79 research outputs found
Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors
Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al
Experimental Study of the Shortest Reset Word of Random Automata
In this paper we describe an approach to finding the shortest reset word of a
finite synchronizing automaton by using a SAT solver. We use this approach to
perform an experimental study of the length of the shortest reset word of a
finite synchronizing automaton. The largest automata we considered had 100
states. The results of the experiments allow us to formulate a hypothesis that
the length of the shortest reset word of a random finite automaton with
states and 2 input letters with high probability is sublinear with respect to
and can be estimated as $1.95 n^{0.55}.
Demonstration of the temporal matter-wave Talbot effect for trapped matter waves
We demonstrate the temporal Talbot effect for trapped matter waves using
ultracold atoms in an optical lattice. We investigate the phase evolution of an
array of essentially non-interacting matter waves and observe matter-wave
collapse and revival in the form of a Talbot interference pattern. By using
long expansion times, we image momentum space with sub-recoil resolution,
allowing us to observe fractional Talbot fringes up to 10th order.Comment: 17 pages, 7 figure
Azimuthal anisotropy at RHIC: the first and fourth harmonics
We report the first observations of the first harmonic (directed flow, v_1),
and the fourth harmonic (v_4), in the azimuthal distribution of particles with
respect to the reaction plane in Au+Au collisions at the Relativistic Heavy Ion
Collider (RHIC). Both measurements were done taking advantage of the large
elliptic flow (v_2) generated at RHIC. From the correlation of v_2 with v_1 it
is determined that v_2 is positive, or {\it in-plane}. The integrated v_4 is
about a factor of 10 smaller than v_2. For the sixth (v_6) and eighth (v_8)
harmonics upper limits on the magnitudes are reported.Comment: 6 pages with 3 figures, as accepted for Phys. Rev. Letters The data
tables are at
http://www.star.bnl.gov/central/publications/pubDetail.php?id=3
Pion, kaon, proton and anti-proton transverse momentum distributions from p+p and d+Au collisions at GeV
Identified mid-rapidity particle spectra of , , and
from 200 GeV p+p and d+Au collisions are reported. A
time-of-flight detector based on multi-gap resistive plate chamber technology
is used for particle identification. The particle-species dependence of the
Cronin effect is observed to be significantly smaller than that at lower
energies. The ratio of the nuclear modification factor () between
protons and charged hadrons () in the transverse momentum
range GeV/c is measured to be
(stat)(syst) in minimum-bias collisions and shows little
centrality dependence. The yield ratio of in minimum-bias d+Au
collisions is found to be a factor of 2 lower than that in Au+Au collisions,
indicating that the Cronin effect alone is not enough to account for the
relative baryon enhancement observed in heavy ion collisions at RHIC.Comment: 6 pages, 4 figures, 1 table. We extended the pion spectra from
transverse momentum 1.8 GeV/c to 3. GeV/
NA49 Results on Single Particle and Correlation Measurements in Central Pb+Pb Collisions
Single-particle spectra and two-particle correlation functions measured by the NA49 collaboration in central Pb+Pb collisions at 158 GeV/nucleon are presented. These measurements are used to study the kinetic and chemical freeze-out conditions in heavy ion collisions. We conclude that large baryon stopping, high baryon density and strong transverse radial flow are achieved in central Pb+Pb collisions at the SPS.Single-particle spectra and two-particle correlation functions measured by the NA49 collaboration in central Pb+Pb collisions at 158 GeV/nucleon are presented. These measurements are used to study the kinetic and chemical freeze-out conditions in heavy ion collisions. We conclude that large baryon stopping, high baryon density and strong transverse radial flow are achieved in central Pb+Pb collisions at the SPS
Mid-rapidity anti-proton to proton ratio from Au+Au collisions at GeV
We report results on the ratio of mid-rapidity anti-proton to proton yields
in Au+Au collisions at \rts = 130 GeV per nucleon pair as measured by the
STAR experiment at RHIC. Within the rapidity and transverse momentum range of
and 0.4 1.0 GeV/, the ratio is essentially independent of
either transverse momentum or rapidity, with an average of for minimum bias collisions. Within errors, no
strong centrality dependence is observed. The results indicate that at this
RHIC energy, although the -\pb pair production becomes important at
mid-rapidity, a significant excess of baryons over anti-baryons is still
present.Comment: 5 pages, 3 figures, accepted by Phys. Rev. Let
Transverse-momentum correlations on from mean- fluctuations in Au-Au collisions at 200 GeV
We present first measurements of the pseudorapidity and azimuth
bin-size dependence of event-wise mean transverse momentum
fluctuations for Au-Au collisions at GeV. We invert that
dependence to obtain autocorrelations on differences
interpreted to represent velocity/temperature
distributions on (). The general form of the autocorrelations
suggests that the basic correlation mechanism is parton fragmentation. The
autocorrelations vary strongly with collision centrality, which suggests that
fragmentation is strongly modified by a dissipative medium in the more central
Au-Au collisions relative to peripheral or p-p collisions. \\Comment: 7 pages, 3 figure
Changes in fitness are associated with changes in hippocampal microstructure and hippocampal volume among older adults
This study investigates the effects of fitness changes on hippocampal microstructure and hippocampal volume. Fifty-two healthy participants aged 59-74 years with a sedentary lifestyle were randomly assigned to either of two levels of exercise intensity. Training lasted for six months. Physical fitness, hippocampal volumes, and hippocampal microstructure were measured before and after training. Hippocampal microstructure was assessed by mean diffusivity, which inversely reflects tissue densityhence, mean diffusivity is lower for more densely packed tissue. Mean changes in fitness did not differ reliably across intensity levels of training, so data were collapsed across groups. Multivariate modeling of pretest-posttest differences using structural equation modeling (SEM) revealed that individual differences in latent change were reliable for all three constructs. More positive changes in fitness were associated with more positive changes in tissue density (i.e., more negative changes in mean diffusivity), andmore positive changes in tissue density were associated with more positive changes in volume. We conclude that fitness-related changes in hippocampal volume may be brought about by changes in tissue density. The relative contributions of angiogenesis, gliogenesis, and/or neurogenesis to changes in tissue density remain to be identified. (C) 2015 Elsevier Inc. All rights reserved
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