l' = e, \mu, \tau$. The measured total cross section, $\sigma (pp \to ZZ) = 7.7 \pm 0.5 (stat.)^{+0.5}_{-0.4} (syst.) \pm 0.4 (theo.) \pm 0.2 (lum.) pb$ for both Z bosons produced in the mass range $m_Z$ within 60 and 120 GeV, is consistent with standard model predictions. Differential cross sections are measured and well described by the theoretical predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ$\gamma$ couplings at the 95% confidence level: $f_4^Z$ in (-0.004,+0.004), $f_5^Z$ in (-0.005,+0.005), $f_4^\gamma$ in (-0.004,+0.004), and $f_5^\gamma$ in (-0.005,+0.005)