2,448 research outputs found
Loop quantum cosmology of Bianchi type IX models
The loop quantum cosmology "improved dynamics" of the Bianchi type IX model
are studied. The action of the Hamiltonian constraint operator is obtained via
techniques developed for the Bianchi type I and type II models, no new input is
required. It is shown that the big bang and big crunch singularities are
resolved by quantum gravity effects. We also present the effective equations
which provide modifications to the classical equations of motion due to quantum
geometry effects.Comment: 20 page
Epigraphene : epitaxial graphene on silicon carbide
This article presents a review of epitaxial graphene on silicon carbide, from
fabrication to properties, put in the context of other forms of graphene.Comment: 46 pages, 322 references, 35 figures. Submitted December 201
sCD4-17b bifunctional protein: Extremely broad and potent neutralization of HIV-1 Env pseudotyped viruses from genetically diverse primary isolates
<p>Abstract</p> <p>Background</p> <p>We previously described a potent recombinant HIV-1 neutralizing protein, sCD4-17b, composed of soluble CD4 attached via a flexible polypeptide linker to an SCFv of the 17b human monoclonal antibody directed against the highly conserved CD4-induced bridging sheet of gp120 involved in coreceptor binding. The sCD4 moiety of the bifunctional protein binds to gp120 on free virions, thereby enabling the 17b SCFv moiety to bind and block the gp120/coreceptor interaction required for entry. The previous studies using the MAGI-CCR5 assay system indicated that sCD4-17b (in concentrated cell culture medium, or partially purified) potently neutralized several genetically diverse HIIV-1 primary isolates; however, at the concentrations tested it was ineffective against several other strains despite the conservation of binding sites for both CD4 and 17b. To address this puzzle, we designed variants of sCD4-17b with different linker lengths, and tested the neutralizing activities of the immunoaffinity purified proteins over a broader concentration range against a large number of genetically diverse HIV-1 primary isolates, using the TZM-bl Env pseudotype assay system. We also examined the sCD4-17b sensitivities of isogenic viruses generated from different producer cell types.</p> <p>Results</p> <p>We observed that immunoaffinity purified sCD4-17b effectively neutralized HIV-1 pseudotypes, including those from HIV-1 isolates previously found to be relatively insensitive in the MAGI-CCR5 assay. The potencies were equivalent for the original construct and a variant with a longer linker, as observed with both pseudotype particles and infectious virions; by contrast, a construct with a linker too short to enable simultaneous binding of the sCD4 and 17b SCFv moieties was much less effective. sCD4-17b displayed potent neutralizing activity against 100% of nearly 4 dozen HIV-1 primary isolates from diverse genetic subtypes (clades A, B, C, D, F, and circulating recombinant forms AE and AG). The neutralization breadth and potency were superior to what have been reported for the broadly neutralizing monoclonal antibodies IgG b12, 2G12, 2F5, and 4E10. The activity of sCD4-17b was found to be similar against isogenic virus particles from infectious molecular clones derived either directly from the transfected producer cell line or after a single passage through PBMCs; this contrasted with the monoclonal antibodies, which were less potent against the PMBC-passaged viruses.</p> <p>Conclusions</p> <p>The results highlight the extremely potent and broad neutralizing activity of sCD4-17b against genetically diverse HIV-1 primary isolates. The bifunctional protein has potential applications for antiviral approaches to combat HIV infection.</p
HIV-1 Coreceptor Activity of CCR5 and Its Inhibition by Chemokines: Independence from G Protein Signaling and Importance of Coreceptor Downmodulation
AbstractHIV-1 infection requires the presence of specific chemokine receptors on CD4+ target cells to enable the fusion reactions involved in virus entry. CCR5 is a major fusion coreceptor for macrophage-tropic HIV-1 isolates. HIV-1 entry and fusion are mediated by the viral envelope glycoprotein (Env) and are inhibited by CCR5 ligands, but the mechanisms are unknown. Here, we test the role of G protein signaling and CCR5 surface downmodulation by two separate approaches: direct inactivation of CCR5 signaling by mutagenesis and inactivation of Gi-type G proteins with pertussis toxin. A CCR5 mutant lacking the last 45 amino acids of the cytoplasmic C-terminus (CCR5306) was created that was expressed on transfected cells at levels comparable to cells expressing CCR5 and displayed normal chemokine binding affinity. CCR5 ligands induced calcium flux and receptor downmodulation in cells expressing CCR5, but not in cells expressing CCR5306. Nevertheless, CCR5 or CCR5306, when coexpressed with CD4, supported comparable HIV-1 Env-mediated cell fusion. Consistent with this, treatment of CCR5-expressing cells with pertussis toxin completely blocked ligand-induced transient calcium flux, but did not affect Env-mediated cell fusion or HIV-1 infection. Also, pertussis toxin did not block chemokine inhibition of Env-mediated cell fusion or HIV-1 infection. However, chemokines inhibited Env-mediated cell fusion less efficiently for CCR5306than for CCR5. We conclude that the C-terminal domain of CCR5 is critical for G protein signaling and receptor downmodulation from the surface, but that neither function is required for CCR5 fusion coreceptor activity. The contrasting phenotypes of CCR5 and CCR5306suggest that coreceptor downmodulation and direct blockage of Env interaction sites both contribute to chemokine inhibition of HIV-1 infection
Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenibresistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. © 2017 American Association for Cancer Research
First direct observation of a nearly ideal graphene band structure
Angle-resolved photoemission and X-ray diffraction experiments show that
multilayer epitaxial graphene grown on the SiC(000-1) surface is a new form of
carbon that is composed of effectively isolated graphene sheets. The unique
rotational stacking of these films cause adjacent graphene layers to
electronically decouple leading to a set of nearly independent linearly
dispersing bands (Dirac cones) at the graphene K-point. Each cone corresponds
to an individual macro-scale graphene sheet in a multilayer stack where
AB-stacked sheets can be considered as low density faults.Comment: 5 pages, 4 figure
Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46.
