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PubMed2002

The micro-macro spectrum of medical informatics challenges: from molecular medicine to transforming health care in a globalizing society.

BACKGROUND: Medical informatics has always encompassed a very broad spectrum of techniques for clinical and biomedical research, education and practice. There has been a concomitant variety of depth of specialization, ranging from the routine application of information processing methods to cutting-edge research on fundamental problems of computer-based systems and their relations to cognition and perception in biomedicine. OBJECTIVES: Challenges for the field can be placed in perspective by considering the scale of each--from the highly detailed scientific problems in bioinformatics and emerging molecular medicine to the broad and complex social problems of introducing medical informatics into web-related global settings. METHODS: The scale of an informatics problem is not only determined by the inherent physical space in which it exists, but also by the conceptual complexity that it involves, reinforcing the need to investigate the semantic web within which medical informatics is defined. RESULTS AND CONCLUSION: Bioinformatics, biomedical imaging and language understanding provide examples that anchor research and practice in biomedical informatics at the detailed, scientific end of the spectrum. Traditional concerns of medical informatics in the clinical arena make up the broad mid-range of the spectrum, while novel social interaction models of competition and cooperation will be needed to understand the implications of distributed health information technology for individual and societal change in an increasingly interconnected world.

Databases, Factual↗
PubMed2002

[Novel full-length cDNA cloning from normal adrenal gland and pheochromocytoma and functional prediction].

OBJECTIVE: To investigate methodology of cloning full-length cDNA from tissues of normal adrenal gland and pheochromocytoma and predict their function. METHODS: 104 samples from normal adrenal gland and 22 samples from pheochromocytoma were examined by expressed sequence tags (EST) sequencing, bioinformatics analysis, in silico cloning, rapid amplification of cDNA ends and RT-PCR. RESULTS: Among the 126 samples of novel full-length cDNA cloning 104 were from normal adrenal gland, and 22 from pheochromocytoma (PC). Among the novel genes 50 were cloned by direct sequencing of clones, 74 by in silico cloning, and 2 by rapid amplification of cDNA ends, and the localization of chromosomes was made with UniGene searching and radiation hybrid (RH) procedure. Comparison of homology and analysis of motif or domain showed that some genes may be important functional genes, such as those coding signaling proteins, proteins associated with ion channel, enzymes involved in hormone production, important transcription factors, translation initiation factors, etc. 7 of the novel full-length cDNAs are new isoforms produced by alternative splicing. CONCLUSION: 126 novel full-length cDNAs have been cloned from adrenal tissues by large-scale EST sequencing and bioinformatic tools in a rather short time, some of which may play an important role in regulating adrenal functions and tumorigenesis of adrenal gland.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2002

Artificial neural networks and gene filtering distinguish between global gene expression profiles of Barrett's esophagus and esophageal cancer.

cDNAmicroarrays, combined with bioinformatics analyses, are becomingincreasingly used in current medical research. Existing analytic methods,particularly those that are unsupervised, often have difficulty recognizing subtle differences among predefined subgroups. In contrast, supervised methods, such as Artificial Neural Networks (ANNs), are able to recognize subtly different biological entities. We applied ANNs in a proof-of-principle study of cDNA microarray data in esophageal cancer (CA) and premalignancy. cDNA microarrays, each containing 8064 clones, were hybridized to RNAs from 22 esophageal lesions, including 14 Barrett's esophagus (BA) metaplasias and 8 esophageal carcinomas (3 squamous cell carcinomas and 5 adenocarcinomas). Scanned cDNA microarray data were analyzed using the bioinformatics software Cluster/TreeView, Significance Analysis of Microarrays (SAM), and ANNs. Cluster analysis based on all 8064 clones on the microarrays was unable to correctly distinguish BA specimens from CA specimens. SAM then selected 160 differentially expressed genes between Barrett's and cancer. Cluster analysis based on this reduced set still misclassified 2 Barrett's as cancers. The ANN was trained on 12 samples and tested against the remaining 10 samples. Using the 160 selected genes, the ANN correctly diagnosed all 10 samples in the test set. Finally, the 160 genes selected by SAM may merit further study as biomarkers of neoplastic progression in the esophagus, as well as in elucidating pathological mechanisms underlying BA and CA.

