274 research outputs found
New limits on a cosmological constant from statistics of gravitational lensing
We present new limits on cosmological parameters from the statistics of
gravitational lensing, based on the recently revised knowledge of the
luminosity function and internal dynamics of E/S0 galaxies that are essential
in lensing high-redshift QSOs. We find that the lens models using updated
Schechter parameters for such galaxies, derived from the recent redshift
surveys combined with morphological classification, are found to give smaller
lensing probabilities than earlier calculated. Inconsistent adoption of these
parameters from a mixture of various galaxy surveys gives rise to systematic
biases in the results. We also show that less compact dwarf-type galaxies which
largely dominate the faint part of the Schechter-form luminosity function
contribute little to lensing probabilities, so that earlier lens models
overestimate incidents of small separation lenses. Applications of the lens
models to the existing lens surveys indicate that reproduction of both the
lensing probability of optical sources and the image separations of optical and
radio lenses is significantly improved in the revised lens models. The
likelihood analyses allow us to conclude that a flat universe with
Omega=0.3(+0.2-0.1) and Omega+Lambda=1 is most preferable, and a
matter-dominated flat universe with Lambda=0 is ruled out at 98 % confidence
level. These new limits are unaffected by inclusion of uncertainties in the
lens properties.Comment: 30 pages, 9 ps figures, AASTeX, ApJ in pres
Discrimination of gamma rays due to inelastic neutron scattering in AGATA
Possibilities of discriminating neutrons and gamma rays in the AGATA
gamma-ray tracking spectrometer have been investigated with the aim of reducing
the background due to inelastic scattering of neutrons in the high-purity
germanium crystals. This background may become a serious problem especially in
experiments with neutron-rich radioactive ion beams. Simulations using the
Geant4 toolkit and a tracking program based on the forward tracking algorithm
were carried out by emitting neutrons and gamma rays from the center of AGATA.
Three different methods were developed and tested in order to find
'fingerprints' of the neutron interaction points in the detectors. In a
simulation with simultaneous emission of six neutrons with energies in the
range 1-5 MeV and ten gamma rays with energies between 150 and 1450 keV, the
peak-to-background ratio at a gamma-ray energy of 1.0 MeV was improved by a
factor of 2.4 after neutron rejection with a reduction of the photopeak
efficiency at 1.0 MeV of only a factor of 1.25.Comment: Accepted for publication in Nuclear Instruments and Methods in
Physics Research, A, 26 May 2009; 13 pages, 5 tables, 12 figure
Toxicogenomic Biomarkers for Liver Toxicity
Toxicogenomics (TGx) is a widely used technique in the preclinical stage of drug development to investigate the molecular mechanisms of toxicity. A number of candidate TGx biomarkers have now been identified and are utilized for both assessing and predicting toxicities. Further accumulation of novel TGx biomarkers will lead to more efficient, appropriate and cost effective drug risk assessment, reinforcing the paradigm of the conventional toxicology system with a more profound understanding of the molecular mechanisms of drug-induced toxicity. In this paper, we overview some practical strategies as well as obstacles for identifying and utilizing TGx biomarkers based on microarray analysis. Since clinical hepatotoxicity is one of the major causes of drug development attrition, the liver has been the best documented target organ for TGx studies to date, and we therefore focused on information from liver TGx studies. In this review, we summarize the current resources in the literature in regard to TGx studies of the liver, from which toxicologists could extract potential TGx biomarker gene sets for better hepatotoxicity risk assessment
Reversing Blood Flows Act through klf2a to Ensure Normal Valvulogenesis in the Developing Heart
Heart valve anomalies are some of the most common congenital heart defects, yet neither the genetic nor the epigenetic forces guiding heart valve development are well understood. When functioning normally, mature heart valves prevent intracardiac retrograde blood flow; before valves develop, there is considerable regurgitation, resulting in reversing (or oscillatory) flows between the atrium and ventricle. As reversing flows are particularly strong stimuli to endothelial cells in culture, an attractive hypothesis is that heart valves form as a developmental response to retrograde blood flows through the maturing heart. Here, we exploit the relationship between oscillatory flow and heart rate to manipulate the amount of retrograde flow in the atrioventricular (AV) canal before and during valvulogenesis, and find that this leads to arrested valve growth. Using this manipulation, we determined that klf2a is normally expressed in the valve precursors in response to reversing flows, and is dramatically reduced by treatments that decrease such flows. Experimentally knocking down the expression of this shear-responsive gene with morpholine antisense oligonucleotides (MOs) results in dysfunctional valves. Thus, klf2a expression appears to be necessary for normal valve formation. This, together with its dependence on intracardiac hemodynamic forces, makes klf2a expression an early and reliable indicator of proper valve development. Together, these results demonstrate a critical role for reversing flows during valvulogenesis and show how relatively subtle perturbations of normal hemodynamic patterns can lead to both major alterations in gene expression and severe valve dysgenesis
Intrinsic molecular subtypes of breast cancers categorized as HER2-positive using an alternative chromosome 17 probe assay
Abstract
