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Biomedical subjects

B Yu

Publications and source records attributed to B Yu.

At least 19 recordsLinked to original sources
PubMed2000

Genetic variants of IL-13 signalling and human asthma and atopy.

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Adult↗
PubMed2000

Repositioning error in low back pain. Comparing trunk repositioning error in subjects with chronic low back pain and control subjects.

STUDY DESIGN: Repositioning error of the trunk was tested in 20 subjects with chronic low back pain and in 20 control subjects. The 3Space Tracker (Polhemus, Colchester, VT), a device that measures three-dimensional position in space, was used to determine the subject's trunk position. OBJECTIVES: To determine whether repositioning error is different in subjects with chronic low back pain than in control subjects. SUMMARY OF BACKGROUND DATA: Proprioception allows the body to maintain proper orientation during static and dynamic activities. In peripheral joint injuries, researchers have demonstrated a loss of some aspects of proprioception and improvement in outcome with retraining. Although the components of proprioception in subjects with low back pain have not been well studied, it is thought that these persons lose some elements of proprioception that can be measured in a quantifiable way. If so, then rehabilitation to improve these deficits is important. In this pilot study, one aspect of proprioception, repositioning error, was examined. METHODS: The subjects attempted to replicate target positions of the trunk in flexion, extension, lateral bending, and lateral rotation. Repositioning error was calculated as the absolute difference between the actual and the subject-replicated target positions. RESULTS: No significant difference was found in repositioning error between the control subjects and the persons with chronic low back pain. CONCLUSIONS: Because proprioception is complex and entails the use of many afferent receptors, it is difficult to measure any one afferent deficiency discretely. The authors believe that this study, in which one aspect of proprioception was measured in an indirect manner, provides important background information on low back position sense. Further studies analyzing aspects of proprioception in subjects with low back pain are recommended.

Adult↗
PubMed2000

Inhibition of subsets of G protein-coupled receptors by empty mutants of G protein alpha subunits in g(o), G(11), and G(16).

We previously reported that the xanthine nucleotide binding G(o)alpha mutant, G(o)alphaX, inhibited the activation of G(i)-coupled receptors. We constructed similar mutations in G(11)alpha and G(16)alpha and characterized their nucleotide binding and receptor interaction. First, we found that G(11)alphaX and G(16)alphaX expressed in COS-7 cells bound xanthine 5'-O-(thiotriphosphate) instead of guanosine 5'-O-(thiotriphosphate). Second, we found that G(11)alphaX and G(16)alphaX interacted with betagamma subunits in the presence of xanthine diphosphate. These experiments demonstrated that G(11)alphaX and G(16)alphaX were xanthine nucleotide-binding proteins, similar to G(o)alphaX. Third, in COS-7 cells, both G(11)alphaX and G(16)alphaX inhibited the activation of G(q)-coupled receptors, whereas only G(16)alphaX inhibited the activation of G(i)-coupled receptors. Therefore, when in the nucleotide-free state, empty G(11)alphaX and G(16)alphaX appeared to retain the same receptor binding specificity as their wild-type counterparts. Finally, we found that G(o)alphaX, G(11)alphaX, and G(16)alphaX all inhibited the endogenous thrombin receptors and lysophosphatidic acid receptors in NIH3T3 cells, whereas G(11)alphaX and G(16)alphaX, but not G(o)alphaX, inhibited the activation of transfected m1 muscarinic receptor in these cells. We conclude that these empty G protein mutants of G(o)alpha, G(11)alpha, and G(16)alpha can act as dominant negative inhibitors against specific subsets of G protein-coupled receptors.

3T3 Cells↗
PubMed2000

The effects of the lower extremity joint motions on the total body motion in sit-to-stand movement.

