摘要:

In this paper we consider the problem of characterizing and modeling large-scale protein-protein association networks using a class of range-dependent graphs which possess appropriate small world properties. These graphs may be employed in representing given association network using a maximum likelihood approach. This in turn annotates every observed association with its ‘range’, representing the tendency for such an association to be transitive. The application of a very rapidly developing field of graph theory to the emerging field of proetemics is novel and allows for a many-to-many relationship between individual proteins and groupings of proteins, which in turn may correspond to distinct functional behavior.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Genetic factors play an important role in the determination of bone mass and osteoporosis. A number of candidate genes have been implicated in osteoporosis, including genes encoding type 1 collagen, vitamin D receptor, estrogen receptor-α (ERα), and others. A number of association studies have been performed with single nucleotide polymorphisms in theERαgene to assess their relation with bone mineral density in pre- and postmenopausal women, as well as the rate of bone loss after menopause and skeletal response to estrogen administration. The polymorphisms studied thus far mostly involved intronic polymorphisms in intron 1. Other less frequently studied polymorphisms include those in exons 1, 4, and 8. Although most studies demonstrated associations with various bone-related parameters, the results are still disputed.Assessing genetic factors includingERαpolymorphisms, if their significances are confirmed, can be helpful in targeting preventive measures to individuals with higher risk of developing osteoporosis and render the preventive effort more cost-effective. Moreover, pharmacogenetically, it may help identify postmenopausal women who tend to have better skeletal responses after estrogen replacement. It is not known, however, if patients who possess favorable polymorphisms in terms of skeletal responsiveness will also have an undesirably higher risk of adverse effects. This issue needs to be further investigated before clinical decisions based on the balance between benefits and risks can be made.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

In clinical practice, two potent and selective catechol-O-methyl transferase (COMT) inhibitors are available for the control of motor fluctuation in patients with Parkinson's disease. However, because of the complexity of fluctuating motor symptoms, it is difficult to evaluate the clinical efficacy of COMT inhibitors in each individual. Therefore, an objective factor predicting the clinical efficacy of COMT inhibitors is needed. Individual variation in COMT activity is regulated by a single nucleotide of theCOMTgene on the long arm of chromosome 22. Therefore, there could be a correlation betweenCOMTgenotype and the clinical efficacy of COMT inhibitors.Three double-blind studies evaluating the efficacy of a single or repeated doses of a COMT inhibitor failed to find significant difference in the improvement in the duration of daily ‘on’ time and degree of motor abilities between patients with differentCOMTgenotypes. Furthermore, there were no significant differences in the severity and frequency of dopaminergic adverse effects between patients with differentCOMTgenotypes. These data suggest that theCOMTgenotype is not a major factor in deciding the clinical efficacy of COMT inhibitors.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Lithium is considered to be the first choice mood stabilizer in recurrent mood disorders. Its widespread and large-scale use is the result of its proven efficacy. In spite of this fact, patients have been observed to show a variable response to lithium treatment: in some cases it is completely effective in preventing manic or depressive relapses, while in other cases it appears to show no influence on the disease course. The possible definition of a genetic liability profile for adverse effects and efficacy will be of great help, as lithium therapy needs at least 6 months to be effective in stabilizing mood disorders. During the last few years, a number of groups have reported possible liability genes. Lithium long-term prophylactic efficacy has been associated with serotonin transporter protein, tryptophan hydroxylase and inositol polyphosphate 1-phosphatase variants. A number of other candidate genes and anonymous markers did not yield positive associations. Therefore, even if some positive results have been reported, no unequivocal susceptibility gene for lithium efficacy has been identified. Although the available data may not currently allow a meaningful prediction of lithium response, future research is aimed at the development of individualized treament of mood disorders, including the possibility of ‘pharmacological genetic counseling’.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The best studied T cell leukemia/lymphoma from a genetic and biochemical point of view is T-cell chronic lymphocytic/prolymphocytic leukemia (T-CLL/T-PLL). This neoplasia commonly shows chromosomal rearrangements at 14q32.1 including translocations [t(14;14)(q11;q32), t(7;14)(q35;q32)], and inversions [inv(14)(q11;q32)]. The investigation of the locus in question at 14q32.1 resulted in the identification of two related genes named T cell leukemia/lymphoma 1 (TCL1) andTCL1b. Both genes are activated in T-CLL/T-PLL by the chromosomal aberrations mentioned above. Mice from a transgenic mouse strain expressing theTCL1gene under the thymocyte specificlckpromoter developed a mature T cell leukemia late in life, thereby demonstrating that over-expression ofTCL1induces the neoplastic transformation of T cells.Biochemically, Tcl1 protein works as a co-factor of the Akt kinase, a key regulator of antiapoptotic and proliferative signals. Tcl1 interacts physically with Akt, increases its kinase activity and facilitates its transport to the nucleus. The pathogenesis of T-CLL/T-PLL may also involve Nur77, a T cell transcription factor required for T cell receptor-mediated apoptosis. Akt phosphorylates Nur77, thereby blocking its DNA-binding ability and rendering the transcription factor inactive.The recently emerged insights into the molecular mechanisms of T cell leukemogenesis will allow for the development of specific pharmacological tools for the treatment of these hematopoietic malignancies.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) are key enzymes in human detoxication of xeno- and endobiotics. Potentially toxic endogenous compounds such as bilirubin, or exogenous compounds such as drugs, pesticides, and carcinogens, are generally transformed into water-soluble glucuronides for excretion in bile and urine.The UGTs are encoded by a multigene family in humans. A relatively small number of human enzymes catalyze the glucuronidation of thousands of compounds. Genetic variations and single nucleotide polymorphisms (SNPs) within theUGTgenes are remarkably common, and lead to genetic polymorphisms. The multiplicity of transferases, some exhibiting overlapping substrate specificity, may provide functional compensation for genetic deficit in some cases. Genetic variation may cause different phenotypes by affecting expression levels or activities of individual UGTs. This inter-individual variation in UGTs has resulted in functional deficit affecting endogenous metabolism and leading to jaundice and other diseases. Disruption of the normal metabolic physiology, by the reduction of bile acid excretion or steroid glucuronidation, may lead to cholestasis and organ dysfunction. Deficient glucuronidation of drugs and xenobiotics have an important pharmacological impact, which may lead to drug-induced adverse reactions, and even cancer. Additional novel polymorphisms in this gene family are yet to be revealed and studied, but will have a profound effect on the development of new drugs and therapies.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Various methods have been developed to transfer and express genes in mammalian cells. Each method, whether virally, non-virally, or physically-based, has unique favorable features, but also drawbacks with respect to meeting desired and specific needs. Baculoviruses have been used since 1983 to express recombinant genes controlled by strong insect-virus promoters in their natural host (insect) cells. Today this is a well-established and easy to handle system for producing large quantities of recombinant proteins for numerous purposes.In 1995 it was first published that recombinant baculoviruses are able to deliver genes into mammalian cells. These genes are expressed provided that they are controlled by a promoter which is active in mammalian cells. Since then, various vector variants have been developed and numerous potential and meaningful applications have been described. It is not surprising that the use of baculovirus vectors as mammalian cell gene delivery vectors is constantly increasing and that the system is undergoing permanent improvements.Based on the convenience of the system to transfer genes into mammalian cells, baculoviruses can be applied in cell-based assays for drug screening to overcome the long periods of time required to generate stable cell lines. Baculovirus vectors are able to deliver very large DNA sequences into mammalian cells and vectors for toxic gene products can also be generated. In addition, baculoviruses are valuable tools for launching viral infection in cases where there is no appropriate cell culture system. Moreover, recent research has shown that the vectors can be appliedin vivo. Depending on the design of the study, baculovirus vectors allow for sustained gene expression or are able to induce an immune response directed against the delivered and/or displayed gene product. The latter offers the opportunity to generate monoclonal antibodies against certain proteins that have failed by other means. In addition, it points to the potential usefulness of baculovirus vectors as new kinds of vaccines. Baculovirus vectors are therefore considered an enabling technology for various product opportunities.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

