Increased entropy of signal transduction in the cancer metastasis phenotype

Studies into the statistical properties of biological networks have led to important biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis. Further exploration of such integrated cancer expression and protein interaction networks will therefore be a fruitful endeavour.Comment: 5 figures, 2 Supplementary Figures and Table

Trapped lipopolysaccharide and LptD intermediates reveal lipopolysaccharide translocation steps across the Escherichia coli outer membrane

Lipopolysaccharide (LPS) is a main component of the outer membrane of Gram-negative bacteria, which is essential for the vitality of most Gram-negative bacteria and plays a critical role for drug resistance. LptD/E complex forms a N-terminal LPS transport slide, a hydrophobic intramembrane hole and the hydrophilic channel of the barrel, for LPS transport, lipid A insertion and core oligosaccharide and O-antigen polysaccharide translocation, respectively. However, there is no direct evidence to confirm that LptD/E transports LPS from the periplasm to the external leaflet of the outer membrane. By replacing LptD residues with an unnatural amino acid p-benzoyl-L-phenyalanine (pBPA) and UV-photo-cross-linking in E.coli, the translocon and LPS intermediates were obtained at the N-terminal domain, the intramembrane hole, the lumenal gate, the lumen of LptD channel, and the extracellular loop 1 and 4, providing the first direct evidence and “snapshots” to reveal LPS translocation steps across the outer membrane

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Identification of disease-causing genes using microarray data mining and gene ontology

Background: One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes. Methods: We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results. Results: The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth. Conclusions: The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers

Dilepton production in proton-proton collisions at BEVALAC energies

The dilepton production in elementary ${pp\to e^{+}e^{-}X}$ reactions at BEVALAC energies $T_{lab}=1\div 5$ GeV is investigated. The calculations include direct ${e^{+}e^{-}}$ decays of the vector mesons $\rho ^{0}$, $\omega$, and $\phi$, Dalitz decays of the $\pi ^{0}$-, $\eta$-, $$-, $\omega$-, and $\phi$-mesons, and of the baryon resonances $$ $...$ . The subthreshold vector meson production cross sections in $pp$ collisions are treated in a way sufficient to avoid double counting with the inclusive vector meson production. The vector meson dominance model for the transition form factors of the resonance Dalitz decays $R\to e^{+}e^{-}N$ is used in an extended form to ensure correct asymptotics which are in agreement with the quark counting rules. Such a modification gives an unified and consistent description of both $R\to N\gamma$ radiative decays and $R\to N\rho (\omega)$ meson decays. The effect of multiple pion production on the experimental efficiency for the detection of the dilepton pairs is studied. We find the dilepton yield in reasonable agreement with the experimental data for the set of intermediate energies whereas at the highest energy $T_{lab}=4.88$ GeV the number of dilepton pairs is likely to be overestimated experimentally in the mass range $M=300\div 700$ MeV.Comment: 25 pages (IOP style), 5 figures, revised manuscript accepted for publication in JP

Nonclassical Fields and the Nonlinear Interferometer

We demonstrate several new results for the nonlinear interferometer, which emerge from a formalism which describes in an elegant way the output field of the nonlinear interferometer as two-mode entangled coherent states. We clarify the relationship between squeezing and entangled coherent states, since a weak nonlinear evolution produces a squeezed output, while a strong nonlinear evolution produces a two-mode, two-state entangled coherent state. In between these two extremes exist superpositions of two-mode coherent states manifesting varying degrees of entanglement for arbitrary values of the nonlinearity. The cardinality of the basis set of the entangled coherent states is finite when the ratio $\chi / \pi$ is rational, where $\chi$ is the nonlinear strength. We also show that entangled coherent states can be produced from product coherent states via a nonlinear medium without the need for the interferometric configuration. This provides an important experimental simplification in the process of creating entangled coherent states.Comment: 21 pages, 2 figure

Performance Analysis of Orthogonal Pairs Designed for an Expanded Eukaryotic Genetic Code

Background: The suppression of amber stop codons with non-canonical amino acids (ncAAs) is used for the site-specific introduction of many unusual functions into proteins. Specific orthogonal aminoacyl-tRNA synthetase (o-aaRS)/amber suppressor tRNA CUA pairs (o-pairs) for the incorporation of ncAAs in S. cerevisiae were previously selected from an E. coli tyrosyl-tRNA synthetase/tRNACUA mutant library. Incorporation fidelity relies on the specificity of the o-aaRSs for their ncAAs and the ability to effectively discriminate against their natural substrate Tyr or any other canonical amino acid. Methodology/Principal Findings: We used o-pairs previously developed for ncAAs carrying reactive alkyne-, azido-, or photocrosslinker side chains to suppress an amber mutant of human superoxide dismutase 1 in S. cerevisiae. We found worse incorporation efficiencies of the alkyne- and the photocrosslinker ncAAs than reported earlier. In our hands, amber suppression with the ncAA containing the azido group did not occur at all. In addition to the incorporation experiments in S. cerevisiae, we analyzed the catalytic properties of the o-aaRSs in vitro. Surprisingly, all o-aaRSs showed much higher preference for their natural substrate Tyr than for any of the tested ncAAs. While it is unclear why efficiently recognized Tyr is not inserted at amber codons, we speculate that metabolically inert ncAAs accumulate in the cell, and for this reason they are incorporated despite being weak substrates for the o-aaRSs. Conclusions/Significance: O-pairs have been developed for a whole plethora of ncAAs. However, a systematic and detaile

A prospective cohort study to investigate parental stress and child health in low-income Chinese families: protocol paper

Introduction Chronic stress has adverse effects on health. Adults and children from low-income families are subject to multiple sources of stress. Existing literature about economic hardship mostly focuses on either adults or children but not both. Moreover, there is limited knowledge on the relationship between parental generalised stress and child health problems. This study aims to explore the bidirectional relationship between parental stress and child health in Chinese low-income families and to identify other modifiable factors influencing this relationship. Methods and analysis This prospective cohort study will sample 254 low-income parent–child pairs and follow them up for 24 months with assessments at three time points (baseline, 12 and 24 months) on parental stress, health-related quality of life (HRQOL) and child health and behaviour using both subjective measures and objective physiological parameters. This study will collect data using standardised measures on HRQOL and behaviours of children as well as on HRQOL, mental health and stress levels of parents along with physiological tests of allostatic load and telomere length. The mediating or moderating effect of family harmony, parenting style and neighbourhood conditions will also be assessed. Data will be analysed using latent growth modelling and cross-lagged path analysis modelling to examine the bidirectional effect of parental stress and child health over time. Mediation and moderation analysis will also be conducted to examine the mechanism by which the variables relate. Ethics and dissemination This study was approved by the institutional review board of the University of Hong Kong—the Hospital Authority Hong Kong West Cluster, reference no: UW 16-415. The study findings will be disseminated through peer-reviewed publications and international conferences.published_or_final_versio