2,639 research outputs found
Chicken CRTAM Binds Nectin-Like 2 Ligand and Is Upregulated on CD8âș αÎČ and γΎ T Lymphocytes with Different Kinetics
During a search for immunomodulatory receptors in the chicken genome, we identified a previously cloned chicken sequence as CRTAM homologue by its overall identity and several conserved sequence features. For further characterization, we generated a CRTAM specific mab. No staining was detectable in freshly isolated cell preparations from thymus, bursa, caecal tonsils, spleen, blood and intestine. Activation of splenocytes with recombinant IL-2 increased rapid CRTAM expression within a 2 h period on about 30% of the cells. These CRTAM+ cells were identified as CD8+ γΎ T lymphocytes. In contrast, CRTAM expression could not be stimulated on PBL with IL-2, even within a 48 h stimulation period. As a second means of activation, T cell receptor (TCR) crosslinking using an anti-αÎČ-TCR induced CRTAM on both PBL and splenocytes. While CRTAM expression was again rapidly upregulated on splenocytes within 2 h, it took 48 h to reach maximum levels of CRTAM expression in PBL. Strikingly, albeit the stimulation of splenocytes was performed with anti-αÎČ-TCR, CRTAM expression after 2 h was mainly restricted to CD8+ γΎ T lymphocytes, however, the longer anti-TCR stimulation of peripheral blood lymphocytes (PBL) resulted in CRTAM expression on αÎČ T lymphocytes. In order to characterize the potential ligand we cloned and expressed chicken Necl-2, a member of the nectin and nectin-like family which is highly homologous to its mammalian counterpart. Three independent assays including a reporter assay, staining with a CRTAM-Ig fusion protein and a cell conjugate assay confirmed the interaction of CRTAM with Necl-2 which could also be blocked by a soluble CRTAM-Ig fusion protein or a CRTAM specific mab. These results suggest that chicken CRTAM represents an early activation antigen on CD8+ T cells which binds to Necl-2 and is upregulated with distinct kinetics on αÎČ versus γΎ T lymphocytes
A Profile Likelihood Analysis of the Constrained MSSM with Genetic Algorithms
The Constrained Minimal Supersymmetric Standard Model (CMSSM) is one of the
simplest and most widely-studied supersymmetric extensions to the standard
model of particle physics. Nevertheless, current data do not sufficiently
constrain the model parameters in a way completely independent of priors,
statistical measures and scanning techniques. We present a new technique for
scanning supersymmetric parameter spaces, optimised for frequentist profile
likelihood analyses and based on Genetic Algorithms. We apply this technique to
the CMSSM, taking into account existing collider and cosmological data in our
global fit. We compare our method to the MultiNest algorithm, an efficient
Bayesian technique, paying particular attention to the best-fit points and
implications for particle masses at the LHC and dark matter searches. Our
global best-fit point lies in the focus point region. We find many
high-likelihood points in both the stau co-annihilation and focus point
regions, including a previously neglected section of the co-annihilation region
at large m_0. We show that there are many high-likelihood points in the CMSSM
parameter space commonly missed by existing scanning techniques, especially at
high masses. This has a significant influence on the derived confidence regions
for parameters and observables, and can dramatically change the entire
statistical inference of such scans.Comment: 47 pages, 8 figures; Fig. 8, Table 7 and more discussions added to
Sec. 3.4.2 in response to referee's comments; accepted for publication in
JHE
Fine-tuning implications for complementary dark matter and LHC SUSY searches
The requirement that SUSY should solve the hierarchy problem without undue
fine-tuning imposes severe constraints on the new supersymmetric states. With
the MSSM spectrum and soft SUSY breaking originating from universal scalar and
gaugino masses at the Grand Unification scale, we show that the low-fine-tuned
regions fall into two classes that will require complementary collider and dark
matter searches to explore in the near future. The first class has relatively
light gluinos or squarks which should be found by the LHC in its first run. We
identify the multijet plus E_T^miss signal as the optimal channel and determine
the discovery potential in the first run. The second class has heavier gluinos
and squarks but the LSP has a significant Higgsino component and should be seen
by the next generation of direct dark matter detection experiments. The
combined information from the 7 TeV LHC run and the next generation of direct
detection experiments can test almost all of the CMSSM parameter space
consistent with dark matter and EW constraints, corresponding to a fine-tuning
not worse than 1:100. To cover the complete low-fine-tuned region by SUSY
searches at the LHC will require running at the full 14 TeV CM energy; in
addition it may be tested indirectly by Higgs searches covering the mass range
below 120 GeV.Comment: References added. Version accepted for publication in JHE
A comparison of methods to adjust for continuous covariates in the analysis of randomised trials
BACKGROUND: Although covariate adjustment in the analysis of randomised trials can be beneficial, adjustment for continuous covariates is complicated by the fact that the association between covariate and outcome must be specified. Misspecification of this association can lead to reduced power, and potentially incorrect conclusions regarding treatment efficacy. METHODS: We compared several methods of adjustment to determine which is best when the association between covariate and outcome is unknown. We assessed (a) dichotomisation or categorisation; (b) assuming a linear association with outcome; (c) using fractional polynomials with one (FP1) or two (FP2) polynomial terms; and (d) using restricted cubic splines with 3 or 5 knots. We evaluated each method using simulation and through a re-analysis of trial datasets. RESULTS: Methods which kept covariates as continuous typically had higher power than methods which used categorisation. Dichotomisation, categorisation, and assuming a linear association all led to large reductions in power when the true association was non-linear. FP2 models and restricted cubic splines with 3 or 5 knots performed best overall. CONCLUSIONS: For the analysis of randomised trials we recommend (1) adjusting for continuous covariates even if their association with outcome is unknown; (2) keeping covariates as continuous; and (3) using fractional polynomials with two polynomial terms or restricted cubic splines with 3 to 5 knots when a linear association is in doubt
Gate-Controlled Ionization and Screening of Cobalt Adatoms on a Graphene Surface
We describe scanning tunneling spectroscopy (STS) measurements performed on
individual cobalt (Co) atoms deposited onto backgated graphene devices. We find
that Co adatoms on graphene can be ionized by either the application of a
global backgate voltage or by the application of a local electric field from a
scanning tunneling microscope (STM) tip. Large screening clouds are observed to
form around Co adatoms ionized in this way, and we observe that some intrinsic
graphene defects display a similar behavior. Our results provide new insight
into charged impurity scattering in graphene, as well as the possibility of
using graphene devices as chemical sensors.Comment: 19 pages, 4 figure
Comparison of Trihalomethanes in Tap Water and Blood: A Case Study in the United States
Background: Epidemiological studies have used various measures to characterize trihalomethane (THM) exposures, but the relationship of these indicators to exposure biomarkers remains unclear
Naturalness and Fine Tuning in the NMSSM: Implications of Early LHC Results
We study the fine tuning in the parameter space of the semi-constrained
NMSSM, where most soft Susy breaking parameters are universal at the GUT scale.
