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Y Z Chen

Publications and source records attributed to Y Z Chen.

At least 19 recordsLinked to original sources

SVM-Prot: Web-based support vector machine software for functional classification of a protein from its primary sequence.

Prediction of protein function is of significance in studying biological processes. One approach for function prediction is to classify a protein into functional family. Support vector machine (SVM) is a useful method for such classification, which may involve proteins with diverse sequence distribution. We have developed a web-based software, SVMProt, for SVM classification of a protein into functional family from its primary sequence. SVMProt classification system is trained from representative proteins of a number of functional families and seed proteins of Pfam curated protein families. It currently covers 54 functional families and additional families will be added in the near future. The computed accuracy for protein family classification is found to be in the range of 69.1-99.6%. SVMProt shows a certain degree of capability for the classification of distantly related proteins and homologous proteins of different function and thus may be used as a protein function prediction tool that complements sequence alignment methods. SVMProt can be accessed at http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi.

Amino Acid Sequence↗

KDBI: Kinetic Data of Bio-molecular Interactions database.

Understanding of cellular processes and underlying molecular events requires knowledge about different aspects of molecular interactions, networks of molecules and pathways in addition to the sequence, structure and function of individual molecules involved. Databases of interacting molecules, pathways and related chemical reaction equations have been developed. The kinetic data for these interactions, which is important for mechanistic investigation, quantitative study and simulation of cellular processes and events, is not provided in the existing databases. We introduce a new database of Kinetic Data of Bio-molecular Interactions (KDBI) aimed at providing experimentally determined kinetic data of protein-protein, protein-RNA, protein-DNA, protein-ligand, RNA-ligand, DNA-ligand binding or reaction events described in the literature. KDBI contains information about binding or reaction event, participating molecules (name, synonyms, molecular formula, classification, SWISS-PROT AC or CAS number), binding or reaction equation, kinetic data and related references. The kinetic data is in terms of one or a combination of the following quantities as given in the literature of a particular event: association/dissociation or on/off rate constant, first/second/third/. order rate constant, equilibrium rate constant, catalytic rate constant, equilibrium association/dissociation constant, inhibition constant and binding affinity constant. Each entry can be retrieved through protein or nucleic acid or ligand name, SWISS-PROT AC number, ligand CAS number and full-text search of a binding or reaction event. KDBI currently contains 8273 entries of biomolecular binding or reaction events involving 1380 proteins, 143 nucleic acids and 1395 small molecules. Hyperlinks are provided for accessing references in Medline and available 3D structures in PDB and NDB. This database can be accessed at http://xin.cz3.nus.edu.sg/group/kdbi/kdbi.asp.

DNA↗

Protein function classification via support vector machine approach.

Support vector machine (SVM) is introduced as a method for the classification of proteins into functionally distinguished classes. Studies are conducted on a number of protein classes including RNA-binding proteins; protein homodimers, proteins responsible for drug absorption, proteins involved in drug distribution and excretion, and drug metabolizing enzymes. Testing accuracy for the classification of these protein classes is found to be in the range of 84-96%. This suggests the usefulness of SVM in the classification of protein functional classes and its potential application in protein function prediction.

Amino Acid Sequence↗

Correlation between normal modes in the 20-200 cm-1 frequency range and localized torsion motions related to certain collective motions in proteins.

In certain biologically relevant collective motions, such as protein domain motions and sub-domain motions, large amplitude movements are localized in one or a few flexible regions consisting of a small number of residues. This paper explores the possible use of normal mode analysis in probing localized vibrational torsion motions in these flexible regions that may be related to certain collective motions. The normal modes of 10 structures of five proteins in different conformation (TRP repressor, calmodulin, calbindin D(9k), HIV-1 protease and troponin C), known to have shear or hinge domain or sub-domain motion, respectively, are analyzed. Our study identifies, for each structure, unique normal modes in the 20-200 cm-1 frequency range, whose corresponding motions are primarily concentrated in the region where large amplitude torsion movements of a known domain or sub-domain motion occur. This suggests possible correlation between normal modes at 20-200 cm-1 frequency range and initial fluctuational motions leading to localized collective motions in proteins, and thus the potential application of normal mode analysis in facilitating the study of biologically important localized motions in biomolecules.

