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PubMed1996

The detection and evaluation of aneugenic chemicals.

Although aneuploidy makes a significant contribution to both somatic and inherited disease the mechanisms by which environmental chemicals may induce numerical chromosome aberrations are only poorly defined. The European Union Project was aimed to further our understanding of those chemical interactions with the components of the mitotic and meiotic cell division cycle which may lead to aneuploidy and to characterise the parameters such as cellular metabolism which may influence the activity of aneugenic chemicals. C-mitosis can be induced by the highly lipophilic polychlorinated biphenyl and the completion of mitosis and cleavage can be modified by agents which deplete cellular levels of reduced glutathione. Modifications of the fidelity of chromosome segregation were produced by inhibiting the functioning of topoisomerase II during chromatid separation. In contrast, the modification of centromere integrity resulted in chromosome breakage as opposed to disturbance of segregation. Modifiers of tubulin assembly and centriolar functioning in somatic cells such as acrylamide, vinblastine and diazepam reproduced their activity in rodent bone marrow and male germ cells. The analysis of chromosome malsegregation in Aspergillus nidulans by a structurally related series of halogenated hydrocarbons was used to develop a QSAR model which had high predictive value for the results of fungal tests for previously untested related chemicals. Metabolic studies of potential aneugens in genetically engineered human lymphoblastoid cells demonstrated the detoxification of the aneugenic activity of chloral hydrate and the activation of 2,3-dichlorobutane, 1,1,2-trichloroethane and trichloroethylene by Phase I biotransforming enzymes. Cell transformation studies in Syrian hamster dermal cultures using a panel of 22 reference and or potential aneugens indicated that 15 of the 22 produced positive results following single exposures. Five of the aneugens which were negative following single exposures produced positive results where cultures were continuously exposed for up to 6 weeks to low concentrations following a single non-transforming exposure to the mutagen dimethyl sulphate. The transformation studies indicate that a significant proportion of chemical aneugens are potential complete carcinogens and/or co-carcinogens. To optimise the enumeration of chromosomes following exposure to potential chemical aneugens whole chromosome paints and centromere specific probes suitable for use in fluorescence in situ hybridisation (FISH) were developed for the rat, mouse and Chinese hamster and selected human probes evaluated for their suitability for routine use. Molecular chromosome probes were used to develop protocols for enumerating chromosomes in metaphase cells and centromeres and micronuclei in interphase cells. The analysis of segregation of specific centromeres in binucleate cells following cytochalasin B treatment was shown to be a potentially valuable system for characterising non-disjunction following chemical exposure. Whole chromosome paints and centromere specific probes were used to demonstrate the presence of dose-response thresholds following treatment with a reference panel of spindle inhibiting chemicals. These data indicate that the FISH technology is suitable for evaluating the relative hazards of low-dose exposures to aneugenic chemicals.

Aneuploidy↗
PubMedDate not supplied

Open computing grid for molecular science and engineering.

Grid is an emerging infrastructure for distributed computing that provides secure and scalable mechanisms for discovering and accessing remote software and data resources. Applications built on this infrastructure have great potential for addressing and solving large scale chemical, pharmaceutical, and material science problems. The article describes the concept behind grid computing and will present the OpenMolGRID system that is an open computing grid for molecular science and engineering. This system provides grid enabled components, such as a data warehouse for chemical data, software for building QSPR/QSAR models, and molecular engineering tools for generating compounds with predefined chemical properties or biological activities. The article also provides an overview about the availability of chemical applications in the grid.

Journal Article↗
PubMed2004

Resistance to signal activation governs design features of the MAP kinase signaling module.

Given its broad influence over numerous cell functions, redesigning the mitogen-activated protein (MAP) kinase signaling module would offer a powerful means to engineer cell behavior. Early challenges include identifying quantitative module features most relevant to biological function and developing simple design rules to predictably modify these features. This computational study delineates how features such as signal amplification, input potency, and dynamic range of output may be tuned by manipulating chief module components. Importantly, the model construction identifies a metric of resistance to signal activation that quantitatively predicts module features and design trade-offs for broad perturbations in kinase and phosphatase expression. Its predictive utility extends to dynamic properties such as signal lifetime, which often dictates MAP kinase effect on cell function. Taken together, we propose that predictably altering MAP kinase signaling by tuning resistance is not only a feasible engineering strategy, but also one exploited by natural systems to allow each MAP kinase to exert pleiotropic effects in a context-dependent manner. External stimuli not only activate kinases, but also alter phosphatase expression and activity, thereby reconfiguring a single module for quantitatively distinct modes of signaling such as transient vs. sustained dynamics, each with unique effects on cell function.

