Ju Wang

Background: The p53 tumor suppressor and its related protein, p73, share a homologous DNA binding domain, and mouse genetics studies have suggested that they have overlapping as well as distinct biological functions. Both p53 and p73 are activated by genotoxic stress to regulate an array of cellular responses. Previous studies have suggested that p53 and p73 independently activate the cellular apoptotic program in response to cytotoxic drugs. The goal of this study was to compare the promoter-binding activity of p53 and p73 at steady state and after genotoxic stress induced by hydroxyurea. Results: We employed chromatin immunoprecipitation, the NimbleGen promoter arrays and a model-based algorithm for promoter arrays to identify promoter sequences enriched in anti-p53 or anti-p73 immunoprecipitates, either before or after treatment with hydroxyurea, which increased the expression of both p53 and p73 in the human colon cancer cell line HCT116-3. We calculated a model-based algorithm for promoter array score for each promoter and found a significant correlation between the promoter occupancy profiles of p53 and p73. We also found that after hydroxyurea treatment, the p53-bound promoters were still bound by p73, but p73 became associated with additional promoters that that did not bind p53. In particular, we showed that hydroxyurea induces the binding of p73 but not p53 to the promoter of MLH3, which encodes a mismatch repair protein, and causes an up-regulation of the MLH3 mRNA. Conclusion: These results suggest that hydroxyurea exerts differential effects on the promoter-binding functions of p53 and p73 and illustrate the power of model-based algorithm for promoter array in the analyses of promoter occupancy profiles of highly homologous transcription factors. © 2009 Huang et al; licensee BioMed Central Ltd.

Background: High throughput screens with RNA interference technology enable loss-of-function analyses of gene activities in mammalian cells. While the construction of genome-scale shRNA libraries has been successful, results of large-scale screening of those libraries can be difficult to analyze because of the relatively high noise levels and the fact that not all shRNAs in a library are equally effective in silencing gene expression. Results: We have screened a library consisting of 43,828 shRNAs directed against 8,500 human genes for functions that are necessary in cell detachment induced by a constitutively activated c-Abl tyrosine kinase. To deal with the issues of noise and uncertainty of knockdown efficiencies, we employed an analytical strategy that combines quantitative data analysis with biological knowledge, i.e. Gene Ontology and pathway information, to increase the power of the RNAi screening technique. Using this strategy we found 16 candidate genes to be involved in Abl-induced disruption of cell adhesion, and verified that the knockdown of IL6ST is associated with enhanced cell attachment. Conclusion: Our results suggest that the power of genome-wide quantitative shRNA screens can be significantly increased when analyzed using a systems biology-based approach to identify functional gene networks. © 2008 Huang et al; licensee BioMed Central Ltd.

In contemporary epistemology, sceptical arguments are motivated either by the closure principle or the underdetermination principle. Therefore, it is very important to figure out the structure of the sceptical argument before coming up with an anti-sceptic strategy. With a review of the debate on the relationship between the two principles from Anthony Brueckner to Kevin McCain, it is argued that while maintaining the weak closed justification , closure and underdetermination are not logically equivalent. As a result, two independent responses are needed to answer the sceptical problem satisfactorily. Also, in order to secure a philosophically significant notion of justification and evidence, reasons are given to hold WCJ*, as opposed to rejecting it. This understanding of the sceptical argument would help to focus the real challenge of scepticism

In this paper, I attempt to show how Davidson’s anti-sceptical argument can respond to the closureRK-based radical scepticism. My approach will focus on the closureRK principle rather than the possibility that our beliefs could be massively wrong. I first review Davidson’s principle of charity and the triangulation argument, and then I extract his theory on content of a belief. According to this theory, content of a belief is determined by its typical cause and other relevant beliefs. With this constraint on content, I argue that doubt must be local. Furthermore, since one cannot rationally believe that one’s commitment to the cause of beliefs could be false, our commitment to the denial of a sceptical hypothesis is not a knowledge-apt belief. Therefore, the closureRK principle is not applicable to rational evaluations of this commitment. As a result, the closureRK-based sceptical argument fails while the closureRK principle remains.