219 research outputs found
Sources in the making of histories of education: proofs, arguments, and other forms of reasoning from the historian’s workplace
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
A Temporal-Causal Modelling Approach to Analyse the Dynamics of Burnout and the Effects of Sleep
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
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
Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model
BACKGROUND:Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING:Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein. SIGNIFICANCE:Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis
Measurement of acoustic attenuation in South Pole ice
Using the South Pole Acoustic Test Setup (SPATS) and a retrievable transmitter deployed in holes drilled for the IceCube experiment, we have measured the attenuation of acoustic signals by South Pole ice at depths between 190 m and 500 m. Three data sets, using different acoustic sources, have been analyzed and give consistent results. The method with the smallest systematic uncertainties yields an amplitude attenuation coefficient α = 3.20 ± 0.57 km−1 between 10 and 30 kHz, considerably larger than previous theoretical estimates. Expressed as an attenuation length, the analyses give a consistent result for λ ≡ 1/α of ∼300 m with 20% uncertainty. No significant depth or frequency dependence has been found
The IceCube Data Acquisition System: Signal Capture, Digitization, and Timestamping
IceCube is a km-scale neutrino observatory under construction at the South
Pole with sensors both in the deep ice (InIce) and on the surface (IceTop). The
sensors, called Digital Optical Modules (DOMs), detect, digitize and timestamp
the signals from optical Cherenkov-radiation photons. The DOM Main Board (MB)
data acquisition subsystem is connected to the central DAQ in the IceCube
Laboratory (ICL) by a single twisted copper wire-pair and transmits packetized
data on demand. Time calibration is maintained throughout the array by regular
transmission to the DOMs of precisely timed analog signals, synchronized to a
central GPS-disciplined clock. The design goals and consequent features,
functional capabilities, and initial performance of the DOM MB, and the
operation of a combined array of DOMs as a system, are described here.
Experience with the first InIce strings and the IceTop stations indicates that
the system design and performance goals have been achieved.Comment: 42 pages, 20 figures, submitted to Nuclear Instruments and Methods
Solar Energetic Particle Spectrum on 13 December 2006 Determined by IceTop
On 13 December 2006 the IceTop air shower array at the South Pole detected a
major solar particle event. By numerically simulating the response of the
IceTop tanks, which are thick Cherenkov detectors with multiple thresholds
deployed at high altitude with no geomagnetic cut-off, we determined the
particle energy spectrum in the energy range 0.6 to 7.6 GeV. This is the first
such spectral measurement using a single instrument with a well defined viewing
direction. We compare the IceTop spectrum and its time evolution with
previously published results and outline plans for improved resolution of
future solar particle spectra.Comment: To appear in Astrophysical Journal Letters, 6 pages, 4 figure
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