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PubMed2003

Integrated, molecular engineering approaches to develop prostate cancer gene therapy.

Gene therapy is a translational science, with the ultimate goal of cancer gene therapy research being to develop effective and safe treatments for patients. In the new millennium, it is imperative to tailor a therapeutic strategy for a particular disease, based on clinical management issues. The desirable regulatory features and therapeutic strategies need to be fully considered before proceeding with molecular engineering of the gene delivery vector. Issues, such as cell-targeted expression, in vivo monitoring of gene delivery and expression, therapeutic strategies, and vector selection that targets the particular disease stage should be addressed. During the validation phase of the study, an objective evaluation in relevant animal models should determine whether the vector meets the desired specifications. Meeting the predetermined criteria should propel the product towards the clinical phase of evaluation. This review will present the conceptual framework that has been applied to developing an integrated and targeted gene therapy for prostate cancer.

Animals↗
PubMed2001

MOLECULAR ENGINEERING OF C4 PHOTOSYNTHESIS.

The majority of terrestrial plants, including many important crops such as rice, wheat, soybean, and potato, are classified as C3 plants that assimilate atmospheric CO2 directly through the C3 photosynthetic pathway. C4 plants such as maize and sugarcane evolved from C3 plants, acquiring the C4 photosynthetic pathway to achieve high photosynthetic performance and high water- and nitrogen-use efficiencies. The recent application of recombinant DNA technology has made considerable progress in the molecular engineering of C4 photosynthesis over the past several years. It has deepened our understanding of the mechanism of C4 photosynthesis and provided valuable information as to the evolution of the C4 photosynthetic genes. It also has enabled us to express enzymes involved in the C4 pathway at high levels and in desired locations in the leaves of C3 plants for engineering of primary carbon metabolism.

Journal Article↗
PubMed2026

Unlocking the molecular engineering of Geobacillus glycoside hydrolases as a source of industrial biocatalysts.

This review examines Geobacillus sensu stricto as a source of thermostable glycoside hydrolases (GH) for biomass conversion, food processing, and enzyme engineering. Recent peer-reviewed literature was assessed with emphasis on taxonomy, genome-based Carbohydrate-Active Enzymes (CAZyme) prediction, biochemical validation, structural data, and engineering case studies. Taxonomic boundaries were interpreted using current Anoxybacillaceae frameworks, with Parageobacillus treated as a related comparator rather than as Geobacillus. The strongest evidence supports GH13 alpha-amylases, xylan-active systems, beta-xylosidases, and selected accessory enzymes. Recent studies also show that genome mining must be coupled with enzymatic assays and product profiling because CAZyme annotation alone does not prove industrial function. Molecular engineering has improved relevant traits, including the longer thermal half-life of engineered G. stearothermophilus alpha-amylase variants, the increased catalytic efficiency of oligo-alpha-1,6-glucosidase variants, and improved AmyS expression in Bacillus subtilis. Geobacillus glycoside hydrolases are best interpreted as process-specific, engineerable biocatalytic templates. Their translation requires reliable taxonomy, functional validation, structural interpretation, scalable expression and testing on realistic substrates. This synthesis also recognises current limitations: many predicted CAZymes still lack biochemical validation, complete cellulolytic systems remain less mature than xylan- and starch-active systems, and scale-up data remain scarce.

Geobacillus↗
PubMed1981

Molecular engineering: An approach to the development of general capabilities for molecular manipulation.

Development of the ability to design protein molecules will open a path to the fabrication of devices to complex atomic specifications, thus sidestepping obstacles facing conventional microtechnology. This path will involve construction of molecular machinery able to position reactive groups to atomic precision. It could lead to great advances in computational devices and in the ability to manipulate biological materials. The existence of this path has implications for the present.

Journal Article↗
PubMed1997

A cell-based immunobiosensor with engineered molecular recognition--Part I: Design feasibility.

