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Biomedical subjects

Y P Yuan

Publications and source records attributed to Y P Yuan.

11 recordsLinked to original sources
PubMed2002

HGVbase: a human sequence variation database emphasizing data quality and a broad spectrum of data sources.

HGVbase (Human Genome Variation database; http://hgvbase.cgb.ki.se, formerly known as HGBASE) is an academic effort to provide a high quality and non-redundant database of available genomic variation data of all types, mostly comprising single nucleotide polymorphisms (SNPs). Records include neutral polymorphisms as well as disease-related mutations. Online search tools facilitate data interrogation by sequence similarity and keyword queries, and searching by genome coordinates is now being implemented. Downloads are freely available in XML, Fasta, SRS, SQL and tagged-text file formats. Each entry is presented in the context of its surrounding sequence and many records are related to neighboring human genes and affected features therein. Population allele frequencies are included wherever available. Thorough semi-automated data checking ensures internal consistency and addresses common errors in the source information. To keep pace with recent growth in the field, we have developed tools for fully automated annotation. All variants have been uniquely mapped to the draft genome sequence and are referenced to positions in EMBL/GenBank files. Data utility is enhanced by provision of genotyping assays and functional predictions. Recent data structure extensions allow the capture of haplotype and genotype information, and a new initiative (along with BiSC and HUGO-MDI) aims to create a central repository for the broad collection of clinical mutations and associated disease phenotypes of interest.

Base Sequence↗
PubMed2001

Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens.

Microsatellite instability (MSI) caused by defective DNA mismatch repair (MMR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects microsatellites in coding regions, translational frameshifts lead to truncated proteins often marked by unique frameshift peptide sequences at their C-terminus. Since MSI tumors show enhanced lymphocytic infiltration and our previous analysis identified numerous coding mono- and dinucleotide repeat-bearing candidate genes as targets of genetic instability, we examined the role of frameshift peptides in triggering cellular immune responses. Using peptide pulsed autologous CD40-activated B cells, we have generated cytotoxic T lymphocytes (CTL) that specifically recognize HLA-A2.1-restricted peptides derived from frameshift sequences. Among 16 frameshift peptides predicted from mutations in 8 different genes, 3 peptides conferred specific lysis of target cells exogenously loaded with cognate peptide. One peptide derived from a (-1) frameshift mutation in the TGFbetaIIR gene gave rise to a CTL bulk culture capable of lysing the MSI colorectal cancer cell line HCT116 carrying this frameshift mutation. Given the huge number of human coding microsatellites and assuming only a fraction being mutated and encoding immunologically relevant peptides in MSI tumors, frameshift protein sequences represent a novel subclass of tumor-specific antigens. It is tempting to speculate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benefit asymptomatic at-risk individuals in HNPCC families by a prophylactic vaccination strategy.

Amino Acid Sequence↗
PubMed2001

Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells.

Microsatellite instability (MSI) caused by deficient DNA mismatch-repair functions is a hallmark of cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome but is also found in about 15% of all sporadic tumors. Most affected microsatellites reside in untranslated intergenic or intronic sequences. However, recently few genes with coding microsatellites were also shown to be mutational targets in MSI-positive cancers and might represent important mutation targets in their pathogenesis. The systematic identification of such genes and the analysis of their mutation frequency in MSI-positive cancers might thus reveal major clues to their functional role in MSI-associated carcinogenesis. We therefore initiated a systematic database search in 33,595 distinctly annotated human genes and identified 17,654 potentially coding mononucleotide repeats (cMNRs) and 2,028 coding dinucleotide repeats (cDNRs), which consist of n > or = 6 and n > or = 4 repeat units, respectively. Expression pattern and mutation frequency of 19 of these genes with the longest repeats were compared between DNA mismatch repair-deficient (MSI(+)) and proficient (MSS) cancer cells. Instability frequencies in these coding microsatellite genes ranged from 10% to 100% in MSI-H tumor cells, whereas MSS cancer cells did not show mutations. RT-PCR analysis further showed that most of the affected genes (10/15) were highly expressed in tumor cells. The approach outlined here identified a new set of genes frequently affected by mutations in MSI-positive tumor cells. It will lead to novel and highly specific diagnostic and therapeutic targets for microsatellite unstable cancers.

Adenocarcinoma↗
PubMed2001

Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity.

The bacterium Porphyromonas gingivalis is a major etiologic agent in the pathogenesis of adult periodontitis in humans. Cysteine proteinases produced by this pathogen, termed gingipains, are considered to be important virulence factors. Among many other potentially deleterious activities, arginine-specific gingipains-R (RgpB and HRgpA) efficiently activate coagulation factors. To further expand knowledge of the interaction between gingipains and the clotting cascade, this study examined their effects on cellular components of the coagulation system. The enzymes induced an increase in intracellular calcium in human platelets at nanomolar concentrations and caused platelet aggregation with efficiency comparable to thrombin. Both effects were dependent on the proteolytic activity of the enzymes. Based on desensitization studies carried out with thrombin and peptide receptor agonists, and immunoinhibition experiments, gingipains-R appeared to be activating the protease-activated receptors, (PAR)-1 and -4, expressed on the surface of platelets. This was confirmed by the finding that HRgpA and RgpB potently activated PAR-1 and PAR-4 in transfected cells stably expressing these receptors. Cumulatively, the results indicate the existence of a novel pathway of host cell activation by bacterial proteinases through PAR cleavage. This mechanism not only represents a new trait in bacterial pathogenicity, but may also explain an emerging link between periodontitis and cardiovascular disease. (Blood. 2001;97:3790-3797)

Adhesins, Bacterial↗
PubMed2001

Is the superior belly of the lateral pterygoid primarily a stabilizer? An EMG study.

