Genomic organization of LPS-specific loci.
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Animals↗
Biomedical subjects
L Wang
Publications and source records attributed to L Wang.
A novel sheep model to study the effect of high rate intracoronary perfusion on cardiac electrophysiology.
UNLABELLED: An increase in coronary flow is known to enhance myocardial metabolism and contractility (the Gregg effect) but the effect on cardiac electrophysiology is unclear. In 5 pentobarbital-anesthetised open-chest sheep, left circumflex coronary artery was perfused with fresh arterial blood at 6 and 10 ml/min respectively in the presence of normal coronary flow. The perfusion was repeated in these animals after treatment with nitro-L-arginine, a nitric oxide synthase inhibitor. The high rate intracoronary perfusion caused a flow-dependent T wave inversion on body surface ECG in all animals (p < 0.01). Pre-treatment with nitro-L-arginine abolished T wave inversion during 6 ml/min perfusion, and diminished the T inversion during 10 ml/min perfusion. CONCLUSION: An increase in coronary flow alters ventricular repolarisation through nitric oxide release from coronary endothelium.
Animals↗
Clinical applications of plasma shock wave lithotripsy in treating postoperative remnant stones impacted in the extra- and intrahepatic bile ducts.
BACKGROUND: Choledochofiberscopy with basket extraction has been used widely to treat postoperative remnant stones in the bile duct system. However, it remains difficult to extract stones impacted in the bile duct system or stones too large to pass through the T-tube fistula. This report describes the efficacy and safety of plasma shock wave lithotripsy (PSWL) in fragmenting and eliminating such remnant stones from the bile duct. METHODS: In 52 patients, 117 remnant stones were fragmented with PSWL and subsequently extracted with choledochofiberscopy. The efficacy and safety of PSWL were observed during and after the procedure. RESULTS: After 116 of 117 remnant stones (99.1%) impacted in the extra- and intrahepatic bile ducts were fragmented successfulIy with PSWL, they were extracted with choledochofiberscopy. There were no significant complications during and after the procedure. CONCLUSION: It appears that PSWL is an effective and safe method for fragmenting remnant stones impacted in the bile duct system and stones too large to pass through the T-tube fistula.
Adult↗
Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection.
A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.
Anti-HIV Agents↗
Design, synthesis, and SAR of heterocycle-containing antagonists of the human CCR5 receptor for the treatment of HIV-1 infection.
Replacement of the large hydantoin-indole moiety from our previous work with a variety of smaller heterocyclic analogues gave rise to potent CCR5 antagonists having binding affinity comparable to the hydantoin analogues. The synthesis, SAR, and biological profiles of this class of antagonists are described.
Anti-HIV Agents↗
Mesotunnels on the silica wall of ordered SBA-15 to generate three-dimensional large-pore mesoporous networks.
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Journal Article↗
Effect of ecNOS polymorphisms and coronary artery disease upon exhaled nitric oxide.
Exhaled nitric oxide (eNO) is thought to arise principally from the airway epithelium. NO regulates smooth muscle tone, and abnormal activity of NO synthase has been implicated in coronary artery disease (CAD). Polymorphisms of endothelial constitutive NO synthase (ecNOS) may affect NO generation and be associated with CAD. It was hypothesised that a polymorphism, such as the ecNOS intron 4 polymorphism (ecNOS4a), affects the levels of eNO via airway epithelial NOS. eNO levels were measured in 53 patients with ischaemic chest pain who had previously been genotyped for ecNOS polymorphisms, with sample enrichment for the ecNOS4a allele. Subjects were also assessed for two other ecNOS polymorphisms (T-786C substitution in the promoter region, and G5557T in exon 7), variably associated with vascular disease. Those homozygous for the 'a' allele (ecNOS4a/a) had a lower mean eNO (9.0 ppb) than those who were heterozygous (ecNOS4a/b, 13.6 ppb), who in turn had a lower level than those homozygous for the wild-type ecNOS4b/b (16.1 ppb). No association of eNO levels was found with the other polymorphisms. Levels of eNO remained significantly lower in the ecNOSa/a subjects than in the ecNOSa/b and ecNOSb/b subjects, even when controlled for angiographic CAD, and smoking habit. In addition, all subjects with CAD had a significantly lower mean eNO (12.1 ppb) than subjects without angiographic CAD (19.9 ppb). In this selected population low levels of eNO were thus associated with presence of the ecNOS4a allele and also with CAD.
