3,970 research outputs found
Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson’s Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice
Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy
Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma
<p>Abstract</p> <p>Background</p> <p>Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing.</p> <p>Methods</p> <p>The vaccine (IDD-3) consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-13 (IL-13), pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity.</p> <p>Results</p> <p>Among 33 patients who received IDD-3 there was one complete response (CR), two partial responses (PR), and six patients had stable disease (SD) lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%). IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by <it>in vitro </it>immune monitoring assays.</p> <p>Conclusions</p> <p>The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma.</p> <p>Clinical trial registration</p> <p>NCT00107159.</p
Measurement of the Crab Nebula Spectrum Past 100 TeV with HAWC
We present TeV gamma-ray observations of the Crab Nebula, the standard
reference source in ground-based gamma-ray astronomy, using data from the High
Altitude Water Cherenkov (HAWC) Gamma-Ray Observatory. In this analysis we use
two independent energy-estimation methods that utilize extensive air shower
variables such as the core position, shower angle, and shower lateral energy
distribution. In contrast, the previously published HAWC energy spectrum
roughly estimated the shower energy with only the number of photomultipliers
triggered. This new methodology yields a much improved energy resolution over
the previous analysis and extends HAWC's ability to accurately measure
gamma-ray energies well beyond 100 TeV. The energy spectrum of the Crab Nebula
is well fit to a log parabola shape with emission up to at least 100 TeV. For the first
estimator, a ground parameter that utilizes fits to the lateral distribution
function to measure the charge density 40 meters from the shower axis, the
best-fit values are
=(2.350.04)10 (TeV cm
s), =2.790.02, and
=0.100.01. For the second estimator, a neural
network which uses the charge distribution in annuli around the core and other
variables, these values are
=(2.310.02)10 (TeV cm
s), =2.730.02, and
=0.060.010.02. The first set of uncertainties are statistical;
the second set are systematic. Both methods yield compatible results. These
measurements are the highest-energy observation of a gamma-ray source to date.Comment: published in Ap
A search for charged massive long-lived particles
We report on a search for charged massive long-lived particles (CMLLPs),
based on 5.2 fb of integrated luminosity collected with the D0 detector
at the Fermilab Tevatron collider. We search for events in which one
or more particles are reconstructed as muons but have speed and ionization
energy loss inconsistent with muons produced in beam collisions.
CMLLPs are predicted in several theories of physics beyond the standard model.
We exclude pair-produced long-lived gaugino-like charginos below 267 GeV and
higgsino-like charginos below 217 GeV at 95% C.L., as well as long-lived scalar
top quarks with mass below 285 GeV.Comment: submitted to Phys. Rev. Letter
Measurement of spin correlation in ttbar production using a matrix element approach
correlation, assuming that the spin of the top quark is either correlated
with the spin of the anti-top quark as predicted by the standard model or is
uncorrelated. For the first time we use a matrix-element-based approach to
study ttbar spin correlation. We use {ttbar -> W+bW-bbar ->l+nubl-nub} final
states produced in ppbar collisions at a center of mass energy sqrt(s)=1.96
TeV, where l denotes an electron or a muon. The data correspond to an
integrated luminosity of 5.4 fb-1 and were collected with the dzero detector at
the Fermilab Tevatron collider. The result agrees with the standard model
prediction. We exclude the hypothesis that the spins of the ttbar are
uncorrelated at the 97.7% C.L.Comment: 7 pages, 3 figures, submitted to Phys. Rev. Let
Journal Staff
We present the first measurements of the differential cross section d sigma/dp(T)(gamma) for the production of an isolated photon in association with at least two b-quark jets. The measurements consider photons with rapidities vertical bar y(gamma)vertical bar < 1.0 and transverse momenta 30 < p(T)(gamma) < 200 GeV. The b-quark jets are required to have p(T)(jet) > 15 GeVand vertical bar y(jet)vertical bar < 1.5. The ratio of differential production cross sections for gamma + 2 b-jets to gamma + b-jet as a function of p(T)(gamma) is also presented. The results are based on the proton-antiproton collision data at root s = 1.96 TeV collected with the D0 detector at the Fermilab Tevatron Collider. The measured cross sections and their ratios are compared to the next- to- leading order perturbative QCD calculations as well as predictions based on the k(T)- factorization approach and those from the sherpa and pythia Monte Carlo event generators
Search for single vector-like quarks in ppbar collisions at sqrt(s) = 1.96 TeV
We present a search for hypothetical vector-like quarks in ppbar collisions
at sqrt(s) = 1.96 TeV. The data were collected by the D0 detector at the
Fermilab Tevatron Collider and correspond to an integrated luminosity of 5.4
fb^(-1). We select events with a final state composed of a W or Z boson and a
jet consistent with a heavy object decay. We observe no significant excess in
comparison to the background prediction and set limits on production cross
sections for vector-like quarks decaying to W+jet and Z+jet. These are the most
stringent mass limits for electroweak single vector-like quark production at
hadron colliders.Comment: submitted to Phys. Rev. Let
Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC
The uncertainty on the calorimeter energy response to jets of particles is
derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the
calorimeter response to single isolated charged hadrons is measured and
compared to the Monte Carlo simulation using proton-proton collisions at
centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009
and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter
response to specific types of particles (positively and negatively charged
pions, protons, and anti-protons) is measured and compared to the Monte Carlo
predictions. Finally, the jet energy scale uncertainty is determined by
propagating the response uncertainty for single charged and neutral particles
to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3%
for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table,
submitted to European Physical Journal
Search for composite and exotic fermions at LEP 2
A search for unstable heavy fermions with the DELPHI detector at LEP is
reported. Sequential and non-canonical leptons, as well as excited leptons and
quarks, are considered. The data analysed correspond to an integrated
luminosity of about 48 pb^{-1} at an e^+e^- centre-of-mass energy of 183 GeV
and about 20 pb^{-1} equally shared between the centre-of-mass energies of 172
GeV and 161 GeV. The search for pair-produced new leptons establishes 95%
confidence level mass limits in the region between 70 GeV/c^2 and 90 GeV/c^2,
depending on the channel. The search for singly produced excited leptons and
quarks establishes upper limits on the ratio of the coupling of the excited
fermio
Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS
The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured
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