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Biomedical subjects

R W Williams

Publications and source records attributed to R W Williams.

At least 91 records · Page 5Linked to original sources
PubMed1994

Role of the intestinal microbiota in the activation of the promutagen 2,6-dinitrotoluene to mutagenic urine metabolites and comparison of GI enzyme activities in germ-free and conventionalized male Fischer 344 rats.

After male germ-free and conventionalized Fischer 344 rats were administered per os (p.o.) 75 mg/kg 2,6-DNT, intestinal nitroreductase, beta-glucuronidase, and azo reductase activities were lower in the cecum and large intestine of germ-free animals. However, there was no significant difference in the small intestinal nitroreductase and azo reductase compared to the conventionalized counterparts. This indicated a potential mucosal source for the enzymes. Urines from germ-free rats (1144 +/- 64 revertants/ml) were less mutagenic than those from conventionalized animals (1467 +/- 171 revertants/ml) in Salmonella typhimurium strain TA98 without S9. In the presence of S9, urine from conventionalized animals (894 +/- 56 revertants/ml) was more mutagenic than that from germ-free rats (686 +/- 60 revertants/ml). The presence of the intestinal flora plays an important role in the activation of 2,6-DNT but other metabolic pathways, such as the small intestinal mucosal and/or hepatic enzymes, are present that can generate excreted genotoxicants.

Animals↗
PubMed1994

Target recognition and visual maps in the thalamus of achiasmatic dogs.

Vision is dependent on ordered neuronal representations or maps of visual space. These maps depend on precise connections between retinal axons and their targets cells. In mammals, nerve fibres from right and left eyes produce congruent maps of contralateral visual space in adjacent layers of the lateral geniculate nucleus (LGN). We have identified an autosomal recessive mutation in Belgian sheepdogs that eliminates the optic chiasm. In these mutants, all retinal axons project into the ipsilateral optic tract, including those originating in the nasal hemiretina that normally cross midline. These animals exhibit a pronounced horizontal nystagmus. The abnormal ipsilaterally directed nasal fibres innervate the LGN as if they had successfully crossed the midline, terminating in the appropriate layer of the nucleus. As a consequence, the LGN contains non-congruent, mirror-image maps of visual space in adjacent layers. These results show that there is a robust affinity between nasal and temporal retinal axons and specific LGN layers even when all retinal axons originate from a single eye.

Animals↗
PubMed1994

The Portable Dictionary of the Mouse Genome: a personal database for gene mapping and molecular biology.

The Portable Dictionary of the Mouse Genome is a database for personal computers that contains information on approximately 10,000 loci in the mouse, along with data on homologs in several other mammalian species, including human, rat, cat, cow, and pig. Key features of the dictionary are its compact size, its network independence, and the ability to convert the entire dictionary to a wide variety of common application programs. Another significant feature is the integration of DNA sequence accession data. Loci in the dictionary can be rapidly resorted by chromosomal position, by type, by human homology, or by gene effect. The dictionary provides an accessible, easily manipulated set of data that has many uses--from a quick review of loci and gene nomenclature to the design of experiments and analysis of results. The Portable Dictionary is available in several formats suitable for conversion to different programs and computer systems. It can be obtained on disk or from Internet Gopher servers (mickey.utmen.edu or anat4.utmen.edu), an anonymous FTP site (nb.utmem.edu in the directory pub/genedict), and a World Wide Web server (http://mickey.utmem.edu/front.html).

Animals↗
PubMed1994

Ossifying fibromyxoid tumour of soft parts--a new tumour of the parotid/zygomatic arch region.

The ossifying fibromyxoid tumour of soft parts was first described as recently as 1989 by Enzinger has not been previously reported in the maxillofacial literature. This tumour has a proven record of recurrence and a potential in a few cases to become malignant and to metastasise. Being such a rare and relatively newly described tumour it has proved to be difficult to diagnose and manage. In order to illustrate these difficulties we describe a case in which such a tumour occurred in the parotid/zygomatic arch region and recurred three times following surgical removal over a period of 24 years. Since the tumour has a pseudo-capsule containing nests of tumour cells, we recommend that it could be removed from the head and neck region with a wide margin of excision.