Calbindins↗

TTD: Therapeutic Target Database.

A number of proteins and nucleic acids have been explored as therapeutic targets. These targets are subjects of interest in different areas of biomedical and pharmaceutical research and in the development and evaluation of bioinformatics, molecular modeling, computer-aided drug design and analytical tools. A publicly accessible database that provides comprehensive information about these targets is therefore helpful to the relevant communities. The Therapeutic Target Database (TTD) is designed to provide information about the known therapeutic protein and nucleic acid targets described in the literature, the targeted disease conditions, the pathway information and the corresponding drugs/ligands directed at each of these targets. Cross-links to other databases are also introduced to facilitate the access of information about the sequence, 3D structure, function, nomenclature, drug/ligand binding properties, drug usage and effects, and related literature for each target. This database can be accessed at http://xin.cz3.nus.edu.sg/group/ttd/ttd.asp and it currently contains entries for 433 targets covering 125 disease conditions along with 809 drugs/ligands directed at each of these targets. Each entry can be retrieved through multiple methods including target name, disease name, drug/ligand name, drug/ligand function and drug therapeutic classification.

Databases, Nucleic Acid↗

CLiBE: a database of computed ligand binding energy for ligand-receptor complexes.

Consideration of binding competitiveness of a drug candidate against natural ligands and other drugs that bind to the same receptor site may facilitate the rational development of a candidate into a potent drug. A strategy that can be applied to computer-aided drug design is to evaluate ligand-receptor interaction energy or other scoring functions of a designed drug with that of the relevant ligands known to bind to the same binding site. As a tool to facilitate such a strategy, a database of ligand-receptor interaction energy is developed from known ligand-receptor 3D structural entries in the Protein Databank (PDB). The Energy is computed based on a molecular mechanics force field that has been used in the prediction of therapeutic and toxicity targets of drugs. This database also contains information about ligand function and other properties and it can be accessed at http://xin.cz3.nus.edu.sg/group/CLiBE.asp. The computed energy components may facilitate the probing of the mode of action and other profiles of binding. A number of computed energies of some PDB ligand-receptor complexes in this database are studied and compared to experimental binding affinity. A certain degree of correlation between the computed energy and experimental binding affinity is found, which suggests that the computed energy may be useful in facilitating a qualitative analysis of drug binding competitiveness.

Binding, Competitive↗

ADME-AP: a database of ADME associated proteins.

Drug absorption, distribution, metabolism and excretion (ADME) often involve interaction of a drug with specific proteins. Knowledge about these ADME-associated proteins is important in facilitating the study of the molecular mechanism of disposition and individual response as well as therapeutic action of drugs. It is also useful in the development and testing of pharmacokinetics prediction tools. Several databases describing specific classes of ADME-associated proteins have appeared. A new database, ADME-associated proteins (ADME-AP), is introduced to provide comprehensive information about all classes of ADME-associated proteins described in the literature including physiological function of each protein, pharmacokinetic effect, ADME classification, direction and driving force of disposition, location and tissue distribution, substrates, synonyms, gene name and protein availability in other species. Cross-links to other databases are also provided to facilitate the access of information about the sequence, 3D structure, function, polymorphisms, genetic disorders, nomenclature, ligand binding properties and related literatures of each protein. ADME-AP currently contains entries for 321 proteins and 964 substrates.

Databases, Protein↗

Computer automated prediction of potential therapeutic and toxicity protein targets of bioactive compounds from Chinese medicinal plants.

Understanding the molecular mechanism and pharmacology of bioactive compounds from Chinese medicinal plants (CMP) is important in facilitating scientific evaluation of novel therapeutic approaches in traditional Chinese medicine. It is also of significance in new drug development based on the mechanism of Chinese medicine. A key step towards this task is the determination of the therapeutic and toxicity protein targets of CMP compounds. In this work, newly developed computer software INVDOCK is used for automated identification of potential therapeutic and toxicity targets of several bioactive compounds isolated from Chinese medicinal plants. This software searches a protein database to find proteins to which a CMP compound can bind or weakly bind. INVDOCK results on three CMP compounds (allicin, catechin and camptotecin) show that 60% of computer-identified potential therapeutic protein targets and 27% of computer-identified potential toxicity targets have been implicated or confirmed by experiments. This software may potentially be used as a relatively fast-speed and low-cost tool for facilitating the study of molecular mechanism and pharmacology of bioactive compounds from Chinese medicinal plants and natural products from other sources.

Animals↗

Construction of a dense comparative map between human chromosome 1p36-->p35 and swine chromosome 6 by using human sequence-tagged sites.

Construction of a comprehensive comparative map between swine and human chromosomes is a prerequisite, in order to select candidate swine genes for traits from the human genome database as well as to understand the evolutionary process of the two species. The present study attempted to use 910 sequence-tagged sites (STSs) localized in human chromosome (HSA) 1p36-->p35 (35 Mbp) for radiation hybrid (RH) mapping to swine chromosomes (SSCs). Out of the 910 STSs subjected to amplification of swine orthologues, primer pairs for 13 STSs were found to amplify the respective orthologues and the STSs were assigned to SSCs. Eleven STSs were assigned to SSC6 in the same order as that in HSA1: SSC6cen-(SHGC-150)-(A006H31)-(X82877)-(A007E03)-(IB404)-(stGDB:371372)-(stSG31658)-(A009Q18)-(stSG14201/A009C01)-(H08335)-qter. One of the remaining two STSs, WI-20819, was assigned to SSCX, and the other, R91D18R, was not linked to any first-generation markers of the IMpRH map with a lod score greater than 3.

Animals↗

Individual allergens as risk factors for asthma and bronchial hyperresponsiveness in Chinese children.

The role of allergen sensitization in the development of asthma in the Chinese is not clear. This study aims to determine the relationship of sensitization to individual allergens, and the development of asthma and bronchial hyperresponsiveness (BHR) in schoolchildren from three Chinese cities: Hong Kong, Beijing and Guangzhou. Community-based random samples of 10-yr-old schoolchildren from three Chinese cities were recruited for study using the International Study of Asthma and Allergies in Childhood (ISAAC) Phase II protocol. Subjects were studied by parental questionnaires (n=10,902), skin-prick tests (n=3,479), and methacholine challenge tests (n=608). The prevalence rates of wheeze in the past 12 months (Hong Kong, 5.8%; Beijing, 3.8%; Guangzhou, 3.4%) and atopy (Hong Kong, 41.2%; Beijing, 23.9%; Guangzhou, 30.8%) were highest in schoolchildren from Hong Kong. Multivariate logistic regression analyses revealed that sensitization to Dermatophagoides pteronyssinus (odds ratio (OR)=4.48; 95% confidence interval (CI): 3.02-6.66), cat (2.59; 1.67-4.03), Dermatophagoides farinae (2.41; 1.65-3.51) and mixed grass pollen (2.85; 1.24-6.50) were significantly associated with current wheeze. Atopy, defined as having > or = 1 positive skin-prick tests, was not an independent risk factor for current wheeze in children from any of the three cities. Furthermore, atopy (OR=2.53; 95% CI: 1.07-5.97), sensitization to cat (3.01; 1.39-6.52) and D. farinae (3.67; 1.93-6.97) were significantly associated with BHR. The authors confirmed that sensitization to house dust mite and cat was significantly associated with current wheeze and bronchial hyperresponsiveness in Chinese schoolchildren. However, the difference in the prevalence rate of atopic sensitization cannot explain the higher prevalence of childhood asthma in Hong Kong, when compared with those children from Beijing and Guangzhou.

Allergens↗

Inhibition of epidermal growth factor receptor tyrosine kinase by chalcone derivatives.

