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  • 1
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    Pervasive epistasis for complex traits [Genetics] (2012)
    National Academy of Sciences
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    Publication Date: 2012-09-26
    Description: Epistasis—nonlinear genetic interactions between polymorphic loci—is the genetic basis of canalization and speciation, and epistatic interactions can be used to infer genetic networks affecting quantitative traits. However, the role that epistasis plays in the genetic architecture of quantitative traits is controversial. Here, we compared the genetic architecture of three Drosophila...
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Urothelial tumor initiation requires deregulation of multiple signaling pathways: implications in target-based therapies (2012)
    Oxford University Press
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    Publication Date: 2012-04-06
    Description: Although formation of urothelial carcinoma of the bladder (UCB) requires multiple steps and proceeds along divergent pathways, the underlying genetic and molecular determinants for each step and pathway remain undefined. By developing transgenic mice expressing single or combinatorial genetic alterations in urothelium, we demonstrated here that overcoming oncogene-induced compensatory tumor barriers was critical for urothelial tumor initiation. Constitutively active Ha-ras (Ras*) elicited urothelial hyperplasia that was persistent and did not progress to tumors over a 10 months period. This resistance to tumorigenesis coincided with increased expression of p53 and all pRb family proteins. Expression of a Simian virus 40 T antigen (SV40T), which disables p53 and pRb family proteins, in urothelial cells expressing Ras* triggered early-onset, rapidly-growing and high-grade papillary UCB that strongly resembled the human counterpart (pTaG3). Urothelial cells expressing both Ras* and SV40T had defective G 1 /S checkpoint, elevated Ras-GTPase and hyperactivated AKT-mTOR signaling. Inhibition of the AKT-mTOR pathway with rapamycin significantly reduced the size of high-grade papillary UCB but hyperactivated mitogen-activated protein kinase (MAPK). Inhibition of AKT-mTOR, MAPK and STAT3 altogether resulted in much greater tumor reduction and longer survival than did inhibition of AKT-mTOR pathway alone. Our studies provide the first experimental evidence delineating the combinatorial genetic events required for initiating high-grade papillary UCB, a poorly defined and highly challenging clinical entity. Furthermore, they suggest that targeted therapy using a single agent such as rapamycin may not be highly effective in controlling high-grade UCB and that combination therapy employing inhibitors against multiple targets are more likely to achieve desirable therapeutic outcomes.
    Print ISSN: 0143-3334
    Electronic ISSN: 1460-2180
    Topics: Medicine
    Published by Oxford University Press
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  • 3
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    Inclination shallowing in Eocene Linzizong sedimentary rocks from Southern Tibet: correction, possible causes and implications for reconstructing the India-Asia collision (2013)
    Oxford University Press
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    Publication Date: 2013-08-13
    Description: A systematic bias towards low palaeomagnetic inclination recorded in clastic sediments, that is, inclination shallowing, has been recognized and studied for decades. Identification, understanding and correction of this inclination shallowing are critical for palaeogeographic reconstructions, particularly those used in climate models and to date collisional events in convergent orogenic systems, such as those surrounding the Neotethys. Here we report palaeomagnetic inclinations from the sedimentary Eocene upper Linzizong Group of Southern Tibet that are ~20° lower than conformable underlying volcanic units. At face value, the palaeomagnetic results from these sedimentary rocks suggest the southern margin of Asia was located ~10°N, which is inconsistent with recent reviews of the palaeolatitude of Southern Tibet. We apply two different correction methods to estimate the magnitude of inclination shallowing independently from the volcanics. The mean inclination is corrected from 20.5° to 40.0° within 95 per cent confidence limits between 33.1° and 49.5° by the elongation/inclination ( E / I ) correction method; an anisotropy-based inclination correction method steepens the mean inclination to 41.3 ± 3.3° after a curve fitting- determined particle anisotropy of 1.39 is applied. These corrected inclinations are statistically indistinguishable from the well-determined 40.3 ± 4.5º mean inclination of the underlying volcanic rocks that provides an independent check on the validity of these correction methods. Our results show that inclination shallowing in sedimentary rocks can be corrected. Careful inspection of stratigraphic variations of rock magnetic properties and remanence anisotropy suggests shallowing was caused mainly by a combination of syn- and post-depositional processes such as particle imbrication and sedimentary compaction that vary in importance throughout the section. Palaeolatitudes calculated from palaeomagnetic directions from Eocene sedimentary rocks of the upper Linzizong Group that have corrected for inclination shallowing are consistent with palaeolatitude history of the Lhasa terrane, and suggest that the India–Asia collision began at ~20°N by 45–55 Ma.
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 4
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    A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer (2013)
    Oxford University Press
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    Publication Date: 2013-06-25
    Description: Background A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Patients and methods Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1–2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m 2 as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored. Results Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%). Conclusions This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer.
