Biomedical subjects

David Becker

Publications and source records attributed to David Becker.

23 records · Page 2Linked to original sources

PubMed2002

Functional studies of human skin disease- and deafness-associated connexin 30 mutations.

Connexin 30 (Cx30) is a component of the gap junction complex. Dominant and recessive mutations in the GJB6 gene encoding Cx30 are associated with a variety of human inherited diseases primarily affecting the epidermis, hair, nail, and/or the inner ear. The underlying mechanism of disease associated with different GJB6 mutations such as the disruption of gap junction mediated intercellular communication is unknown. Towards understanding these disease mechanisms, transfection studies were performed in a keratinocyte cell line and in HeLa cells using EGFP tagged wildtype Cx30 and mutant Cx30 constructs harbouring dominant disease-associated GJB6 mutations. For all three of the skin disease-associated Cx30 mutations investigated, impaired trafficking of the protein to the plasma membrane was observed thus preventing the formation of functional Cx30 gap junctions. In contrast, the deafness-associated mutation T5M-Cx30/EGFP trafficked to the membrane but defective channel activity was observed following dye transfer studies.

Base Sequence↗

PubMed2002

Purinergic and muscarinic modulation of the cell cycle and calcium signaling in the chick retinal ventricular zone.

Spontaneous calcium transients occur in the ventricular zone of the chick retina and result from the endogenous release of neurotransmitters in the absence of action potentials. Calcium transients resulting from the activation of purinergic and muscarinic receptors occur in a mixed population of interphase and mitotic cells, whereas those produced by ionotropic GABA and glutamate receptors are mostly restricted to the interphase population, the GABA responses primarily coming from cells that express the neuronal marker TuJ-1. Muscarinic and purinergic receptors can act respectively as a brake and an accelerator on mitosis, whereas GABA and glutamate receptors are without effect. Our results suggest that the balance between muscarinic and purinergic activation acts to control the rate of retinal proliferation in early development.

Aniline Compounds↗

PubMed2001

Bicarbonate enhances peroxidase activity of Cu,Zn-superoxide dismutase. Role of carbonate anion radical and scavenging of carbonate anion radical by metalloporphyrin antioxidant enzyme mimetics.

Much evidence exists for the increased peroxidase activity of copper, zinc superoxide dismutase (SOD1) in oxidant-induced diseases. In this study, we measured the peroxidase activity of SOD1 by monitoring the oxidation of dichlorodihydrofluorescein (DCFH) to dichlorofluorescein (DCF). Bicarbonate dramatically enhanced DCFH oxidation to DCF in a SOD1/H(2)O(2)/DCFH system. Peroxidase activity could be measured at a lower H(2)O(2) concentration ( approximately 1 microm). We propose that DCFH oxidation to DCF is a sensitive index for measuring the peroxidase activity of SOD1 and familial amyotrophic lateral sclerosis SOD1 mutants and that the carbonate radical anion (CO(3)) is responsible for oxidation of DCFH to DCF in the SOD1/H(2)O(2)/bicarbonate system. Bicarbonate enhanced H(2)O(2)-dependent oxidation of DCFH to DCF by spinal cord extracts of transgenic mice expressing SOD1(G93A). The SOD1/H(2)O(2)/HCO(3)(-)-dependent oxidation was mimicked by photolysis of an inorganic cobalt carbonato complex that generates CO(3). Metalloporphyrin antioxidants that are usually considered as SOD1 mimetic or peroxynitrite dismutase effectively scavenged the CO(3) radical. Implications of this reaction as a plausible protective mechanism in inflammatory cellular damage induced by peroxynitrite are discussed.

Amino Acids, Aromatic↗

PubMedDate not supplied

Reducing long-term remedial costs by transport modeling optimization.

The Department of Defense (DoD) Environmental Security Technology Certification Program and the Environmental Protection Agency sponsored a project to evaluate the benefits and utility of contaminant transport simulation-optimization algorithms against traditional (trial and error) modeling approaches. Three pump-and-treat facilities operated by the DoD were selected for inclusion in the project. Three optimization formulations were developed for each facility and solved independently by three modeling teams (two using simulation-optimization algorithms and one applying trial-and-error methods). The results clearly indicate that simulation-optimization methods are able to search a wider range of well locations and flow rates and identify better solutions than current trial-and-error approaches. The solutions found were 5% to 50% better than those obtained using trial-and-error (measured using optimal objective function values), with an average improvement of approximately 20%. This translated into potential savings ranging from 600,000 dollars to 10,000,000 dollars for the three sites. In nearly all cases, the cost savings easily outweighed the costs of the optimization. To reduce computational requirements, in some cases the simulation-optimization groups applied multiple mathematical algorithms, solved a series of modified subproblems, and/or fit "meta-models" such as neural networks or regression models to replace time-consuming simulation models in the optimization algorithm. The optimal solutions did not account for the uncertainties inherent in the modeling process. This project illustrates that transport simulation-optimization techniques are practical for real problems. However, applying the techniques in an efficient manner requires expertise and should involve iterative modification to the formulations based on interim results.

Algorithms↗

PubMedDate not supplied

Connexins and gap junctions in the inner ear.

Mutations in the genes for three different isotypes of the gap junction channel protein connexin are associated with deafness. This indicates an important role for gap junctions in auditory function and provides an opportunity to explore structure-function relationships in the connexin molecule. We have been examining the distribution of gap junctions and the pattern of connexin expression in the mature inner ear and during development, and the effect of specific mutations on the processing and functionality of the expressed connexin proteins in an in vitro system.

Cochlea↗