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Biomedical subjects

W Xu

Publications and source records attributed to W Xu.

At least 181 records · Page 10Linked to original sources
PubMed2000

TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.

B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.

Amino Acid Sequence↗
PubMed2000

Highly efficient synthesis of 1-thioglycosides in solution and solid phase using iminophosphorane bases.

Disaccharides of 1-thioglycosides, an important class of glycomimics, can be synthesized by direct S-alkylation in exceptionally high yields when iminophosphorane bases are employed. The reaction conditions employed appear to be general and stereospecific. Axial and equatorial 4-triflates and primary tosylates of alkyl pyranosides provided excellent yields of thio-disaccharides without substantial elimination products. The iminophosphorane bases also proved to be useful in solid support-bound couplings of thioglycosides though with lower efficiency.

Alkylation↗
PubMed2000

Novel benzofuran and benzothiophene biphenyls as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties.

Insulin resistance in the liver and peripheral tissues, together with a pancreatic cell defect, are the common causes of Type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibition of PTPases may be an effective method in the treatment of Type 2 diabetes. We have identified two novel series of benzofuran/benzothiophene biphenyl oxo-acetic acids and sulfonyl-salicylic acids as potent inhibitors of PTP1B with good oral antihyperglycemic activity. To assist in the design of these inhibitors, crystallographic studies have attempted to identify enzyme inhibitor interactions. Resolution of crystal complexes has suggested that the inhibitors bind to the enzyme active site and are held in place through hydrogen bonding and van der Waals interactions formed within two hydrophobic pockets. In the oxo-acetic acid series, hydrophobic substitutents at position-2 of the benzofuran/benzothiophene biphenyl framework interacted with Phe182 of the catalytic site and were very critical to the intrinsic activity of the molecule. The hydrophobic region of the catalytic-site pocket was exploited and taken advantage by hydrophobic substituents at either the alpha-carbon or the ortho aromatic positions of the oxo-acetic acid moiety. Similar ortho aromatic substitutions on the salicylic acid-type inhibitors had no effect, primarily due to the different orientation of these inhibitors in the catalytic site. The most active inhibitors of both series inhibited recombinant human PTP1B with phosphotyrosyl dodecapeptide TRDI(P)YETD(P)Y(P)YRK as the source of the substrate with IC(50) values in the range of 20-50 nM. Compound 68 was one of the most active compounds in vivo, normalizing plasma glucose levels at the 25 mg/kg dose (po) and the 1 mg/kg dose (ip). Compound 68 was also selective against several other PTPases.

Administration, Oral↗
PubMed2000

Nicotinic acetylcholine receptors in the autonomic control of bladder function.

Micturition is achieved through complex neurological mechanisms involving somatic, autonomic and central components. This article briefly reviews recent findings on the autonomic control of urinary bladder function. Neuronal nicotinic acetylcholine receptors mediate fast synaptic transmission in autonomic ganglia, and activation of nicotinic receptors in parasympathetic bladder neurons produces contraction of the detrusor muscle. Autonomic ganglia contain transcripts for the alpha(3), alpha(4), alpha(5), alpha(7), beta(2) and beta(4) nicotinic subunits, which can assemble to form multiple nicotinic receptor subtypes, but the exact nicotinic receptor subunit composition in bladder ganglia is unknown. Mutant mice lacking the alpha(3) or the beta(2) and the beta(4) nicotinic subunits have enlarged bladders with dribbling urination and develop urinary infection and bladder stones. Bladder strips from alpha(3) null mice do not respond to nicotine but contract when stimulated with a muscarinic agonist or electric field stimulation. Mice lacking the beta(2) subunit have no overt bladder phenotype, and their bladders contract in response to nicotine. Surprisingly, bladder strips from beta(4) mutant mice do not respond to nicotine despite the absence of major bladder dysfunction in vivo. These findings suggest that nicotinic receptors containing the alpha(3) and the beta(4) subunits are necessary for normal bladder function.

Animals↗
PubMed2000

Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9.

