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PubMed2006

CellCircuits: a database of protein network models.

CellCircuits (http://www.cellcircuits.org) is an open-access database of molecular network models, designed to bridge the gap between databases of individual pairwise molecular interactions and databases of validated pathways. CellCircuits captures the output from an increasing number of approaches that screen molecular interaction networks to identify functional subnetworks, based on their correspondence with expression or phenotypic data, their internal structure or their conservation across species. This initial release catalogs 2019 computationally derived models drawn from 11 journal articles and spanning five organisms (yeast, worm, fly, Plasmodium falciparum and human). Models are available either as images or in machine-readable formats and can be queried by the names of proteins they contain or by their enriched biological functions. We envision CellCircuits as a clearinghouse in which theorists may distribute or revise models in need of validation and experimentalists may search for models or specific hypotheses relevant to their interests. We demonstrate how such a repository of network models is a novel systems biology resource by performing several meta-analyses not currently possible with existing databases.

Animals↗

PubMed2006

Hypervariability within the Rifin, Stevor and Pfmc-2TM superfamilies in Plasmodium falciparum.

The human malaria parasite, Plasmodium falciparum, possesses a broad repertoire of proteins that are proposed to be trafficked to the erythrocyte cytoplasm or surface, based upon the presence within these proteins of a Pexel/VTS erythrocyte-trafficking motif. This catalog includes large families of predicted 2 transmembrane (2TM) proteins, including the Rifin, Stevor and Pfmc-2TM superfamilies, of which each possesses a region of extensive sequence diversity across paralogs and between isolates that is confined to a proposed surface-exposed loop on the infected erythrocyte. Here we express epitope-tagged versions of the 2TM proteins in transgenic NF54 parasites and present evidence that the Stevor and Pfmc-2TM families are exported to the erythrocyte membrane, thus supporting the hypothesis that host immune pressure drives antigenic diversity within the loop. An examination of multiple P.falciparum isolates demonstrates that the hypervariable loop within Stevor and Pfmc-2TM proteins possesses sequence diversity across isolate boundaries. The Pfmc-2TM genes are encoded within large amplified loci that share profound nucleotide identity, which in turn highlight the divergences observed within the hypervariable loop. The majority of Pexel/VTS proteins are organized together within sub-telomeric genome neighborhoods, and a mechanism must therefore exist to differentially generate sequence diversity within select genes, as well as within highly defined regions within these genes.

Amino Acid Sequence↗

PubMed2004

Generation of longer 3' cDNA fragments from massively parallel signature sequencing tags.

Massively Parallel Signature Sequencing (MPSS) is a powerful technique for genome-wide gene expression analysis, which, similar to SAGE, relies on the production of short tags proximal to the 3'end of transcripts. A single MPSS experiment can generate over 10(7) tags, providing a 10-fold coverage of the transcripts expressed in a human cell. A significant fraction of MPSS tags cannot be assigned to known transcripts (orphan tags) and are likely to be derived from transcripts expressed at very low levels (approximately 1 copy per cell). In order to explore the potential of MPSS for the characterization of the human transcriptome, we have adapted the GLGI protocol (Generation of Longer cDNA fragments from SAGE tags for Gene Identification) to convert MPSS tags into their corresponding 3' cDNA fragments. GLGI-MPSS was applied to 83 orphan tags and 41 cDNA fragments were obtained. The analysis of these 41 fragments allowed the identification of novel transcripts, alternative tags generated from polymorphic and alternatively spliced transcripts, as well as the detection of artefactual MPSS tags. A systematic large-scale analysis of the genome by MPSS, in combination with the use of GLGI-MPSS protocol, will certainly provide a complementary approach to generate the complete catalog of human transcripts.

Alternative Splicing↗

PubMed2026

Motif-centered analyses reveal universal and tissue-specific mutagenic mechanisms operating in the human body.

