We describe a novel secondary-electron ion microscope (SEIM), designed for diagnostics of the upcoming sub-micron Columbia University charged-particle microbeam. This secondary-electron ion ...microscope allows much higher resolutions, at higher single particle detection efficiencies, than previously available, for rapid and accurate diagnostics of sub-micron charged-particle beams. Based on ion electron-emission microscopy (IEEM) and photo-electron microscopy (PEM), the SEIM involves conversion of the incident projectiles on a secondary-electron emitting film. The ejected electrons are focused using a unipolar electrostatic lens and conical electrostatic mirror to form a magnified image on a microchannel plate (MCP). The flight path of the electrons includes two 45° bends; this “folded” geometry results in lower aberrations than a “straight” design, and enables efficient beam imaging down to 100nm resolution with >50% single electron transfer efficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Using a recently described method for efficiently deriving homozygous targeted alleles in embryonic stem cells, we produced chimeric mice whose tissues were derived partially from embryonic stem ...cells bearing homozygous deletion of the mouse immunoglobulin heavy-chain joining (JH) region. Characterization of these chimeric mice indicated that homozygous JHdeletion leads to arrest of B-cell development at an early stage, resulting in a total lack of peripheral B cells and serum IgM. These results were confirmed in mice containing the homozygous JHdeletion in their germ line. This novel B-cell-deficient mouse strain provides a tool for studying the recombination and expression of exogenous immunoglobulin genes introduced into the mouse germ line.*
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
A model for the structural relaxation of grain boundaries (GBs) in nanostructured materials (NSMs) by diffusion-accommodated rigid body translations along GBs is proposed. The model is based on the ...results of recent computer simulations that have demonstrated that the GBs in NSMs retain a high-energy structure with random translational states due to severe geometrical constraints applied from neighboring grains (J. Appl. Phys. 78 (1995) 847; Scripta Metall. Mater. 33 (1995) 1245). The shear stresses within a GB caused by non-optimized rigid-body translations (RBTs) can be accommodated by diffusive flow of atoms along a GB. This mechanism is particularly important for low-angle and vicinal GBs, the energy of which noticeably depends on the rigid body translations. At moderate and high temperatures the model yields relaxation times that are very short and therefore GBs in NSMs can attain an equilibrium structure with optimized rigid body translations. In contrast, at room temperature the model predicts that in some metals non-equilibrium structures can be preserved for a long time, which may result in the observation of grain boundary structures different from those in coarse grained polycrystals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Following partial hepatectomy (PH), there is a rapid and highly orchestrated series of biochemical events which occur prior to cellular proliferation. Some of these events are presumably intimately ...linked with the eventual regeneration of the liver, whereas others are likely to be stress related or required for the continued differentiated function of the liver while regeneration is occurring. The regulation of the AP-1 transcription factor c-Jun during hepatic regeneration has been studied here. There is a progressive increase in c-Jun-mRNA levels after sham operation, one-third PH, and two-thirds PH. A concomitant increase in activating protein 1 (AP-1) binding activity is also observed. The c-Jun protein is a major constituent of the AP-1 complex in quiescent and early regenerating liver. The activity of c-Jun amino-terminal kinase (JNK), which phosphorylates the activation domain of the c-Jun protein, is markedly stimulated after one-third and two-thirds PH. c-Jun amino-terminal kinase-1 is a constituent of this stimulated JNK activity after PH. When primary cultures of adult rat hepatocytes are incubated with epidermal growth factor or transforming growth factor-alpha, AP-1 transcriptional activity is increased and the activation domain of the c-Jun protein is further potentiated. Phosphopeptide mapping of the endogenous c-Jun protein in proliferating cultured hepatocytes demonstrates phosphorylation of the c-Jun activation domain. Pretreatment of animals prior to PH with a neutralizing antibody to tumour necrosis factor-alpha (TNFalpha), inhibits hepatocyte DNA synthesis and JNK activation. It is concluded that the stimulation of one-third or two-thirds PH activates JNK through a mechanism that requires TNFalpha, which phosphorylates the c-Jun activation domain in hepatocytes, resulting in enhanced transcription of AP-1-dependent genes. Although nuclear factor-kappa B (NFkappaB) binding activity is induced during liver regeneration following PH, the physiological consequence of this induction is unknown. The role of NFkappaB during liver regeneration has been assessed by delivering to the liver a super-repressor of NFkappaB activity using an adenoviral vector expressing a mutated form of IkappaB. This adenovirus (Ad5IkappaB) was almost exclusively expressed in the liver and inhibited NFkappaB DNA binding activity and transcriptional activity in cultured cells as well as in the liver in vivo. Following PH, Ad5IkappaB, but not a control adenovirus (Ad5betagal), resulted in the induction of apoptosis as demonstrated by histological staining and TUNEL analysis. In addition, infection with Ad5IkappaB but not Ad5betagal decreased the mitotic index following PH. These two phenomena, increased apoptosis and cell cycle arrest, were associated with liver failure in animals infected with the ad5IkappaB but not Ad5betagal as demonstrated by elevated serum bilirubin and ammonia levels. Thus, the induction of NFkappaB during liver regeneration following PH appears to be a required event to prevent apoptosis and to allow for normal cell cycle progression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Liver fibrosis is a highly dynamic process in which multiple genes interact with environmental factors. Recent human epidemiologic studies have identified possible polymorphisms in a number of ...candidate genes that influence the progression of liver fibrosis. These genetic factors could explain the broad spectrum of responses to the same etiologic agent found in patients with chronic liver diseases. Polymorphisms in genes encoding immunoregulatory proteins, proinflammatory cytokines, and fibrogenic factors may influence disease progression in patients with alcohol-induced liver disease, primary biliary cirrhosis, or chronic hepatitis C. However, some of the studies have yielded contradictory results. For example, conflicting results have been obtained in studies assessing the role of mutations in the hemochromatosis gene on fibrosis progression in patients with chronic hepatitis C. Large-scale, well-designed studies are required to clarify the actual role of this factor and other genetic variants in liver fibrosis. (H
EPATOLOGY 2003;37:493-503.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The relationship between gender and alcohol-induced liver disease is complex; however, endotoxin is most likely involved. Recently, it was reported that estriol activated Kupffer cells by ...upregulation of the endotoxin receptor CD14. Therefore, the purpose of this work was to study how estriol sensitizes Kupffer cells. Rats were given estriol (20 mg/kg ip), and Kupffer cells were isolated 24 h later. After addition of lipopolysaccharide (LPS), intracellular Ca2+ concentration was measured using a microspectrofluorometer with the fluorescent indicator fura 2, and tumor necrosis factor-alpha was measured by ELISA. CD14 was evaluated by Western analysis. One-half of the rats given estriol intraperitoneally 24 h before an injection of a sublethal dose of LPS (5 mg/kg) died within 24 h, whereas none of the control rats died. Mortality was prevented totally by sterilization of the gut with antibiotics. A similar pattern was obtained with liver histology and serum transaminases. Translocation of horseradish peroxidase was increased about threefold in gut segments by treatment with estriol. This increase was not altered by treatment with nonabsorbable antibiotics. On the other hand, endotoxin levels were increased to 60-70 pg/ml in plasma of rats treated with estriol. As expected, this increase was prevented (<20 pg/ml) by antibiotics. In isolated Kupffer cells, LPS-induced increases in intracellular Ca2+ concentration, tumor necrosis factor-alpha production, and CD14 were increased, as previously reported. All these phenomena were blocked by antibiotics. Therefore, it is concluded that estriol treatment in vivo sensitizes Kupffer cells to LPS via mechanisms dependent on increases in CD14. This is most likely due to elevated portal blood endotoxin caused by increased gut permeability.
Summary
The enhancement of oncogenic transformation in the C3H10T½ system by protraction of a high-LET irradiation has been widely reported. Prima facie, the results are inconsistent in that some but ...not all experiments have shown an enhancement. That the reported data follow a clear pattern is shown, and a model whose predictions are quantitatively consistent with these trends is discussed. The model, developed from that originally suggested by Rossi and Kellerer (1986), postulates that cells are especially sensitive to radiation during some period of their cycle. A sensitive period of about 1 h is shown to yield predictions consistent with all available data. If the suggested model is realistic and applicable to human cells in vivo, little enhancement would be expected for high-LET radiations such as from radon daughters or HZE cosmic rays, though an effect might be expected from trapped protons on astronauts in earth orbit. For fission neutrons a time-dependent factor of N = 2 in the formula for dose equivalent (H = DQN) might be appropriate for very low dose rates, if a quality factor Q = 10 were applied. If Q was taken as 20, then a value of N = 1 would probably be adequate.
Ferrochelatase catalyzes the chelation of ferrous iron and protoporphyrin to form heme. It is expressed as a housekeeping gene in all cells, but is upregulated during erythropoiesis. Ferrochelatase ...activity is deficient in the inherited disease protoporphyria as a result of heterogeneous mutations. Although human ferrochelatase is transcribed from a single promoter in both nonerythroid and erythroid cells, previous studies using transient transfection assays failed to demonstrate erythroid-specific increased expression from 4.0 kb of the human ferrochelatase promoter containing the erythroid cis-elements, GATA and NF-E2. The present study analyzes the in vivo regulation of the ferrochelatase gene to provide insights into the mechanism of its erythroid-specific enhancement. Transgenic (TG) mouse lines were generated in which the luciferase reporter gene was driven by either a 150-bp ferrochelatase minimal promoter (-0.15 TG) or by a 4.0 kb extended 5' upstream region (-4.0 TG). Expression of the -4.0 TG transgene was generally consistent with the endogenous gene during embryonic development and in nonerythroid and erythroid tissues as demonstrated by Northern blotting and mRNA in situ hybridization. The -4.0 TG was expressed at a higher level than the -0.15 TG in nonerythroid and erythroid tissues, including during extramedullary erythropoiesis induced by n-acetylphenylhydrazine injection. The enhanced erythroid expression of the -4.0 TG correlates with the appearance of a DNase I hypersensitive site in the 5' flanking region of the transgene. Therefore, in the context of chromosomal integration, the 5' flanking region of the ferrochelatase gene is necessary and sufficient to confer high levels of transgene expression in erythroid tissue.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Activation of hepatic stellate cells (HSCs) and other resident mesenchymal cells into myofibroblasts expressing alpha smooth muscle actin (αSMA) and collagen I is a key event in liver fibrogenesis. ...However, the temporal expression profiles of αSMA and collagen I genes in these cells is unknown. To address this question, we studied αSMA and collagen α1(I) transcriptional patterns in primary cultures of HSCs, and additionally, in an in vivo model of secondary biliary fibrosis using transgenic mice that express the Discomsoma sp. red fluorescent protein (RFP) and the enhanced green fluorescent protein (EGFP) reporter genes under direction of the mouse αSMA and collagen α1(I) promoter/enhancers, respectively. The αSMA‐RFP mice were crossed with collagen‐EGFP mice to generate double transgenic mice. Reporter gene expression in cultured HSCs demonstrated that both transgenes were induced at day 3 with continued expression through day 14. Interestingly, αSMA and collagen α1(I) transgenes were not coexpressed in all cells. Flow cytometry analysis showed three different patterns of gene expression: αSMA‐RFP positive cells, collagen‐EGFP positive cells, and cells expressing both transgenes. αSMA‐only and αSMA/collagen expressing cells showed higher expression levels of synaptophysin, reelin, MMP13, TIMP1, and ICAM‐1 compared to collagen‐only expressing cells, as assessed by real‐time PCR. Following bile duct ligation, αSMA and collagen α1(I) transgenes were differentially expressed by peribiliary, parenchymal and vascular fibrogenic cells. Peribiliary cells preferentially expressed collagen α1(I), while parenchymal myofibroblasts expressed both αSMA and collagen α1(I). In conclusion, these data demonstrate heterogeneity of gene expression in myofibroblastic cells during active fibrogenesis. These reporter mice provide a useful tool to further characterize fibrogenic cell types and to evaluate antifibrotic drugs. (HEPATOLOGY 2004.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
On the basis of literature ab initio data, we show that diamond nanorods would have a brittle fracture force and a zero strain stiffness that exceeds carbon nanotubes for radii greater than about 1−3 ...nm, depending on the orientation of the diamond nanorod. The energetic stability of diamond nanorods is predicted by molecular modeling to be comparable to single-walled carbon nanotubes. It is concluded that diamond nanorods represent an important and viable target structure for synthesis.
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IJS, KILJ, NUK, PNG, UL, UM
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