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R W Williams

Publications and source records attributed to R W Williams.

At least 37 records · Page 2Linked to original sources
PubMed2001

Complex trait analysis of the mouse striatum: independent QTLs modulate volume and neuron number.

BACKGROUND: The striatum plays a pivotal role in modulating motor activity and higher cognitive function. We analyzed variation in striatal volume and neuron number in mice and initiated a complex trait analysis to discover polymorphic genes that modulate the structure of the basal ganglia. RESULTS: Brain weight, brain and striatal volume, neuron-packing density and number were estimated bilaterally using unbiased stereological procedures in five inbred strains (A/J, C57BL/6J, DBA/2J, BALB/cJ, and BXD5) and an F2 intercross between A/J and BXD5. Striatal volume ranged from 20 to 37 mm3. Neuron-packing density ranged from approximately 50,000 to 100,000 neurons/mm3, and the striatal neuron population ranged from 1.4 to 2.5 million. Inbred animals with larger brains had larger striata but lower neuron-packing density resulting in a narrow range of average neuron populations. In contrast, there was a strong positive correlation between volume and neuron number among intercross progeny. We mapped two quantitative trait loci (QTLs) with selective effects on striatal architecture. Bsc10a maps to the central region of Chr 10 (LRS of 17.5 near D10Mit186) and has intense effects on striatal volume and moderate effects on brain volume. Stnn19a maps to distal Chr 19 (LRS of 15 at D19Mit123) and is associated with differences of up to 400,000 neurons among animals. CONCLUSION: We have discovered remarkable numerical and volumetric variation in the mouse striatum, and we have been able to map two QTLs that modulate independent anatomic parameters.

Animals↗
PubMed2001

Covalently bound ionene polyelectrolyte-silica gel stationary phases for HPLC.

Micelle-mimetic ionene-based stationary phases for high-performance liquid chromatography (HPLC) are prepared by attaching [3,16]- and [3,22]-ionenes to aminopropyl silica through a carbon-nitrogen bond. These [x,y]-ionenes are polyelectrolytic molecules consisting of dimethylammonium charge centers interconnected by alternating alkyl chain segments containing x and y methylene groups, some of which can form aggregate species whose properties mimic those of conventional surfactant micelles. These ionene-bonded stationary phases were characterized using different recommended HPLC test mixtures. Test solute chromatographic behavior on the ionene phases was found to be similar to that of intermediate oligomeric or polymeric C-18 and/or phenyl phases, depending upon the specific test mixture employed. In addition, the phases exhibit significant solute shape recognition ability. The ionene stationary phases were successfully employed for the separation of the components of the recommended ASTM reversed-phase test mixture, as well as for ortho-, meta- and para-disubstituted benzenes and other positional or geometric isomeric compounds. The ionene materials allow for chromatographic separations under either reversed-phase or ion-exchange conditions. The retention mechanism on these multimodal phases can occur by hydrophobic partitioning or electrostatic interactions, depending upon the characteristics of the components of the analyte mixture (neutral or anionic). The effects of alteration of the percent organic modifier, flow rate and temperature of the mobile phase on chromatographic retention and efficiency on these phases were briefly examined.

Journal Article↗
PubMed2001

Scaled quantum mechanical force field for alanyl-alanine peptide in solution.

We have obtained ab initio scale factors and assigned frequencies for the alanine-alanine peptide in water. Calculations were performed on the isolated acidic and basic Ala-Ala structures, two one-water basic Ala-Ala supermolecules, and one two-water acidic and one two-water basic Ala-Ala supermolecules. Force constants were scaled using the experimentally determined Raman and Fourier transform infrared vibrational frequencies of four isotopic species of Ala-Ala in water at pH 13 and pH 1. Most of the 4-31G scale factors were transferable from smaller molecules. All but one scale factor were directly transferable between the pH 1 and pH 13 species for coordinates unchanged by protonation in both the isolated and two-water supermolecule structures. Scale factors for nonpolar coordinates were transferable between all Ala-Ala species with only a few small changes. Good agreement was obtained between the calculated and experimental frequencies for all isotopic species and structures.

Dipeptides↗
PubMed2001

Identification of quantitative trait loci controlling activation of TRBV4 CD8+ T cells during murine gamma-herpesvirus-induced infectious mononucleosis.