Administration, Oral↗
Identification of species in Aspergillus section Flavi based on sequencing of the mitochondrial cytochrome b gene.
The partial sequences of the mitochondrial (mt) cytochrome b gene (402 bp) were determined for species of Aspergillus section Flavi. On the basis of identities of DNA sequences, 77 strains were divided into seven DNA types, from D-1 to D-7. The type strains of A. sojae, A. parasiticus, A. flavus and A. oryzae together, A. tamarii, and A. nomius were placed in DNA types D-1. D-2, D-4, D-5 and D-7, respectively. These species could be differentiated from each other. Furthermore, two other DNA types, D-3 and D-6 were found. DNA type D-3 was closely related to A. parasiticus (D-2) and included one strain that deposited as A. flatus var. flavus and produced aflatoxins B and G. DNA types D-6 included one strain named A. flavus and closely related to A. tamarii. The observations of conidial wall texture by SEM (Scanning Electron Microscopy) supported the relationships derived from the cytochrome b gene. The production of aflatoxins was also examined. Using the DNA sequence of cytochrome b gene, several strains were reidentified. The derived amino acids sequences were all the same in the studied strains. The mt cytochrome b gene is useful and reliable in distinguishing and identifying the species in Aspergillus section Flavi.
Amino Acid Sequence↗
Human V gamma 2V delta 2 T cells produce IFN-gamma and TNF-alpha with an on/off/on cycling pattern in response to live bacterial products.
Whereas cytokine production in alphabeta T cells is rapidly regulated by exposure to peptide Ag, the mechanisms regulating cytokine production by gammadelta T cells are unknown. In this study, we demonstrate that human Vgamma2Vdelta2 T cells produce IFN-gamma and TNF-alpha as early as 2 h after Ag exposure, and that they produce these cytokines in a dose- and time- dependent manner in response to stimulation with a live bacterial product, iso-butylamine (IBA), but not to dead bacteria or LPS. gammadelta T cells began, ceased, and then resumed IFN-gamma and TNF-alpha generation in an on/off/on cycling pattern, both in vitro and in vivo, depending on the presence or absence of IBA. IFN-gamma and TNF-alpha, whose optimum production was dependent on IBA-stimulated gammadelta T cells, were critical for monocyte-mediated killing of Escherichia coli. By limiting cytokine production to periods of direct contact with live bacteria, gammadelta T cells focus their resources at the site of infection, while limiting systemic immunopathology. Thus, human gammadelta T cells may mediate innate resistance to extracellular bacteria via tightly regulated cytokine production without necessarily expanding in number.
Animals↗
Endotoxin impairs biliary transport of sparfloxacin and its glucuronide in rats.
The effect of endotoxin on glucuronidation and hepatobiliary transport of quinolone antimicrobial agents was investigated in rats using sparfloxacin and p-nitrophenyl glucuronide as model drugs. The biliary clearance experiments were performed 24 h after a single intraperitoneal injection of endotoxin (1 mg/kg). Endotoxin significantly delayed the disappearance of sparfloxacin from plasma and increased plasma concentration of its glucuronide after intravenous injection of sparfloxacin (10 mg/kg). Significant decreases in the systemic clearance of sparfloxacin and the biliary clearance of sparfloxacin and the glucuronide were observed. Endotoxin had no effect on in vitro glucuronidation activity using p-nitrophenol as a substrate. When p-nitrophenyl glucuronide (8 mg/kg) was administered in endotoxin-pretreated rats, significant decreases in the systemic clearance, biliary clearance and renal clearance of p-nitrophenyl glucuronide were observed. These findings suggest that endotoxin decreases the biliary excretion of sparfloxacin and its glucuronide probably due to impairment of their hepatobiliary transport systems and renal handling.
