2,365 research outputs found
Construction of -strong Feller Processes via Dirichlet Forms and Applications to Elliptic Diffusions
We provide a general construction scheme for -strong Feller
processes on locally compact separable metric spaces. Starting from a regular
Dirichlet form and specified regularity assumptions, we construct an associated
semigroup and resolvents of kernels having the -strong Feller
property. They allow us to construct a process which solves the corresponding
martingale problem for all starting points from a known set, namely the set
where the regularity assumptions hold. We apply this result to construct
elliptic diffusions having locally Lipschitz matrix coefficients and singular
drifts on general open sets with absorption at the boundary. In this
application elliptic regularity results imply the desired regularity
assumptions
Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma
BackgroundRecently, oncogenic G protein alpha subunit q (GNAQ) mutations have been described in about 50% of uveal melanomas and in the blue nevi of the skin.MethodsGNAQ exon 5 was amplified from 75 ciliary body and choroidal melanoma DNAs and sequenced directly. GNAQ mutation status was correlated with disease-free survival (DFS), as well as other clinical and histopathological factors, and with chromosomal variations detected by FISH and CGH.ResultsOf the 75 tumour DNA samples analysed, 40 (53.3%) harboured oncogenic mutations in GNAQ codon 209. Univariate and multivariate analysis showed that GNAQ mutation status was not significantly correlated with DFS.ConclusionThe GNAQ mutation status is not suitable to predict DFS. However, the high frequency of GNAQ mutations may render it a promising target for therapeutic intervention
Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites
A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB
FCNC Effects in a Minimal Theory of Fermion Masses
As a minimal theory of fermion masses we extend the SM by heavy vectorlike
fermions, with flavor-anarchical Yukawa couplings, that mix with chiral
fermions such that small SM Yukawa couplings arise from small mixing angles.
This model can be regarded as an effective description of the fermionic sector
of a large class of existing flavor models and thus might serve as a useful
reference frame for a further understanding of flavor hierarchies in the SM.
Already such a minimal framework gives rise to FCNC effects through exchange of
massive SM bosons whose couplings to the light fermions get modified by the
mixing. We derive general formulae for these corrections and discuss the bounds
on the heavy fermion masses. Particularly stringent bounds, in a few TeV range,
come from the corrections to the Z couplings.Comment: 19 pages, 1 figur
Flavourful Production at Hadron Colliders
We ask what new states may lie at or below the TeV scale, with sizable
flavour-dependent couplings to light quarks, putting them within reach of
hadron colliders via resonant production, or in association with Standard Model
states. In particular, we focus on the compatibility of such states with
stringent flavour-changing neutral current and electric-dipole moment
constraints. We argue that the broadest and most theoretically plausible
flavour structure of the new couplings is that they are hierarchical, as are
Standard Model Yukawa couplings, although the hierarchical pattern may well be
different. We point out that, without the need for any more elaborate or
restrictive structure, new scalars with "diquark" couplings to standard quarks
are particularly immune to existing constraints, and that such scalars may
arise within a variety of theoretical paradigms. In particular, there can be
substantial couplings to a pair of light quarks or to one light and one heavy
quark. For example, the latter possibility may provide a flavour-safe
interpretation of the asymmetry in top quark production observed at the
Tevatron. We thereby motivate searches for diquark scalars at the Tevatron and
LHC, and argue that their discovery represents one of our best chances for new
insight into the Flavour Puzzle of the Standard Model.Comment: 18 pp., 8 figures, references adde
The Molecular Clockwork of the Fire Ant Solenopsis invicta
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication
Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.
Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation
Neutral Gauge Boson Contributions to the Dimuon Charge Asymmetry in B Decays
Recently, the D0 Collaboration measured the CP-violating like-sign dimuon
charge asymmetry in neutral B decays, finding a 3.2sigma difference from the
standard-model (SM) prediction. A non-SM charge asymmetry a_sl^s suggests a
new-physics (NP) contribution to Bs-Bsbar mixing. In this case, in order to
explain the measured value of a_sl^s within its 1sigma range, NP must be
present in Gamma_12^s, the absorptive part of the mixing. In this paper, we
examine whether such an explanation is possible in models with flavor-changing
Z (ZFCNC) or Z' (Z'FCNC) gauge bosons. The models must also reproduce the
measured values of the indirect CP asymmetry S_psi-phi in Bs -> J/psi phi, and
Delta Gamma_s, the Bs-Bsbar width difference. We find that the ZFCNC model
cannot reproduce the present measured values of S_psi-phi and a_sl^s within
their 1sigma ranges. On the other hand, in the Z'FCNC model, the values of all
three observables can be simultaneously reproduced.Comment: 18 pages, 7 figures, JHEP format. Some ZFCNC equations corrected,
ZFCNC analysis redone, references added, conclusions unchange
The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation
Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of
endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed
Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients
<p>Abstract</p> <p>Background</p> <p>L1 cell adhesion molecule (CD171) is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST) as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker.</p> <p>Methods</p> <p>Using a sensitive enzyme-linked immunosorbent assay (ELISA), soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data.</p> <p>Results</p> <p>Median levels of soluble L1 were significantly higher (<it>p </it>< 0.001; Mann-Whitney U test) in sera of GIST patients compared to healthy individuals. Median soluble L1 levels were particularly elevated in patients with recurrence and relapse (<it>p </it>< 0.05; Mann Whitney U test).</p> <p>Conclusion</p> <p>These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy.</p
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