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Biomedical subjects

L Wang

Publications and source records attributed to L Wang.

At least 1,009 records · Page 56Linked to original sources
PubMed1999

Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells.

Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase required for T cell development and activated by cytokines that utilize the interleukin-2 (IL-2) receptor common gamma chain (gamma(c)). Genetic inactivation of JAK3 is manifested as severe combined immunodeficiency disease (SCID) in humans and mice. These findings have suggested that JAK3 represents a pharmacological target to control certain lymphoid-derived diseases. Here we provide novel evidence that AG-490 potently inhibits the autokinase activity of JAK3 and tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription 5a and 5b (STAT5a/b). Similar inhibitory effects were observed with other cytokines that use gamma(c). AG-490 also inhibited IL-2-mediated proliferative growth in human T cells with an IC50) = 25 microM that was partially recoverable. Moreover, we demonstrate that this inhibitor prevented tetanus toxoid antigen-specific T cell proliferation and expansion but failed to block activation of Zap70 or p56Lck after anti-CD3 stimulation of human T cells. Taken together, these findings suggest that AG-490 inhibits the JAK3-mediated Type II signaling pathway but not the T cell receptor-derived Type I pathway and possesses therapeutic potential for T cell-derived pathologies such as graft-versus-host disease, allergy, and autoimmune disorders.

Animals↗
PubMed1999

Glycoprotein 330/megalin (LRP-2) has low prevalence as mRNA and protein in brain microvessels and choroid plexus.

Prior studies indicated that glycoprotein 330 (gp330)/megalin mediates transcytosis of apolipoprotein J (apoJ) with Alzheimer's amyloide-peptide (Abeta) across the vascular membranes of the central nervous system (CNS). Here we show the presence of gp330/megalin mRNA and gp330-like immunoepitopes in brain capillaries and choroid plexus and their absence from brain parenchyma. By polymerase chain reaction (PCR) we estimated 1.2 x 10(5) molecules (1 pg) of gp330/megalin mRNA/microg total brain capillary RNA, which is 3% of that in kidney RNA. However, gp330 mRNA was not detected by in situ hybridization in vascular CNS tissue, presumably because of low transcript prevalence. The ratio of gp330 protein:RNA was 17-fold higher in choroid plexus vs brain capillaries, which implies tissue specific regulation of the protein and mRNA prevalence. We conclude that gp330/megalin mRNA and protein are expressed in brain capillaries and choroid plexus in small amounts that are consistent with the observed activities of this endocytosing receptor in the regulation of apoJ and Abeta uptake by the CNS.

Animals↗
PubMed1999

An Analysis of Higher Order Vibration-Torsion-Rotation Interactions and Spectra for a Molecule with an Internal Rotor.

Motivated by attempts to answer the questions (i) if the same order of magnitude is really appropriate for the torsional angular momentum terms P2gamma and the rotational angular momentum term P2 (or P2a), (ii) how to systematically analyze various higher order interaction effects, especially the torsional effects, and (iii) if a reduced Hamiltonian can be used to fit observed spectroscopic data to an accuracy approaching experimental uncertainties over a significant range of quantum states, a detailed discussion is presented on the order of magnitude of a Hamiltonian term Hmln for molecules with an internal rotation. A new scheme of the ordering by magnitude is proposed to analyze the vibration-torsion-rotation (VTR) interactions, in which the importance of the torsional problem is emphasized. The contact transformation technique is applied to the VTR Hamiltonian, which makes it possible to analyze clearly various higher order VTR interactions and their effects in the VTR spectra of the molecule. The resulting formulas are applicable to analyze observed spectra. A reduced torsion-rotation Hamiltonian for the molecule with C3v(M) symmetry is given in the new ordering scheme. As an application, a total of 568 microwave lines with vt </= 3, J </= 42 and K </= 8 for CH318OH have been fitted to 64 molecular constants by using the reduced Hamiltonian with a root mean square (rms) of 0.262 MHz, where the A and E substates are treated simultaneously. About 35 newly assigned lines are added to our former fitting data (M. Ikeda, Y. B. Duan, S. Tsunekawa, and K. Takagi, ApJS, 117, 249 (1998)). Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Combined adenine phosphoribosyltransferase and N-acetylgalactosamine-6-sulfate sulfatase deficiency.

