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PubMed2002

The acidic ribosomal P proteins.

The acidic ribosomal P proteins (pI 3-4) are unique among ribosomal constituents: the only molecules on the ribosomes existing in multiple copies, they form a hetero-oligomeric complex (P1/P2)(2) recognizable as a lateral protuberance on the 60S ribosomal subunit, which is thought to be directly involved in interactions with elongation factors during the course of protein synthesis. The role of P proteins in translation is still vague; however, they might possess two functional roles-the proteins may increase performance of ribosomes and/or change ribosomal specificity toward different subset of mRNAs. Furthermore, there are also indications that P proteins might be involved in transcription and DNA repair. Also, P proteins are important antigens in autoimmune diseases, infections caused by protozoan parasites, and in molds.

Amino Acid Sequence↗

PubMed1991

Identification of a novel transcription unit in the human insulin-like growth factor-II gene.

The human insulin-like growth factor-II (hIGF-II) gene has until now been thought to be composed of eight exons, including three independent leader exons. In the present study two additional exons, one leader exon and one alternatively used ordinate exon, have been newly identified. They were abundantly expressed in human histiocytoma tissue, generating mRNA species of about 5.0 kb in length. The new leader exon shows significant sequence similarity with the rE1 exon, previously reported to be transcribed only in the rat, and is mapped at nearly the same genomic location as in the rat. On the other hand, sequence similarity with another exon in the corresponding region of the rat genome was also found. It was, however, obvious that the rat sequence would not work as an active exon, since both splice acceptor and donor sites were deviated considerably from the consensus sequences. It has thus become apparent that the complex transcription unit of a single-copy hIGF-II gene comprises at least 10 exons, including four leader exons, one alternative exon and three common protein-coding exons.

Amino Acid Sequence↗

PubMed1999

Molecular and cytogenetic characterization of a transgene locus that induces silencing and methylation of homologous promoters in trans.

One type of homology-dependent gene silencing in transgenic plants involves a silencing locus that is able to transcriptionally inactivate and methylate an unlinked target locus with which it shares sequence identity in promoter regions. In a manner resembling paramutation of endogenous genes, the target locus reactivates and loses methylation progressively over several generations after segregating away from the silencing locus, which autonomously acquires stable methylation. To investigate the origins of trans-silencing ability and susceptibility, we have analyzed the structures, flanking DNA sequences and chromosomal locations of a nopaline synthase promoter silencing locus, H2, and a sensitive target locus, K81. A partially resistant target locus, K alpha has been characterized molecularly. The complex and scrambled H2 locus comprises six copies of the nopaline synthase promoter, two of which are collinear with prokaryotic non-T-DNA sequences, and is integrated close to a region of intercalary heterochromatin. These features probably contribute collectively to the silencing ability because H2 subclones reintroduced into random locations in the K81 genome did not frequently induce silencing. Both the K81 and K alpha loci have simple structures, although the former contains non-T-DNA prokaryotic sequences that are also present at H2, and they are flanked by low copy plant DNA. H2 and K81 might interact effectively because they are present on morphologically similar chromosomes from the T subgenome of allotetraploid tobacco.

Amino Acid Oxidoreductases↗

PubMed2004

Spontaneous separation of bi-stable biochemical systems into spatial domains of opposite phases.

Bi-stable chemical systems are the basic building blocks for intracellular memory and cell fate decision circuits. These circuits are built from molecules, which are present at low copy numbers and are slowly diffusing in complex intracellular geometries. The stochastic reaction-diffusion kinetics of a double-negative feedback system and a MAPK phosphorylation-dephosphorylation system is analysed with Monte-Carlo simulations of the reaction-diffusion master equation. The results show the geometry of intracellular reaction compartments to be important both for the duration and the locality of biochemical memory. Rules for when the systems lose global hysteresis by spontaneous separation into spatial domains in opposite phases are formulated in terms of geometrical constraints, diffusion rates and attractor escape times. The analysis is facilitated by a new efficient algorithm for exact sampling of the Markov process corresponding to the reaction-diffusion master equation.

Adaptation, Physiological↗

PubMed1985

Gene amplification: an example of accelerated evolution in tumorigenic cells.

During selection for methotrexate resistance, tumorigenic CHEF/16 cells and derivatives from CHEF/16 tumors underwent amplification of the dihydrofolate reductase gene (DHFR) at accelerated rates compared with closely related nontumorigenic CHEF/18 cells. "Dot blot" analysis showed that the CHEF/16 cells contained many more copies of the DHFR gene than did the CHEF/18 cells, when assayed at similar elevated levels of methotrexate resistance. Chromosome analysis of cell samples taken at several time points during amplification revealed large differences between the nontumorigenic CHEF/18 cells and the two tumorigenic cell lines. The tumorigenic cells developed few chromosome rearrangements over a 4-log increase in methotrexate resistance, other than increased length of a single chromosome, which was shown by in situ hybridization to contain most or all of the amplified DHFR gene copies. In contrast, the CHEF/18 cells underwent complex, progressive changes in almost every chromosome, and in situ hybridization suggested a dispersed pattern of gene amplification. The data support the hypothesis that unregulated amplification is a pathological process, occurring readily in neoplastic but rarely in normal cells, that together with other chromosomal disturbances contributes to the rapid evolution and progression of cancer.

Animals↗

PubMed1993

Biotinylated diaminopyridine: an approach to tagging oligosaccharides and exploring their biology.

Fluorescent tagging of free oligosaccharides by reductive amination permits sensitive detection and fractionation of these molecules. To expand the scope of this approach, we have synthesized a fluorescent reagent, 2-amino-(6-amidobiotinyl)pyridine. This reagent can tag oligosaccharides under nondegradative conditions with high efficiency. The resulting adducts show excellent fractionation by reverse-phase HPLC with sensitive detection in the low picomole range. When combined with sequential exoglycosidase digestion, stepwise sequencing of the sugar chains is possible. The biotinyl group can also be used to recover the sugar chain from reaction mixtures. The high-affinity interaction of the biotinyl group with multivalent avidin or streptavidin can be used to create the functional equivalent of neoglycoproteins carrying multiple copies of oligosaccharides of defined structure. These complexes allow the production of IgG antibodies directed against the oligosaccharide chain. They can also harness the power of (strept)avidin-biotin technology for the detection and isolation of oligosaccharide-specific receptors from native sources of recombinant libraries.

Alkaline Phosphatase↗

PubMed2000

Human immunodeficiency virus (HIV) type 1 antibodies in perinatal HIV-1 infection: association with human HIV-1 transmission, infection, and disease progression. For the Women and Infants Transmission Study.

Anti -human immunodeficiency virus (HIV) type 1 antibodies in 242 pregnant women and 238 infants were measured at birth and at 1, 2, 4, and 6 months after birth, to estimate their association with perinatal transmission and infant disease progression. Maternal anti-p24 (P=.01) and anti-gp120 (P=.04) antibodies were inversely associated with vertical transmission rates, independent of maternal percentage of CD4 cells, hard drug use, duration of ruptured membranes, serum albumin levels, serum vitamin A levels, and quantitative HIV-1 peripheral mononuclear blood cell culture, but not with maternal plasma immune complex dissociated p24 or HIV-1 RNA copy number, both of which were highly correlated with antibodies. From ages 1-2 months, anti-gp120, -gp41, -p31, and -p66 decayed to a greater extent in infected than in uninfected infants. Infected infants produced anti-p24 antibody by age 2 months, anti-p17 by 4 months, and anti-p41 and anti-gp120 by 6 months. As early as birth, infants with rapid disease progression had lower levels of anti-p24 than did infants whose disease did not rapidly progress, but not independently of HIV-1 RNA levels.

Cohort Studies↗

PubMed1999

Disruption of a dynamin homologue affects endocytosis, organelle morphology, and cytokinesis in Dictyostelium discoideum.

The identification and functional characterization of Dictyostelium discoideum dynamin A, a protein composed of 853 amino acids that shares up to 44% sequence identity with other dynamin-related proteins, is described. Dynamin A is present during all stages of D. discoideum development and is found predominantly in the cytosolic fraction and in association with endosomal and postlysosomal vacuoles. Overexpression of the protein has no adverse effect on the cells, whereas depletion of dynamin A by gene-targeting techniques leads to multiple and complex phenotypic changes. Cells lacking a functional copy of dymA show alterations of mitochondrial, nuclear, and endosomal morphology and a defect in fluid-phase uptake. They also become multinucleated due to a failure to complete normal cytokinesis. These pleiotropic effects of dynamin A depletion can be rescued by complementation with the cloned gene. Morphological studies using cells producing green fluorescent protein-dynamin A revealed that dynamin A associates with punctate cytoplasmic vesicles. Double labeling with vacuolin, a marker of a postlysosomal compartment in D. discoideum, showed an almost complete colocalization of vacuolin and dynamin A. Our results suggest that that dynamin A is likely to function in membrane trafficking processes along the endo-lysosomal pathway of D. discoideum but not at the plasma membrane.

Amino Acid Sequence↗

PubMed2001

The ADP ribosylation factor-nucleotide exchange factors Gea1p and Gea2p have overlapping, but not redundant functions in retrograde transport from the Golgi to the endoplasmic reticulum.

The activation of the small ras-like GTPase Arf1p requires the action of guanine nucleotide exchange factors. Four Arf1p guanine nucleotide exchange factors have been identified in yeast: Sec7p, Syt1p, Gea1p, and its homologue Gea2p. We identified GEA2 as a multicopy suppressor of a sec21-3 temperature-sensitive mutant. SEC21 encodes the gamma-subunit of coatomer, a heptameric protein complex that together with Arf1p forms the COPI coat. GEA1 and GEA2 have at least partially overlapping functions, because deletion of either gene results in no obvious phenotype, whereas the double null mutant is inviable. Conditional mutants defective in both GEA1 and GEA2 accumulate endoplasmic reticulum and Golgi membranes under restrictive conditions. The two genes do not serve completely overlapping functions because a Deltagea1 Deltaarf1 mutant is not more sickly than a Deltaarf1 strain, whereas Deltagea2 Deltaarf1 is inviable. Biochemical experiments revealed similar distributions and activities for the two proteins. Gea1p and Gea2p exist both in membrane-bound and in soluble forms. The membrane-bound forms, at least one of which, Gea2p, can be visualized on Golgi structures, are both required for vesicle budding and protein transport from the Golgi to the endoplasmic reticulum. In contrast, Sec7p, which is required for protein transport within the Golgi, is not required for retrograde protein trafficking.

ADP-Ribosylation Factors↗

PubMed2006

Computational methodologies for modelling, analysis and simulation of signalling networks.

This article is a critical review of computational techniques used to model, analyse and simulate signalling networks. We propose a conceptual framework, and discuss the role of signalling networks in three major areas: signal transduction, cellular rhythms and cell-to-cell communication. In order to avoid an overly abstract and general discussion, we focus on three case studies in the areas of receptor signalling and kinase cascades, cell-cycle regulation and wound healing. We report on a variety of modelling techniques and associated tools, in addition to the traditional approach based on ordinary differential equations (ODEs), which provide a range of descriptive and analytical powers. As the field matures, we expect a wider uptake of these alternative approaches for several reasons, including the need to take into account low protein copy numbers and noise and the great complexity of cellular organisation. An advantage offered by many of these alternative techniques, which have their origins in computing science, is the ability to perform sophisticated model analysis which can better relate predicted behaviour and observations.

Algorithms↗

PubMed1997

Memory and executive functions in amnesic and non-amnesic patients with aneurysms of the anterior communicating artery.

Ruptured and repaired anterior communicating artery (ACoA) aneurysm can result in devastating impairments involving memory, executive function, confabulation and personality change. Importantly, traditional cerebral areas implicated in amnesia are not damaged, yet amnesia can still be manifested. While ACoA patients show normal visual-constructional skills (i.e. copy scores) on the Rey-Osterrieth complex figure test, recall is often impaired. What is unclear is whether impaired recall is attributable to problems in encoding, accelerated rates of forgetting, retrieval or some combination. To disentangle these issues, we examined 10 patients with ruptured aneurysms of the ACoA, using the Rey-organizational and extended memory procedure which uses an organizational procedure for enhancing immediate recall and provides added sensitivity by combining recall with non-recall measures (e.g. recognition, spatial discrimination and spatial assembly). The major findings were: (i) immediate recall in amnesics was improved by providing an organizational strategy; (ii) following the organization trials, amnesics and non-amnesics retained information to a comparable extent over a 30-min delay; (iii) two subgroups of amnesics emerged, those subjects impaired in acquisition and a second group with impaired retrieval; (iv) all subjects showed preserved memory on non-recall measures. These findings have important implications with respect to using organizational strategies in cognitive treatments and in using non-recall measures in improving the validity and reliability of patient assessment.

Adult↗

PubMed2006

Comparative genomic hybridization and prenatal diagnosis.