    Print ISSN: 0923-7534
    Electronic ISSN: 1569-8041
    Topics: Medicine
    Published by Oxford University Press
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  • 5
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    (-)-Epigallocatechin-3-gallate, a potential inhibitor to human dicarbonyl/L-xylulose reductase (2013)
    Oxford University Press
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    Publication Date: 2013-07-24
    Description: Dicarbonyl/ l -xylulose reductase (DCXR), mainly catalysing the reduction of α-dicarbonyl compounds and l -xylulose, belongs to the short-chain dehydrogenase/reductase superfamily. Its enzyme activity can be inhibited by short-chain fatty acids. In this study, a novel DCXR inhibitor named (–)-epigallocatechin-3-gallate (EGCG) was reported. First, we overexpressed recombinant human DCXR in Escherichia coli , purified the enzyme by affinity chromatography and measured its activity. The inhibition effects of EGCG and its analogues on DCXR were determined subsequently, and EGCG showed the strongest inhibition with 50% inhibition concentration value of 78.8 μM. The surface plasmon resonance analysis also indicated that the equilibrium dissociation constant ( K D ) reached to 7.11 x 10 –8 M, which implied a high affinity between EGCG and DCXR. From enzyme kinetic analysis, EGCG acted as a mixed inhibitor against its forward and reverse substrates and the coenzyme, reduced nicotinamide adenine dinucleotide phosphate (NADPH). However, the inhibition is pH dependent. The molecular docking finally showed that EGCG formed several hydrogen bonds with the Thr190 residue of DCXR, and the model was further verified by site-directed mutagenesis. Therefore, EGCG is a potential inhibitor to human DCXR.
    Print ISSN: 0021-924X
    Electronic ISSN: 1756-2651
    Topics: Biology , Chemistry and Pharmacology
    Published by Oxford University Press on behalf of The Japanese Biochemical Society (JBS).
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  • 6
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    An Update of DIVERGE Software for Functional Divergence Analysis of Protein Family (2013)
    Oxford University Press
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    Publication Date: 2013-06-19
    Description: DIVERGE is a software system for phylogeny-based analyses of protein family evolution and functional divergence. It provides a suite of statistical tools for selection and prioritization of the amino acid sites that are responsible for the functional divergence of a gene family. The synergistic efforts of DIVERGE and other methods have convincingly demonstrated that the pattern of rate change at a particular amino acid site may contain insightful information about the underlying functional divergence following gene duplication. These predicted sites may be used as candidates for further experiments. We are now releasing an updated version of DIVERGE with the following improvements: 1) a feasible approach to examining functional divergence in nearly complete sequences by including deletions and insertions (indels); 2) the calculation of the false discovery rate of functionally diverging sites; 3) estimation of the effective number of functional divergence-related sites that is reliable and insensitive to cutoffs; 4) a statistical test for asymmetric functional divergence; and 5) a new method to infer functional divergence specific to a given duplicate cluster. In addition, we have made efforts to improve software design and produce a well-written software manual for the general user.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis (2013)
    Oxford University Press
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    Publication Date: 2013-07-26
    Description: Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174 - ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3–13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 ( P combined 〈 5 x 10 –8 ). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    MethHC: a database of DNA methylation and gene expression in human cancer (2015)
    Oxford University Press
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    Publication Date: 2015-01-16
    Description: We present MethHC ( http://MethHC.mbc.nctu.edu.tw ), a database comprising a systematic integration of a large collection of DNA methylation data and mRNA/microRNA expression profiles in human cancer. DNA methylation is an important epigenetic regulator of gene transcription, and genes with high levels of DNA methylation in their promoter regions are transcriptionally silent. Increasing numbers of DNA methylation and mRNA/microRNA expression profiles are being published in different public repositories. These data can help researchers to identify epigenetic patterns that are important for carcinogenesis. MethHC integrates data such as DNA methylation, mRNA expression, DNA methylation of microRNA gene and microRNA expression to identify correlations between DNA methylation and mRNA/microRNA expression from TCGA (The Cancer Genome Atlas), which includes 18 human cancers in more than 6000 samples, 6548 microarrays and 12 567 RNA sequencing data.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Time-variant clustering for cell fate decision [Systems Biology] (2014)
    National Academy of Sciences
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    Publication Date: 2014-11-05
    Description: Both spatial characteristics and temporal features are often the subjects of concern in physical, social, and biological studies. This work tackles the clustering problems for time course data in which the cluster number and clustering structure change with respect to time, dubbed time-variant clustering. We developed a hierarchical model that...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 10
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    Association Between Changes in Exposure to Air Pollution and Biomarkers of Oxidative Stress in Children Before and During the Beijing Olympics (2015)
    Oxford University Press
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    Publication Date: 2015-04-08
    Description: It is not known whether exposure to air pollutants causes systemic oxidative stress in children. We investigated the association between exposure to air pollution and biomarkers of oxidative stress in relation to a governmental air quality intervention implemented during the 2008 Beijing Olympic Games. We studied 36 schoolchildren during 5 time periods before and during the Olympic Games in Beijing (June 2007–September 2008). The oxidative stress biomarkers 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and malondialdehyde were measured in urine samples collected daily during each period. Generalized estimating equations were used to examine the relationship between repeated biomarker measurements and ambient air pollutant levels. During the Olympic intervention period, substantial reductions in air pollution (–19% to –72%), urinary 8-oxodG concentrations (–37.4%; 95% confidence interval: –53.5, –15.7), and urinary malondialdehyde concentrations (–25.3%; 95% confidence interval: –34.3, –15.1) were found. Malondialdehyde and 8-oxodG were significantly associated with concentrations of black carbon, fine particulate matter with an aerodynamic with diameter less than 2.5 μm, sulfur dioxide, nitrogen dioxide, and carbon monoxide. Biomarker changes per each interquartile-range increase in pollutants were largest at lag 0 or lag 1. In a 2-pollutant model, the most robust associations were for black carbon. These findings suggest that exposure to black carbon leads to systemic oxidative stress in children.
    Print ISSN: 0002-9262
    Electronic ISSN: 1476-6256
    Topics: Medicine
    Published by Oxford University Press
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