Adult↗
PubMed1993

Potentiation of 2,6-dinitrotoluene genotoxicity in Fischer-344 rats by pretreatment with Aroclor 1254.

Pretreatment of Fischer 344 rats for 5 weeks with Aroclor 1254, a commercial mixture of polychlorinated biphenyls, potentiated the genotoxicity of 2,6-dinitrotoluene (DNT), a component of an industrial chemical used in the production of polyurethane foams. This interaction resulted from Aroclor 1254-mediated bioactivation of DNT to markedly greater levels of the genotoxic metabolites, that were excreted in urine and formed DNA adducts in the liver. A significant increase in the excretion of mutagenic urinary DNT metabolites was observed after the first week of Aroclor 1254 treatment, peaked at week 2 and then declined by nearly 25% at week 4. Nevertheless, by week 5, there was almost a 4-fold increase in the formation of hepatic DNA adducts. Significantly elevated hepatic metabolism and increased beta-glucuronidase in the small intestine and cecum, at 4 weeks, may account for the increased adducts and decreased urinary mutagens. Altered nitroreductase activity, reduced pH, and changes in the microfloral population may also play a role in the effect of Aroclor 1254 on the bioactivation of DNT. Such chemical interactions could be important to predictive risk assessment because the overall cancer risk of the mixture would exceed that determined by the current guidelines for chemical mixtures.

Animals↗
PubMed1993

Conformational preference functions for predicting helices in membrane proteins.

A suite of FORTRAN programs, PREF, is described for calculating preference functions from the data base of known protein structures and for comparing smoothed profiles of sequence-dependent preferences in proteins of unknown structure. Amino acid preferences for a secondary structure are considered as functions of a sequence environment. Sequence environment of amino acid residue in a protein is defined as an average over some physical, chemical, or statistical property of its primary structure neighbors. The frequency distribution of sequence environments in the data base of soluble protein structures is approximately normal for each amino acid type of known secondary conformation. An analytical expression for the dependence of preferences on sequence environment is obtained after each frequency distribution is replaced by corresponding Gaussian function. The preference for the alpha-helical conformation increases for each amino acid type with the increase of sequence environment of buried solvent-accessible surface areas. We show that a set of preference functions based on buried surface area is useful for predicting folding motifs in alpha-class proteins and in integral membrane proteins. The prediction accuracy for helical residues is 79% for 5 integral membrane proteins and 74% for 11 alpha-class soluble proteins. Most residues found in transmembrane segments of membrane proteins with known alpha-helical structure are predicted to be indeed in the helical conformation because of very high middle helix preferences. Both extramembrane and transmembrane helices in the photosynthetic reaction center M and L subunits are correctly predicted. We point out in the discussion that our method of conformational preference functions can identify what physical properties of the amino acids are important in the formation of particular secondary structure elements.

Animals↗
PubMed1993

Rapid evolution of the visual system: a cellular assay of the retina and dorsal lateral geniculate nucleus of the Spanish wildcat and the domestic cat.

The large Spanish wildcat, Felis silvestris tartessia, has retained features of the Pleistocene ancestor of the modern domestic cat, F. catus. To gauge the direction and magnitude of short-term evolutionary change in this lineage, we have compared the retina, the optic nerve, and the dorsal lateral geniculate nucleus (LGN) of Spanish wildcats and their domestic relatives. Retinas of the two species have the same area. However, densities of cone photoreceptors are higher in wildcat--over 100% higher in the area centralis--whereas rod densities are as high, or higher, in the domestic lineage. Densities of retinal ganglion cells are typically 20-100% higher across the wildcat retina, and the total ganglion cell population is nearly 70% higher than in the domestic cat. These differences are confined to the populations of beta and gamma retinal ganglion cells. In contrast, the population of alpha cells is almost precisely the same in both species. The wildcat LGN is much larger than that of the domestic cat and contains approximately 50% more neurons. However, cell size does not differ appreciably in either the retina or LGN of these species. The differences in total numbers of ganglion cells and LGN neurons correspond neatly to the overall decline in brain size in the domestic lineage and to allometric predictions based on average species differences in body size. We suggest that an increase in the severity of naturally occurring cell death is the most plausible mechanism that can account for the rapid evolutionary reduction in cell populations in this feline lineage.