IntroductionGuanine nucleotide binding proteins (G-proteins) represent the targets for >50% of all therapeutics. There is substantial interindividual variation in response to agonists and antagonists directed to these receptors, which may, in part, be due to genetic polymorphisms. As a class, the sequence variability of G-protein-coupled receptor (GPCR) genes has not been characterized.Study designThis variability was investigated by sequencing promoter, 5′- and 3′-UTR, coding blocks, and intron-exon boundaries, of 64 GPCR genes in an ethnically diverse group of 82 individuals.ResultsOf the 675 single-nucleotide variations found, 61% occurred in ≥1% of the population sample and the nature of these 412 single nucleotide polymorphisms (SNPs) was assessed. 5′-UTR (p = 0.002) and coding (p = 0.006) SNPs were observed more often in GPCR genes, compared with 309 non-GPCR genes similarly interrogated. The prevalence of non-synonymous coding SNPs was unexpectedly high, with 65% of GPCR genes having at least one. Intron-containing genes had half as many non-synonymous coding SNPs compared with intronless genes (p = 0.0009), suggesting that when introns are not available coding regions provide sites for variation. A distinct relationship between the prevalence of non-synonymous SNPs and receptor structural domains was evident (p = 0.0006 by ANOVA), with variability being most prominent in the transmembrane spanning domains (38%) and the intracellular loops (24%). Phosphoregulatory domains, particularly the carboxy terminus, often the site for agonist-promoted phosphorylation by G-protein coupled receptor kinases, were the least polymorphic (8%).ConclusionsThere is substantial genetic variability in potentially pharmacologically relevant coding and noncoding regions of GPCRs. Such variability should be considered in the development of new agents, or optimization of existing agents, targeted to these receptors.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS