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Biomedical subjects

B Lu

Publications and source records attributed to B Lu.

At least 37 records · Page 2Linked to original sources
PubMed2001

Molecular cloning and functional characterization of the canine androgen receptor.

Sex steroids, including testosterone, play a major role in determining peak bone mass in mammals and the subsequent loss of total bone mass with advancing age. Testosterone, and its active metabolite dihydrotestosterone (DHT), bind with high affinity to the androgen receptor (AR), a member of the nuclear hormone receptor superfamily. These receptors function as transcription factors, binding together with accessory proteins to specific DNA response elements in the promoters of androgen responsive genes. To further characterize AR function in a model species of relevance to bone and pharmaceutical research, we cloned a partial canine AR from a canine kidney cDNA library and then cloned the remaining 5' segment by PCR from canine ventral prostate cDNA. The complete sequence obtained was 3577 bp. This sequence contained a single open reading frame of 2721 bp, potentially encoding a protein of 907 amino acids with a predicted molecular weight of 98.7 kD. Sequence analysis of the protein encoded by this open reading frame reveals that the modular domains providing the DNA binding and ligand binding functions are identical to those reported for eight other mammalian ARs. Northern analysis of poly-A+ RNA from ventral prostate revealed three very low abundance transcripts of approximately 9 kb and RT-PCR analysis showed relatively high expression of AR in canine ventral prostate, testis, and kidney, with lower levels detectable in spleen, skeletal muscle, heart, and liver. Competition binding studies using 3H-DHT as ligand demonstrated specific displacement by DHT, testosterone, and the anabolic steroid stanozolol, with IC50 values of 1.3, 2.5 and 3.8 nM, respectively. Binding of DHT also resulted in the stimulation of an androgen responsive-luciferase reporter following cotransfection with the canine AR into 293 cells. Immunohistochemistry using an antibody directed to the C-terminal 19 amino acids of the human AR showed strong staining of the secretory epithelial cells in canine ventral prostate. Together, these data indicate that we have cloned the canine AR and that its functional DNA binding and ligand binding domains are absolutely conserved with those reported for eight other species.

Amino Acid Sequence↗
PubMed2001

PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling.

Wnt signalling regulates beta-catenin-dependent developmental processes through the Dishevelled protein (Dsh). Dsh regulates two distinct pathways, one mediated by beta-catenin and the other by Jun kinase (JNK). We have purified a Dsh-associated kinase from Drosophila that encodes a homologue of Caenorhabditis elegans PAR-1, a known determinant of polarity during asymmetric cell divisions. Treating cells with Wnt increases endogenous PAR-1 activity coincident with Dsh phosphorylation. PAR-1 potentiates Wnt activation of the beta-catenin pathway but blocks the JNK pathway. Suppressing endogenous PAR-1 function inhibits Wnt signalling through beta-catenin in mammalian cells, and Xenopus and Drosophila embryos. PAR-1 seems to be a positive regulator of the beta-catenin pathway and an inhibitor of the JNK pathway. These findings show that PAR-1, a regulator of polarity, is also a modulator of Wnt-beta-catenin signalling, indicating a link between two important developmental pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2001

PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation.

Signaling mechanisms underlying neurotrophic regulation of synaptic transmission are not fully understood. Here we show that neurotrophin-3 (NT3)-induced potentiation of synaptic transmission at the neuromuscular synapses is blocked by inhibition of phosphoinositide-3 kinase, phospholipase C-gamma or the downstream IP3 receptors of phospholipase C-gamma, but not by inhibition of MAP kinase. However, neither stimulation of Ca2+ release from intracellular stores by photolysis of caged IP3, nor expression of a constitutively active phosphoinositide-3 kinase (PI3K*) in presynaptic motoneurons alone is sufficient to enhance transmission. Photo-uncaging of IP3 in neurons expressing PI3K* elicits a marked synaptic potentiation, mimicking the NT3 effect. These results reveal an involvement of PI3 kinase in transmitter release, and suggest that concomitant activation of PI3 kinase and IP3 receptors is both necessary and sufficient to mediate the NT3-induced synaptic potentiation.

Animals↗
PubMed2001

Defective T cell activation and autoimmune disorder in Stra13-deficient mice.

