887 research outputs found
CTLA-4 Activation of Phosphatidylinositol 3-Kinase (PI 3-K) and Protein Kinase B (PKB/AKT) Sustains T-Cell Anergy without Cell Death
The balance of T-cell proliferation, anergy and apoptosis is central to immune function. In this regard, co-receptor CTLA-4 is needed for the induction of anergy and tolerance. One central question concerns the mechanism by which CTLA-4 can induce T-cell non-responsiveness without a concurrent induction of antigen induced cell death (AICD). In this study, we show that CTLA-4 activation of the phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. CTLA-4 ligation induced PI 3K activation as evidenced by the phosphorylation of PKB/AKT that in turn inactivated GSK-3. The level of activation was similar to that observed with CD28. CTLA-4 induced PI 3K and AKT activation also led to phosphorylation of the pro-apoptotic factor BAD as well as the up-regulation of BcL-XL. In keeping with this, CD3/CTLA-4 co-ligation prevented apoptosis under the same conditions where T-cell non-responsiveness was induced. This effect was PI 3K and PKB/AKT dependent since inhibition of these enzymes under conditions of anti-CD3/CTLA-4 co-ligation resulted in cell death. Our findings therefore define a mechanism by which CTLA-4 can induce anergy (and possibly peripheral tolerance) by preventing the induction of cell death
A frequentist framework of inductive reasoning
Reacting against the limitation of statistics to decision procedures, R. A.
Fisher proposed for inductive reasoning the use of the fiducial distribution, a
parameter-space distribution of epistemological probability transferred
directly from limiting relative frequencies rather than computed according to
the Bayes update rule. The proposal is developed as follows using the
confidence measure of a scalar parameter of interest. (With the restriction to
one-dimensional parameter space, a confidence measure is essentially a fiducial
probability distribution free of complications involving ancillary statistics.)
A betting game establishes a sense in which confidence measures are the only
reliable inferential probability distributions. The equality between the
probabilities encoded in a confidence measure and the coverage rates of the
corresponding confidence intervals ensures that the measure's rule for
assigning confidence levels to hypotheses is uniquely minimax in the game.
Although a confidence measure can be computed without any prior distribution,
previous knowledge can be incorporated into confidence-based reasoning. To
adjust a p-value or confidence interval for prior information, the confidence
measure from the observed data can be combined with one or more independent
confidence measures representing previous agent opinion. (The former confidence
measure may correspond to a posterior distribution with frequentist matching of
coverage probabilities.) The representation of subjective knowledge in terms of
confidence measures rather than prior probability distributions preserves
approximate frequentist validity.Comment: major revisio
General Minimal Flavor Violation
A model independent study of the minimal flavor violation (MFV) framework is
presented, where the only sources of flavor breaking at low energy are the up
and down Yukawa matrices. Two limits are identified for the Yukawa coupling
expansion: linear MFV, where it is truncated at the leading terms, and
nonlinear MFV, where such a truncation is not possible due to large third
generation Yukawa couplings. These are then resummed to all orders using
non-linear sigma-model techniques familiar from models of collective breaking.
Generically, flavor diagonal CP violating (CPV) sources in the UV can induce
O(1) CPV in processes involving third generation quarks. Due to a residual U(2)
symmetry, the extra CPV in B_d-\bar B_d mixing is bounded by CPV in B_s-\bar
B_s mixing. If operators with right-handed light quarks are subdominant, the
extra CPV is equal in the two systems, and is negligible in processes involving
only the first two generations. We find large enhancements in the up type
sector, both in CPV in D-\bar D mixing and in top flavor violation.Comment: 5 pages and no figure
Exploring novel correlations in trilepton channels at the LHC for the minimal supersymmetric inverse seesaw model
We investigate signatures of the minimal supersymmetric inverse seesaw model
at the large hadron collider (LHC) with three isolated leptons and large
missing energy (3\ell + \mET or 2\ell + 1\tau + \mET, with \ell=e,\mu) in the
final state. This signal has its origin in the decay of chargino-neutralino
(\chpm1\ntrl2) pair, produced in pp collisions. The two body decays of the
lighter chargino into a charged lepton and a singlet sneutrino has a
characteristic decay pattern which is correlated with the observed large
atmospheric neutrino mixing angle. This correlation is potentially observable
at the LHC by looking at the ratios of cross sections of the trilepton + \mET
channels in certain flavour specific modes. We show that even after considering
possible leading standard model backgrounds these final states can lead to
reasonable discovery significance at the LHC with both 7 TeV and 14 TeV
center-of-mass energy.Comment: 28 pages, 9 .eps figures. 3 new figures and discussions on LHC
observables added, minor modifications in text and in the abstract, 23 new
references added, matches with the published version in JHE
Ten years of major equestrian injury: are we addressing functional outcomes?
