Biomedical subjects

Yang Dai

Publications and source records attributed to Yang Dai.

15 recordsLinked to original sources

PubMed2006

Assessing protein similarity with Gene Ontology and its use in subnuclear localization prediction.

BACKGROUND: The accomplishment of the various genome sequencing projects resulted in accumulation of massive amount of gene sequence information. This calls for a large-scale computational method for predicting protein localization from sequence. The protein localization can provide valuable information about its molecular function, as well as the biological pathway in which it participates. The prediction of localization of a protein at subnuclear level is a challenging task. In our previous work we proposed an SVM-based system using protein sequence information for this prediction task. In this work, we assess protein similarity with Gene Ontology (GO) and then improve the performance of the system by adding a module of nearest neighbor classifier using a similarity measure derived from the GO annotation terms for protein sequences. RESULTS: The performance of the new system proposed here was compared with our previous system using a set of proteins resided within 6 localizations collected from the Nuclear Protein Database (NPD). The overall MCC (accuracy) is elevated from 0.284 (50.0%) to 0.519 (66.5%) for single-localization proteins in leave-one-out cross-validation; and from 0.420 (65.2%) to 0.541 (65.2%) for an independent set of multi-localization proteins. The new system is available at http://array.bioengr.uic.edu/subnuclear.htm. CONCLUSION: The prediction of protein subnuclear localizations can be largely influenced by various definitions of similarity for a pair of proteins based on different similarity measures of GO terms. Using the sum of similarity scores over the matched GO term pairs for two proteins as the similarity definition produced the best predictive outcome. Substantial improvement in predicting protein subnuclear localizations has been achieved by combining Gene Ontology with sequence information.

Algorithms↗

PubMed2006

Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro.

Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose-adjusted trough blood concentrations compared with homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites, 13-O-desmethyl tacrolimus (13-DMT) (major), 15-O-desmethyl tacrolimus, 31-O-desmethyl tacrolimus (31-DMT), and 12-hydroxy tacrolimus (12-HT), were generated by human liver microsomes and heterologously expressed CYP3A4 and CYP3A5. The unbound tacrolimus concentration was low (4-15%) under all incubation conditions. For CYP3A4 and CYP3A5, V(max) was 8.0 and 17.0 nmol/min/nmol enzyme and K(m,u) was 0.21 and 0.21 muM, respectively. The intrinsic clearance of CYP3A5 was twice that of CYP3A4. The formation rates of 13-DMT, 31-DMT, and 12-HT were >or=1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared with those with a homozygous CYP3A5*3/*3 genotype. Tacrolimus disappearance clearances were 15.9 +/- 9.8 ml/min/mg protein and 6.1 +/- 3.6 ml/min/mg protein, respectively, for the two genotypes. In vitro to in vivo scaling using both liver microsomes and recombinant enzymes yielded higher predicted in vivo tacrolimus clearances for patients with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney.

Algorithms↗

PubMed2006

Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan.

PURPOSE: Several studies have demonstrated significant interactions between immunosuppressants (e.g., cyclosporin A) and chemotherapeutic drugs that are BCRP substrates (e.g., irinotecan), resulting in increased bioavailability and reduced clearance of these agents. One possible mechanism underlying this observation is that the immunosuppressants modulate the pharmacokinetics of these drugs by inhibiting BCRP. Therefore, the aim of this study was to determine whether the immunosuppressants cyclosporin A, tacrolimus and sirolimus are inhibitors and/or substrates of BCRP. METHODS: First, the effect of the immunosuppressants on BCRP efflux activity in BCRP-expressing HEK cells was measured by flow cytometry. RESULTS: Cyclosporin A, tacrolimus and sirolimus significantly inhibited BCRP-mediated efflux of pheophorbide A, mitoxantrone and BODIPY-prazosin. The EC(50) values of cyclosporin A, tacrolimus and sirolimus for inhibition of BCRP-mediated pheophorbide A efflux were 4.3 +/- 1.9 microM, 3.6 +/- 1.8 microM and 1.9 +/- 0.4 microM, respectively. Cyclosporin A, tacrolimus and sirolimus also effectively reversed resistance of HEK cells to topotecan and mitoxantrone conferred by BCRP. When direct efflux of cyclosporin A, tacrolimus and sirolimus was measured, these compounds were found not to be transported by BCRP. Consistent with this finding, BCRP did not confer resistance to the immunosuppressants in HEK cells. CONCLUSION: These results indicate that cyclosporin A, tacrolimus and sirolimus are effective inhibitors but not substrates of BCRP. These findings could explain the altered pharmacokinetics of BCRP substrate drugs when co-administered with the immunosuppressants and suggest that pharmacokinetic modulation by the immunosuppressants may improve the therapeutic outcome of these drugs.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Direct prediction of T-cell epitopes using support vector machines with novel sequence encoding schemes.

New peptide encoding schemes are proposed to use with support vector machines for the direct recognition of T cell epitopes. The methods enable the presentation of information on (1) amino acid positions in peptides, (2) neighboring side chain interactions, and (3) the similarity between amino acids through a BLOSUM matrix. A procedure of feature selection is also introduced to strengthen the prediction. The computational results demonstrate competitive performance over previous techniques.

Amino Acid Sequence↗

PubMed2005

Prediction of MHC class II binding peptides based on an iterative learning model.

BACKGROUND: Prediction of the binding ability of antigen peptides to major histocompatibility complex (MHC) class II molecules is important in vaccine development. The variable length of each binding peptide complicates this prediction. Motivated by a text mining model designed for building a classifier from labeled and unlabeled examples, we have developed an iterative supervised learning model for the prediction of MHC class II binding peptides. RESULTS: A linear programming (LP) model was employed for the learning task at each iteration, since it is fast and can re-optimize the previous classifier when the training sets are altered. The performance of the new model has been evaluated with benchmark datasets. The outcome demonstrates that the model achieves an accuracy of prediction that is competitive compared to the advanced predictors (the Gibbs sampler and TEPITOPE). The average areas under the ROC curve obtained from one variant of our model are 0.753 and 0.715 for the original and homology reduced benchmark sets, respectively. The corresponding values are respectively 0.744 and 0.673 for the Gibbs sampler and 0.702 and 0.667 for TEPITOPE. CONCLUSION: The iterative learning procedure appears to be effective in prediction of MHC class II binders. It offers an alternative approach to this important prediction problem.

Journal Article↗

PubMed2005

An SVM-based system for predicting protein subnuclear localizations.

BACKGROUND: The large gap between the number of protein sequences in databases and the number of functionally characterized proteins calls for the development of a fast computational tool for the prediction of subnuclear and subcellular localizations generally applicable to protein sequences. The information on localization may reveal the molecular function of novel proteins, in addition to providing insight on the biological pathways in which they function. The bulk of past work has been focused on protein subcellular localizations. Furthermore, no specific tool has been dedicated to prediction at the subnuclear level, despite its high importance. In order to design a suitable predictive system, the extraction of subtle sequence signals that can discriminate among proteins with different subnuclear localizations is the key. RESULTS: New kernel functions used in a support vector machine (SVM) learning model are introduced for the measurement of sequence similarity. The k-peptide vectors are first mapped by a matrix of high-scored pairs of k-peptides which are measured by BLOSUM62 scores. The kernels, measuring the similarity for sequences, are then defined on the mapped vectors. By combining these new encoding methods, a multi-class classification system for the prediction of protein subnuclear localizations is established for the first time. The performance of the system is evaluated with a set of proteins collected in the Nuclear Protein Database (NPD). The overall accuracy of prediction for 6 localizations is about 50% (vs. random prediction 16.7%) for single localization proteins in the leave-one-out cross-validation; and 65% for an independent set of multi-localization proteins. This integrated system can be accessed at http://array.bioengr.uic.edu/subnuclear.htm. CONCLUSION: The integrated system benefits from the combination of predictions from several SVMs based on selected encoding methods. Finally, the predictive power of the system is expected to improve as more proteins with known subnuclear localizations become available.

Algorithms↗

PubMed2005

Patterns and localization of gene expression during intramembranous bone regeneration in the rat femoral marrow ablation model.

Tissue formation and repair are dependent upon cascades of biological events, but the signals involved and the possible gene coexpression patterns during intramembranous bone repair are only poorly understood. We sought to place this mode of regeneration in context by profiling quantitative gene expression for a panel of 39 genes between days 1 and 14 following rat femoral marrow ablation. In situ hybridization was employed to localize a subset of genes. Additionally, principal components analysis was conducted to identify underlying factors suggestive of coexpression patterns. During inflammation (days 1-5), several genes, including cyclooxygenase-1 and -2, showed downregulation. Other proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, exhibited increasing levels around day 5. During repair (days 3-10), growth factors, receptors, and inhibitor genes for transforming growth factor- beta; basic fibroblast growth factor; bone morphogenetic proteins 2, 4, and 7; vascular endothelial growth factor; and insulin-like growth factor-I were upregulated. In addition, the gene for core binding factor-alpha1 and markers of osteoblast function such as alkaline phosphatase, collagen type I, osteonectin, osteopontin, and osteocalcin had peak expression at day 5 or 7. The remodeling phase (days 10-14) was characterized by peaks for cytokines associated with osteoclastic activity including receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand (RANKL), cathepsin K, tumor necrosis factor-alpha, interleukin-6, and cyclooxygenase-2. In situ hybridization showed that the most common sites of increased signal were within osteoblastic cells on trabecular and endosteal surfaces. Principal components analysis identified eight underlying factors that together explained over 80% of the variance in the data.

Animals↗

PubMed2005

Local application of rhTGF-beta2 modulates dynamic gene expression in a rat implant model.

Various anabolic agents, including transforming growth factor-beta (TGF-beta), have been shown to enhance intramembranous bone regeneration and strengthen the mechanical connection between implant and host skeleton, a prerequisite for clinical success with orthopedic and dental implants. Mechanisms underlying these observations at the level of the gene have received little attention. A rat model was used to examine levels of gene transcription for 21 "osteogenic" genes by real-time polymerase chain reaction at days 1, 3, 5, 7, 10, 14, and 28 in a control group and a group in which the implant was treated with 1 microg recombinant human TGF-beta2 (n = 42, equally divided among the 2 groups and 7 time points). Genes were chosen to represent three functional categories: (1) growth factors, their receptors and antagonists; (2) bone differentiation markers; and (3) inflammation markers. Examination of the transcription profiles showed that nine genes had up-regulated or down-regulated expression levels without a change in timing and 12 genes had accelerated or delayed expression profiles with or without a concomitant change in maximal or minimal expression. The earliest changes (days 1-3) involved accelerated expression profiles for IGF-1R and VEGF and up-regulation of TGF-beta2, TbetaRI, BMP-2, BMP-7, and Cbfa1. Furthermore, principal components analyses showed that some subsets of genes were co-expressed in both groups, although the temporal relationship of these subsets was altered following growth factor treatment. Thus, in addition to changes in individual transcription profiles, the regulatory connections between sets of co-expressed genes may also be affected by exogenously delivered anabolic agents during bone regeneration.

Animals↗

PubMed2004

In vitro metabolism of cyclosporine A by human kidney CYP3A5.

