PharmGED: pharmacogenetic effect database.
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Databases, Genetic↗
Biomedical subjects
B Xie
Publications and source records attributed to B Xie.
PharmGED: Pharmacogenetic Effect Database.
Prediction and elucidation of pharmacogenetic effects is important for facilitating the development of personalized medicines. Knowledge of polymorphism-induced and other types of drug-response variations is needed for facilitating such studies. Although databases of pharmacogenetic knowledge, polymorphism and toxicogenomic information have appeared, some of the relevant data are provided in separate web-pages and in terms of relatively long descriptions quoted from literatures. To facilitate easy and quick assessment of the relevant information, it is helpful to develop databases that provide all of the information related to a pharmacogenetic effect in the same web-page and in brief descriptions. We developed a database, Pharmacogenetic Effect Database (PharmGED), for providing sequence, function, polymorphism, affected drugs and pharmacogenetic effects. PharmGED can be accessed at http://bidd.cz3.nus.edu.sg/phg/ free of charge for academic use. It currently contains 1825 entries covering 108 disease conditions, 266 distinct proteins, 693 polymorphisms, 414 drugs/ligands cited from 856 references.
Animals↗
Cause and pre-alarm control of bulking and foaming by Microthrix parvicella--a case study in triple oxidation ditch at a wastewater treatment plant.
The cause and control of foaming and bulking in triple oxidation ditch at a wastewater treatment plant (WWTP) were investigated. The results showed that the foaming and bulking was mainly caused by the excessive propagation of Microthrix parvicella, and mostly occurred in the cold winter and spring. Batch and continuous flow experiments indicated that biological techniques such as reducing sludge retention time (SRT) and increasing F/M ratio, chemical methods such as addition of chlorine (NaOCl), quaternary ammonium salt (QAS), or cationic polyacrylamide flocculants (PAM), polyaluminum salt (PAC) could decrease Sludge Volume Index (SVI) and control foaming and bulking at different levels. In practical application, the shorter SRT was effective to control foaming and bulking in initial stage, although it took longer time. Addition of 10gClkgMLSSd(-1) could gradually change the activated sludge with serious foaming and bulking to normal state within a week. Pre-alert control strategies should be established for the control of filamentous foaming and bulking.
Actinobacteria↗
Prediction of the functional class of lipid binding proteins from sequence-derived properties irrespective of sequence similarity.
Lipid binding proteins play important roles in signaling, regulation, membrane trafficking, immune response, lipid metabolism, and transport. Because of their functional and sequence diversity, it is desirable to explore additional methods for predicting lipid binding proteins irrespective of sequence similarity. This work explores the use of support vector machines (SVMs) as such a method. SVM prediction systems are developed using 14,776 lipid binding and 133,441 nonlipid binding proteins and are evaluated by an independent set of 6,768 lipid binding and 64,761 nonlipid binding proteins. The computed prediction accuracy is 78.9, 79.5, 82.2, 79.5, 84.4, 76.6, 90.6, 79.0, and 89.9% for lipid degradation, lipid metabolism, lipid synthesis, lipid transport, lipid binding, lipopolysaccharide biosynthesis, lipoprotein, lipoyl, and all lipid binding proteins, respectively. The accuracy for the nonmember proteins of each class is 99.9, 99.2, 99.6, 99.8, 99.9, 99.8, 98.5, 99.9, and 97.0%, respectively. Comparable accuracies are obtained when homologous proteins are considered as one, or by using a different SVM kernel function. Our method predicts 86.8% of the 76 lipid binding proteins nonhomologous to any protein in the Swiss-Prot database and 89.0% of the 73 known lipid binding domains as lipid binding. These findings suggest the usefulness of SVMs for facilitating the prediction of lipid binding proteins. Our software can be accessed at the SVMProt server (http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi).
Algorithms↗
Effects of perceived peer isolation and social support availability on the relationship between body mass index and depressive symptoms.