PURPOSE OF REVIEW: Microarray-based comparative genomic hybridization (array-CGH) which detects aneuploidies and submicroscopic deletions and duplications in one assay is now offered for genetic diagnosis in children and adults. Its application to prenatal diagnosis is still limited, but very promising. We predict that array-CGH on fetal DNA obtained through amniocentesis or chorionic villus sampling and in the future possibly through noninvasive collection from the maternal cervix or blood, will transform the practice of prenatal diagnosis. RECENT FINDINGS: The power of array-CGH for genetic diagnosis and gene discovery is supported by recent studies. Most arrays for clinical use carry large DNA fragments, but alternative designs containing oligonucleotides will move into the clinic. Some oligonucleotide arrays can simultaneously analyze DNA copy number and single nucleotide polymorphisms, thereby adding potential assessment of uniparental disomy and paternity. Recent array-CGH studies have revealed extensive interindividual copy number variation of genomic segments, unanticipated complexity of apparently balanced translocations, and new phenotypes associated with DNA deletions and duplications. These observations affect counseling for prenatal diagnosis by array-CGH. SUMMARY: We believe that array-CGH will be embraced as a tool for prenatal diagnosis of chromosomal defects, but its introduction into clinical practice should proceed with caution by experienced laboratories.

Aneuploidy↗

PubMed2006

The introgression of a functional nuclear gene from Poa to Festuca ovina.

In sheep's fescue, Festuca ovina, genes coding for the cytosolic enzyme phosphoglucose isomerase, PGIC, are not only found at the standard locus, PgiC1, but also at a segregating second locus, PgiC2. We have used PCR-based sequencing to characterize the molecular structure and evolution of five PgiC1 and three PgiC2 alleles in F. ovina. The three PgiC2 alleles were complex in that they carried two gene copies: either two active genes or one active and one pseudogene. All the PgiC2 sequences were very similar to each other but highly diverged from the five PgiC1 sequences. We also sequenced PgiC genes from several other grass species. Phylogenetic analysis of these sequences indicates that PgiC2 has introgressed into F. ovina from the distant genus Poa. Such an introgression may, for example, follow from a non-standard fertilization with more than one pollen grain, or a direct horizontal gene transfer mediated by a plant virus.

Alleles↗

PubMed1997

The flagellin N-methylase gene fliB and an adjacent serovar-specific IS200 element in Salmonella typhimurium.

The cloning and molecular genetic analysis of a locus mapping within the flagellar gene (fli) complex of Salmonella typhimurium is reported. A copy of the insertion element IS200 was located in a noncoding stretch of DNA upstream of the fliA gene. Comparative nucleotide sequence analysis showed that this copy of IS200 was 711 bp long and that its flanking regions contained no features common to other characterized insertion sites of this element. The element was located 37 bp downstream of an ORF whose product was shown by interspecific transfer and amino acid analysis to carry out N-methylation of selected lysine residues in Salmonella flagellin. The sequence and phenotype of this ORF identified it as fliB, encoding the only prokaryotic N-methylase acting on amino groups to have been characterized to date. It was found to be conserved among all clinically significant serovars of Salmonella. The IS200 insertion site is of particular interest since it was conserved in all but two rare evolutionary lines of S. typhimurium, and was absent from 85 Salmonella strains belonging to 37 other serovars. It is thus a phylogenetically significant marker at the serovar level.

Amino Acid Sequence↗

PubMed2004

Gene conversion and the evolution of protocadherin gene cluster diversity.

The synaptic cell adhesion molecules encoded by the protocadherin gene cluster are hypothesized to provide a molecular code involved in the generation of synaptic complexity in the developing brain. Variation in copy number and sequence content of protocadherin cluster genes among vertebrate species could reflect adaptive differences in protocadherin function. We have completed an analysis of zebrafish protocadherin cluster genes. Zebrafish have two unlinked protocadherin clusters, DrPcdh1 and DrPcdh2. Like mammalian protocadherin clusters, DrPcdh1 has both alpha and gamma variable and constant region exons. A consensus protocadherin promoter motif sequence identified in mammals is also conserved in zebrafish. Few orthologous relationships, however, are apparent between zebrafish and mammalian protocadherin proteins. Here we show that protocadherin cluster genes in human, mouse, rat, and zebrafish are subject to striking gene conversion events. These events are restricted to regions of the coding sequence, particularly the coding sequences of ectodomain 6 and the cytoplasmic domain. Diversity among paralogs is restricted to particular ectodomains that are excluded from conversion events. Conversion events are also strongly correlated with an increase in third-position GC content. We propose that the combination of lineage-specific duplication, restricted gene conversion, and adaptive variation in diversified ectodomains drives vertebrate protocadherin cluster evolution.

Animals↗

PubMed2003

Predicting human minisatellite polymorphism.

