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Articles by L Zhu
Total Records ( 10 ) for L Zhu
  L Zhu , J Wang , J Mu , H Wang , C Zhang , X Liu , X Yan , L Dai and D. Ma

Human tissue factor pathway inhibitor-2 (hTFPI-2) is a serine protease inhibitor and its inhibitory activity is enhanced by heparin. The Kunitz domain 3 and C-terminal of hTFPI-2 (hTFPI-2/KD3C), which has the activity toward heparin calcium, have been successfully expressed in Pichia pastoris and purified by SP-Sepharose and heparin-Sepharose chromatography. The Fourier transformed infrared spectroscopy (FTIR), Raman spectroscopy, and circular dichroism (CD) experiment results implied that hTFPI-2/KD3C contained small contents of -helix and β-strand, but large amounts of random coil and two kinds of disulfide bonds, gauche-gauche-gauche (ggg) and trans-gauche-trans (tgt). The interaction of hTFPI-2/KD3C with heparin calcium was investigated by CD. It was found that heparin calcium induced β-strands in hTFPI-2/KD3C to different extents depending on the ratio of hTFPI-2/KD3C and heparin calcium.

  J Li , A Dai , R Hu , L Zhu and S. Tan

Oxidative stress is one of the major pathogenesis of chronic obstructive pulmonary disease (COPD). -Glutamylcysteine synthetase (-GCS) is one of the paramount antioxidant enzymes in COPD. Peroxisome proliferator-activated receptor-gamma (PPAR) is a ligand-activated transcription factor, which is activated by specific ligands such as rosiglitazone (RGZ), exerting multiple biological effects. PPAR coactivator-1 (PGC-1) is a PPAR coactivator, which binds to PPAR by induction of PPAR ligands, co-activating PPAR target genes. Growing evidence has suggested that PPAR/PGC-1 can regulate multiple antioxidant genes. However, the effect of PPAR/PGC-1 on -GCS during the development of COPD remains unclear. Here, we measured the expression levels of PPAR, PGC-1 and -GCS, -GCS activity and reactive oxygen species (ROS) contents in lungs of rats treated by cigarette smoke (CS) + lipopolysaccharide (LPS) and CS + LPS + RGZ, as well as lungs of patients suffered from COPD. Compared with lungs from CS + LPS-treated rats, lungs of RGZ-treated rats demonstrated markedly lower ROS contents, and remarkable increase of -GCS activity and increase of the expression levels of PPAR, PGC-1, and -GCS. Furthermore, compared with controls, expression levels of PPAR, PGC-1, and -GCS significantly increased in the lungs of mild COPD patients, and progressively decreased in lungs of patients with moderate and severe COPD. -GCS protein was positively correlated with FEV1%. PPAR and PGC-1 proteins were positively correlated with -GCS activity and mRNA level. In conclusion, -GCS showed compensatory upregulation in the early stage of COPD, which progressively decompensate with increasing COPD severity. The activation of the PPAR/PGC-1 pathway may protect against COPD progression by upregulating -GCS and relieving oxidative stress.

  L Zhu , T. J Stalker , K. P Fong , H Jiang , A Tran , I Crichton , E. K Lee , K. B Neeves , S. F Maloney , H Kikutani , A Kumanogoh , E Pure , S. L Diamond and L. F. Brass

Objective— In dyslipidemic states, platelets become hyperreactive, secreting molecules that promote atherosclerosis. We have shown that the semaphorin family member, sema4D (CD100), is expressed on the surface of platelets and proposed that its role includes promoting thrombus growth by binding to nearby platelets and endothelial cells, both of which express sema4D receptors. Here we tested the hypothesis that deleting sema4D will attenuate the adverse consequences of dyslipidemia on platelets and the vessel wall.

Methods and Results— Platelet function and atherosclerotic lesion formation were measured in LDLR(–/–) and sema4D(–/–)LDLR(–/–) mice after 6 months on a high-fat diet. All of the mice developed the dyslipidemia expected on this diet in the absence of functional LDL receptors. However, when compared to LDLR(–/–) mice, sema4D(–/–) LDLR(–/–) mice had reduced lipid deposition in the descending aorta, a 6-fold decrease in the frequency of arterial occlusion and a reduction to near wild-type levels in the accumulation of platelets after injury. These differences were retained ex vivo, with a marked decrease in platelet accumulation on collagen under flow and in platelet aggregation.