OBJECTIVE: To examine relationships between body mass index (BMI) and psychological correlates in Chinese school adolescents during the period of economic transition. DESIGN: Baseline data of 1655 Chinese adolescents aged 11-15 y were retrieved from a longitudinal smoking cessation and health promotion program in Wuhan, China. Assessments of body weight and height, depressive symptoms, perceived peer isolation (PPI) and perceived availability of social support (PASS) were collected. RESULTS: Based on the International Obesity Task Force (IOTF) age-and sex-specific BMI cutoffs, 12.5% of boys and 9.2% of girls were overweight. In girls, high BMI was significantly related to higher self-reported depressive symptoms, and was dominantly mediated by PPI. On the contrary, high BMI boys reported significantly lower levels of PPI although high PPI level aggravated depressive symptoms. For both girls and boys, the observed effect of PPI on the relationship between BMI and depressive symptoms was sustained only in low PASS boys and girls. CONCLUSIONS: The present study revealed different effects of PPI on the association of BMI and depressive symptoms between boys and girls, which were buffered by levels of PASS. The findings of this study may contribute to our understanding of the influences of psychological correlates in pediatric overweight in the Eastern cultural environment.
Adolescent↗
Trends in exploration of therapeutic targets.
Lead discovery against a preselected therapeutic target is a key component in modern drug development. Continuous effort and increasing interest has been directed at the search for new targets, which has led to the identification of a growing number of them. Data from the therapeutic target database, at http://bidd.nus.edu.sg/group/cjttd/ttd.asp, show that, as of July 2004, the number of documented targets of marketed and investigational drugs has reached 1,174 distinct proteins (including subtypes) and 27 nucleic acids, 239 of which are targets of the marketed drugs. Analysis of these targets, particularly those of recently approved drugs and patented investigational agents, provide useful hints about general trends of target exploration and current focus in drug discovery for the treatment of high impact diseases needing effective or more treatment options.
Databases, Factual↗
MoViES: molecular vibrations evaluation server for analysis of fluctuational dynamics of proteins and nucleic acids.
Analysis of vibrational motions and thermal fluctuational dynamics is a widely used approach for studying structural, dynamic and functional properties of proteins and nucleic acids. Development of a freely accessible web server for computation of vibrational and thermal fluctuational dynamics of biomolecules is thus useful for facilitating the relevant studies. We have developed a computer program for computing vibrational normal modes and thermal fluctuational properties of proteins and nucleic acids and applied it in several studies. In our program, vibrational normal modes are computed by using modified AMBER molecular mechanics force fields, and thermal fluctuational properties are computed by means of a self-consistent harmonic approximation method. A web version of our program, MoViES (Molecular Vibrations Evaluation Server), was set up to facilitate the use of our program to study vibrational dynamics of proteins and nucleic acids. This software was tested on selected proteins, which show that the computed normal modes and thermal fluctuational bond disruption probabilities are consistent with experimental findings and other normal mode computations. MoViES can be accessed at http://ang.cz3.nus.edu.sg/cgi-bin/prog/norm.pl.
Computational Biology↗
TRMP: a database of therapeutically relevant multiple pathways.
UNLABELLED: Disease processes often involve crosstalks between proteins in different pathways. Different proteins have been used as separate therapeutic targets for the same disease. Synergetic targeting of multiple targets has been explored in combination therapy of a number of diseases. Potential harmful interactions of multiple targeting have also been closely studied. To facilitate mechanistic study of drug actions and a more comprehensive understanding the relationship between different targets of the same disease, it is useful to develop a database of known therapeutically relevant multiple pathways (TRMPs). Information about non-target proteins and natural small molecules involved in these pathways also provides useful hint for searching new therapeutic targets and facilitate the understanding of how therapeutic targets interact with other molecules in performing specific tasks. The TRMPs database is designed to provide information about such multiple pathways along with related therapeutic targets, corresponding drugs/ligands, targeted disease conditions, constituent individual pathways, structural and functional information about each protein in the pathways. Cross links to other databases are also introduced to facilitate the access of information about individual pathways and proteins. AVAILABILITY: This database can be accessed at http://bidd.nus.edu.sg/group/trmp/trmp.asp and it currently contains 11 entries of multiple pathways, 97 entries of individual pathways, 120 targets covering 72 disease conditions together with 120 sets of drugs directed at each of these targets. Each entry can be retrieved through multiple methods including multiple pathway name, individual pathway name and disease name. SUPPLEMENTARY INFORMATION: http://bidd.nus.edu.sg/group/trmp/sm.pdf
Biomarkers↗
Modulated angle beam ultrasonic spectroscopy for evaluation of imperfect interfaces and adhesive bonds.
