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Inflammation is a key physiological response to infection and injury and, although usually beneficial, it can also be damaging to the host. The liver is a prototypical example in this regard because inflammation helps to resolve liver injury, but it also underlies the aetiology of pathologies such as fibrosis and hepatocellular carcinoma. Liver cells sense their environment, including the inflammatory environment, through the activities of receptor-mediated signal transduction pathways. These pathways are organized in a complex interconnected network, and it is becoming increasingly recognized that cellular adaptations result from the quantitative integration of multi-pathway network activities, rather than isolated pathways causing particular phenotypes. Therefore comprehending liver cell signalling in inflammation requires a scientific approach that is appropriate for studying complex networks. In the present paper, we review our application of systems analyses of liver cell signalling in response to inflammatory environments. Our studies feature broad measurements of cell signalling and phenotypes in response to numerous experimental perturbations reflective of inflammatory environments, the data from which are analysed using Boolean and fuzzy logic models and regression-based methods in order to quantitatively relate the phenotypic responses to cell signalling network states. Our principal biological insight from these studies is that hepatocellular carcinoma cells feature uncoupled inflammatory and growth factor signalling, which may underlie their immune evasion and hyperproliferative properties. [ABSTRACT FROM AUTHOR]

We present a method for high fidelity lithographic patterning on polydimethylsiloxane (PDMS) surfaces employing traditional cleanroom equipment and commercially available materials that overcomes previous problems in PDMS processing. To illustrate this method, an electrostatically actuated microfluidic pump and rectangular diffraction gratings were fabricated on PDMS. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is most commonly caused by deletion of a residue (ΔF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) protein. The misfolded mutant protein is retained in the ER (endoplasmic reticulum) and is not trafficked to the cell surface (misprocessed mutant). Corrector molecules such as corr-2b or corr-4a are small molecules that increase the amount of functional CFTR at the cell surface. Correctors may function by stabilizing CFTR at the cell surface or by promoting folding in the ER. To test whether correctors promoted folding of CFTR in the ER, we constructed double-cysteine CFTR mutants that would be retained in the ER and only undergo cross-linking when the protein folds into a native structure. The mature form, but not the immature forms, of M348C(TM6)/T1142C(TM12) (where TM is transmembrane segment), T351C(TM6)/T1142C(TM12) and W356C(TM6)/W1145C(TM12) mutants were efficiently cross-linked. Mutations to the COPII (coatamer protein II) exit motif (Y563KDAD567) were then made in the cross-linkable cysteine mutants to prevent the mutant proteins from leaving the ER. Membranes were prepared from the mutants expressed in the absence or presence of correctors and subjected to disulfide cross-linking analysis. The presence of correctors promoted folding of the mutants as the efficiency of cross-linking increased from approx. 2–5% to 22–35%. The results suggest that correctors interact with CFTR in the ER to promote folding of the protein into a native structure. [ABSTRACT FROM AUTHOR]

The most common cause of CF (cystic fibrosis) is the deletion of Phe508 (ΔF508) in the CFTR [CF TM (transmembrane) conductance regulator] chloride channel. One major problem with ΔF508 CFTR is that the protein is defective in folding so that little mature protein is delivered to the cell surface. Expression of ΔF508 CFTR in the presence of small molecules known as correctors or pharmacological chaperones can increase the level of mature protein. Unfortunately, the efficiency of corrector-induced maturation of ΔF508 CFTR is probably too low to have therapeutic value and approaches are needed to increase maturation efficiency. We postulated that expression of ΔF508 CFTR in the presence of multiple correctors that bound to different sites may have an additive effect on maturation. In support of this mechanism, we found that expression of P-glycoprotein (CFTR's sister protein) processing mutants in the presence of two compounds that bind to different sites (rhodamine B and Hoechst 33342) had an additive effect on maturation. Therefore we tested whether expression of ΔF508 CFTR in the presence of combinations of three different classes of corrector molecules would increase its maturation efficiency. It was found that the combination of the quinazoline VRT-325 together with the thiazole corr-2b or bisaminomethylbithiazole corr-4a doubled the steady-state maturation efficiency of ΔF508 CFTR (approx. 40% of total CFTR was mature protein) compared with expression in the presence of a single compound. The additive effect of the correctors on ΔF508 CFTR maturation suggests that they directly interact at different sites of the protein. [ABSTRACT FROM AUTHOR]

The first sequencing of a complete organism genome occurred in 1995. Since then there has been an explosion of information, with a new organism being sequenced nearly every week. This rapid development of genomics is providing unparalleled opportunities in toxicology, ecology, and risk assessment. This paper provides an overview of some possible applications of this new information in ecological and human risk assessment. [ABSTRACT FROM AUTHOR]