The aim of the present study was to compare the activity levels within the two bellies of the lateral pterygoid muscle between different jaw positions to test the hypothesis that the upper head is primarily a stabilizer. Electromyographic (EMG) recordings, using monopolar concentric needle electrodes, were made from 14 healthy subjects during mandibular rest position (RP), clenching in intercuspal position and jaw opening, first about 10 mm and then about 25 mm. Both bellies had very little activity during RP. The activity level of the superior belly was high during clenching and large opening (LO) with a dip during low opening degree. This pattern differed from that of the inferior belly where the activity was relatively low during clenching and then gradually increased to its highest level during LO. The results support that the lower belly is primarily a jaw opener while the superior belly acts as a stabilizer keeping the disc and condyle in a functionally stable position during clenching and jaw movements.

Action Potentials↗
PubMed2000

Re-annotating the Mycoplasma pneumoniae genome sequence: adding value, function and reading frames.

Four years after the original sequence submission, we have re-annotated the genome of Mycoplasma pneumoniae to incorporate novel data. The total number of ORFss has been increased from 677 to 688 (10 new proteins were predicted in intergenic regions, two further were newly identified by mass spectrometry and one protein ORF was dismissed) and the number of RNAs from 39 to 42 genes. For 19 of the now 35 tRNAs and for six other functional RNAs the exact genome positions were re-annotated and two new tRNA(Leu) and a small 200 nt RNA were identified. Sixteen protein reading frames were extended and eight shortened. For each ORF a consistent annotation vocabulary has been introduced. Annotation reasoning, annotation categories and comparisons to other published data on M.pneumoniae functional assignments are given. Experimental evidence includes 2-dimensional gel electrophoresis in combination with mass spectrometry as well as gene expression data from this study. Compared to the original annotation, we increased the number of proteins with predicted functional features from 349 to 458. The increase includes 36 new predictions and 73 protein assignments confirmed by the published literature. Furthermore, there are 23 reductions and 30 additions with respect to the previous annotation. mRNA expression data support transcription of 184 of the functionally unassigned reading frames.

Amino Acid Sequence↗
PubMed2000

HGBASE: a database of SNPs and other variations in and around human genes.

Human genome polymorphism is expected to play a key role in defining the etiologic basis of phenotypic differences between individuals in aspects such as drug responses and common disease predisposition. Relevant functional DNA changes will probably be located in or near to transcribed sequences, and include many single nucleotide polymorphisms. To aid the future analysis of such genome variation, HGBASE (Human Genic Bi-Allelic SEquences) was constructed as a means to gather human gene-linked polymorphisms from all possible public sources, and show these as a non-redundant set of records in a standardized and user-friendly database endowed with text and sequence based search facilities. After 1 year of presence on the WWW, the HGBASE project has compiled data for over 22 000 records, and this number continues to triple every 6-12 months with data harvested or submitted from all major public genome databases and published literature from the previous decade. Extensive annotation enhancement, internal consistency checking and manual review of every record is undertaken to address potential errors and deficiencies sometimes present in the original source data. The fully polished and comprehensive database is made freely available to all at http://hgbase.cgr.ki.se

Databases, Factual↗
PubMed2000

NAIL-Network Analysis Interface for Linking HMMER results.

SUMMARY: Network Analysis Interface for Linking HMMER results (NAIL) is a web-based tool for the analysis of results from a HMMER protein database-search. NAIL facilitates the selection of protein hits and the creation of an alignment, which can be used for a new sequence similarity search.

Databases, Factual↗
PubMed2000

[Identification of the barley chromosome in wheat by GISH and RFLP].

The barley chromosome in wheat was identified by genomic in situ hybridization (GISH) in which biotin labelled total genomic DNA of barley Betzes was used as probe and the unlabelled total DNA of common wheat Chinese Spring (CS) as blocking DNA. A series of wheat materials were tested as follows: two disomic alien substitution and monosomic alien addition lines, 2n = 43; two monosomic alien substitution lines, 2n = 42; seven disomic alien substitution lines, 2n = 42. RFLP probe psr131 on the short arm of the homologous group 2 was used to analyze the barley chromosome in wheat. The result indicated that there was a same band in barley Betzes and substitution line A5. The chromosome 2A of A5 was substituted by the chromosome 2H of barley. These materials will be useful in transferring the valuable genes in the chromosome 2H to wheat.

Chromosomes↗
PubMed1998

Towards detection of orthologues in sequence databases.

MOTIVATION: Numerous homologous sequences from diverse species can be retrieved from databases using programs such as BLAST. However, due to multigene families, evolutionary relationship often cannot be easily determined and proper functional assignment becomes difficult. Thus, discrimination between orthologues and paralogues within BLAST output lists of homologous sequences becomes more and more important. RESULT: We therefore developed a method that attempts to construct a reconciled tree from a gene tree of selected sequences and its corresponding phylogenetic tree of the species involved (species tree). An interface on the Web is developed to enable users to analyse the BLAST result. BLAST outputs are parsed and, for the selected sequences, multiple alignments are constructed either globally or for local regions. Bootstrapped trees are returned and compared with the expected species tree. In cases of discrepancies, gene duplications are assumed and a reconciled tree is computed. The reconciled tree shows probable orthologues and paralogues as predicted.

Computational Biology↗