191 research outputs found
Biomarkers and Mechanisms of FANCD2 Function
Genetic or epigenetic inactivation of the pathway formed by the Fanconi anemia (FA) and BRCA1 proteins occurs in several cancer types, making the affected tumors potentially hypersensitive to DNA cross-linkers and other chemotherapeutic agents. It has been proposed that the inability of FA/BRCA-defective cells to form subnuclear foci of effector proteins, such as FANCD2, can be used as a biomarker to aid individualization of chemotherapy. We show that FANCD2 inactivation not only renders cells sensitive to cross-links, but also oxidative stress, a common effect of cancer therapeutics. Oxidative stress sensitivity does not correlate with FANCD2 or RAD51 foci formation, but associates with increased γH2AX foci levels and apoptosis. Therefore, FANCD2 may protect cells against cross-links and oxidative stress through distinct mechanisms, consistent with the growing notion that the pathway is not linear. Our data emphasize the need for multiple biomarkers, such as γH2AX, FANCD2, and RAD51, to capture all pathway activities
Molecular Signatures of the Primitive Prostate Stem Cell Niche Reveal Novel Mesenchymal-Epithelial Signaling Pathways
Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system.We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2), lipid metabolism (e.g., Srebp1) and cell migration (e.g., Areb6 and Rreb1). Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche.We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may be common to mammalian niches in general. This study provides a comprehensive source for further studies of mesenchymal/epithelial interactions in the prostate stem cell niche. The elucidation of pathways in the normal primitive niche may provide greater insight into mechanisms subverted during abnormal proliferative and oncogenic processes. Understanding these events may result in the development of specific targeted therapies for prostatic diseases such as benign prostatic hypertrophy and carcinomas
Variations in concerns reported on the Patient Concerns Inventory (PCI) in head and neck cancer patients from different health settings across the world
Background: The aim was to collate and contrast patient concerns from a range of different head and neck cancer follow-up clinics around the world. Also, we sought to explore the relationship, if any, between responses to the patient concerns inventory (PCI) and overall quality of life (QOL). Methods: Nineteen units participated with intention of including 100 patients per site as close to a consecutive series as possible in order to minimize selection bias. Results: There were 2136 patients with a median total number of PCI items selected of 5 (2-10). “Fear of the cancer returning” (39%) and “dry mouth” (37%) were most common. Twenty-five percent (524) reported less than good QOL. Conclusion: There was considerable variation between units in the number of items selected and in overall QOL, even after allowing for case-mix variables. There was a strong progressive association between the number of PCI items and QOL
Co-formulation of the rF1V plague vaccine with depot-formulated cytokines enhances immunogenicity and efficacy to elicit protective responses against aerosol challenge in mice
This study evaluated a depot-formulated cytokine-based adjuvant to improve the efficacy of the recombinant F1V (rF1V) plague vaccine and examined the protective response following aerosol challenge in a murine model. The results of this study showed that co-formulation of the Alhydrogel-adsorbed rF1V plague fusion vaccine with the depot-formulated cytokines recombinant human interleukin 2 (rhuIL-2) and/or recombinant murine granulocyte macrophage colony-stimulating factor (rmGM-CSF) significantly enhances immunogenicity and significant protection at lower antigen doses against a lethal aerosol challenge. These results provide additional support for the co-application of the depot-formulated IL-2 and/or GM-CSF cytokines to enhance vaccine efficacy
Quantum state preparation and macroscopic entanglement in gravitational-wave detectors
Long-baseline laser-interferometer gravitational-wave detectors are operating
at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within
a broad frequency band. Such a low classical noise budget has already allowed
the creation of a controlled 2.7 kg macroscopic oscillator with an effective
eigenfrequency of 150 Hz and an occupation number of 200. This result, along
with the prospect for further improvements, heralds the new possibility of
experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical
behavior of objects in the realm of everyday experience - using
gravitational-wave detectors. In this paper, we provide the mathematical
foundation for the first step of a MQM experiment: the preparation of a
macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum
state, which is possible if the interferometer's classical noise beats the SQL
in a broad frequency band. Our formalism, based on Wiener filtering, allows a
straightforward conversion from the classical noise budget of a laser
interferometer, in terms of noise spectra, into the strategy for quantum state
preparation, and the quality of the prepared state. Using this formalism, we
consider how Gaussian entanglement can be built among two macroscopic test
masses, and the performance of the planned Advanced LIGO interferometers in
quantum-state preparation
Accurate water maser positions from HOPS
We report on high spatial resolution water maser observations, using the Australia Telescope Compact Array, towards water maser sites previously identified in the H2O southern Galactic Plane Survey (HOPS). Of the 540 masers identified in the single-dish observations of Walsh et al. (2011), we detect emission in all but 31 fields. We report on 2790 spectral features (maser spots), with brightnesses ranging from 0.06 Jy to 576 Jy and with velocities ranging from −238.5 to +300.5 kms−1. These spectral features are grouped into 631 maser sites. We have compared the positions of these sites to the literature to associate the sites with astrophysical objects. We identify 433 (69 per cent) with star formation, 121 (19 per cent) with evolved stars and 77 (12 per cent) as unknown. We find that maser sites associated with evolved stars tend to have more maser spots and have smaller angular sizes than those associated with star formation. We present evidence that maser sites associated with evolved stars show an increased likelihood of having a velocity range between 15 and 35 kms−1 compared to other maser sites. Of the 31 non-detections, we conclude they were not detected due to intrinsic variability and confirm previous results showing that such variable masers