YesFunding provided by the Open Access Authors Fund
The potential of kaolin as a reinforcing filler for rubber composites with new sulfur cure systems
This paper was accepted for publication in the journal Journal of Reinforced Plastics and Composites and the definitive published version is available at https://doi.org/10.1177/0731684417712070.The effect of a large amount of kaolin (China clay) on the viscosity, cure, hardness, Young’s modulus, tensile strength, elongation at break, stored energy density at break, tear energy and compression set resistance of some sulfur-cured natural rubber, polybutadiene rubber and ethylene-propylene-diene rubber composites was investigated. The kaolin surface had been pre-treated with 3-mercaptopropyltrimethoxysilane to improve its dispersion in the rubbers. For
natural rubber, the hardness and Young’s modulus improved, tensile strength and tear energy were unchanged and the remaining properties deteriorated when kaolin was added. The viscosity increased and the scorch and optimum
cure times decreased whilst the cure rate rose with kaolin. For polybutadiene rubber and ethylene-propylene-diene rubber, with the exception of the compression set resistance, all the properties including the viscosity gained from the kaolin. The kaolin was found to be extending or non-reinforcing filler for natural rubber, and highly reinforcing for polybutadiene rubber and EPDM. In addition, the scorch and optimum cure times and cure rate of polybutadiene rubber benefitted, whereas with the exception of the scorch time, the optimum cure time and cure rate of ethylene-propylenediene rubber were adversely affected by kaolin
The Fourth Bioelectronic Medicine Summit "Technology Targeting Molecular Mechanisms": current progress, challenges, and charting the future.
There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit "Technology targeting molecular mechanisms" took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here
A fuzzy feature fusion method for auto-segmentation of gliomas with multi-modality diffusion and perfusion magnetic resonance images in radiotherapy
The difusion and perfusion magnetic resonance (MR) images can provide functional information about
tumour and enable more sensitive detection of the tumour extent. We aimed to develop a fuzzy feature
fusion method for auto-segmentation of gliomas in radiotherapy planning using multi-parametric
functional MR images including apparent difusion coefcient (ADC), fractional anisotropy (FA) and
relative cerebral blood volume (rCBV). For each functional modality, one histogram-based fuzzy model
was created to transform image volume into a fuzzy feature space. Based on the fuzzy fusion result
of the three fuzzy feature spaces, regions with high possibility belonging to tumour were generated
automatically. The auto-segmentations of tumour in structural MR images were added in fnal autosegmented gross tumour volume (GTV). For evaluation, one radiation oncologist delineated GTVs for
nine patients with all modalities. Comparisons between manually delineated and auto-segmented GTVs
showed that, the mean volume diference was 8.69% (±5.62%); the mean Dice’s similarity coefcient
(DSC) was 0.88 (±0.02); the mean sensitivity and specifcity of auto-segmentation was 0.87 (±0.04)
and 0.98 (±0.01) respectively. High accuracy and efciency can be achieved with the new method,
which shows potential of utilizing functional multi-parametric MR images for target defnition in
precision radiation treatment planning for patients with gliomas
Estimation of the severity of breathlessness in the emergency department: a dyspnea score
BACKGROUND: Dyspnea is a frequent complaint in emergency departments (ED). It has a significant amount of subjective and affective components, therefore the dyspnea scores, based on the patients' rating, can be ambiguous. Our purpose was to develop and validate a simple scoring system to evaluate the severity of dyspnea in emergency care, based on objectively measured parameters. METHODS: We performed a double center, prospective, observational study including 350 patients who were admitted in EDs with dyspnea. We evaluated the patients' subjective feeling about dyspnea and applied our Dyspnea Severity Score (DSS), rating the dyspnea in 7 Dimensions from 0 to 3 points. The DSS was validated using the deterioration of pH, base-excess and lactate levels in the blood gas samples (Objective Classification Scale (OCS) 9 points and 13 points groups). RESULTS: All of the Dimensions correlated closely with the OCS values and with the subjective feeling of the dyspnea. Using multiple linear regression analysis we were able to decrease the numbers of Dimensions from seven to four without causing a significant change in the determination coefficient in any OCS groups. This reduced DSS values (exercise tolerance, cooperation, cyanosis, SpO2 value) showed high sensitivity and specificity to predict the values of OCS groups (the ranges: AUC 0.77-0.99, sensitivity 65-100%, specificity 64-99%). There was a close correlation between the subjective dyspnea scores and the OCS point values (p /=7 points without correction factors) can be useful at the triage or in pre-hospital care
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