Adenocarcinoma↗
PubMed2002

[Screening and analysis of early cardiopathology-related gene in type 2 diabetes mellitus].

OBJECTIVE: To screen and analyze early cardiopathology related gene in type 2 diabetes mellitus (DM). METHODS: (1) To develop a rat model of type 2 DM, SD rats were injected with streptozotocin (STZ, 15 mg/kg) after high caloric diet had been given for two months. (2) After establishment of the model for half a month, one and a half month and six months respectively, dissected myocardium was observed under electron microscope. (3) After establishment of the model for half a month, myocardium was analyzed with fluorescence labelled mRNA differential display. Positive clones were BLAST after conformed by Northern blot. Via the application of bioinformatics, the function and structure of unknown sequences were predicted. RESULTS: (1) The model of type 2 DM developed with the character of lightly impaired islet function and insulin resistance. (2) Diabetic cardiomyopathy was verified by the ultrastructural change of myocardium which became serious with time. (3) Screened and conformed clones were muscle carnitine palmitoyltransferase 1 and 8 and novel sequences were named DCM1, 2, 5, 6, 8, 11, 12, 16, which had been submitted to Genbank. DCM 5 was predicted to play a role of catalysis or signal conduction via the application of bioinformatics. CONCLUSIONS: The altered mRNA expression of these genes suggested that they were candidates for a role in the development of cardiopathy prior to the ultrastructural alterations of myocardium. The change of key enzyme in energy metabolism may be the initial factor during heart functional disorder. Further investigation was required for reverse intervention of diabetic cardiopathy in early period.

Animals↗
PubMed2002

An integrative model for in-silico clinical-genomics discovery science.

Human Genome discovery research has set the pace for Post-Genomic Discovery Research. While post-genomic fields focused at the molecular level are intensively pursued, little effort is being deployed in the later stages of molecular medicine discovery research, such as clinical-genomics. The objective of this study is to demonstrate the relevance and significance of integrating mainstream clinical informatics decision support systems to current bioinformatics genomic discovery science. This paper is a feasibility study of an original model enabling novel "in-silico" clinical-genomic discovery science and that demonstrates its feasibility. This model is designed to mediate queries among clinical and genomic knowledge bases with relevant bioinformatic analytic tools (e.g. gene clustering). Briefly, trait-disease-gene relationships were successfully illustrated using QMR, OMIM, SNOMED-RT, GeneCluster and TreeView. The analyses were visualized as two-dimensional dendrograms of clinical observations clustered around genes. To our knowledge, this is the first study using knowledge bases of clinical decision support systems for genomic discovery. Although this study is a proof of principle, it provides a framework for the development of clinical decision-support-system driven, high-throughput clinical-genomic technologies which could potentially unveil significant high-level functions of genes.

Artificial Intelligence↗
PubMed2003

SNP analysis and presentation in the Pharmacogenetics of Membrane Transporters Project.

The multidisciplinary UCSF Pharmacogenetics of Membrane Transporters project seeks to systematically identify sequence variants in transporters and to determine the functional significance of these variants through evaluation of relevant cellular and clinical phenotypes. The project is structured around four interacting cores: genomics, cellular phenotyping, clinical phenotyping, and bioinformatics. The bioinformatics core is responsible for collecting, storing, and analyzing the information obtained by the other cores and for presenting the results, in particular, for the genomic data. Most of this process is automated using locally developed software written in Python, an open source language well suited for rapid, modular development that meets requirements that are themselves constantly evolving. Here we present the details of transforming ABI trace file data into useful information for project investigators and a description of the types of data analysis and display that we have developed.

Amino Acid Sequence↗
PubMed2003

Integr8: enhanced inter-operability of European molecular biology databases.