In our previous study, butein, a chalcone derivative, was found to be an inhibitor of tyrosine kinases and the inhibition was ATP-competitive. In this work, chalcone and seven chalcone derivatives were used to analyse the relationship between the structure of these compounds and their inhibition of tyrosine kinase activity. Three of chalcone derivatives, including butein, marein and phloretin, were found to have an ability to inhibit the tyrosine kinase activity of epidermal growth factor receptor (EGFR) in vitro. IC(50) was 8 microM for butein, 19 microM for marein and 25 microM for phloretin. The structural characterisations of these inhibitors suggest that the hydroxylations at C4 and C4' of these molecules may be required for them to act as EGFR tyrosine kinase inhibitors. The inhibition of EGF-induced EGFR tyrosine phosphorylation by butein was also observed in human hepatocellular carcinoma HepG2 cells, while marein and phloretin were inactive at the doses tested. Molecular modelling suggests that butein, marein and phloretin can be docked into the ATP binding pocket of EGFR. Hydrogen bonds and hydrophobic interaction appear to be important in the binding of these inhibitors to EGFR.

Amino Acid Sequence↗

Restoration of decreased N-methyl-d-asparate receptor activity by brain-derived neurotrophic factor in the cultured hippocampal neurons: involvement of cAMP.

Brain-derived neurotrophic factor (BDNF) may play an important role in the modulation of N-methyl-d-asparate (NMDA) receptor function. To elucidate the underlying mechanisms, whole-cell patch-clamp recording was used to assess the effect of BDNF on the responses of cultured hippocampal neurons to the glutamate receptor agonist NMDA. We found that peak amplitude of NMDA-evoked currents in cultured hippocampal pyramidal neurons at Day 18 in vitro decreased significantly compared to that of NMDA currents at Day 10 or 14. Interestingly, NMDA-evoked currents were greatly enhanced by BDNF (50 ng/ml) in cultured neurons at Day 18, but not at Day 10 or 14. Treatment with Rp-cAMP abolished the potentiating effects of BDNF on NMDA current. Elevating the amount of cytosolic cAMP by preincubation with forskolin or Sp-cAMP also enhanced NMDA currents as effectively as BDNF in 18-day-old hippocampal neurons. Measurement of the cellular content of cAMP by RIA indicated that cultured hippocampal neurons showed decreased basal cAMP levels at the time NMDA currents were decreased and BDNF increased the decreased cAMP levels. Taken together, these results suggest that BDNF may restore decreased NMDA receptor activity in cultured hippocampal neurons by the cAMP pathway.

Animals↗

Expression of estrogen receptor (ER)-alpha and -beta immunoreactivity in hippocampal cell cultures with special attention to GABAergic neurons.

This study investigated the expression patterns of estrogen receptor-alpha (ER alpha) and -beta (ER beta) in the cultured hippocampal cells of neonatal rats by combined application of cell culture and immunocytochemistry. The results revealed that the expression difference between ER alpha and ER beta seemed to be not obvious in the cultured hippocampal cells of neonatal rats. Moreover, immunoreactivity for either ER alpha or ER beta was observed to be localized in the majority of not only neurons but also astrocytes. The coexpression of both ER alpha and ER beta in the same individual cell was also demonstrated by the double-label immunocytochemistry. Western blot analysis showed that immunoreactivity for ER alpha in the neonatal hippocampal tissues was much higher than in the adult (became rather weak), although there was not such a great difference of immunoreactivity for ER beta. The data also provide direct evidence for the expression of ER subtypes within GABAergic neurons in hippocampal cell cultures and suggest that estrogen's effect on the hippocampus may be mediated at least in part by its ER-containing GABAergic neurons.

Aging↗

Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2.

