Biomedical subjects

X J Wang

Publications and source records attributed to X J Wang.

At least 19 recordsLinked to original sources

PubMed2002

Surface-roughness wakefield measurements at brookhaven accelerator test facility.

An experiment has been carried out at the Brookhaven Accelerator Test Facility to investigate the effect of a surface-roughness wakefield in narrow beam tubes with artificially created bumps. The measurements show that the synchronous modes decay significantly due to the randomization of the roughness pattern. It is pointed out that this decay mechanism has not been investigated in the previous experiment at DESY and the investigators' conclusion does not apply for surface-roughness wakefields in real surfaces.

Journal Article↗

PubMed2002

Fundamental and harmonic microbunching in a high-gain self-amplified spontaneous-emission free-electron laser.

Electron beam microbunching in both the fundamental and second harmonic in a high-gain self-amplified spontaneous emission free-electron laser (SASE FEL) was experimentally characterized using coherent transition radiation. The microbunching factors for both modes (b(1) and b(2)) approach unity, an indication of FEL saturation. These measurements are compared to the predictions of FEL simulations. The simultaneous capture of the microbunching and SASE radiation for individual micropulses correlate the longitudinal electron beam structure with the FEL gain.

Journal Article↗

PubMed2002

Modeling for point-non-point source effluent trading: perspective of non-point sources regulation in China.

In the past decades, little abatement efforts have been implemented on China's non-point source water pollution, and studies aiming at non-point sources regulation were also rare. Watershed abatement trading between point and non-point sources may serve as a cost-effective way to deal with the problem. The inherent uncertainty of non-point emissions, however, could affect the feasibility and outcome of point-non-point effluent trading. The purpose of this paper is to model the watershed point-non-point abatement trading incorporating the uncertainty of non-point source emissions, and to examine its impacts on trading equilibrium and trading ratio. The uncertainties of non-point emissions were taken into consideration by setting an acceptable probability by which the watershed emission constraints were achieved. Using the watershed optimization model, the optimal abatement allocation and trading ratio were explicitly illustrated. It was found that they were affected significantly by the variances of non-point emissions, the reliability requirement assigned to the non-point abatement, and the marginal abatement costs of point and non-point sources. Since the variances of non-point emissions may increase or decrease at the abatement level, the impacts of these factors were discussed in different circumstances. Based on the illumination of the trading model, future directions and implications of point-non-point trading in China were discussed.

Journal Article↗

PubMed2002

Experimental characterization of nonlinear harmonic radiation from a visible self-amplified spontaneous emission free-electron laser at saturation.

Nonlinear harmonic radiation was observed using the VISA self-amplified, spontaneous emission (SASE) free-electron laser (FEL) at saturation. The gain lengths, spectra, and energies of the three lowest SASE FEL modes were experimentally characterized. The measured nonlinear harmonic gain lengths and center spectral wavelengths decrease with harmonic number, n, which is consistent with nonlinear harmonic theory. Both the second and third nonlinear harmonics energies are about 1% of the fundamental energy. These experimental results demonstrate for the first time the feasibility of using nonlinear harmonic SASE FEL radiation to produce coherent, femtosecond x rays.

Journal Article↗

PubMed2001

Inducible expression of transforming growth factor beta1 in papillomas causes rapid metastasis.

Transforming growth factor beta1 (TGF-beta1) acts as a tumor suppressor at early stages of carcinogenesis, however, it has also been suggested to promote tumor progression at late stages. To determine at which stage and by what mechanisms this functional switch occurs, we have generated gene-switch-TGF-beta1 mice in which TGF-beta1 transgene expression can be induced in skin tumors at specific stages. These mice were exposed to a chemical carcinogenesis protocol, which allows tumorigenesis to develop in progressive stages from benign papillomas to malignant carcinomas. Remarkably, TGF-beta1 transgene induction in papillomas rapidly induced metastasis. This function is in sharp contrast to its tumor suppressive effect when TGF-beta1 transgene expression was induced early in the protocol. Transgenic papillomas exhibited down-regulation of TGF-beta receptors and their signal transducer, the Smads, and loss of the invasion suppressor E-cadherin/catenin complex in the cell membrane. These molecules were lost only in malignant carcinomas in control mice at a much later stage. Furthermore, transgenic papillomas exhibited elevated expression of matrix metalloproteinases and increased angiogenesis. Our study suggests that TGF-beta1 overexpression may directly induce tumor metastasis by initiating events necessary for invasion. Down-regulation of TGF-beta signaling components in tumor epithelia selectively abolishes growth inhibition, thus, switching the role of TGF-beta1 to a metastasis promoter.

Animals↗

PubMed2001

Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis.

Presenilin 1 (PS1) is required for the proteolytic processing of Notch and the beta-amyloid precursor protein (APP), molecules that play pivotal roles in cell-fate determination during development and Alzheimer's disease pathogenesis, respectively. In addition, PS1 interacts with beta-catenin and promotes its turnover through independent mechanisms. Consistent with this activity, we report here that PS1 is important in controlling epidermal cell proliferation in vivo. PS1 knockout mice that are rescued through neuronal expression of human PS1 transgene develop spontaneous skin cancers. PS1-null keratinocytes exhibit higher cytosolic beta-catenin and beta-catenin/lymphoid enhancer factor-1/T cell factor (beta-catenin/LEF)-mediated signaling. This effect can be reversed by reintroducing wild-type PS1, but not a PS1 mutant active in Notch processing but defective in beta-catenin binding. Nuclear beta-catenin protein can be detected in tumors. Elevated beta-catenin/LEF signaling is correlated with activation of its downstream target cyclin D1 and accelerated entry from G(1) into S phase of the cell cycle. This report demonstrates a function of PS1 in adult tissues, and our analysis suggests that deregulation of beta-catenin pathway contributes to the skin tumor phenotype.

Animals↗

PubMed2001

NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin.

BACKGROUND: The phase II enzyme NAD(P)H :quinone oxidoreductase 1 (NQO1) catalyzes quinone detoxification, protecting cells from redox cycling, oxidative stress, mutagenicity, and cytotoxicity induced by quinones and its precursors. We have used NQO1(-/-) C57BL/6 mice to show that NQO1 protects them from skin cancer induced by the polycyclic aromatic hydrocarbon benzo[a]pyrene. Herein, we used NQO1(-/-) mice to investigate whether NQO1 also protects them against 7,12-dimethylbenz[a]anthracene (DMBA), where methyl substituents diminish primary quinone formation. METHODS: Dorsal skin of NQO1(-/-) or wild-type C57BL/6 mice was shaved. When tested as a complete carcinogen, DMBA (500 or 750 microg in 100 microL of acetone) alone was applied to the shaved area. When tested as a tumor initiator, DMBA (200 or 400 nmol in 100 microL of acetone) was applied to the shaved area; 1 week later, twice-weekly applications of phorbol 12-myristate 13-acetate (PMA)-10 microg dissolved in 200 microL of acetone-to the same area began and were continued for 20 weeks. Tumor development was monitored in all mice (12-15 per group). All statistical tests were two-sided. RESULTS: When DMBA (750 microg) was tested as a complete carcinogen, about 50% of the DMBA-treated NQO1(-/-) mice but no DMBA-treated wild-type mouse developed skin tumors. When DMBA (both concentrations) was used as a tumor initiator, NQO1(-/-) mice developed larger tumors at a greater frequency than their wild-type littermates. Twenty-three weeks after the first PMA treatment in the tumor initiator test, all 30 NQO1(-/-) mice given 400 nmol of DMBA had developed skin tumors, compared with 33% (10 of 30) of treated wild-type mice (P<.001). CONCLUSIONS: NQO1(-/-) mice are more susceptible to DMBA-induced skin cancer than are their wild-type littermates, suggesting that NQO1 may protect cells from DMBA carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

EGF-dependent translocation of green fluorescent protein-tagged PLC-gamma1 to the plasma membrane and endosomes.

Growth factor-dependent translocation of phospholipase C-gamma1 (PLC-gamma1) was investigated using a green fluorescent protein-tagged PLC-gamma1 (PLC-gamma1-GFP) expressed in human epidermoid carcinoma A-431 cells. In the absence of growth factors, PLC-gamma1-GFP was present throughout the cytoplasm of A-431 cells. Treatment of the cells with epidermal growth factor (EGF) produced a very rapid redistribution of PLC-gamma1-GFP to the plasma membrane in a nonuniform manner. This translocation to the plasma membrane was insensitive to an inhibitor of phosphatidylinositol 3-kinase and was independent of cell adhesion. However, the translocation was disrupted by an agent which depolymerizes the actin cytoskeleton. At later times following the addition of EGF, PLC-gamma1-GFP appeared associated with intracellular vesicles. Stimulation of A-431 cells by Texas red-conjugated EGF for more than 10 min resulted in punctate intracellular PLC-gamma1-GFP distribution that colocalized with Texas red-conjugated EGF. This suggests that PLC-gamma1 is translocated to endosomes after EGF treatment, probably by associating with the internalized and autophosphorylated EGF receptor. Fractionation studies demonstrated that the EGF-induced plasma membrane-localized PLC-gamma1 is concentrated in caveolae microdomains. Disruption of caveolae with methyl-beta-cyclodextrin resulted in the ablation of EGF-induced, but not bradykinin-induced, mobilization of intracellular Ca(2+). This treatment, however, only partially decreased PLC-gamma1 membrane translocation.

Caveolae↗

PubMed2001

Characterization of a high-gain harmonic-generation free-electron laser at saturation.

We report on an experimental investigation characterizing the output of a high-gain harmonic-generation (HGHG) free-electron laser (FEL) at saturation. A seed CO2 laser at a wavelength of 10.6 microm was used to generate amplified FEL output at 5.3 microm. Measurement of the frequency spectrum, pulse duration, and correlation length of the 5.3 microm output verified that the light is longitudinally coherent. Investigation of the electron energy distribution and output harmonic energies provides evidence for saturated HGHG FEL operation.

Journal Article↗

PubMed2001

Modeling translocation of particles on one-dimensional polymer lattices.

We introduce a general random walk model that is an extension of the random walk model proposed by Berg. The model can be used to describe a particle's translocation along a polymeric lattice with a nonuniform distribution of obstacles. These obstacles are representative of DNA-bound proteins, of drugs, and of a DNA packing environment. Using this model in the bacteriophage replication process, we show the effects of random obstacles on an ATP-driven particle's translocation along single-stranded DNA. The principal finding is that the average statistical time of the translocation process decreases with the increase of an obstacle's strength. We also find an interesting relation between the average statistical time and the DNA chain length. Our results can be used to explain some physiological phenomena. They show the usefulness of our model in an analysis of the effect of random obstacles on particles' translocation along one-dimensional polymer lattices.

Adenosine Triphosphate↗

PubMed2001

Elements involved in the regulation of the StAR gene.

The steroidogenic acute regulatory protein (StAR) mediates the transfer of cholesterol from the outer to the inner mitochondrial membrane, the regulated step in steroidogenesis. A most interesting facet of this protein is the manner in which its expression is acutely regulated. In this regard, a number of studies have concentrated on the search for consensus cis regulatory elements within its promoter, and, more importantly, on whether these elements are involved in its expression. This short review will summarize some of the findings that have been reported concerning the nature of how the expression of this gene is regulated.

Animals↗

PubMed2001

Exponential gain and saturation of a self-amplified spontaneous emission free-electron laser.

Self-amplified spontaneous emission in a free-electron laser has been proposed for the generation of very high brightness coherent x-rays. This process involves passing a high-energy, high-charge, short-pulse, low-energy-spread, and low-emittance electron beam through the periodic magnetic field of a long series of high-quality undulator magnets. The radiation produced grows exponentially in intensity until it reaches a saturation point. We report on the demonstration of self-amplified spontaneous emission gain, exponential growth, and saturation at visible (530 nanometers) and ultraviolet (385 nanometers) wavelengths. Good agreement between theory and simulation indicates that scaling to much shorter wavelengths may be possible. These results confirm the physics behind the self-amplified spontaneous emission process and forward the development of an operational x-ray free-electron laser.

Journal Article↗

PubMed2001

Oxidative stress-induced phospholipase C-gamma 1 activation enhances cell survival.

Phospholipase C-gamma1 (PLC-gamma1) is rapidly activated in response to growth factor stimulation and plays an important role in regulating cell proliferation and differentiation through the generation of the second messengers diacylglycerol and inositol 1,4,5-trisphosphate, leading to the activation of protein kinase C (PKC) and increased levels of intracellular calcium, respectively. Given the existing overlap between signaling pathways that are activated in response to oxidant injury and those involved in responding to proliferative stimuli, we investigated the role of PLC-gamma1 during the cellular response to oxidative stress. Treatment of normal mouse embryonic fibroblasts (MEF) with H2O2 resulted in time- and concentration-dependent tyrosine phosphorylation of PLC-gamma1. Phosphorylation could be blocked by pharmacological inhibitors of Src family tyrosine kinases or the epidermal growth factor receptor tyrosine kinase, but not by inhibitors of the platelet-derived growth factor receptor or phosphatidylinositol 3-kinase. To investigate the physiologic relevance of H2O2-induced tyrosine phosphorylation of PLC-gamma1, we compared survival of normal MEF and PLC-gamma1-deficient MEF following exposure to H2O2. Treatment of PLC-gamma1-deficient MEF with H2O2 resulted in rapid cell death, whereas normal MEF were resistant to the stress. Pretreatment of normal MEF with a selective pharmacological inhibitor of PLC-gamma1, or inhibitors of inositol trisphosphate receptors and PKC, increased their sensitivity to H2O2, whereas treatment of PLC-gamma1-deficient MEF with agents capable of directly activating PKC and enhancing calcium mobilization significantly improved their survival. Finally, reconstitution of PLC-gamma1 protein expression in PLC-gamma1-deficient MEF restored cell survival following H2O2 treatment. These findings suggest an important protective function for PLC-gamma1 activation during the cellular response to oxidative stress.

Alleles↗

PubMed2001

Role of TGFbeta signaling in skin carcinogenesis.

The TGFbeta signaling pathway is one of the most important mechanisms in the maintenance of epithelial homeostasis. Alterations leading to either the repression or enhancement of this pathway have been shown to affect cancer development. Although TGFbeta inhibits growth of normal epithelial cells, it is paradoxically overexpressed in many epithelial cancers. It has been postulated that TGFbeta acts as a tumor suppressor at the early stages of carcinogenesis, but overexpression of TGFbeta at late stages of carcinogenesis may be a critical factor for tumor invasion and metastasis. The detailed mechanisms regulating this functional switch of TGFbeta remain to be elucidated. The relevance of the TGFbeta signaling pathway to the development of primary epithelial tumors in man has been further substantiated by the discovery of mutations in TGFbeta receptors and in the downstream signaling mediators, the Smads. The epidermis is one of the major targeting tissues for TGFbeta signaling. Chemical carcinogenesis studies have revealed a paradoxical effect of TGFbeta on skin carcinogenesis: inhibition of papilloma formation but promotion of malignant conversion. In addition, deletion of the TGFbeta type II receptor accelerates skin carcinogenesis. This review focuses on our current understanding of the role of TGFbeta signaling in skin carcinogenesis.

Animals↗

PubMed2001

Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders.

Stem cells are crucial for the formation and maintenance of tissues and organs. The role of stem cells in the pathogenesis of mosaic skin disorders remains unclear. To study the molecular and cellular basis of mosaicism, we established a mouse model for the autosomal-dominant skin blistering disorder, epidermolytic hyperkeratosis (MIM 113800), which is caused by mutations in either keratin K1 or K10. This genetic model allows activation of a somatic K10 mutation in epidermal stem cells in a spatially and temporally controlled manner using an inducible Cre recombinase. Our results indicate that lack of selective pressure against certain mutations in epidermal stem cells leads to mosaic phenotypes. This finding has important implications for the development of new strategies for somatic gene therapy of dominant genodermatoses.

Animals↗

PubMed2001

An inducible mouse model for epidermolysis bullosa simplex: implications for gene therapy.

The Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease inherited in an autosomal-dominant fashion. Here we report the generation of a mouse model that allows focal activation of a mutant keratin 14 allele in epidermal stem cells upon topical administration of an inducer, resulting in EBS phenotypes in treated areas. Using laser capture microdissection, we show that induced blisters healed by migration of surrounding nonphenotypic stem cells into the wound bed. This observation provides an explanation for the lack of mosaic forms of EBS-DM. In addition, we show that decreased mutant keratin 14 expression resulted in normal morphology and functions of the skin. Our results have important implications for gene therapy of EBS and other dominantly inherited diseases.

Animals↗

PubMed2001

Smads mediate signaling of the TGFbeta superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis.

The Smads are the signaling mediators of the TGFbeta superfamily. In the present study, we examined Smad expression in mouse epidermis and chemically-induced skin tumors. Mutations in Smad2 and -4 genes were also screened. Transcripts of Smad1 through -5 were constantly expressed in the epidermis regardless of changes in TGFbeta signaling, state of differentiation and stages of carcinogenesis. Smad7 transcripts were barely detectable in keratinocytes, but were induced by TGFbeta1 treatment and in chemically-induced skin tumors. At the protein level, Smad1 was detected throughout the epidermis, whereas Smad2 through -5 exhibited greater levels in suprabasal layers than basal keratinocytes. In cultured keratinocytes, Smad2, -3 and -4 underwent nuclear translocation upon TGFbeta1 treatment. Furthermore, nuclear translocation of Smads correlated with decreased BrdU labeling in proliferative keratinocytes. Although no mutations were detected in the Smad2 and -4 genes in tumors, proteins of Smad1 through -5 were partially or completely lost in carcinomas. These data document that Smads are expressed at high levels in the epidermis and mediate signaling of the TGFbeta superfamily. During skin carcinogenesis, loss of Smad1 through -5 and overexpression of Smad7 may contribute to the loss of growth inhibition mediated by TGFbeta superfamily members, thus resulting in tumor progression.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

Identification of a motif in the carboxyl terminus of CXCR2 that is involved in adaptin 2 binding and receptor internalization.

Agonist treatment of cells expressing the chemokine receptor, CXCR2, induces receptor phosphorylation and internalization through a dynamin-dependent mechanism. In the present study, we demonstrate that a carboxyl terminus-truncated mutant of CXCR2 (331T), which no longer undergoes agonist-induced phosphorylation, continues to undergo ligand-induced internalization in HEK293 cells. This mutant receptor exhibits reduced association with beta-arrestin 1 but continues to exhibit association with adaptin 2 alpha and beta subunits. Replacing Leu320-321 and/or Ile323-Leu324 with Ala (LL320,321AA, IL323,324AA, and LLIL320,321,323,324AAAA) in wild-type CXCR2 or 331T causes little change in ligand binding and signaling through Ca(2+) mobilization but greatly impairs the agonist-induced receptor sequestration and ligand-mediated chemotaxis. The LL320,321AA, IL323,324AA, and LLIL320,321,323,324AAAA mutants of CXCR2 exhibit normal binding to beta-arrestin 1 but exhibit decreased binding to adaptin 2alpha and beta. These data demonstrate a role for the LLKIL motif in the carboxyl terminus of CXCR2 in receptor internalization and cell chemotaxis and imply a role for adaptin 2 in the endocytosis of CXCR2.

Adaptor Protein Complex alpha Subunits↗