OBJECTIVE: The purpose of this study is to investigate the effects of lower extremity joint angular motions on the whole body linear motions in a sit-to-stand movement using a biomechanical model that describes the whole body linear velocity vector as functions of lower extremity joint angular velocities. DESIGN: Two-dimensional video analysis of whole body and joint kinematics. BACKGROUND: A biomechanical model that describes the whole body linear motions as functions of lower extremity joint angular motions is needed to provide clinically relevant information in clinical services and scientific research. METHODS: The linear velocity vector of the whole body motion during the sit-to-stand movement was partitioned into horizontal and vertical components and expressed as functions of lower extremity joint angular velocities for 10 healthy subjects. The coefficient of joint contribution to the whole body linear velocity vector was determined for each joint in each direction. RESULTS: The ankle and hip angular motions are critical to the development of the forward horizontal velocity of the whole body during the sit-to-stand movement. The knee and hip angular motions are critical to the development of the upward vertical velocity of the whole body during the sit-to-stand movement. CONCLUSIONS: The hip, knee, and ankle joint angular motions have various roles in whole body motions in different directions of the sit-to-stand movement. RELEVANCE: The model and the results of this study can be applied to study the control strategies, falls, and assessments of functional impairments in the sit-to-stand movement.

Adult↗
PubMed1999

pH-dependent peptide binding properties of the type I diabetes-associated I-Ag7 molecule: rapid release of CLIP at an endosomal pH.

MHC class II molecules and invariant chain assemble at a neutral pH in the endoplasmic reticulum and are transported to a low pH compartment where the invariant chain is trimmed to the class II-associated invariant chain peptide (CLIP). For many major histocompatibility complex class II molecules, DM is required for rapid removal of CLIP, which allows binding of antigenic peptides. Since I-Ag7 confers susceptibility to type I diabetes in NOD mice, the biochemical requirements for peptide loading were examined using soluble I-Ag7 expressed in insect cells. I-Ag7 formed long-lived complexes with naturally processed peptides from transferrin and albumin, whereas several peptides that represent T cell epitopes of islet autoantigens were poor binders. I-Ag7-peptide complexes were not sodium dodecyl sulfate (SDS) resistant, indicating that SDS sensitivity may be an intrinsic property of I-Ag7. Complexes of I-Ag7 and CLIP formed at a neutral pH, but rapidly dissociated at pH 5. This rapid dissociation was due to a poor fit of M98 of CLIP in the P9 pocket of I-Ag7, since substitution of M98 by a negatively charged residue greatly enhanced the stability of the complex. These biochemical properties of I-Ag7 result in the rapid generation of empty molecules at an endosomal pH and have a global effect on peptide binding by I-Ag7.

Amino Acid Sequence↗
PubMed1999

Disordered water within a hydrophobic protein cavity visualized by x-ray crystallography.

Water in the hydrophobic cavity of human interleukin 1beta, which was detected by NMR spectroscopy but was invisible by high resolution x-ray crystallography, has been mapped quantitatively by measurement and phasing of all of the low resolution x-ray diffraction data from a single crystal. Phases for the low resolution data were refined by iterative density modification of an initial flat solvent model outside the envelope of the atomic model. The refinement was restrained by the condition that the map of the difference between the electron density distribution in the full unit cell and that of the atomic model be flat within the envelope of the well ordered protein structure. Care was taken to avoid overfitting the diffraction data by maintaining phases for the high resolution data from the atomic model and by a resolution-dependent damping of the structure factor differences between data and model. The cavity region in the protein could accommodate up to four water molecules. The refined solvent difference map indicates that there are about two water molecules in the cavity region. This map is compatible with an atomic model of the water distribution refined by using XPLOR. About 70% of the time, there appears to be a water dimer in the central hydrophobic cavity, which is connected to the outside by two constricted channels occupied by single water molecules approximately 40% of the time on one side and approximately 10% on the other.

Computer Simulation↗
PubMed1999

An online locus-specific mutation database for familial hypertrophic cardiomyopathy.

The aim of this locus-specific mutation database was to provide an online resource that contains summarised and updated information on familial hypertrophic cardiomyopathy (FHC)-associated mutations and related data, for researchers and clinicians. It also serves as a means of publishing previously unpublished data, which could be of value in understanding genotype/phenotype correlations. There are 123 FHC-associated mutations catalogued along with ancillary information. By implementing the cgi/http method, remote users can query the database via the HTML interface on the Web browser and obtain data of relevance to them. The online service is available on http://www.angis.org.au/Databases/Heart.