OBJECTIVES: The increasing production of molecular biology data in the post-genomic era, and the proliferation of databases that store it, require the development of an integrative layer in database services to facilitate the synthesis of related information. The solution of this problem is made more difficult by the absence of universal identifiers for biological entities, and the breadth and variety of available data. METHODS: Integr8 was modelled using UML (Universal Modelling Language). Integr8 is being implemented as an n-tier system using a modern object-oriented programming language (Java). An object-relational mapping tool, OJB, is being used to specify the interface between the upper layers and an underlying relational database. RESULTS: The European Bioinformatics Institute is launching the Integr8 project. Integr8 will be an automatically populated database in which we will maintain stable identifiers for biological entities, describe their relationships with each other (in accordance with the central dogma of biology), and store equivalences between identified entities in the source databases. Only core data will be stored in Integr8, with web links to the source databases providing further information. CONCLUSIONS: Integr8 will provide the integrative layer of the next generation of bioinformatics services from the EBI. Web-based interfaces will be developed to offer gene-centric views of the integrated data, presenting (where known) the links between genome, proteome and phenotype.

Computational Biology↗
PubMed2003

Modelling the immunogenicity of therapeutic proteins using T cell epitope mapping.

A new approach to designing therapeutic proteins is emerging, due to an improved understanding of T cell modulation of the immune response and new methods for modelling T cell epitopes using bioinformatics. In silico T cell epitope-mapping using the bioinformatics, when combined with other ex silico means of evaluating MHC-peptide and T cell interaction such as tetramers and HLA transgenic mice, enables the evaluation of dysfunctional immune responses to therapeutic proteins. This approach may even permit researchers to develop means of modulating anticipated adverse effects. The pocket profile method for developing T cell epitope prediction tools is reviewed here, and a comparison between the pocket profile method and the extended anchor method for epitopes restricted by the class II allele HLA DR B*0101 is described.

Animals↗
PubMed2003

Putative hAPN receptor binding sites in SARS_CoV spike protein.

AIM: To obtain the information of ligand-receptor binding between the S protein of SARS-CoV and CD13, identify the possible interacting domains or motifs related to binding sites, and provide clues for studying the functions of SARS proteins and designing anti-SARS drugs and vaccines. METHODS: On the basis of comparative genomics, the homology search, phylogenetic analyses, and multi-sequence alignment were used to predict CD13 related interacting domains and binding sites in the S protein of SARS-CoV. Molecular modeling and docking simulation methods were employed to address the interaction feature between CD13 and S protein of SARS-CoV in validating the bioinformatics predictions. RESULTS: Possible binding sites in the SARS-CoV S protein to CD13 have been mapped out by using bioinformatics analysis tools. The binding for one protein-protein interaction pair (D757-R761 motif of the SARS-CoV S protein to P585-A653 domain of CD13) has been simulated by molecular modeling and docking simulation methods. CONCLUSION: CD13 may be a possible receptor of the SARS-CoV S protein, which may be associated with the SARS infection. This study also provides a possible strategy for mapping the possible binding receptors of the proteins in a genome.

Amino Acid Sequence↗
PubMed2003

[cDNA cloning, subcellular localization and tissue expression of a new human Krüppel-like transcription factor: human basic Krüppel-like factor (hBKLF)].

