Dopamine D2 receptor and obesity.
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Body Mass Index↗
Biomedical subjects
J Chen
Publications and source records attributed to J Chen.
The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis.
Copper plays a fundamental role in the biochemistry of all aerobic organisms. The delivery of this metal to specific intracellular targets is mediated by metallochaperones. To elucidate the role of the metallochaperone Atox1, we analyzed mice with a disruption of the Atox1 locus. Atox1(-/-) mice failed to thrive immediately after birth, with 45% of pups dying before weaning. Surviving animals exhibited growth failure, skin laxity, hypopigmentation, and seizures because of perinatal copper deficiency. Maternal Atox1 deficiency markedly increased the severity of Atox1(-/-) phenotype, resulting in increased perinatal mortality as well as severe growth retardation and congenital malformations among surviving Atox1(-/-) progeny. Furthermore, Atox1-deficient cells accumulated high levels of intracellular copper, and metabolic studies indicated that this defect was because of impaired cellular copper efflux. Taken together, these data reveal a direct role for Atox1 in trafficking of intracellular copper to the secretory pathway of mammalian cells and demonstrate that this metallochaperone plays a critical role in perinatal copper homeostasis.
Animals↗
Continuous production of poly-3-hydroxybutyrate by Ralstonia eutropha in a two-stage culture system.
Poly-3-hydroxybutyrate (PHB) is mainly accumulated by Ralstonia eutropha under unbalanced growth conditions, which limits its production in batch or fed-batch modes. The continuous production of PHB was investigated in a two-stage continuous culture system. The first-stage produced cell mass giving the maximal cell dry weight of 27.1 g l(-1) at 0.21 h(-1) of dilution rate. High specific cell growth rate results in the decrease of PHB synthesis under glucose-limited and nitrogen-rich conditions in the first-stage. The second-stage produced PHB giving the maximal PHB concentration of 47.6 g l(-1) at 0.14 h(-1) of dilution rate. Specific PHB synthetic rate reached highest value at low dilution rate under nitrogen-limited condition in the second-stage, and decreased with the increase of ammonium concentration in the culture. In the continuous culture system, the maximal PHB productivity could reach 1.43 g l(-1) h(-1) at a dilution rate of 0.12 h(-1), but with relatively low PHB content of 47.6%. Maximal yield of PHB on glucose could reach 0.36 g g(-1) glucose at 0.075 h(-1) of dilution rate with relatively high PHB productivity of 1.23 g l(-1) h(-1) and PHB content of 72.1%, respectively.
Cupriavidus necator↗
Effectiveness of beta-blocker therapy after acute myocardial infarction in elderly patients with chronic obstructive pulmonary disease or asthma.
OBJECTIVES: We evaluated the use and effectiveness of beta-blocker therapy after acute myocardial infarction (AMI) for elderly patients with chronic obstructive pulmonary disease (COPD) or asthma. BACKGROUND: Because patients with COPD and asthma have largely been excluded from clinical trials of beta-blocker therapy for AMI, the extent to which these patients would benefit from beta-blocker therapy after AMI is not well defined. METHODS: Using data from the Cooperative Cardiovascular Project, we examined the relationship between discharge use of beta-blockers and one-year mortality in patients with COPD or asthma who were not using beta-agonists, patients with COPD or asthma who were concurrently using beta-agonists and patients with evidence of severe disease (use of prednisone or previous hospitalization for COPD or asthma) compared with patients without COPD or asthma. RESULTS: Of 54,962 patients without contraindications to beta-blockers, patients with COPD or asthma (20%) were significantly less likely to be prescribed beta-blockers at discharge after AMI. After adjusting for demographic and clinical factors, we found that beta-blockers were associated with lower one-year mortality in patients with COPD or asthma who were not on beta-agonist therapy (relative risk [RR] = 0.85, 95% confidence interval [CI] 0.73 to 1.00), similar to patients without COPD or asthma (RR = 0.86, 95% CI 0.81 to 0.92). A survival benefit for beta-blockers was not found among patients concurrently using beta-agonists or with severe COPD or asthma. CONCLUSIONS: Beta-blocker therapy after AMI may be beneficial for COPD or asthma patients with mild disease. A survival benefit was not found for elderly AMI patients with more severe pulmonary disease.