Somatic mutations are inevitable in human genomes and can lead to cancer initiation and tumor progression. Although many mutagenic processes have been linked to cancer, their activities in normal tissues before malignant transformation remain poorly characterized. Here, we analyzed the mutation profiles of 10,625 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C→T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We also identified a second clock-like motif, T→C substitutions in aTn motif associated with exposure to small epoxides and other SN2 electrophiles, in several tissues. Motifs associated with other environmental and chemical mutagens showed sporadic and tissue-specific mutagenesis. APOBEC-induced C→T and C→G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most tissues. Together, our analyses elucidated several cancer-associated mutagenic processes in normal tissues and provided a robust analytical framework for quantifying mutagenic activities from somatic mutation catalogs.

Humans↗

PubMed2004

Database and structural characterization of intermolecular interactions in nucleic acid and protein complex.

Protein-nucleic acid interactions and manners in which they control cellular communication are interesting subjects. Structural interaction data based on three-dimensional structure provide the valuable information for understanding these interactions. The database cataloging the interaction motifs of nucleic acid moieties has been developed. DNA/RNA molecules with the specific three-dimensional structure, express the specific structural and biological functions. The polymorphic nature of recognition interactions and/or motifs in protein-nucleic acid complex are generated from a variety of week forces, such as hydrogen bonds and hydrophobic interactions. The geometrical parameters about hydrogen bond and base stacking would provide the tolerant aspect for these characterizations. The tentative database including these geometrical parameters with the species and physical properties of the surrounding amino acids has been constructed. The user can obtain the selected list with several descriptors for the structure definition and sequence properties.

Databases, Nucleic Acid↗

PubMed2005

Usability of the kink parameters for nucleic acid structure in database.

DNA/RNA molecules with the specific three-dimensional structure, express the specific structural and biological functions. The knowledge integration based on three dimensional structures can be used to explain biochemical observations, to predict biological functions and to design drugs specific to a given complex system. The database cataloging the interaction motifs of nucleic acid moieties has been developed. Skew matrix, a kind of kink parameter, affords the structural description between the adjacent moieties. The proper values in skew matrix have the good properties, i.e., impregnable and flexible presentation. The geometrical parameters about hydrogen bond and base stacking would also provide the tolerant aspect for stereochemical bioinformatics. The tentative database including these parameters with the species and physical properties of the surrounding nucleic acid components and amino acids has been constructed.

Amino Acids↗

PubMed2006

Usability of BioCon2 for nucleic acid structures in database.

With the specific three-dimensional structure, DNA/RNA molecules express the specific structural and catalytic functions. The knowledge integration based on three dimensional structures can be used to explain biochemical observations, to predict biological functions and to design drugs specific to a given complex system. In the large RNAs, the helical stems close to each other with specific arrangement. The polymorphic nature of multiple stranded helical structure of nucleic acid relates a promising technique of achieving base sequence specific recognition and hence artificial gene regulation. The database cataloging the interaction motifs of nucleic acid moieties has been developed. Skew matrix, a kind of kink parameter, affords the structural description between the adjacent moieties. The program BioCon2 for estimating these skew matrix and cataloguing for multiple stranded helices has been developed. New version allows for the good properties, i.e., impregnable and flexible presentation of multiple helices. The tentative database including these parameters with the species and physical properties of the surrounding nucleic acid components and amino acids has been constructed.

Databases, Nucleic Acid↗

PubMed2000

Use of horizontal ultrathin gel electrophoresis to analyze allelic deletions in chromosome band 11p15.5 in gliomas.

The prognosis for most patients with astrocytic glioma is poor, and postoperative life expectancy has not significantly improved in the last decade despite advances in diagnosis, surgery, and adjuvant therapy. Progress has been made, however, in cataloging the genetic alterations that occur in these tumors. Studying the allelic changes using loss of heterozygosity analysis has proven to be a reliable and rapid way of identifying genetic alterations fundamental to the pathology of this disease. In this study, we used a series of fluorescent-labeled markers and a new horizontal ultrathin gel electrophoresis technology (HUGE; GeneSys Technologies, Inc.) to analyze loss of heterozygosity on 11p15 in a series of 24 matched normal/tumor glioma pairs that included both anaplastic astrocytomas and glioblastomas. These studies significantly narrowed the region harboring a putative 11p15.5 glioma-associated gene and further suggest that a second gene involved in the pathogenesis of brain tumors may exist, centromeric, in bands 11p15.5-p15.4.

Alleles↗

PubMed1976

Strokes in children.

Nine cases have been presented in detail to illustrate some of the varied causes of sudden neurological deficit in childhood: arteriovenous malformation, cryptic hamartoma, berry aneurysm, mycotic aneurysm, intraspinal arteriovenous malformation, brain tumor, migraine, arteritis, and multiple sclerosis. The Boston Children's Hospital experience with aneurysms and intracranial arteriovenous malformation has been summarized. It is noteworthy that a cutaneous hemangioma overlay one cranial and one intraspinal arteriovenous malformation. One small but deep cerebral arteriovenous malformation apparently destroyed itself after its second hemorrhage. Not only have multiple sclerosis and a brain tumor mimicked a vascular lesion, but a series of vascular accidents was misdiagnosed first as multiple sclerosis then as a thalamic tumor. The many possible causes of childhood strokes has been thoroughly cataloged in the Report of the Joint Committee for Stroke Facilities in 1973 (11). Children may be more susceptible to strokes because of congenital abnormalities such as congenital heart disease, hemophilia, and sickle cell anemia, or by diseases which more commonly occur in this age group, such as leukemia. The likelihood of brain abscess in cyanotic congenital heart disease is stressed. Arteriographic studies in our series have been safe; however, there have been reports of probable worsening of symptoms in children with multiple cerebral occlusive lesions in the presence of homocystinuria.

Adolescent↗

PubMed1998

Serine protease inhibitors expressed in the process of budding of tunicates as revealed by EST analysis.

To identify genes expressed during budding of the tunicate Polyandrocarpa misakiensis, we isolated and sequenced 624 clones from a directionally constructed cDNA library to prepare a catalog of expressed sequence tags (ESTs). A total of 233 ESTs matched genes of known sequence in the SwissProt database. About 24% out of them showed high similarity to ribosomal proteins, twice the value (12%) of pre-budding animals. ESTs involved in the respiratory chain also appeared with significant redundancy, suggesting that tunicate budding is accompanied by the enhancement of energy conversion as well as protein synthesis. Serine protease inhibitor (serpin) afforded another striking example of a gene that was highly expressed in the process of budding. The deduced amino acid sequences of five serpin cDNAs all had two consensus signatures of the Kazal's type of secretory protease inhibitor, one of which had an active site for trypsin and the other for elastase. In line with this, recombinant GST-fusion protein showed both trypsin and elastase inhibitor activities. In accordance with the EST analysis, the hemolymph taken from the budding stage showed the highest activity of trypsin inhibitor. We discuss a possible role that Polyandrocarpa serpins may play in bud development by counteracting trypsin-like serine protease, which could facilitate dedifferentiation of formative tissues.

Amino Acid Sequence↗

PubMed1980

Nucleotide sequence of 5S ribosomal RNA from Lingula anatina. A study on the molecular evolution of 5S ribosomal RNA from a living fossil.

By chromatography on columns of DEAE-Sephadex A-50 and Sephadex G-100, and electrophoresis on polyacrylamide gel, 5S rRNA was purified from a low-molecular-weight RNA fraction extracted from the total tissues of Lingula anatina. Complete digests of the 5S rRNA with RNase T1 [EC 3.1.4.8] and pancreatic RNase [EC 3.1.4.22] were sequenced by conventional column chromatography procedures. The nucleotide sequence of this RNA was determined mainly by a chemical method for sequencing the RNA 3' end-labeled with 32P (1), with the complement of the oligonucleotide catalog obtained by the complete RNase digestions of the RNA. By comparing the sequences of several invertebrate, vertebrate, and Chlorella 5S rRNAs, a phylogenic tree of the rRNAs was constructed and the time of divergence of Lingula was estimated.