The FLD4585 clone from the cDNA library of human fetal liver may encode a hematopoietic related transcription factor. Here we tried to clone its full-length cDNA from the 22 weeks-gestation human fetal liver and study its functional domains, genomic structure, chromosomal localization, subcellular site and expression pattern. To obtain the full-length cDNA of FLD4585 clone, 5' RACE technique was used. Bioinformatics was used to analyze its genomic structure, chromosomal localization and potential functional domains. Its subcellular localization was shown by GFP fusion technique. The expression pattern was studied by Northern blot, RT-PCR and Western blot. The results show the full-length cDNA encoded by FLD4585 clone is 1810 bp long and encodes a 345 amino acids protein with high homology to mouse BKLF (basic Krüppel-like factor). Its characteristic C-terminal three contiguous C2H2 zinc fingers place it within the family of Krüppel-like factors. Bioinformatics studies show hBKLF gene spans over 33 kb on chromosome 4p15.2-4p16.1 and contains 6 exons and 5 introns. GFP-hBKLF fusion technique showed hBKLF was present in the nuclei of COS-7 cells in a punctate pattern, whereas it was absent in the nucleoli. By Northern blot, hBKLF has two transcripts, one between 4.4 kb-7.5 kb and the other between 1.35 kb-2.4 kb. The larger transcript exists widely in human tissues. However, the smaller transcript was more restricted in blood leukocytes, liver and bone marrow. RT-PCR showed erythrocytes and granulocytes could both express hBKLF and its level increased as they matured. The expression level in fetal liver decreased as it developed towards adult liver and its hematopoietic function gradually lost. Taken together, in this paper we have successfully cloned the full length cDNA of hBKLF. Expression study suggests it may have broad functions in vivo, especially the functions in hematopoietic tissues.

Amino Acid Sequence↗
PubMed2003

Prioritizing the human genome: knowledge management for drug discovery.

This review covers recent methods to create a manageable subset of drug targets for development by prioritizing novel genes from the Human Genome Project. The ability to organize genomic data into a distinct set of drug discovery assets can be viewed as a form of knowledge management. While bioinformatics systems have been built to manage genomics-based data, the central theme in creating any bioinformatics infrastructure should be organization-specific knowledge management.

Animals↗
PubMed2003

[Advances in the applications of DNA chips and proteomics approaches for neurosciences].

DNA chips and proteomics are two of the recently developed high-throughput technologies that allow us to simultaneously analyze the expression levels of multiple genes and the interactions of their products in the brain. Their applications in neuroscience provide us with the unprecedented opportunities for understanding of the brain. A typical gene chip experiment contains a series of steps, including preparations (or purchase) of DNA chips, target DNA and probes, hybridization of chips with target DNA, chip scanning, and imaging analysis. The technologies in proteomics are more complicated, which comprise of three main aspects of technologies: protein isolation, identification and bioinformatic analysis of data. If protein isolation is based on 2-D, it includes the preparation of protein sample, 2-D, staining gels, spot excision, proteolysis, mass spectrometry of purified protein and finally undergoing bioinformatic analysis. Here we review the two technologies with emphasis on their applications in neurosciences. The challenges, advantages and disadvantages of the two techniques, and perspectives for their developments are discussed.

Animals↗
PubMed2003

[In silico data mining of the human programmed cell death 5 (PDCD5) sequences].

OBJECTIVE: To lay foundation for the functional studies of programmed cell death 5 (PDCD5) and develop new technical pathway for bioinformatics analysis of human functional genes. METHODS: Using PDCD5 as the target molecule, intensive bioinformatics analysis of the nucleic acid and protein sequences were conducted. Data mining and comprehensive analysis by sequence against database similarity searching, ortholog structure comparison, expression profile analysis and gene "neighbor" listing were performed. RESULTS: Two human putative pseudogenes on chromosomes 12 and 5, and one mouse putative pseudogene on chromosome 1 were identified. The methanobacterium thermoautotrophicum ortholog was classified as the same fold as ubiquitin and ribosomal protein S13. The C. elegans ortholog, ubiquitin and IAP (inhibitor of apoptosis proteins) belonged to the same expression profile cluster. This cluster was related to biosynthesis and protein synthesis. PDCD5 orthologs in various genomes were adjacent to various ribosomal proteins on the chromosome. CONCLUSION: The human genome contains at least two processed pseudogenes of PDCD5. Besides the relationship with cell apoptosis, PDCD5 is predicted to have functional relationship with ubiquitin and participate in the translation regulation.

Amino Acid Sequence↗
PubMed2003

From immunome to vaccine: epitope mapping and vaccine design tools.