The basic helix-loop-helix/leucine zipper (bHLH/ZIP) microphthalmia-associated transcription factor (MITF) regulates transcription of genes encoding enzymes essential for melanin biosynthesis in melanocytes and retinal pigmented epithelial cells. To determine how MITF activity is regulated, we used the yeast two-hybrid system to identify proteins expressed by human melanoma cells that interact with MITF. The majority of clones that showed positive interaction with a 158-amino-acid region of MITF containing the bHLH/ZIP domain (aa 168-325) encoded the ubiquitin conjugating enzyme hUBC9. The association of MITF with hUBC9 was further confirmed by an in vitro GST pull-down assay. Although hUBC9 is known to interact preferentially with SENTRIN/SUMO1, in vitro transcription/translation analysis demonstrated greater association of MITF with ubiquitin than with SENTRIN. Importantly, cotransfection of MITF and hUBC9 expression vectors resulted in MITF protein degradation. MITF protein was stabilized by the proteasome inhibitor MG132, indicating the role of the ubiquitin-proteasome system in MITF degradation. Serine 73, which is located in a region rich in proline, glutamic acid, serine, and threonine (PEST), regulates MITF protein stability, since a serine to alanine mutation prevented hUBC9-mediated MITF (S73A) degradation. Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished MITF (K201R) degradation by hUBC9 in vivo. Our experiments indicate that by targeting MITF for proteasome degradation, hUBC9 is a critical regulator of melanocyte differentiation.

DNA-Binding Proteins↗
PubMed2000

The CCTTT polymorphism in the NOS2A gene is associated with dementia with Lewy bodies.

We report the analysis of the allele distribution of a (CCTTT)n pentanucleotide repeat within the promoter region of the NOS2A gene in DNA samples from patients with autopsy confirmed Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) type. A significant difference was observed in the allelic distribution between the control group and the DLB group (chi2 = 15.175, df = 5; p<0.01), with an increased occurrence of the eight and nine repeat alleles, and a marked under representation of the 11 repeat allele. Genotype frequencies in the DLB group also differed significantly from controls (p<0.012). These results suggest that variations in the NOS2A gene may predispose to the development of DLB.

Alleles↗
PubMed2000

Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations: assessment of the NOS2A gene and predisposition to infectious disease.

Allelic frequencies of a (CCTTT)(n) pentanucleotide repeat in the NOS2A promoter region were determined in a total of 1393 unrelated individuals from five specific population groups in four continents: Africa, Europe, Asia, and the Caribbean. There were highly significant differences in allele frequencies between the ethnically diverse populations. The repeat variation may have implications for the selective pressure of malaria or other infectious diseases that may operate at the NOS2 locus.

DNA↗
PubMed2000

Ultrafast primary processes in PS I from Synechocystis sp. PCC 6803: roles of P700 and A(0).

The excitation transport and trapping kinetics of core antenna-reaction center complexes from photosystem I of wild-type Synechocystis sp. PCC 6803 were investigated under annihilation-free conditions in complexes with open and closed reaction centers. For closed reaction centers, the long-component decay-associated spectrum (DAS) from global analysis of absorption difference spectra excited at 660 nm is essentially flat (maximum amplitude <10(-5) absorbance units). For open reaction centers, the long-time spectrum (which exhibits photobleaching maxima at approximately 680 and 700 nm, and an absorbance feature near 690 nm) resembles one previously attributed to (P700(+) - P700). For photosystem I complexes excited at 660 nm with open reaction centers, the equilibration between the bulk antenna and far-red chlorophylls absorbing at wavelengths >700 nm is well described by a single DAS component with lifetime 2.3 ps. For closed reaction centers, two DAS components (2.0 and 6.5 ps) are required to fit the kinetics. The overall trapping time at P700 ( approximately 24 ps) is very nearly the same in either case. Our results support a scenario in which the time constant for the P700 --> A(0) electron transfer is 9-10 ps, whereas the kinetics of the subsequent A(0) --> A(1) electron transfer are still unknown.

