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The Silicon Cell initiative aims to understand cellular systems on the basis of the characteristics of their components. As a tool to achieve this, detailed kinetic models at the network reaction level are being constructed. Such detailed kinetic models are extremely useful for medical and biotechnological applications and form strong tools for fundamental studies. Several recently constructed detailed kinetic models on metabolism (glycolysis), signal transduction (EGF receptor), and the eukaryotic cell cycle (Saccharomyces cerevisiae) have been used to exemplify the Silicon Cell project. These models are stored and made accessible via the JWS Online Cellular Systems Modeling project, a web-based repository of kinetic models. Using a web-browser the models can be interrogated via a user-friendly graphical interface. The goal of the two projects is to combine models on parts of cellular systems and ultimately to construct detailed kinetic models at the cellular level.
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PMID:The Silicon Cell initiative: working towards a detailed kinetic description at the cellular level. 1592 80

Systems Biology aims to understand quantitatively how properties of biological systems can be understood as functions of the characteristics of, and interactions between their macromolecular components. Whereas, traditional biochemistry focused on isolation and characterization of cellular components, the challenge for Systems Biology lies in integration of this knowledge and the knowledge about molecular interactions. Computer models play an important role in this integration. We here discuss an approach with which we aim to link kinetic models on small parts of metabolism together, so as to form detailed kinetic models of larger chunks of metabolism, and ultimately of the entire living cell. Specifically, we will discuss techniques that can be used to model a sub-network in isolation of a larger network of which it is a part, while still maintaining the dynamics of the larger complete network. We will start by outlining the JWS online system, the silicon cell project, and the type of models we propose. JWS online is a model repository, which can be used for the storage, simulation and analysis of kinetic models. We advocate to integrate a top-down approach, where measurements on the complete system are used to derive fluxes in a detailed structural model, with a bottom-up approach, consisting of the integration of molecular mechanism-based detailed kinetic models into the structural model.
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PMID:Towards building the silicon cell: a modular approach. 1624 36

In this study the fabrication and characterization of an electrically conductive composite material comprised of poly(epsilon-caprolactone) (PCL), polyaniline (PANi), and bioactive mesoporous silicon (BioSilicon) is discussed. The influence of PANi and silicon on calcium phosphate induction was assessed via ex vitro calcification analyses (by acellular simulated body fluid (SBF) exposure) both with and without electrical bias. Acceleration of calcium phosphate formation is one possible desirable feature of "smart" synthetic scaffolds for selected orthopedic-relevant applications. In addition, electrical stability assays were performed in growth medium (DMEM) to determine the stability of such structures to bias in an authentic electrolyte during a typical cell experiment. The cytocompatibility of the composites was evaluated in vitro using human kidney fibroblasts (HEK 293) cell proliferation assays, along with more orthopedically relevant mesenchymal stem cells from mouse stroma. Importantly, these composites demonstrate accelerated calcification in SBF when electrical bias is applied cathodically to the scaffold. Furthermore, these scaffolds exhibit noncytotoxic behavior in the presence of fibroblasts over an 8-day culture period, and attachment of stromal cells to the semiconducting scaffold was directly imaged via scanning electron microscopy. Overall, these results suggest that materials of this type of composition have potential merit as a biomaterial.
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PMID:Accelerated calcification in electrically conductive polymer composites comprised of poly(epsilon-caprolactone), polyaniline, and bioactive mesoporous silicon. 1764 28

Systems Biology requires a tight integration of experimental data and detailed computer models to obtain a quantitative understanding of the system under study. To facilitate this integration a standardization of data and model representation and storage is important. We illustrate here such an integration using JWS Online, the modeling tool developed in our group. We follow the approach of the Silicon Cell project for the construction and validation of kinetic models and discuss some issues with respect to storage of experimental data and models. The majority of the published kinetic models for biological systems have been developed for metabolic networks and this will be our focus in this manuscript. It is not our aim to present here an all encompassing method for data and model integration, but rather to present our work on this topic to start a discussion in which the different initiatives, methods and tools can be compared.
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PMID:Data and model integration using JWS Online. 1782 87

This paper presents a fully integrated PVDF-on-silicon pyroelectric sensor array. The pyroelectric sensor has two main features: a subpixel low noise charge amplifier and a self-absorbing layered structure. The integrated low noise charge amplifier is implemented in a standard CMOS process technology. It is located directly under the sensing structure, maximizing the pixel fill factor. The self-absorbing pyroelectric sensor is a three-layer stack, consisting of a conductive polymer as an absorber layer and front electrode, a thin PVDF film as the pyroelectric material, and a rear metal layer acting as a reflector layer and rear electrode. The manufacture of the pyroelectric sensor array requires five maskless post-CMOS processing steps and is compatible with any n-well, double metal, double polysilicon, CMOS process. The array has an average pixel voltage sensitivity of 2200 V/W at 100 Hz, an NEP of 2.4/spl times/10/sup -11/ W//spl radic/Hz at 100 Hz, and a specific detectivity of 4.4/spl times/10/sup 8/ cm /spl radic/Hz/W at 100 Hz.
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PMID:An integrated 16/spl times/16 PVDF pyroelectric sensor array. 1823 87

The small dimension and particle shape of silica in gypsum used to prepare moulds for lost wax casting might be responsible for the high prevalence of silicosis in gold jewellery. To test this hypothesis, human pulmonary epithelial cell (BEAS-2B) cultures were exposed to two samples of silica with different crystal micro-morphologies: Silica Powder (Silica P) which is used in casting gold jewellery, and no powder Silica (Silica F). Extracellular matrix (ECM) production was evaluated using radio-labelled precursors and quantified by RT-PCR analysis. Expression of basic fibroblast growth factor (FGF2) and its receptor (FGFR2) was also evaluated. The results demonstrated Silica P particles had a very fine lamellar crystalline structure while Silica F was characterized by larger rounded crystals. Silica P stimulated collagen production significantly more than Silica F and downregulated laminin and metalloprotease expression. Both silica samples down-regulated FGF2 but only Silica F enhanced FGF2 receptor expression. In conclusion each Silica sample promoted a profibrotic lung microenvironment in a different manner and also elicited different FGF2 signalling pathways. The data confirm that different micromorphology of Silica particles affects the fibrogenic potential and the molecular mechanisms of dust pathogenicity.
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PMID:Comparative in vitro studies on the fibrogenic effects of two samples of silica on epithelial bronchial cells. 1826 Dec 61

We are developing superconducting transition-edge bolometers for far-infrared and millimeter wavelengths. The bolometers described here are suspended by thin legs of silicon nitride for thermal isolation. At frequencies between 200 mHz and 10-50 Hz these devices show white noise at their thermal fluctuation limit (NEP approximately 10(-17) W/ radicalHz). At higher frequencies a broad peak appears in the noise spectrum, which we attribute to a combination of thermal fluctuations in complex thermal circuits and electrothermal feedback. Detailed noise calculations fit the noise measured in three different devices that were specifically designed to test the model. We discuss how changes in bolometer materials can shift the noise peak above the frequency range of interest for most applications.
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PMID:Model for excess noise in voltage-biased superconducting bolometers. 1836 26

