684 research outputs found
Identification of a Negative Allosteric Site on Human α4β2 and α3β4 Neuronal Nicotinic Acetylcholine Receptors
Acetylcholine-based neurotransmission is regulated by cationic, ligand-gated ion channels called nicotinic acetylcholine receptors (nAChRs). These receptors have been linked to numerous neurological diseases and disorders such as Alzheimer's disease, Parkinson's disease, and nicotine addiction. Recently, a class of compounds has been discovered that antagonize nAChR function in an allosteric fashion. Models of human α4β2 and α3β4 nicotinic acetylcholine receptor (nAChR) extracellular domains have been developed to computationally explore the binding of these compounds, including the dynamics and free energy changes associated with ligand binding. Through a blind docking study to multiple receptor conformations, the models were used to determine a putative binding mode for the negative allosteric modulators. This mode, in close proximity to the agonist binding site, is presented in addition to a hypothetical mode of antagonism that involves obstruction of C loop closure. Molecular dynamics simulations and MM-PBSA free energy of binding calculations were used as computational validation of the predicted binding mode, while functional assays on wild-type and mutated receptors provided experimental support. Based on the proposed binding mode, two residues on the β2 subunit were independently mutated to the corresponding residues found on the β4 subunit. The T58K mutation resulted in an eight-fold decrease in the potency of KAB-18, a compound that exhibits preferential antagonism for human α4β2 over α3β4 nAChRs, while the F118L mutation resulted in a loss of inhibitory activity for KAB-18 at concentrations up to 100 µM. These results demonstrate the selectivity of KAB-18 for human α4β2 nAChRs and validate the methods used for identifying the nAChR modulator binding site. Exploitation of this site may lead to the development of more potent and subtype-selective nAChR antagonists which may be used in the treatment of a number of neurological diseases and disorders
Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine
Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe
Mapping and Mass Measurement of the Cold Dust in NGC 205 with Spitzer
We present observations at 3.6, 4.5, 5.8, 8, 24, 70 & 160um of NGC 205, the
dwarf elliptical companion of M31, obtained with the Spitzer Space Telescope.
The point sources subtracted images at 8 and 24um display a complex and
fragmented infrared emission coming from both very small dust particles and
larger grains. The extended dust emission is spatially concentrated in three
main emission regions, seen at all wavelengths from 8 to 160um. These regions
lie approximately along NGC 205's semi-major axis and range from ~100 to 300 pc
in size. Based on our mid-to-far infrared flux density measurements alone, we
derive a total dust mass estimate of the order of 3.2e4 solar masses, mainly at
a temperature of ~20K. The gas mass associated with this component matches the
predicted mass returned by the dying stars from the last burst of star
formation in NGC 205 (~0.5 Gyr ago). Analysis of the Spitzer data combined with
previous 1.1mm observations over a small central region or "Core'' (18"
diameter), suggest the presence of very cold (~12K) dust and a dust mass about
sixteen times higher than is estimated from the Spitzer measurements alone.
Assuming a gas to dust mass ratio of 100, these two datasets, i.e.with and
without the millimeter observations, suggest a total gas mass range of 3.2e6 to
5e7 solar masses.Comment: PDF, 10 pages, simulated ApJ, accepted for publicatio
Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons
The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions
VAMOS: a Pathfinder for the HAWC Gamma-Ray Observatory
VAMOS was a prototype detector built in 2011 at an altitude of 4100m a.s.l.
in the state of Puebla, Mexico. The aim of VAMOS was to finalize the design,
construction techniques and data acquisition system of the HAWC observatory.
HAWC is an air-shower array currently under construction at the same site of
VAMOS with the purpose to study the TeV sky. The VAMOS setup included six water
Cherenkov detectors and two different data acquisition systems. It was in
operation between October 2011 and May 2012 with an average live time of 30%.
Besides the scientific verification purposes, the eight months of data were
used to obtain the results presented in this paper: the detector response to
the Forbush decrease of March 2012, and the analysis of possible emission, at
energies above 30 GeV, for long gamma-ray bursts GRB111016B and GRB120328B.Comment: Accepted for pubblication in Astroparticle Physics Journal (20 pages,
10 figures). Corresponding authors: A.Marinelli and D.Zaboro
Approaching disorder-free transport in high-mobility conjugated polymers.