In order to clone candidate tumor suppressor genes whose loss contributes to the pathogenesis of neuroblastoma (NB), we performed polymerase chain reaction (PCR) screening using a high-density sequence tagged site-content map within a commonly deleted region (chromosome band 1p36) in 24 NB cell lines. We found a approximately 480 kb homozygously deleted region at chromosome band 1p36.2 in one of the 24 NB cell lines, NB-1, and cloned the human homologue (KIF1B-beta) of the mouseKif1B-beta gene in this region. The KIF1B-beta gene had at least 47 exons, all of which had a classic exon-intron boundary structure. Mouse Kif1B is a microtubule-based putative anterograde motor protein for the transport of mitochondria in neural cells. We performed mutational analysis of the KIF1B-beta gene in 23 cell lines using 46 sets of primers and also an allelic imbalance (AI) analysis of KIF1B-beta in 50 fresh NB samples. A missense mutation at codon 1554, GTG (Gly) to ATG (Met), silent mutations at codon 409 (ACG to ACA) and codon 1721 (ACC to ACT), and polymorphisms at codon 170, GAT (Asp) to GAA (Glu), and at codon 1087, TAT (Tyr), to TGT (Cys), were all identified, although their functional significances remain to be determined. The AI for KIF1B-beta was slightly higher (38%) than those for the other two markers (D1S244, D1S1350) (35 and 32%) within the commonly deleted region (1p36). Reverse transcriptase-PCR analysis of the KIF1B-beta gene revealed obvious expression in all NB cell lines except NB-1, although decreased expression of the KIF1B-beta gene was found in a subset of early- and advanced-stage NBs. These results suggest that the KIF1B-beta gene may not be a candidate for tumor suppressor gene of NB.

Amino Acid Sequence↗

Expression of estrogen receptor -alpha and -beta immunoreactivity in the cultured neonatal suprachiasmatic nucleus: with special attention to GABAergic neurons.

This study investigated the expression patterns of estrogen receptor -alpha (ERalpha) and -beta (ERbeta) in cultured cells of the suprachiasmatic nucleus (SCN) in neonatal rats by combined application of cell culture and double-label immunocytochemistry. The results revealed that the immunoreactivity for either ERalpha or ERbeta (with predominance of ERbeta) was localized in not only neurons but also astrocytes. The co-expression of both ERalpha and ERbeta in the same individual cell was also demonstrated by the double-label immunocytochemistry. The observations also provide a direct evidence for the differential expression of ER subtypes within GABAergic SCN neurons in vitro and suggest that estrogen's effect on the SCN may be mediated at least in part by its ER-containing GABAergic neurons.

Animals↗

A BAC-based STS-content map spanning a 35-Mb region of human chromosome 1p35-p36.

We have devised a mapping method for rapid assembly and ordering of bacterial artificial chromosome (BAC) clones on a radiation hybrid (RH) panel, using sequence-tagged sites (STSs) and PCR. The protocol consists of two rounds of two-dimensional screening from a limited number of BACs to correspond each to an STS. In the first round, STSs are assembled in the RH bins and ordered according to PCR signals derived from 384-well microtiter plates (MTPs) in which BAC clones have been arrayed. In the second round, individual BAC clones are isolated from the MTPs to build a contig. We applied this method to a 35-Mb region spanning human chromosome 1p35-p36 and assembled 1366 BACs in 11 contigs, the longest being about 20 Mb. The working draft sequences of the human genome have been integrated into the contigs to validate the accuracy.

Chromosome Mapping↗

Ligand-protein inverse docking and its potential use in the computer search of protein targets of a small molecule.

Ligand-protein docking has been developed and used in facilitating new drug discoveries. In this approach, docking single or multiple small molecules to a receptor site is attempted to find putative ligands. A number of studies have shown that docking algorithms are capable of finding ligands and binding conformations at a receptor site close to experimentally determined structures. These algorithms are expected to be equally applicable to the identification of multiple proteins to which a small molecule can bind or weakly bind. We introduce a ligand-protein inverse-docking approach for finding potential protein targets of a small molecule by the computer-automated docking search of a protein cavity database. This database is developed from protein structures in the Protein Data Bank (PDB). Docking is conducted with a procedure involving multiple-conformer shape-matching alignment of a molecule to a cavity followed by molecular-mechanics torsion optimization and energy minimization on both the molecule and the protein residues at the binding region. Scoring is conducted by the evaluation of molecular-mechanics energy and, when applicable, by the further analysis of binding competitiveness against other ligands that bind to the same receptor site in at least one PDB entry. Testing results on two therapeutic agents, 4H-tamoxifen and vitamin E, showed that 50% of the computer-identified potential protein targets were implicated or confirmed by experiments. The application of this approach may facilitate the prediction of unknown and secondary therapeutic target proteins and those related to the side effects and toxicity of a drug or drug candidate. Proteins 2001;43:217-226.

Computer Simulation↗