Conclusions— These results show that loss of sema4D expression reduces the platelet hyperactivity otherwise found in dyslipidemia, and confers protection against the development of atherosclerosis.

  L Zhu , T Wang and L. Ferre

In the context of sufficient dimension reduction, the goal is to parsimoniously recover the central subspace of a regression model. Many inverse regression methods use slicing estimation to recover the central subspace. The efficacy of slicing estimation depends heavily upon the number of slices. However, the selection of the number of slices is an open and long-standing problem. In this paper, we propose a discretization-expectation estimation method, which avoids selecting the number of slices, while preserving the integrity of the central subspace. This generic method assures root-n consistency and asymptotic normality of slicing estimators for many inverse regression methods, and can be applied to regressions with multivariate responses. A BIC-type criterion for the dimension of the central subspace is proposed. Comprehensive simulations and an illustrative application show that our method compares favourably with existing estimators.

  L Zhu , H Koistinen , U Landegren and U. H. Stenman

Background: Prostate specific antigen (PSA)–1-protease inhibitor complex (PSA-API) is a minor form of PSA in serum. It may be useful for prostate cancer (PCa) diagnosis, but its specific detection is hampered by nonspecific background. To avoid this, we developed an immunoassay for PSA-API based on proximity ligation.

Methods: We used a monoclonal antibody (mAb) to total PSA (tPSA) to capture PSA, while using another anti-tPSA mAb together with an anti-API mAb as probes. We measured PSA-API by quantification of amplified DNA strands conjugated to the probes. We measured serum PSA-API in 84 controls and 55 men with PCa who had PSA concentrations of 4.0–10 µg/L.

Results: The detection limit of the assay was 6.6 ng/L. The proportion of PSA-API to tPSA (%PSA-API) tended to be lower in men with PCa (2.8%) than without cancer (3.3%) but was not statistically significant (P = 0.363). When used alone, %PSA-API [area under the curve (AUC) 0.546] did not improve detection of PCa, whereas %fPSA (AUC 0.710) and the sum of %fPSA and %PSA-API (AUC 0.723) did. At 90% diagnostic sensitivity, the diagnostic specificity for cancer was not significantly better for %fPSA + %PSA-API than for %fPSA alone (36% vs 30%).

Conclusions: Proximity ligation eliminated nonspecific background, enabling accurate measurement of PSA-API in serum specimens with moderately increased tPSA. The combined use of %PSA-API and %fPSA provided a modest improvement for PCa detection, but based on the current study cohort, it is uncertain whether the improvement has clinical utility. .

  Z Tian , C Rizzon , J Du , L Zhu , J. L Bennetzen , S. A Jackson , B. S Gaut and J. Ma

In flowering plants, the accumulation of small deletions through unequal homologous recombination (UR) and illegitimate recombination (IR) is proposed to be the major process counteracting genome expansion, which is caused primarily by the periodic amplification of long terminal repeat retrotransposons (LTR-RTs). However, the full suite of evolutionary forces that govern the gain or loss of transposable elements (TEs) and their distribution within a genome remains unclear. Here, we investigated the distribution and structural variation of LTR-RTs in relation to the rates of local genetic recombination (GR) and gene densities in the rice (Oryza sativa) genome. Our data revealed a positive correlation between GR rates and gene densities and negative correlations between LTR-RT densities and both GR and gene densities. The data also indicate a tendency for LTR-RT elements and fragments to be shorter in regions with higher GR rates; the size reduction of LTR-RTs appears to be achieved primarily through solo LTR formation by UR. Comparison of indica and japonica rice revealed patterns and frequencies of LTR-RT gain and loss within different evolutionary timeframes. Different LTR-RT families exhibited variable distribution patterns and structural changes, but overall LTR-RT compositions and genes were organized according to the GR gradients of the genome. Further investigation of non-LTR-RTs and DNA transposons revealed a negative correlation between gene densities and the abundance of DNA transposons and a weak correlation between GR rates and the abundance of long interspersed nuclear elements (LINEs)/short interspersed nuclear elements (SINEs). Together, these observations suggest that GR and gene density play important roles in shaping the dynamic structure of the rice genome.

  P. A Bradbury , D Tu , L Seymour , P. K Isogai , L Zhu , R Ng , N Mittmann , M. S Tsao , W. K Evans , F. A Shepherd , N. B Leighl and on behalf of the NCIC Clinical Trials Group Working Group on Economic Analysis

The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non–small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib.


Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer–related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio.


The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94 638 per life-year gained (95% confidence interval = $52 359 to $429 148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number.


With an incremental cost-effectiveness ratio of $94 638 per life-year gained, erlotinib treatment for patients with previously treated advanced non–small cell lung cancer is marginally cost-effective. The use of molecular predictors of benefit for targeted agents may help identify more or less cost-effective subgroups for treatment.

  J. Q Zhu , L Zhu , X. W Liang , F. Q Xing , H Schatten and Q. Y. Sun

The cause of polycystic ovary syndrome (PCOS), a complex endocrine disorder, is unknown, but its familial aggregation implies underlying genetic influences. Hyperandrogenemia is regarded as a major endocrine character of the PCOS. In this study, we employed bisulfite sequencing and bisulfite restriction analysis to investigate the DNA methylation status of LHR, AR, FSHR and H19 in dehydroepiandrosterone (DHEA)-induced mouse PCOS model. The result showed that methylation of LHR was lost in ovary from induced PCOS mouse. However, AR, FSHR and H19 had similar methylation pattern in DHEA-treated group and control groups. These data provide evidence for close linkage between DNA demethylation of LHR and PCOS.

  W Cai , M Torreggiani , L Zhu , X Chen , J. C He , G. E Striker and H. Vlassara

Advanced glycated end-product receptor 1 (AGER1) protects against vascular disease promoted by oxidants, such as advanced glycated end products (AGEs), via inhibition of reactive oxygen species (ROS). However, the specific AGEs, sources, and pathways involved remain undefined. The mechanism of cellular NADPH oxidase (NOX)-dependent ROS generation by defined AGEs, N-carboxymethyl-lysine- and methylglyoxal (MG)-modified BSA, was assessed in AGER1 overexpressing (AGER1+ EC) or knockdown (sh-mRNA-AGER1+ EC) human aortic endothelial (EC) and ECV304 cells, and aortic segments from old (18 mo) C57BL6-F2 mice, propagated on low-AGE diet (LAGE), or LAGE supplemented with MG (LAGE+MG). Wild-type EC and sh-mRNA-AGER1+ EC, but not AGER1+ EC, had high NOX p47phox and gp91phox activity, superoxide anions, and NF-B p65 nuclear translocation in response to MG and N-carboxymethyl-lysine. These events involved epidermal growth factor receptor-dependent PKC- redox-sensitive Tyr-311 and Tyr-332 phosphorylation and were suppressed in AGER1+ ECs and enhanced in sh-mRNA-AGER1+ ECs. Aortic ROS, PKC- Tyr-311, and Tyr-332 phosphorylation, NOX expression, and nuclear p65 in older LAGE+MG mice were significantly increased above that in age-matched LAGE mice, which had higher levels of AGER1. In conclusion, circulating AGEs induce NADPH-dependent ROS generation in vascular aging in both in vitro and in vivo models. Furthermore, AGER1 provides protection against AGE-induced ROS generation via NADPH.

  L Zhu , J Crothers , R Zhou and J. G. Forte

Ezrin is an important membrane/actin cytoskeleton linker protein, especially in epithelia. Ezrin has two important binding domains: an NH2-terminal region that binds to plasma membrane and a COOH-terminal region that binds to F-actin only after a conformational activation by phosphorylation at Thr567 of ezrin. The present experiments were undertaken to investigate the detailed cellular changes in the time course of expression of ezrin-T567 mutants (nonphosphorylatable T567A and permanent phospho-mimic T567D) in parietal cells and to assess ezrin distribution and its influence on the elaborate membrane recruitment processes of these cells. T567A mutant and wild-type (WT) ezrin were consistently localized to the apical plasma membrane, even with overexpression. On the other hand, T567D went first to apical membrane at early times and low expression levels, then accumulated mainly at the basal surface after 24 h. Overexpression of WT or T567A led to incorporation of internal membranes to apical vacuoles, while overexpression of T567D led to large incorporation of apical and intracellular membranes (including H-K-ATPase) to the basal surface. Differences in polar distribution of ezrin suggest a role for the linker protein in promoting formation and plasticity of membrane surface projections, forming the basis for a novel theory for ezrin as an organizer and regulator of membrane recruitment. A model simulating the cellular distribution of ezrin and its associated membrane- and F-actin-binding forms is given to predict redistributions observed with phosphorylation and mutant overexpression, and it can easily be modified as more specific information regarding binding constants and specific sites becomes available.

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