Conjugated polymers enable the production of flexible semiconductor devices that can be processed from solution at low temperatures. Over the past 25 years, device performance has improved greatly as a wide variety of molecular structures have been studied. However, one major limitation has not been overcome; transport properties in polymer films are still limited by pervasive conformational and energetic disorder. This not only limits the rational design of materials with higher performance, but also prevents the study of physical phenomena associated with an extended π-electron delocalization along the polymer backbone. Here we report a comparative transport study of several high-mobility conjugated polymers by field-effect-modulated Seebeck, transistor and sub-bandgap optical absorption measurements. We show that in several of these polymers, most notably in a recently reported, indacenodithiophene-based donor-acceptor copolymer with a near-amorphous microstructure, the charge transport properties approach intrinsic disorder-free limits at which all molecular sites are thermally accessible. Molecular dynamics simulations identify the origin of this long sought-after regime as a planar, torsion-free backbone conformation that is surprisingly resilient to side-chain disorder. Our results provide molecular-design guidelines for 'disorder-free' conjugated polymers.We gratefully acknowledge financial support from the Engineering and Physical Sciences Research Council (EPSRC) through a programme grant (EP/G060738/1) and the Technology Strategy Board (TSB) (PORSCHED project). D. Venkateshvaran acknowledges financial support from the Cambridge Commonwealth Trust through a Cambridge International Scholarship. K. Broch acknowledges post-doctoral fellowship support from the German Research Foundation (DFG). Mateusz Zelazny acknowledges funding from the NanoDTC in Cambridge. The work in Mons was supported by the European Commission / Région Wallonne (FEDER – Smartfilm RF project), the Interuniversity Attraction Pole program of the Belgian Federal Science Policy Office (PAI 7/05), Programme d’Excellence de la Région Wallonne (OPTI2MAT project) and FNRS-FRFC. D.B. and J.C. are FNRS Research Fellows.This is the accepted manuscript. The final version's available from Nature at http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13854.html
New Young Star Candidates in the Taurus-Auriga Region as Selected From WISE
The Taurus Molecular Cloud subtends a large solid angle on the sky, in excess
of 250 square degrees. The search for legitimate Taurus members to date has
been limited by sky coverage as well as the challenge of distinguishing members
from field interlopers. The Wide-field Infrared Survey Explorer (WISE) has
recently observed the entire sky, and we take advantage of the opportunity to
search for young stellar object (YSO) candidate Taurus members from a ~260
square degree region designed to encompass previously-identified Taurus
members. We use near- and mid-infrared colors to select objects with apparent
infrared excesses and incorporate other catalogs of ancillary data to present:
a list of rediscovered Taurus YSOs with infrared excesses (taken to be due to
circumstellar disks), a list of rejected YSO candidates (largely galaxies), and
a list of 94 surviving candidate new YSO-like Taurus members. There is likely
to be contamination lingering in this candidate list, and follow-up spectra are
warranted.Comment: Accepted to ApJ
Strangelet search at RHIC
Two position sensitive Shower Maximum Detector (SMDs) for Zero-Degree
Calorimeters (ZDCs) were installed by STAR before run 2004 at both upstream and
downstream from the interaction point along the beam axis where particles with
small rigidity are swept away by strong magnetic field. The ZDC-SMDs provides
information about neutral energy deposition as a function of transverse
position in ZDCs. We report the preliminary results of strangelet search from a
triggered data-set sampling 100 million Au+Au collisions at top RHIC energy.Comment: Strange Quark Matter 2004 conference proceedin
Pion interferometry in Au+Au collisions at sqrt[sNN]=200GeV
We present a systematic analysis of two-pion interferometry in Au+Au collisions at sqrt[sNN]=200GeV using the STAR detector at Relativistic Heavy Ion Collider. We extract the Hanbury-Brown and Twiss radii and study their multiplicity, transverse momentum, and azimuthal angle dependence. The Gaussianness of the correlation function is studied. Estimates of the geometrical and dynamical structure of the freeze-out source are extracted by fits with blast-wave parametrizations. The expansion of the source and its relation with the initial energy density distribution is studied
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