Elaboration and TEM structural study of interfaces in composites produced by precipitation

Model ceramic matrix composites have been manufactured in a wide range of materials using the precipitation of a metal (Cu, Ni, Cr) in a ceramic matrix (nitride AIN or oxides MgO, Al2O3) providing, in each case low energy configurations at the heterophase interfaces. In connection to microelectronic applications, copper metallic particles precipitate in AIN after implantation by copper ions and anneal of the ceramic matrix. Faceted particles are imaged by HRTEM and are associated to a low energy structural and chemical configuration. Internal reduction experiments have been carried out on (Mg,Ni)O, (Mg,Cu)O and (Al,Cr)2O3 mixed oxides; the morphology, chemical composition and orientation relationship of the different precipitates are obtained through TEM observations and discussed in terms of interfacial energy and precipitate growth mechanism and kinetics. Conventional and high resolution TEM in conjonction to structural models have allowed a comprehensive description of the interface

Software fault-tolerance by design diversity DEDIX: A tool for experiments

The use of multiple versions of a computer program, independently designed from a common specification, to reduce the effects of an error is discussed. If these versions are designed by independent programming teams, it is expected that a fault in one version will not have the same behavior as any fault in the other versions. Since the errors in the output of the versions are different and uncorrelated, it is possible to run the versions concurrently, cross-check their results at prespecified points, and mask errors. A DEsign DIversity eXperiments (DEDIX) testbed was implemented to study the influence of common mode errors which can result in a failure of the entire system. The layered design of DEDIX and its decision algorithm are described

The statistical mechanics of complex signaling networks : nerve growth factor signaling

It is becoming increasingly appreciated that the signal transduction systems used by eukaryotic cells to achieve a variety of essential responses represent highly complex networks rather than simple linear pathways. While significant effort is being made to experimentally measure the rate constants for individual steps in these signaling networks, many of the parameters required to describe the behavior of these systems remain unknown, or at best, estimates. With these goals and caveats in mind, we use methods of statistical mechanics to extract useful predictions for complex cellular signaling networks. To establish the usefulness of our approach, we have applied our methods towards modeling the nerve growth factor (NGF)-induced differentiation of neuronal cells. Using our approach, we are able to extract predictions that are highly specific and accurate, thereby enabling us to predict the influence of specific signaling modules in determining the integrated cellular response to the two growth factors. We show that extracting biologically relevant predictions from complex signaling models appears to be possible even in the absence of measurements of all the individual rate constants. Our methods also raise some interesting insights into the design and possible evolution of cellular systems, highlighting an inherent property of these systems wherein particular ''soft'' combinations of parameters can be varied over wide ranges without impacting the final output and demonstrating that a few ''stiff'' parameter combinations center around the paramount regulatory steps of the network. We refer to this property -- which is distinct from robustness -- as ''sloppiness.''Comment: 24 pages, 10 EPS figures, 1 GIF (makes 5 multi-panel figs + caption for GIF), IOP style; supp. info/figs. included as brown_supp.pd

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Multiple inducers of the Drosophila heat shock locus 93D (hsr omega): inducer-specific patterns of the three transcripts

The Drosophila hsr omega locus produces one of the largest and most active heat shock puffs, yet it does not encode a heat shock protein. Instead, this locus produces a distinctive set of three transcripts, all from the same start site. The largest transcript, omega 1, is limited to the nucleus and appears to have a role there. A second nuclear transcript, omega 2, is produced by alternative termination and contains the sequence found in the 5' 20-25% of omega 1 (depending on the Drosophila species). The cytoplasmic transcript, omega 3, is produced by removal of a 700-bp intron from omega 2. All three hsr omega RNAs are produced constitutively and production is enhanced by heat shock. In addition to being a member of the set of heat shock puffs, the hsr omega puff is induced by agents that do not affect other heat shock loci, suggesting that hsr omega is more sensitive to environmental changes than other loci. We report here that agents that induce puffing of hsr omega loci in polytene nuclei also lead to an increase in hsr omega transcripts in diploid cells. We also show that the relative levels of omega 1 and omega 3 can be modulated independently by several agents. All drugs that inhibit translation, either initiation or elongation, stabilize the omega 3 transcript, which normally turns over within minutes in control cells. Drugs (such as benzamide and colchicine) that induce puffing of hsr omega, but not other heat shock loci, lead to large increases in omega 1. Although the constitutive level of omega 1 is relatively stable, the drug-induced excess is lost rapidly when the drug is withdrawn. The relative levels of hsr omega transcripts may reflect different states in cellular metabolism

