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M Q Zhang

Publications and source records attributed to M Q Zhang.

At least 37 records · Page 2Linked to original sources
PubMed1999

Histamine H1 receptor ligands. Part I. Novel thiazol-4-ylethanamine derivatives: synthesis and in vitro pharmacology.

A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H1-receptor activities. The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the phenyl ring, showed weak H1-agonistic activity with pD2 values ranging from 4.35 to 5.36. When the phenyl group was replaced by a benzyl group, the resulting compounds all exhibited weak H1-antagonistic activity (pA2: 4.14-4.82).

Animals↗
PubMed1999

Purification and characterization of human RNPS1: a general activator of pre-mRNA splicing.

Biochemical purification of a pre-mRNA splicing activity from HeLa cells that stimulates distal alternative 3' splice sites in a concentration-dependent manner resulted in the identification of RNPS1, a novel general activator of pre-mRNA splicing. RNPS1 cDNAs, encoding a putative nucleic-acid-binding protein of unknown function, were previously identified in mouse and human. RNPS1 is conserved in metazoans and has an RNA-recognition motif preceded by an extensive serine-rich domain. Recombinant human RNPS1 expressed in baculovirus functionally synergizes with SR proteins and strongly activates splicing of both constitutively and alternatively spliced pre-mRNAs. We conclude that RNPS1 is not only a potential regulator of alternative splicing but may also play a more fundamental role as a general activator of pre-mRNA splicing.

Alternative Splicing↗
PubMed1999

Promoter analysis of co-regulated genes in the yeast genome.

The use of high density DNA arrays to monitor gene expression at a genome-wide scale constitutes a fundamental advance in biology. In particular, the expression pattern of all genes in Saccharomyces cerevisiae can be interrogated using microarray analysis where cDNAs are hybridized to an array of more than 6000 genes in the yeast genome. In an effort to build a comprehensive Yeast Promoter Database and to develop new computational methods for mapping upstream regulatory elements, we started recently in an on going collaboration with experimental biologists on analysis of large-scale expression data. It is well known that complex gene expression patterns result from dynamic interacting networks of genes in the genetic regulatory circuitry. Hierarchical and modular organization of regulatory DNA sequence elements are important information for our understanding of combinatorial control of gene expression. As a bioinformatics attempt in this new direction, we have done some computational exploration of various initial experimental data. We will use cell-cycle regulated gene expression as a specific example to demonstrate how one may extract promoter information computationally from such genome-wide screening. Full report of the experiments and of the complete analysis will be published elsewhere when all the experiments are to be finished later in this year (Spellman, P.T., et al. 1998. Mol. Biol. Cell 9, 3273-3297).

Base Sequence↗
PubMed1999

Detection of polyadenylation signals in human DNA sequences.

We present polyadq, a program for detection of human polyadenylation signals. To avoid training on possibly flawed data, the development of polyadq began with a de novo characterization of human mRNA 3' processing signals. This information was used in training two quadratic discriminant functions that polyadq uses to evaluate potential polyA signals. In our tests, polyadq predicts polyA signals with a correlation coefficient of 0.413 on whole genes and 0.512 in the last two exons of genes, substantially outperforming other published programs on the same data set. polyadq is also the only program that is able to consistently detect the ATTAAA variant of the polyA signal.

DNA↗
PubMed1999

Periodical distribution of transcription factor sites in promoter regions and connection with chromatin structure.

Nucleosomes regulate transcriptional initiation when positioned in the promoter area. This may require the transcription factor (TF) sites to be correlated with the nucleosome positions and phased on the nucleosome surface. If this is the case, one would expect a periodical distribution of TF sites in the vicinity of promoters, with the nucleosomal period of 10.1-10.5 bp. We examined the distributions of putative binding sites of 323 different TFs along 1, 057 sequences of the Eukaryotic Promoter Database (release 50) [Cavin Perier, R., Junier, T. & Bucher, P. (1998) Nucleic Acids Res. 26, 353-357] and of 218 TFs on 673 sequences of the Lead Exon Database of human promoter sequences. We obtained a statistically significant overrepresentation of TF sites distributed with the main period of 10.1-10.5 bp in the region -50 to +120 around the transcription start site and in few locations nearby. Correlation of the positioning of the TF sites with the nucleosomes is further reinforced by sequence-directed mapping of the nucleosomes, a method previously developed.