Animals↗
A repressor-response regulator gene pair controlling jadomycin B production in Streptomyces venezuelae ISP5230.
A second regulatory gene (jadR(1)) is located immediately upstream of the putative repressor gene (jadR(2)) in the jad cluster for biosynthesis of the antibiotic jadomycin B in Streptomyces venezuelae ISP5230. It encodes a 234-amino acid polypeptide with a sequence resembling those of response regulator proteins in two-component control systems. Features in the conserved C-terminal domain of JadR(1) place the protein in the OmpR-PhoB subfamily of response regulators. In mutants where jadR(1) was deleted or disrupted, jadomycin B was not produced, implying that the gene has an essential role in biosynthesis of the antibiotic. Cloning jadR(1) from S. venezuelae in pJV73A, and introducing additional copies of the gene into the wild-type parent by plasmid transformation gave unstable strains with pJV73A integrated into the chromosome. The transformants initially showed increased production of jadomycin B but gave lower titers as excess copies of jadR(1) were lost; mature cultures stabilized with a wild-type level of antibiotic production. The mutant from which jadR(1) had been deleted could not be transformed with pJV73A. Altering the composition of jadR genes in the chromosome by integration of vectors carrying intact and disrupted copies of jadR(1) and jadR(2) provided evidence that the two genes form a regulatory pair different in function from previously reported two-component systems controlling antibiotic biosynthesis in streptomycetes.
Alleles↗
A first comparison of the human multifocal visual evoked magnetic field and visual evoked potential.
Our objectives were to determine the feasibility of recording reliable multifocal visual evoked magnetic fields (mfVEFs), to investigate the maximum stimulus eccentricity for which the mfVEF responses can be obtained, and to study how this changes with checksize (spatial frequency tuning). Using a checksize of 30', we recorded 8-channel pattern-onset mfVEFs three times to obtain responses from 19 channels located around the inion. Multifocal visual evoked potentials (mfVEPs) were recorded under the same conditions. Eccentricity changes with spatial frequency were studied using checksizes from 7.5' to 60'. We obtained, for the first time, reliable mfVEFs, and found they could be elicited from more peripheral stimulus elements than could mfVEPs. The larger the checksize, the greater the eccentricity reached.
Adult↗
A unique ring-expanded acyclic nucleoside analogue that inhibits both adenosine deaminase (ADA) and guanine deaminase (GDA; guanase): synthesis and enzyme inhibition studies of 4,6-diamino-8H-1-hydroxyethoxymethyl-8-iminoimidazo[4,5-e][1,3]diazepine.
The synthesis and enzyme inhibition studies of a novel ring-expanded acyclic nucleoside analogue are reported. Compound has been found to be a competitive inhibitor of both adenosine deaminase (ADA) and guanine deaminase (GDA; guanase) with K(i)'s equal to 1.52+/-0.34 x 10(-4) M and 2.97+/-0.25 x 10(-5) M, respectively. Inhibition of two enzymes of purine metabolism may bear beneficial implications in antiviral therapy.
Adenosine Deaminase Inhibitors↗
Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein.
The BCR-ABL oncogene is central in the pathogenesis of chronic myeloid leukemia (CML). Here, tandem nanospray mass spectrometry was used to demonstrate cell surface HLA-associated expression of the BCR-ABL peptide KQSSKALQR on class I-negative CML cells transfected with HLA-A*0301, and on primary CML cells from HLA-A3-positive patients. These patients mounted a cytotoxic T-lymphocyte response to KQSSKALQR that also killed autologous CML cells, and tetramer staining demonstrated the presence of circulating KQSSKALQR-specific T cells. The findings are the first demonstration that CML cells express HLA-associated leukemia-specific immunogenic peptides and provide a sound basis for immunization studies against BCR-ABL.
Adult↗
Activation of melanoma antigen tumor antigens occurs early in lung carcinogenesis.
