Biomedical subjects

J M Olson

Publications and source records attributed to J M Olson.

At least 37 records · Page 2Linked to original sources

PubMed2001

A novel UDP-glucose transferase is part of the callose synthase complex and interacts with phragmoplastin at the forming cell plate.

Using phragmoplastin as a bait, we isolated an Arabidopsis cDNA encoding a novel UDP-glucose transferase (UGT1). This interaction was confirmed by an in vitro protein--protein interaction assay using purified UGT1 and radiolabeled phragmoplastin. Protein gel blot results revealed that UGT1 is associated with the membrane fraction and copurified with the product-entrapped callose synthase complex. These data suggest that UGT1 may act as a subunit of callose synthase that uses UDP-glucose to synthesize callose, a 1,3-beta-glucan. UGT1 also interacted with Rop1, a Rho-like protein, and this interaction occurred only in its GTP-bound configuration, suggesting that the plant callose synthase may be regulated by Rop1 through the interaction with UGT1. The green fluorescent protein--UGT1 fusion protein was located on the forming cell plate during cytokinesis. We propose that UGT1 may transfer UDP-glucose from sucrose synthase to the callose synthase and thus help form a substrate channel for the synthesis of callose at the forming cell plate.

Arabidopsis↗

PubMed2001

The heritability of attitudes: a study of twins.

The genetic basis of individual differences in attitudes was examined in a survey of 195 pairs of monozygotic twins and 141 pairs of same-sex dizygotic twins. A principal components analysis of the 30 attitude items in the survey identified 9 attitude factors, of which 6 yielded significant heritability coefficients. Nonshared environmental factors accounted for the most variance in the attitude factors. Possible mediators of attitude heritability were also assessed, including personality traits, physical characteristics, and academic achievement. Analyses showed that several of these possible mediators correlated at a genetic level with the heritable attitude factors, suggesting that the heritability of the mediator variables might account for part of the heritable components of some attitudes. There was also some evidence that highly heritable attitudes were psychologically "stronger" than less heritable attitudes.

Achievement↗

PubMed2000

Ascertainment adjustment: where does it take us?

It is commonly assumed that the parameter estimates of a statistical genetics model that has been adjusted for ascertainment will estimate parameters in the general population from which the ascertained subpopulation was originally drawn. We show that this is true only in certain restricted circumstances. More generally, ascertainment-adjusted parameter estimates reflect parameters in the ascertained subpopulation. In many situations, this shift in perspective is immaterial: the parameters of interest are the same in the ascertained sample and in the population from which it was drawn, and it is therefore irrelevant to which population inferences are presumed to apply. In other circumstances, however, this is not so. This has important implications, particularly for studies investigating the etiology of complex diseases.

Computer Simulation↗

PubMed2000

Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving at least hormonal, environmental, and genetic factors. Familial aggregation, a 2%-3% sibling recurrence rate, monozygotic twin concordance >20%, association with several candidate genes, as well as the results of five genome scans support a genetic component. We present here the results of a genome scan of 126 pedigrees multiplex for SLE, including 469 sibling pairs (affected and unaffected) and 175 affected relative pairs. Using the revised multipoint Haseman-Elston regression technique for concordant and discordant sibling pairs and a conditional logistic regression technique for affected relative pairs, we identify a novel linkage to chromosome 4p16-15.2 (P=.0003 and LOD=3.84) and present evidence of an epistatic interaction between chromosome 4p16-15.2 and chromosome 5p15 in our European American families. We confirm the evidence of linkage to chromosome 4p16-15.2 in European American families using data from an independent pedigree collection. In addition, our data support the published results of three independent studies for nine purportedly linked regions and agree with the previously published results from a subset of these data for three regions. In summary, results from two new analytical techniques establish and confirm linkage with SLE at 4p16-15.2, indicate epistasis between 4p16-15.2 and 5p15, and confirm other linkage effects with SLE that have been reported elsewhere.

Africa↗

PubMed2000

Decreased expression of striatal signaling genes in a mouse model of Huntington's disease.

To understand gene expression changes mediated by a polyglutamine repeat expansion in the human huntingtin protein, we used oligonucleotide DNA arrays to profile approximately 6000 striatal mRNAs in the R6/2 mouse, a transgenic Huntington's disease (HD) model. We found diminished levels of mRNAs encoding components of the neurotransmitter, calcium and retinoid signaling pathways at both early and late symptomatic time points (6 and 12 weeks of age). We observed similar changes in gene expression in another HD mouse model (N171-82Q). These results demonstrate that mutant huntingtin directly or indirectly reduces the expression of a distinct set of genes involved in signaling pathways known to be critical to striatal neuron function.

Adenylyl Cyclases↗

PubMed2000

Ascertainment bias in the estimation of sibling genetic risk parameters.