Animals↗
PubMed1999

Large-scale gene expression data analysis: a new challenge to computational biologists.

The use of high-density DNA arrays to monitor gene expression at a genome-wide scale constitutes a fundamental advance in biology. In particular, the expression pattern of all genes in Saccharomyces cerevisiae can be interrogated using microarray analysis where cDNAs are hybridized to an array of each of the approximately 6000 genes in the yeast genome. In this survey I review three recent experiments related to transcriptional regulation and discuss the great challenge for computational biologists trying to extract functional information from such large-scale gene expression data.

Animals↗
PubMed1998

Pombe: a gene-finding and exon-intron structure prediction system for fission yeast.

A special program developed by the authors, called Pombe, identifies protein coding regions in the Schizosaccharomyces pombe genome. Linear discriminant analysis was applied to predict 5'-terminal, internal, 3'-terminal exons (coding-exon) and introns. The accuracy of the prediction was tested by cross verifications. The sensitivity, specificity and correlation coefficient for the internal exon prediction were 98.5%, 99.9% and 98.3% respectively at the nucleotide level. Open reading frames were studied and used to predict intron-less genes: 99.0% of such genes were identified with correct stopping sites. The gene structure was determined by dynamic programming and the prediction achieved 97.0% correlation coefficient at the nucleotide level. The program is available at http:(/)/clio.cshl.org/genefinder.

Algorithms↗
PubMed1998

Synthesis and structure-activity relationships of carboxyflavones as structurally rigid CysLT1 (LTD4) receptor antagonists.

The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT1 receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [3H]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT1 affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT1 affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT1 receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT1 receptor antagonists known to date, and they are useful in the development of a CysLT1 antagonist model, which is discussed in the companion paper.

Animals↗
PubMed1998

Development of a three-dimensional CysLT1 (LTD4) antagonist model with an incorporated amino acid residue from the receptor.

This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4) receptor antagonists. Several different structural classes of CysLT1 antagonists were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'-[2-(2-quinolinyl)ethenyl]flavone (1, VUF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT1 antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an acidic function were taken as the matching points. In order to optimize the fitting of acidic moieties of all antagonists, an arginine residue from the receptor was proposed as the interaction site for the acidic moieties. Incorporation of this amino acid residue into the model revealed additional interactions between the guanidine group and the nitrogen atoms of quinoline-containing CysLT1 antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of CysLT1 antagonists. The alignment of Montelukast (MK-476) suggests the presence of an additional pocket in the binding site for CysLT1 antagonists. The derived model should be useful for a better understanding of the molecular recognition of the leukotriene CysLT1 receptor.

Arginine↗
PubMed1998

Identification of protein-coding regions in Arabidopsis thaliana genome based on quadratic discriminant analysis.

A new method (MZEF) for predicting internal coding exons in genomic DNA sequences has been developed. This method is based on a prediction algorithm that uses the quadratic discriminant function for multivariate statistical pattern recognition. With improved feature measures, an Arabidopsis thaliana-specific implementation of MZEF is completed and made available to the plant genome community.

Algorithms↗
PubMed1998

Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization.

We sought to create a comprehensive catalog of yeast genes whose transcript levels vary periodically within the cell cycle. To this end, we used DNA microarrays and samples from yeast cultures synchronized by three independent methods: alpha factor arrest, elutriation, and arrest of a cdc15 temperature-sensitive mutant. Using periodicity and correlation algorithms, we identified 800 genes that meet an objective minimum criterion for cell cycle regulation. In separate experiments, designed to examine the effects of inducing either the G1 cyclin Cln3p or the B-type cyclin Clb2p, we found that the mRNA levels of more than half of these 800 genes respond to one or both of these cyclins. Furthermore, we analyzed our set of cell cycle-regulated genes for known and new promoter elements and show that several known elements (or variations thereof) contain information predictive of cell cycle regulation. A full description and complete data sets are available at http://cellcycle-www.stanford.edu

Base Sequence↗
PubMed1998

Statistical features of human exons and their flanking regions.

