Gender diagnosticity and androgen receptor gene CAG repeat sequence.

The gender diagnosticity (GD) approach of Lippa (1995) was used to evaluate the relationship of within-sex differences in psychological masculinity-femininity to a genetic characteristic, the length of a repeated CAG sequence in the X-linked androgen receptor (AR) gene. Previously assessed adult samples in Australia and Sweden were used for this purpose. A weak relationship (correlations in the range .11 to .14) was obtained in both countries. Additional data from adolescent twins from Australia (12-, 14-, 16-year-olds) did not confirm such a relationship at those ages, especially for males. The fact that this sample consisted of twins permitted two kinds of within-pair comparisons: (1) Did the dizygotic twin who had the longer AR sequence have the higher GD score? (2) Was one twin's GD score more highly correlated with the other twin's AR score in MZ than in DZ pairs? The answer in both cases was negative. Clarification of these relationships will require large samples and measurements at additional ages.     

Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker

Hsp70 chaperones assist in protein folding, disaggregation, and membrane translocation by binding to substrate proteins with an ATP-regulated affinity that relies on allosteric coupling between ATP-binding and substrate-binding domains. We have studied single- and two-domain versions of the E. coli Hsp70, DnaK, to explore the mechanism of interdomain communication. We show that the interdomain linker controls ATPase activity by binding to a hydrophobic cleft between subdomains IA and IIA. Furthermore, the domains of DnaK dock only when ATP binds and behave independently when ADP is bound. Major conformational changes in both domains accompany ATP-induced docking: of particular importance, some regions of the substrate-binding domain are stabilized, while those near the substrate-binding site become destabilized. Thus, the energy of ATP binding is used to form a stable interface between the nucleotide- and substrate-binding domains, which results in destabilization of regions of the latter domain and consequent weaker substrate binding.     

Tumor endothelial marker 8 enhances tumor immunity in conjunction with immnization against differentiation Ag

BACKGROUND: We have previously shown that xenogenic DNA vaccines encoding rat neu and melanosomal differentiation Ag induce tumor immunity. Others have developed vaccines targeting tumor neovasculature. Tumor endothelial marker 8 (TEM8) is expressed in the neovasculature of human tumors, and in the mouse melanoma B16, but its expression is limited in normal adult tissues. We describe a DNA vaccine combining xenogeneic tumor Ag and TEM8. METHODS: In-situ hybridization was used to detect TEM8 RNA in mouse tumors. Mice transgenic for the rat neu proto-oncogene were immunized with DNA vaccines encoding TEM8 and the extracellular domain of rat neu and challenged with the 233-VSGA1 breast cancer cell line. In parallel experiments, C57BL/6 mice were immunized with TEM8 and human tyrosinase-related protein 1 (hTYRP1/hgp75) and challenged with B16F10 melanoma. RESULTS: TEM8 was expressed in the stroma of transplantable mouse breast and melanoma tumors. In both model systems, TEM8 DNA had no activity as a single agent but significantly enhanced the anit-tumor immunity of neu and hTYRP1/hgp75 DNA vaccines when given in concert. The observed synergy was dependent upon CD8+ T cells, as depletion of this cell population just prior to tumor challenge obviated the effect of the TEM8 vaccine in both tumor models. DISCUSSION: A local immune responses to TEM8 may increase inflammation or tumor necrosis within the tumor, resulting in improved Ag presentation of HER2/neu and hTYRP1/hgp75. Alternatively, TEM8 expression in host APC may act more as an adjuvant than an immunologic target.     

Annotation and query of tissue microarray data using the NCI Thesaurus

Background  

The Stanford Tissue Microarray Database (TMAD) is a repository of data serving a consortium of pathologists and biomedical researchers. The tissue samples in TMAD are annotated with multiple free-text fields, specifying the pathological diagnoses for each sample. These text annotations are not structured according to any ontology, making future integration of this resource with other biological and clinical data difficult.     

The geographical distribution of lymphatic filariasis infection in Malawi

Background

Papua New Guinea is the only endemic country in the Western Pacific Region that has not yet introduced a countrywide programme to eliminate lymphatic filariasis. However, on Misima Island in Milne Bay Province, government and private sectors have collaborated to implement a pilot elimination programme. Although interim evaluation indicated that the programme has been parasitologically successful, an appreciation that sustainable health gains depend on understanding and accommodating local beliefs prompted this qualitative study.

Methods

We investigated Misima community members knowledge and attitudes about lymphatic filariasis and the elimination programme. A combination of focus groups and key informant interviews were used to explore participants perceptions of health; knowledge of the aetiology and symptoms of filariasis, elephantiasis and hydrocele; attitudes towards the disease and mass drug distribution; and the social structure and decision-making protocols within the villages.