A novel bioelectronic sensor is described in which living immune cells are transformed into unique biotransducer couples by engineering their molecular recognition for preselected antigens of clinical interest. This 'hybrid' biosensor, constructed with mast cells interfaced to a microfabricated thermoelectric device with the use of biomolecular linkages, is capable of detecting antigens in real time by transducing minute heat changes arising from antigen-induced mast cell activation processes. The thermoelectric approach was selected based upon preliminary bioenergetic calculations which indicated that metabolic changes arising from mast cell antigen recognition result in a significant increase in exothermic heat relative to basal metabolic conditions. Experimental studies confirmed that mast cell activation and degranulation can be discriminated theramally from basal metabolic activity. Results obtained from microcalorimetry experiments using cultured mast cells (MC/9) mucosal-like mast cell line), and harvested mast cells (rat peritoneal mast cells) indicated that detectable increases in heat output (-3 +/- 0.5 pW/cell, mean peak output) immediately followed cell activation. The construction of a miniature hybrid immunobiosensor device was made possible by bioelectronic coupling achieved with the use of cellular adhesive proteins that immobilized non-adherent (MC/9) cells as well as adherent (RBL-2H3 rat basophilic leukemia) cells to the thermopile. Results from preliminary tests conducted on a hybrid biosensor prototype validated the design feasibility of a miniature, living cell immunodiagnostic biosensor. Such cell-based hybrid biosensor approaches may greatly extend the capability for selective, rapid, on-site, antigen detection for a wide range of clinically relevant antigens and offer new approaches to in vitro diagnostics.

Animals↗
PubMed2005

Molecular engineering of antiferromagnetic rings for quantum computation.

The substitution of one metal ion in a Cr-based molecular ring with dominant antiferromagnetic couplings allows the engineering of its level structure and ground-state degeneracy. Here we characterize a Cr7Ni molecular ring by means of low-temperature specific-heat and torque-magnetometry measurements, thus determining the microscopic parameters of the corresponding spin Hamiltonian. The energy spectrum and the suppression of the leakage-inducing S mixing render the Cr7Ni molecule a suitable candidate for the qubit implementation, as further substantiated by our quantum-gate simulations.

Journal Article↗
PubMed1991

The molecular engineering of pertussis toxoid.

The demand for a safer pertussis vaccine has led to the development of acellular vaccine products. We have sought to manufacture a component vaccine based upon the genetic inactivation of pertussis toxin derived by recombinant DNA technology and protein engineering. Rational site-directed mutagenesis of the S1 subunit of pertussis toxin has resulted in an enzymatically-deactivated polypeptide which retains its immunogenic potential. Mutagenic analysis of the other subunits of this toxin has permitted a delineation of the structural determinants involved in its recognition of cellular receptors. The in vitro assembly of holotoxin species possessing selectively engineered subunits may facilitate the production of a molecularly-defined genetic toxoid for pertussis prophylaxis.

Genetic Engineering↗
PubMed2002

Molecular engineering of semiconductor surfaces and devices.

Grafting organic molecules onto solid surfaces can transfer molecular properties to the solid. We describe how modifications of semiconductor or metal surfaces by molecules with systematically varying properties can lead to corresponding trends in the (electronic) properties of the resulting hybrid (molecule + solid) materials and devices made with them. Examples include molecule-controlled diodes and sensors, where the electrons need not to go through the molecules (action at a distance), suggesting a new approach to molecule-based electronics.

Journal Article↗
PubMed2004

Molecular engineering of a backwards-moving myosin motor.

All members of the diverse myosin superfamily have a highly conserved globular motor domain that contains the actin- and nucleotide-binding sites and produces force and movement. The light-chain-binding domain connects the motor domain to a variety of functionally specialized tail domains and amplifies small structural changes in the motor domain through rotation of a lever arm. Myosins move on polarized actin filaments either forwards to the barbed (+) or backwards to the pointed (-) end. Here, we describe the engineering of an artificial backwards-moving myosin from three pre-existing molecular building blocks. These blocks are: a forward-moving class I myosin motor domain, a directional inverter formed by a four-helix bundle segment of human guanylate-binding protein-1 and an artificial lever arm formed by two alpha-actinin repeats. Our results prove that reverse-direction movement of myosins can be achieved simply by rotating the direction of the lever arm 180 degrees.

Actinin↗
PubMed2005

Molecular engineering of octupolar NLO molecules and materials based on bipyridyl metal complexes.

