The identification of small molecules that inhibit the sequence-specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible ...factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1alpha and HIF-1beta proteins containing the basic-helix-loop-helix and PAS domains. Expressed recombinant HIF-1alpha and HIF-1beta proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compounds previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compounds identified, echinomycin (NSC-13502), a small-molecule known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1alpha and HIF-1beta proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-kappaB (NF-kappaB) consensus sequences. Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-kappaB to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters.
The sidereal time dependence of MiniBooNE νe and ν¯e appearance data is analyzed to search for evidence of Lorentz and CPT violation. An unbinned Kolmogorov–Smirnov (K–S) test shows both the νe and ...ν¯e appearance data are compatible with the null sidereal variation hypothesis to more than 5%. Using an unbinned likelihood fit with a Lorentz-violating oscillation model derived from the Standard Model Extension (SME) to describe any excess events over background, we find that the νe appearance data prefer a sidereal time-independent solution, and the ν¯e appearance data slightly prefer a sidereal time-dependent solution. Limits of order 10−20 GeV are placed on combinations of SME coefficients. These limits give the best limits on certain SME coefficients for νμ→νe and ν¯μ→ν¯e oscillations. The fit values and limits of combinations of SME coefficients are provided.
We have computed the gravitational wave signal from supernova core collapse by using the most realistic input physics available at present. We start from state-of-the-art progenitor models of ...rotating and nonrotating massive stars and simulate the dynamics of their core collapse by integrating the equations of axisymmetric hydrodynamics, together with the Boltzmann equation for the neutrino transport, including an elaborate description of neutrino interactions, and a realistic equation of state. Using the Einstein quadrupole formula we compute the quadrupole wave amplitudes, the Fourier wave spectra, the amount of energy radiated in the form of gravitational waves, and the signal-to-noise ratios for the Laser Interferometer Gravitational-Wave Observatory (LIGO) I and the tuned Advanced LIGO (LIGO II) interferometers resulting from both nonradial mass motion and anisotropic neutrino emission. The simulations demonstrate that the dominant contribution to the gravitational wave signal is produced by neutrino-driven convection behind the supernova shock. For stellar cores rotating at the extreme of current stellar evolution predictions, the core bounce signal is detectable (S/N > ~ 7) with LIGO II for a supernova up to a distance of approx5 kpc, whereas the signal from postshock convection is observable (S/N > ~ 7) with LIGO II up to a distance of approx100 kpc and with LIGO I to a distance of approx5 kpc. If the core is nonrotating, its gravitational wave emission can be measured with LIGO II up to a distance of approx15 kpc (S/N > ~ 8), while the signal from the Ledoux convection in the deleptonizing nascent neutron star can be detected up to a distance of approx10 kpc (S/N > ~ 8). Both kinds of signals are generically produced by convection in any core-collapse supernova.
The MiniBooNE detector Aguilar-Arevalo, A.A.; Anderson, C.E.; Bartoszek, L.M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2009, Letnik:
599, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The MiniBooNE neutrino detector was designed and built to look for
ν
μ
→
ν
e
oscillations in the
(
sin
2
2
θ
,
Δ
m
2
)
parameter space region where the LSND experiment reported a signal. The ...MiniBooNE experiment used a beam energy and baseline that were an order of magnitude larger than those of LSND so that the backgrounds and systematic errors would be completely different. This paper provides a detailed description of the design, function, and performance of the MiniBooNE detector.
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