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  • 1
    Publication Date: 2012-05-16
    Description: The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    Publication Date: 2013-11-26
    Description: We continue recent work on computable structure theory in the setting of 1 . We prove the analogue of a result from Fokina et al. (2012 J. Symbolic Logic, 77, 122–132) saying that isomorphism of computable structures lies ‘on top’ among 1 1 equivalence relations on . Our equivalence relations are on 1 . In the standard setting, 1 1 sets are characterized in terms of paths through trees. In the setting of 1 , we use a new characterization of 1 1 sets that involves clubs in 1 . Finally, we present some new results about 1 -computable categoricity for fields.
    Print ISSN: 0955-792X
    Electronic ISSN: 1465-363X
    Topics: Computer Science , Mathematics
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  • 3
    Publication Date: 2019-07-17
    Description: The atomic deuterium-to-hydrogen abundance ratio has been evaluated for the sight line toward the hot O subdwarf BD+28(sup circ) 4211. High signal-to-noise ratio (S/N is approx. 100) observations covering the wavelength range 905 to 1187 angstroms at a wavelength resolving power of lambda/Delta/lambda at approx. 20,000 were obtained with the Far Ultraviolet Spectroscopic Explorer (FUSE) satellite. BD+28(sup circ) 4211 is approx. 00 pc away with a total H I column density of approx. 10(exp 19)/sq cm, much higher than is typically found in the local interstellar medium (ISM). The deuterium column density was measured by analyzing several D I Lyman series transitions (Lyman delta, C, epsilon, eta, theta, iota with curve of growth and profile fitting techniques, after determining which lines were free of interference from other interstellar species and narrow stellar features. The neutral hydrogen column density was measured by an analysis of the Lyman-alpha profile using HST/Space Telescope Imaging Spectrograph (STIS) and Goddard High Resolution Spectrograph (GHRS) spectra. The stellar spectrum of BD+28(sup circ) 4211 was modelled to assist in determining the sensitivity of H I (Ly-alpha) and D I to the continuum placement and to identify stellar transitions. The D I and H I column densities, their uncertainties, and potential sources of systematic error will be presented. This work is based on data obtained for the FUSE Guaranteed Time Team by the NASA-CNES-CSA FUSE mission operated by the Johns Hopkins University. Financial support to U. S. participants has been provided in part by NASA contract NAS5-32985.
    Keywords: Astrophysics
    Type: Jan 01, 2001; San Diego, CA; United States
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  • 4
    Publication Date: 2019-07-10
    Description: The neutral hydrogen and the ionized helium absorption in the spectra of high-redshift quasi-stellar objects (QSOs) are unique probes of structure in the universe at epochs intermediate between the earliest density fluctuations seen in the cosmic background radiation and the distribution of galaxies visible today. We present Far-Ultraviolet Spectroscopic Explorer (FUSE) observations of the line of sight to the QSO HE2347-4342 in the 1000-1187 angstrom band at a resolving power of 15,000. Above redshift z = 2.7, the IGM is largely opaque in He II Ly-alpha (304 angstroms). At lower redshifts, the optical depth gradually decreases to a mean value tau = 1 at z = 2.4. We resolve the He II Ly-alpha absorption as a discrete forest of absorption lines in the z = 2.3 - 2.7 redshift range. Approximately 50% of these spectral features have H I counterparts with column densities N(sub HI) 〉 10(exp 12.3)/sq cm visible in a Keck spectrum. These account for most of the observed opacity in He II Ly-alpha. The remainder have N(sub HI) 〈 10(exp 12.3)/sq cm, below the threshold for current observations. A short extrapolation of the power-law distribution of H I column densities to lower values can account for these new absorbers. The He II to H I column density ratio eta averages approximately 80, consistent with photoionization of the IGM by a hard ionizing spectrum resulting from the integrated light of quasars at high redshift, but there is considerable scatter. Values of eta 〉 100 in many locations indicate that there may be localized contributions from starbursts or heavily filtered QSO radiation.
