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PubMed1996

Genome polymorphism of human adenoviruses of subgenus C.

The genome of adenovirus (AV) types 1, 2, and 5 is known to be very variable as evidenced by the great number of genome types described (36, 61, and 35 for AV1, 2, and 5 respectively). Physical maps were constructed for nearly all of the restriction or R-variants by biochemical methods and by adapting restriction fragments of defined molecular weight. The alterations found with seven DNA restriction endonucleases were mapped on the genome. Altered restriction sites, found for the genome types of each of the three serotypes, appeared to be randomly distributed over the genome, although mutations seemed to occur preferentially on distinct sites of the genome. Many strains, especially those of AV5, were genomically much more related with one another than with the prototype. This finding is compatible with the interpretation that the related strains were derived from an unknown common ancestor.

Adenoviruses, Human↗

PubMed2005

Oxidative chemistry in the GFP active site leads to covalent cross-linking of a modified leucine side chain with a histidine imidazole: implications for the mechanism of chromophore formation.

The mechanism of chromophore biosynthesis in green fluorescent protein (GFP) is triggered by a spontaneous main chain cyclization reaction of residues 65-67. Here, we demonstrate that the initially colorless Y66L variant, designed to trap chromophore precursor states, is oxidatively modified to generate yellow chromophores that absorb at 412 and 374 nm. High- and low-pH crystal structures determined to 2.0 and 1.5 A resolution, respectively, are consistent with pi-orbital conjugation of a planar Leu66-derived adduct with the imidazolinone ring, which is approximately 90 and 100% dehydrated, respectively. Time-, base-, and oxygen-dependent optical properties suggest that the yellow chromophores are generated from a 338 nm-absorbing intermediate, interpreted to be the Y66L analogue of the wild-type GFP chromophore. Generation of this species is catalyzed by a general base such as formate, and proceeds via a cyclization-oxidation-dehydration mechanism. The data suggest that a hydration-dehydration equilibrium exists in the cyclic form of the peptide, and that dehydration is favored upon extensive conjugation with the modified side chain. We conclude that the mechanism of GFP chromophore biosynthesis is not driven by the aromatic character of residue 66. In the low-pH X-ray structure, a highly unusual cross-link is observed between His148 and the oxidized Leu66 side chain, suggesting a conjugate addition reaction of the imidazole nitrogen to the highly electrophilic diene group of the yellow chromophore. The reactivity described here further expands the chemical diversity observed in the active site of GFP-like proteins, and may allow for covalent attachment of functional groups to the protein scaffold for catalytic purposes.

Amino Acid Substitution↗

PubMed2004

A cell-based screen for function of the four-helix bundle protein Rop: a new tool for combinatorial experiments in biophysics.

Combinatorial methodologies have revolutionized studies in biomolecular function, but they have so far proven less useful for understanding macromolecular structure and stability. This is largely because of the difficulty of screening libraries of molecules for biophysical properties, and the difficulty of interpreting structural effects in complicated molecules. Here, we report a novel, robust, cell-based screen for function of the four-helix bundle protein, Rop. By expression of green fluorescent protein from a ColE1 plasmid, the screen reports the copy number of the plasmid, which is modulated in Escherichia coli by Rop. We have engineered the screen so that the fluorescent phenotype can correspond to either Rop activity or lack thereof. We have used the screen to demonstrate with systematically constructed Rop core variants that not all molecules that bind small stem-loop RNAs in vitro are active in vivo. Rop is well understood from structural work and systematic mutations, which makes it possible to construct rational, targeted libraries. This screen makes it possible to rapidly interrogate such libraries effectively for proper protein folding and stability. In addition to its intended utility for combinatorial experiments in biophysics, the screen will allow further dissection of the mechanism of Rop-mediated plasmid copy number regulation in vivo.

Bacterial Proteins↗

PubMed2006

Concordance of functional in vitro data and epidemiological associations in complex disease genetics.

