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Articles by J Zhu
Total Records ( 17 ) for J Zhu
  S Xenariou , H. D Liang , U Griesenbach , J Zhu , R Farley , L Somerton , C Singh , P. K Jeffery , R. K Scheule , S. H Cheng , D. M Geddes , M Blomley and E. W. F. W. Alton
 

The aim of the study was to assess if low-frequency ultrasound (US), in the range of 30–35 kHz, increases non-viral gene transfer to the mouse lung. US is greatly attenuated in the lung due to large energy losses at the air/tissue interfaces. The advantages of low-frequency US, compared with high-frequency US are: (i) increased cavitation (responsible for the formation of transient pores in the cell membrane) and (ii) reduced energy losses during lung penetration. Cationic lipid GL67/plasmid DNA (pDNA), polyethylenimine (PEI)/pDNA and naked pDNA were delivered via intranasal instillation and the animals were then exposed to US (sonoporation) at 0.07 or 0.1 MPa for 10 min. Under these conditions, US did not enhance GL67 or PEI-mediated transfection. It did, however, increase naked pDNA gene transfer by approximately 4 folds. Importantly, this was achieved in the absence of microbubbles, which are crucial for the commonly used high-frequency (1 MHz) sonoporation but may not be able to withstand nebulization in a clinically relevant setup. Lung hemorrhage was also assessed and shown to increase with US pressure in a dose-dependent manner. We have thus, established that low-frequency US can enhance lung gene transfer with naked pDNA and this enhancement is more effective than the previously reported 1 MHz US.

  C Bian , F Zhang , F Wang , Z Ling , M Luo , H Wu , Y Sun , J Li , B Li , J Zhu , L Tang , Y Zhou , Q Shi , Y Ji , L Tian , G Lin , Y Fan , N Wang and B. Sun
 

DNA immunization is an efficient method for high-affinity monoclonal antibody generation. Here, we describe the generation of several high-quality monoclonal antibodies (mAbs) against retinol-binding protein 4 (RBP4), an important marker for kidney abnormality and dysfunction, with a combination method of DNA priming and protein boost. The mAbs generated could bind to RBP4 with high sensitivity and using these mAbs, an immunocolloidal gold fast test strip was constructed. The strip can give a result in <5 min and is very sensitive with a detection limit of about 1 ng/ml. A small-scale clinical test revealed that the result of this strip was well in accordance with that of an enzyme-labeled immunosorbent assay kit currently available on the market. Consequently, it could be useful for more convenient and faster RBP4 determination in the clinic.

  Z Xia , G Jin , J Zhu and R. Zhou
 

Motivation: Mapping the antigenic and genetic evolution pathways of influenza A is of critical importance in the vaccine development and drug design of influenza virus. In this article, we have analyzed more than 4000 A/H3N2 hemagglutinin (HA) sequences from 1968 to 2008 to model the evolutionary path of the influenza virus, which allows us to predict its future potential drifts with specific mutations.

Results: The mutual information (MI) method was used to design a site transition network (STN) for each amino acid site in the A/H3N2 HA sequence. The STN network indicates that most of the dynamic interactions are positioned around the epitopes and the receptor binding domain regions, with strong preferences in both the mutation sites and amino acid types being mutated to. The network also shows that antigenic changes accumulate over time, with occasional large changes due to multiple co-occurring mutations at antigenic sites. Furthermore, the cluster analysis by subdividing the STN into several subnetworks reveals a more detailed view about the features of the antigenic change: the characteristic inner sites and the connecting inter-subnetwork sites are both responsible for the drifts. A novel five-step prediction algorithm based on the STN shows a reasonable accuracy in reproducing historical HA mutations. For example, our method can reproduce the 2003–2004 A/H3N2 mutations with ~70% accuracy. The method also predicts seven possible mutations for the next antigenic drift in the coming 2009–2010 season. The STN approach also agrees well with the phylogenetic tree and antigenic maps based on HA inhibition assays.

  Y Zheng , J Zhu and A. Roy
 

A powerful technique for inference concerning spatial dependence in a random field is to use spectral methods based on frequency domain analysis. Here we develop a nonparametric Bayesian approach to statistical inference for the spectral density of a random field. We construct a multi-dimensional Bernstein polynomial prior for the spectral density and devise a Markov chain Monte Carlo algorithm to simulate from the posterior of the spectral density. The posterior sampling enables us to obtain a smoothed estimate of the spectral density as well as credible bands at desired levels. Simulation shows that our proposed method is more robust than a parametric approach. For illustration, we analyse a soil data example.

  Y Lin , Q Fu , J Zhu , J. M Miller and J. E. Van Eyk
  BACKGROUND:

With myocardial infarction (MI), cardiac troponin is released from the heart into circulation, where it can be detected with immunoassays independently quantifying cardiac troponin I (cTnI) or cTnT. There is, however, no single immunoassay that sequentially probes the posttranslational modification status of cTnI or directly characterizes whether circulating cTnI is bound to cTnC and/or cTnT. Here we describe the development of a qualitative immunoassay to directly probe the primary and ternary structure of circulating cTnI through diffractive optics technology (dotLab® System, Axela).

METHODS:

Anti-cTnI antibody 8I-7 was immobilized on a patterned sensor to capture cTnI. One or more detector antibodies were sequentially introduced to probe for amino acid sequence integrity or phosphorylation status of cTnI, or its association with cTnC and/or cTnT. Respective immunocaptures were recorded as real-time diffractive intensities (DIs), and the DI differences were analyzed. Each immunodetection was independent of the others but was done in a single sequential assay.

RESULTS:

This diffraction-based immunoassay successfully characterized cTnI. The unamplified assay determined whether cTnI was degraded at N-terminus and/or C-terminus or phosphorylated. Sequential application of multiple detector antibodies without an antibody-stripping step enables real-time interrogation of 5 different epitopes of cTnI, or direct detection of the cTn complex (cTnI–cTnC–cTnT) in a single sequential assay. Finally, this assay was optimized with amplification to directly detect circulating cTnI bound to cTnC and cTnT in serum from an MI patient.

CONCLUSIONS:

The dot® Immunoassay is the first qualitative sequential immunoassay to address the direct interactions of the troponin subunits and various modified forms of cTnI.

  X. J He , Y. F Hsu , S Zhu , H. L Liu , O Pontes , J Zhu , X Cui , C. S Wang and J. K. Zhu
 

RNA-directed DNA methylation (RdDM) is a conserved mechanism for epigenetic silencing of transposons and other repetitive elements. We report that the rdm4 (RNA-directed DNA Methylation4) mutation not only impairs RdDM, but also causes pleiotropic developmental defects in Arabidopsis. Both RNA polymerase II (Pol II)- and Pol V-dependent transcripts are affected in the rdm4 mutant. RDM4 encodes a novel protein that is conserved from yeast to humans and interacts with Pol II and Pol V in plants. Our results suggest that RDM4 functions in epigenetic regulation and plant development by serving as a transcriptional regulator for RNA Pol V and Pol II, respectively.

  Z Tu , C Argmann , K. K Wong , L. J Mitnaul , S Edwards , I. C Sach , J Zhu and E. E. Schadt
 

Insulin resistance is one of the dominant symptoms of type 2 diabetes (T2D). Although the molecular mechanisms leading to this resistance are largely unknown, experimental data support that the insulin signaling pathway is impaired in patients who are insulin resistant. To identify novel components/modulators of the insulin signaling pathway, we designed siRNAs targeting over 300 genes and tested the effects of knocking down these genes in an insulin-dependent, anti-lipolysis assay in 3T3-L1 adipocytes. For 126 genes, significant changes in free fatty acid release were observed. However, due to off-target effects (in addition to other limitations), high-throughput RNAi-based screens in cell-based systems generate significant amounts of noise. Therefore, to obtain a more reliable set of genes from the siRNA hits in our screen, we developed and applied a novel network-based approach that elucidates the mechanisms of action for the true positive siRNA hits. Our analysis results in the identification of a core network underlying the insulin signaling pathway that is more significantly enriched for genes previously associated with insulin resistance than the set of genes annotated in the KEGG database as belonging to the insulin signaling pathway. We experimentally validated one of the predictions, S1pr2, as a novel candidate gene for T2D.

  X Yang , B Zhang , C Molony , E Chudin , K Hao , J Zhu , A Gaedigk , C Suver , H Zhong , J. S Leeder , F. P Guengerich , S. C Strom , E Schuetz , T. H Rushmore , R. G Ulrich , J. G Slatter , E. E Schadt , A Kasarskis and P. Y. Lum
 

Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

  R Zhao , J Zhu , X Ji , J Cai , F Wan , Q Li , B Zhong , S Tucker and D. Wang
  Objective

To assess the resectability rate of patients with initially unresectable liver-only metastases from colorectal cancer (CRC) after treatment with irinotecan/capecitabine.

Methods

Patients received irinotecan (240 mg/m2) as a 30 min intravenous infusion on day 1 and capecitabine (1000 mg/m2) orally bid for 14 days beginning on day 2. Treatment was repeated every 3 weeks. The protocol encouraged two to four cycles of irinotecan/capecitabine after recovery from surgery.

Results

Between May 2004 and February 2007, 48 patients entered in the study. Forty-seven (97.9%) of the 48 patients were assessable for response. The overall response rate before surgery was 56.3% (95% CI, 42.3–70.3%) in the treated population, including 2 non-confirmed complete response (CR), 18 partial responses (PR) and 7 non-confirmed PR. Twenty-three (47.9%) of 29 patients with tumor shrinkage proceeded to surgical intervention. Twenty of the 23 patients had a complete resection (S-CR). With a median follow-up time of 32 months (range, 24–38 months), the overall median time to progression and overall survival for all patients were 16.7 months (95% CI, 10.0–23.4 months) and 27.5 months (95% CI, 23.6–31.4 months) for all patients. The 1- 2- and 3-year overall survival estimates were 79.2% (95% CI, 67.7–90.7%), 60.4% (95% CI, 46.6–74.3%) and 29.2% (95% CI, 16.3–42.0%), respectively. Grade 3 diarrhea occurred in eight (17.0%) patients. The most common Grade 3/4 hematological adverse event was neutropenia in 8.5% of the patients. There were no treatment-related deaths during this study.

Conclusions

Irinotecan/capecitabine appears to be a safe and very effective regimen in selected patients with unresectable liver metastases from CRC, but who are treated with a curative intent.

  C Wang , D. C Popescu , C Wu , J Zhu , W Macklin and Y. Wang
 

We describe a novel fluorescent dye, 3-(4-aminophenyl)-2H-chromen-2-one (termed case myelin compound or CMC), that can be used for in situ fluorescent imaging of myelin in the vertebrate nervous system. When administered via intravenous injection into the tail vein, CMC selectively stained large bundles of myelinated fibers in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, CMC readily entered the brain and selectively localized in myelinated regions such as the corpus callosum and cerebellum. CMC also selectively stained myelinated nerves in the PNS. The staining patterns of CMC in a hypermyelinated mouse model were consistent with immunohistochemical staining. Similar to immunohistochemical staining, CMC selectively bound to myelin sheaths present in the white matter tracts. Unlike CMC, conventional antibody staining for myelin basic protein also stained oligodendrocyte cytoplasm in the striatum as well as granule layers in the cerebellum. In vivo application of CMC was also demonstrated by fluorescence imaging of myelinated nerves in the PNS. (J Histochem Cytochem 58:611–621, 2010)

  J Zhu , B Lee , K. K Buhman and J. X. Cheng
 

The absorptive cells of the small intestine, enterocytes, are not generally thought of as a cell type that stores triacylglycerols (TGs) in cytoplasmic lipid droplets (LDs). We revisit TG metabolism in enterocytes by ex vivo and in vivo coherent anti-Stokes Raman scattering (CARS) imaging of small intestine of mice during dietary fat absorption (DFA). We directly visualized the presence of LDs in enterocytes. We determined lipid amount and quantified LD number and size as a function of intestinal location and time post-lipid challenge via gavage feeding. The LDs were confirmed to be primarily TG by biochemical analysis. Combined CARS and fluorescence imaging indicated that the large LDs were located in the cytoplasm, associated with the tail-interacting protein of 47 kDa. Furthermore, in vivo CARS imaging showed real-time variation in the amount of TG stored in LDs through the process of DFA. Our results highlight a dynamic, cytoplasmic TG pool in enterocytes that may play previously unexpected roles in processes, such as regulating postprandial blood TG concentrations.

  J Zhu , J Gardner , C. R Pullinger , J. P Kane , J. F Thompson and O. L. Francone
 

Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations controlling the levels of risk factors associated with the development of the disease continues. Multiple genetic association studies suggest the involvement of procollagen C-proteinase enhancer-2 (PCPE2) in modulating HDL-C levels. Therefore biochemical and mechanistic studies were undertaken to determine whether there might be a basis for a role of PCPE2 in HDL biogenesis. Our studies indicate that PCPE2 accelerates the proteolytic processing of pro-apolipoprotein (apo) AI by enhancing the cleavage of the hexapeptide extension present at the N terminus of apoAI. Surface Plasmon Resonance and immunoprecipitation studies indicate that PCPE2 interacts with BMP-1 and pro-apoAI to form a ternary pro-apoAI/BMP-1/PCPE2 complex. The most favorable interaction among these proteins begins with the association of BMP-1 to pro-apoAI followed by the binding of PCPE2 which further stabilizes the complex. PCPE2 resides, along with apoAI, on the HDL fraction of lipoproteins in human plasma supporting a relationship between HDL and PCPE2. Taken together, the findings from our studies identify a new player in the regulation of apoAI post-translational processing and open a new avenue to the study of mechanisms involved in the regulation of apoAI synthesis, HDL levels, and potentially, cardiovascular disease.

  C Zhang , S Zheng , Y Wang , Y Zhao , J Zhu and L. Ge
 

Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor-encoding gene, RUNX2. To correlate different RUNX2 mutations with CCD clinical spectrum, we studied six independent Chinese CCD patients. In five patients, mutations were detected in the coding region of the RUNX2 gene, including two frameshift mutations and three missense mutations. Of these mutations, four were novel and one had previously been reported. All the detected mutations were exclusively clustered within the Runt domain that affected conserved residues in the Runt domain. In vitro green fluorescent protein fusion studies showed that the three mutations—R225L, 214fs and 172fs—interfered with nuclear accumulation of RUNX2 protein, while T200I mutation had no effect on the subcellular distribution of RUNX2. There was no marked phenotypic difference between patients in craniofacial and clavicles features, while the expressivity of supernumerary teeth in our patient cohort had a striking variation, even among family members. The occurrence of intrafamilial clinical variability raises the view that hypomorphic effects and genetic modifiers may alter the clinical expressivity of these mutations. Our results provide new genetic evidence that mutations involved in RUNX2 contribute to CCD.

  J Zhu , X Wu , S Goel , N. M Gowda , S Kumar , G Krishnegowda , G Mishra , R Weinberg , G Li , M Gaestel , T Muta and D. C. Gowda
 

Proinflammatory responses induced by Plasmodium falciparum glycosylphosphatidylinositols (GPIs) are thought to be involved in malaria pathogenesis. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2) in the regulation of tumor necrosis factor- (TNF-) and interleukin (IL)-12, two of the major inflammatory cytokines produced by macrophages stimulated with GPIs. We show that MK2 differentially regulates the GPI-induced production of TNF- and IL-12. Although TNF- production was markedly decreased, IL-12 expression was increased by 2–3-fold in GPI-stimulated MK2–/– macrophages compared with wild type (WT) cells. MK2–/– macrophages produced markedly decreased levels of TNF- than WT macrophages mainly because of lower mRNA stability and translation. In the case of IL-12, mRNA was substantially higher in MK2–/– macrophages than WT. This enhanced production is due to increased NF-B binding to the gene promoter, a markedly lower level expression of the transcriptional repressor factor c-Maf, and a decreased binding of GAP-12 to the gene promoter in MK2–/– macrophages. Thus, our data demonstrate for the first time the role of MK2 in the transcriptional regulation of IL-12. Using the protein kinase inhibitors SB203580 and U0126, we also show that the ERK and p38 pathways regulate TNF- and IL-12 production, and that both inhibitors can reduce phosphorylation of MK2 in response to GPIs and other toll-like receptor ligands. These results may have important implications for developing therapeutics for malaria and other infectious diseases.

  H Bayir , A. A Kapralov , J Jiang , Z Huang , Y. Y Tyurina , V. A Tyurin , Q Zhao , N. A Belikova , I. I Vlasova , A Maeda , J Zhu , H. M Na , P. G Mastroberardino , L. J Sparvero , A. A Amoscato , C. T Chu , J. T Greenamyre and V. E. Kagan
 

Damage of presynaptic mitochondria could result in release of proapoptotic factors that threaten the integrity of the entire neuron. We discovered that -synuclein (Syn) forms a triple complex with anionic lipids (such as cardiolipin) and cytochrome c, which exerts a peroxidase activity. The latter catalyzes covalent hetero-oligomerization of Syn with cytochrome c into high molecular weight aggregates. Syn is a preferred substrate of this reaction and is oxidized more readily than cardiolipin, dopamine, and other phenolic substrates. Co-localization of Syn with cytochrome c was detected in aggregates formed upon proapoptotic stimulation of SH-SY5Y and HeLa cells and in dopaminergic substantia nigra neurons of rotenone-treated rats. Syn-cardiolipin exerted protection against cytochrome c-induced caspase-3 activation in a cell-free system, particularly in the presence of H2O2. Direct delivery of Syn into mouse embryonic cells conferred resistance to proapoptotic caspase-3 activation. Conversely, small interfering RNA depletion of Syn in HeLa cells made them more sensitive to dopamine-induced apoptosis. In human Parkinson disease substantia nigra neurons, two-thirds of co-localized Syn-cytochrome c complexes occurred in Lewy neurites. Taken together, these results indicate that Syn may prevent execution of apoptosis in neurons through covalent hetero-oligomerization of cytochrome c. This immediate protective function of Syn is associated with the formation of the peroxidase complex representing a source of oxidative stress and postponed damage.

 
 
 
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