The 2013 update of the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines recommend using an alternative chromosome 17 probe assay to resolve HER2 results determined to be equivocal by immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH). However, it is unclear if cases considered HER2-positive (HER2+) by the alternative probe method are similar to those classified as HER2+ by traditional IHC and FISH criteria and benefit the same from HER2-targeted therapies. We studied the clinical and pathologic features of all 31 breast cancers classified as HER2+ by the alternative probe method at our institution since 2013 and determined their PAM50 intrinsic molecular subtypes. For comparison, we analyzed 19 consecutive cases that were classified as HER2+ by traditional FISH criteria during the same time period. Thirty (97%) cancers in the alternative probe cohort were estrogen receptor (ER)-positive (ER+), while only 9/19 (47%) of traditional HER2 controls were ER+ (p = 0.0002). Sufficient tissue for intrinsic subtype analysis was available for 20/31 cancers in the alternative probe cohort and 9/19 in the traditional HER2+ group. None (0%) of the 20 alternative probe-positive cases were of the HER2-enriched intrinsic subtype, while 8/9 (89%) of those HER2+ by traditional FISH criteria were HER2-enriched (p = 0.0001). These findings suggest that breast cancers classified as HER2+ only by the alternative probe method are biologically distinct from those classified as HER2+ by traditional criteria, and raises questions as to whether or not they derive the same benefit from HER2-targeted therapies
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types
Identification of target genes of transcription factor activator protein 2 gamma in breast cancer cells
<p>Abstract</p> <p>Background</p> <p>Activator protein 2 gamma (AP-2γ) is a member of the transcription factor activator protein-2 (AP-2) family, which is developmentally regulated and plays a role in human neoplasia. AP-2γ has been found to be overexpressed in most breast cancers, and have a dual role to inhibit tumor initiation and promote tumor progression afterwards during mammary tumorigensis.</p> <p>Methods</p> <p>To identify the gene targets that mediate its effects, we performed chromatin immunoprecipitation (ChIP) to isolate AP-2γ binding sites on genomic DNA from human breast cancer cell line MDA-MB-453.</p> <p>Results</p> <p>20 novel DNA fragments proximal to potential AP-2γ targets were obtained. They are categorized into functional groups of carcinogenesis, metabolism and others. A combination of sequence analysis, reporter gene assays, quantitative real-time PCR, electrophoretic gel mobility shift assays and immunoblot analysis further confirmed the four AP-2γ target genes in carcinogenesis group: ErbB2, CDH2, HPSE and IGSF11. Our results were consistent with the previous reports that ErbB2 was the target gene of AP-2γ. Decreased expression and overexpression of AP-2γ in human breast cancer cells significantly altered the expression of these four genes, indicating that AP-2γ directly regulates them.</p> <p>Conclusion</p> <p>This suggested that AP-2γ can coordinate the expression of a network of genes, involving in carcinogenesis, especially in breast cancer. They could serve as therapeutic targets against breast cancers in the future.</p
VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC
A Heart-Hand Syndrome Gene: Tfap2b Plays a Critical Role in the Development and Remodeling of Mouse Ductus Arteriosus and Limb Patterning
BACKGROUND: Patent ductus arteriosus (PDA) is one of the most common forms of congenital heart disease. Mutations in transcription factor TFAP2B cause Char syndrome, a human disorder characterized by PDA, facial dysmorphysm and hand anomalies. Animal research data are needed to understand the mechanisms. The aim of our study was to elucidate the pathogenesis of Char syndrome at the molecular level. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression of Tfap2b during mouse development was studied, and newborns of Tfap2b-deficient mice were examined to identify phenotypes. Gel shift assays had been carried out to search for Tfap2 downstream genes. Promoters of candidate genes were cloned into a reporter construct and used to demonstrate their regulation by Tfap2b in cell transfection. In situ hybridizations showed that the murine transcription factor Tfap2b was expressed during the entire development of mouse ductus arteriosus. Histological examination of ductus arteriosus from Tfap2b knockout mice 6 hours after birth revealed that they were not closed. Consequently, the lungs of Tfap2b(-/-) mice demonstrated progressive congestion of the pulmonary capillaries, which was postulated to result secondarily from PDA. In addition, Tfap2b was expressed in the limb buds, particularly in the posterior limb field during development. Lack of Tfap2b resulted in bilateral postaxial accessory digits. Further study indicated that expressions of bone morphogenetic protein (Bmp) genes, which are reported to be involved in the limb patterning and ductal development, were altered in limb buds of Tfap2b-deficient embryos, due to direct control of Bmp2 and Bmp4 promoter activity by Tfap2b. CONCLUSIONS/SIGNIFICANCE: Tfap2b plays important roles in the development of mouse ductus arteriosus and limb patterning. Loss of Tfap2b results in altered Bmp expression that may cause the heart-limb defects observed in Tfap2b mouse mutants and Char syndrome patients. The Tfap2b knockout mouse may add to the very limited available animal models of PDA
Theory of Low-Mass Stars and Substellar Objects
Since the discovery of the first bona-fide brown dwarfs and extra-solar
planets in 1995, the field of low mass stars and substellar objects has
considerably progressed, both from theoretical and observational
viewpoints.Recent developments in the physics entering the modeling of these
objects have led to significant improvements in the theory and to a better
understanding of their mechanical and thermal properties. This theory can now
be confronted with observations directly in various observational diagrams
(color-color, color-magnitude, mass-magnitude, mass-spectral type), a stringent
and unavoidable constraint which became possible only recently, with the
generation of synthetic spectra. In this paper, we present the current
state-of-the-art general theory of low-mass stars and sub-stellar objects, from
one solar mass to one Jupiter mass, regarding primarily their interior
structure and evolution. This review is a natural complement to the previous
review on the atmosphere of low-mass stars and brown dwarfs (Allard et al
1997). Special attention is devoted to the comparison of the theory with
various available observations. The contribution of low-mass stellar and
sub-stellar objects to the Galactic mass budget is also analysed.Comment: 81 pages, Latex file, uses aasms4.sty, review for Annual Review of
Astronomy and Astrophysics, vol. 38 (2000
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