Background. We conducted a randomised, controlled trial of cognitive-existential group therapy (CEGT) for women with early stage breast cancer receiving adjuvant chemotherapy with the aim of improving mood and mental attitude to cancer. Methods. Women were randomised to 20 sessions of weekly group therapy plus 3 relaxation classes or to a control arm receiving 3 relaxation classes. Assessments, independently done at baseline, 6 and 12 months, included a structured psychiatric interview and validated questionnaires covering mood, attitudes to cancer, family relationships, and satisfaction with therapy. Results. Three hundred and three of 491 (62%) eligible patients participated over 3 years. Distress was high pre-intervention: 10% were diagnosed as suffering from major depression, 27% from minor depression and 9% from anxiety disorders. On an intention-to-treat analysis, there was a trend for those receiving group therapy (n=154) to have reduced anxiety (p=0.05, 2-sided) compared to controls (n=149). Women in group therapy also showed a trend towards improved family functioning compared to controls (p=0.07, 2-sided). The women in the groups reported greater satisfaction with their therapy (p<0.001, 2-sided), appreciating the support and citing better coping, self-growth and increased knowledge about cancer and its treatment. They valued the CEGT therapy. Overall effect size for the group intervention was small (d=0.25), with cancer recurrence having a deleterious effect in three of the 19 therapy groups. Psychologists as a discipline achieved a moderate mean effect size (d=0.52). Conclusion. CEGT is a useful adjuvant psychological therapy for women with early stage breast cancer. Interaction effects between group members and therapists are relevant to outcome. Group-as-a-whole effects are powerful, but the training and experience of the therapist is especially critical to an efficacious outcome. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A new loading method with laterally-constrained configuration was proposed to study the energy conversion behavior of dielectric elastomer generator (DEG) based on experimental tests and theoretical calculation. The influence of lateral pre-stretch ratio and the loading rate on the energy transformation of DEG (VHB 4905) was investigated under both the quadrangular and triangular harvesting schemes, and the latter shows higher energy density and conversion efficiency than the former. The energy density increases with the lateral pre-stretch ratio at the range of 2 to 4, with the maximum value of 76 mJ g−1 for the quadrangular cycle and 186 mJ g−1 for the triangular cycle at the loading rate of 90 mm s−1 (strain rate of 2 s−1), respectively. The advantage of larger lateral pre-stretch ratio is mainly attributed to the increased capacitance density of the elastomer membrane at the maximum stretch, which enlarges the operational area confined by multiple failure limits on the voltage-charge work-conjugate plane. As the loading rate decreases, the energy density within each cycle decreases monotonically due to the increased charges leakage. Since the mechanical energy loss within a single cycle decreases at the lower loading rate, the conversion efficiency for the triangular cycle shows slight increase at the lower loading rate, with the maximum value of 15.4% for stretching rate of 50 mm s−1 (strain rate of 1.11 s−1). [ABSTRACT FROM AUTHOR]

Finding the precise correspondence between lattice operators and the continuum fields that describe their long-distance properties is a largely open problem for strongly interacting critical points. Here, we solve this problem essentially completely in the case of the three-state Potts model, which exhibits a phase transition described by a strongly interacting ‘parafermion’ conformal field theory. Using symmetry arguments, insights from integrability, and extensive simulations, we construct lattice analogues of nearly all the relevant and marginal physical fields governing this transition. This construction includes chiral fields such as the parafermion. Along the way we also clarify the structure of operator product expansions between order and disorder fields, which we confirm numerically. Our results both suggest a systematic methodology for attacking non-free field theories on the lattice and find broader applications in the pursuit of exotic topologically ordered phases of matter. [ABSTRACT FROM AUTHOR]

As model compounds for the biologically important heparan sulfate, eight systematically modified heparin derivatives were studied by synchrotron radiation circular dichroism (SRCD), which is sensitive to uronic acid confor- mation. Substitution pattern altered uronic acid conformation, even when structural changes were made in adjacent glucosamine residues (e.g. 6-O-desulfation) and did not involve a chromophore. SRCD spectra of these derivatives following conversion to the Na, K, Mg2, Ca2, Mn2, Cu2 and Fe3 cation forms revealed that almost all substitution/cation combinations resulted in unique spectra, showing that each was structurally distinct. The detailed effects that binding Na, K, Mg2 and Ca2 ions had on a 2-de-O-sulfated derivative was also studied by NMR, revealing that subtle changes in conformation (by NOE) and flexibility (by T2 measurements) resulted. Conversion to the K and Cu2 ion forms also drastically modified biological activity, from inactive to active, in a cell-based assay of fibroblast growth factor-receptor (FGF2/FGFR1c) signalling and this effect was not reproduced by free cations. These observations could explain the often-contradictory data concerning structure–activity relationships for these derivatives in the literature and, furthermore, argue strongly against the established trend of considering sequence as a complete structural definition. It also provides additional means of modifying the activity of these polysaccharides and suggests a possible additional level of control in biological systems. There are also obvious potential applications for these findings in the biotechnology sphere. [ABSTRACT FROM AUTHOR]