Stra13, a basic helix-loop-helix transcription factor, is up-regulated upon activation of CD4+ T cells. Here we show that Stra13-deficient mice exhibit defects in several phases of CD4+ T cell activation. In vivo, Stra13 deficiency results in ineffective elimination of activated T and B cells, which accumulate progressively, leading to lymphoid organ hyperplasia. Consequently, aging Stra13-/- mice develop autoimmune disease characterized by accumulation of spontaneously activated T and B cells, circulating autoantibodies, infiltration of T and B lymphocytes in several organs and immune complex deposition in glomeruli. Our studies identify Stra13 as a key regulator of lymphocyte activation that is vital for maintenance of self-tolerance and for constraint of autoimmunity.

Aging↗
PubMed2001

GDNF acutely modulates excitability and A-type K(+) channels in midbrain dopaminergic neurons.

Glial cell line-derived neurotrophic factor (GDNF) prevents lesion-induced death of midbrain dopaminergic neurons, but its function in normal brain remains uncertain. Here we show that GDNF acutely and reversibly potentiated the excitability of cultured midbrain neurons by inhibiting transient A-type K(+) channels. The effects of GDNF were limited to large, tyrosine hydroxylase (TH)-positive dopaminergic neurons, and were mediated by mitogen associated protein (MAP) kinase. Application of GDNF also elicited a MAP kinase-dependent enhancement of the excitability in dopaminergic neurons in midbrain slice. These results demonstrate an acute regulation of GDNF on ion channels and its underlying signaling mechanism, and reveal an unexpected role of GDNF in normal midbrain dopaminergic neurons.

4-Aminopyridine↗
PubMed2001

Coronary artery motion during the cardiac cycle and optimal ECG triggering for coronary artery imaging.

RATIONALE AND OBJECTIVES: Our purpose was to investigate the motion characteristics of the coronary arteries and determine optimal electrocardiographic (ECG) trigger time during the cardiac cycle to minimize motion artifacts. METHODS: Contrast-enhanced multislice movie studies of electron beam tomography (EBT) images were performed on 70 subjects. The EBT datasets, which covered an entire cardiac cycle at 58-ms intervals, were acquired for a short-axis view of the heart with ECG triggering. The pixel values along x and y axes were measured at multiple intervals during the cardiac cycle to establish the motion distance and velocity of three major coronary arteries. RESULTS: Coronary artery motion varied greatly throughout the cardiac cycle in three major coronary arteries and increased with the patient's baseline heart rate. The greatest and lowest velocities of coronary arterial movement during the cardiac cycle were determined. Based on the lowest velocity of right coronary artery movement during the cardiac cycle, the optimal ECG trigger times were located at approximately 35% (31.4%-37.6%) or 70% (68.7%-71.4%) of the R-R interval in patients whose resting heart rate was < or =70 beats per minute (bpm); at 50% (47.2%-61.1%) of the R-R interval in the 71- to 100-bpm group; and at 55% (52.8%-59.1%) of the R-R interval in the >100-bpm group. Our data demonstrated that the motion characteristics of the left circumflex artery were quite similar to those of the right coronary artery and that the left anterior descending coronary artery had no significant differences in motion throughout the cardiac cycle. A minimum scan speed of 35.4 to 75.5 ms per slice is needed to completely diminish cardiac motion artifacts (in-plane coronary artery motion with <1-mm displacement). CONCLUSIONS: For coronary artery screening, the optimal ECG trigger time should be determined according to the patient's heart rate, thus greatly reducing motion and motion artifacts during 100-ms acquisitions.

Adult↗
PubMed2001

Effect of electrocardiogram triggering on reproducibility of coronary artery calcium scoring.

PURPOSE: To test the hypothesis that computed tomographic (CT) scanning during early rather than middle diastole can significantly reduce the interscan variability of coronary artery calcium (CAC) scores. MATERIALS AND METHODS: Five hundred thirty-eight patients were initially enrolled; 282 of them were found to have CAC at electron-beam CT and underwent repeat scanning to measure interscan variability with different electrocardiogram (ECG) triggers. Eight patients were excluded owing to respiratory motion; thus, 274 asymptomatic patients were examined. Patients were randomly assigned to different ECG trigger interval groups: 40% (group 1), 50% (group 2), 60% (group 3), and 80% (group 4). Patients in whom more than one-third of sections had greater than 10% ECG trigger variability were classified in the untriggered group (group 5). Interscan variation was compared among all five groups. RESULTS: Interscan variabilities in CAC groups 1-5 were 11.5%, 15.3%, 20.3%, 17.4%, and 33.1%, respectively, for total calcium area, and 15.0%, 23.3%, 25.6%, 24.0%, and 42.4%, respectively, for total calcium score. CAC score variability was reduced by 34%; and calcium area variability, by 38% in group 1, as compared with the reduced variabilities in group 4 (P <.01 for both measures). Breath holding was adequate in 812 cases, and ECG triggering was correct in 790 of cases. CONCLUSION: Study results strongly support the use of an ECG trigger of 40% rather than 80% of the R-R interval in electron-beam CT calcium studies.

Calcium↗
PubMed2001

Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine [correction of pyrazolidinone-piperidine] growth hormone secretagogue.

Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine [corrected] GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50 = 3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of G H in a dose-dependent manner. Plasma insulin-like growth factor-I (IGF-I) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-I levels.

Administration, Oral↗
PubMed2001

[Ecological industrial garden: an ideal model of sustainable development].

There exist different kinds of views on the connotation of sustainable development of the society. In this paper, analysis from several aspects including certainty and necessity, the whole and the parts, development and limitation to the issue is given. Meanwhile, it can be shown from a summarized analysis to the models of sustainable development that the models consist of two kinds, theory one and practical one. A tentative plan of ecological industrial garden establishment in areas whose local conditions are permitted is put forward to promote its transformation rapidly from theory to practice, and it is regarded as a more perfect model for social sustainable development in the future.

Ecology↗
PubMed2001

Evaluation of coronary artery bypass graft patency using three-dimensional reconstruction and flow study of electron beam tomography.

OBJECTIVE: To establish and evaluate two protocols for the noninvasive visualization and assessment of coronary artery bypass graft (CABG) patency on electron beam tomography (EBT). METHODS: Two hundred and fourteen consecutive patients who underwent coronary artery bypass graft surgery were scanned using both EBT angiography with 3-dimensional reconstruction and EBT flow study with time-density-curve analysis. RESULTS: There were 589 CABGs evaluated in this study (10 grafts were excluded because of artifacts). Among them, 133 (98.5%) of 135 arterial grafts were patent, and 345 (77.7%) of 444 saphenous-vein grafts were patent. Within 5 years or between 5 and 10 years after operation, arterial graft patency exceeded venous graft patency (P < 0.001). Three-dimensional EBT angiography achieved higher sensitivity, specificity and accuracy (97.7%, 94.1% and 96.7%, respectively) than did EBT flow study (88.4%, 82.4% and 85.2%, respectively) for evaluating occlusion or patency of CABG. The intra-graft flow of patent arterial and venous grafts were 4.9 +/- 2.2 ml.min-1.g-1 and 6.9 +/- 2.8 ml.min-1.g-1, respectively (P < 0.001). CONCLUSION: The combination of EBT three-dimensional reconstruction and flow study can be more effective in the assessment of CABG anatomy and quantification of patent CABG blood flow.

Adult↗
PubMed2001

[Biocompatibility of HA/TCP biphasic ceramics with co-cultured human osteoblasts in vitro].

The biocompatibility of HA/TCP ceramic was evaluated by investigation of attachment and growth of osteoblasts on biomaterial, as well as monitoring the effects of biomaterial on expression of functional phenotypes of co-cultured osteoblasts in vitro. When co-cultured with HA/TCP ceramics, osteoblasts firstly attached to the surface of HA/TCP disk, then attached to notches and grew into the micropores of biomaterial during further culture period. At last, the ceramics were almost packed with osteoblasts. Additionally, osteoblasts co-cultured with HA/TCP were similar to osteoblasts cultured under normal condition in osteoblastic phenotypes; the secreted lots of collagen type I, possess strong activity of Alkaline Phosphatase and mineralized extracellular matrix. The fact that osteoblasts could grow well on HA/TCP ceramics and the biomaterial did not affect their physiological function suggest that HA/TCP ceramic is biocompatible with human osteoblasts.

Biocompatible Materials↗
PubMed2001

[Clinical and pathological characteristics of heroin spongiform leukoencephalopathy in China].