The murine gamma-herpesvirus, MHV-68, shares important biological and genetic features with the human gamma-herpesvirus, Epstein-Barr virus. Following intranasal infection, mice develop an infectious mononucleosis-like syndrome accompanied by increased numbers of activated CD8+ T cells in the blood. A consistent feature of the CD8+ T-cell activation is a marked increase in the frequency of cells expressing a TRBV4+ T-cell receptor. Previous studies suggested that the magnitude of TRBV4 expansion varied significantly among mouse strains, and was influenced by both MHC and non-MHC genes. Detailed analysis of strains with high (C57BL/6) or low (DBA/2) TRBV4 CD8+ T-cell expansion showed that differences in the degree of expansion were not a consequence of variation in genetic susceptibility to the viral infection. Rather, the magnitude of the TRBV4 CD8+ T-cell expansion correlated with differences in expression of the unidentified stimulatory ligand on activated, latently infected B cells. In the present study, analysis of TRBV4 expansion in C57BL/6, DBA/2, B6D2 F1 mice, BXD recombinant inbred strains, and the progeny of C57BL/6xDBA/2 F1 hybrids backcrossed to C57BL/6 demonstrated strong cumulative dominance of the low DBA/2 trait and moderately high heritability (h2 approximately 0.5). Two quantitative trait loci (QTLs) strongly associated with variance in TRBV4 expansion were identified using simple and composite mapping procedures. The first QTL is located on Chromosome (Chr) 17, near or proximal to H2. The second QTL is located on Chr 6 in a region spanning the Tcrb and Cd8a loci.

Animals↗
PubMed2001

Genetic dissection of the olfactory bulbs of mice: QTLs on four chromosomes modulate bulb size.

Olfaction is influenced by a complex mix of environmental and genetic factors that modulate the production, migration, and maturation of cells in the olfactory bulbs. In this study we analyzed effects of sex, age, body weight, and brain weight on olfactory bulb size in sexually mature mice. We then used regression corrected values (residuals) to map quantitative trait loci (QTLs) that selectively modulate bulb weight. This biometric analysis has relied on an F2 intercross between C57BL/6J (B6) and DBA/2J (D2) inbred strains and a large sample of 35 BXD recombinant inbred (RI) strains. Bilateral bulb weight in adult mice ranges from 10 to 30 mg. Half of this remarkable variation can be predicted from differences in brain weight, sex, body weight, and age. A 100-mg difference in brain weight is associated with a 4.4-mg difference in bulb weight. Bulbs gain in weight by 0.2 mg/week--a 1% increase that continues until at least 300 days of age. Males tend to have slightly larger bulbs than females. By combining data from both related crosses (F2 and RI) we identified four QTLs with selective effects on bulb size (genomewide p < .05). Bulb4a is located on chromosome 4 (Chr 4) and Bulb6a is located on Chr 6. Alleles inherited from B6 at both of these loci increase bulb weight by 0.5-1.0 mg. Bulb11a is located on proximal Chr 11 and Bulb17a is located on the proximal part of Chr 17. In contrast to the first two QTLs, B6 alleles at these two loci decrease bulb weight by 0.5-1.0 mg. Collectively, the four loci account for 20% of the phenotypic variance in bulb weight.

Alleles↗
PubMed2001

QTL analysis and genomewide mutagenesis in mice: complementary genetic approaches to the dissection of complex traits.

Quantitative genetics and quantitative trait locus (QTL) mapping have undergone a revolution in the last decade. Progress in the next decade promises to be at least as rapid, and strategies for fine-mapping QTLs and identifying underlying genes will be radically revised. In this Commentary we address several key issues: first, we revisit a perennial challenge--how to identify individual genes and allelic variants underlying QTLs. We compare current practice and procedures in QTL analysis with novel methods and resources that are just now being introduced. We argue that there is no one standard of proof for showing QTL = gene; rather, evidence from several sources must be carefully assembled until there is only one reasonable conclusion. Second, we compare QTL analysis with whole-genome mutagenesis in mice and point out some of the strengths and weakness of both of these phenotype-driven methods. Finally, we explore the advantages and disadvantages of naturally occurring vs mutagen-induced polymorphisms. We argue that these two complementary genetic methods have much to offer in efforts to highlight genes and pathways most likely to influence the susceptibility and progression of common diseases in human populations.

Alleles↗
PubMed2001

The influence of human activity patterns on personal PM exposure: a comparative analysis of filter-based and continuous particle measurements.