Animals↗

PubMed1981

The nucleotide sequence of 5S ribosomal RNA from Schizosaccharomyces pombe.

The nucleotide sequence of 5S rRNA from the fission yeast, S. pombe, has been established by post labeling procedures combined with cataloging RNase T1- and A-oligonucleotides derived from unlabeled 5S rRNA. The sequence consists of 119 nucleotides without a modified base and shows more dissimilarities (at 38 positions) from that of S. cerevisiae than from that of humans (at 33 positions).

Ascomycota↗

PubMed1992

Phylogeny of five fungus-like protoctistan Phytophthora species, inferred from the internal transcribed spacers of ribosomal DNA.

Ribosomal DNA variation was used to study evolutionary relationships among five fungal-like protoctistan Phytophthora species. On the basis of morphological and ecological characteristics, four of these species--P. palmivora, P. megakarya, P. capsici, and P. citrophthora--were once thought to be related. Variation within a species was extensively studied in a fifth, outgroup species--P. cinnamomi--known, on the basis of ecological, isozyme, and mitochondrial DNA studies, to be variable. Internal transcribed spacer regions (ITS I, between the 18S and 5.8S rDNAs; and ITS II, between the 5.8S and 25S rDNAs) from 27 isolates of these five species were analyzed by polymerase chain reaction amplification and direct sequencing. Intraspecific variability was undetected or low. Interspecific nucleotide difference was 0.3%-14.6%, and comparisons of variable regions permitted the evaluation of phylogenetic relationships among species. Both neighbor-joining and parsimony analysis of ITS variability support a close relationship between cacao isolates of P. capsici and P. citrophthora and a common lineage for P. palmivora and P. megakarya. Large distance values were estimated between P. cinnamomi and the other species. Inferred relationships based on ITS variability were compared with those based on other characters. The catalog of sequences provides the information necessary to design taxon-specific probes potentially useful in taxonomic, ecological, and population-level studies.

Base Sequence↗

PubMedDate not supplied

Combining estimates from complementary surveys: a case study using prevalence estimates from national health surveys of households and nursing homes.

OBJECTIVES: When a single survey does not cover a domain of interest, estimates from two or more complementary surveys can be combined to extend coverage. The purposes of this article are to discuss and demonstrate the benefits of combining estimates from complementary surveys and to provide a catalog of the analytic issues involved. METHODS: The authors present a case study in which data from the National Health Interview Survey and the National Nursing Home Survey were combined to obtain prevalence estimates for several chronic health conditions for the years 1985, 1995, and 1997. The combined prevalences were estimated by ratio estimation, and the associated variances were estimated by Taylor linearization. The survey weights, stratification, and clustering were reflected in the estimation procedures. RESULTS: In the case study, for the age group of 65 and older, the combined prevalence estimates for households and nursing homes are close to those for households alone. For the age group of 85 and older, however, the combined estimates are sometimes substantially different from the household estimates. Such differences are seen both for estimates within a single year and for estimates of trends across years. CONCLUSIONS: Several general issues regarding comparability arise when there is a goal of combining complementary survey data. As illustrated by this case study, combining estimates can be very useful for improving coverage and avoiding misleading conclusions.

Aged↗

PubMed1993

The SBASE domain library: a collection of annotated protein segments.