Chlorophyll↗
PubMed2000

Control of ion and fluid transport by putative second messengers in different segments of the Malpighian tubules of the black field cricket Teleogryllus oceanicus.

The differences in second messenger control of secretion were investigated in the distal and main segments of the Malpighian tubules of the black field cricket Teleogryllus oceanicus. Secretion by the main segment was considerably increased by corpora cardiaca extract and db-cAMP. Corpora cardiaca had no effect on secreted fluid composition or intracellular elemental composition but db-cAMP increased Na(+) and Cl(-) transport, as measured by x-ray microanalysis of secreted fluids and cells. Secretion by the main segment was considerably increased by forskolin and by Sp-cAMP. Secretion in the distal segment was abolished by corpora cardiaca extract but was unaffected by db-cAMP and only slightly reduced by 8-bromo-cAMP. However, Sp-cAMP increased secretion but forskolin reduced secretion. The responses of the distal segment suggest the possibility of a multiplicity of controls through different protein kinases and adenylyl cyclases. Secretion rate in the main segment was also increased by cGMP but distal segment secretion was unaffected. Secretion from both segments was increased by 5-HT. In the main segment secretion rate was increased by Ca-ionophore and thapsigargin and decreased by verapamil. This suggests a role for Ca(2+) as a controlling second messenger. In the distal segment only Ca-ionophore had an effect on secretion rate, which was reduced. Secretion rates in both segments were decreased in Ca-free saline. In saline in which Sr(2+) replaced Ca(2+), secretion rate in the main segment was greatly increased whilst that of the distal segment was decreased, suggesting that Sr(2+) could substitute for Ca(2+) as a second messenger.

Journal Article↗
PubMed2000

Retinoic acid reduces the yield of herpes simplex virus in Vero cells and alters the N-glycosylation of viral envelope proteins.

Treatment of Vero cells with all-trans-retinoic acid (RA) decreased the production of infectious herpes simplex virus (HSV) by 1000-10000-fold when compared with control cultures. Levels of total HSV envelope glycoproteins gB, gC and gD produced following RA treatment, were comparable with those found in control cultures. Following 24 h of RA treatment, lower molecular weight variants of gB, gC and gD were produced in addition to the typical molecular mass of each protein found in control samples. Between 24 and 48 h of RA treatment, the proportion of the lower molecular mass variants increased. When control and RA treated samples were incubated with peptide N-glycosidase F (PNGase F), which removes N-glycosylated sugars, the molecular weights of the respective gB, gC and gD proteins produced were comparable in both the groups, indicating that RA did not alter the primary sequence of viral proteins during protein synthesis or increase viral protein proteolysis. RA treatment increased [3H]mannose incorporation into glycoproteins in HSV infected cells but did not change [3H]glucosamine incorporation. We conclude that RA treatment does not reduce the synthesis of three major viral envelope glycoproteins but alters their N-glycosylation and postulate that the inhibitory effect of RA is related to its action on N-glycosylation.

Animals↗
PubMed2000

Simulation of mixed convection flow in a room with a two-layer turbulence model.

Most indoor airflows are mixed convection. In order to simulate mixed convection accurately and efficiently, this paper uses a two-layer turbulence model. The two-layer model combines a one-equation model for near wall flow together with the standard k-epsilon model for outer-wall flow. The model has been used to predict the mixed convection by displacement ventilation in an office. The computed results agree well with the corresponding airflow pattern and the distributions of air temperature, air velocity, air velocity fluctuation, and tracer-gas concentration. The model can predict correctly heat transfer from a wall where the standard k-epsilon model and re-normalization group (RNG) k-epsilon model with wall functions often fails. The computing cost required by the two-layer model is comparable to that of the standard k-epsilon model and RNG k-epsilon model and is significantly less than that by a low-Reynolds number model.

Air Movements↗
PubMed2000

Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents.