We describe a Czech patient with combined adenine phosphoribosyltransferase (APRT) deficiency (2,8-dihydroxyadenine urolithiasis) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency (mucopolysaccharidosis Type IVA, Morquio disease A). Adenine and its extremely insoluble derivative, 2,8-dihydroxyadenine, were identified in the urine, and APRT deficiency was confirmed in erythrocytes. There was excessive excretion of keratan sulfate in the urine, and GALNS deficiency was confirmed in leukocytes. GALNS and APRT are both located on chromosome 16q24.3, suggesting that the patient had a deletion involving both genes. PCR amplification of genomic DNA indicated that a novel junction was created by the fusion of sequences distal to GALNS exon 2 and proximal to APRT exon 3, and that the size of the deleted region was approximately 100 kb. The deletion breakpoints were localized within GALNS intron 2 and APRT intron 2. Several other genes, including the alpha subunit of cytochrome B (CYBA), which is deleted or mutated in the autosomal form of chronic granulomatous disease, are located in the 16q24.3 region, but PCR amplification showed that this gene was present in the proband. A patient with hemizygosity for GALNS deficiency and APRT deficiency has been reported from Japan recently. These findings indicate that: (i) APRT is located telomeric to GALNS; (ii) GALNS and APRT are transcribed in the same orientation (centromeric to telomeric); and (iii) combined APRT/GALNS deficiency may be more common than hitherto realized.

Adenine Phosphoribosyltransferase↗
PubMed1999

Immunization of mice with live oral vaccine based on a Salmonella enterica (sv Typhimurium) aroA strain expressing the Escherichia coli O111 O antigen.

Shiga toxin-producing Escherichia coli strains of serogroup O111 are the most frequently isolated non-O157 strains causing outbreaks of gastroenteritis with haemolytic uraemic syndrome (HUS). O antigen is a major antigen in Gram-negative bacteria, and it has been shown that O111 is a protective antigen. Attenuated Salmonella enterica sv Typhimurium aroA strain STM-1 was used as a live carrier to express the E. coli O111 O antigen. Mice immunized intraperitoneally produced serum immunoglobulin G, and mice immunized orally produced serum immunoglobulin G and secretory immunoglobulin A in the intestine against E. coli O111 cells as determined by enzyme-linked immunosorbent assays.

Administration, Oral↗
PubMed1999

Brain segmentation and the generation of cortical surfaces.

This paper describes methods for white matter segmentation in brain images and the generation of cortical surfaces from the segmentations. We have developed a system that allows a user to start with a brain volume, obtained by modalities such as MRI or cryosection, and constructs a complete digital representation of the cortical surface. The methodology consists of three basic components: local parametric modeling and Bayesian segmentation; surface generation and local quadratic coordinate fitting; and surface editing. Segmentations are computed by parametrically fitting known density functions to the histogram of the image using the expectation maximization algorithm [DLR77]. The parametric fits are obtained locally rather than globally over the whole volume to overcome local variations in gray levels. To represent the boundary of the gray and white matter we use triangulated meshes generated using isosurface generation algorithms [GH95]. A complete system of local parametric quadratic charts [JWM+95] is superimposed on the triangulated graph to facilitate smoothing and geodesic curve tracking. Algorithms for surface editing include extraction of the largest closed surface. Results for several macaque brains are presented comparing automated and hand surface generation.

Algorithms↗
PubMed1999

Development of novel benzimidazole riboside compounds for treatment of cytomegalovirus disease.

Benzimidazole ribosides are a new class of compounds with novel mechanisms of action against CMV. One compound in this series, BDCRB, inhibits CMV DNA processing by the UL89 gene product (putative terminase), but rapid metabolism to an inactive compound makes it unsuitable for development as a medicine. Another benzimidazole analogue, 1263W94, has many characteristics that make it an attractive candidate for development, including high potency in vitro, selectivity, good oral bioavailability, and lower toxicity than therapies currently available for treatment of CMV disease. Initial clinical trials have provided encouraging results, including good tolerability and linear pharmacokinetics over a wide dose range. Ongoing and planned clinical trials that will study the safety and tolerability of repeated dosing and evaluate the in vivo antiviral activity and ocular penetration of 1263W94, will help to determine the potential of this drug as an improved therapy for CMV disease.

Antiviral Agents↗
PubMed1999

Factors affecting broadband ultrasound attenuation results of the calcaneus using a gel-coupled quantitative ultrasound scanning system.