PURPOSE: We aimed to assess whether epidemiological evidence on genetic associations for complex diseases concord with in vitro functional data. METHODS: We examined 36 studies on bi-allelic markers and 23 studies on haplotypes where investigators had addressed both epidemiological associations and the functional effect of the same gene variants in luciferase reporter systems in vitro. RESULTS: There was no correlation between epidemiological odds ratios and luciferase activity ratios (-0.09, P = 0.60). Luciferase activity ratios could not tell whether a probed epidemiologic association would be significant or not (area under receiver operating characteristics curve, 0.52). Luciferase results usually were qualitatively similar across cell lines and experimental conditions, with some exceptions. A luciferase activity ratio of 1.44 adequately separated statistically significant from non-significant functional differences (area under receiver operating characteristics curve, 0.95). Binary and continuous disease outcomes usually gave concordant results; other in vitro methods, in particular EMSA, agreed with luciferase results. Selective reporting and use of different variants and contrasts between functional and epidemiological analyses were common in these studies. CONCLUSIONS: In vitro biological data and epidemiology provide independent lines of evidence on complex diseases. We provide suggestions for improving the design and reporting of studies addressing both in vitro and epidemiological effects.

Alleles↗

PubMed1975

A preliminary genetic interpretation of the esterase isozymes of human tissues.

1. The esterase isozymes of human tissues have been investigated using the technique of starch-gel electrophoresis. Conventional naphthyl-azo dye linked stains and new fluorogenic staining methods were used to detect the isozymes. 2. Multiple isozymes were identified in every tissue and they were characterized in terms of their electrophoretic mobility, tissue distribution, developmental changes in utero, substrate specificity, inhibition properties and molecular weight. On these criteria 13 sets of esterase isozymes were identified, in addition to the esterase isozymes due to cholinesterase and carbonic anhydrase. 3. The data suggest that the 13 sets of isozymes are determined by at least nine different structural gene loci. 4. No electrophoretic variants were identified in a limited population survey of post-mortem tissues from adults and foetuses, except for the previously described esterase D (ESD) phenotypes.

Electrophoresis, Starch Gel↗

PubMed2003

A contribution to the development of a psychoanalytical methodology for research into language: A systematic study of narration as an expression of sexuality.

Systematic research on language has a solid starting point in Freudian hypotheses on sexuality. This theory is the semantic ground for categorising narrations and providing a basis for the research method. The author places his research in the frame of the systematisation of the Freudian theory of substitute formations in the preconscious. He affirms that these formations are influenced in a particular way by each variant of sexuality. The author proposes an inventory (in Freudian terms) of those variants of sexuality, and he affirms that they can be detected in the discourse. Five universal scenes having the status of a canon, with specific features for each of the ways in which sexuality is manifested, make up narrations. The author describes the features of each narration and provides some examples. He also examines problems related to the use of the method (the coexistence of different variants of sexuality in a single fragment of a narration and the successive steps in the use of the method). The author briefly considers some other problems: the analysis of defences, the study of words and theoretical research. Finally, he examines the validity and reliability of the method.

Adult↗

PubMed2002

Divergent distribution of HIV-1 drug-resistant variants on and off antiretroviral therapy.

OBJECTIVE: To investigate the distribution of drug-resistant HIV-1 variants in plasma RNA and peripheral blood monuclear cell (PBMC) DNA at treatment failure while on therapy and after stopping therapy. DESIGN: Fifty-eight patients failing their first highly active antiretroviral treatment while on therapy and 50 patients after a median of 18.6 weeks after treatment interruption following multiple treatment failures were analysed. METHODS: Paired plasma HIV-1 RNA and PBMC HIV-1 DNA were used for genotypic antiretroviral resistance testing. Drug resistance was computed by using the Stanford on-line genotype interpretation system. RESULTS: The extent of drug resistance was larger in plasma RNA than in PBMC DNA in the on-therapy group (P=0.004) and in PBMC DNA than in plasma RNA in the off-therapy group (P=0.04). Interpretation of genotype based on PBMC DNA and plasma RNA in the on-therapy and in the off-therapy group would have missed detection of resistance to one or more drugs in 21 and 22% of the patients, respectively, compared to interpretation based on the other blood compartment. In a subset of 27 patients for whom a sample before stopping therapy was available, there was a significant decrease in the number of RNA (mean 8.1 to 5.3, P=0.004), but not DNA (mean 6.8 to 5.7, P=0.143), resistance mutations following treatment interruption. CONCLUSION: While plasma RNA is the material of choice for early detection of drug resistance while on therapy, analysis of PBMC DNA may additionally support and possibly improve sensitivity of resistance testing in the absence of therapy.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Complex recombination events at the hypermutable minisatellite CEB1 (D2S90).

Some minisatellite structures are the site of high rates of DNA recombination in non-pathological situations, with an excess of motif insertion events and a locus-dependent sex-specific mutation bias. We previously reported the cloning of the hypermutable minisatellite locus CEB1 (D2S90), remarkable for its 13% mutation rate in the male germline (compared to approximately 0.4% in female). We have sought to analyse the mechanisms underlying the addition or deletion of motifs at this locus using the minisatellite variant repeat mapping technique. This is possible with a high precision due to the extreme sequence polymorphism seen between different motifs. No crossing-over event was observed among 38 informative neomutations. Four of the 19 informative mutant alleles with an addition of motifs are interallelic events, the others are intra-allelic. Overall, the insertion and deletion mutations are spread along the alleles, although the subset of interallelic events shows clustering towards the analysed end. The apparently complex recombination events observed can all be interpreted as a succession of elementary duplications-deletions of inter- as well as intra-chromosomal origin, suggesting a model in which sister chromatid as well as conversion-like exchanges are involved in these mutation processes.

Alleles↗

PubMed2026

A Guide for Exploring Pleiotropic Associations in Genome-Wide Association Studies Using Summary Statistics.

Genome-wide association studies (GWAS) have shown that pleiotropy, whereby a single genetic variant or gene influences multiple traits, is common in complex human diseases. Detecting cross-phenotype associations from GWAS summary statistics remains challenging because of small effect sizes, extensive multiple testing, heterogeneous effects, and possible differences in effect direction across traits. Methods that jointly analyze multiple traits can improve the ability to detect pleiotropic signals while retaining the practical advantages of summary statistic-based analyses. Although a range of statistical approaches has been developed for this purpose, practical guidance on their application, assumptions, and interpretation remains limited. This tutorial reviews several widely used methods for pleiotropy detection from GWAS summary statistics, including ASSET, PLACO, GPA, CPBayes, and GCPBayes, and demonstrates their application using breast and thyroid cancer datasets. We also highlight the importance of accounting for effect heterogeneity, correlation, and biological group structure at the gene and pathway levels in the detection and interpretation of pleiotropic association signals.

Genome-Wide Association Study↗

PubMed2001

Ly49A allelic variation and MHC class I specificity.

The Ly49 family of natural killer (NK) cell receptors is encoded by a polygenic genetic locus. Allelic forms have been described and their expression appears to be regulated. The best-characterized Ly49 molecule, the C57BL/6 form of Ly49A, is an NK cell inhibitory receptor that binds H2Dd. To determine whether differences between Ly49a alleles may have functional consequences, allelic variants of Ly49a were cloned from several inbred mouse strains. Stable transfectants expressing each Ly49a allelic variant were generated and tested for reactivity with a panel of monoclonal antibodies (mAbs A1, JR9.318, YE1/32, and YE1/48) that recognize the C57BL/6 form of Ly49A. Binding to H2Dd was also assessed using fluorescently labeled H2Dd tetramers. Furthermore, cytotoxicity assays were performed using anti-Ly49A mAb-separated interleukin-2-activated NK cells. We show that despite binding to fluorescently labeled H2Dd tetramers, the Ly49A+ NK cells from representative mouse strains displayed significantly different degrees of inhibition with H2Dd targets. These results can be interpreted in the light of recent structural data on the Ly49A-H2Dd complex. Thus, the Ly49 family displays functionally significant allelic polymorphism which adds to the repertoire of NK cell receptors.

