A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain.

The paper presents studies of Bose-Einstein Correlations (BEC) for pairs of like-sign charged particles measured in the kinematic range [Formula: see text] 100 MeV and [Formula: see text] 2.5 in proton collisions at centre-of-mass energies of 0.9 and 7 TeV with the ATLAS detector at the CERN Large Hadron Collider. The integrated luminosities are approximately 7 [Formula: see text]b[Formula: see text], 190 [Formula: see text]b[Formula: see text] and 12.4 nb[Formula: see text] for 0.9 TeV, 7 TeV minimum-bias and 7 TeV high-multiplicity data samples, respectively. The multiplicity dependence of the BEC parameters characterizing the correlation strength and the correlation source size are investigated for charged-particle multiplicities of up to 240. A saturation effect in the multiplicity dependence of the correlation source size parameter is observed using the high-multiplicity 7 TeV data sample. The dependence of the BEC parameters on the average transverse momentum of the particle pair is also investigated.

Inducible activation of nuclear factor (NF)-κB is one of the principal mechanisms through which resistant prostate cancer cells are protected from radiotherapy. We hypothesised that inactivation of inducible NF-κB with a novel NF-κB inhibitor, DHMEQ, would increase the therapeutic effects of radiotherapy.

The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-κB pathway. The TGF-β-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-κB signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1(+/-)/IL-10(-/-) mouse model of colitis and colon tumorigenesis. We show that MUC1-C promotes NF-κB-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-κB signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-κB. Targeting MUC1-C thus suppresses the TAK1NF-κB pathway, downregulates BCL-XL and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1NF-κB signaling contributes to intestinal inflammation and colon cancer progression.

No abstract available

Measurements of transverse energy-energy correlations and their associated asymmetries in multi-jet events using the ATLAS detector at the LHC are presented. The data used correspond to s = 8 TeV proton-proton collisions with an integrated luminosity of 20.2 fb - 1 . The results are presented in bins of the scalar sum of the transverse momenta of the two leading jets, unfolded to the particle level and compared to the predictions from Monte Carlo simulations. A comparison with next-to-leading-order perturbative QCD is also performed, showing excellent agreement within the uncertainties. From this comparison, the value of the strong coupling constant is extracted for different energy regimes, thus testing the running of α s ( μ ) predicted in QCD up to scales over 1 TeV . A global fit to the transverse energy-energy correlation distributions yields α s ( m Z ) = 0.1162 ± 0.0011 (exp.) - 0.0070 + 0.0084 (theo.) , while a global fit to the asymmetry distributions yields a value of α s ( m Z ) = 0.1196 ± 0.0013 (exp.) - 0.0045 + 0.0075 (theo.) .

No abstract available

IL-31, which is described as a pruritogenic cytokine, is linked to the itching that is associated with allergic and non-allergic eczema, but the precise pruritogenic mechanism of IL-31 and its potential as a therapeutic target for atopic dermatitis (AD) have not been determined.

Systemic sclerosis (SSc) is a connective tissue disorder with excessive fibrosis of the skin and various internal organs. Although SSc is a heterogeneous disease, it has been reported that the particular antinuclear antibodies (ANA) are often indicative of clinical features, disease course and overall severity.

In polarized epithelial cells, agonists trigger Ca2+ waves and oscillations. These patterns may be caused by the compartmentalization of inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ pools into specific regions. We have investigated the relationship between the distribution of IP3 receptors (IP3Rs) and the spatiotemporal pattern of Ca2+ signaling in the duct cells of the rat submandibular gland (SMG). Using immunofluorescence, although labeling was somewhat heterogeneous, the IP3Rs were colocalized to the apical pole of the duct cells. Immunoelectron microscopy identified small apical vesicles bearing IP3R2 in some types of duct cells. Real-time confocal imaging of intact ducts demonstrated that, after carbachol stimulation, an initial Ca2+ spike occurred in the apical region. Subsequently, repetitive Ca2+ spikes spread from the apical to the middle cytoplasm. These apical Ca2+ initiation sites were found only in some "pioneer cells," rather than in all duct cells. We performed both Ca2+ imaging and immunofluorescence on the same ducts and detected the strongest immunosignals of IP3R2 in the Ca2+ initiation sites of the pioneer cells. The subcellular localization and expression level of IP3Rs correlated strongly with the spatiotemporal nature of the intracellular Ca2+ signal and distinct Ca2+ responses among the rat SMG duct cells.

