423 research outputs found
Iterative algorithms for monotone inclusion problems, fixed point problems and minimization problems
Prediction of lethal and synthetically lethal knock-outs in regulatory networks
The complex interactions involved in regulation of a cell's function are
captured by its interaction graph. More often than not, detailed knowledge
about enhancing or suppressive regulatory influences and cooperative effects is
lacking and merely the presence or absence of directed interactions is known.
Here we investigate to which extent such reduced information allows to forecast
the effect of a knock-out or a combination of knock-outs. Specifically we ask
in how far the lethality of eliminating nodes may be predicted by their network
centrality, such as degree and betweenness, without knowing the function of the
system. The function is taken as the ability to reproduce a fixed point under a
discrete Boolean dynamics. We investigate two types of stochastically generated
networks: fully random networks and structures grown with a mechanism of node
duplication and subsequent divergence of interactions. On all networks we find
that the out-degree is a good predictor of the lethality of a single node
knock-out. For knock-outs of node pairs, the fraction of successors shared
between the two knocked-out nodes (out-overlap) is a good predictor of
synthetic lethality. Out-degree and out-overlap are locally defined and
computationally simple centrality measures that provide a predictive power
close to the optimal predictor.Comment: published version, 10 pages, 6 figures, 2 tables; supplement at
http://www.bioinf.uni-leipzig.de/publications/supplements/11-01
Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness–a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer
A case–control study of selenium in nails and prostate cancer risk in British men
In view of the experimental evidence suggesting that the micronutrient selenium reduces prostate cancer risk, we investigated the association between the selenium level in fingernails, a measure of long-term selenium intake, and prostate cancer risk in a case-control study among 656 British men, conducted in 1989-1992. Nail clippings were taken at the time of recruitment and selenium concentration, measured using neutron activation techniques, was successfully assayed for 300 case-control pairs and varied six-fold among the controls (0.59 p.p.m.; interquartile range, 0.50-0.71 p.p.m.). Nail selenium concentration was not significantly associated with prostate cancer risk: men in the highest quartile of nail selenium had a slightly increased risk compared with men in the lowest quartile (OR 1.24, 95 CI, 0.73-2.10); for advanced prostate cancer, men in the highest quartile had a slightly reduced risk compared with men in the lowest quartile (OR 0.78, 95% CI, 0.27-2.25). These results suggest that selenium is not strongly associated with prostate cancer risk in British men
Evolving surface finite element method for the Cahn-Hilliard equation
We use the evolving surface finite element method to solve a Cahn- Hilliard equation on an evolving surface with prescribed velocity. We start by deriving the equation using a conservation law and appropriate transport for- mulae and provide the necessary functional analytic setting. The finite element method relies on evolving an initial triangulation by moving the nodes according to the prescribed velocity. We go on to show a rigorous well-posedness result for the continuous equations by showing convergence, along a subse- quence, of the finite element scheme. We conclude the paper by deriving error estimates and present various numerical examples
Effects of two common polymorphisms in the 3' untranslated regions of estrogen receptor β on mRNA stability and translatability
Estrogen signaling is mediated by estrogen receptors (ERs), ERα and ERβ. Aberrant
estrogen signaling is involved in breast cancer development. ERα is one of the key
biomarkers for diagnosis and treatment of breast cancer. Unlike ERα, ERβ is still not
introduced as a marker for diagnosis and established as a target of therapy. Numerous
studies suggest antiproliferative effects of ERβ, however its role remains to be fully
explored. Albeit important, ERα is not a perfect marker, and some aspects of ERα
function are still unclear. This thesis aims to characterize distinct molecular facets of
ER action relevant for breast cancer and provide valuable information for ER-based
diagnosis and treatment design.
In PAPER I, we analyzed the functionality of two common single
nucleotide polymorphisms in the 3’ untranslated regions of ERβ, rs4986938 and
rs928554, which have been extensively investigated for association with various
diseases. A significant difference in allelic expression was observed for rs4986938 in
breast tumor samples from heterozygous individuals. However, no difference in mRNA
stability or translatability between the alleles was observed.