Results

Focus group discussions proved inferior to key informant interviews for gathering rich data. Study participants did not consider lymphatic filariasis ("pom") a major health problem but were generally positive about mass drug administration campaigns. A variety of conditions were frequently and incorrectly attributed to filariasis. Participants expressed the belief that individuals infected with filariasis always had visible manifestations of disease. A common misconception was that taking drugs during campaigns provided long-term immunity against disease. The role of mosquito vectors in transmission was not generally appreciated and certain clinical presentations, particularly hydrocele, were associated with supernatural forces. Multiple adverse events were associated with mass drug administration campaigns and most study participants mentioned community members who did not participate in campaigns.

Conclusion

Important issues requiring educational intervention and elimination activity modification in the Misima region were identified during this study. Research outcomes should assist Papua New Guinea in developing and implementing a national elimination strategy and inform discussions regarding the appropriateness of current elimination strategies.     

A graphical approach to multi-locus match probability computation: revisiting the product rule

The genealogical relationships of individuals in a finite population can create statistical non-independence of alleles at unlinked loci. In this paper, we introduce a flexible graphical method for computing the probabilities that two individuals in a finite, randomly mating population have the same haplotype or genotype at several loci. This method allows us to generalize the analysis of Laurie and Weir [2003. Dependency effects in multi-locus match probabilities. Theor. Popul. Biol. 63, 207-219] to cases with more loci and other models of mating. We show that monogamy increases the probabilities of genotypic matches at unlinked loci and that the effect of monogamy increases with the number L of loci. We conjecture a sharp upper bound on the effect of monogamy for a given L.     

Linkage analysis of a model quantitative trait in humans: finger ridge count shows significant multivariate linkage to 5q14.1

The finger ridge count (a measure of pattern size) is one of the most heritable complex traits studied in humans and has been considered a model human polygenic trait in quantitative genetic analysis. Here, we report the results of the first genome-wide linkage scan for finger ridge count in a sample of 2,114 offspring from 922 nuclear families. Both univariate linkage to the absolute ridge count (a sum of all the ridge counts on all ten fingers), and multivariate linkage analyses of the counts on individual fingers, were conducted. The multivariate analyses yielded significant linkage to 5q14.1 (Logarithm of odds [LOD] = 3.34, pointwise-empirical p-value = 0.00025) that was predominantly driven by linkage to the ring, index, and middle fingers. The strongest univariate linkage was to 1q42.2 (LOD = 2.04, point-wise p-value = 0.002, genome-wide p-value = 0.29). In summary, the combination of univariate and multivariate results was more informative than simple univariate analyses alone. Patterns of quantitative trait loci factor loadings consistent with developmental fields were observed, and the simple pleiotropic model underlying the absolute ridge count was not sufficient to characterize the interrelationships between the ridge counts of individual fingers.     

Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci

Twin cohorts provide a unique advantage for investigations of the role of genetics and environment in the etiology of variation in common complex traits by reducing the variance due to environment, age, and cohort differences. The GenomEUtwin (http://www.genomeutwin.org) consortium consists of eight twin cohorts (Australian, Danish, Dutch, Finnish, Italian, Norwegian, Swedish, and United Kingdom) with the total resource of hundreds of thousands of twin pairs. We performed quantitative trait locus (QTL) analysis of one of the most heritable human complex traits, adult stature (body height) using genome-wide scans performed for 3,817 families (8,450 individuals) derived from twin cohorts from Australia, Denmark, Finland, Netherlands, Sweden, and United Kingdom with an approximate ten-centimorgan microsatellite marker map. The marker maps for different studies differed and they were combined and related to the sequence positions using software developed by us, which is publicly available (https://apps.bioinfo.helsinki.fi/software/cartographer.aspx). Variance component linkage analysis was performed with age, sex, and country of origin as covariates. The covariate adjusted heritability was 81% for stature in the pooled dataset. We found evidence for a major QTL for human stature on 8q21.3 (multipoint logarithm of the odds 3.28), and suggestive evidence for loci on Chromosomes X, 7, and 20. Some evidence of sex heterogeneity was found, however, no obvious female-specific QTLs emerged. Several cohorts contributed to the identified loci, suggesting an evolutionarily old genetic variant having effects on stature in European-based populations. To facilitate the genetic studies of stature we have also set up a website that lists all stature genome scans published and their most significant loci (http://www.genomeutwin.org/stature_gene_map.htm).