An experimental method incorporating high frequency pulsed angle beam ultrasonic measurements modulated by low frequency vibrations of a bonded structure is described. This method uses parametric/nonlinear mixing between high and low frequencies to characterize adhesive degradation. It is demonstrated that good quality (undamaged) bonds exhibit little dependence of ultrasonic signature on the overlay of low frequency vibration loads; however, environmentally degraded or imperfect bonds exhibit strong modulation of the resonance frequency of the ultrasonic signal reflected from the bond. The results are interpreted using a model for normal and oblique wave interaction with two nonlinear interfaces separated by an adhesive layer under quasi-static stress modulation.
Journal Article↗
Establishment of a highly efficient transformation system for pepper (Capsicum annuum L.).
Application of modern genetic manipulation has been limited in pepper ( Capsicum annuum L.) due to the lack of an efficient transformation system. Following the development of an efficient protocol for in vitro regeneration of pepper cotyledons, we investigated the key factors affecting transformation and established a highly efficient genetic transformation system using the pepper cotyledon as starting material. In this system, cotyledon explants are preconditioned for 2 days on kanamycin (km)-free DM1 medium [Murashige and Skoog (MS) salts/Gamborg B5 vitamins basal medium supplemented with 20 g/l sucrose, 5,000 mg/l DJ nutrients and a hormone combination of 1.0 mg/l indoleacetic acid (IAA) and 5.0 mg/l 6-benzyladenine (BA) solidified with 0.7% agar, pH 5.8], followed by co-cultivation with Agrobacterium tumefaciens on DM1 for 2 days and delay selection on DM1 with 500 mg/l carbenicillin (carb) for 2 days. The explants are then placed on DM1 containing 10 mg/l AgNO(3), 50 mg/l km-sulfate and 500 mg/l carb. After 4-5 weeks, the explants with buds are transferred to EM1 medium (MS salts/Gamborg B5 vitamins basal medium supplemented with 20 g/l sucrose, 5,000 mg/l DJ nutrients, 10 mg/l AgNO(3) and a hormone combination of 1.0 mg/l IAA, 3.0 mg/l BA and 2.0 mg/l gibberellic acid, solidified with 0.7% agar, pH 5.8) with 50 mg/l kanamycin and 500 mg/l carbenicillin for the elongation of buds. After 3-6 weeks, 1- to 2-cm-long elongated shoots are excised and planted on RM1 medium (MS basal medium supplemented with a hormone combination of 0.2 mg/l NAA and 0.1 mg/l IAA, solidified with 0.8% agar, pH 5.8) with 25 mg/l km and 200 mg/l carb for rooting. We tested four genotypes of pepper, and all presented a high differentiation efficiency (81.3% on average), elongation rate (61.5%) and rooting efficiency (89.5%). Polymerase chain reaction analysis results showed that 40.8% of the regenerated plantlets were transgenic plants.
Adenine↗
Secondary sulphonylurea failure: what pathogenesis is responsible?
Sulphonylurea (SU) stimulates insulin secretion by pancreatic beta-cells and is generally used as a first-line treatment for type 2 diabetes. However, after long-term SU treatment (six months or over), some patients begin to show an increase in blood glucose once again (secondary SU failure). Two theories have been put forward to explain this failure--dysfunction of the proinsulin conversion machinery or insulin resistance. However, the primary pathogenesis behind secondary SU failure still needs to be investigated. Using a reliable technique that specifically identifies intact proinsulin (IPI), total proinsulin (TPI) and specific insulin (SI), this study aims to discover if a defect in the proinsulin converting mechanism plays a role in SU failure. Three groups were recruited for this study: healthy controls (n=8), SU responders (n=38) and secondary SU failures (n= 46). Serum concentrations of insulin-related molecules released in response to a standard glucose challenge test were compared between the groups. It was found that total SI was lower in the patient groups (P<0.05 compared to the control group), while TPI and IPI showed no distinct difference between the three groups (P>0.05). TPI:SI ratio and IPI:SI ratio showed marked increases in the patient groups (P<0.05 compared to control group), with no obvious quantitative difference between SU responders and secondary SU failures (P>0.05). Similar results for the Homa Insulin Resistant Index were found between the two patient groups. Interestingly, blood glucose at 180 mins after glucose challenge was significantly higher in the secondary SU failure group (P<0.05), with no correlation to SI, while the SU responder group showed good correlation between the parameters (P<0.05). We conclude that type 2 diabetes is associated with obvious dysfunction in the proinsulin-converting process and shows severe SI deficiency in responding to glucose challenge. Dysfunction of the proinsulin conversion mechanism was not an extra cause responsible for SU failure.
Adult↗
Inverse ultrasonic determination of imperfect interfaces and bulk properties of a layer between two solids.
A method for determination of the complete set of physical, geometrical, and interfacial properties of an isotropic layer embedded between two known solids is discussed. These properties are: Lamé elastic moduli, density and thickness of the layer, and complex normal and transverse interfacial stiffnesses between the layer and the substrates. The properties are combined in the form of eight nondimensional parameters, which are determined from experimental reflection spectra at two incident angles: normal and oblique. The conditions for simultaneous determination of bulk layer properties and the interface normal and transverse springs with losses and the stability of the inversion method against data scatter are addressed. The inversion model is validated by experiment on normal and angular ultrasonic reflectivity from a layer between two semispaces in dry mechanical contact and from an environmentally degraded adhesive joint. The layer properties were measured independently, showing good agreement with the reconstructed results.
Journal Article↗
Bone mass and density response to a 12-month trial of calcium and vitamin D supplement in preadolescent girls.
BACKGROUND: Maximal bone acquisition in adolescent girls through dietary and lifestyle practices is advocated to prevent or minimize the development of osteoporosis and its associated complications in later life. Longitudinal investigations of bone acquisition in children and adolescents have utilized areal bone mineral density (BMD, mg/cm(2)) as a measure of bone mass and strength. Peripheral quantitative computed tomography (pQCT), which provides a three-dimensional display of data, separate analyses of bone compartments, and bone mass in terms of volumetric BMD (vBMD, mg/cm(3)), has recently been introduced for clinical use. OBJECTIVE: To assess the impact of a 12-month daily calcium supplement on total and trabecular bone acquisition as measured by pQCT in preadolescent girls. DESIGN: Early adolescent Caucasian girls (aged 12 years, Tanner Stage 2) were enrolled in a randomized trial of daily calcium supplement (TX, 800 mg calcium carbonate and 400 IU vitamin D) or placebo (C). Body weight, height, and distal tibia measurements by pQCT were obtained at enrollment, 6 and 12 months. Pubertal status and physical activity records were assessed at baseline and 12 months. Three-day food intake records were completed every three months. RESULTS: Seventy-one girls completed the 12-month trial (TX=35, C=36). No differences were found for age, weight, height, body mass index, pubertal maturation, or reported physical activity at enrollment or during the study. Average intakes during the study were 1524 mg calcium and 496 IU vitamin D (TX) versus 865 mg calcium and 160 IU vitamin D (C) per day. Baseline total bone values were similar, however, trabecular values were greater in TX girls despite randomization. Percent changes were calculated to adjust for baseline differences. Because of the small cortical thickness at the 10% site (mean values < 1.6 mm), cortical mass and density were not analyzed. The percent changes for trabecular bone mineral content (BMC, mg) and vBMD were significantly greater in TX girls (+4.1% BMC and +1.0% vBMD TX versus -1.6% BMC and -2.0% vBMD C, p<0.006; ANCOVA) after 12 months of supplement. Trabecular bone area (BA, cm(2)) and total bone change, however, did not differ between groups. CONCLUSIONS: Daily calcium and vitamin D supplementation promotes greater trabecular BMC and vBMD acquisition in preadolescent girls. The single site selected for pQCT evaluation in this study did not allow evaluation of the cortical bone compartment. Future studies that utilize the pQCT technique need to incorporate multiple measurement sites to better assess total, cortical, and trabecular bone.
Journal Article↗
Determination of embedded layer properties using adaptive time-frequency domain analysis.
A general model for determination of the complete set of acoustical and geometrical properties of an isotropic layer embedded between isotropic or anisotropic multilayered solids is developed. These properties include density, longitudinal and shear elastic moduli, layer thickness, and loss factors, simultaneously determined from two measurements, one at normal and one at oblique incidence. The inversion model is an extension of the method proposed by Lavrentyev and Rokhlin [J. Acoust. Soc. Am. 102, 3467 (1997)] which is applicable to thick substrates. In this new method, the inversion model mimics an experiment by using the same time-domain gating of the signal reflected from the embedded layer. This allows application of this method to layered solids when reflections from different layers overlap in the time domain. The sensitivity of the method, its stability against data scatter, and the effect of the oblique incident angle are evaluated. The effect of plane-wave approximation versus beam approximation in the inverse algorithm is discussed. Experimental results are given to demonstrate examples of adhesive layer property reconstruction.
Journal Article↗
Cross-electron-transfer reactions of the [Cu(II/I)(bite)](2+/+) redox couple.
A series of outer-sphere cross-electron-transfer reactions involving the [Cu(bite)](2+/+) redox couple has been investigated in acetonitrile at 25 degrees C. In this complex, the bite ligand is a macrocyclic N(2)S(2) ligand with a 2,2'-biphenyl moiety as its backbone. The reaction of [Cu(II)(bite)](2+) with [Ru(hfac)(3)](-) produces [Cu(I)(bite)](+) and [Ru(hfac)(3)] reversibly with K = 1.9. The rate law is second order in both directions, with a rate constant of (8.22 +/- 0.27) x 10(2) M(-1) s(-1) in the forward direction. Rate constants were also obtained for the irreversible reactions of three Co(II) clathrochelates with [Cu(bite)](2+). The oxidation of [Cu(bite)](+) by [Fe(bpy)(3)](3+) was studied in order to obtain a rate constant for oxidation as well as reduction. Application of the Marcus cross relationship to these rate constants gives apparent self-exchange rate constants that are reasonably consistent yet unusually low, with an average value of 1.0 x 10(-2) M(-1) s(-1). The self-consistence of the apparent self-exchange rate constants implies that all of the cross reactions proceed through the same intermediate, and hence, the outer-sphere self-exchange reaction should have a second-order rate law with k = 1.0 x 10(-2) M(-1) s(-1). The much faster first-order self-exchange process reported previously for the [Cu(bite)](2+/+) couple in acetone implies a more efficient mechanism for the self-exchange reaction than for the cross reactions, such as an inner-sphere mechanism. Cyclic voltammograms of [Cu(bite)](n+) are strongly sensitive to the nature of the working electrode, thus precluding the use of these data in interpreting the homogeneous redox kinetics.
Journal Article↗
Focal adhesion kinase activates Stat1 in integrin-mediated cell migration and adhesion.
Recent studies suggest that focal adhesion kinase (FAK) is important for cell migration. We now suggest a mechanism by which FAK activates the signal transducer and activator of transcription (STAT) pathway, regulating cell adhesion and migration. In particular, we observe that FAK is capable of activating Stat1, but not Stat3. Co-immunoprecipitation and in vitro binding assays demonstrate that Stat1 is transiently and directly associated with FAK during cell adhesion, and Stat1 is activated in this process. FAK with a C-terminal deletion (FAKDeltaC14) completely abolishes this interaction, indicating this association is dependent on the C-terminal domain of FAK, which is required for FAK localization at focal contacts. Moreover, Stat1 activation during cell adhesion is diminished in FAK-deficient cells, correlating with decreased migration in these cells. Finally, we show that depletion of Stat1 results in an enhancement of cell adhesion and a decrease in cell migration. Thus, our results have demonstrated, for the first time, a critical signaling pathway from integrin/FAK to Stat1 that reduces cell adhesion and promotes cell migration.
Blotting, Western↗
Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo.
Matriptase and its cognate, Kunitz-type serine protease inhibitor, HAI-1, comprise a newly characterized extracellular matrix-degrading protease system that may function as an epithelial membrane activator for other proteases and latent growth factors. Both enzyme and inhibitor have been detected in breast cancer cells, immortalized mammary epithelial cells, and human milk, but not in cultured fibroblasts nor in fibrosarcoma cells. To test the hypothesis that this system is expressed by normal breast epithelium, invasive breast cancers, and other cancers of an epithelial origin (carcinomas) but not in cancers of a mesenchymal origin, we have expanded our expression analysis of matriptase and HAI-1 in vitro and in vivo. Matriptase and HAI-1 were detected at the protein and mRNA levels both in hormone-dependent and hormone-independent cultured breast cancer cells, and this expression correlated with the expression of the epithelial markers E-cadherin or ZO-1. However, none of the breast cancer cell lines tested that express the mesenchymal marker vimentin express matriptase or HAI-1, consistent with an epithelial-selective expression of this system. Expression of matriptase, as determined by Western blot analysis, was observed in primary human breast, gynecological, and colon carcinomas, but not in stromal-derived ovarian tumors and human sarcomas of various origins and histological grades. The epithelial-selective expression of matriptase and HAI-1 was further confirmed in human breast cancers by immunohistochemistry and in situ hybridization, where the expression of the protease and the inhibitor were found in the carcinoma cells and in surrounding normal breast epithelia. The expression of the matriptase/HAI-1 system by malignant epithelial cells in vivo suggests a possible role for this protease in multiple aspects of the pathophysiology of epithelial malignancy, including invasion and metastasis.
Biomarkers↗
Diet-gene interactions in estrogen-induced mammary carcinogenesis in the ACI rat.
It is well accepted that hormonal, dietary and genetic factors each influence breast cancer risk. However, the underlying mechanisms and the extent to which these factors interact are largely unknown. We have demonstrated that the female ACI rat exhibits a unique genetically conferred propensity to develop mammary cancers when treated with physiological levels of 17beta-estradiol (E2). More recently, we have mapped to rat chromosome 5 a strong genetic modifier of susceptibility to E2-induced mammary cancers, termed estrogen-induced mammary cancer 1 (Emca1), and have identified potential Emca1 candidate genes. Because estrogens have been inextricably linked to the genesis of breast cancer in humans, the ACI rat model has the potential to reveal novel physiologically relevant insights into how the contributory actions of E2 are modified by specific dietary factors. In the present study, we have examined the ability of a 40% restriction of dietary energy consumption to inhibit E2-induced mammary carcinogenesis. The hypothesis tested was that energy restriction will inhibit mammary carcinogenesis even when circulating E2 remains elevated through administration of exogenous hormone. The data presented herein strongly suggest that energy restriction inhibits E2-induced mammary carcinogenesis in the ACI rat at least partly by retarding progression of atypical hyperplastic foci to carcinoma.
Animals↗