tend to be weaker and have simpler spectra with fewer peaks
Searching for a Stochastic Background of Gravitational Waves with LIGO
The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed
the fourth science run, S4, with significantly improved interferometer
sensitivities with respect to previous runs. Using data acquired during this
science run, we place a limit on the amplitude of a stochastic background of
gravitational waves. For a frequency independent spectrum, the new limit is
. This is currently the most sensitive
result in the frequency range 51-150 Hz, with a factor of 13 improvement over
the previous LIGO result. We discuss complementarity of the new result with
other constraints on a stochastic background of gravitational waves, and we
investigate implications of the new result for different models of this
background.Comment: 37 pages, 16 figure
Prevalence of Coxiella burnetii in clinically healthy German sheep flocks
<p>Abstract</p> <p>Background</p> <p>Current epidemiological data on the situation of <it>Coxiella (C.) burnetii </it>infections in sheep are missing, making risk assessment and the implementation of counteractive measures difficult. Using the German state of Thuringia as a model example, the estimated sero-, and antigen prevalence of <it>C. burnetii </it>(10% and 25%, respectively) was assessed at flock level in 39/252 randomly selected clinically healthy sheep flocks with more than 100 ewes and unknown abortion rate.</p> <p>Results</p> <p>The CHECKIT™ Q-fever Test Kit identified 11 (28%) antibody positive herds, whereas real-time PCR revealed the presence of <it>C. burnetii </it>DNA in 2 (5%) of the flocks. Multiple-locus variable number of tandem repeats analysis of 9 isolates obtained from one flock revealed identical profiles. All isolates contained the plasmid QpH1.</p> <p>Conclusions</p> <p>The results demonstrate that <it>C. burnetii </it>is present in clinically inconspicuous sheep flocks and sporadic flare-ups do occur as the notifications to the German animal disease reporting system show. Although <it>C. burnetii </it>infections are not a primary veterinary concern due to the lack of significant clinical impact on animal health (with the exception of goats), the eminent zoonotic risk for humans should not be underestimated. Therefore, strategies combining the interests of public and veterinary public health should include monitoring of flocks, the identification and culling of shedders as well as the administration of protective vaccines.</p
Highly Volcanic Exoplanets, Lava Worlds, and Magma Ocean Worlds:An Emerging Class of Dynamic Exoplanets of Significant Scientific Priority
Highly volcanic exoplanets, which can be variously characterized as 'lava
worlds', 'magma ocean worlds', or 'super-Ios' are high priority targets for
investigation. The term 'lava world' may refer to any planet with extensive
surface lava lakes, while the term 'magma ocean world' refers to planets with
global or hemispherical magma oceans at their surface. 'Highly volcanic
planets', including super-Ios, may simply have large, or large numbers of,
active explosive or extrusive volcanoes of any form. They are plausibly highly
diverse, with magmatic processes across a wide range of compositions,
temperatures, activity rates, volcanic eruption styles, and background
gravitational force magnitudes. Worlds in all these classes are likely to be
the most characterizable rocky exoplanets in the near future due to
observational advantages that stem from their preferential occurrence in short
orbital periods and their bright day-side flux in the infrared. Transit
techniques should enable a level of characterization of these worlds analogous
to hot Jupiters. Understanding processes on highly volcanic worlds is critical
to interpret imminent observations. The physical states of these worlds are
likely to inform not just geodynamic processes, but also planet formation, and
phenomena crucial to habitability. Volcanic and magmatic activity uniquely
allows chemical investigation of otherwise spectroscopically inaccessible
interior compositions. These worlds will be vital to assess the degree to which
planetary interior element abundances compare to their stellar hosts, and may
also offer pathways to study both the very young Earth, and the very early form
of many silicate planets where magma oceans and surface lava lakes are expected
to be more prevalent. We suggest that highly volcanic worlds may become second
only to habitable worlds in terms of both scientific and public long-term
interest.Comment: A white paper submitted in response to the National Academy of
Sciences 2018 Exoplanet Science Strategy solicitation, from the NASA Sellers
Exoplanet Environments Collaboration (SEEC) of the Goddard Space Flight
Center. 6 pages, 0 figure
Geophysical and atmospheric evolution of habitable planets
The evolution of Earth-like habitable planets is a complex process that depends on the geodynamical and geophysical environments. In particular, it is necessary that plate tectonics remain active over billions of years. These geophysically active environments are strongly coupled to a planet's host star parameters, such as mass, luminosity and activity, orbit location of the habitable zone, and the planet's initial water inventory. Depending on the host star's radiation and particle flux evolution, the composition in the thermosphere, and the availability of an active magnetic dynamo, the atmospheres of Earth-like planets within their habitable zones are differently affected due to thermal and nonthermal escape processes. For some planets, strong atmospheric escape could even effect the stability of the atmosphere
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