Phase diagram of the two-chain Hubbard model

We have calculated the charge gap and spin gap for the two-chain Hubbard model as a function of the on-site Coulomb interaction and the interchain hopping amplitude. We used the density matrix renormalization group method and developed a method to calculate separately the gaps numerically for the symmetric and antisymmetric modes with respect to the exchange of the chain indices. We have found very different behaviors for the weak and strong interaction cases. Our calculated phase diagram is compared to the one obtained by Balents and Fisher using the weak coupling renormalization group technique.Comment: 4 pages, 6 figures, to appear in PR

Time lagged information theoretic approaches to the reverse engineering of gene regulatory networks

Background: A number of models and algorithms have been proposed in the past for gene regulatory network (GRN) inference; however, none of them address the effects of the size of time-series microarray expression data in terms of the number of time-points. In this paper, we study this problem by analyzing the behaviour of three algorithms based on information theory and dynamic Bayesian network (DBN) models. These algorithms were implemented on different sizes of data generated by synthetic networks. Experiments show that the inference accuracy of these algorithms reaches a saturation point after a specific data size brought about by a saturation in the pair-wise mutual information (MI) metric; hence there is a theoretical limit on the inference accuracy of information theory based schemes that depends on the number of time points of micro-array data used to infer GRNs. This illustrates the fact that MI might not be the best metric to use for GRN inference algorithms. To circumvent the limitations of the MI metric, we introduce a new method of computing time lags between any pair of genes and present the pair-wise time lagged Mutual Information (TLMI) and time lagged Conditional Mutual Information (TLCMI) metrics. Next we use these new metrics to propose novel GRN inference schemes which provides higher inference accuracy based on the precision and recall parameters. Results: It was observed that beyond a certain number of time-points (i.e., a specific size) of micro-array data, the performance of the algorithms measured in terms of the recall-to-precision ratio saturated due to the saturation in the calculated pair-wise MI metric with increasing data size. The proposed algorithms were compared to existing approaches on four different biological networks. The resulting networks were evaluated based on the benchmark precision and recall metrics and the results favour our approach. Conclusions: To alleviate the effects of data size on information theory based GRN inference algorithms, novel time lag based information theoretic approaches to infer gene regulatory networks have been proposed. The results show that the time lags of regulatory effects between any pair of genes play an important role in GRN inference schemes

Local Network Topology in Human Protein Interaction Data Predicts Functional Association

The use of high-throughput techniques to generate large volumes of protein-protein interaction (PPI) data has increased the need for methods that systematically and automatically suggest functional relationships among proteins. In a yeast PPI network, previous work has shown that the local connection topology, particularly for two proteins sharing an unusually large number of neighbors, can predict functional association. In this study we improved the prediction scheme by developing a new algorithm and applied it on a human PPI network to make a genome-wide functional inference. We used the new algorithm to measure and reduce the influence of hub proteins on detecting function-associated protein pairs. We used the annotations of the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) as benchmarks to compare and evaluate the function relevance. The application of our algorithms to human PPI data yielded 4,233 significant functional associations among 1,754 proteins. Further functional comparisons between them allowed us to assign 466 KEGG pathway annotations to 274 proteins and 123 GO annotations to 114 proteins with estimated false discovery rates of <21% for KEGG and <30% for GO. We clustered 1,729 proteins by their functional associations and made functional inferences from detailed analysis on one subcluster highly enriched in the TGF-β signaling pathway (P<10−50). Analysis of another four subclusters also suggested potential new players in six signaling pathways worthy of further experimental investigations. Our study gives clear insight into the common neighbor-based prediction scheme and provides a reliable method for large-scale functional annotation in this post-genomic era

Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia

The epigenetic impact of DNA methylation in chronic myelogenous leukemia (CML) is not completely understood. To elucidate its role we analyzed 120 patients with CML for methylation of promoter-associated CpG islands of 10 genes. Five genes were identified by DNA methylation screening in the K562 cell line and 3 genes in patients with myeloproliferative neoplasms. The CDKN2B gene was selected for its frequent methylation in myeloid malignancies and ABL1 as the target of BCR-ABL translocation. Thirty patients were imatinib-naïve (mostly treated by interferon-alpha before the imatinib era), 30 were imatinib-responsive, 50 were imatinib-resistant, and 10 were imatinib-intolerant. We quantified DNA methylation by bisulfite pyrosequencing. The average number of methylated genes was 4.5 per patient in the chronic phase, increasing significantly to 6.2 in the accelerated and 6.4 in the blastic phase. Higher numbers of methylated genes were also observed in patients resistant or intolerant to imatinib. These patients also showed almost exclusive methylation of a putative transporter OSCP1. Abnormal methylation of a Src suppressor gene PDLIM4 was associated with shortened survival independently of CML stage and imatinib responsiveness. We conclude that aberrant DNA methylation is associated with CML progression and that DNA methylation could be a marker associated with imatinib resistance. Finally, DNA methylation of PDLIM4 may help identify a subset of CML patients that would benefit from treatment with Src/Abl inhibitors