Adrenergic beta-Antagonists↗
Activation of p53 by roscovitine-mediated suppression of MDM2 expression.
The p53 tumor suppressor is regulated by the MDM2 oncoprotein. Overexpression of MDM2 maintains p53 at low levels and contributes to the functional inactivation of p53 in a subset of tumors. We found that treatment with roscovitine and olomoucin, which were originally developed as cyclin-dependent kinase (CDK) inhibitors, can efficiently stabilize and activate nuclear p53 in tumor cells with MDM2 amplification or cytoplasmic p53. These inhibitors block the degradation of p53 without affecting p53-MDM2 binding and the nuclear shuttling function of p53 and MDM2. Roscovitine also induces stabilization of the p53 Ala-315 mutant, indicating that it does not act by regulating the CDK phosphorylation of serine 315. Roscovitine induces down-regulation of MDM2 expression at both protein and mRNA levels. Ectopic expression of MDM2 can abrogate the ability of roscovitine to induce p53 stabilization. Low concentrations of roscovitine cooperate with the DNA-damaging agent camptothecin to activate p53 in a synergistic fashion. These results show that the small molecule CDK inhibitors can be used to activate p53 through their potent inhibitory effect on MDM2 expression and may be useful as sensitizing agents for other DNA-damaging drugs.
Cell Compartmentation↗
Left-to-right gradient of atrial frequencies during acute atrial fibrillation in the isolated sheep heart.
BACKGROUND: Recent studies demonstrated spatiotemporal organization in atrial fibrillation (AF). We hypothesized that waves emanating from sources in the left atrium (LA) undergo fragmentation, resulting in left-to-right frequency gradient. Our objective was to characterize impulse propagation across Bachmann's bundle (BB) and the inferoposterior pathway (IPP) during AF. METHODS AND RESULTS: In 13 Langendorff-perfused sheep hearts, AF was induced in the presence of acetylcholine (ACh). Fast Fourier transform of optical and bipolar electrode recordings was performed. Frequency-dependent changes in the left-to-right dominant frequency (DF) gradient were studied by perfusing D600 (2 micromol/L) and by increasing ACh concentration from 0.2 to 0.5 micromol/L. BB and IPP were subsequently ablated. At baseline, a left-to-right decrease in DFs occurred along BB and IPP, resulting in an LA-right atrium (RA) frequency gradient of 5.7+/-1.4 HZ: Left-to-right impulse propagation was present in 81+/-5% and 80+/-10% of cases along BB and IPP, respectively. D600 decreased the highest LA frequency from 19.7+/-4.4 to 16.2+/-3.9 Hz (P<0.01) and raised RA DF from 8.6+/-2.0 to 10.7+/-1.8 Hz (P<0.05). An increase in ACh concentration increased the LA-RA frequency gradient from 4.9+/-1.8 to 8.9+/-1.8 Hz (P<0.05). Ablation of BB and IPP decreased RA DF from 10.9+/-1.2 to 9.0+/-1.5 Hz (P<0.01) without affecting LA DF (16.8+/-1.5 versus 16.9+/-1.8 Hz, P=NS). CONCLUSIONS: Left-to-right impulse propagation and frequency-dependent changes in the LA-RA frequency gradient during AF strongly support the hypothesis that this arrhythmia is the result of high-frequency periodic sources in the LA, with fibrillatory conduction away from such sources.
Acetylcholine↗
Appropriate initiation of the strand exchange reaction promoted by RecA protein requires ATP hydrolysis.
The DNA-dependent ATPase activity of the Escherichia coli RecA protein has been recognized for more than two decades. Yet, the role of ATP hydrolysis in the RecA-promoted strand exchange reaction remains unclear. Here, we demonstrate that ATP hydrolysis is required as part of a proofreading process during homology recognition. It enables the RecA-ssDNA complex, after determining that the strand-exchanged duplex is mismatched, to dissociate from the synaptic complex, which allows it to re-initiate the search for a "true" homologous region. Furthermore, the results suggest that when non-homologous sequences are present at the proximal end, ATP hydrolysis is required to allow ssDNA-RecA to reinitiate the strand exchange from an internal homologous region.