Computer Simulation↗
PubMed2005

Generation and molecular characterization of new temperature-sensitive plasmids intended for genetic engineering of Pasteurellaceae.

Temperature-sensitive (TS) plasmids were generated through chemical mutagenesis of a derivative of the streptomycin resistance parent plasmid pD70, isolated from Mannheimia hemolytica serotype 1. Three TS plasmids which failed to replicate at or above 42 degrees C in M. hemolytica but which were fully functional below 31 degrees C were selected for further analysis. Two of the TS plasmids were shown by sequencing to possess unique single-base-pair mutations. The third TS plasmid contained a unique base pair substitution and a second mutation that had been previously identified. These mutations were clustered within a 200-bp region of the presumed plasmid origin of replication. Site-directed single-nucleotide substitutions were introduced into the wild-type pD70 origin of replication to confirm that mutations identified by sequencing had conferred thermoregulated replication. Deletion analysis on the wild-type pD70 plasmid replicon revealed that approximately 720 bp are necessary for plasmid maintenance. Replication of the TS plasmids was thermoregulated in Pasteurella multocida and Haemophilus somnus as well. To consistently transform H. somnus with TS plasmid, in vitro DNA methylation with commercially available HhaI methyltransferase was necessary to protect against the organism's restriction enzyme HsoI (recognition sequence 5'-GCGC-3') characterized herein.

Animals↗
PubMed1995

The genetic engineering of microbial solvent production.

Although the production of acetone and butanol by Clostridium strains was a thriving industrial fermentation process, it is no longer competitive with the chemical synthesis of solvents and has been discontinued. However, studies on the molecular biology of Clostridium strains suggest that genetic engineering for improved solvent production is feasible, and could result in the revival of the industrial fermentation process.

1-Butanol↗
PubMed1991

Repacking protein interiors.

Several goals of protein engineering may be achieved through redesign and repacking of protein interiors. The effects of interior apolar substitutions on protein stability depend strongly on the site of the substitution. One reason for this is that protein interiors have properties both of apolar liquids and of crystalline solids. Substitutions at interior sites affect the stability of a protein by changing the hydrophobicity, but each site in a protein has a characteristic energy associated with introducing packing changes, and the net stability depends on both of these factors.

Models, Chemical↗
PubMed2006

Schwarz meets Schwann: design and fabrication of biomorphic and durataxic tissue engineering scaffolds.

Tissue engineering is a discipline at the leading edge of the field of computer assisted intervention. This multidisciplinary engineering science attempts to meet the reparative and regenerative needs of tissues and organs based on the notion of design and fabrication of scaffolds- porous, three-dimensional "trellis-like" biomimetic structures that, on implantation, provide a viable environment to recuperate and regenerate damaged cells. Existing scaffold fabrication strategies produce sub-optimal porous labyrinths with contra-naturam straight edges. The biomorphic geometry that mimics the secundam-naturam substrate would be one that is continuous through all space, partitioned into two not-necessarily-equal sub-spaces by a non-intersecting, two-sided surface. Minimal surface geometry is not only ideal to describe such a space but is also the preferentially assumed geometry in natural and pathological or manipulated cells. We present results on the premier attempt in computer-controlled fabrication, modulation, and mechanical characterization of tissue engineering scaffolds based on triply periodic minimal surfaces (TPMS). We also present novel strategies to realize coterminous seeding-feeding networks thereby guaranteeing blood/nutrient supply to the proliferating cells at close proximity. This initiative of linking Schwann's 1838 cell theory with Schwarz's 1865 discovery of TPMS is a significant step to fabricate the previously elusive optimal biomorphic tissue analogs.

Animals↗
PubMed2006

Recent developments in polymeric nanoparticle engineering and their applications in experimental and clinical oncology.

Promising results have come from attempts to direct drugs, nucleic acids and diagnostic agents to tumours by using polymeric nanoparticles. Such carriers are versatile; their encapsulation capacity, drug release profile, and biological performance vary with their chemical makeup, morphology, and size. Polymeric nanoparticles may therefore be engineered for therapeutic and diagnostic purposes in accordance with the type, developmental stage and location of the cancer as well as the required route of administration. This article examines recent developments in design and engineering of polymeric nanoparticles and related platforms to include supramolecular systems such as nanocapsules and nanoparticle-based hydrogels, and assesses their potential diagnostic and therapeutic applications in experimental and clinical oncology.