Animals↗
PubMed1993

Lumbar disc disease. Microdiscectomy.

This article discusses a rationale for the use of microsurgical technique when treating lumbar disc herniations. The rigid surgical discipline of microlumbar discectomy is presented along with a suggested means to best preserve the future competence of the anulus fibrosis.

Humans↗
PubMed1992

Structure of clonal and polyclonal cell arrays in chimeric mouse retina.

One of the most striking results of recent cell-lineage studies of vertebrate retina is the marked variability in the size and types of clones marked by retroviral transfection and dye injection of embryonic progenitor cells. Is this variability due to microenvironmental modulation of cell determination, to lineage restriction, or to experimental perturbation of the progenitor cells? We have taken advantage of species-specific DNA probes to mark groups of lineage-related cells in experimental mouse chimeras. This method of marking cells has two distinct advantages over previous methods: direct manipulation of progenitor cells is avoided, and clones are established at an earlier stage of retinal development. The most notable feature of retinal cohorts in chimeras is their structural uniformity--each is a solid radial array that contains the same ratio of major cell types as the retina itself. This is true even of the smallest monoclonal cohorts, which contain fewer than 200 cells. Our results provides compelling empirical support for the hypothesis that the murine retina is made up of hundreds of relatively homogeneous radial units, each derived from single retinal precursor cells. This finding is inconsistent with micro-environmental modulation of clone structure early in development. We raise the possibility that the heterogeneity among clones marked by dye injection and transfection is due to progressive lineage restriction or to experimental perturbation of the retinal progenitor cells.

Animals↗
PubMed1992

Lineage versus environment in embryonic retina: a revisionist perspective.

The idea that microenvironmental cues act alone late in development to determine a cell's phenotype has dominated recent discussion of, retinal development, and has successfully displaced the notion of any role for cell lineage in the process of cell determination. We argue that there is, in fact, evidence favoring a degree of lineage restriction during the development of the vertebrate retina. We propose that environmental factors modulate a process of progressive lineage restriction. In this model, progenitor cells are viewed as having unequal potential, and their progeny are viewed as being committed to one of the major retinal cell classes before the stage at which they become postmitotic.

Animals↗
PubMed1992

Development of source testing, analytical, and mutagenicity bioassay procedures for evaluating emissions from municipal and hospital waste combustors.

Incineration is currently being used for disposal of about 10% of the solid waste generated in the United States, and this percentage will likely increase as land disposal declines. Siting new incinerators, however, is often controversial because of concerns related to the possibility of adverse health effects and environmental contamination from long-term exposure to stack emissions. Specific concerns relate to the adequacies of a) stack emission testing protocols, b) existing regulations, and c) compliance monitoring and enforcement of regulations. U.S. Environmental Protection Agency laboratories are cooperatively conducting research aimed at developing new testing equipment and procedures that will allow a more comprehensive assessment of the complex mixture of organics that is present in stack emissions. These efforts are directed specifically toward developing source testing equipment and procedures, analytical procedures, and bioassay procedures. The objectives of this study were to field test two types of high-volume source dilution samplers, collect stack samples for use in developing analytical and mutagenicity bioassay procedures, and determine mutagenicity of organics associated with emission particles from two municipal waste combustors and a hospital waste combustor. Data are presented for particle concentrations and emission rates, extractable organic concentrations and emission rates, and Salmonella (Ames) mutagenic potency and emission rates. The mutagenic emission rates and emission factors are compared to other incinerators and combustion sources.