Measurements of normalized differential cross-sections of top-quark pair production are presented as a function of the top-quark, [Formula: see text] system and event-level kinematic observables in proton-proton collisions at a centre-of-mass energy of [Formula: see text]. The observables have been chosen to emphasize the [Formula: see text] production process and to be sensitive to effects of initial- and final-state radiation, to the different parton distribution functions, and to non-resonant processes and higher-order corrections. The dataset corresponds to an integrated luminosity of 20.3 fb[Formula: see text], recorded in 2012 with the ATLAS detector at the CERN Large Hadron Collider. Events are selected in the lepton+jets channel, requiring exactly one charged lepton and at least four jets with at least two of the jets tagged as originating from a b-quark. The measured spectra are corrected for detector effects and are compared to several Monte Carlo simulations. The results are in fair agreement with the predictions over a wide kinematic range. Nevertheless, most generators predict a harder top-quark transverse momentum distribution at high values than what is observed in the data. Predictions beyond NLO accuracy improve the agreement with data at high top-quark transverse momenta. Using the current settings and parton distribution functions, the rapidity distributions are not well modelled by any generator under consideration. However, the level of agreement is improved when more recent sets of parton distribution functions are used.

The reconstruction of the signal from hadrons and jets emerging from the proton-proton collisions at the Large Hadron Collider (LHC) and entering the ATLAS calorimeters is based on a three-dimensional topological clustering of individual calorimeter cell signals. The cluster formation follows cell signal-significance patterns generated by electromagnetic and hadronic showers. In this, the clustering algorithm implicitly performs a topological noise suppression by removing cells with insignificant signals which are not in close proximity to cells with significant signals. The resulting topological cell clusters have shape and location information, which is exploited to apply a local energy calibration and corrections depending on the nature of the cluster. Topological cell clustering is established as a well-performing calorimeter signal definition for jet and missing transverse momentum reconstruction in ATLAS.

Studies of the spin and parity quantum numbers of the Higgs boson in the [Formula: see text] final state are presented, based on proton-proton collision data collected by the ATLAS detector at the Large Hadron Collider, corresponding to an integrated luminosity of 20.3 fb[Formula: see text] at a centre-of-mass energy of [Formula: see text] TeV. The Standard Model spin-parity [Formula: see text] hypothesis is compared with alternative hypotheses for both spin and CP. The case where the observed resonance is a mixture of the Standard-Model-like Higgs boson and CP-even ([Formula: see text]) or CP-odd ([Formula: see text]) Higgs boson in scenarios beyond the Standard Model is also studied. The data are found to be consistent with the Standard Model prediction and limits are placed on alternative spin and CP hypotheses, including CP mixing in different scenarios.

There is currently no uniform definition of cutaneous lupus erythematosus (CLE) upon which to base a study population for observational and interventional trials. A preliminary questionnaire was derived from and sent to a panel of CLE experts which demonstrated consensus agreement that (1) there is a need for new definitions for CLE (2) CLE is distinct from systemic lupus erythematosus and that a CLE grouping scheme should remain apart from current systemic lupus erythematosus schema (3) current CLE grouping schemes are inadequate around communication, prognostic information and to meet the needs of researchers, clinicians, patients and payers.

Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p<0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.

Distributions of transverse momentum [Formula: see text] and the related angular variable [Formula: see text] of Drell–Yan lepton pairs are measured in 20.3 fb[Formula: see text] of proton–proton collisions at [Formula: see text] TeV with the ATLAS detector at the LHC. Measurements in electron-pair and muon-pair final states are corrected for detector effects and combined. Compared to previous measurements in proton–proton collisions at [Formula: see text] TeV, these new measurements benefit from a larger data sample and improved control of systematic uncertainties. Measurements are performed in bins of lepton-pair mass above, around and below the Z-boson mass peak. The data are compared to predictions from perturbative and resummed QCD calculations. For values of [Formula: see text] the predictions from the Monte Carlo generator ResBos are generally consistent with the data within the theoretical uncertainties. However, at larger values of [Formula: see text] this is not the case. Monte Carlo generators based on the parton-shower approach are unable to describe the data over the full range of [Formula: see text] while the fixed-order prediction of Dynnlo falls below the data at high values of [Formula: see text]. ResBos and the parton-shower Monte Carlo generators provide a much better description of the evolution of the [Formula: see text] and [Formula: see text] distributions as a function of lepton-pair mass and rapidity than the basic shape of the data.