The objectives of this study were to characterize and compare the metabolic profile of cyclosporine A (CsA) catalyzed by CYP3A4, CYP3A5 and human kidney and liver microsomes, and to evaluate the impact of the CYP3A5 polymorphism on product formation from parent drug and its primary metabolites. Three primary CsA metabolites (AM1, AM9 and AM4N) were produced by heterologously expressed CYP3A4. In contrast, only AM9 was formed by CYP3A5. Substrate inhibition was observed for the formation of AM1 and AM9 by CYP3A4, and for the formation of AM9 by CYP3A5. Microsomes isolated from human kidney produced only AM9 and the rate of product formation (2 and 20 microM CsA) was positively associated with the detection of CYP3A5 protein and presence of the CYP3A5*1 allele in 4 of the 20 kidneys tested. A kinetic experiment with the most active CYP3A5*1-positive renal microsomal preparation yielded an apparent Km (15.5 microM) similar to that of CYP3A5 (11.3 microM). Ketoconazole (200 nM) inhibited renal AM9 formation by 22-55% over a CsA concentration range of 2-45 microM. Using liver microsomes paired with similar CYP3A4 content and different CYP3A5 genotypes, the formation of AM9 was two-fold higher in CYP3A5*1/*3 livers, compared to CYP3A5*3/*3 livers. AM19 and AM1c9, two of the major secondary metabolites of CsA, were produced by CsA, AM1 and AM1c when incubated with CYP3A4, CYP3A5, kidney microsomes from CYP3A5*1/*3 donors and all liver microsomes. Also, the formation of AM19 and AM1c9 was higher from incubations with liver and kidney microsomes with a CYP3A5*1/*3 genotype, compared to those with a CYP3A5*3/*3 genotype. Together, the data demonstrate that CYP3A5 may contribute to the formation of primary and secondary metabolites of CsA, particularly in kidneys carrying the wild-type CYP3A5*1 allele.

Biotransformation↗

PubMed2003

Antisense knockdown of neuronal nitric oxide synthase antagonizes nitrous oxide-induced behavior.

The behavioral effects of nitrous oxide (N(2)O) were antagonized by non-specific inhibitors of nitric oxide synthase (NOS). To identify the isoform of NOS involved in this response, mice were pretreated with an antisense oligodeoxynucleotide (AS-ODN) against neuronal NOS, and then tested in a light/dark exploration paradigm. The AS-ODN but not the mismatch ODN significantly antagonized N(2)O induced behavior and also reduced NOS activity in the cerebellum and hippocampus. These results implicate neuronal NOS in the N(2)O response.

Analysis of Variance↗

PubMed2003

Antagonism of nitrous oxide-induced anxiolytic-like behavior in the mouse light/dark exploration procedure by pharmacologic disruption of endogenous nitric oxide function.

RATIONALE: Previous studies have shown the anxiolytic-like effects of nitrous oxide (N(2)O) to be sensitive to antagonism by non-specific inhibitors of nitric oxide synthase (NOS). OBJECTIVES: The present study was conducted to demonstrate further the involvement of nitric oxide (NO) and ascertain whether a specific isoform of NOS is involved in N(2)O-induced behavior in mice. METHODS: Male NIH Swiss mice were tested in the light/dark exploration test to determine how N(2)O-induced behavior was affected by the following pretreatments: the NO scavenger hemoglobin (Hb); the selective nNOS-inhibitor S-methyl- l-thiocitrulline (SMTC); the selective eNOS-inhibitor N(5)-(1-iminoethyl)- l-ornithine ( l-NIO); and the selective iNOS-inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT). Furthermore, NOS activity was assessed in the whole brain as well as five brain areas of N(2)O- versus room air-exposed mice to determine the effects of N(2)O on NOS activity. RESULTS: The behavioral effects of N(2)O in the light/dark exploration test were significantly attenuated following pretreatment with Hb (2.0 nmol, i.c.v.), SMTC (0.3 micro g and 1.0 micro g per mouse, i.c.v.) and the higher dose of l-NIO (30 mg/kg, s.c.). However, the N(2)O-induced behavioral effect was unaltered by pretreatment with either the lower dose of l-NIO (10 mg/kg, s.c.) or AMT (1.0 mg/kg and 3.0 mg/kg, s.c.). Finally exposure to 50% N(2)O for 15 min significantly increased NOS activity in the cerebellum and corpus striatum but not in other brain regions or whole brain. CONCLUSION: These findings provide further support for the hypothesis that NO is involved in N(2)O-induced anxiolytic-like behavior and that this NO is the product of nNOS enzyme activity.

Anesthetics, Inhalation↗

PubMed2003

Enteric disposition and recycling of flavonoids and ginkgo flavonoids.