    Keywords: Astrophysics
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  • 5
    Publication Date: 2019-07-10
    Description: High-resolution spectra of the hot white dwarf G191-B2B covering the wavelength region 905-1187A were obtained with the Far Ultraviolet Spectroscopic Explorer (FUSE). This data was used in conjunction with existing high-resolution Hubble Space Telescope STIS observations to evaluate the total H(sub I), D(sub I), O(sub I) and N(sub I) column densities along the line of sight. Previous determinations of N(D(sub I)) based upon GHRS (Goddard High Resolution Spectrograph) and STIS (Space Telescope Imaging Spectrograph) observations were controversial due to the saturated strength of the D(sub I) Lyman alpha line. In the present analysis the column density of D(sub I) has been measured using only the unsaturated Lyman beta and Lyman gamma lines observed by FUSE. A careful inspection of possible systematic uncertainties tied to the modeling of the stellar continuum or to the uncertainties in the FUSE instrumental character series has been performed. The column densities derived are: log N(D(sub I)) = 13.40+/-0.07, log N(O(sub I)) = 14.86+/-0.07, and log N(N(sub I)) = 13.87+/-0.07 quoted with 2sigma, uncertainties. The measurement of the H(sub I) column density by profile fitting of the Lyman alpha line has been found to be unsecure. If additional weak hot interstellar components are added to the three detected clouds along the line of sight, the H(sub I)) column density can be reduced quite significantly, even though the signal-to-noise ratio and spectral resolution at Lyman alpha are excellent. The new estimate of N(H(sub I)) toward G191-B2B reads: logN(H (sub I)) = 18.18+/-0.18 (2sigma uncertainty), so that the average (D/H) ratio on the line of sight is: (D/H)= 1.66(+0.9/-0.6) x 10(exp -5) (2sigma uncertainty).
    Keywords: Astrophysics
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  • 6
    Publication Date: 2019-07-10
    Description: Observations obtained with the Far Ultraviolet Spectroscopic Explorer (FUSE) have been used to determine the column densities of D I, O I, and N I along seven sight lines that probe the local interstellar medium (LISM) at distances from 37 pc to 179 pc. Five of the sight lines are within the Local Bubble and two penetrate the surrounding H I wall. Reliable values of N(H I) were determined for five of the sight lines from HST data, IUE data, and published EUVE measurements. The weighted mean of DI/H I for these five sight lines is (1.52 +/- 0.08) x l0(exp -5)(1 sigma uncertainty in the mean). It is likely that the D I/H I ratio in the Local Bubble has a single value. The D I/O I ratio for the five sight lines within the Local Bubble is (3.76 +/- 0.20) x 10(esp -2). It is likely that O I column densities can serve as a proxy for H I in the Local Bubble. The weighted mean for O I/ H I for the seven FUSE sight lines is (3.03 +/- 0.21) x 10(esp -4), comparable to the weighted mean (3.43 +/- 0.15) x 10(exp -4) reported for 13 sight lines probing larger distances and higher column densities. The FUSE weighted mean of N I/ H I for five sight lines is half that reported by Meyer et al. for seven sight lines with larger distances and higher column densities. This result combined with the variability of O I/ N I (six sight lines) indicates that at the low column densities found in the LISM, nitrogen ionization balance is important. Thus, unlike O I, N I cannot be used as a proxy for H I or as a metallicity indicator in the LISM.
    Keywords: Geophysics
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  • 7
    Publication Date: 2019-07-10
    Description: We present measurements of the column densities of interstellar D I and O I made with the Far Ultraviolet Spectroscopic Explorer (FUSE), and of H I made with the International Ultraviolet Explorer (IUE) toward the sdOB star Feige 110 [(l,b) = (74.09 deg., - 59.07 deg.); d = 179(sup +265, sub -67) pc; Z = -154(sup +57, Sub -227 pc). Our determination of the D I column density made use of curve of growth fitting and profile fitting analyses, while our O I column density determination used only curve of growth techniques. The H I column density was estimated by fitting the damping wings of the interstellar Ly(lpha) profile. We find log N(D I) = 15.47 +/- 0.06, log N(O I) = 16.73 +/- 0.10, and log N(H I) = 20.14(sup +0.13, sub -0.20) (all errors 2(sigma)). This implies D/H = (2.14 +/- 0.82) x 10(esp -5), D/O = (5.50(sup + 1.64, sub -133)) x 10(exp -2), and O/H = (3.89 +/- 1.67) x 10(exp -4). Taken with the FUSE results reported in companion papers and previous measurements of the local interstellar medium, this suggests the possibility of spatial variability in D/H for sight lines exceeding approx. 100 pc. This result may constrain models which characterize the mixing time and length scales of material in the local interstellar medium.
    Keywords: Geophysics
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  • 8
    Publication Date: 2008-08-01
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2008-08-22
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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