Alleles↗

PubMed1996

Similar, and similar concepts.

This paper analyzes English symmetrical predicates such as collide and match. Its point of departure is an analysis of the concept 'similar' from Tversky (1977) that appears to show that similarity is psychologically asymmetrical. One basis for this claim from Tversky is that the sentences North Korea is similar to Red China and Red China is similar to North Korea are assessed as differing in meaning by experimental subjects; this seems to imply that the symmetrical entailment (R x, y <--> R y, x) fails for this concept. Five experiments are presented that show: (1) the apparent asymmetry of similar is reproduced for 20 predicates that are intuitively thought to be symmetrical, including equal and identical; (2) unique linguistic-interpretative properties hold for these symmetrical words, such as reciprocal interpretation when they appear intransitively, for example, North Korea and Red China are similar; (3) the asymmetrical interpretation of subject-complement constructions containing the symmetrical words is a consequence of general linguistic-interpretive principles. On the basis of the experimental findings, we offer an analysis of symmetrical predication. One major claim of the analysis is that symmetry is a property of lexical items and has no special syntax, that is, that John meets is semantically but not syntactically anomalous. A second claim is that the structural positioning of noun phrases in sentences containing symmetricals--rather than inherent semantic properties of the noun phrases themselves--sets their status as Figure and Ground (as described by Talmy, 1985) or Variant and Referent (as described by Tversky, 1977) in the comparison, even if the nouns are nonsense items. Finally, the behavior of symmetrical predicates is shown to vary as a function of their differing lexical class assignments and collateral semantic designations, such as activity versus state. Most generally, it is claimed that a deeper understanding of symmetrical terms comes from analyzing the semantics of syntactic structures in which they appear.

Humans↗

PubMed2003

Genes and gene polymorphisms associated with periodontal disease.

The scientific literature during the last ten years has seen an exponential increase in the number of reports claiming links for genetic polymorphisms with a variety of medical diseases, particularly chronic immune and inflammatory conditions. Recently, periodontal research has contributed to this growth area. This new research has coincided with an increased understanding of the genome which, in turn, has permitted the functional interrelationships of gene products with each other and with environmental agents to be understood. As a result of this knowledge explosion, it is evident that there is a genetic basis for most diseases, including periodontitis. This realization has fostered the idea that if we can understand the genetic basis of diseases, genetic tests to assess disease risk and to develop etiology-based treatments will soon be reality. Consequently, there has been great interest in identifying allelic variants of genes that can be used to assess disease risk for periodontal diseases. Reports of genetic polymorphisms associated with periodontal disease are increasing, but the limitations of such studies are not widely appreciated. While there have been dramatic successes in the identification of mutations responsible for rare genetic conditions, few genetic polymorphisms reported for complex genetic diseases have been demonstrated to be clinically valid, and fewer have been shown to have clinical utility. Although geneticists warn clinicians on the over-enthusiastic use and interpretation of their studies, there continues to be a disparity between the geneticists and the clinicians in the emphasis placed on genes and genetic polymorphism associations. This review critically reviews genetic associations claimed for periodontal disease. It reveals that, despite major advances in the awareness of genetic risk factors for periodontal disease (with the exception of periodontitis associated with certain monogenetic conditions), we are still some way from determining the genetic basis of both aggressive and chronic periodontitis. We have, however, gained considerable insight into the hereditary pattern for aggressive periodontitis. Related to our understanding that it is autosomal-dominant with reduced penetrance comes a major clinically relevant insight into the risk assessment and screening for this disease, in that we appreciate that parents, offspring, and siblings of patients affected with aggressive periodontitis have a 50% risk of this disease also. Nevertheless, we must exercise caution and proper scientific method in the pursuit of clinically valid and useful genetic diagnostic tests for chronic and aggressive periodontitis. We must plan our research using plausible biological arguments and carefully avoid the numerous bias and misinterpretation pitfalls inherent in researching genetic associations with disease.