OBJECTIVE: The objective of this study was to determine the intestinal and microbial disposition of flavonoids and how these disposition processes affect their enteric recycling. DESIGN: Studies were performed using a perfused rat intestinal model or using enrichment cultures and a pure isolate of Enterococcus avium (LY1). RESULTS: In the rat intestine, aglycones, such as quercetin and apigenin, were as permeable (P*(eff) > or = 2) as compounds such as propranolol (100% absorption). However, a significant portion of the absorbed aglycones was conjugated and the metabolites were excreted into the lumen. Flavonoid glycosides, such as isoquercitrin and apigenin-7-O-glucoside, also had high apparent P*(eff) values (> or = 2) in the upper small intestine because of rapid hydrolysis. However, isoquercitrin was absorbed much slower (P*(eff) < or = 0.7, p < 0.05) when hydrolysis was absent or inhibited by 20 mmol gluconolactone. Absorption of other intact glycosides was similar to intact isoquercitrin and was much slower than the corresponding aglycones (P*(eff) < or = 0.7, p < 0.05). Intestinal bacteria, such as LY1, hydrolyzed the flavonoid glycosides used in the study. Excreted glycosidases were involved in the hydrolysis of glycosides because glycosides were poorly taken up by LY1. In conclusion, glycosidase-catalyzed hydrolysis is a critical first step in the intestinal and microbial disposition of flavonoid glycosides. Aglycones were not only rapidly absorbed, but also rapidly metabolized into phase II conjugates, which were then excreted back into the lumen. Therefore, intestinal and microbial glycosidases and intestinal phase II enzymes make a significant contribution to the disposition of flavonoids via the proposed enteric and enterohepatic recycling scheme.

Animals↗

PubMed2003

[The advance of research on pathogenesis of acquired pure red cell aplastic anemia caused by cellular immune abnormalities].

Pure red cell aplastic anemia (PRCA) is a group of heterogeneous disorders characterized by erythropoiesis failure or disorder of bone marrow function. PRCA can be classified as congenital and acquired types. The recent researches have shown that cellular immune abnormalities are main reasons to cause PRCA. This review will focus on the focus points: T lymphocytes abnormalities, change of T-cell subset phenotypes, abnormality of cellular clonality, and effects of related cytokines in PRCA.

Humans↗

PubMed2003

Prevention of pancreaticojejunal anastomotic leakage after pancreaticoduodenectomy with separate internal drainage of bile and pancreatic fluid.

OBJECTIVE: To introduce a new reconstructional procedure to decrease the complications after pancreaticoduodenectomy. METHODS: Separate internal drainage of bile and pancreatic fluid in pancreaticoduodenectomy was performed in 256 patients. The digestive tract was reconstructed with Child method, with invaginated pancreaticojejunostomy using a long silastic tube to drain pancreatic fluid internally, an end-to-side choledochojejunostomy and an end-to-side duodenojejunostomy or gastrojejunostomy. Gastrostomy drainage was also performed. RESULTS: No complications of pancreatic leakage were found. CONCLUSION: The separate internal drainage of bile and pancreatic fluid plays an important role in preventing pancreaticojejunal anastomotic leakage.

Adult↗

PubMedDate not supplied

Prediction of MHC class II binders using the ant colony search strategy.

OBJECTIVE: Predictions of the binding ability of antigen peptides to major histocompatibility complex (MHC) class II molecules are important in vaccine development. The variable length of each binding peptide complicates this prediction. METHODOLOGY: Motivated by the search properties of the ant colony system (ACS), a method for the identification of an alignment for a given set of short protein peptides has been developed. This alignment is further used for the derivation of a position specific scoring matrix. The distinguishing feature of this method is the use of the collective optimized search strategy of ants for the selection of the alignment. RESULTS: The performance of the new model has been evaluated with several benchmark datasets. It achieves better or comparable results as compared to the performance of existing methods. CONCLUSION: The experiments demonstrate that the predictive performance of the scoring matrix embodies several promising characteristics.

Algorithms↗