297 research outputs found
Constraint methods for determining pathways and free energy of activated processes
Activated processes from chemical reactions up to conformational transitions
of large biomolecules are hampered by barriers which are overcome only by the
input of some free energy of activation. Hence, the characteristic and
rate-determining barrier regions are not sufficiently sampled by usual
simulation techniques. Constraints on a reaction coordinate r have turned out
to be a suitable means to explore difficult pathways without changing potential
function, energy or temperature. For a dense sequence of values of r, the
corresponding sequence of simulations provides a pathway for the process. As
only one coordinate among thousands is fixed during each simulation, the
pathway essentially reflects the system's internal dynamics. From mean forces
the free energy profile can be calculated to obtain reaction rates and insight
in the reaction mechanism. In the last decade, theoretical tools and computing
capacity have been developed to a degree where simulations give impressive
qualitative insight in the processes at quantitative agreement with
experiments. Here, we give an introduction to reaction pathways and
coordinates, and develop the theory of free energy as the potential of mean
force. We clarify the connection between mean force and constraint force which
is the central quantity evaluated, and discuss the mass metric tensor
correction. Well-behaved coordinates without tensor correction are considered.
We discuss the theoretical background and practical implementation on the
example of the reaction coordinate of targeted molecular dynamics simulation.
Finally, we compare applications of constraint methods and other techniques
developed for the same purpose, and discuss the limits of the approach
Detecting a stochastic gravitational wave background with the Laser Interferometer Space Antenna
The random superposition of many weak sources will produce a stochastic
background of gravitational waves that may dominate the response of the LISA
(Laser Interferometer Space Antenna) gravitational wave observatory. Unless
something can be done to distinguish between a stochastic background and
detector noise, the two will combine to form an effective noise floor for the
detector. Two methods have been proposed to solve this problem. The first is to
cross-correlate the output of two independent interferometers. The second is an
ingenious scheme for monitoring the instrument noise by operating LISA as a
Sagnac interferometer. Here we derive the optimal orbital alignment for
cross-correlating a pair of LISA detectors, and provide the first analytic
derivation of the Sagnac sensitivity curve.Comment: 9 pages, 11 figures. Significant changes to the noise estimate
Calibration and Characterization of the IceCube Photomultiplier Tube
Over 5,000 PMTs are being deployed at the South Pole to compose the IceCube
neutrino observatory. Many are placed deep in the ice to detect Cherenkov light
emitted by the products of high-energy neutrino interactions, and others are
frozen into tanks on the surface to detect particles from atmospheric cosmic
ray showers. IceCube is using the 10-inch diameter R7081-02 made by Hamamatsu
Photonics. This paper describes the laboratory characterization and calibration
of these PMTs before deployment. PMTs were illuminated with pulses ranging from
single photons to saturation level. Parameterizations are given for the single
photoelectron charge spectrum and the saturation behavior. Time resolution,
late pulses and afterpulses are characterized. Because the PMTs are relatively
large, the cathode sensitivity uniformity was measured. The absolute photon
detection efficiency was calibrated using Rayleigh-scattered photons from a
nitrogen laser. Measured characteristics are discussed in the context of their
relevance to IceCube event reconstruction and simulation efforts.Comment: 40 pages, 12 figure
Familial Adenomatous Polyposis-Associated Desmoids Display Significantly More Genetic Changes than Sporadic Desmoids
Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression
Modeling Activity and Target-Dependent Developmental Cell Death of Mouse Retinal Ganglion Cells Ex Vivo
Programmed cell death is widespread during the development of the central nervous system and serves multiple purposes including the establishment of neural connections. In the mouse retina a substantial reduction of retinal ganglion cells (RGCs) occurs during the first postnatal week, coinciding with the formation of retinotopic maps in the superior colliculus (SC). We previously established a retino-collicular culture preparation which recapitulates the progressive topographic ordering of RGC projections during early post-natal life. Here, we questioned whether this model could also be suitable to examine the mechanisms underlying developmental cell death of RGCs. Brn3a was used as a marker of the RGCs. A developmental decline in the number of Brn3a-immunolabelled neurons was found in the retinal explant with a timing that paralleled that observed in vivo. In contrast, the density of photoreceptors or of starburst amacrine cells increased, mimicking the evolution of these cell populations in vivo. Blockade of neural activity with tetrodotoxin increased the number of surviving Brn3a-labelled neurons in the retinal explant, as did the increase in target availability when one retinal explant was confronted with 2 or 4 collicular slices. Thus, this ex vivo model reproduces the developmental reduction of RGCs and recapitulates its regulation by neural activity and target availability. It therefore offers a simple way to analyze developmental cell death in this classic system. Using this model, we show that ephrin-A signaling does not participate to the regulation of the Brn3a population size in the retina, indicating that eprhin-A-mediated elimination of exuberant projections does not involve developmental cell death
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