The melanoma antigen (MAGE)-encoding genes are expressed in various tumor types, including lung, and are thought to be silent in all normal tissues except testis. In search of biomarkers for early lung cancer detection and cancer risk assessment, we investigated frequencies of expressional activation of MAGE-A1, -A3, and -B2 genes in non-small cell lung cancers (NSCLCs). Expression of these genes was evaluated by reverse transcription-PCR (RT-PCR) in 20 primary NSCLC samples and corresponding normal lung tissues as well as in 20 bronchial brush specimens from former smokers without lung cancer. mRNA in situ hybridization was done to confirm the gene expression pattern at the cellular level. Methylation-specific PCR was performed to evaluate the hypomethylation status of CpG sites in the promoter regions of these genes. Among the 20 primary NSCLC samples analyzed, 14 (70%) expressed MAGE-A1 and 17 (85%) each expressed MAGE-A3 and MAGE-B2. A substantial number of normal lung tissues adjacent to NSCLC also had a detectable level of MAGE expression (65, 75, and 80% for MAGE-A1, -A3, and -B2, respectively). We found that 7 (35%), 10 (50%), and 11 (55%) of the adjacent normal lung tissue samples exhibited promoter hypomethylation at MAGE-A1, -A3, and -B2, respectively, compared with 15 (75%), 16 (80%), and 16 (80%) of the NSCLC samples. Among the 20 bronchial epithelium samples from former smokers, 7 (35%), 10 (50%), and 12 (60%) had also detectable -A1, -A3, and -B2 expression, respectively. Activation of MAGE-A1, -A3, and -B2 genes is common not only in NSCLC but also in bronchial epithelium with severe carcinogen insult. These results suggest that MAGE genes may be activated very early in lung carcinogenesis and may be considered as targets for lung cancer prevention.
Aged↗
Costimulation blockade promotes the apoptotic death of graft-infiltrating T cells and prolongs survival of hepatic allografts from FLT3L-treated donors.
BACKGROUND: Mouse liver grafts are accepted across major histocompatibility complex (MHC) barriers and induce donor-specific tolerance without immunosuppressive therapy. By contrast, hepatic allografts from donors treated with the hematopoietic growth factor fms-like tyrosine kinase 3 ligand (FL), which dramatically increases hepatic interstitial dendritic cells (DC), are rejected acutely (median survival time 5 days). This switch from tolerance to rejection is associated with a marked reduction in apoptotic activity of graft-infiltrating T cells. We hypothesized that T-cell costimulation, provided by markedly enhanced numbers of donor antigen presenting cells (APCs), might inhibit apoptosis, promote expansion of T helper 1 cells and play a key role in acute liver rejection. METHODS: C3H (H2k) recipients of orthotopic liver grafts from FL-treated B10 (H2b) donors were given cytotoxic T-lymphocyte antigen 4: immunoglobulin (CTLA4Ig), a chimeric fusion protein that blocks the B7-CD28 costimulatory pathway, or control human immunoglobulin (200 microg) on the day of transplantation (day 0). Livers and spleens were removed on day 4. Cryostat sections were stained for interleukin (IL)-12 or by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL). Expression of mRNA encoding interferon (IFN)-gamma and IL-10 was determined by RNase protection assay. Suspensions of graft-infiltrating cells (GICs) and spleen cells were analyzed for apoptotic (TUNEL+) T-cell subsets by flow cytometry. CTL activity of GICs and circulating alloantibody levels were determined by cytotoxicity assays. RESULTS: Survival of liver grafts from FL donors was markedly prolonged by CTLA4Ig administration. This effect was associated with reductions in IFN-gamma and IL-10 gene transcripts within the GIC population, and with decreases in donor-specific CTL and NK cell activities and circulating anti-donor alloantibody levels. At the same time, there were marked increases in TUNEL+ CD4+ and especially CD8+ cells, both within the grafts and in the spleens of CTLA4Ig-treated mice. CONCLUSIONS: Signaling via the B7-CD28 pathway appears to play a key role in the switch from tolerance to rejection that is precipitated by markedly enhanced numbers of donor DCs. Inhibition of acute liver allograft rejection by CTLA4Ig, linked to restoration of apoptotic activity of graft-infiltrating T cells, further suggests that deletion of these cells may be critical for promotion of long-term allograft survival.