We discuss the dependence of the fine tuning on the soft Susy breaking
parameters M_1/2 and m0, and on the Higgs masses in NMSSM specific scenarios
involving large singlet-doublet Higgs mixing or dominant Higgs-to-Higgs decays.
Whereas these latter scenarios allow a priori for considerably less fine tuning
than the constrained MSSM, the early LHC results rule out a large part of the
parameter space of the semi-constrained NMSSM corresponding to low values of
the fine tuning.Comment: 19 pages, 10 figures, bounds from Susy searches with ~1/fb include
Development of an in vitro periodontal biofilm model for assessing antimicrobial and host modulatory effects of bioactive molecules
Background:
Inflammation within the oral cavity occurs due to dysregulation between microbial biofilms and the host response. Understanding how different oral hygiene products influence inflammatory properties is important for the development of new products. Therefore, creation of a robust host-pathogen biofilm platform capable of evaluating novel oral healthcare compounds is an attractive option. We therefore devised a multi-species biofilm co-culture model to evaluate the naturally derived polyphenol resveratrol (RSV) and gold standard chlorhexidine (CHX) with respect to anti-biofilm and anti-inflammatory properties.<p></p>
Methods:
An in vitro multi-species biofilm containing <i>S. mitis, F. nucleatum, P. Gingivalis</i> and <i>A. Actinomycetemcomitans</i> was created to represent a disease-associated biofilm and the oral epithelial cell in OKF6-TERT2. Cytotoxicity studies were performed using RSV and CHX. Multi-species biofilms were either treated with either molecule, or alternatively epithelial cells were treated with these prior to biofilm co-culture. Biofilm composition was evaluated and inflammatory responses quantified at a transcriptional and protein level.<p></p>
Results:
CHX was toxic to epithelial cells and multi-species biofilms at concentrations ranging from 0.01-0.2%. RSV did not effect multi-species biofilm composition, but was toxic to epithelial cells at concentrations greater than 0.01%. In co-culture, CHX-treated biofilms resulted in down regulation of the inflammatory chemokine IL-8 at both mRNA and protein level. RSV-treated epithelial cells in co-culture were down-regulated in the release of IL-8 protein, but not mRNA.<p></p>
Conclusions:
CHX possesses potent bactericidal properties, which may impact downstream inflammatory mediators. RSV does not appear to have bactericidal properties against multi-species biofilms, however it did appear to supress epithelial cells from releasing inflammatory mediators. This study demonstrates the potential to understand the mechanisms by which different oral hygiene products may influence gingival inflammation, thereby validating the use of a biofilm co-culture model.<p></p>
Functional alpha-1B adrenergic receptors on human epicardial coronary artery endothelial cells
Alpha-1-adrenergic receptors (α1-ARs) regulate coronary arterial blood flow by binding catecholamines, norepinephrine (NE), and epinephrine (EPI), causing vasoconstriction when the endothelium is disrupted. Among the three α1-AR subtypes (α1A, α1B, and α1D), the α1D subtype predominates in human epicardial coronary arteries and is functional in human coronary smooth muscle cells (SMCs). However, the presence or function of α1-ARs on human coronary endothelial cells (ECs) is unknown. Here we tested the hypothesis that human epicardial coronary ECs express functional α1-ARs. Cultured human epicardial coronary artery ECs were studied using quantitative real-time reverse transcription polymerase chain reaction, radioligand binding, immunoblot, and 3H-thymidine incorporation. The α1B-subtype messenger ribonucleic acid (mRNA) was predominant in cultured human epicardial coronary ECs (90â95% of total α1-AR mRNA), and total α1-AR binding density in ECs was twice that in coronary SMCs. Functionally, NE and EPI through the α1B subtype activated extracellular signal-regulated kinase (ERK) in ECs, stimulated phosphorylation of EC endothelial nitric oxide synthase (eNOS), and increased deoxyribonucleic acid (DNA) synthesis. These results are the first to demonstrate α1-ARs on human coronary ECs and indicate that the α1B subtype is predominant. Our findings provide another potential mechanism for adverse cardiac effects of drug antagonists that nonselectively inhibit all three α1-AR subtypes
Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease
Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD
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