ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Given the biological complexity of viral infections, the variability of the host response, and the safety concerns related to viral-mediated gene transfer, recent studies have made use of DNA mircoarrays to integrate multi-layered experimental approaches aimed at completely clarifying virus-host interactions. Particular attention has been given to those viruses that are implicated in clinical use and/or in life-threatening diseases.Examples of such use can be divided into three main categories, including: (i) the use of microarrays to study viral expression; (ii) the use of microarrays to analyze the host response to viral infection; and (iii) the use of microarrays to characterize the host response to viral vector-mediated transduction. Significant information on virus- and viral vector-host interactions can be obtained with the microarray approach, including the recognition of master pathways of virally-induced responses, the identification of new target genes for specific viruses, and indications on the molecular toxicity of specific gene transfer vectors currently used for gene therapy trials (in particular, adeno-associated viruses and adenovirus-derived vectors). We predict that the development of accessible repositories containing most of the DNA microarray data on viral infections will certainly help to elucidate the puzzling pictures of different viral infections. This will be crucially important for the correct handling of viral diseases and the intelligent amelioration of viral vectors for gene therapy.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Dust mites are a major source of indoor allergens. They contain a large number of components that react with immunoglobulin (Ig) E in individuals with allergies and are capable of inducing sensitization, and allergic respiratory and cutaneous diseases. With a significant proportion of the population affected in some way by mite allergies, it is essential that we improve our understanding of these organisms so that control strategies could be defined and its allergens better understood. Thus, we have initiated a project using the expressed sequence tagging (EST) strategy to study the major species of dust mites associated with allergic diseases, in particular, the American house dust mite,Dermatophagoides farinae, as well asBlomia tropicalis, the most prevalent mite in domestic tropical dwellings. The work has recently been expanded to include ‘storage’ mites such asTyrophagus putrescentiae,Acarus siro,Lepidoglyphus destructor,Glycyphagus domesticus,Suidasia medanensis, andAleuroglyphus ovatus.More than 50% of the initial 3000 ESTs from theD. farinaeandB. tropicalisdust mites showed significant matches to known genes and were categorized into eight functional groups (such as proteins involved in metabolism, gene expression, protein synthesis, cell signaling, etc.). Of specific interest, however, were the homologs to known mite allergens, in addition to a number of sequences bearing significant homology to allergens from non-mite sources previously not known to exist in mites. The availability of these allergen sequences has facilitated their expression and subsequent characterization in our laboratory in terms of their IgE-binding reactivity.The wealth of sequence information, generated via the EST project, has also facilitated the identification of polymorphic forms of allergens, the investigation of differential gene expression under various environmental conditions via DNA microarrays, as well as the analysis of protein level expression profiling via the proteomics approach. Additionally, ESTs have also ameliorated the understanding of the phylogenetic relationships between mites, and enabled the isolation of gene products crucial for life processes so that mite control strategies can be more effectively devised. Taken together, the utilization of the EST strategy has opened up numerous new avenues by which the allergist can engage more effectively in the study of dust mites with the ultimate aim of developing appropriate treatment regimens for mite-induced allergy.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

The genomic revolution has created a wealth of information regarding the fundamental genetic code that defines the inner workings of a cell. However, it has become clear that analyzing genome sequences alone will not lead to new therapies to fight human disease. Rather, an understanding of protein function within the context of complex cellular networks will be required to facilitate the discovery of novel drug targets and, subsequently, new therapies directed against them.The past ten years has seen a dramatic increase in technologies that allow large-scale, systems-based methods for analysis of global biological processes and disease states. In the field of proteomics, several well-established methods persist as a means to resolve and analyze complex mixtures of proteins derived from cells and tissues. However, the resolving power of these methods is often challenged by the diverse and dynamic nature of the proteome. The field of activity-based proteomics, or chemical proteomics, has been established in an attempt to focus proteomic efforts on subsets of physiologically important protein targets. This new approach to proteomics is centered around the use of small molecules termed activity-based probes (ABPs) as a means to tag, enrich, and isolate, distinct sets of proteins based on their enzymatic activity.Chemical probes can be ‘tuned’ to react with defined enzymatic targets through the use of chemically reactive warhead groups, fused to selective binding elements that control their overall specificity. As a result, ABPs function as highly specific, mechanism-based reagents that provide a direct readout of enzymatic activity within complex proteomes. Modification of protein targets by an ABP facilitates their purification and isolation, thereby eliminating many of the confounding issues of dynamic range in protein abundance. In this review, we outline recent advances in the field of chemical proteomics. Specifically, we highlight how this technology can be applied to advance the fields of biomarker discovery,in vivoimaging, and small molecule screening and drug target discovery.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

