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At least 487 records · Page 27Linked to original sources
PubMed2000

The use of peptides in Diogenesis: a novel approach to drug discovery and phenomics.

The Diogenesis Process is an integrated drug discovery platform that allows target validation, partner identification, and the identification of small molecule drug candidates for protein:protein interactions. Diogenesis utilizes the well-established methods of peptide display, synthetic and recombinant peptide production, in vitro biochemical and cell-based testing to form a universal drug discovery engine with distinct advantages over competing protocols. The process creates a library of diverse peptides, and selects rare and unique binders that identify and simplify surface "hot spots" on protein targets through which target activity can be regulated. In many cases, these peptide "Surrogates" have the minimal sequence and structural information needed to induce a change in the biological activity of the target; in pharmacological terms, only after inducing agonism or antagonism. The use of Surrogates in hot spot identification also allows subdivision of rather large surface domains into smaller domains that alone, or in combination with another subdomain, offers sufficient territory for modification of target activity. These Surrogates, in turn, provide the necessary ligands to develop appropriate Site Directed Assays (SDAs) for each essential subdomain. The SDAs provide the screening mode for finding competitive small molecules by high throughput screening. The other arm of the Diogenesis system is an application in the new area of "Phenomics." This part of the discovery process is a form of phenotypic analysis of genomic information that has also been referred to as "functional" genomics. Phenomics, done via the Diogenesis system, uses peptide Surrogates as modifiers of the activity of, and identifiers of the partners of, gene products of known and unknown function. Actually, in many instances, the same Surrogate isolated for use in Phenomics will be used to create SDAs for discovery of small molecule drug candidates. In this simple fashion, the two applications of Diogenesis are integrated to provide savings in research time and money.

Amino Acid Sequence↗
PubMed2000

Informatics issues in large-scale sequence analysis: elucidating the protein kinases of C. elegans.

With the availability of the nearly complete genomic sequence of C. elegans, the first multicellular organism to be sequenced, molecular biology has definitely entered the postgenomic era. Annotation of the genomic sequence, which refers to identifying the genes and other biologically relevant sections of the genome, is an important and nontrivial next step. A first-pass annotation will be necessarily incomplete but will drive further biological experiments, which in turn will help to annotate the genome better. Given the scale of the genome sequence analysis, it is clear that the annotation should be automated as much as possible without sacrificing the quality of analysis. In this work, we outline our approach to identifying the protein kinases of C. elegans from the genomic sequence. We describe new tools we have developed for analysis, management and visualization of genomic data. By developing modular and scalable solutions, this study has provided a framework for future analysis of the Drosophila and human genomes.

Animals↗
PubMed1989

A general method for detecting rearrangements in a bacterial genome.

An effective method was developed to monitor genome rearrangement in bacteria. The whole procedure consists of five steps. (i) Genomic DNAs of reference cells and test cells are digested with the same restriction enzyme. (ii) The DNA restriction fragments from the test cells are radioactively labeled. (iii) The labeled DNA fragments of test cells are mixed with unlabeled DNA fragments from reference cells that are 100- to 1000-fold in excess and the mixture is electrophoresed in an agarose gel. (iv) After electrophoresis, DNA fragments are alkali-denatured; this is followed by renaturation in situ in the gel. The labeled rearranged DNA fragments from the test cells will renature much slower, as compared with the nonrearranged fragments, since in this location of the gel these rearranged fragments do not have a counterpart in the driver DNA, which is in excess. (v) The DNA gel is electrophoresed in a second dimension perpendicular to the first dimension after renaturation. The denatured rearranged DNAs are revealed after autoradiography, since single-stranded DNA fragments have higher electrophoretic mobility than double-stranded fragments of the same sizes. This process of detection has been demonstrated in this report by using Escherichia coli HB101 as the reference strain and E. coli HB101 carrying lambda phage DNA (1:1 genomic ratio) as the test strain.

Bacteriophage lambda↗
PubMed1980

Epidemic outbreaks of adenovirus 7 with special reference to the pathogenicity of adenovirus genome type 7b.

Adenovirus type 7 (Ad 7) is the serotype among the 36 recognized adenovirus types which most frequently has been associated with severe illness. Three different epidemic patterns of Ad 7 infection can be distinguished: 1) the first appears during the winter among infants with median age below two years, has characteristic symptoms of high fever and pneumonia and an outcome that may be fatal: 2) the second appears in the fall among children with median age seven years, has characteristic symptoms of high fever, pneumonia, abdominal symptoms and meningism and an outcome that is favorable; 3) and the third has been seen as acute respiratory disease among military recruits. In the United States, the last mentioned outbreaks require prophylaxis in the form of a live enteric-coated vaccine. DNA restriction site mapping demonstrated the occurrence of three distinct viral entities of Ad 7, which have been designated Ad 7 prototype, Ad 7a (the vaccine strain) and the Ad 7b genome type. In the present study, 36 isolates obtained from outbreaks with the first and the second epidemic patterns were analyzed by restriction endonucleases Bam HI and Sma I. All were identified as the newly recognized Ad 7b genome type. It is concluded that this genome type is responsible for a large portion of the severe infections caused by Ad 7. The epidemic nature of Ad 7 and the severe illness noted among infants indicate that vaccination of institutionalized infants could be considered during years when Ad 7 epidemics appear.

Adenoviridae Infections↗
PubMed2005

Genome-wide identification and testing of superior reference genes for transcript normalization in Arabidopsis.

Gene transcripts with invariant abundance during development and in the face of environmental stimuli are essential reference points for accurate gene expression analyses, such as RNA gel-blot analysis or quantitative reverse transcription-polymerase chain reaction (PCR). An exceptionally large set of data from Affymetrix ATH1 whole-genome GeneChip studies provided the means to identify a new generation of reference genes with very stable expression levels in the model plant species Arabidopsis (Arabidopsis thaliana). Hundreds of Arabidopsis genes were found that outperform traditional reference genes in terms of expression stability throughout development and under a range of environmental conditions. Most of these were expressed at much lower levels than traditional reference genes, making them very suitable for normalization of gene expression over a wide range of transcript levels. Specific and efficient primers were developed for 22 genes and tested on a diverse set of 20 cDNA samples. Quantitative reverse transcription-PCR confirmed superior expression stability and lower absolute expression levels for many of these genes, including genes encoding a protein phosphatase 2A subunit, a coatomer subunit, and an ubiquitin-conjugating enzyme. The developed PCR primers or hybridization probes for the novel reference genes will enable better normalization and quantification of transcript levels in Arabidopsis in the future.

Arabidopsis↗
PubMed2005

Genomic alterations detected by comparative genomic hybridization in primary lung adenocarcinomas with special reference to the relationship with DNA ploidy.

To clarify the clinicopathological and biological significance of genomic alterations in pulmonary adenocarcinomas, we examined chromosomal DNA sequence copy number aberrations (DSCNAs) and DNA ploidy in 42 surgically resected specimens by comparative genomic hybridization (CGH) and laser scanning cytometry (LSC), respectively. The number of DSCNA did not affect the size of carcinoma or number of nodal metastasis. More than 60% of carcinomas showed a 1q21-23 gain or 13q21 loss. Gains of 9q22-33 and 10q26-qter and a loss of 15q14-qter were significantly associated with nodal metastasis (p<0.05). Of 42 pulmonary adenocarcinomas, 32 (76%) showed DNA aneuploidy. The number of DSCNAs in aneuploid carcinomas was larger than that in diploid carcinomas (p<0.01). Our results suggest that diploid and aneuploid types are cytogenetically different in pulmonary adenocarcinomas and aneuploid carcinomas are genetically more unstable and aggressive than diploid carcinomas.

Adenocarcinoma↗
PubMed1982

Ubiquitous transposon-like repeats B1 and B2 of the mouse genome: B2 sequencing.

Mouse genome contains two major families of short interspersed repeats in more than 10(5) copies scattered throughout the whole genome. They are referred to as B1 and B2 sequences since they were first isolated from the genome library by means of a dsRNA-B probe /1/. In this work, two copies of the B2 family were sequenced and compared with the previously sequenced B1 repeat /2/. A B2 ubiquitous repeat is ca. 190 bp long. The members of the family deviate in 3-5% of nucleotides from the consensus sequence. B2 contains regions of homology to the RNA polymerase III split promoter and to 4.5S snRNA I. Both B1 and B2 contain regions which resemble junctions between exons and introns. In contrast to B1, B2 does not contain apparent homologies to papova viral replication origins and a human Alu sequence. One side of the B2 repeat is represented by a very AT-rich sequence (ca. 30 bp long) followed with an oligo (dA) stretch 10-15 nucleotides long. This region of the repeat is the most variable one. The whole unit is flanked with 15-16 bp direct repeats different in sequenced copies of B2. The same is true of some copies of the B1 family. The properties of B1 and B2 repeats suggest that they may represent a novel class of transposon-like elements in eukaryotic genome. A possible role of B-type repeats in genome reorganization, DNA replication and pre-mRNA processing is discussed.

Animals↗
PubMed2004

Metagenomics: application of genomics to uncultured microorganisms.

Metagenomics (also referred to as environmental and community genomics) is the genomic analysis of microorganisms by direct extraction and cloning of DNA from an assemblage of microorganisms. The development of metagenomics stemmed from the ineluctable evidence that as-yet-uncultured microorganisms represent the vast majority of organisms in most environments on earth. This evidence was derived from analyses of 16S rRNA gene sequences amplified directly from the environment, an approach that avoided the bias imposed by culturing and led to the discovery of vast new lineages of microbial life. Although the portrait of the microbial world was revolutionized by analysis of 16S rRNA genes, such studies yielded only a phylogenetic description of community membership, providing little insight into the genetics, physiology, and biochemistry of the members. Metagenomics provides a second tier of technical innovation that facilitates study of the physiology and ecology of environmental microorganisms. Novel genes and gene products discovered through metagenomics include the first bacteriorhodopsin of bacterial origin; novel small molecules with antimicrobial activity; and new members of families of known proteins, such as an Na(+)(Li(+))/H(+) antiporter, RecA, DNA polymerase, and antibiotic resistance determinants. Reassembly of multiple genomes has provided insight into energy and nutrient cycling within the community, genome structure, gene function, population genetics and microheterogeneity, and lateral gene transfer among members of an uncultured community. The application of metagenomic sequence information will facilitate the design of better culturing strategies to link genomic analysis with pure culture studies.

Biotechnology↗
PubMed2002

Construction and analysis of a human-chimpanzee comparative clone map.

The recently released human genome sequences provide us with reference data to conduct comparative genomic research on primates, which will be important to understand what genetic information makes us human. Here we present a first-generation human-chimpanzee comparative genome map and its initial analysis. The map was constructed through paired alignment of 77,461 chimpanzee bacterial artificial chromosome end sequences with publicly available human genome sequences. We detected candidate positions, including two clusters on human chromosome 21 that suggest large, nonrandom regions of difference between the two genomes.

Animals↗
PubMed1998

Systematic Prediction of Orthologous Units of Genes in the Complete Genomes.

In order to fully make use of the vast amount of information in the complete genome sequences, we are developing a genome-scale system for predicting gene functions and cellular functions. The system makes use of the information of sequence similarity, the information of positional correlations in the genome, and the reference knowledge stored as the ortholog group tables in KEGG (Kyoto Encyclopedia of Genes and Genomes). The ortholog group table summarizes orthologous and paralogous relations among different organisms for a set of genes that are considered to form a functional unit, such as a conserved portion of the metabolic pathway or a molecular machinery for the membrane transport. At the moment, the ortholog group table is constructed for the cases where the genes are clustered in physically close positions in the genome for at least one organism. In this paper, we describe the system and the actual analysis of the complete genome of Pyrococcus horikoshii to identify ABC transporters.

Journal Article↗
PubMed2000

Intrinsic protein disorder in complete genomes.

Intrinsic protein disorder refers to segments or to whole proteins that fail to fold completely on their own. Here we predicted disorder on protein sequences from 34 genomes, including 22 bacteria, 7 archaea, and 5 eucaryotes. Predicted disordered segments > or = 50, > or = 40, and > or = 30 in length were determined as well as proteins estimated to be wholly disordered. The five eucaryotes were separated from bacteria and archaea by having the highest percentages of sequences predicted to have disordered segments > or = 50 in length: from 25% for Plasmodium to 41% for Drosophila. Estimates of wholly disordered proteins in the bacteria ranged from 1% to 8%, averaging to 3 +/- 2%, estimates in various archaea ranged from 2 to 11%, plus an apparently anomalous 18%, averaging to 7 +/- 5% that drops to 5 +/- 3% if the high value is discarded. Estimates in the 5 eucarya ranged from 3 to 17%. The putative wholly disordered proteins were often ribosomal proteins, but in addition about equal numbers were of known and unknown function. Overall, intrinsic disorder appears to be a common, with eucaryotes perhaps having a higher percentage of native disorder than archaea or bacteria.

Animals↗
PubMed2025

A high-quality genomic catalog of the human oral microbiome broadens its phylogeny and clinical insights.