OBJECTIVE: To observe the clinical, image and pathological characteristics of Heroin Spongiform Leukoencephalopathy(HSLE). METHODS: Clinical, CT and MRI analysis of 28 cases, brain autopsies of 2 cases and brain biopsies of 8 cases with HE, Loyez and Congo Red staining and observation through electron microscope. RESULTS: The clinic, image and pathologic characteristics of HSLE: (1) the history of inhalation of heated heroin vapor; (2) among 28 cases with HSLE, recurrence of HSLE was found in 17 cases during the abstinence, in 8 cases 1-2 month after abstinence, in 2 cases 4 month after abstinence and in 1 case after inhaling large amount of heroin; (3) the majority of cases were described with the acute onset characterized by cerebellar signs; (4) pyramidal tract lesion was frequently involved, but sensory system usually remained normal; (5) CSF test was normal; (6) CT and MRI revealed extensive symmetric white matter lesions in cerebra and cerebellum; (7) spongiform vacuoles degeneration of white matter was the main morphological change. CONCLUSIONS: Spongiform leukoencephalopathy may be considered if a patient who had a history of inhaling heated heroin vapor showed acute cerebellar signs. Spongiform vacuoles degeneration of cerebral white matter was the main pathological change.

Adult↗
PubMed2000

Requirement of the chemokine receptor CXCR3 for acute allograft rejection.

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein-coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-gamma-inducible protein of 10 kD (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T cell alpha chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3(-/)-) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3(-/)- allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR(+/+) mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

Acute Disease↗
PubMed2000

Interferon gamma signaling alters the function of T helper type 1 cells.

One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon gamma receptor (IFN-gammaR), whereas Th1 cells do not express the second chain of the IFN-gammaR (IFN-gammaR2) and are therefore unresponsive to IFN-gamma. To determine whether the regulation of IFN-gammaR2 expression, and therefore IFN-gamma responsiveness, is important for the differentiation of naive CD4(+) T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-gammaR2 is controlled by the CD2 promoter and enhancer. CD4(+) T cells from IFN-gammaR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-gamma production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-gammaR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-gamma-unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.

Animals↗
PubMed2000

Activity- and Ca(2+)-dependent modulation of surface expression of brain-derived neurotrophic factor receptors in hippocampal neurons.

Brain-derived neurotrophic factor (BDNF) has been shown to regulate neuronal survival and synaptic plasticity in the central nervous system (CNS) in an activity-dependent manner, but the underlying mechanisms remain unclear. Here we report that the number of BDNF receptor TrkB on the surface of hippocampal neurons can be enhanced by high frequency neuronal activity and synaptic transmission, and this effect is mediated by Ca(2+) influx. Using membrane protein biotinylation as well as receptor binding assays, we show that field electric stimulation increased the number of TrkB on the surface of cultured hippocampal neurons. Immunofluorescence staining suggests that the electric stimulation facilitated the movement of TrkB from intracellular pool to the cell surface, particularly on neuronal processes. The number of surface TrkB was regulated only by high frequency tetanic stimulation, but not by low frequency stimulation. The activity dependent modulation appears to require Ca(2+) influx, since treatment of the neurons with blockers of voltage-gated Ca(2+) channels or NMDA receptors, or removal of extracellular Ca(2+), severely attenuated the effect of electric stimulation. Moreover, inhibition of Ca(2+)/calmodulin-dependent kinase II (CaMKII) significantly reduced the effectiveness of the tetanic stimulation. These findings may help us to understand the role of neuronal activity in neurotrophin function and the mechanism for receptor tyrosine kinase signaling.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB.

The neurotrophin BDNF has been shown to modulate long-term potentiation (LTP) at Schaffer collateral-CA1 hippocampal synapses. Mutants in the BDNF receptor gene trkB and antibodies to its second receptor p75NTR have been used to determine the receptors and cells involved in this response. Inhibition of p75NTR does not detectably reduce LTP or affect presynaptic function, but analyses of newly generated trkB mutants implicate TrkB. One mutant has reduced expression in a normal pattern of TrkB throughout the brain. The second mutant was created by cre-loxP-mediated removal of TrkB in CA1 pyramidal neurons of this mouse. Neither mutant detectably impacts survival or morphology of hippocampal neurons. TrkB reduction, however, affects presynaptic function and reduces the ability of tetanic stimulation to induce LTP. Postsynaptic glutamate receptors are not affected by TrkB reduction, indicating that BDNF does not modulate plasticity through postsynaptic TrkB. Consistent with this, elimination of TrkB in postsynaptic neurons does not affect LTP. Moreover, normal LTP is generated in the mutant with reduced TrkB by a depolarization-low-frequency stimulation pairing protocol that puts minimal demands on presynaptic terminal function. Thus, BDNF appears to act through TrkB presynaptically, but not postsynaptically, to modulate LTP.

Animals↗