Silica is a factor in the induction of acute injury and chronic pulmonary fibrosis. In 1996, silica was also listed as a human carcinogen by the International Agency for Research on Cancer (IARC). However, the molecular mechanisms involved in its pathologic effects are not well understood. We found that exposure of human embryonic lung fibroblasts (HELF) to crystalline silica for 2h decreased cyclin D1 and cyclin-dependent kinase 4 (CDK4) expression levels. Extracellular signal-regulated protein kinase (ERKs), c-Jun NH2-terminal amino kinase (JNKs), and p38 kinase, as well as their downstream transcription factor, AP-1, had different effects on the regulation of expression levels of cyclin D1 and CDK4 alterations induced by silica. Silica activates multiple signal transduction pathways involved in coordinating cellular responses to stress. We established the requirements for ERK and JNK, members of the mitogen-activated protein kinase (MAPK) family, in mediating G1 phase arrest of HELF induced by silica. Silica treatment activated ERK in a dose-dependent manner. AG126 (a chemical inhibitor of the ERK signaling pathway) and the dominant negative mutant of ERK2 (a molecular inhibitor of ERK2) prevented decreases in cyclin D1 and CDK4 expression levels. A chemical inhibitor of JNK, SP600125, prevented the decreased expression of both cyclin D1 and CDK4, whereas SB203580, a chemical inhibitor of p38, did not. Interestingly, curcumin prevented the decrease in DK4 expression, but not in cyclin D1. These results demonstrate that ERKs and JNKs are responsible for the decrease of cyclin D1 and CDK4 expression levels in HELF induced by silica. Activator protein-1 (AP-1) was responsible for the decrease of CDK4 expression level, but not that of cyclin D1. The findings help to explain the mechanisms of diseases induced by silica.
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PMID:Downregulation of cyclin D1-CDK4 protein in human embryonic lung fibroblasts (HELF) induced by silica is mediated through the ERK and JNK pathway. 1870 51

Nanostructured materials are ubiquitous in tissue engineering, drug delivery, and biosensing applications. Nonetheless, little is known about the inflammatory response of materials differing in surface nanoarchitecture. Here we report human monocyte viability and morphology, in addition to inflammatory cytokines (IL-1alpha and B, IL-6, IL-10, IFN-alpha and gamma, TNF-alpha, IL-12, MIP-1alpha and beta), and reactive oxygen species production on several nanostructured surfaces, compared to flat surfaces of the same material. The surfaces studied were titiania nanotubes, short and long silicon oxide, and polycaprolactone nanowires. The results indicate that inflammation on titanium, polycaprolactone, and silicon oxide materials can be reduced by restructuring the surface with nanoarchitecture. Nanostructured surfaces display a reduced inflammation response compared to a respective flat control, with significant differences between titanium and nanotubular titanium. Little difference is observed in the inflammatory response between short and long nanowires of PCL and silicon oxide. All surfaces are significantly less inflammatory than the positive control, lipopolysaccharide. Additionally, we show that flat titanium is more inflammatory than silicon oxide and polycaprolactone. This study shows that nanoarchitecture can be used to reduce the inflammatory response of human monocytes in vitro.
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PMID:In vitro inflammatory response of nanostructured titania, silicon oxide, and polycaprolactone. 1898 78

Biocompatible oils are used in a variety of medical applications ranging from vaccine adjuvants to vehicles for oral drug delivery. To enable such nonpolar organic phases to serve as reservoirs for delivery of hydrophilic compounds, we explored the ability of block copolymer micelles in organic solvents to sequester proteins for sustained release across an oil-water interface. Self-assembly of the block copolymer, poly(-caprolactone)-block-poly(2-vinyl pyridine) (PCL-b-P2VP), was investigated in toluene and oleic acid, a biocompatible naturally occurring fatty acid. Micelle formation in toluene was characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM) imaging of micelles cast onto silicon substrates. Cryogenic transmission electron microscopy confirmed a spherical morphology in oleic acid. Studies of homopolymer solubility implied that micelles in oleic acid consist of a P2VP corona and a PCL core, while P2VP formed the core of micelles assembled in toluene. The loading of two model proteins (ovalbumin (ova) and bovine serum albumin (BSA)) into micelles was demonstrated with loadings as high as 7.8% wt of protein per wt of P2VP in oleic acid. Characterization of block copolymer morphology in the two solvents after protein loading revealed spherical particles with similar size distributions to the as-assembled micelles. Release of ova from micelles in oleic acid was sustained for 12-30 h upon placing the oil phase in contact with an aqueous bath. Unique to the situation of micelle assembly in an oily phase, the data suggest protein is sequestered in the P2VP corona block of PCL-b-P2VP micelles in oleic acid. More conventionally, protein loading occurs in the P2VP core of micelles assembled in toluene.
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PMID:Block copolymer micelles as nanocontainers for controlled release of proteins from biocompatible oil phases. 1923 32


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