This study aimed to assess the factors that may influence the distribution and description of broadband ultrasound attenuation (BUA) and to identify specific criteria for diagnostic consideration when collecting BUA reference data. Two hundred Caucasian women (aged 20-79 years) without a history of atraumatic fractures or medicines known to affect bone metabolism were selected for this study. Medical and menstrual history, medication usage, family history of osteoporosis (FHO), physical activity, activities of daily living (ADL), dietary calcium intake, as well as smoking and alcohol consumption were obtained. Broadband ultrasound attenuation (BUA, dB/MHz) was determined in the right foot using a new gel-coupled ultrasound system. BUA was significantly associated with age (p<0.001), body weight (p<0.001), level of physical activity (p = 0.024) and dietary calcium intake (p = 0.023). Smoking, alcohol and coffee consumption and ADL were not associated with BUA (p>0.05). There were no differences in BUA (p>0.05) between those women who reported taking medications or had diseases (known to not affect bone metabolism), were using contraceptives, taking vitamin/mineral supplements and/or had traumatic fractures and their counterparts who did not report these characteristics. Premenopausal women with a FHO had significantly lower BUA values compared with those without a FHO (p = 0.013). When those participants with a FHO were removed from the sample, the peak BUA value was 1.1-4.4% higher and the variability (SD) was reduced by about 3.3-9.3% depending on which age range was used to define the peak BUA value. Consequently, an additional 4.5% of the population were classified as having a T-score <-2. Our results suggest that the impact on BUA of risk factors such as a FHO, body weight, physical activity and dietary calcium intake is similar to that on bone mineral density obtained by dual-energy X-ray absorptiometry (DXA), and thus provides further information on the comparability of quantitative ultrasound and DXA for assessment of risk of fracture. The criteria for calculating the T-score need further study to determine whether young adults with FHO should be included and what cutoff age range should be used in collecting peak values of quantitative ultrasound parameters.

Adult↗
PubMed1999

Evidence for Phex haploinsufficiency in murine X-linked hypophosphatemia.

Mutations in the PHEX gene (phosphate-regulating gene with homology to endopeptidases on the X-chromosome) are responsible for X-linked hypophosphatemia (HYP). We previously reported the full-length coding sequence of murine Phex cDNA and provided evidence of Phex expression in bone and tooth. Here, we report the cloning of the entire 3.5-kb 3'UTR of the Phex gene, yielding a total of 6248 bp for the Phex transcript. Southern blot and RT-PCR analyses revealed that the 3' end of the coding sequence and the 3'UTR of the Phex gene, spanning exons 16 to 22, are deleted in Hyp, the mouse model for HYP. Northern blot analysis of bone revealed lack of expression of stable Phex mRNA from the mutant allele and expression of Phex transcripts from the wild-type allele in Hyp heterozygous females. Expression of the Phex protein in heterozygotes was confirmed by Western analysis with antibodies raised against a COOH-terminal peptide of the mouse Phex protein. Taken together, these results indicate that the dominant pattern of Hyp inheritance in mice is due to Phex haploinsufficiency.

3' Untranslated Regions↗
PubMed1999

MuERVC: a new family of murine retrovirus-related repetitive sequences and its relationship to previously known families.

Characterization of a new murine endogenous retrovirus-related sequence named MuERVC-C105 is reported. This sequence was found to be most similar to the murine leukemia C-type retroviruses and to murine defective endogenous retrovirus-like families MuRRS and MuRVY, although MuERVC-C105 has a novel LTR. MuERVC-C105, like MuRRS and MuRVY, represents a family of retrovirus-like sequences characterized by many defects in its reading frames. Phylogenetic analyses, in particular analysis of nonsynonymous and synonymous nucleotide substitutions in the descent of these sequences, revealed that the MuERVC-C105, MuRRS, and MuRVY families were each derived from a different nondefective retroviral ancestor, thus justifying the new family name MuERVC. These nondefective ancestors cluster together with Gibbon Ape Leukemia Virus, but were nearly as distinct from each other as are other subgroups of murine leukemia virus (MoMLV, BaEV, GALV). The analysis further indicated that, in spite of the high density of defects in these three families, most of their divergence from their common ancestor was as nondefective retroviruses.

Amino Acid Sequence↗
PubMed1999

Myocardial protection by insulin is dependent on phospatidylinositol 3-kinase but not protein kinase C or KATP channels in the isolated rabbit heart.

Because tyrosine kinase blockade prevents protection by ischemic preconditioning (p.c.) in several species, activation of tyrosine kinase appears to be critical for cardioprotection. The tyrosine kinase's identity, however, is unknown. The present study tested whether activation of a receptor tyrosine kinase, the insulin receptor, could mimic p.c. and if the mechanism of protection was similar to that of p.c. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Infarct size in control hearts was 32.6 +/- 2.3%. A 5-min infusion of insulin (5 mU/ml) followed by a 10-min washout period prior to ischemia significantly reduced infarction to 14.7 +/- 2.1% (P < 0.05). The tyrosine kinase inhibitor genistein (50 microM) given around the insulin infusion blocked protection (28.9 +/- 2.8%). However, when present during the onset of ischemia, genistein had no effect on protection triggered by insulin (14.0 +/- 2.4%; P < 0.05). Inhibition of either PKC by polymyxin B (50 microM) or KATP channels by 5-hydroxydecanoate (100 microM) also failed to prevent protection by insulin (17.5 +/- 3.2% and 17.6 +/- 3.0%, respectively). However, the reduction in infarct size by insulin was significantly attenuated by wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K, 28.3 +/- 2.2%). Insulin was still able to protect the heart when given only during the reperfusion period (13.2 +/- 3.4%). P.c. reduced infarction to 12.8 +/- 2.0% (P < 0.05) and still offered significant protection in the presence of wortmannin (22.1 +/- 2.4%; P < 0.05). In conclusion, activation of the insulin receptor reduces infarct size in the rabbit heart even when instituted upon reperfusion. However, the mechanism of protection is quite different from that of p.c. and involves activation of PI3K but not PKC or KATP channels.