It is now obvious that the rate-limiting step in high throughput experimentation is neither data acquisition nor analysis, but rather our ability to interpret data on a genome-wide scale. Indeed, the explosion of data sampling capacity combined with increasing publication rates greatly impairs our ability to find meaning in vast collections of data. In order to support data interpretation, bioinformatic tools are needed to identify critical information contained in large bodies of literature. However, extracting knowledge embedded in free text is an arduous task, compounded in the biomedical field by an inconsistent gene nomenclature, domain-specific language and restricted access to full text articles.This paper presents a selection of currently available biomedical literature mining software. These tools rely on statistic and, more recently, semantic analyses (Natural Language Processing) to automatically extract information from the literature. In addition, a literature mining strategy has been developed to explore patterns of term occurrences in abstracts. This method automatically identifies relevant keywords in collections of abstracts, and uses a pattern discovery algorithm to generate a visual interface for exploring functional associations among genes. Term occurrence heatmaps can also be combined with gene expression profiles to provide valuable functional annotations. Furthermore, as demonstrated with tumor cell line literature profiling results, this approach can be applied to a variety of themes beyond genomic data analysis. Altogether, these examples illustrate how literature analysis can be employed to support knowledge discovery in biomedical research.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

BackgroundThe cytochrome P450 isoenzymes CYP2C19 and CYP2D6 catalyze reactions involved in the metabolism of many widely used drugs. Their polymorphisms give rise to important interindividual and interethnic variability in the metabolism and disposition of several therapeutic agents and may cause differences in clinical response to some drugs. Individuals who carry two null alleles of either gene are known as poor metabolizers (PMs), while those who carry more than two copies of the functionalCYP2D6gene are ultrarapid metabolizers (UMs).AimThe aim of the current study was to genotype Israelis from four different ethnic backgrounds with respect toCYP2C19andCYP2D6.Study designPolymorphisms of theCYP2C19andCYP2D6genes were determined by genotyping the four ethnic groups using PCR and/or restriction fragment length polymorphism (RFLP) analysis. The groups consisted of three Jewish communities, Yemenite Jews ( n = 36), Sephardic Jews (n = 47), Ethiopian Jews (n = 28), and one Arabian population, Bedouins (n = 50).ResultsCYP2C19*2 allele frequencies ranged from 12.0 to 19.6% among the four ethnic groups. Within the study population, theCYP2C19*3 gene was only found in one Bedouin individual, in the heterozygous state (CYP2C19*1/*3). In each group, one individual was homozygous forCYP2C19*2, and were predicted to be PMs. The data revealed a high prevalence ofCYP2D6*2, *4, *10, *41, and gene duplication, followed by *5 and *17, while *3 was very rare. The frequencies of theCYP2D6*4, *10, and *17 alleles andCYP2D6gene duplication were significantly different among the four groups. However, theCYP2D6*2, *3, and *5 and *41 alleles showed similar frequencies in the four groups. Four (8.5%) Sephardic Jews and one (2.0%) Bedouin were found with the genotypeCYP2D6*4/*4 (two null alleles), and were thus presumably PMs. A total of 15 individuals, distributed in all groups, were found with functionalCYP2D6gene duplications. The frequencies of predicted UMs (duplication ofCYP2D6) were 17.8% (5/28) and 12.8% (6/47) in Ethiopian Jews and Sephardic Jews, respectively, which were higher than that of Yemenite Jews (5.6%, 2/36) and Bedouins (4.0%, 2/50).ConclusionsThis is the first study of theCYP2D6gene polymorphism in Israeli ethnic groups, either Jewish or Arab. Furthermore, this is also the first study of theCYP2C19gene polymorphism in Jewish or Arab subgroups living in Israel. The frequencies of various alleles for theCYP2D6gene are significantly different among the ethnic groups in Israel. These new findings may have important clinical implications in administrating drugs metabolized by CYP2D6 and for CYP2D6-related adverse drug reactions in the Israeli population.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS