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Articles by Y Chen
Total Records ( 27 ) for Y Chen
  X Mu , Y Chen , S Wang , X Huang , H Pan and M. Li

Vascular endothelial growth factor-correlated chemokine 1 (VCC-1), a novel chemokine, is hypothesized to be associated with carcinogenesis. VCC-1 is expressed in hepatocellular carcinoma (HCC) cells, but its function remains unknown. To investigate the molecular effects of VCC-1 on HCC cells, the HCC cell line SMMC7721 was stably transfected with the recombinant plasmid pcDNA3.1/VCC-1. Our data demonstrated that overexpression of VCC-1 in SMMC7721 cells significantly enhanced the cellular proliferation, invasive ability, and tumor growth, when compared with both empty vector control cells and parental cells. These results strongly suggest that VCC-1 plays an important role in SMMC7721 invasion and tumor growth, and indicate that VCC-1 may serve as a potential biomarker for anti-HCC therapies.

  M Li , Y Chen , Z Liu , F Shen , X Bian and Y. Meng

Ribosome-inactivating proteins (RIPs) are a family of enzymes that depurinate rRNA and inhibit protein biosynthesis. Here we report the purification, apoptosis-inducing activity, and polyethylene glycol (PEG) modification of RIP from the bitter melon seeds. The protein has a homogenous N-terminal sequence of N-Asp-Val-Ser-Phe-Arg. Moreover, the RIP displayed strong apoptosis-inducing activity and suppressed cancer cell growth. This might be attributed to the activation of caspases-3. To make it available for in vivo application, the immunogenicity of RIP was reduced by chemical modification with 20 kDa (mPEG)2-Lys-NHS. The inhibition activity of both PEGylated and non-PEGylated RIP against cancer cells was much stronger than against normal cells, and the antigenicity of PEGylated RIP was reduced significantly. Our results suggested that the PEGylated RIP might be potentially developed as anti-cancer drug.

  L Chen , S Xu , X Zeng , J Li , W Yin , Y Chen , Z Shao and W. Jin

Chemokine C-X-C motif ligand 12 (CXCL12) is a potent chemotactic and angiogenic factor that has been proposed to play a role in organ-specific metastasis and angiogenic activity in several malignancies. In this study, we found that the overexpression of c-myb could elevate CXCL12 mRNA level and CXCL12 promoter activity in human T47D and MCF-7 breast cancer cells. Chromatin immunoprecipitation assay demonstrated that c-myb could bind to the CXCL12 promoter in the cells transfected with c-myb expression vector. c-myb siRNA attenuated CXCL12 promoter activity and the binding of c-myb to the CXCL12 promoter in T47D and MCF-7 cells. These results indicated that c-myb could activate CXCL12 promoter transcription.

  Y Zhao , J Liu , Q Hong , C Yang , L Chen , Y Chen , Q Wang , K Zhao and W. Jin

Overexpression of multidrug resistance 1 (MDR1) in cancer remains one of the major causes for the failure of chemotherapy. In the present study, we found that MyoD and PEA3 could activate P-glycoprotein (P-gp) expression in SGC7901 cells. Knockdown of MyoD and PEA3 attenuated MDR1 expression and increased the sensitivity of multidrug resistant cancer cells to cytotoxic drugs that were transported by P-gp in SGC7901/VCR cells. MyoD or PEA3 could bind to the E-box and PEA3 sites on the MDR1 promoter and activate its transcription. The regulation of MDR1 expression by MyoD and PEA3 may provide potential ways to overcome MDR in cancer treatment.

  L. L Zhu , Y Liu , A. F Cui , D Shao , J. C Liang , X. J Liu , Y Chen , N Gupta , F. D Fang and Y. S. Chang

Peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) is a key regulator of cellular energy metabolism and regulates processes such as adaptive thermogenesis, hepatic gluconeogenesis, fatty acid oxidation, and mitochondrial biogenesis by coactivating numerous nuclear receptors and transcription factors. Here, we demonstrate the presence of the ERR binding site in the regulatory sequence of the glucokinase gene and that PGC-1 coactivates ERR to stimulate the transcription of glucokinase. Simultaneous overexpression of PGC-1 and ERR potently induced the glucokinase gene expression and its enzymatic activity in primary hepatocytes; however, expression of either PGC-1 or ERR alone had no significant effect. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed the interaction of ERR with the glucokinase promoter. Finally, the knockdown of endogenous ERR with specific siRNA (siERR) or pharmacological inhibition of ERR with XCT790 attenuated insulin-induced glucokinase expression. Taken together, this research identifies glucokinase as a novel target of PGC-1/ERR and underscores the regulatory function of ERR in insulin-dependent enzyme regulation.

  Y Chen , B. A Briesacher , T. S Field , J Tjia , D. T Lau and J. H. Gurwitz

Background  Serious safety concerns related to the use of antipsychotics have not decreased the prescribing of these agents to nursing home (NH) residents. We assessed the extent to which resident clinical characteristics and institutional prescribing practice were associated with antipsychotic prescribing.

Methods  Antipsychotic prescribing was assessed for a nationwide, cross-sectional population of 16 586 newly admitted NH residents in 2006. We computed facility-level antipsychotic rates based on the previous year's (2005) prescribing patterns. Poisson regressions with generalized estimating equations were used to identify the likelihood of resident-level antipsychotic medication use in 2006, given 2005 facility-level prescribing pattern and NH resident indication for antipsychotic therapy (psychosis, dementia, and behavioral disturbance).

Results  More than 29% (n = 4818) of study residents received at least 1 antipsychotic medication in 2006. Of the antipsychotic medication users, 32% (n = 1545) had no identified clinical indication for this therapy. Residents entering NHs with the highest facility-level antipsychotic rates were 1.37 times more likely to receive antipsychotics relative to those entering the lowest prescribing rate NHs, after adjusting for potential clinical indications (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.24-1.51). The elevated risk associated with facility-level prescribing rates was apparent for only NH residents with dementia but no psychosis (RR, 1.40; 95% CI, 1.23-1.59) and residents without dementia or psychosis (RR, 1.54; 95% CI, 1.24-1.91).

Conclusions  The NH antipsychotic prescribing rate was independently associated with the use of antipsychotics in NH residents. Future research is needed to determine why such a prescribing culture exists and whether it could result in adverse health consequences.

  Y Chen and K. Y. Liang

This paper considers the asymptotic distribution of the likelihood ratio statistic T for testing a subset of parameter of interest , , , based on the pseudolikelihood , where is a consistent estimator of , the nuisance parameter. We show that the asymptotic distribution of T under H0 is a weighted sum of independent chi-squared variables. Some sufficient conditions are provided for the limiting distribution to be a chi-squared variable. When the true value of the parameter of interest, , or the true value of the nuisance parameter, , lies on the boundary of parameter space, the problem is shown to be asymptotically equivalent to the problem of testing the restricted mean of a multivariate normal distribution based on one observation from a multivariate normal distribution with misspecified covariance matrix, or from a mixture of multivariate normal distributions. A variety of examples are provided for which the limiting distributions of T may be mixtures of chi-squared variables. We conducted simulation studies to examine the performance of the likelihood ratio test statistics in variance component models and teratological experiments.

  Q ZhuGe , M Zhong , W Zheng , G. Y Yang , X Mao , L Xie , G Chen , Y Chen , M. T Lawton , W. L Young , D. A Greenberg and K. Jin

A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that, compared with control brain vascular tissue, Notch-1 signalling was activated in smooth muscle and endothelial cells of the lesional tissue. Western blotting showed an activated form of Notch-1 in brain arteriovenous malformations, irrespective of clinical presentation and with or without preoperative embolization, but not in normal cerebral vessels from controls. In addition, the Notch-1 ligands Jagged-1 and Delta-like-4 and the downstream Notch-1 target Hes-1 were increased in abundance and activated in human brain arteriovenous malformations. Finally, increased angiogenesis was found in adult rats treated with a Notch-1 activator. Our findings suggest that activation of Notch-1 signalling is a phenotypic feature of brain arteriovenous malformations, and that activation of Notch-1 in normal vasculature induces a pro-angiogenic state, which may contribute to the development of vascular malformations.

  N Bhatnagar , X Li , Y Chen , X Zhou , S. H Garrett and B. Guo

Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently showed that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor–induced apoptosis in colon cancers. Here, we show that APC mutation rendered colon cancer cells resistant to butyrate-induced apoptosis due to the failure of butyrate to down-regulate survivin in these cells. Another cancer-preventive agent, 3,3'-diindolylmethane (DIM), was identified to be able to down-regulate survivin in colon cancers expressing mutant APC. DIM inhibited survivin mRNA expression and promoted survivin protein degradation through inhibition of p34cdc2-cyclin B1–mediated survivin Thr34 phosphorylation. Pretreatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/butyrate combination treatment induced the expression of proapoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. Whereas overexpression of survivin blocked DIM/butyrate–induced apoptosis, knocking down of survivin by small interfering RNA increased butyrate-induced apoptosis in colon cancer cells. We further showed that DIM was able to down-regulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APCmin/+ mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer.

  W. T Wong , X. Y Tian , Y Chen , F. P Leung , L Liu , H. K Lee , C. F Ng , A Xu , X Yao , P. M Vanhoutte , G. L Tipoe and Y. Huang

Bone morphogenic protein (BMP)4 can stimulate superoxide production and exert proinflammatory effects on the endothelium. The underlying mechanisms of how BMP4 mediates endothelial dysfunction and hypertension remain elusive.


To elucidate the cellular pathways by which BMP4-induced endothelial dysfunction is mediated through oxidative stress–dependent upregulation of cyclooxygenase (COX)-2.

Methods and Results:

Impaired endothelium-dependent relaxations, exaggerated endothelium-dependent contractions, and reactive oxygen species (ROS) production were observed in BMP4-treated mouse aortae, which were prevented by the BMP4 antagonist noggin. Pharmacological inhibition with thromboxane prostanoid receptor antagonist or COX-2 but not COX-1 inhibitor prevented BMP4-induced endothelial dysfunction, which was further confirmed with the use of COX-1–/– or COX-2–/– mice. Noggin and knockdown of BMP receptor 1A abolished endothelium-dependent contractions and COX-2 upregulation in BMP4-treated aortae. Apocynin and tempol treatment were effective in restoring endothelium-dependent relaxations, preventing endothelium-dependent contractions and eliminating ROS overproduction and COX-2 overexpression in BMP4-treated aortae. BMP4 increased p38 mitogen-activated protein kinase (MAPK) activity through a ROS-sensitive mechanism and p38 MAPK inhibitor prevented BMP4-induced endothelial dysfunction. COX-2 inhibition blocked the effect of BMP4 without affecting BMP4-induced ROS overproduction and COX-2 upregulation. Importantly, renal arteries from hypertensive rats and humans showed higher levels of COX-2 and BMP4 accompanied by endothelial dysfunction.


We show for the first time that ROS serve as a pathological link between BMP4 stimulation and the downstream COX-2 upregulation in endothelial cells, leading to endothelial dysfunction through ROS-dependent p38 MAPK activation. This BMP4/ROS/COX-2 cascade is important in the maintenance of endothelial dysfunction in hypertension.

  S Weinsheimer , H Kim , L Pawlikowska , Y Chen , M. T Lawton , S Sidney , P. Y Kwok , C. E McCulloch and W. L. Young

Background— Brain arteriovenous malformations (BAVMs) are a tangle of abnormal vessels directly shunting blood from the arterial to venous circulation and an important cause of intracranial hemorrhage (ICH). EphB4 is involved in arterial-venous determination during embryogenesis; altered signaling could lead to vascular instability resulting in ICH. We investigated the association of single-nucleotide polymorphisms (SNPs) and haplotypes in EPHB4 with risk of ICH at clinical presentation in patients with BAVM.

Methods and Results— Eight haplotype-tagging SNPs spanning 29 kb were tested for association with ICH presentation in 146 white patients with BAVM (phase I: 56 ICH, 90 non-ICH) using allelic, haplotypic, and principal components analysis. Associated SNPs were then genotyped in 102 additional cases (phase II: 37 ICH, 65 non-ICH), and data were combined for multivariable logistic regression. Minor alleles of 2 SNPs were associated with reduced risk of ICH presentation (rs314313_C, P=0.005; rs314308_T, P=0.0004). Overall, haplotypes were also significantly associated with ICH presentation (2=17.24, 6 df, P=0.008); 2 haplotypes containing the rs314308 T allele (GCCTGGGT, P=0.003; GTCTGGGC, P=0.036) were associated with reduced risk. In principal components analysis, 2 components explained 91% of the variance and complemented haplotype results by implicating 4 SNPs at the 5' end, including rs314308 and rs314313. These 2 SNPs were replicated in the phase II cohort, and combined data resulted in greater significance (rs314313, P=0.0007; rs314308, P=0.00008). SNP association with ICH presentation persisted after adjusting for age, sex, BAVM size, and deep venous drainage.

Conclusions— EPHB4 polymorphisms are associated with risk of ICH presentation in patients with BAVM, warranting further study.

  J. R Gayen , K Zhang , S. P RamachandraRao , M Mahata , Y Chen , H. S Kim , R. K Naviaux , K Sharma , S. K Mahata and D. T. O'Connor

Oxidative stress, an excessive production of reactive oxygen species (ROS) outstripping antioxidant defense mechanisms, occurs in cardiovascular pathologies, including hypertension. In the present study, we used biochemical, physiological, and pharmacological approaches to explore the role of derangements of catecholamines, ROS, and the endothelium-derived relaxing factor nitric oxide (NO) in the development of a hyperadrenergic model of hereditary hypertension: targeted ablation (knockout [KO]) of chromogranin A (Chga) in the mouse.

Methods and Results—

Homozygous (–/–) Chga gene knockout (KO) mice were compared with wild-type (WT, +/+) control mice. In the KO mouse, elevations of systolic and diastolic blood pressure were accompanied by not only elevated catecholamine (norepinephrine and epinephrine) concentrations but also increased ROS (H2O2) and isoprostane (an index of lipid peroxidation), as well as depletion of NO. Renal transcript analyses implicated changes in Nox1/2, Xo/Xdh, and Sod1,2 mRNAs in ROS elevation by the KO state. KO alterations in blood pressure, catecholamines, H2O2, isoprostane, and NO could be abrogated or even normalized (rescued) by either sympathetic outflow inhibition (with clonidine) or NADPH oxidase inhibition (with apocynin). In cultured renal podocytes, H2O2 production was substantially augmented by epinephrine (probably through β2-adrenergic receptors) and modestly diminished by norepinephrine (probably through 1-adrenergic receptors).


ROS appear to play a necessary role in the development of hyperadrenergic hypertension in this model, in a process mechanistically linking elevated blood pressure with catecholamine excess, renal transcriptional responses, ROS elevation, lipid peroxidation, and NO depletion. Some of the changes appear to be dependent on transcription, whereas others are immediate. The cycle could be disrupted by inhibition of either sympathetic outflow or NADPH oxidase. Because common genetic variation at the human CHGA locus alters BP, the results have implications for antihypertensive treatment as well as prevention of target-organ consequences of the disease. The results document novel pathophysiological links between the adrenergic system and oxidative stress and suggest new strategies to probe the role and actions of ROS within this setting.

  J. A Ronald , Y Chen , A. J. L Belisle , A. M Hamilton , K. A Rogers , R. A Hegele , B Misselwitz and B. K. Rutt

Background— Inflammation and neovascularization play critical roles in the stability of atherosclerotic plaques. Whole-body quantitative assessment of these plaque features may improve patient risk-stratification for life-threatening thromboembolic events and direct appropriate intervention. In this report, we determined the utility of the MR contrast agent gadofluorine-M (GdF) for staging plaque stability and compared this to the conventional agent Gd-DTPA.

Methods and Results— Five control and 7 atherosclerotic rabbits were sequentially imaged after administration of Gd-DTPA (0.2 mmol/kg) and GdF (0.1 mmol/kg) using a T1-weighted pulse sequence on a 3-T MRI scanner. Diseased aortic wall could be distinguished from normal wall based on wall-to-muscle contrast-to-noise values after GdF administration. RAM-11 (macrophages) and CD-31 (endothelial cells) immunostaining of MR-matched histological sections revealed that GdF accumulation was related to the degree of inflammation at the surface of plaques and the extent of core neovascularization. Importantly, an MR measure of GdF accumulation at both 1 and 24 hours after injection but not Gd-DTPA at peak enhancement was shown to correlate with a quantitative histological morphology index related to these 2 plaque features.

Conclusions— GdF-enhanced MRI of atherosclerotic plaques allows noninvasive quantitative information about plaque composition to be acquired at multiple time points after injection (within 1 and up to 24 hours after injection). This dramatically widens the imaging window for assessing plaque stability that is currently attainable with clinically approved MR agents, therefore opening the possibility of whole-body (including coronary) detection of unstable plaques in the future and potentially improved mitigation of cataclysmic cardiovascular events.

  G. W Woodfield , M. J Hitchler , Y Chen , F. E Domann and R. J. Weigel

Purpose: Transcriptional regulation of estrogen receptor- (ER) involves both epigenetic mechanisms and trans-active factors, such as TFAP2C, which induces ER transcription through an AP-2 regulatory region in the ER promoter. Attempts to induce endogenous ER expression in ER-negative breast carcinomas by forced overexpression of TFAP2C have not been successful. We hypothesize that epigenetic chromatin structure alters the activity of TFAP2C at the ER promoter.

Experimental Design: DNA methylation, histone acetylation, and chromatin accessibility were examined at the ER promoter in a panel of breast carcinoma cell lines. TFAP2C and polymerase II binding were analyzed by chromatin immunoprecipitation. Epigenetic chromatin structure was altered using drug treatment with 5-aza-2'-deoxycytidine (AZA) and trichostatin A (TSA).

Results: The ER promoter in the ER-negative lines MDA-MB-231, MCF10A, and MCF7-5C show CpG island methylation, histone 3 lysine 9 deacetylation, and decreased chromatin accessibility compared with ER-positive cell lines MCF7 and T47-D. Treatment with AZA/TSA increased chromatin accessibility at the ER promoter and allowed TFAP2C to induce ER expression in ER-negative cells. Chromatin immunoprecipitation analysis showed that binding of TFAP2C to the ER promoter is blocked in ER-negative cells but that treatment with AZA/TSA enabled TFAP2C and polymerase II binding.

Conclusion: We conclude that the activity of TFAP2C at specific target genes depends upon epigenetic chromatin structure. Furthermore, the combination of increasing chromatin accessibility and inducing TFAP2C provides a more robust activation of the ER gene in ER-negative breast cancer cells.

  L Cheng , Y Chen , C Chen , J Ma , L Shu , A. V Vasilakos and N. Xiong

Considering sensor nodes deployed densely and uniformly a mobile sink moving through the sensing field queries a specific area of interest for monitoring information. The Query packet, injected by the mobile sink, is routed to the specific area and the corresponding Response packet is expected to return via multi-hop communication. In this paper, we analyze such a network model to address the problem of efficient data collection for mobile wireless monitoring applications. We first propose a meeting position-aware routing (MPAR) protocol for routing the Response packet efficiently and then propose an efficient query-based data collection scheme (QBDCS) for mobile wireless monitoring applications based on the MPAR. In order to minimize the energy consumption and packet delivery latency, the QBDCS chooses the optimal query time of injecting the Query packet and tailors the routing mechanism for sensor nodes forwarding packets. Simulation study has verified the analysis and demonstrated that the QBDCS can significantly reduce the energy consumption and end to end delivery latency.

  B Wen , Y Chen and W. L. Fitch

Nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, has been associated with incidences of skin rash and hepatotoxicity in patients. Although the mechanism of idiosyncratic hepatotoxicity remains unknown, it is proposed that metabolic activation of nevirapine and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether nevirapine undergoes cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. Liquid chromatography-tandem mass spectrometry analysis of incubations containing nevirapine and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed the formation of a GSH conjugate derived from the addition of the sulfydryl nucleophile to nevirapine. No other GSH conjugates were detected, including conjugates of oxidized metabolites of nevirapine. These findings are consistent with a bioactivation sequence involving initial P450-catalyzed dehydrogenation of the aromatic nucleus with a 4-methyl group in nevirapine to an electrophilic quinone methide intermediate, which is subsequently attacked by glutathione yielding the sulfydryl conjugate. Formation of the nevirapine GSH conjugate was primarily catalyzed by heterologously expressed recombinant CYP3A4 and, to a lesser extent, CYP2D6, CYP2C19, and CYP2A6. In addition, the quinone methide reactive metabolite was a mechanism-based inactivator of CYP3A4, with inactivation parameters KI = 31 µM and kinact = 0.029 min–1, respectively. It is proposed that formation of the quinone methide intermediate may represent a rate-limiting step in the initiation of nevirapine-mediated hepatotoxicity.

  B Wen , Y Chen and W. L. Fitch

Nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, has been associated with incidences of skin rash and hepatotoxicity in patients. Although the mechanism of idiosyncratic hepatotoxicity remains unknown, it is proposed that metabolic activation of nevirapine and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether nevirapine undergoes cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. Liquid chromatography-tandem mass spectrometry analysis of incubations containing nevirapine and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed the formation of a GSH conjugate derived from the addition of the sulfydryl nucleophile to nevirapine. No other GSH conjugates were detected, including conjugates of oxidized metabolites of nevirapine. These findings are consistent with a bioactivation sequence involving initial P450-catalyzed dehydrogenation of the aromatic nucleus with a 4-methyl group in nevirapine to an electrophilic quinone methide intermediate, which is subsequently attacked by glutathione yielding the sulfydryl conjugate. Formation of the nevirapine GSH conjugate was primarily catalyzed by heterologously expressed recombinant CYP3A4 and, to a lesser extent, CYP2D6, CYP2C19, and CYP2A6. In addition, the quinone methide reactive metabolite was a mechanism-based inactivator of CYP3A4, with inactivation parameters KI = 31 µM and kinact = 0.029 min–1, respectively. It is proposed that formation of the quinone methide intermediate may represent a rate-limiting step in the initiation of nevirapine-mediated hepatotoxicity.

  Y Chen , Y Yamaguchi , Y Tsugeno , J Yamamoto , T Yamada , M Nakamura , K Hisatake and H. Handa

Transcription elongation factor DSIF/Spt4–Spt5 is capable of promoting and inhibiting RNA polymerase II elongation and is involved in the expression of various genes. While it has been known for many years that DSIF inhibits elongation in collaboration with the negative elongation factor NELF, how DSIF promotes elongation is largely unknown. Here, an activity-based biochemical approach was taken to understand the mechanism of elongation activation by DSIF. We show that the Paf1 complex (Paf1C) and Tat-SF1, two factors implicated previously in elongation control, collaborate with DSIF to facilitate efficient elongation. In human cells, these factors are recruited to the FOS gene in a temporally coordinated manner and contribute to its high-level expression. We also show that elongation activation by these factors depends on P-TEFb-mediated phosphorylation of the Spt5 C-terminal region. A clear conclusion emerging from this study is that a set of elongation factors plays nonredundant, cooperative roles in elongation. This study also shows unambiguously that Paf1C, which is generally thought to have chromatin-related functions, is involve directlyd in elongation control.

  B Hu , K Lefort , W Qiu , B. C Nguyen , R. D Rajaram , E Castillo , F He , Y Chen , P Angel , C Brisken and G. P. Dotto

Epithelial–mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that maintenance of the hair follicle keratinocyte cell fate is defective in mice with mesenchymal deletion of the CSL/RBP-J gene, the effector of "canonical" Notch signaling. Hair follicle reconstitution assays demonstrate that this can be attributed to an intrinsic defect of dermal papilla cells. Similar consequences on hair follicle differentiation result from deletion of Wnt5a, a specific dermal papilla signature gene that we found to be under direct Notch/CSL control in these cells. Functional rescue experiments establish Wnt5a as an essential downstream mediator of Notch–CSL signaling, impinging on expression in the keratinocyte compartment of FoxN1, a gene with a key hair follicle regulatory function. Thus, Notch/CSL signaling plays a unique function in control of hair follicle differentiation by the underlying mesenchyme, with Wnt5a signaling and FoxN1 as mediators.

  S Li , T Hu , Y Chen , X Wang , T Liu , G Ma and Z. Su

Carboxylmethylated konjac glucomannan (CKGM) is a carboxylmethylated polymer of mannose and glucose that is derived from the plant Amorphophallus konjac cultivated in East Asia. The CKGM solution had a high volume-expanding efficacy and was evaluated as a plasma substitute in the present study. Ameliorative hemorrhagic shock rabbits were used as the model animals. The in vivo hemodynamic and hemorheologic properties, including blood pressure, blood viscosity, hematocrit, erythrocyte deformation index and erythrocyte aggregation index, were measured in animals treated in the CKGM solution. The in vitro colloid osmotic pressure (COP) of the CKGM solution was measured to estimate its plasma-expanding efficacy. These parameters of the CKGM-treated group were compared with groups exposed to four other treatments: human serum albumin (HSA), hydroxyethyl starch (HES), polygeline and normal saline. The CKGM solution showed an exceptionally higher COP than other therapy solutions. For example, the COP of 1% (weight in volume [w/v]) CKGM solution is comparable to those of 6% (w/v) HES solution and 5% (w/v) HSA solution. Accordingly, the CKGM solution can be transfused in a much lower dosage while maintaining its plasma-expanding efficacy. The CKGM-treated group showed an improved intravascular persistence and good hemodynamic and hemorheological properties. Biopsy analysis suggested no organ dysfunction in the group treated in CKGM solution. Moreover, the high plasma-expanding efficacy and inexpensive availability of the CKGM solution may facilitate its clinical application as a potential plasma substitute.

  Z Xiao , G Li , Y Chen , M Li , F Peng , C Li , F Li , Y Yu , Y Ouyang and Z. Chen

Formalin-fixed, paraffin-embedded (FFPE) tissue specimens represent a potentially valuable resource for protein biomarker investigations. In this study, proteins were extracted by a heat-induced antigen retrieval technique combined with a retrieval solution containing 2% SDS from FFPE tissues of normal nasopharyngeal epithelial tissues (NNET) and three histological types of nasopharyngeal carcinoma (NPC) with diverse differentiation degrees. Then two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling was employed to quantitatively identify the differentially expressed proteins among the types of NPC FFPE tissues. Our study resulted in the identification of 730 unique proteins, the distributions of subcellular localizations and molecular functions of which were similar to those of the proteomic database of human NPC and NNET that we had set up based on the frozen tissues. Additionally, the relative expression levels of cathepsin D, keratin8, SFN, and stathmin1 identified and quantified in this report were consistent with the immunohistochemistry results acquired in our previous study. In conclusion, we have developed an effective approach to identifying protein changes in FFPE NPC tissues utilizing iTRAQ technology in conjunction with an economical and easily accessible sample preparation method. (J Histochem Cytochem 58:517–527, 2010)

  Y Chen and M. A. Young

Thyroid hormone receptor (TR), as a member of the nuclear hormone receptor family, can recognize and bind different classes of DNA response element targets as either a monomer, a homooligomer, or a heterooligomer. We report here the first crystal structure of a homodimer TR DNA-binding domain (DBD) in complex with an inverted repeat class of thyroid response element (TRE). The structure shows a nearly symmetric structure of the TR DBD assembled on the F2 TRE where the base recognition contacts in the homodimer DNA complex are conserved relative to the previously published structure of a TR-9-cis-retinoic acid receptor heterodimer DNA complex. The new structure also reveals that the T-box region of the DBD can function as a structural hinge that enables a large degree of flexibility in the position of the C-terminal extension helix that connects the DBD to the ligand-binding domain. Although the isolated TR DBDs exist as monomers in solution, we have measured highly cooperative binding of the two TR DBD subunits onto the inverted repeat DNA sequence. This suggests that elements of the DBD can influence the specific TR oligomerization at target genes, and it is not just interactions between the ligand-binding domains that are responsible for TR oligomerization at target genes. Mutational analysis shows that intersubunit contacts at the DBD C terminus account for some, but not all, of the cooperative homodimer TR binding to the inverted repeat class TRE.

  Y Chen , T Asano , M. T Fujiwara , S Yoshida , Y Machida and Y. Yoshioka

Plastids are maintained in cells by proliferating prior to cell division and being partitioned to each daughter cell during cell division. It is unclear, however, whether cells without plastids are generated when plastid division is suppressed. The crumpled leaf (crl) mutant of Arabidopsis thaliana is a plastid division mutant that displays severe abnormalities in plastid division and plant development. We show that the crl mutant contains cells lacking detectable plastids; this situation probably results from an unequal partitioning of plastids to each daughter cell. Our results suggest that crl has a partial defect in plastid expansion, which is suggested to be important in the partitioning of plastids to daughter cells when plastid division is suppressed. The absence of cells without detectable plastids in the accumulation and replication of chloroplasts 6 (arc6) mutant, another plastid division mutant of A. thaliana having no significant defects in plant morphology, suggests that the generation of cells without detectable plastids is one of the causes of the developmental abnormalities seen in crl plants. We also demonstrate that plastids with trace or undetectable amounts of chlorophyll are generated from enlarged plastids by a non-binary fission mode of plastid replication in both crl and arc6.

  Y Chen and S. Ahmad

When high-energy protons interact in beam delivery systems and are stopped in patients, a fraction of beam will undergo nuclear interactions that release secondary particles, in particular, neutrons of different energies. The GEANT4 Monte Carlo Code was used to simulate the interaction of 250 MeV proton beam in tissue and iron to calculate the energy and angular distributions of generated protons, neutrons and photons, and thus provide H* (10), the ambient dose equivalent. A modular physics list by utilising electromagnetic interactions and hadronic interactions was constructed. Three different GEANT4 models that include the low-energy parameterisation, binary cascade and pre-compound model with Bertini cascade for proton inelastic interactions were compared. The findings suggest that the models play critical roles in terms of secondary particle generation. Further benchmarks are necessary to select the best model predicting a realistic scenario.

  Y Sumi , T Woehrle , Y Chen , Y Yao , A Li and W. G. Junger

Formyl peptide receptor-induced chemotaxis of neutrophils depends on the release of ATP and autocrine feedback through purinergic receptors. Here, we show that adrenergic receptor signaling requires similar purinergic feedback mechanisms. Real-time RT-PCR analysis revealed that human embryonic kidney (HEK)-293 cells express several subtypes of adrenergic (1-, 2-, and β-receptors), adenosine (P1), and nucleotide receptors (P2). Stimulation of Gq-coupled 1-receptors caused release of cellular ATP and MAPK activation, which was blocked by inhibiting P2 receptors with suramin. Stimulation of Gi-coupled 2-receptors induced weak ATP release, while Gs-coupled β-receptors caused accumulation of extracellular ADP and adenosine. β-Receptors triggered intracellular cAMP signaling, which was blocked by scavenging extracellular adenosine with adenosine deaminase or by inhibiting A2a adenosine receptors with SCH58261. These findings suggest that adrenergic receptors require purinergic receptors to elicit downstream signaling responses in HEK-293 cells. We evaluated the physiological relevance of these findings using mouse aorta tissue rings. Stimulation of 1-receptors induced ATP release and tissue contraction, which was reduced by removing extracellular ATP with apyrase or in the absence of P2Y2 receptors in aorta rings from P2Y2 receptor knockout mice. We conclude that, like formyl peptide receptors, adrenergic receptors require purinergic feedback mechanisms to control complex physiological processes such as smooth muscle contraction and regulation of vascular tone.

  Y Chen , C Qian , C Guo , F Ge , X Zhang , X Gao , S Shen , B Lian , K Kitazato , Y Wang and S. Xiong

Nucleoside diphosphate phosphate transferase A (NDPK-A) has been shown to play critical roles in the regulation of proliferation, differentiation, growth and apoptosis of cells. Our previous study suggested that the disulphide cross-linkage between cysteine 4 (C4) and cysteine 145 (C145) of NDPK-A might be a possible regulator of its activity. To confirm this hypothesis, the C145 residue of NDPK-A was mutated to serine, and the isomerization and biological activities of the mutant were investigated and compared with those of its wild-type counterpart. It was found the C145S mutation eliminated the intramolecular disulphide bond (DB) and prevented the formation of intermolecular DB, which was known to dissociate the hexameric NDPK-A into dimeric one. We also demonstrated that the C145S mutation didn’t affect the autologous hexamerization of this protein, and the mutant had increased bioactivities including phosphate transferase and DNase. These findings support the hypothesis that the formation of DBs in NDPK-A is involved in the regulation of the oligomerization and bioactivity of this multiple function protein, and that C145 is a key residue in the regulation of NDPK-A. In addition, the C145S mutant that we have constructed might be an attractive candidate for use in applications that require NDPK-A.

  G Fu , Y Chen , M Yu , A Podd , J Schuman , Y He , L Di , M Yassai , D Haribhai , P. E North , J Gorski , C. B Williams , D Wang and R. Wen

Phospholipase C1 (PLC1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLC1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLC1. We demonstrate that PLC1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-B. Importantly, PLC1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLC1 is essential for T cell development, activation, and tolerance.

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