Human herpesvirus 6 (HHV-6) employs the complement regulator CD46 (membrane cofactor protein) as a receptor for fusion and entry into target cells. Like other known herpesviruses, HHV-6 encodes multiple glycoproteins, several of which have been implicated in the entry process. In this report, we present evidence that glycoprotein H (gH) is the viral component responsible for binding to CD46. Antibodies to CD46 co-immunoprecipitated an approximately 110-kDa protein band specifically associated with HHV-6-infected cells. This protein was identified as gH by selective depletion with an anti-gH monoclonal antibody, as well as by immunoblot analysis with a rabbit hyperimmune serum directed against a gH synthetic peptide. In reciprocal experiments, a monoclonal antibody against HHV-6 gH was found to co-immunoprecipitate CD46. Studies using monoclonal antibodies directed against specific CD46 domains, as well as engineered constructs lacking defined CD46 regions, demonstrated a close correspondence between the CD46 domains involved in the interaction with gH and those previously shown to be critical for HHV-6 fusion (i.e. short consensus repeats 2 and 3)
Adaptive computation of gravitational waves from black hole interactions
We construct a class of linear partial differential equations describing
general perturbations of non-rotating black holes in 3D Cartesian coordinates.
In contrast to the usual approach, a single equation treats all radiative modes simultaneously, allowing the study of wave perturbations of black
holes with arbitrary 3D structure, as would be present when studying the full
set of nonlinear Einstein equations describing a perturbed black hole. This
class of equations forms an excellent testbed to explore the computational
issues of simulating black spacetimes using a three dimensional adaptive mesh
refinement code. Using this code, we present results from the first fully
resolved 3D solution of the equations describing perturbed black holes. We
discuss both fixed and adaptive mesh refinement, refinement criteria, and the
computational savings provided by adaptive techniques in 3D for such model
problems of distorted black holes.Comment: 16 Pages, RevTeX, 13 figure
Large area and structured epitaxial graphene produced by confinement controlled sublimation of silicon carbide
After the pioneering investigations into graphene-based electronics at
Georgia Tech (GT), great strides have been made developing epitaxial graphene
on silicon carbide (EG) as a new electronic material. EG has not only
demonstrated its potential for large scale applications, it also has become an
invaluable material for fundamental two-dimensional electron gas physics
showing that only EG is on route to define future graphene science. It was long
known that graphene mono and multilayers grow on SiC crystals at high
temperatures in ultra-high vacuum. At these temperatures, silicon sublimes from
the surface and the carbon rich surface layer transforms to graphene. However
the quality of the graphene produced in ultrahigh vacuum is poor due to the
high sublimation rates at relatively low temperatures. The GT team developed
growth methods involving encapsulating the SiC crystals in graphite enclosures,
thereby sequestering the evaporated silicon and bringing growth process closer
to equilibrium. In this confinement controlled sublimation (CCS) process, very
high quality graphene is grown on both polar faces of the SiC crystals. Since
2003, over 50 publications used CCS grown graphene, where it is known as the
"furnace grown" graphene. Graphene multilayers grown on the carbon-terminated
face of SiC, using the CCS method, were shown to consist of decoupled high
mobility graphene layers. The CCS method is now applied on structured silicon
carbide surfaces to produce high mobility nano-patterned graphene structures
thereby demonstrating that EG is a viable contender for next-generation
electronics. Here we present the CCS method and demonstrate several of
epitaxial graphene's outstanding properties and applications
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