X-ray-absorption fine-structure study of ZnSexTe1−x alloys

X-ray-absorption fine-structure experiments at different temperatures in ZnSexTe1−x (x=0, 0.1, 0.2, 0.55, 0.81, 0.93, 0.99, and 1.0) have been performed in order to obtain information about the structural relaxation and disorder effects occurring in the alloys. First and second neighbor distance distributions have been characterized at the Se and Zn K edges, using multiple-edge and multiple-scattering data analysis. The first neighbor distance distribution was found to be bimodal. The static disorder associated with the Zn–Te distance variance did not depend appreciably on composition. On the other hand, the static disorder associated with the Zn–Se distance increased as the Se content diminished. Using the bonding angle information provided by our experiments the point of view of the anion has been related to that of the cation. The resulting structural model indicates that Zn tetrahedra surrounding the anions remain essentially undistorted, but forced to tilt from their ideal zincblende orientation to accommodate the minority element. The main origin of structural disorder is [email protected] ; [email protected]

The UCLA Design Diversity Experiment (DEDIX) system: A distributed testbed for multiple-version software

To establish a long-term research facility for experimental investigations of design diversity as a means of achieving fault-tolerant systems, a distributed testbed for multiple-version software was designed. It is part of a local network, which utilizes the Locus distributed operating system to operate a set of 20 VAX 11/750 computers. It is used in experiments to measure the efficacy of design diversity and to investigate reliability increases under large-scale, controlled experimental conditions

Meta-analysis of the impact of successful chronic total occlusion percutaneous coronary intervention on left ventricular systolic function and reverse remodeling

We sought to examine the impact of coronary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on left ventricular (LV) function.We performed a systematic review and meta-analysis of studies published between January 1980 and November 2017 on the impact of successful CTO PCI on LV function.A total of 34 observational studies including 2735 patients were included in the meta-analysis. Over a weighted mean follow-up of 7.9 months, successful CTO PCI was associated with an increase in LV ejection fraction by 3.8% (95%CI 3.0-4.7, P < 0.0001, I2 = 45%). In secondary analysis of 15 studies (1248 patients) that defined CTOs as occlusions of at least 3-month duration and reported follow-up of at least 3-months after the procedure, successful CTO PCI was associated with improvement in LV ejection fraction by 4.3% (95%CI [3.1, 5.6], P < 0.0001). In the 10 studies (502 patients) that reported LV end-systolic volume, successful CTO PCI was associated with a decrease in LV end-systolic volume by 4 mL, (95%CI -6.0 to -2.1, P < 0.0001, I2 = 0%). LV end-diastolic volume was reported in 9 studies with 403 patients and did not significantly change after successful CTO PCI (-2.3 mL, 95%CI -5.7 to 1.2 mL, P = 0.19, I2 = 0%).Successful CTO PCI is associated with a statistically significant improvement in LV ejection fraction and decrease in LV end-systolic volume, that may reflect a beneficial effect of CTO recanalization on LV remodeling. The clinical implications of these findings warrant further investigation

VEGF receptors on PC12 cells mediate transient activation of ERK1/2 and Akt: comparison of nerve growth factor and vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) and endostatin are angiogenic and anti-angiogenic molecules, respectively, that have been implicated in neurogenesis and neuronal survival. Using alkaline phosphatase fusion proteins, we show that the PC12 neuronal cell line contains cell membrane receptors for VEGF but not for endostatin and the collagen XV endostatin homologue. Immunocytochemistry confirmed that proliferating and differentiated PC12 cells express VEGF receptors 1, 2 and neuropilin-1. While no functional effects of VEGF on PC12 cell proliferation and differentiation could be observed, a slight VEGF-induced reduction of caspase-3 activity in differentiated apoptotic PC12 cells was paralleled by transient activation of ERK1/2 and Akt. In direct comparison, nerve growth factor proved to be a strikingly more potent neuroprotective agent than VEGF