Coordination compounds are of particular interest for the design of new chromophores with large nonlinear optical (NLO) susceptibilities. They offer a wide range of metals with different oxidation states and ligands, which can give rise to tunable electronic properties. Metal ions are excellent templates to build 2D and 3D octupolar NLO-phores. Their associations with functionalized bipyridyl ligands give rise to octahedral and tetrahedral metal complexes with large first-order hyperpolarizabilities. The ability to functionalize these octupoles allows their incorporation into macromolecular architectures such as polymers and metallodendrimers, We also show in this Account two approaches to induce noncentrosymmetry at the macroscopic level, either by supramolecular organization or by the all optical poling procedure.

2,2'-Dipyridyl↗
PubMed2004

Reversion of molecularly engineered, partially attenuated, very virulent infectious bursal disease virus during infection of commercial chickens.

A molecularly cloned, tissue culture-adapted infectious bursal disease virus (BD-3tc) was generated from a very virulent strain by the reverse genetics approach following site-directed mutagenesis (Q253H and A284T in VP2). The pathogenicity of BD-3tc was tested in commercial chickens. The wild-type strain (BD-3wt) and the molecularly cloned parental strain (BD-3mc) were included for comparison. The subclinical course of the disease, with delayed and milder pathological lesions followed by quick follicular regeneration in the bursa of Fabricius in BD-3tc-inoculated birds, suggested that these amino acid substitutions made BD-3tc partially attenuated. However, severe bursa atrophy was observed at 14 days after inoculation. Reverse transcription-polymerase chain reaction coupled with restriction enzyme analysis revealed that both point mutations in BD-3tc had reverted 14 days after inoculation. Further investigations demonstrated that the codon for amino acid at position 284 had already reverted to the wild-type phenotype (T284A) 3 days after inoculation.

Animals↗
PubMed2001

Structure of a genetically engineered molecular motor.

Molecular motors move unidirectionally along polymer tracks, producing movement and force in an ATP-dependent fashion. They achieve this by amplifying small conformational changes in the nucleotide-binding region into force-generating movements of larger protein domains. We present the 2.8 A resolution crystal structure of an artificial actin-based motor. By combining the catalytic domain of myosin II with a 130 A conformational amplifier consisting of repeats 1 and 2 of alpha-actinin, we demonstrate that it is possible to genetically engineer single-polypeptide molecular motors with precisely defined lever arm lengths and specific motile properties. Furthermore, our structure shows the consequences of mutating a conserved salt bridge in the nucleotide-binding region. Disruption of this salt bridge, which is known to severely inhibit ATP hydrolysis activity, appears to interfere with formation of myosin's catalytically active 'closed' conformation. Finally, we describe the structure of alpha-actinin repeats 1 and 2 as being composed of two rigid, triple-helical bundles linked by an uninterrupted alpha-helix. This fold is very similar to the previously described structures of alpha-actinin repeats 2 and 3, and alpha-spectrin repeats 16 and 17.

Actinin↗
PubMed2002

Molecular engineering of a two-step transcription amplification (TSTA) system for transgene delivery in prostate cancer.

Gene therapy is founded on the concept that tissue-specific promoters can express heterologous genes for molecular imaging or therapeutic applications. The engineering of cell-specific enhancers to improve potency and the development of two-step transcriptional activation (TSTA) approaches have significantly improved the efficacy of transgene expression. Here we combine these technologies to create a robust, titratable, androgen-responsive system targeted to prostate cancer cells. Our "chimeric" TSTA system uses a duplicated variant of the prostate-specific antigen (PSA) gene enhancer to express GAL4 derivatives fused to one, two, or four VP16 activation domains. We targeted the resulting activators to cells with reporter templates bearing one, two, or five GAL4 binding sites upstream of firefly luciferase. We monitored activity via firefly luciferase assays in transfected cell extracts and in live nude mice using a cooled charge-coupled device (CCD) imaging system. In this system, we found that firefly luciferase expression in prostate cancer cells can be varied over an 800-fold range. We also found that a single plasmid bearing the optimized enhancer, GAL4-VP16 derivative, and reporter expressed firefly luciferase at 20-fold higher levels than the cytomegalovirus enhancer. We discuss the implications of this strategy and its application to molecular imaging and therapy.

Animals↗