Biomedical Engineering↗
PubMed2000

Field applications of genetically engineered microorganisms for bioremediation processes.

Genetically engineered microorganisms (GEMs) have shown potential for bioremediation applications in soil, groundwater, and activated sludge environments, exhibiting enhanced degradative capabilities encompassing a wide range of chemical contaminants. However, the vast majority of studies pertaining to genetically engineered microbial bioremediation are supported by laboratory-based experimental data. In general, relatively few examples of GEM applications in environmental ecosystems exist. Unfortunately, the only manner in which to fully address the competence of GEMs in bioremediation efforts is through long-term field release studies. It is therefore essential that field studies be performed to acquire the requisite information for determining the overall effectiveness and risks associated with GEM introduction into natural ecosystems.

Biodegradation, Environmental↗
PubMed2005

Arming antibodies: prospects and challenges for immunoconjugates.

Immunoconjugates--monoclonal antibodies (mAbs) coupled to highly toxic agents, including radioisotopes and toxic drugs (ineffective when administered systemically alone)--are becoming a significant component of anticancer treatments. By combining the exquisite targeting specificity of mAbs with the enhanced tumor-killing power of toxic effector molecules, immunoconjugates permit sensitive discrimination between target and normal tissue, resulting in fewer toxic side effects than most conventional chemotherapeutic drugs. Two radioimmunoconjugates, ibritumomab tiuxetan (Zevalin) and tositumomab-131I (Bexxar), and one drug conjugate, gemtuzumab ozogamicin (Mylotarg), are now on the market. For the next generation of immunoconjugates, advances in protein engineering will permit greater control of mAb targeting, clearance and pharmacokinetics, resulting in significantly improved delivery to tumors of radioisotopes and potent anticancer drugs. Pre-targeting strategies, which separate the two functions of antibody-based localization and delivery or generation of the toxic agent into two steps, also promise to afford superior tumor targeting and therapeutic efficacy. Several challenges in optimizing immunoconjugates remain, however, including poor intratumoral mAb uptake, normal tissue conjugate exposure and issues surrounding drug potency and conditional release from mAb carriers. Nonetheless, highly promising results from preclinical models will continue to drive the clinical development of this therapeutic class.

Aminoglycosides↗
PubMed2005

Biosynthesis of an elastin-mimetic polypeptide with two different chemical functional groups within the repetitive elastin fragment.

A new protein engineering strategy was utilized to synthesize an elastin-mimetic polypeptide. The primary structure represents an elastic motif composed of thirty amino acids with one lysine and one glutamic acid per repeat unit EMM = (VPGVG VPGKG VGPVG VPGVG VPGEG VPGIG). The gene was constructed using a Seamless Cloning method by generating three DNA cassettes which all encoded the EMM repeat unit, but with different flanking restriction recognition sites. The DNA cassettes were assembled to yield a gene that could be directly cloned into the multiple cloning site of pBluescript II SK+. The resulting gene (EMM)(7) with approximately 650 base pairs in length was further cloned into the expression vector pET-28b. Protein biosynthesis in E. coli strain BLR(DE3) resulted in the 21.5 kDa repeating polypeptide His(6)-(EMM)(7) yielding up to 50 mg . L(-1) of cell culture. Secondary structure analysis by far UV circular dichroism revealed a minimum at 197 nm and a shoulder at 218 nm indicative for a random coil with some type II beta-turn conformation content. Lower critical solution temperature (LCST) behavior strongly depends on salt and polypeptide concentration. Importantly, first cross-linking experiments indicate successful hydrogel formation with a surface structure reminiscent to natural elastin as visualized by SEM micrographs.

Base Sequence↗
PubMed2002

Cell-wall engineering of living bacteria.

The cell walls of living bacteria were chemically modified by adding cell-wall precursors. As the precursors to be incorporated into the cell wall, UDP-MurNAc pentapeptide, lipid I, and lipid II derivatives were synthesized. The aimed compounds were attached to the amine residue of lysine at the pentapeptide moiety. Fluorescein-attached UDP-MurNAc pentapeptide was efficiently incorporated into both Gram-positive and Gram-negative bacteria. In the case of Gram-negative bacteria, such as Escherichia coli, the permeability of the outer membrane (lipopolysaccharide layer) was enhanced by EDTA treatment before the incorporation. For Gram-positive bacteria, UDP-MurNAc derivatives were incorporated in the cell wall without EDTA treatment due to the lack of the lipopolysaccharide layer. Furthermore, instead of dyes, a ketone group was attached to the UDP-MurNAc pentapeptide. The ketone group was also delivered to the bacterial cell wall of lactic acid bacteria, giving a platform to attach large molecules on the surface.