Adenosine Triphosphatases↗
Microarray analysis of Tbx2-directed gene expression: a possible role in osteogenesis.
Tbx2 is a member of the developmentally important transcriptional regulatory T-box gene family, whose target genes have not been well characterized. In an attempt to identify genes that may be regulated by Tbx2, mouse cDNA microarrays were used to analyze differential gene expression profiles, comparing stably transfected NIH3T3 cells overexpressing Tbx2 and vector-transfected controls. Among 8734 genes, 107 genes were up-regulated by 2-fold or greater, and 66 genes were down-regulated by 2-fold or greater. Caveolin, pleiotrophin (osf-1), osteoblast-specific factor-2 (osf-2) and collagen type I alpha were among the genes upregulated in the Tbx2-overexpressing cells, whereas cadherin 3, tenascin C, and insulin-like growth factor binding protein 10/CYR61 (IBP10) were among the genes downregulated. Northern blot analysis confirmed the correlation of expression of several genes, including IBP10 and osf-2, in fibroblast NIH3T3 and rat osteosarcoma ROS17/2.8 cells differentially expressing Tbx2. In ROS17/2.8 cells transfected with antisense Tbx2, osf-2 was downregulated, whereas transfection of sense Tbx2 upregulated this gene. Interestingly, the expression of pleiotrophin (osf-1) and collagen I alpha with Tbx2 transfection showed an inverse regulatory correlation between NIH3T3 and ROS17/2.8 cells. Thus, Tbx2 can act as both a repressor and activator, and the cellular context can influence the effect on gene expression. Although the data do not address whether Tbx2 directly mediates the transcriptional effect, a number of candidate genes possess putative T-box gene regulatory elements. The results support the hypothesis that Tbx2 may be an important modulator of bone development. Further functional cluster analysis indicates that Tbx2 might also be involved in the regulation of cell cycle and cell adhesion.
3T3 Cells↗
Cloning and characterization of human and mouse mitochondrial elongation factor G, GFM and Gfm, and mapping of GFM to human chromosome 3q25.1-q26.2.
Similar to the translational system in the cell cytoplasm, the initiation, elongation, and termination of protein synthesis in the mitochondria of eukaryotes are catalyzed by several protein factors. These factors, from the viewpoint of evolution, are more closely related to the corresponding prokaryotic factors than to those in the eukaryotic cytoplasm. In this paper, we isolated two cDNAs coding for human and mouse mitochondrial elongation factor G (GFM and Gfm, respectively). The GFM cDNA, which is 3481 bp in length, predicts a protein of 751 amino acids sharing 84 and 42% identity and 88 and 62% similarity to rat EF-G(mt) and Escherichia coli EF-G, respectively, and 24% identity and 39% similarity to human EF-2, the equivalent of EF-G in the cytoplasm. The mouse Gfm cDNA is 2564 bp and contains an intact open reading frame that encodes 751 amino acids showing 89% sequence identity and 94% similarity to human GFM. Northern blot analysis of human GFM revealed three transcripts of 3.8, 3.4, and 2.9 kb. The first two were expressed at high levels in heart, skeletal muscle, and testis, at moderate levels in liver and kidney, and at low levels in other tissues including brain, placenta, and lung, while the last transcript was expressed only in testis. The relative abundance of GFM was consistent with the observations for human EF-Tu(mt) and EF-Ts(mt), the other two mitochondrial elongation factors, indicating that the three factors were expressed at corresponding levels. The expression pattern of mouse Gfm was also determined, which showed that Gfm was expressed as a 3.0-kb transcript, abundantly in heart, skeletal muscle, kidney, and testis. In addition, GFM was assigned to human chromosome 3q25.1-q26.2 by the radiation hybrid mapping method. The genomic organization of GFM was also analyzed by comparing this cDNA with a genomic DNA sequence (Accession No. AC010936), which showed that GFM contained 18 exons and spanned at least 40 kb.
Amino Acid Sequence↗
Role of the core region of the PufX protein in inhibition of reconstitution of the core light-harvesting complexes of Rhodobacter sphaeroides and Rhodobacter capsulatus.
PufX, the protein encoded by the pufX gene of Rhodobacter capsulatus and Rhodobacter sphaeroides, has been further characterized. The mature forms of these proteins contain 9 and 12 fewer amino acids, respectively, at the C-terminal end of the protein than are encoded by their pufX genes. To identify the portion of PufX responsible for inhibition of LH1 formation in reconstitution experiments, different regions (N-terminus and several core regions containing different lengths of the C-terminus) of Rb. sphaeroides and Rb. capsulatus PufX were chemically synthesized. Neither the N- nor C-terminal polypeptides of Rb. sphaeroides were inhibitory to LH1 reconstitution. However, all core segments were active, causing 50% inhibition at a concentration ratio of between 3:1 and 6:1 relative to the LH1 alpha-polypeptides whose concentrations were 3-4 microM. CD measurements indicated that the core segment containing 39 amino acids of Rb. sphaeroides PufX exhibited 47% alpha-helix in trifluoroethanol while the core segment containing 43 amino acids of Rb. capsulatus PufX exhibited 59 and 55% alpha-helix in trifluoroethanol and in 0.80% octylglucoside in water, respectively. Approximately 50% alpha-helix was also indicated by a PHD (Burkhard-Rost) structure prediction. Binding of bacteriochlorophyll to these PufX core segments is implicated.
Amino Acid Sequence↗
Racial differences in the use of cardiac catheterization after acute myocardial infarction.
BACKGROUND: Several studies have reported that black patients are less likely than white patients to undergo cardiac catheterization after acute myocardial infarction. The role of the race of the physician in this pattern is unknown. METHODS: We analyzed data from the Cooperative Cardiovascular Project, a study of Medicare beneficiaries hospitalized for acute myocardial infarction in 1994 and 1995, to evaluate whether differences between black patients and white patients in the use of cardiac catheterization within 60 days after acute myocardial infarction varied according to the race of their attending physician. RESULTS: Our study cohort consisted of 35,676 white and 4039 black patients with acute myocardial infarction who were treated by 17,550 white and 588 black physicians. Black patients had lower rates of cardiac catheterization than white patients, regardless of whether their attending physician was white (rate of catheterization, 38.4 percent vs. 45.7 percent; P< 0.001) or black (38.2 percent vs. 49.6 percent, P<0.001). We did not find a significant interaction between the race of the patients and the race of the physicians in the use of cardiac catheterization. The adjusted mortality rate among black patients was lower than or similar to that among white patients for up to three years after the infarction. CONCLUSIONS: Racial differences in the use of cardiac catheterization are similar among patients treated by white physicians and those treated by black physicians, suggesting that this pattern of care is independent of the race of the physician.
Aged↗
Synthesis and structural characterization of the novel cluster compound.
Reaction of [Mo3Y(mu-S)3(dtp)4(H2O)] (Y = O, S; dtp = S2P(OC2H5)2(-)) with HgI2 gave the novel compound [[Mo3S7(dtp)3]4 x I][(HgI3)3] x 4H2O (1), which contains a [[Mo3S7(dtp)3]4 x I] tetramer and (HgI3)-. Compound 1 has been characterized by IR, Raman, UV/Vis, and NMR spectroscopy and single-crystal X-ray diffraction analysis. It is shown that this formation process can be referred to as a new cluster reaction. The structure and spectroscopic data of the tetramer is also compared with that of the related discrete cluster [Mo3S7(dtp)3 x I]. Crystal data: space group F23, a = 26.786(3) A, V = 19218.7(4) A3, Z = 4, R = 0.059.
Journal Article↗
Quantitative calculations of antibody--antigen binding: steroid--DB3 binding energies by the linear interaction energy method.
Linear interaction energy/molecular dynamics calculations have been used to compute steroid/antibody binding energies. The absolute binding affinities of 10 steroids to antibody DB3 and of a hapten to catalytic antibody 1E9 are computed and compared to experiment. A detailed analysis of the molecular origins of the observed binding patterns is provided. The binding energy of an untested steroid is predicted.