Animals↗
PubMed1999

Microdissection and microcloning of rye (Secale cereale L.) chromosome 1R.

Chromosome 1R was microdissected and collected from mitotic metaphase spreads of rye (Secale cereale L.) by using glass needles. The isolated chromosomes were amplified in vitro by Sau3A linker adaptor-mediated polymerase chain reaction (PCR). After amplification, the presence of rye-specific DNA was verified by Southern hybridization. The second-round PCR products from five 1R chromosomes were cloned into a plasmid vector to create a chromosome-specific library, which produced approximately 220,000 recombinant clones. Characterization of the microclone library showed that the 172 clones evaluated ranged in size from 300-1800 bp with an average size of 950 bp, of which approximately 42% were medium/high copy and 58% were low/unique copy clones. Chromosome in situ hybridization confirmed that the PCR products from microdissected chromosomes originated from chromosome 1R, indicating that many chromosome 1R-specific sequences were present in the library.

Base Sequence↗
PubMed1999

Correlation of magnetic resonance imaging parameters with clinical disability in multiple sclerosis: a preliminary study.

Magnetic resonance imaging (MRI) is frequently used to monitor new treatments in multiple sclerosis (MS), but its role is limited by the uncertain relationship between MRI parameters and clinical disability. A brain MRI study using nine MRI parameters was undertaken in 15 MS patients with a wide spectrum of disability to evaluate the relationship between each parameter and disability. A strong correlation was found between disability (measured using Kurtzke's EDSS) and total lesion load on both proton density (PD; r = 0.79) and T1 (r = 0.71) weighted sequences. There was also a strong correlation of disability with average lesion magnetisation transfer ratio (MTR; r = -0.74) and calculated T1 (r = 0.71) but not with calculated T2 or the average signal intensity of lesions on the conventional T1-weighted, PD-weighted and heavily T2-weighted images. Thus, four parameters which measured either the extent of lesions (PD lesion load) or their pathological severity (MTR, calculated T1, hypointense T1-lesion load) were correlated significantly with disability. While this suggests that such parameters will be useful in treatment trial monitoring, further multi-parameter MRI studies, of larger cohorts and using a wider range of techniques, are indicated.

Adult↗
PubMed1999

1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis.

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86-1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27-2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62-10.38 mM; controls, median 7.77 mM, range 6.60-9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group.

Adult↗
PubMed1999

The transcriptional activator CorR is involved in biosynthesis of the phytotoxin coronatine and binds to the cmaABT promoter region in a temperature-dependent manner.

A modified two-component regulatory system consisting of the histidine protein kinase CorS and two highly homologous response regulators, CorR and CorP, controls biosynthesis of the polyketide phytotoxin coronatine (COR) by Pseudomonas syringae pv. glycinea PG4180 in a temperature-dependent manner. COR synthesis is maximal at 18 degrees C but does not occur at 28 degrees C. Fusions of CorR and CorP to the maltose-binding protein (MBP) were overproduced in Escherichia coli and P. syringae PG4180, and tested for functionality by complementation of corR and corP mutants of PG4180, respectively. The cmaABT promoter region was defined by deletion mapping, and the DNA-binding capability of CorR and CorP was examined by gel retardation assays. When overproduced in P. syringae at 18 degrees C and purified, MBP-CorR was shown to bind specifically to a 218-bp DNA fragment corresponding to positions -841 to -623 bp upstream of the transcriptional start site of the cmaABT operon. In contrast, MBP-CorP and MBP itself, when overproduced in P. syringae and E. coli at 18 degrees C and 28 degrees C, respectively, did not bind to the 218-bp fragment or to any other DNA fragment analyzed. The CorP protein lacks typical DNA-binding motifs, suggesting that it might modulate the function of CorR. However, addition of purified MBP-CorP did not alter the DNA-binding activity of MBP-CorR. On the other hand, this activity was completely abolished when MBPCorR was overproduced at 28 degrees C or in a corS mutant, indicating that the binding of CorR depended on the growth temperature at which it was produced and was controlled by CorS. In addition, overproduction of MBP-CorR in a corP mutant of PG4180 also yielded inactive protein, underlining the importance of CorP for CorR activation. We propose that CorR is activated by CorS at low temperature and that CorP is required for this activation before CorR can bind to DNA.

ATP-Binding Cassette Transporters↗