Dynamic Status of REST in the Mouse ESC Pluripotency Network

<div><h3>Background</h3><p>REST is abundantly expressed in mouse embryonic stem cells (ESCs). Many genome-wide analyses have found REST to be an integral part of the ESC pluripotency network. However, experimental systems have produced contradictory findings: (1) REST is required for the maintenance of ESC pluripotency and loss of REST causes increased expression of differentiation markers, (2) REST is not required for the maintenance of ESC pluripotency and loss of REST does not change expression of differentiation markers, and (3) REST is not required for the maintenance of ESC pluripotency but loss of REST causes decreased expression of differentiation markers. These reports highlight gaps in our knowledge of the ESC network.</p> <h3>Methods</h3><p>Employing biochemical and genome-wide analyses of various culture conditions and ESC lines, we have attempted to resolve some of the discrepancies in the literature.</p> <h3>Results</h3><p>We show that Rest+/− and Rest−/− AB-1 mutant ESCs, which did not exhibit a role of REST in ESC pluripotency when cultured in the presence of feeder cells, did show impaired self-renewal when compared with the parental cells under feeder-free culture conditions, but only in early passage cells. In late passage cells, both Rest+/− and Rest−/− AB-1 ESCs restored pluripotency, suggesting a passage and culture condition-dependent response. Genome-wide analysis followed by biochemical validation supported this response and further indicated that the restoration of pluripotency was associated by increased expression of the ESC pluripotency factors. E14Tg2a.4 ESCs with REST-knockdown, which earlier showed a REST-dependent pluripotency when cultured under feeder-free conditions, as well as Rest−/− AB-1 ESCs, showed no REST-dependent pluripotency when cultured in the presence of either feeder cells or laminin, indicating that extracellular matrix components can rescue REST's role in ESC pluripotency.</p> <h3>Conclusions</h3><p>REST regulates ESC pluripotency in culture condition- and ESC line-dependent fashion and ESC pluripotency needs to be evaluated in a context dependent manner.</p> </div

Extracellular cues provided by feeder cells compensate for REST-mediated loss of self-renewal and pluripotency in E14Tg2a.4 ESCs.

<p>(A,B) Rest Mediated pluripotency is influenced by extracellular environment in E14Tg2a.4 ESCs. (A) MEF feeder cells and (B) the extracellular matrix component, laminin, countered lowered self-renewal in E14Tg2a.4 ESCs treated with siRNA mediated knockdown of REST (siRest). Percentages of self-renewing colonies in ES, NT and siRest treated cells after alkaline phosphatase assay are shown for each conditions (as labeled on x-axis). Both MEF and laminin condition resulted in maintenance of self-renewal compared to gelatin condition after siRest treatment. Number above bars are p-values (n = 3). Error bars are standard error of means. (C) Laminin maintains the expression of pluripotent markers in siRest treated E14Tg2a.4 ESCs. ESCs transfected with siRest or NT were plated on gelatin- or laminin-coated surfaces and were analyzed by QRT-PCR assays to determine the expression levels of Sox2, Nanog, and Oct4 transcripts. Number above bars are p-values (n = 3). Error bars are standard error of means. (D,E) Laminin counters lowered self-renewal and pluripotency due to loss of REST in shRest-mediated stable knock-down of REST in ESCs. (D) shRest lowered self-renewal when cells were cultured on gelatin but not on laminin. Percentages of self-renewing colonies in shRest and NT cells are shown for each conditions (as labeled on x-axis). Number above bars are p-values (n = 3). Error bars are standard error of means. (E) Stable shRest lines, when compared to shNT lines, of ESCs showed decreased levels of REST proteins when the cells were cultured either on gelatin or on laminin; however, the levels of Sox2, Nanog, and Oct4 were decreased only when cells were cultured on gelatin but not laminin.</p

Rest+/− and Rest−/− AB-1 ESCs cultured in the absence of feeder cells show impaired self-renewal that is restored upon prolonged culture.

<p>(A, B) Alkaline phosphatase based self-renewal assay shows that the self-renewal efficiency of the N9 (Rest^+/−) and N8 (Rest^−/−) ESCs was significantly lower than that of the parental AB-1 ESCs at passage 2 but not at passage 10. (A) quantification of self-renewal assays. (B) representative pictures of colonies from self-renewal assays. The numbers under the lines show p-values (n = 3). Error bars are standard error of means. Cells were cultured in absence of feeder cells and in presence of LIF. (C) Venn diagram showing comparison of genes that showed a significant change in expression during the transition between passage 2 and passage 10 by genome-wide expression profiling. N9 (Rest^+/−) and N8 (Rest^−/−) cells showed significant changes in gene expression (N9 ∼965 and N8 ∼1296) compared to WT cells (∼65). (D, E, F and G) Heat map showing comparison of 50 genes with the highest fold changes that were either (D and F) up-regulated or (E and G) down-regulated in Rest+/− and Rest−/− cells during the transition from passage 2 to passage 10 to the expression of these genes in ES and differentiating cells based on FunGenES database.</p

Comparison of expression levels of genes for WT (N6), N9 (Rest^+/−) and N8 (Rest^−/−) during the transition between passage 2 and passage 10 when cultured on gelatin.

<p>Decreased expression (−ve values); increased expression (+ve values).</p