Aggressive Periodontitis↗

PubMed2007

Multiplex pyrosequencing for DNA variation analysis.

Pyrosequencing technique has been widely used to perform both single-nucleotide polymorphism detection and quantitative DNA methylation analysis. Simplex Pyrosequencing is sufficient to interrogate more than one polymorphic site if these gene variants are within the reach of the sequencing reaction. For polymorphisms far apart from each other or located on different genes, multiple simplex analyses are required. To reduce the number of simplex reactions, multiplex Pyrosequencing becomes a useful alternative method. The multiplex reaction is performed in the presence of single or multiple templates with several sequencing primers. Factors such as primer selection for the PCR and Pyrosequencing reaction, generation of optimal nucleotide dispensation order, use of internal and external controls, preparation of instrumentation, and Pyrogram interpretation are essential to the success of the multiplexing. In this chapter, the mouse 45S rRNA gene is used to present two general multiplex Pyrosequencing protocols for determining DNA methylation and allele frequency in the spacer promoter region of this gene.

Animals↗

PubMed2003

Variant alleles on the penta E locus in the PowerPlex 16 kit.

Penta E in the PowerPlex 16 kit is a pentanucleotide tandem repeat marker located on Chromosome 15, containing an AAAGA repeat motif. Variant alleles (18.4 and 19.4) were found in the Japanese population. A sequence analysis revealed that both the variant alleles had a partial repeat motif of AAAA, resulting in one-base-shorter alleles compared to known alleles. Despite the relatively large amplicon sizes (379 to 474 bp) of Penta E, an accurate allele assignment can be reliably made by capillary electrophoresis. However, alleles differing in size by only one base (e.g., 18.4 and 19) were not separated and appeared as a single broad peak. The Genotyper software assigned one of the component alleles to this peak. Therefore, such broad peaks require careful interpretation so as to not overlook the other component allele contained by the peak. As an index to recognize a peak containing two alleles, the ratio of peak area to peak height was found to be useful.

Alleles↗

PubMed1979

Pagetoid reticulosis. A further case report with a review of the literature.

A further case of pagetoid reticulosis (PR) was studied, and the findings were compared with 18 previous case reports in the literature. There seem to be two variants: The generalized type (Ketron-Goodman) with disseminated lesions and a poor prognosis, and the localized type (Woringer-Kolopp), with a single lesion usually located on the extremities with a good prognosis (if the lesion can be totally cleared by excision or highdose-radiation). The basic criterion of diagnosis is a very strong cellular infiltrate within the epidermis, but usually weak in the upper dermis. The etiology of PR remains unclear: In some cases a T-cell lymphoma seems a likely interpretation. In others, epidermal infiltrating cells are not typically lymphoid, but remain morphologically unclassifiable.

Adult↗

PubMed1981

A neuropsychological study of the stable syndrome of hysteria.