To facilitate gene finding and for the investigation of human molecular genetics on a genome scale, we present a comprehensive survey on various statistical features of human exons. We first show that human exons with flanking genomic DNA sequences can be classified into 12 mutually exclusive categories. This classification could serve as a standard for future studies so that direct comparisons of results can be made. A database for eight categories (related to human genes in which coding regions are split by introns) was built from GenBank release 87.0 and analyzed by a number of methods to characterize statistical features of these sequences that may serve as controls or regulatory signals for gene expression. The statistical information compiled includes profiles of signals for transcription, splicing and translation, various compositional statistics and size distributions. Further analyses reveal novel correlations and constraints among different splicing features across an internal exon that are consistent with the Exon Definition model. This information is fundamental for a quantitative view of human gene organization, and should be invaluable for individual scientists to design human molecular genetics experiments.

Adenine↗
PubMed1998

Identification of human gene core promoters in silico.

Identification of the 5'-end of human genes requires identification of functional promoter elements. In silico identification of those elements is difficult because of the hierarchical and modular nature of promoter architecture. To address this problem, I propose a new stepwise strategy based on initial localization of a functional promoter into a 1- to 2-kb (extended promoter) region from within a large genomic DNA sequence of 100 kb or larger and further localization of a transcriptional start site (TSS) into a 50- to 100-bp (corepromoter) region. Using positional dependent 5-tuple measures, a quadratic discriminant analysis (QDA) method has been implemented in a new program-CorePromoter. Our experiments indicate that when given a 1- to 2-kb extended promoter, CorePromoter will correctly localize the TSS to a 100-bp interval approximately 60% of the time. [Figure 3 can be found in its entirety as an online supplement at http://www.genome.org.]

Analysis of Variance↗
PubMed1998

A discrimination study of human core-promoters.

A core-promoter, approximately from -60 bp upstream to +40 bp downstream of a RNA polymerase (RNAP) II transcription start site (TSS), binds to the preinitiation complex (PIC) and determine the position of TSS. Using position-specific k-tuple feature variables, a quadratic discriminant analysis (QDA) method is shown to be very effective in identifying human core-promoters.

Base Sequence↗
PubMed1997

Synthesis and structure-activity relationships of carboxylated chalcones: a novel series of CysLT1 (LTD4) receptor antagonists.

The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.

Animals↗
PubMed1997

Identification of protein coding regions in the human genome by quadratic discriminant analysis.

A new method for predicting internal coding exons in genomic DNA sequences has been developed. This method is based on a prediction algorithm that uses the quadratic discriminant function for multivariate statistical pattern recognition. Substantial improvements have been made (with only 9 discriminant variables) when compared with existing methods: HEXON [Solovyev, V. V., Salamov, A. A. & Lawrence, C. B. (1994) Nucleic Acids Res. 22, 5156-5163] (based on linear discriminant analysis) and GRAIL2 [Uberbacher, E. C. & Mural, R. J. (1991) Proc. Natl. Acad. Sci. USA 88, 11261-11265] (based on neural networks). A computer program called MZEF is freely available to the genome community and allows users to adjust prior probability and to output alternative overlapping exons.

Base Sequence↗
PubMed1995

(Piperidinylalkoxy)chromones: novel antihistamines with additional antagonistic activity against leukotriene D4.

A series of novel chromone derivatives, in which the chromone moiety is connected to a (diphenylmethylene)-, (diphenylmethyl)-, or (diphenylmethoxy)piperidine via an alkyloxy spacer, were synthesized as antiallergic and antiasthmatic agents. In addition to their potent antihistaminic activity, the compounds also inhibit contraction in guinea pig ileum induced by leukotriene D4. When analyzed by radioligand binding assays in guinea pig lung membranes, one of the compounds, 7-[[3-[4-(diphenylmethylene)piperidin-1- yl]propyl]oxy]-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran, showed dissociation constants (KD) of 5.62 nM and 2.34 microM for H1- and LTD4-receptors, respectively. In vivo at the dose of 10 mg/kg, the compound inhibited the histamine- and LTD4-induced increase of vascular permeability in guinea pigs by 95 and 30%, respectively. The inhibition of LTD4-induced increase in vascular permeability by the compound was increased to 56% when a dose of 50 mg/kg was employed. Similar to terfenadine, the compound does not readily occupy the brain H1-receptors when given intraperitoneally to mice, implying no sedating side effects.

Animals↗