Abatacept↗
Enhancement of the p300 HAT activity by HIV-1 Tat on chromatin DNA.
HIV-1 Tat is able to form a ternary complex with P/CAF and p300 and increase the affinity for CDK9/P-TEFb CTD kinase complex. Our previous study demonstrated that Tat binds to p300/CBP in the minimal HAT domain (aa 1253-1790) and that the interaction results in a change of conformation on p300/CBP. Here, we show that the Tat-p300 interaction increases the HAT activity of p300 on histone H4 that is associated with nucleosomal DNA and not with free histones. Nucleosomal histone H4 was acetylated on lysines 8, 12, and 16. Acetylation of H4 was inhibited by Lys-coenzyme A (CoA), a selective inhibitor of p300 acetyltransferase activity. Unexpectedly, we also found that Tat could autoacetylate itself, which was specific to lysine residues 41 and 71. Peptides lacking these two lysines could not enhance the HAT activity of p300. Comparison of the sequences of Tat with other HIV-1 clades and HAT containing transcription factors indicated sequence identity in the acetyl-CoA binding motif A, KGXG. Furthermore, when utilizing an in vitro transcription assay, as well as a Tat mutant virus, we found that ectopic expression of only wild-type Tat in the presence of p300, and not a lysine 41 Tat mutant, could activate HIV-1 chromatin DNA, as evidenced by the absence of HIV-1 virion antigen. Therefore, transcription of integrated viral DNA in vivo requires the HAT activity of coactivators that are modulated by Tat to derepress the HIV-1 chromatin structure and aid in activated transcription.
Acetyl-CoA C-Acetyltransferase↗
Influence of polyamine architecture on the transport and topoisomerase II inhibitory properties of polyamine DNA-intercalator conjugates.
An efficient five-step synthetic method was developed to access a series of spermine derivatives containing appended acridine, anthracene, and 7-chloroquinoline motifs. The derivatives were composed of a spermine fragment covalently tethered at its N4 and N9 positions to an aromatic nucleus via an aliphatic chain (e.g., 8: acridine -[C4 aliphatic tether]-spermine-[C4 aliphatic tether]-acridine). The distance separating the spermine and aromatic nuclei was altered via different tethers composed of four or five methylene units. These bis ligands (8, 9, 12, and 13) were shown to inhibit human DNA topoisomerase II (topo II) activity at 5 microM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermine conjugates 8 and 9 to inhibit topo II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridine controls (at 5 microM). The parent polyamines, spermine (5 microM) and spermidine (10 microM), had little effect on topo II activity. In general, the bis-substituted spermine derivatives (8, 9, 12, and 13) were more efficient topo II inhibitors at 5 microM than their monosubstituted spermidine counterparts (22-25) at 10 microM. Within the bisintercalator spermine series, insertion of an additional methylene unit (i.e., C5 tethers) increased potency 2-fold (8, bis-C4-acridine, 47 h IC(50) = 40 microM; 9, bis-C5-acridine, IC(50) = 17 microM). Comparison of the bis- and monoacridine spermine motifs (8 and 17) revealed a 4-fold increase in potency for the latter architecture (94 h IC(50) for 8, 74 microM; for 17, 17 microM). In general the bisintercalators (8, 9, 12, and 13) behaved as cytostatic agents, while the monosubstituted acridine and anthracene derivatives (22-25) were cytotoxic. Anthracene-containing conjugates were generally more toxic than their acridine counterparts in an L1210 (murine leukemia) cell assay. Of the conjugates tested the (monointercalator)-spermine motif (e.g., 17) had the highest affinity for the L1210 polyamine transporter as revealed by spermidine protection experiments.
Acridines↗