Nitric-oxide synthase (NOS) activity has been detected in many human tumours, although its function is unclear. Here we show that exposure of cells to nitric oxide (NO) results in a 4-5-fold increase in expression of the DNA-dependent protein-kinase catalytic subunit (DNA-PKcs), one of the key enzymes involved in repairing double-stranded DNA breaks. This NO-mediated increase in enzymatically active DNA-PK not only protects cells from the toxic effects of NO, but also provides crossprotection against clinically important DNA-damaging agents, such as X-ray radiation, adriamycin, bleomycin and cisplatin. The NO-mediated increase in DNA-PKcs described here demonstrates the presence of a new and highly effective NO-mediated mechanism for DNA repair.

Animals↗
PubMed2000

Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection.

Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque model has been developed that mimics the mucosal exposure that can occur during intrapartum HIV-1 transmission. To develop immunoprophylaxis against intrapartum HIV-1 transmission, we used SHIV-vpu+ (refs. 5,6), a chimeric simian-human virus that encodes the env gene of HIV-IIIB. Several combinations of human monoclonal antibodies against HIV-1 have been identified that neutralize SHIV-vpu+ completely in vitro through synergistic interaction. Here, we treated four pregnant macaques with a triple combination of the human IgG1 monoclonal antibodies F105, 2G12 and 2F5. All four macaques were protected against intravenous SHIV-vpu+ challenge after delivery. The infants received monoclonal antibodies after birth and were challenged orally with SHIV-vpu+ shortly thereafter. We found no evidence of infection in any infant during 6 months of follow-up. This demonstrates that IgG1 monoclonal antibodies protect against mucosal lentivirus challenge in neonates. We conclude that epitopes recognized by the three monoclonal antibodies are important determinants for achieving substantial protection, thus providing a rational basis for AIDS vaccine development.

Animals↗
PubMed2000

Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development.

Histone acetyltransferases regulate transcription, but little is known about the role of these enzymes in developmental processes. Gcn5 (encoded by Gcn5l2) and Pcaf, mouse histone acetyltransferases, share similar sequences and enzymatic activities. Both interact with p300 and CBP (encoded by Ep300 and Crebbp, respectively), two other histone acetyltransferases that integrate multiple signalling pathways. Pcaf is thought to participate in many of the cellular processes regulated by p300/CBP (refs 2-8), but the functions of Gcn5 are unknown in mammalian cells. Here we show that the gene Pcaf is dispensable in mice. In contrast, Gcn5l2-null embryos die during embryogenesis. These embryos develop normally to 7.5 days post coitum (d.p.c.), but their growth is severely retarded by 8.5 d.p.c. and they fail to form dorsal mesoderm lineages, including chordamesoderm and paraxial mesoderm. Differentiation of extra-embryonic and cardiac mesoderm seems to be unaffected. Loss of the dorsal mesoderm lineages is due to a high incidence of apoptosis in the Gcn5l2 mutants that begins before the onset of morphological abnormality. Embryos null for both Gcn5l2 and Pcaf show even more severe defects, indicating that these histone acetyltransferases have overlapping functions during embryogenesis. Our studies are the first to demonstrate that specific acetyltransferases are required for cell survival and mesoderm formation during mammalian development.

Abnormalities, Multiple↗
PubMed2000

Studies of renal injury III: lipid-induced nephropathy in type II diabetes.