We seek to define sequence-based predictive criteria to identify polymorphic and hypermutable minisatellites in the human genome. Polymorphism of a representative pool of minisatellites, selected from human chromosomes 21 and 22, was experimentally measured by PCR typing in a population of unrelated individuals. Two predictive approaches were tested. One uses simple repeat characteristics (e.g., unit length, copy number, nucleotide bias) and a more complex measure, termed HistoryR, based on the presence of variant motifs in the tandem array. We find that HistoryR and percentage of GC are strongly correlated with polymorphism and, as predictive criteria, reduce by half the number of repeats to type while enriching the proportion with heterozygosity >/=0.5, from a background level of 43% to 59%. The second approach uses length differences between minisatellites in the two releases of the human genome sequence (from the public consortium and Celera). As a predictor, this similarly enriches the number of polymorphic minisatellites, but fails to identify an unexpectedly large number of these. Finally, typing of the highly polymorphic minisatellites in large families identified one new hypermutable minisatellite, located in a predicted coding sequence. This may represent the first coding human hypermutable minisatellite.

Chromosomes, Human, Pair 21↗

PubMed2005

A pathway-specific transcriptional regulatory gene for nikkomycin biosynthesis in Streptomyces ansochromogenes that also influences colony development.

DNA sequence analysis of a 7.5 kb XhoI DNA fragment from the region flanking the nikkomycin biosynthesis gene cluster in Streptomyces ansochromogenes revealed one 3.3 kb open reading frame (ORF), designated sanG. The deduced product of sanG (1061 amino acids), which is similar to PimR of Streptomyces natalensis, contains an OmpR-like DNA binding domain in its N-terminal portion and A- and B-type nucleotide binding motifs in the middle of the protein. Disruption of sanG abolished nikkomycin biosynthesis, reduced sporulation and led to brown pigment accumulation. All aspects of this complex phenotype were complemented by a single copy sanG which was integrated into the chromosome. The introduction of multiple copies of sanG resulted in increased nikkomycin production. S1 mapping results indicated that sanG is transcribed from at least three promoters (P1, P2 and P3), P1 being strongly upregulated when production of nikkomycins starts. Two putative transcription units for nikkomycin biosynthesis, starting from sanN and sanO, are dependent on the expression of sanG, whereas a putative transcription unit starting from sanF was not regulated by sanG. These results suggested that sanG encodes a transcriptional activator important for nikkomycin biosynthesis that, unusually, also has pleiotropic effects on secondary metabolism and development.

Amino Acid Sequence↗

PubMed2004

Ruminococcus albus 8 mutants defective in cellulose degradation are deficient in two processive endocellulases, Cel48A and Cel9B, both of which possess a novel modular architecture.

The cellulolytic bacterium Ruminococcus albus 8 adheres tightly to cellulose, but the molecular biology underpinning this process is not well characterized. Subtractive enrichment procedures were used to isolate mutants of R. albus 8 that are defective in adhesion to cellulose. Adhesion of the mutant strains was reduced 50% compared to that observed with the wild-type strain, and cellulose solubilization was also shown to be slower in these mutant strains, suggesting that bacterial adhesion and cellulose solubilization are inextricably linked. Two-dimensional polyacrylamide gel electrophoresis showed that all three mutants studied were impaired in the production of two high-molecular-mass, cell-bound polypeptides when they were cultured with either cellobiose or cellulose. The identities of these proteins were determined by a combination of mass spectrometry methods and genome sequence data for R. albus 8. One of the polypeptides is a family 9 glycoside hydrolase (Cel9B), and the other is a family 48 glycoside hydrolase (Cel48A). Both Cel9B and Cel48A possess a modular architecture, Cel9B possesses features characteristic of the B(2) (or theme D) group of family 9 glycoside hydrolases, and Cel48A is structurally similar to the processive endocellulases CelF and CelS from Clostridium cellulolyticum and Clostridium thermocellum, respectively. Both Cel9B and Cel48A could be recovered by cellulose affinity procedures, but neither Cel9B nor Cel48A contains a dockerin, suggesting that these polypeptides are retained on the bacterial cell surface, and recovery by cellulose affinity procedures did not involve a clostridium-like cellulosome complex. Instead, both proteins possess a single copy of a novel X module with an unknown function at the C terminus. Such X modules are also present in several other R. albus glycoside hydrolases and are phylogentically distinct from the fibronectin III-like and X modules identified so far in other cellulolytic bacteria.

Amino Acid Sequence↗