Particulate matter (PM) exposure data from the U.S. Environmental Protection Agency (EPA)-sponsored 1998 Baltimore and 1999 Fresno PM exposure studies were analyzed to identify important microenvironments and activities that may lead to increased particle exposure for select elderly (>65 years old) subjects. Integrated 24-hr filter-based PM2.5 or PM10 mass measurements [using Personal Environmental Monitors (PEMs)] included personal measurements, indoor and outdoor residential measurements, and measurements at a central indoor site and a community monitoring site. A subset of the participants in each study wore passive nephelometers that continuously measured (1-min averaging time) particles ranging in size from 0.1 to approximately 10 microm. Significant activities and locations were identified by a statistical mixed model (p < 0.01) for each study population based on the measured PM2.5 or PM10 mass and time activity data. Elevated PM concentrations were associated with traveling (car or bus), commercial locations (store, office, mall, etc.), restaurants, and working. The modeled results were compared to continuous PM concentrations determined by the nephelometers while participants were in these locations. Overall, the nephelometer data agreed within 6% of the modeled PM2.5 results for the Baltimore participants and within approximately 20% for the Fresno participants (variability was due to zero drift associated with the nephelometer). The nephelometer did not agree as well with the PM10 mass measurements, most likely because the nephelometer optimally responds to fine particles (0.3-2 microm). Approximately one-half (54 +/- 31%; mean +/- standard deviation from both studies) of the average daily PM2.5 exposure occurred inside residences, where the participants spent an average of 83 +/- 10% of their time. These data also showed that a significant portion of PM2.5 exposure occurred in locations where participants spent only 4-13% of their time.

Activities of Daily Living↗
PubMed2001

Anxiety-related behaviors in the elevated zero-maze are affected by genetic factors and retinal degeneration.

Anxiety levels were tested in an elevated zero-maze for 8 inbred strains of mice that are used widely in biomedical and behavioral research. Strain differences were observed for activity, latency to enter an open quadrant, open time, and defecation, demonstrating that genetic factors mediate anxiety in this paradigm. Three of the strains have the rdl mutation that causes retinal degeneration and were less anxious in the maze. To discern whether visual acuity is a source of difference on the maze, anxiety levels were tested in a congenic strain in which the rdl allele has been replaced with the wild-type allele. The congenic strain, with normal vision, had higher levels of anxiety. This study provides baseline data for the selection and use of any of these strains in pharmacological challenges in the maze, and provides a starting point for the identification of strains that may have appropriate backgrounds for targeted mutation studies.

Alleles↗
PubMed2000

Structure of the cone photoreceptor mosaic in the retinal periphery of adult humans: analysis as a function of age, sex, and hemifield.

We have analyzed variation in the structure of the human photoreceptor mosaic as a function of age, sex, and retinal location using the nearest neighbor and density recovery profile methods. In contrast to most previous work, we have focused our analysis on the mid- and far-peripheral human retina. Video-enhanced differential interference contrast optics was used to characterize differences in the nasal and temporal periphery of unstained wholemounts from 12 males and 12 females ranging in age from 15- to 83-years-old. At sites matched for cone density (approximately 5,000 cones/mm2), the mosaic is far more orderly in the temporal than in the nasal periphery. This is true at all ages and in both sexes. Despite their increased local order, regularity ratios of adjacent temporal fields tend to be much more variable than are those of adjacent nasal fields. These marked nasal-temporal differences are eliminated when eccentricity is held constant and cone density is allowed to vary. There is a mild, statistically significant age-related decline in the regularity of the cone mosaic, but only in the nasal periphery. There are no significant differences in the precision of the cone mosaic between sexes. The equivalence of the regularity of the mosaic at matched eccentricities, but not at matched cone densities, suggests that the irregularity of the mosaic is secondary to developmental gradients and, more generally, to reduced selection for high acuity vision in the retinal periphery.

Adolescent↗
PubMed2000

Use of a continuous nephelometer to measure personal exposure to particles during the U.S. Environmental Protection Agency Baltimore and Fresno Panel studies.