Air Pollutants↗
PubMed1991

The structure of human acidic fibroblast growth factor and its interaction with heparin.

The secondary and tertiary structure of recombinant human acidic fibroblast growth factor (aFGF) has been characterized by a variety of spectroscopic methods. Native aFGF consists of ca. 55% beta-sheet, 20% turn, 10% alpha-helix, and 15% disordered polypeptide as determined by laser Raman, circular dichroism, and Fourier transform infrared spectroscopy; the experimentally determined secondary structure content is in agreement with that calculated by the semi-empirical methods of Chou and Fasman (Chou, P. Y., and Fasman, G. C., 1974, Biochemistry 13, 222-244) and Garnier et al. (Garnier, J. O., et al., 1978, J. Mol. Biol. 120, 97-120). Using the Garnier et al. algorithm, the major secondary structure components of aFGF have been assigned to specific regions of the polypeptide chain. The fluorescence spectrum of native aFGF is unusual in that it is dominated by tyrosine fluorescence despite the presence of a tryptophan residue in the protein. However, tryptophan fluorescence is resolved upon excitation above 295 nm. The degree of tyrosine and tryptophan solvent exposure has been assessed by a combination of ultraviolet absorption, laser Raman, and fluorescence spectroscopy; the results suggest that seven of the eight tyrosine residues are solvent exposed while the single tryptophan is partially inaccessible to solvent in native aFGF, consistent with recent crystallographic data. Denaturation of aFGF by extremes of temperature or pH leads to spectroscopically distinct conformational states in which contributions of tyrosine and tryptophan to the fluorescence spectrum of the protein vary. The protein is unstable at physiological temperatures. Addition of heparin or other sulfated polysaccharides does not affect the spectroscopic characteristics of native aFGF. These polymers do, however, dramatically stabilize the native protein against thermal and acid denaturation as determined by differential scanning calorimetry, circular dichroism, and fluorescence spectroscopy. The interaction of aFGF with such polyanions may play a role in controlling the activity of this growth factor in vivo.

Algorithms↗
PubMed1991

Designed coiled-coil proteins: synthesis and spectroscopy of two 78-residue alpha-helical dimers.

Receptor-adhesive modular proteins are nongenetic proteins designed to contain ligand, spacer, coil, and linker modules and to interact strongly with integrins or other types of cell-surface receptors. We have designed, chemically synthesized, and characterized a 39-residue peptide chain having a 6-residue ligand module (Gly-Arg-Gly-Asp-Ser-Pro-) for adherence to Arg-Gly-Asp-binding integrin receptors, a 3-residue spacer module (-Gly-Tyr-Gly-) for flexibility, and a 30-residue coil module [-(Arg-Ile-Glu-Ala-Ile-Glu-Ala) 4-Arg-Cys-NH2] containing four 7-residue repeats for dimerization. This chain was designed to form a 78-residue noncovalent dimer (P39) by folding the coils of two chains into an alpha-helical coiled coil through hydrophobic interaction of eight pairs of Ile residues. Air oxidation of P39 gave P78, a 78-residue covalent dimer having a disulfide bridge linking its C termini. Raman spectroscopy indicated that both synthetic proteins have high alpha-helical content. Ultraviolet circular dichroic spectroscopy indicated that both dimers contain stable alpha-helical coiled coils. Its C-terminal disulfide bridge renders P78 significantly more stable than P39 to thermal denaturation or denaturation by urea. The coiled coil of P39 was 30% unfolded near 55 degrees C and half-unfolded in 8 M urea, while that of P78 was 30% unfolded only near 85 degrees C. These studies have demonstrated the feasibility of using these ligand, spacer, and coil modules to construct the designed coiled-coil proteins P39 and P78, a stage in the nanometric engineering of receptor-adhesive modular proteins.

Amino Acid Sequence↗