The sibling recurrence risk, sibling relative risk, and locus-specific sibling relative risk are fundamental quantities in genetic epidemiologic research and are often estimated without accounting for the sampling scheme. For data generated under some genetic models, bias of estimates may be large if the sampling method is incorrectly modeled. In this paper, we explore the relationship between ascertainment of sibships and estimation and interpretation of genetic risk parameters. In particular, we observe that, although traditional definitions of these population parameters are consistent with each other, implied assumptions about ascertainment and the nature of ascertainment correction differ. In the absence of ascertainment correction, unbiased estimation of sibling recurrence risk and overall sibling relative risk requires single ascertainment, while unbiased estimation of locus-specific sibling relative risk requires complete ascertainment.

Bias↗

PubMed2000

Correcting for ascertainment bias of relative-risk estimates obtained using affected-sib-pair linkage data.

Locus-specific sibling relative risk is often estimated using affected-sib-pair lod score analysis of affected sibships and may be used to decide whether to continue or discontinue the search for additional susceptibility genes. We showed that relative-risk estimates obtained using affected-sib-pair data are asymptotically unbiased when each pair is given a weight inversely proportional to the sibship ascertainment probability. Here we show by simulation that the extent of the bias of relative risks estimated using the incorrect ascertainment weights is small for dominant models, but large for single-locus recessive models and some two-locus heterogeneity models. Since in practice the ascertainment scheme is often unknown, we investigate methods for jointly estimating ascertainment and relative risks from affected-sibship data. Given a sufficient sample size, a reasonable estimate of relative risk may always be obtained using only affected pairs from sibships with two affected and no unaffected siblings. This estimate, which has a large variance, may then be used in a three-stage procedure (which we call the alpha method) to estimate consistently both the ascertainment probabilities and the relative risks with greater precision. We additionally propose correction factors to eliminate small-sample bias of relative risks and investigate the bias due to error in the estimate of disease locus location.

Bias↗

PubMed2000

Haseman and Elston revisited.

Haseman and Elston (H-E) [1972] proposed a method to detect quantitative trait loci by linkage to a marker. The squared sib-pair trait difference is regressed on the proportion of marker alleles the pair is estimated to share identical by descent: a significantly negative regression coefficient suggests linkage. It has been shown that a maximum likelihood method that directly models the sib-pair covariance has more power. This increase in power can also be obtained using the H-E regression procedure by changing the dependent variable from the squared difference to the mean-corrected product of the sibs' trait values. Multiple sibs in a sibship can be accommodated by allowing for the correlations between pairs of products in a generalized least squares procedure. Multiple trait loci, including epistatic interactions, involve only multiple linear regression. Multivariate traits can use the method of Amos et al. [1990] to find the linear function of the traits that maximizes the evidence for linkage, which now leads more simply to a test of significance. Multiple markers can be the basis of a multipoint analysis. Results of simulation studies for a continuous trait are presented that investigate Type I error and power. A similar general scheme can be used to study affected sib pairs, testing whether their identity by descent sharing probabilities are greater than would be expected in the absence of linkage, and to study other types of relative pairs.

Alleles↗

PubMed2000

Generation of neurons by transient expression of neural bHLH proteins in mammalian cells.

Basic helix-loop-helix (bHLH) transcription factors are known to function during mammalian neurogenesis. Here we show that transient transfection of vectors expressing neuroD2, MASH1, ngn1 or related neural bHLH proteins, with their putative dimerization partner E12, can convert mouse P19 embryonal carcinoma cells into differentiated neurons. Transfected cells express numerous neuron-specific proteins, adopt a neuronal morphology and are electrically excitable. Thus, the expression of neural bHLH proteins is sufficient to confer a neuronal fate on uncommitted mammalian cells. Neuronal differentiation of transfected cells is preceded by elevated expression of the cyclin-dependent kinase inhibitor p27(Kip1) and cell cycle withdrawal. This demonstrates that the bHLH proteins can link neuronal differentiation to withdrawal from the cell cycle, possibly by activating the expression of p27(Kip1). The ability to generate mammalian neurons by transient expression of neural bHLH proteins should create new opportunities for studying neurogenesis and devising neural repair strategies.

Animals↗

PubMed1999

Genetic mapping of complex traits.

Statistical genetic mapping methods are powerful tools for finding genes that contribute to complex human traits. Mapping methods combine knowledge of the biological mechanisms of inheritance and the randomness inherent in those mechanisms to locate, with increasing precision, trait genes on the human genome. We provide an overview of the two major classes of mapping methods, genetic linkage analysis and linkage disequilibrium analysis, and related concepts of genetic inheritance.

Chromosome Mapping↗

PubMed1999

Linkage of chromosome 1 markers to alcoholism-related phenotypes by sib pair linkage analysis of principal components.

