1,105 research outputs found
LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.
The DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low
Cascades with Adjoint Matter: Adjoint Transitions
A large class of duality cascades based on quivers arising from non-isolated
singularities enjoy adjoint transitions - a phenomenon which occurs when the
gauge coupling of a node possessing adjoint matter is driven to strong coupling
in a manner resulting in a reduction of rank in the non-Abelian part of the
gauge group and a subsequent flow to weaker coupling. We describe adjoint
transitions in a simple family of cascades based on a Z2-orbifold of the
conifold using field theory. We show that they are dual to Higgsing and produce
varying numbers of U(1) factors, moduli, and monopoles in a manner which we
calculate. This realizes a large family of cascades which proceed through
Seiberg duality and Higgsing. We briefly describe the supergravity limit of our
analysis, as well as a prescription for treating more general theories. A
special role is played by N=2 SQCD. Our results suggest that additional light
fields are typically generated when UV completing certain constructions of
spontaneous supersymmetry breaking into cascades, potentially leading to
instabilities.Comment: 29 pages, a few typos fixed, improved discussion, added figure; now
there is 1 figur
Chiral Generations on Intersecting 5-branes in Heterotic String Theory
We show that there exist two 27 and one 27 bar of E6, net one D=4, N=1 chiral
matter supermultiplet as zero modes localized on the intersection of two
5-branes in the E8 x E8 heterotic string theory. The smeared intersecting
5-brane solution is used via the standard embedding to construct a heterotic
background, which provides, after a compactification of some of the transverse
dimensions, a five-dimensional Randall-Sundrum II like brane-world set-up in
heterotic string theory. As a by-product, we present a new proof of anomaly
cancellation between those from the chiral matter and the anomaly inflow onto
the brane without small instanton.Comment: 26 pages, 5 figures; references added, typo correcte
A Comparative Study of the Effectiveness of Adaptive Filter Algorithms, Spectral Kurtosis and Linear Prediction in Detection of a Naturally Degraded Bearing in a Gearbox
A slice of AdS_5 as the large N limit of Seiberg duality
A slice of AdS_5 is used to provide a 5D gravitational description of 4D
strongly-coupled Seiberg dual gauge theories. An (electric) SU(N) gauge theory
in the conformal window at large N is described by the 5D bulk, while its
weakly coupled (magnetic) dual is confined to the IR brane. This framework can
be used to construct an N = 1 MSSM on the IR brane, reminiscent of the original
Randall-Sundrum model. In addition, we use our framework to study
strongly-coupled scenarios of supersymmetry breaking mediated by gauge forces.
This leads to a unified scenario that connects the extra-ordinary gauge
mediation limit to the gaugino mediation limit in warped space.Comment: 47 Pages, axodraw4j.st
Homology of 54K protein of signal-recognition particle, docking protein and two E. coli proteins with putative GTP-binding domains
Primordial Black Holes: sirens of the early Universe
Primordial Black Holes (PBHs) are, typically light, black holes which can
form in the early Universe. There are a number of formation mechanisms,
including the collapse of large density perturbations, cosmic string loops and
bubble collisions. The number of PBHs formed is tightly constrained by the
consequences of their evaporation and their lensing and dynamical effects.
Therefore PBHs are a powerful probe of the physics of the early Universe, in
particular models of inflation. They are also a potential cold dark matter
candidate.Comment: 21 pages. To be published in "Quantum Aspects of Black Holes", ed. X.
Calmet (Springer, 2014
New AdS solitons and brane worlds with compact extra-dimensions
We construct new static, asymptotically AdS solutions where the conformal
infinity is the product of Minkowski spacetime and a sphere . Both
globally regular, soliton-type solutions and black hole solutions are
considered. The black holes can be viewed as natural AdS generalizations of the
Schwarzschild black branes in Kaluza-Klein theory. The solitons provide new
brane-world models with compact extra-dimensions. Different from the
Randall-Sundrum single-brane scenario, a Schwarzschild black hole on the Ricci
flat part of these branes does not lead to a naked singularity in the bulk.Comment: 28 pages, 4 figure
Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial
BACKGROUND: Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer. METHODS: JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III-IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed. FINDINGS: Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1-14·9); 11·1 months (7·0-15·3) for the avelumab maintenance group, 11·0 months (7·4-14·5) for the avelumab combination group, and 10·2 months (6·7-14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5-not estimable [NE]) with avelumab maintenance, 18·1 months (14·8-NE) with avelumab combination treatment, and NE (18·2 months-NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05-1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83-1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3-4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (<1%) patient in the avelumab maintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumab combination group (due to disease progression). INTERPRETATION: Although no new safety signals were observed, results do not support the use of avelumab in the frontline treatment setting. Alternative treatment regimens are needed to improve outcomes in patients with advanced epithelial ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany
Results from PAMELA, ATIC and FERMI : Pulsars or Dark Matter ?
It is well known that the dark matter dominates the dynamics of galaxies and
clusters of galaxies. Its constituents remain a mystery despite an assiduous
search for them over the past three decades. Recent results from the
satellite-based PAMELA experiment detect an excess in the positron fraction at
energies between 10-100 GeV in the secondary cosmic ray spectrum. Other
experiments namely ATIC, HESS and FERMI show an excess in the total electron
(\ps + \el) spectrum for energies greater 100 GeV. These excesses in the
positron fraction as well as the electron spectrum could arise in local
astrophysical processes like pulsars, or can be attributed to the annihilation
of the dark matter particles. The second possibility gives clues to the
possible candidates for the dark matter in galaxies and other astrophysical
systems. In this article, we give a report of these exciting developments.Comment: 27 Pages, extensively revised and significantly extended, to appear
in Pramana as topical revie
- …