SBASE is a database of annotated protein domain sequences representing various structural, functional, ligand binding and topogenic segments of proteins. The current release of SBASE contains 27,211 entries which are provided with standardized names in order to facilitate retrieval. SBASE is cross-referenced to the major protein and nucleic acid databanks as well as to the PROSITE catalog of protein sequence patterns [Bairoch, A. (1992) Nucleic Acids Res., 20, Suppl., 2013-2118]. SBASE can be used to establish domain homologies through database search using programs such as FASTA [Lipman and Pearson (1985) Science, 227, 1436-1441], FASTDB [Brutlag et al. (1990) Comp. Appl. Biosci., 6, 237-245] or BLAST3 [Altschul and Lipman (1990) Proc. Natl. Acad. Sci. USA, 87, 5509-5513], which is especially useful in the case of loosely defined domain types for which efficient consensus patterns cannot be established. The use of SBASE is illustrated on the DNA binding protein Brain-4. The database and a set of search and retrieval tools are freely available on request to the authors or by anonymous 'ftp' file transfer from < ftp.icgeb.trieste.it >.

Amino Acid Sequence↗

PubMed2002

SAGE profiling and demonstration of differential gene expression along the axial developmental gradient of lignifying xylem in loblolly pine (Pinus taeda).

Wood formation has been studied extensively at the cellular and biochemical levels, but remains poorly understood with respect to gene expression and regulation. As a first step toward identifying genes specifically involved in wood formation and characterizing their roles in determining wood quality, serial analysis of gene expression (SAGE) was used to quantify gene expression in lignifying xylem from a single, 10-year-old loblolly pine (Pinus taeda L.). Two SAGE libraries were generated based on lignifying xylem isolated from either the upper (crown) or lower (base) portions of the trunk. Over 85,000 tags representing a maximum of 27,398 expressed genes were analyzed from the crown wood library, and more than 65,000 tags, representing a maximum of 25,983 expressed genes, were analyzed in the base wood library. Combining these data sets to reflect the sum of genes expressed in lignifying xylem, 150,855 tags were cataloged, representing a maximum of 42,641 different genes. Currently, this study represents the most extensive analysis of its kind in a higher plant and provides a quantitative description of the transcriptome representing the lignifying xylem of a 10-year-old loblolly pine.

DNA, Complementary↗

PubMed2001

Guidelines for genetic nomenclature and community governance for the model legume Medicago truncatula.

At the 2nd Medicago meeting (a satellite of the 1999 IS-MPMI meeting in Amsterdam), investigators perceived a need for standardization of genetic nomenclature in Medicago truncatula, due to the rapid growth of research on this species in the past few years. Establishment of such standards grew out of discussions begun at this meeting and continued electronically throughout the M. truncatula community. The proposed standards presented here are the consensus results of those discussions. In addition to standards for gene nomenclature, a method for community governance and a website for cataloging gene names and submitting new ones are presented. The purpose of implementing these guidelines is to help maintain consistency in the literature, to avoid redundancy, to contribute to the accuracy of databases, and, in general, to aid the international collaborations that have made M. truncatula a model system for legume biology.

Genes, Bacterial↗

PubMed1992

Immunoglobulin gene expression only in the right cells at the right time.

Study of immunoglobulin gene transcriptional control has disclosed a complexity that rivals that of the antibody repertoire itself. Although some DNA sequences that regulate transcription of these genes were identified almost a decade ago, additional regulatory sequences continue to be discovered, some in regions far removed (as much as 200 kb) from the actual site of transcription. This has invoked models of regulation in which the higher-order structure of chromatin must be taken into account. Within the regulatory DNA sequences themselves, there is a bewildering array of sites that bind proteins and a growing catalog of proteins that can bind each of those sites. The proteins are believed to be the physical link between the regulatory DNA sequences and the protein machinery actually carrying out transcription. Specific interactions among proteins that can bind the same site and among proteins that bind different sites have been described. A challenge remaining is to identify those interactions that occur in vivo and that lead to progressively more efficient Ig production in the developing B cell, but which disallow Ig production in non-B cells.

Animals↗