In population exposure studies, personal exposure to PM is typically measured as a 12- to 24-hr integrated mass concentration. To better understand short-term variation in personal PM exposure, continuous (1-min averaging time) nephelometers were worn by 15 participants as part of two U.S. Environmental Protection Agency (EPA) longitudinal PM exposure studies conducted in Baltimore County, MD, and Fresno, CA. Participants also wore inertial impactor samplers (24-hr integrated filter samples) and recorded their daily activities in 15-min intervals. In Baltimore, the nephelometers correlated well (R2 = 0.66) with the PM2.5 impactors. Time-series plots of personal nephelometer data showed each participant's PM exposure to consist of a series of peaks of relatively short duration. Activities corresponding to a significant instrument response included cooking, outdoor activities, transportation, laundry, cleaning, shopping, gardening, moving between microenvironments, and removing/putting on the instrument. On average, 63-66% of the daily PM exposure occurred indoors at home (about 2/3 of which occurred during waking hours), primarily due to the large amount of time spent in that location (an average of 72-77%). Although not a reference method for measuring mass concentration, the nephelometer did help identify PM sources and the relative contribution of those sources to an individual's personal exposure.

Activities of Daily Living↗
PubMed2000

The 1999 Fresno particulate matter exposure studies: comparison of community, outdoor, and residential PM mass measurements.

Two collaborative studies have been conducted by the U.S. Environmental Protection Agency (EPA) National Exposure Research Laboratory (NERL) and National Health and Environmental Effects Research Laboratory to determine personal exposures and physiological responses to particulate matter (PM) of elderly persons living in a retirement facility in Fresno, CA. Measurements of PM and other criteria air pollutants were made inside selected individual residences within the retirement facility and at a central outdoor site on the premises. In addition, personal PM exposure monitoring was conducted for a subset of the participants, and ambient PM monitoring data were available for comparison from the NERL PM research monitoring platform in central Fresno. Both a winter (February 1-28, 1999) and a spring (April 19-May 16, 1999) study were completed so that seasonal effects could be evaluated. During the spring study, a more robust personal exposure component was added, as well as a more detailed evaluation of physical factors, such as air-exchange rate, that are known to influence the penetration of particles into the indoor environment. In this paper, comparisons are made among measured personal PM exposures and PM mass concentrations measured at the NERL Fresno Platform site, outside on the premises of the retirement facility, and inside selected residential apartments at the facility during the two 28-day study periods. The arithmetic daily mean personal PM2.5 exposure during the winter study period was 13.3 micrograms/m3, compared with 9.7, 20.5, and 21.7 micrograms/m3 for daily mean overall apartment, outdoor, and ambient (i.e., platform) concentrations, respectively. The daily mean personal PM2.5 exposure during the spring study period was 11.1 micrograms/m3, compared with 8.0, 10.1, and 8.6 micrograms/m3 for the daily mean apartment, outdoor, and ambient concentrations, respectively.

Aged↗
PubMed1999

Extrinsic modulation of retinal ganglion cell projections: analysis of the albino mutation in pigmentation mosaic mice.

Tyrosinase is a key enzyme involved in the synthesis of melanin in the retinal pigment epithelium (RPE). Mice that are homozygous for the albino allele at the tyrosinase locus have fewer retinal ganglion cells with uncrossed projections at the optic chiasm. To determine the site of the albino gene action we studied the projections of retinal ganglion cells in two types of pigmentation mosaic mice. First, we generated mosaic mice that contain a translocated allele of the wild-type tyrosinase on one X chromosome but that also have the lacZ reporter transgene on the opposite X chromosome. In these lacZ/tyrosinase mice, which are homozygous for the albino allele on chromosome 7, X-inactivation ensures that tyrosinase cannot be functional within 50% of the retinal ganglion cells and that these individual cells can be identified by their expression of the lacZ reporter gene product, beta-galactosidase. The proportion of uncrossed retinal ganglion cells expressing beta-galactosidase was found to be identical to the proportion that did not express it, indicating that the albino mutation associated with axonal behavior at the optic chiasm must affect ganglion cells in a cell-extrinsic manner. Second, to determine whether the RPE is the source of the extrinsic signal, we generated aggregation chimeras between pigmented and albino mice. In these mosaic mice, the extent of the uncrossed projection corresponded with the amount of pigmented cells within the RPE, but did not correspond with the genotypes of neural retinal cells. These studies demonstrate that the albino mutation acts indirectly upon retinal ganglion cells, which in turn respond by making axonal guidance errors at the optic chiasm.

Albinism↗
PubMed1999

Asymmetric connections, duplicate layers, and a vertically inverted map in the primary visual system.

