On the complexity of color-avoiding site and bond percolation

The mathematical analysis of robustness and error-tolerance of complex networks has been in the center of research interest. On the other hand, little work has been done when the attack-tolerance of the vertices or edges are not independent but certain classes of vertices or edges share a mutual vulnerability. In this study, we consider a graph and we assign colors to the vertices or edges, where the color-classes correspond to the shared vulnerabilities. An important problem is to find robustly connected vertex sets: nodes that remain connected to each other by paths providing any type of error (i.e. erasing any vertices or edges of the given color). This is also known as color-avoiding percolation. In this paper, we study various possible modeling approaches of shared vulnerabilities, we analyze the computational complexity of finding the robustly (color-avoiding) connected components. We find that the presented approaches differ significantly regarding their complexity.Comment: 14 page

A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies

A promising direction in drug development is to exploit the ability of natural killer cells to kill antibody-labeled target cells. Monoclonal antibodies and drugs designed to elicit this effect typically bind cell-surface epitopes that are overexpressed on target cells but also present on other cells. Thus it is important to understand adhesion of cells by antibodies and similar molecules. We present an equilibrium model of such adhesion, incorporating heterogeneity in target cell epitope density and epitope immobility. We compare with experiments on the adhesion of Jurkat T cells to bilayers containing the relevant natural killer cell receptor, with adhesion mediated by the drug alefacept. We show that a model in which all target cell epitopes are mobile and available is inconsistent with the data, suggesting that more complex mechanisms are at work. We hypothesize that the immobile epitope fraction may change with cell adhesion, and we find that such a model is more consistent with the data. We also quantitatively describe the parameter space in which binding occurs. Our results point toward mechanisms relating epitope immobility to cell adhesion and offer insight into the activity of an important class of drugs.Comment: 13 pages, 5 figure

Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

Cross-Platform Comparison of Microarray-Based Multiple-Class Prediction

High-throughput microarray technology has been widely applied in biological and medical decision-making research during the past decade. However, the diversity of platforms has made it a challenge to re-use and/or integrate datasets generated in different experiments or labs for constructing array-based diagnostic models. Using large toxicogenomics datasets generated using both Affymetrix and Agilent microarray platforms, we carried out a benchmark evaluation of cross-platform consistency in multiple-class prediction using three widely-used machine learning algorithms. After an initial assessment of model performance on different platforms, we evaluated whether predictive signature features selected in one platform could be directly used to train a model in the other platform and whether predictive models trained using data from one platform could predict datasets profiled using the other platform with comparable performance. Our results established that it is possible to successfully apply multiple-class prediction models across different commercial microarray platforms, offering a number of important benefits such as accelerating the possible translation of biomarkers identified with microarrays to clinically-validated assays. However, this investigation focuses on a technical platform comparison and is actually only the beginning of exploring cross-platform consistency. Further studies are needed to confirm the feasibility of microarray-based cross-platform prediction, especially using independent datasets

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Establishment of a New Cell Line from Lepidopteran Epidermis and Hormonal Regulation on the Genes

When an insect molts, old cuticle on the outside of the integument is shed by apolysis and a new cuticle is formed under the old one. This process is completed by the epidermal cells which are controlled by 20-hydroxyecdysone (20E) and juvenile hormone. To understand the molecular mechanisms of integument remolding and hormonal regulation on the gene expression, an epidermal cell line from the 5th instar larval integument of Helicoverpa armigera was established and named HaEpi. The cell line has been cultured continuously for 82 passages beginning on June 30, 2005 until now. Cell doubling time was 64 h. The chromosomes were granular and the chromosome mode was from 70 to 76. Collagenase I was used to detach the cells from the flask bottom. Non-self pathogen AcMNPV induced the cells to apoptosis. The cell line was proved to be an epidermal cell line based on its unique gene expression pattern. It responded to 20E and the non-steroidal ecdysone agonist RH-2485. Its gene expression could be knocked down using RNA interference. Various genes in the cell line were investigated based on their response to 20E. This new cell line represents a platform for investigating the 20E signaling transduction pathway, the immune response mechanism in lepidopteran epidermis and interactions of the genes

Long-term effect of respiratory training for chronic obstructive pulmonary disease patients at an outpatient clinic: a randomised controlled trial