UNLABELLED: Studies of renal injury III: Lipid-induced nephropathy in type II diabetes. BACKGROUND: Nephrotoxicity from elevated circulating lipids occurs in experimental and clinical situations. We tested the hypothesis that lipid-induced nephropathy causes advanced renal failure in rats with type II diabetes and dyslipidemia. METHODS: First generation (F1) hybrid rats derived from the spontaneous hypertensive heart failure rat (SHHF/Gmi-fa) and the LA/NIH-corpulent rat (LA/N-fa) were studied for 41 weeks while being on specific diets. Group 1 (14 rats) ingested 11.5% protein, 47.9% fat, and 40.6% carbohydrate. Group 2 (8 rats) ingested 26.9% protein, 16.7% animal fat, and 56.4% carbohydrate, and group 3 (20 rats) ingested 20.2% protein, 40.4% soy and coconut oil, and 39.4% carbohydrate. RESULTS: Hyperglycemia was more severe in rat groups 1 and 2 than in group 3. In contrast, circulating cholesterol and hydroperoxide levels were highest in group 3, intermediate in group 2, and lowest in group 1. Group 3 had severe renal failure secondary to glomerulosclerosis and tubulointerstitial disease, with striking deposition of the lipid peroxidation stress biomarker 4-hydroxynonenal in glomeruli and renal microvessels. Moreover, in group 3, increased arterial wall thickness also connoted vascular injury. In contrast, the glycoxidation stress biomarkers pentosidine and carboxymethyl-lysine were preferentially localized to renal tubules of hyperglycemic rats in groups 1 and 2 and did not segregate with the most severe renal injury. Glomerular and interstitial fibrosis was accompanied by proportional increases in renal transforming growth factor-beta1 levels, which were threefold higher in the hypercholesterolemic rats of group 3 than in the hyperglycemic rats of group 1. CONCLUSIONS: Acquisition of non-nodular glomerular sclerosis and tubulointerstitial disease is dependent on lipoxidation stress in rats with type II diabetes. On the other hand, in the absence of hypercholesterolemia, prolonged glycoxidation stress does not appear to be uniquely nephrotoxic.

Animals↗
PubMed2000

Quality of life in schizophrenia: a comparison of instruments. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.

Health-related quality of life in schizophrenia can be assessed by direct patient response or by a rating based on a structured interview. This study compares both types of instruments using a series of five standards: (1) sensitivity to change over time, (2) sensitivity to treatment effect, (3) correlation with symptom severity, (4) correlation with global clinical ratings, and (5) correlation with other measures of health-related quality of life. Four hundred and twenty-three inpatients with schizophrenia participating in a clinical trial comparing clozapine and haloperidol (VA Cooperative Study in Health Services #17) were evaluated using multiple measures of health-related quality of life (Lehman Quality of Life Interview; Heinrichs-Carpenter-Hanlon Quality of Life Scale; Strauss-Carpenter Level of Function scale, and clinical response.) The Quality of Life Interview showed less sensitivity to change and treatment effect, as well as lower correlations with all other measures than the Quality of Life Scale and the Level of Function scale. The latter scales showed high sensitivity to both change and treatment effect, and moderate-high correlations with other measures and with each other. The Quality of Life Scale and the Level of Function scale rater assessments appeared to be substantially more sensitive to subtle change and treatment effects than the patient-reported Quality of Life Interview for clinical trials. Health-related quality of life in schizophrenia is a more heterogeneous concept than previously appreciated.

Adult↗
PubMed2000

The description of outcomes in Medicare patients hospitalized with peptic ulcer disease.

OBJECTIVE: The objective of this study was to describe outcomes of care for Medicare patients hospitalized with peptic ulcer disease from 1992 through 1997 and to identify factors related to cost, length of stay, and readmission rates. METHODS: General descriptive statistics were obtained from Medicare inpatient claims data by year, endoscopy grouping, diagnosis related group code, and principal diagnosis code. From abstracted clinical data, associations were derived for length of stay, readmission rates, and the following processes of care: screening or treatment for Helicobacter pylori; screening for nonsteroidal antiinflammatory drug (NSAID) use; and the performance of endoscopy. The Acute Physiology and Chronic Health Evaluation method was used to estimate patient health status for the study. RESULTS: During the 6-yr study, there were 878,212 claims, which constituted 1.3% of the total Medicare claims. The total Medicare payment for peptic ulcer claims was estimated at $4.8 billion. The inpatient mortality rate was 4.5%. Readmission rates remained relatively constant during the study period but decreased significantly when NSAID screening was documented during the hospitalization. Admission rates, length of stay, and mortality declined progressively during the study period. A reduction in length of stay of approximately 1 day was observed when screening or treatment for H. pylori, screening for NSAID use, or the performance of endoscopy was documented. CONCLUSIONS: Peptic ulcer disease has an important impact on the Medicare population with respect to cost, recurrence, and mortality. Adherence to selected processes of care is associated with shorter length of stay and lower readmission rates.

Aged↗