Ten patients with the stable syndrome of hysteria were matched for age, sex, handedness, and full-scale WAIS IQ with ten controls, ten psychotic depressives and ten schizophrenics. All were subjected to an extensive neuropsychological test battery. Compared to the controls, the hysteria group exhibited bifrontal impairment (R = L) and, globally, greater dysfunction of the nondominant hemisphere. A G analysis provided a complete separation between the hysteria and controls. However, a D-index analysis showed that the hysteria group was more impaired than normals and depressives because of greater dysfunction of the dominant hemisphere, whilst schizophrenia showed greater nondominant hemisphere dysfunction than hysteria. Further, a cluster analysis on the 40 subjects produced three clusters: normal controls, depressives, and a schizophrenia-hysteria grouping. These findings are interpreted as suggesting that dominant hemisphere dysfunction is fundamentally related to the syndrome of hysteria and that the dysfunction of the nondominant hemisphere is brought about by associated features: the female excess, the emotional instability and dysphoric mood, the presence of asymmetrical pain, and conversion symptomatology. It is further argued, in view of the familial associations, that hysteria in the female is a syndrome equivalent to psychopathy in the male (who also exhibits dominant hemisphere dysfunction) and might represent in the female a (relatively benign) variant of schizophrenia characterized by imprecise verbal communications, a subtle form of affective incongruity, together with the conversion parameter.

Adult↗

PubMed2004

NQO1 C609T polymorphism in distinct entities of pediatric hematologic neoplasms.

BACKGROUND AND OBJECTIVES: NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that protects cells against mutagenicity from free radicals and toxic oxygen metabolites. The gene coding for NQO1 is subject to a genetic polymorphism at nucleotide position 609 (C-->T) of the human NQO1 cDNA. Heterozygous individuals (C/T) have intermediate activity and homozygotes for the variant allele (T/T) are deficient in NQO1 activity. In previous studies, genotypes conferring lower NQO1 activity have been associated with an increased risk of acute leukemia, particularly infant leukemia carrying MLL/AF4 fusion genes. In the present study, we investigated this association in our population and extended the analysis to other subgroups of pediatric hematologic neoplasms characterized by specific fusion genes. DESIGN AND METHODS: We genotyped 138 patients with childhood acute lymphoblastic leukemia (ALL) carrying distinct fusion genes (MLL/AF4=35; BCR/ABL=31; TEL/AML1=72), 71 cases of pediatric sporadic Burkitt's lymphoma and 190 healthy control individuals for the NQO1 C609T polymorphism. RESULTS: When compared to the healthy control group, only children with Burkitt's lymphoma significantly more often had NQO1 genotypes associated with lower NQO1 activity (odds ratio, 1.81; p=0.036), predominantly at a younger age (< 9 years at diagnosis: odds ratio, 3.02; p=0.003). INTERPRETATION AND CONCLUSIONS: Our results suggest that in our population the NQO1 C609T polymorphism does not confer an increased risk of the investigated entities of childhood ALL. However, there may be a modulating role for NQO1 in the pathogenesis of pediatric sporadic Burkitt's lymphoma.

Adolescent↗

PubMed1981

Chemical and morphological studies on garfish peripheral nerves.

Gangliosides were extracted, separated by thin layer chromatography, and quantitated in three cranial nerves of the garfish (Lepisosteus osseus): the completely unmyelinated olfactory nerve (OLF), and two nerves composed of both myelinated and unmyelinated fibers, viz., the main trunk of the maxillary nerve (MAX) and a branch of the maxillary nerve (BR-MAX). Morphological studies on each of these nerves were done to verify that the OLF had been excised free of any contamination from the accompanying myelinated BR-MAX, to aid in the interpretation of the biochemical findings, and to clarify the nature of the OLF supporting cell. The chief chemical findings were (1) documentation of the presence of gangliosides in nerves previously thought not to contain them, (2) demonstration that gangliosides can be associated with unmyelinated nerves, (3) demonstration of a greater proportion of one simple ganglioside (G-6) in the OLF but greater proportions of two complex gangliosides (G-2 and G-0) in the MAX and BR-MAX, and (4) that either GM4 or a variant of the GM3 is present in OLF. The morphological findings with respect to the difficulty of ascribing only peripheral nervous system characteristics to the OLF supporting cell are discussed in relation to the ganglioside band chromatographing slightly ahead of GM4 in the OLF.

Animals↗