996 research outputs found
Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.
Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg block. In addition, we provide new views on Mg and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations
Expression and Cellular Immunogenicity of a Transgenic Antigen Driven by Endogenous Poxviral Early Promoters at Their Authentic Loci in MVA
CD8+ T cell responses to vaccinia virus are directed almost exclusively against early gene products. The attenuated strain modified vaccinia virus Ankara (MVA) is under evaluation in clinical trials of new vaccines designed to elicit cellular immune responses against pathogens including Plasmodium spp., M. tuberculosis and HIV-1. All of these recombinant MVAs (rMVA) utilize the well-established method of linking the gene of interest to a cloned poxviral promoter prior to insertion into the viral genome at a suitable locus by homologous recombination in infected cells. Using BAC recombineering, we show that potent early promoters that drive expression of non-functional or non-essential MVA open reading frames (ORFs) can be harnessed for immunogenic expression of recombinant antigen. Precise replacement of the MVA orthologs of C11R, F11L, A44L and B8R with a model antigen positioned to use the same translation initiation codon allowed early transgene expression similar to or slightly greater than that achieved by the commonly-used p7.5 or short synthetic promoters. The frequency of antigen-specific CD8+ T cells induced in mice by single shot or adenovirus-prime, rMVA-boost vaccination were similarly equal or marginally enhanced using endogenous promoters at their authentic genomic loci compared to the traditional constructs. The enhancement in immunogenicity observed using the C11R or F11L promoters compared with p7.5 was similar to that obtained with the mH5 promoter compared with p7.5. Furthermore, the growth rates of the viruses were unimpaired and the insertions were genetically stable. Insertion of a transgenic ORF in place of a viral ORF by BAC recombineering can thus provide not only a potent promoter, but also, concomitantly, a suitable insertion site, potentially facilitating development of MVA vaccines expressing multiple recombinant antigens
Search for a Technicolor omega_T Particle in Events with a Photon and a b-quark Jet at CDF
If the Technicolor omega_T particle exists, a likely decay mode is omega_T ->
gamma pi_T, followed by pi_T -> bb-bar, yielding the signature gamma bb-bar. We
have searched 85 pb^-1 of data collected by the CDF experiment at the Fermilab
Tevatron for events with a photon and two jets, where one of the jets must
contain a secondary vertex implying the presence of a b quark. We find no
excess of events above standard model expectations. We express the result of an
exclusion region in the M_omega_T - M_pi_T mass plane.Comment: 14 pages, 2 figures. Available from the CDF server (PS with figs):
http://www-cdf.fnal.gov/physics/pub98/cdf4674_omega_t_prl_4.ps
FERMILAB-PUB-98/321-
Comparative Genome Analysis Reveals an Absence of Leucine-Rich Repeat Pattern-Recognition Receptor Proteins in the Kingdom Fungi
Background: In plants and animals innate immunity is the first line of defence against attack by microbial pathogens. Specific molecular features of bacteria and fungi are recognised by pattern recognition receptors that have extracellular domains containing leucine rich repeats. Recognition of microbes by these receptors induces defence responses that protect hosts against potential microbial attack. Methodology/Principal Findings: A survey of genome sequences from 101 species, representing a broad cross-section of the eukaryotic phylogenetic tree, reveals an absence of leucine rich repeat-domain containing receptors in the fungal kingdom. Uniquely, however, fungi possess adenylate cyclases that contain distinct leucine rich repeat-domains, which have been demonstrated to act as an alternative means of perceiving the presence of bacteria by at least one fungal species. Interestingly, the morphologically similar osmotrophic oomycetes, which are taxonomically distant members of the stramenopiles, possess pattern recognition receptors with similar domain structures to those found in plants. Conclusions: The absence of pattern recognition receptors suggests that fungi may possess novel classes of patternrecognition receptor, such as the modified adenylate cyclase, or instead rely on secretion of anti-microbial secondary metabolites for protection from microbial attack. The absence of pattern recognition receptors in fungi, coupled with their abundance in oomycetes, suggests this may be a unique characteristic of the fungal kingdom rather than a consequence o
Top Quark Mass Measurement from Dilepton Events at CDF II with the Matrix-Element Method
We describe a measurement of the top quark mass using events with two charged
leptons collected by the CDF II detector from collisions with TeV at the Fermilab Tevatron. The likelihood in top mass is
calculated for each event by convoluting the leading order matrix element
describing
with detector resolution functions. The presence of background events in the
data sample is modeled using similar calculations involving the matrix elements
for major background processes. In a data sample with integrated luminosity of
340 pb, we observe 33 candidate events and measure This
measurement represents the first application of this method to events with two
charged leptons and is the most precise single measurement of the top quark
mass in this channel.Comment: 21 pages, 14 figure
Search for New Physics in Lepton + Photon + X Events with L=305 pb-1 of ppbar Collisions at roots=1.96 TeV
We present results of a search for anomalous production of events containing
a charged lepton (either electron or muon) and a photon, both with high
transverse momentum, accompanied by additional signatures, X, including missing
transverse energy (MET) and additional leptons and photons. We use the same
kinematic selection criteria as in a previous CDF search, but with a
substantially larger data set, 305 pb-1, a ppbar collision energy of 1.96 TeV,
and the upgraded CDF II detector. We find 42 Lepton+Photon+MET events versus a
standard model expectation of 37.3 +- 5.4 events. The level of excess observed
in Run I, 16 events with an expectation of 7.6 +- 0.7 events (corresponding to
a 2.7 sigma effect), is not supported by the new data. In the signature of
Multi-Lepton+Photon+X we observe 31 events versus an expectation of 23.0 +- 2.7
events. In this sample we find no events with an extra photon or MET and so
find no events like the one ee+gg+MET event observed in Run I.Comment: 7 pages, 3 figures, 1 table. Accepted to PR
Measurement of the Dipion Mass Spectrum in X(3872) -> J/Psi Pi+ Pi- Decays
We measure the dipion mass spectrum in X(3872)--> J/Psi Pi+ Pi- decays using
360 pb-1 of pbar-p collisions at 1.96 TeV collected with the CDF II detector.