Using the Collaborative Study on the Genetics of Alcoholism data and affected-sib-pair linkage methods, Reich et al. [1998] reported linkage of alcohol dependence to a region near D1S1588 on chromosome 1. In this paper, we assessed the ability of multivariate sib-pair linkage analysis of the neurophysiologic measurements (including age and sex) to evaluate evidence for linkage to chromosome 1. Principal components of 16 neurophysiologic measurements, plus age and sex, were analyzed separately using sib-pair linkage analysis, and a cumulative sum of the resulting t2-statistics computed at each point on the chromosome. The first four principal components, which accounted for 74% of the total variation, showed little or no evidence for linkage in the D1S1588 region, while the remaining components showed substantial evidence for linkage. We conclude that potentially important linkage results can be missed if investigators limit attention only to major sources of variability.

Age Factors↗

PubMed1999

Thyroid development in relation to the development of endothermy in the red-winged blackbird (Agelaius phoeniceus).

We investigated the development of thyroid function during the transition to endothermy in red-winged blackbirds (Agelaius phoeniceus). Thermoregulatory capabilities of blackbirds improve markedly over their relatively short nestling period (10-12 days), with the most striking improvements occurring between days 6 and 8. We hypothesized that the development of endothermy in these birds is dependent in part on the development of thyroid function. We assessed thyroid development by measuring changes in thyroid gland histology and plasma concentrations of thyroxine (T4) and triiodothyronine (T3) during the nestling period. To gain insight into the role of thyroid maturation in the context of thermoregulation, we compared plasma thyroid hormone profiles in nestlings exposed to cold temperatures to those maintained at thermoneutral temperatures. The overall size of the thyroid (as cross-sectional area) increased during nestling development, with the fastest growth occurring just before the development of endothermy. By day 8, it reached the size typical of that in adults. Follicular cell height of the thyroid glands increased in nestlings up to day 6 and then decreased for the rest of the nestling period. The mean area of individual follicles increased up to day 8 of nestling life and then decreased. Individual nestlings were capable of strong endothermic responses at 7 to 8 days of age and had significantly decreased plasma T4 concentrations following cold exposure, suggesting increased T4 to T3 deiodination to maintain the plasma concentrations of the more metabolically active T3. The patterns of plasma T4 and T3 during nestling development were consistent with those of nestlings of other altricial species of birds that have been studied. Overall, the patterns of thyroid development observed were consistent with the hypothesis that the functional development of the thyroid is critical to the development of endothermic capabilities and that thyroid hormones play a role in endothermic responses to cold temperatures.

Animals↗

PubMed1999

Overview of QTL mapping software and introduction to map manager QT.

At least ten software packages are available for marker-based detection and localization of loci contributing to quantitative traits in experimental animals and plants. Many of these have unique strengths or situations in which they are particularly useful. Six were developed by or in collaboration with plant geneticists and may not be well known to mammalian geneticists. These software packages are reviewed here and compared with a previously undescribed program, Map Manager QT, a Mac OS microcomputer program for mapping quantitative trait loci in populations derived from backcrosses, intercrosses, and recombinant inbred lines. Map Manager QT is an enhanced version of Map Manager Classic (Map Manager v2.6.5, Manly 1993), designed for mapping Mendelian loci. This review describes the methods Map Manager QT uses for mapping quantitative trait loci and describes other features that differ from those in Map Manager Classic. A complete description of both Map Manager Classic and Map Manager QT is available in the user manual, the on-line version of which can be found at http://mcbio.med.buffalo.edu/MMM/MMM.ht ml.

Animals↗

PubMed1999

Relationship estimation by Markov-process models in a sib-pair linkage study.

The results of sib-pair linkage studies may be compromised if a substantial number of putative sib pairs are not actually sib pairs. For classification of pairs in a sib-pair genome scan, I propose multipoint methods that are based on a Markov-process model of allele sharing along the chromosome. These methods can be implemented by standard algorithms that compute multipoint marker allele-sharing probabilities for sib pairs. When marker data from at least half the genome are used, misclassification rates are small. The methods will be implemented in an upcoming version of the computer software package S.A.G.E.

Alleles↗

PubMed1999

A general conditional-logistic model for affected-relative-pair linkage studies.

Model-free LOD-score methods are often employed to detect linkage between marker loci and common diseases, with samples of affected sib pairs. Although extensions of the basic one-disease-locus model have been proposed that allow separate inclusion of other types of affected relative pairs, discordant relative pairs, covariates, or additional disease loci, a unified framework that can handle all of these features has been lacking. In this report, I propose a conditional-logistic parameterization that generalizes easily to include all of these features. Two data examples, one using simulated data and one using type 1 diabetes, illustrate applications of the models.

Alleles↗

PubMed1999

The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells.