Bacteria↗
PubMed2003

A collagen-based scaffold for a tissue engineered human cornea: physical and physiological properties.

Stabilized collagen-glycosaminoglycan scaffolds for tissue engineered human corneas were characterized. Hydrated matrices were constructed by blending type I collagen with chondroitin sulphates (CS), with glutaraldehyde crosslinking. A corneal keratocyte cell line was added to the scaffolds with or without corneal epithelial and endothelial cells. Constructs were grown with or without ascorbic acid. Wound-healing was evaluated in chemical-treated constructs. Native, noncrosslinked gels were soft with limited longevity. Crosslinking strengthened the matrix yet permitted cell growth. CS addition increased transparency. Keratocytes grown within the matrix had higher frequencies of K+ channel expression than keratocytes grown on plastic. Ascorbic acid increased uncrosslinked matrix degradation in the presence of keratocytes, while it enhanced keratocyte growth and endogenous collagen synthesis in crosslinked matrices. Wounded constructs showed recovery from exposure to chemical irritants. In conclusion, this study demonstrates that our engineered, stabilized matrix is well-suited to function as an in vitro corneal stroma.

Animals↗
PubMed2002

A molecular assembly system that renders antigens of choice highly repetitive for induction of protective B cell responses.

Virus like particles (VLPs) are known to induce potent B cell responses in the absence of adjuvants. Moreover, epitope-specific antibody responses may be induced by VLPs that contain peptides inserted in their immunodominant regions. However, due to steric problems, the size of the peptides capable of being incorporated into VLPs while still permitting capsid assembly, is rather limited. While peptides genetically fused to either the N- or C-terminus of VLPs present fewer assembly problems, the immune responses obtained against such epitopes are often limited, most likely because the epitopes are not optimally exposed. In addition, such particles may be less stable in vivo. Here, we show that peptides and proteins engineered to contain a free cys can be chemically coupled to VLPs formed from the hepatitis B core antigen (HBcAg) containing a lys in the immuno-dominant region. By using this approach steric hindrance of capsid assembly is abrogated. Peptides or protein coupled to VLPs in an oriented fashion are shown to induce strong and protective B cell responses even against self-epitopes in the absence of adjuvants. This molecular assembly system may be used to induce strong B cell responses against most antigens.

Animals↗
PubMed2000

Engineering of heterologous cytochrome P450 in Acinetobacter sp.: application for pollutant degradation.

Many organisms do not contain the necessary biochemical armoury to carry out the initial oxidative attack of many pollutant chemicals. In the present study, Acinetobacter sp. strain BD413 has been genetically engineered to express the cytochrome P450 xenobiotic-metabolising enzyme CYP105D1 from Streptomyces griseus that has in its repertoire a diverse array of organic pollutants. Further, it is shown that the transformed Acinetobacter calcoaceticus strain BD413 can grow on pollutants unlike control bacteria not expressing cytochrome P450 and that was reflected in release of radiolabel with growth on radiolabelled chlortoluron. We show that cytochrome P450 can enhance the biodegrading repertoire of A. calcoaceticus and discuss the application of such results to bioremediation strategies.

Acinetobacter calcoaceticus↗
PubMed2004

Modelling soot and SOF emissions from a diesel engine.

Modelling of soot and SOF emissions from a typical European turbocharged diesel engine has been made. The model consists of a detailed kinetic mechanism with 472 reactions (120 chemical species) and data from the thermodynamic diagnostic procedure of the combustion process of the engine. The forward kinetic constants were obtained from literature and the background constants from a self-developed non-linear fitting routine based on the Marquardt algorithm. The dilution and mixing processes inside the engine are represented by a simple Wiebe function. The system of ordinary differential equations is solved with the Rosenbrock method for rigid systems and using the interpolating Lagrange polynomials to calculate the heat capacity of each species at the corresponding temperature. The kinetic model has been implemented in Digital Visual Fortran 6.0. The model has been executed for five different fuels and three mixtures of biodiesel and reference diesel operating under three diverse conditions from the European transient urban/extraurban Certification Cycle and the results of soot and SOF predicted are compared with experimental data.

Air Pollutants↗