Since the publication of the complete genome of a pathogenic bacterium in 1995, more than 50 bacterial pathogens have been sequenced and at least 120 additional projects are currently underway. Faced with the expanding volume of information now available from genome databases, vaccinologists are turning to epitope mapping tools to screen vaccine candidates. Bioinformatics tools such as EpiMatrix and Conservatrix, which search for unique or multi-HLA-restricted (promiscuous) T cell epitopes and can find epitopes that are conserved across variant strains of the same pathogen, have accelerated the process of epitope mapping. Additional tools for screening epitopes for similarity to 'self' (BlastiMer) and for assembling putative epitopes into strings if they overlap (EpiAssembler) have been developed at EpiVax. Tools that map proteasome cleavage sires are available on the Internet. When used together, these bioinformatics tools offer a significant advantage over traditional methods of vaccine design since high throughput screening and design is performed in silico, followed by confirmatory studies in vitro. These new tools are being used to develop novel vaccines and therapeutics for the prevention and treatment of infectious diseases such as HIV, hepatitis C, tuberculosis, and some cancers. More recent applications of the tools involve deriving novel vaccine candidates directly from whole genomes, an approach that has been named 'genome to vaccine'.

Allergy and Immunology↗
PubMed2004

Molecular biological analysis of genotyping and phylogeny of severe acute respiratory syndrome associated coronavirus.

BACKGROUND: SARS-CoV is the causative agent of severe acute respiratory syndrome (SARS) which has been associated with outbreaks of SARS in Guangdong, Hong Kong and Beijing of China, and other regions worldwide. SARS-CoV from human has shown some variations but its origin is still unknown. The genotyping and phylogeny of SARS-CoV were analyzed and reported in this paper. METHODS: Full or partial genomes of 44 SARS-CoV strains were collected from GenBank. The genotype, single nucleotide polymorphism and phylogeny of these SARS-CoV strains were analyzed by molecular biological, bioinformatic and epidemiological methods. RESULTS: There were 188 point mutations in the 33 virus full genomes with the counts of mutation mounting to 297. Further analysis was carried out among 36 of 188 loci with more than two times of mutation. All the 36 mutation loci occurred in coding sequences and 22 loci were non-synonymous. The gene mutation rates of replicase 1AB, S2 domain of spike glycoprotein and nucleocapsid protein were lower (0.079% - 0.103%). There were 4 mutation loci in S1 domain of spike glycoprotein. The gene mutation rate of ORF10 was the highest (3.333%) with 4 mutation loci in this small domain (120 bp) and 3 of 4 loci related to deletion mutation. By bioinformatics processing and analysis, the nucleotides at 7 loci of genome (T:T:A:G:T:C:T/C:G:G:A:C:T:C) can classify SARS-CoV into two types. Therefore a novel definition is put forward that according to these 7 loci of mutation, 40 strains of SARS-CoV in GenBank can be grouped into two genotypes, T:T:A:G:T:C:T and C:G:G:A:C:T:C, and named as SARS-CoV Yexin genotype and Xiaohong genotype. The two genotypes can be further divided into some sub-genotypes. These genotypes can also be approved by phylogenetic tree of three levels of 44 loci of mutation, spike glycoprotein gene and complete genome sequence. Compared to various strains among SARS-CoV Yexin genotype and Xiaohong genotype, GD01 strain of Yexin genotype is more closely related to SARS-CoV like-virus from animals. CONCLUSION: The results mentioned above suggest that SARS-CoV is responding to host immunological pressures and experiencing variation which provide clues, information and evidence of molecular biology for the clinical pathology, vaccine developing and epidemic investigation.

Evolution, Molecular↗
PubMed2003

[Preliminary analysis of gene expression profiles in oral cancer with microarray technique].