In PAPER II, we provided a more comprehensive understanding of ERβ
function independent of ERα. A global gene expression analysis in a HEK293/ERβ cell
model identified a set of ERβ-regulated genes. Gene Ontology (GO) analysis showed
that they are involved in cell-cell signaling, morphogenesis and cell proliferation.
Moreover, ERβ expression resulted in a significant decrease in cell proliferation.
In PAPER III, using the human breast cancer MCF-7/ERβ cell model,
we demonstrated, for the first time, the binding of ERα/β heterodimers to various
DNA-binding regions in intact chromatin.
In PAPER IV, we investigated a potential cross-talk between estrogen
signaling and DNA methylation by identifying their common target genes in MCF-7
cells. Gene expression profiling identified around 150 genes regulated by both 17β-
estradiol (E2) and a hypomethylating agent 5-aza-2’-deoxycytidine. Based on GO
analysis, CpG island prediction analysis and previously reported ER binding regions,
we selected six genes for further analysis. We identified BTG3 and FHL2 as direct
target genes of both pathways. However, our data did not support a direct molecular
interplay of mediators of estrogen and epigenetic signaling at promoters of regulated
genes.
In PAPER V, we further explored the interactions between estrogen
signaling and DNA methylation, with focus on DNA methyltransferases (DNMT1,
DNMT3a and DNMT3b). E2, via ERα, up-regulated DNMT1 and down-regulated
DNMT3a and DNMT3b mRNA expression. Furthermore, DNMT3b interacted with
ERα. siRNA-mediated DNMT3b depletion increased the expression of two genes,
CDKN1A and FHL2. We proposed that the molecular mechanism underlying
regulation of FHL2 and CDKN1A gene expression involves interplay of DNMT3b and
ERα.
In conclusion, the studies presented in this thesis contribute to the knowledge of ERβ
function, and give additional insight into the cross-talk mechanisms underlying ERα
signaling with ERβ and with DNA methylation pathways
Theorems on existence and global dynamics for the Einstein equations
This article is a guide to theorems on existence and global dynamics of
solutions of the Einstein equations. It draws attention to open questions in
the field. The local-in-time Cauchy problem, which is relatively well
understood, is surveyed. Global results for solutions with various types of
symmetry are discussed. A selection of results from Newtonian theory and
special relativity that offer useful comparisons is presented. Treatments of
global results in the case of small data and results on constructing spacetimes
with prescribed singularity structure or late-time asymptotics are given. A
conjectural picture of the asymptotic behaviour of general cosmological
solutions of the Einstein equations is built up. Some miscellaneous topics
connected with the main theme are collected in a separate section.Comment: Submitted to Living Reviews in Relativity, major update of Living
Rev. Rel. 5 (2002)
Clinical significance of the nuclear receptor co-regulator DC-SCRIPT in breast cancer: an independent retrospective validation study
Contains fulltext :
88921.pdf (publisher's version ) (Open Access
Turnover of BRCA1 Involves in Radiation-Induced Apoptosis
Background: Germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) increase the susceptibility to tumorigenesis. The function of BRCA1 is to regulate critical cellular processes, including cell cycle progression, genomic integrity, and apoptosis. Studies on the regulation of BRCA1 have focused intensely on transcription and phosphorylation mechanisms. Proteolytic regulation of BRCA1 in response to stress signaling remains largely unknown. The manuscript identified a novel mechanism by which BRCA1 is regulated by the ubiquitin-dependent degradation in response to ionization. Methodology/Principal Findings: Here, we report that severe ionization triggers rapid degradation of BRCA1, which in turn results in the activation of apoptosis. Ionization-induced BRCA1 turnover is mediated via an ubiquitin-proteasomal pathway. The stabilization of BRCA1 significantly delays the onset of ionization-induced apoptosis. We have mapped the essential region on BRCA1, which mediates its proteolysis in response to ionization. Moreover, we have demonstrated that BRCA1 protein is most sensitive to degradation when ionization occurs during G2/M and S phase. Conclusions/Significance: Our results suggest that ubiquitin-proteasome plays an important role in regulating BRCA1 during genotoxic stress. Proteolytic regulation of BRCA1 involves in ionization-induced apoptosis. © 2010 Liu et al
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