Objective: To assess the effect of respiratory training (RT ) on lung function, activity tolerance and acute exacerbation frequency with chronic obstructive pulmonary disease (COPD). Design: A randomised controlled trial. Setting: Outpatient clinic and home of the COPD patients, Zhengzhou City, China. Subjects: Sixty participants with COPD were randomised into two groups: an intervention group ( n = 30) which received the RT in self-management and a control group ( n = 30) that received an education program during the study. Intervention: Pulmonary function, activity tolerance and frequency of acute exacerbation of these COPD patients were evaluated before and after the program. The intervention and control programs were delivered at monthly out - patient clinic visits over a period of 12 months. The pulmonary rehabilitation (PR) program was conducted by a physiotherapist (who delivered RT to the participant over a minimum of 1 h per visit) for the intervention group, whereas the control group received routine health education provided by physiotherapists. The intervention group patients were then instructed to perform exercises at home as taught in the RT at least 5 days per week at home. Results: After 12 months of RT, the lung function and the activity tolerance of the COPD patients in the intervention group were significantly improved and the exacerbation frequency was also decreased. Conclusion: Long-term RT can improve lung function and activity tolerance while decreasing the frequency of acute exacerbation for COPD patient

Chiral U(1) flavor models and flavored Higgs doublets: the top FB asymmetry and the Wjj

We present U(1) flavor models for leptophobic Z' with flavor dependent couplings to the right-handed up-type quarks in the Standard Model, which can accommodate the recent data on the top forward-backward (FB) asymmetry and the dijet resonance associated with a W boson reported by CDF Collaboration. Such flavor-dependent leptophobic charge assignments generally require extra chiral fermions for anomaly cancellation. Also the chiral nature of U(1)' flavor symmetry calls for new U(1)'-charged Higgs doublets in order for the SM fermions to have realistic renormalizable Yukawa couplings. The stringent constraints from the top FB asymmetry at the Tevatron and the same sign top pair production at the LHC can be evaded due to contributions of the extra Higgs doublets. We also show that the extension could realize cold dark matter candidates.Comment: 40 pages, 10 figures, added 1 figure and extended discussion, accepted for publication in JHE

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency &gt;3%, and were also present in the mutant library, had fitness levels that were &gt;40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

A meta-analysis for the effect of prophylactic GTN on the incidence of post-ERCP pancreatitis and on the successful rate of cannulation of bile ducts

<p>Abstract</p> <p>Background</p> <p>Glyceryl trinitrate (GTN) has been shown to be able to relax the sphincter of Oddi (SO) both in animals and humans. Theoretically, the use of these compounds during and after endoscopic retrograde cholangiopancreatgraphy (ERCP) could relax the biliary and pancreatic sphincters, facilitating cannulation of common bile duct (CBD) during the procedure, or minimizing potential pancreatic outflow obstruction after the procedure. However, clinical trials evaluating the protective effect of GTN on the post-endoscopic retrograde cholangiopancreatgraphy pancreatitis (PEP) have yielded inconclusive results. This meta-analysis is to systematically assess the effect of prophylactic administration of glyceryl trinitrate (GTN) on the prevention of PEP and the effect on the cannulation of bile ducts.</p> <p>Methods</p> <p>By searching PubMed (1966 to September 2009), CENTRAL (Cochrane Controlled trials Register; issue 3, 2009) and EMBASE.com (1984 to September 2009), two independent reviewers systematically identified prospective randomized controlled trials (RCTs) detecting the effect of prophylactic GTN on the incidence of PEP and on the cannulation of bile ducts. A meta-analysis of these clinical trials was then performed.</p> <p>Results</p> <p>There are 55/899(6.1%) patients suffering PEP in the treatment group versus 95/915(10.4%) patients in the placebo group. The overall pooled risk of PEP was significantly lower in the GTN group than in the placebo group (OR 0.56, 95% CI: 0.40 to 0.79, p = 0.001). Subgroup analyses suggested that GTN administered by the sublingual form (OR 0.34,95% CI:0.16 to 0.75, p = 0.007) is more effective than transdermal route(OR 0.64,95% CI:0.40 to 1.01, p = 0.05), and the protective effect of GTN was far more obvious in the centers with high incidence of PEP (OR 0.40, 95% CI:0.24 to 0.67, p = 0.0006) than those centers with a low incidence of PEP (OR 0.75, 95% CI: 0.47 to 1.20, p = 0.22). Additionally, the meta-analysis suggests that GTN was not helpful for the cannulation of bile ducts.</p> <p>Conclusion</p> <p>We concluded that prophylactic administration of GTN may significantly reduce the incidence of PEP and not be helpful for the cannulation of bile ducts.</p