OBJECTIVE: To study the difference in gene expression between oral squamous cell carcinoma tissue and their surrounding normal tissue by microarray so as to investigate the preliminary mechanism of pathogenesis of oral cancer. METHODS: The tissues from 5 patients with oral squamous cell carcinoma tissue and their surrounding normal tissue from the same patients were analyzed by cDNA microarray technology(including 4124 genes). Total RNAs were isolated from two tissues, and then were reversely transcribed to cDNAs with the incorporations of fluorescent dUTP,for preparing the hybridization probes. The mixed probes were then hybridized to the cDNA microarray. After high-stringent washing, the cDNA microarray was scanned for the fluorescent signals and showed the differences between the two tissues. Bioinformatical analysis of those genes had been performed. RESULTS: Among the 4124 target genes, there were 37(0.89%)genes whose expression levels differed between the carcinoma and their surrounding normal tissues in all 5 cases. Bioinformatical analysis of those genes suggested that they may be related to the multistep process of carcinogenesis. CONCLUSION: cDNA microarray technique can simultaneously screen the different expressions of genes from 2 different kinds of tissue. Further analysis of the obtained genes will help to understand the molecular mechanism of malignant carcinoma.

Aged↗
PubMed2004

Prospecting for new group A streptococcal vaccine candidates.

BACKGROUND & OBJECTIVES: Most group A streptococcal (GAS) vaccine strategies focused on the surface M protein of the GAS. However, vaccine based on M protein have some drawbacks. In the present study, we used two approaches to identify new proteins and peptides that may have utility as vaccine candidates. METHODS: A whole gel elution procedure was used to separate GAS surface antigens into 9 size fractionated pools. Mice were vaccinated with each pool and antibody titre, opsonic ability and protective capacity measured. In an alternative approach BioInformatics was used to identify putative GAS surface proteins. Peptides from within these proteins were then selected on the basis of predicted antigenicity or location. These peptides were conjugated to keyhole lymphocyanin (KLH) and immunogenicity measured in a mouse model. RESULTS: One pool of GAS surface proteins (approximately 29kDa) induced antibodies that were both opsonic and potentially protective. Immunoflourescent microscopy demonstrated that these antibodies bound to the surface of M1 GAS. Amino acid sequencing subsequently identified superoxide dismutase as the major antigen in this pool. A BioInformatic search of the M1 GAS genome and subsequent analysis identified several peptides that fulfilled criteria as potential vaccine candidates. Each peptide when conjugated to KLH was able to induce a strong antibody response. INTERPRETATION & CONCLUSION: Several new antigens were identified that may have potential as vaccine targets. A future GAS vaccine may have multiple peptide epitopes, providing protection against multiple GAS strains.

Amino Acid Sequence↗
PubMed2004

[Molecular cloning for an alternatively splicing cDNA of human PKNOX1 gene and it's expression analysis].

Down's syndrome (DS) is the most common chromosomal abnormality in live born infants. The cloning and characterization of genes on HC21 are necessary steps for the understanding of the molecular basis of Down's syndrome. To search for new Down's syndrome related genes, we have used bioinformatics analysis and rapid amplification of cDNA ends to identify an alternatively splicing cDNA of human PKNOX1 in Down's syndrome critical region on the long arm of human chromosome 21. The alternatively splicing full length cDNA of human PKNOX1, named PKNOX1B, is 2 793 bp in length and encodes a 405 amino acid protein. Bioinformatical studies show PKNOX1B gene spans over 58 kb on chromosome 21q22.3 and contains 11 exons and 10 introns. The predicted molecule weight of PKNOX1B is 44.628 kDa, and the deduced iso-electric point is 6.28. Compared with PKNOX1 gene, PKNOX1B is 30 aa shorter at the C terminus than PKNOX1 owing to alternative splice between (10th exon and 11th exon) last two exons. PKNOX1B posses a same homeobox-domain as PKNOX1, so the isoform of PKNOX1 may be involved in the genetic control of development like other members of homeobox-containing gene family. RT-PCR results showed that PKNOX1B is expressed in all examined tissues except in marrow tissue. By Northern blot, PKNOX1 has three transcripts in adult testis, one about 5 kb, second about 2.9 kb, and third about 2 kb. The two larger transcript is expressed in all examined tissues, but the smallest transcript is only expressed actively in adult testis, so that it may play potential roles in spermatogenesis.

Alternative Splicing↗