The spectrum is fit with predictions for odd C-parity (3S1, 1P1, and 3DJ)
charmonia decaying to J/Psi Pi+ Pi-, as well as even C-parity states in which
the pions are from Rho0 decay. The latter case also encompasses exotic
interpretations, such as a D0-D*0Bar molecule. Only the 3S1 and J/Psi Rho
hypotheses are compatible with our data. Since 3S1 is untenable on other
grounds, decay via J/Psi Rho is favored, which implies C=+1 for the X(3872).
Models for different J/Psi-Rho angular momenta L are considered. Flexibility in
the models, especially the introduction of Rho-Omega interference, enable good
descriptions of our data for both L=0 and 1.Comment: 7 pages, 4 figures -- Submitted to Phys. Rev. Let
Measurement of the B0 anti-B0 oscillation frequency using l- D*+ pairs and lepton flavor tags
The oscillation frequency Delta-md of B0 anti-B0 mixing is measured using the
partially reconstructed semileptonic decay anti-B0 -> l- nubar D*+ X. The data
sample was collected with the CDF detector at the Fermilab Tevatron collider
during 1992 - 1995 by triggering on the existence of two lepton candidates in
an event, and corresponds to about 110 pb-1 of pbar p collisions at sqrt(s) =
1.8 TeV. We estimate the proper decay time of the anti-B0 meson from the
measured decay length and reconstructed momentum of the l- D*+ system. The
charge of the lepton in the final state identifies the flavor of the anti-B0
meson at its decay. The second lepton in the event is used to infer the flavor
of the anti-B0 meson at production. We measure the oscillation frequency to be
Delta-md = 0.516 +/- 0.099 +0.029 -0.035 ps-1, where the first uncertainty is
statistical and the second is systematic.Comment: 30 pages, 7 figures. Submitted to Physical Review
Search for New Particles Decaying to top-antitop in proton-antiproton collisions at squareroot(s)=1.8 TeV
We use 106 \ipb of data collected with the Collider Detector at Fermilab to
search for narrow-width, vector particles decaying to a top and an anti-top
quark. Model independent upper limits on the cross section for narrow, vector
resonances decaying to \ttbar are presented. At the 95% confidence level, we
exclude the existence of a leptophobic \zpr boson in a model of
topcolor-assisted technicolor with mass M_{\zpr} 480 \gev for natural
width = 0.012 M_{\zpr}, and M_{\zpr} 780 \gev for =
0.04 M_{\zpr}.Comment: The CDF Collaboration, submitted to PRL 25-Feb-200
Search for Higgs Boson Decaying to b-bbar and Produced in Association with W Bosons in p-pbar Collisions at sqrt{s}=1.96 TeV
We present a search for Higgs bosons decaying into b-bbar and produced in
association with W bosons in p-pbar collisions at sqrt{s}=1.96 TeV. This search
uses 320 pb-1 of the dataset accumulated by the upgraded Collider Detector at
Fermilab. Events are selected that have a high-transverse momentum electron or
muon, missing transverse energy, and two jets, one of which is consistent with
a hadronization of a b quark. Both the number of events and the dijet mass
distribution are consistent with standard model background expectations, and we
set 95% confidence level upper limits on the production cross section times
branching ratio for the Higgs boson or any new particle with similar decay
kinematics. These upper limits range from 10 pb for mH=110 GeV/c2 to 3 pb for
mH=150 GeV/c2.Comment: 7 pages, 3 figures; updated title to published versio
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