The oral microbiome is increasingly linked to human health. To further examine this microbial community, we present the human reference oral microbiome (HROM), with 72,641 high-quality genomes from 3,426 species, including 2,019 previously unidentified species, improving metagenomic sequence read classification over existing catalogs. Notably, HROM unveils 1,137 previously uncharacterized candidate phyla radiation (CPR) species, establishing Patescibacteria as the most prevalent phylum in the oral microbiota and distinct from environmental Patescibacteria. Additionally, an oral CPR subclade is associated with periodontitis, complementing Porphyromonas gingivalis in predicting disease. Finally, comparing HROM with reference genomes of the gut microbiome reveals taxonomic and functional divergence between these microbiomes. HROM contains 42 ectopic oral species, and their relative abundance in gut microbiota is predictive of intestinal, cardiovascular, and liver diseases. Thus, HROM offers an expanded view of the oral microbiome and highlights the clinical importance of further examining the links between oral microbes and systemic disorders.

Humans↗
PubMed2005

Estimation of the extent of linkage disequilibrium in seven regions of the porcine genome.

Linkage disequilibrium (LD) refers to the correlation among neighboring alleles, reflecting non-random patterns of association between alleles at (nearby) loci. A better understanding of LD in the porcine genome is of direct relevance for identification of genes and mutations with a certain effect on the traits of interest. Here, 215 SNPs in seven genomic regions were genotyped in individuals of three breeds. Pairwise linkage disequilibrium was calculated for all marker pairs. To estimate the extent of LD, all pairwise LD values were plotted against the distance between the markers. Based on SNP markers in four genomic regions analyzed in three panels from populations of Large White, Dutch Landrace, and Meishan origin, useful LD is estimated to extend for approximately 40 to 60 kb in the porcine genome.

Animals↗
PubMed2002

Molecular-evolutionary mechanisms for genomic disorders.

Molecular studies of unstable regions in the human genome have identified region-specific low-copy repeats (LCRs). Unlike highly repetitive sequences (e.g. Alus and LINEs), LCRs are usually of 10-400 kb in size and exhibit > or = 95-97% similarity. According to computer analyses of available sequencing data, LCRs may constitute >5% of the human genome. Through the process of non-allelic homologous recombination using paralogous genomic segments as substrates, LCRs have been shown to facilitate meiotic DNA rearrangements associated with disease traits, referred to as genomic disorders. In addition, this LCR-based complex genome architecture appears to play a major role in both primate karyotype evolution and human tumorigenesis.

Animals↗
PubMed2003

The human hyaluronan synthase genes: genomic structures, proximal promoters and polymorphic microsatellite markers.

The glycosaminoglycan (GAG) hyaluronan (HA) is a key component of the vertebrate extracellular matrix (ECM) and is synthesised by the HA synthase (HAS) enzymes HAS1, HAS2 and HAS3 at the plasma membrane. Accumulating evidence emphasises the relevance of HA metabolism in an increasing number of processes of clinical interest including renal fibrosis and peritoneal mesothelial wound healing. In the present study, the genomic sequences and organisation of the genes encoding the human HAS isoforms were deduced, in silico, from reference cDNA and genomic sequence data. These data were confirmed in vitro by sequencing of PCR-amplified HAS exons and flanking genomic sequences, comparison with sequence data for the corresponding murine Has orthologues, rapid amplification of 5' cDNA ends analysis and luciferase reporter assays on putative proximal promoter sequences. The HAS1 gene comprised five exons, with the translation start site situated 9bp from the 3' end of exon 1. In contrast, the genomic structures for HAS2 and both HAS3 variants spanned four exons, exon 1 forming a discrete 5'-untranslated region (5'-UTR) and the translation start site lying at nucleotide 1 of exon 2. Dinucleotide microsatellite loci were identified in intron 1 of HAS1 and HAS2, and immediately upstream of the HAS3 gene and their utility as linkage markers demonstrated in genomic DNA (gDNA) studies. We thus present a comprehensive resource for mutation detection screening of all HAS exons and/or linkage analysis of each HAS gene in a variety of disorders for which they are attractive candidates.

Animals↗
PubMed2000

AFLP fingerprint analysis of Bradyrhizobium strains isolated from Faidherbia albida and Aeschynomene species.

The diversity of Bradyrhizobium isolates from Faidherbia albida and Aeschynomenee species was assessed using AFLP analysis, a high-resolution genomic fingerprinting technique. Reference strains from Bradyrhizobium japonicum, Bradyrhizobium elkanii and Bradyrhizobium liaoningense were included for comparison. At a similarity level of 50%, a total of 34 different groups were obtained by cluster analysis of the genomic fingerprints. Four of these clusters correspond to the three reference species, demonstrating the large diversity of the isolates studied. Comparison with other data demonstrates that AFLP has a higher resolution than restriction analysis of 16S rRNA genes, SDS-PAGE analysis of proteins and phenotypic analysis. Results of the latter two methods showed little correspondence with the genotypic data.

Acacia↗