Upon activation, brain microglial cells release proinflammatory mediators, such as nitric oxide (NO), which may play an important role in the central nervous system antibacterial, antiviral, and antitumor activities. However, excessive release of NO has been postulated to elicit immune-mediated neurodegenerative inflammatory processes and to cause brain injury. In the present study, the effect of cannabinoids on the release of NO from endotoxin/cytokine-activated rat cortical microglial cells was evaluated. A drug dose-dependent (0.1 microM-8 microM) inhibition of NO release from rat microglial cells was exerted by the cannabinoid receptor high-affinity binding enantiomer (-)-CP55940. In contrast, a minimal inhibitory effect was exerted by the lower affinity binding paired enantiomer (+)-CP56667. Pretreatment of microglial cells with the Galphai/Galphao protein inactivator pertussis toxin, cyclic AMP reconstitution with the cell-permeable analog dibutyryl-cAMP, or treatment of cells with the Galphas activator cholera toxin, resulted in reversal of the (-)-CP55940-mediated inhibition of NO release. A similar reversal in (-)-CP55940-mediated inhibition of NO release was effected when microglial cells were pretreated with the central cannabinoid receptor (CB1) selective antagonist SR141716A. Mutagenic reverse transcription-polymerase chain reaction, Western immunoblot assay using a CB1 receptor amine terminal domain-specific antibody, and cellular colocalization of CB1 and the microglial marker Griffonia simplicifolia isolectin B4 confirmed the expression of the CB1 receptor in rat microglial cells. Collectively, these results indicate a functional linkage between the CB1 receptor and cannabinoid-mediated inhibition of NO production by rat microglial cells.

Animals↗

PubMed1999

Genetic linkage analysis of multicase families with fibromyalgia syndrome.

OBJECTIVE: Based on the reports of familial aggregation of fibromyalgia (FM) syndrome, we investigated its possible genetic linkage to HLA by studying multicase families. METHODS: Forty Caucasian multicase families with a diagnosis of FM (American College of Rheumatology criteria) in 2 or more first degree relatives were investigated. Eighty-five affected and 21 unaffected members of 41 sibships were studied. Depression symptomology was assessed by Zung Self-rating Depression Scale (SDS). HLA typing was performed for A, B, and DRB 1 alleles, and haplotypes were determined with no knowledge of the subject's diagnosis. We investigated genetic linkage to the HLA region by evaluating sibships in multicase families. RESULTS: Sibship analysis showed significant genetic linkage of FM to the HLA region (p = 0.028). Subgroup analysis was also performed for 17 families where the proband was also noted to have depression (with an SDS index value > or =60). We found that the presence of depression did not influence the observed results (p = 0.22). CONCLUSION: . Our study of 40 multicase families confirms existence of a possible gene for FM that is linked with the HLA region. Our results should be regarded as preliminary and their independent confirmation by other studies is warranted.

Adult↗

PubMed1998

Treatment of diencephalic syndrome with chemotherapy: growth, tumor response, and long term control.

BACKGROUND: The diencephalic syndrome (DS), which is manifested by progressive emaciation and failure to thrive in an apparently alert, cheerful infant, usually is due to a low grade hypothalamic glioma. Treatment with aggressive surgery and/or radiotherapy is variably successful in controlling disease and may result in severe neurologic sequelae. Chemotherapy recently has been shown to be effective in patients with low grade gliomas of childhood, but it is used infrequently in those with DS. METHODS: The authors evaluated the efficacy of a regimen of carboplatin and vincristine on improving weight, causing tumor shrinkage, and delaying the need for alternative therapies in seven children (ages 9-20 months; median age, 11 months) with DS. Five patients weighed less than the 5th percentile for their age at the start of the study, one weighed within the 10th percentile, and one weighed within the 25th percentile. RESULTS: At follow-up (range, 6-54 months; median, 28 months), the patients' weights had increased by 66-95% (median, 80%). On magnetic resonance imaging, four patients had a >50% reduction in tumor mass, one had a 25-50% reduction, and two had stable disease. In those patients with radiographic response to treatment, weight gain was accomplished with oral feedings in four of five patients, whereas those with stable disease required nasogastric, nasojejunal, or gastrostomy tube supplementation to maintain weight. Disease progression occurred at a median of 24 months after initiation of chemotherapy, and two patients remained free of progressive disease at last follow-up. Five patients were alive a median of 59 months from diagnosis. The need for radiation or other therapies was delayed in six of seven children. Therapy was tolerated without significant toxicities. CONCLUSION: The authors conclude that treatment of DS with a carboplatin and vincristine regimen results in demonstrable weight gain, may result in tumor shrinkage, and in some cases, significantly delays the need for alternative therapies.

Antineoplastic Combined Chemotherapy Protocols↗