Algorithms↗
Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis.
Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl(4)-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [(3)H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.
Animals↗
Assay of protein tyrosine phosphatases by using matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
A nonradioactive assay for protein tyrosine phosphatases (PTPs), employing a tyrosine-phosphorylated peptide as a substrate, has been developed and applied to analyze purified enzymes, cell extracts, and immunoprecipitates. The reaction was followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) in a linear and positive ion mode with delayed extraction. MALDI-TOF MS detects a loss of peptide mass by 80 Da as a result of dephosphorylation and, more importantly, it yields phospho-peptide to dephosphorylated product peak intensity ratios proportional to their concentration ratios. A strong bias of the MALDI-TOF MS toward detection of the non-phospho-peptide allows accurate detection of small fractions of dephosphorylation. The method is highly sensitive and reproducible. It can be applied to general assays of protein phosphatases with various phospho-peptides as substrates.
Oligopeptides↗
FYVE-DSP2, a FYVE domain-containing dual specificity protein phosphatase that dephosphorylates phosphotidylinositol 3-phosphate.
We have recently isolated FYVE-DSP1, a FYVE domain-containing dual specificity protein phosphatase (R. Zhao, Y. Qi, and Z. J. Zhao, Biochem. Biophys. Res. Commun. 270, 222--229 (2000)). Here, we report a novel isozyme that we designated FYVE-DSP2. FYVE-2 contains a single FYVE domain at the C-terminus, and it shares approximately 47% overall sequence identity with FYBE-DSP1. Genomic sequence analyses revealed that the FYVE-DSP1 and FYVE-DSP2 genes share similar intron/exon organization. They are localizedon human chromosome 22q12 and chromosome 17, respectively. Like FYVE-DSP1, recombinant FYVE-DSP2 dephosphorylated low-molecular-weight phosphatase substrate para-nitrophenylphosphate, and its activity was inhibited by sodium vanadate. More importantly, our study also revealed that both FYVE-DSP1 and FYVE-DSP2 efficiently and specifically dephosphorylated phosphotidylinositol 3-phosphate. Subcellular fractionation demonstrated partition of FYVE-DSP1 and FYVE-DSP2 in membrane fractions, and immunofluorescent cell staining showed perinuclear localization of the enzymes. FYVE-DSP2 is expressed in many human tissues with an alternatively spliced isoform expressed in the kidney. Together with two homologous hypothetical proteins found in Caenorhabditis elegans and Drosophila, FYVE-DSP1 and FYVE-DSP2 form a subfamilyof phosphatases that may have an importantrole in cellular processes.
Adenoviridae↗
Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways.
The tumor suppressor p53 binding protein 1 (53BP1) binds to the DNA-binding domain of p53 and enhances p53-mediated transcriptional activation. 53BP1 contains two breast cancer susceptibility gene 1 COOH terminus (BRCT) motifs, which are present in several proteins involved in DNA repair and/or DNA damage-signaling pathways. Thus, we investigated the potential role of 53BP1 in DNA damage-signaling pathways. Here, we report that 53BP1 becomes hyperphosphorylated and forms discrete nuclear foci in response to DNA damage. These foci colocalize at all time points with phosphorylated H2AX (gamma-H2AX), which has been previously demonstrated to localize at sites of DNA strand breaks. 53BP1 foci formation is not restricted to gamma-radiation but is also detected in response to UV radiation as well as hydroxyurea, camptothecin, etoposide, and methylmethanesulfonate treatment. Several observations suggest that 53BP1 is regulated by ataxia telangiectasia mutated (ATM) after DNA damage. First, ATM-deficient cells show no 53BP1 hyperphosphorylation and reduced 53BP1 foci formation in response to gamma-radiation compared with cells expressing wild-type ATM. Second, wortmannin treatment strongly inhibits gamma-radiation-induced hyperphosphorylation and foci formation of 53BP1. Third, 53BP1 is readily phosphorylated by ATM in vitro. Taken together, these results suggest that 53BP1 is an ATM substrate that is involved early in the DNA damage-signaling pathways in mammalian cells.
Ataxia Telangiectasia Mutated Proteins↗