The achiasmatic mutation is a remarkable and rare visual system mutation carried in a line of black sheepdogs. In affected animals, the optic chiasm is missing, and each retina projects entirely to the ipsilateral hemisphere. As a result of this navigational error, maps of visual space in the lateral geniculate nucleus (LGN) have a unique structure with mirror reversals of field position across the A-A1 border. Animals also have a persistent and severe congenital nystagmus. In this report we analyze a novel variant of the achiasmatic mutation, one in which retinal axons from only one eye successfully cross midline and in which the great majority of fibers from both eyes terminate in a single lateral geniculate nucleus. The dominant optic tract contains four times as many axons as the other tract. The hyperinnervated LGN has a lamination pattern consisting of duplicate and partly interwoven layers. A multiunit mapping study of visual cortex (primarily area 17 along the marginal gyrus) shows that receptive field topography and orientation selectivity are normal. The size of central binocular visual space is nearly normal and is flanked by monocular domains in the periphery. However, there is an inexplicable vertical inversion in the orientation of the cortical representation: superior fields are located rostrally, and inferior fields are located caudally. Despite a host of drastic abnormalities at all level of the visual system, from retina to cortex, this animal was behaviorally indistinguishable from normal dogs and did not have any detectable oculomotor abnormalities.

Animals↗
PubMed1999

Prion domain initiation of amyloid formation in vitro from native Ure2p.

The [URE3] non-Mendelian genetic element of Saccharomyces cerevisiae is an infectious protein (prion) form of Ure2p, a regulator of nitrogen catabolism. Here, synthetic Ure2p1-65 were shown to polymerize to form filaments 40 to 45 angstroms in diameter with more than 60 percent beta sheet. Ure2p1-65 specifically induced full-length native Ure2p to copolymerize under conditions where native Ure2p alone did not polymerize. Like Ure2p in extracts of [URE3] strains, these 180- to 220-angstrom-diameter filaments were protease resistant. The Ure2p1-65-Ure2p cofilaments could seed polymerization of native Ure2p to form thicker, less regular filaments. All filaments stained with Congo Red to produce the green birefringence typical of amyloid. This self-propagating amyloid formation can explain the properties of [URE3].

Amyloid↗
PubMed1999

The PERIANTHIA gene encodes a bZIP protein involved in the determination of floral organ number in Arabidopsis thaliana.

Mutations in the PERIANTHIA (PAN) gene of Arabidopsis thaliana specifically transform flowers from tetramerous to largely pentamerous, which is a characteristic of flowers of ancestral plants. We have cloned the PAN gene and here we show that it encodes a member of the basic region/leucine zipper class of transcription factors. Immunohistochemical analysis shows that the encoded protein is present in the apical meristem, the floral meristem, each whorl of organ primordia, and in ovule primordia during wild-type flower development. PAN expression occurs independently of genes affecting floral meristem identity, floral meristem size, or floral organ number. The near absence of a phenotype in transgenic plants overexpressing PAN and the contrast between the broad expression of PAN and the specificity of its mutant phenotype suggest that its activity may be regulated post-translationally or by the presence of partner proteins. Based on these results and on data reported previously, we propose models for the role of PAN in the evolution of flower pattern in the mustard family.

Amino Acid Sequence↗
PubMed1999

A targeted screen to detect recessive mutations that have quantitative effects.

A key problem in mutagenesis research is developing methods that are sufficiently sensitive to detect a wide range of abnormal phenotypes. Major variants may be easy to identify, but it can be difficult to detect mutations that have subtle effects, particularly on a complex genetic background. This paper describes a targeted mutagenesis protocol with enough sensitivity to detect recessive mutations that have modest quantitative effects. The procedure relies on consomic inbred strains of mice-strains in which one homologous pair of chromosomes of an inbred strain has been replaced with the corresponding pair from a donor strain. Mice that carry the desired donor chromosome-the target of the screen-are mutagenized and bred back to the original recipient strain. The first-generation progeny (G1) that are heterozygous only for the donor chromosome are also bred back to the recipient strain. G2 animals that inherit nonrecombinant donor chromosomes are identified by genotyping. These animals may be backcrossed repeatedly to the recipient strain to dilute off-target mutations, but ultimately, nonrecombinant G2 animals are bred to each other. Their G3 progeny are genotyped at markers spaced at 5- to 10-cM intervals to identify mating pairs that are homozygous for shared segments of the mutagenized donor chromosome. Entire litters of G4 progeny that are homozygous for defined intervals are screened. By comparing phenotypes within and among litters of nearly isogenic G4 animals, mutations can be verified and simultaneously mapped with a precision of 5-10 cM. This method has the potential to consistently detect mutations that have effects on trait means of well under one standard deviation.

Animals↗