Alternative Splicing↗
PubMed1999

The influence of the p53 gene on the in vitro chemosensitivity of colorectal cancer cells.

PURPOSE: The p53 gene is considered one of the most important in the control of apoptosis, and its mutations have a close relationship with chemosensitivity. The aim of this work was to investigate the role of p53 in the apoptosis of colorectal cancer cells in vitro, induced by 5-fluorouracil (5-FU) and hydroxy-camptothecin (HCPT). METHODS: A total of 39 colorectal cancer samples from patients were treated in vitro with 5-FU (10 microg/ml), 5-FU (10 microg/ml) + leucovorin (5 microg/ml), HCPT (0.1 microg/ml) and HCPT (0.1 microg/ml) + Salvia mitorrhiza (6 microl), using an in situ terminal deoxynucleotidyltransferase assay to detect chemosensitivity. p53 gene mutations from tumor DNA were detected, after amplification by the polymerase chain reaction of exons 5-8, by non-radioactive single-strand conformation polymorphism. RESULTS: p53 gene mutations were observed in 43.6% (17/39) of colorectal carcinomas, when the terminal deoxynucleotidyltransferase assay was used to detect the tumor apoptotic rate. Cells with mutated p53 had lower chemosensitivity than those without (p < 0.01). CONCLUSION: Routine assessment of p53 status may be helpful in selecting patients with the wildtype p53 gene, who have a predictably better response to chemotherapy.

Adult↗
PubMed1999

GABA(B) auto- versus hetero-receptor sensitivity: implications for novel pharmacotherapy.

After uncoupling G-protein dependent post-synaptic GABA(B) receptors--without altering GABA(B) nerve terminal receptors--we demonstrate that the GABA(B) agonist, CGP44533, exhibits less efficacy and potency at GABA(B) auto- versus hetero-receptors. CGP44533 (1 and 10 microM) depressed monosynaptic GABA(A)-mediated transmission by 2 and 35%, but depressed glutamate mediated transmission by 41 and 78%, respectively. These data suggest a differential pharmacological sensitivity for CGP44533 at glutamate versus GABA releasing neurons.

Animals↗
PubMed1999

Horizontal-to-vertical velocity conversion in the triple jump.

The aim of this study was to determine the effects of selected factors on horizontal-to-vertical velocity conversion in the triple jump. An understanding of this conversion is important not only for studies on the techniques of the triple jump, but also for other jumping events. Ten elite jumpers were studied. Three-dimensional kinematic data were collected for at least four complete trials in the same competition for each athlete. The loss in horizontal velocity and the gain in vertical velocity during each support phase were calculated for each trial. The loss in horizontal velocity was found to be a linear function of the gain in vertical velocity. The slope of this linear function, A1, is referred to as the horizontal-to-vertical velocity conversion coefficient. The loss in horizontal velocity increased as the gain in vertical velocity increased. The sensitivity of the loss in horizontal velocity to the gain in vertical velocity increased as the magnitude of A1 increased. Further studies are required on the optimum techniques of the triple jump.

Biomechanical Phenomena↗
PubMed1999

Drug resistance mutations can effect dimer stability of HIV-1 protease at neutral pH.

The monomer-dimer equilibrium for the human immunodeficiency virus type 1 (HIV-1) protease has been investigated under physiological conditions. Dimer dissociation at pH 7.0 was correlated with a loss in beta-sheet structure and a lower degree of ANS binding. An autolysis-resistant mutant, Q7K/L33I/L63I, was used to facilitate sedimentation equilibrium studies at neutral pH where the wild-type enzyme is typically unstable in the absence of bound inhibitor. The dimer dissociation constant (KD) of the triple mutant was 5.8 microM at pH 7.0 and was below the limit of measurement (approximately 100 nM) at pH 4.5. Similar studies using the catalytically inactive D25N mutant yielded a KD value of 1.0 microM at pH 7.0. These values differ significantly from a previously reported value of 23 nM obtained indirectly from inhibitor binding measurements (Darke et al., 1994). We show that the discrepancy may result from the thermodynamic linkage between the monomer-dimer and inhibitor binding equilibria. Under conditions where a significant degree of monomer is present, both substrates and competitive inhibitors will shift the equilibrium toward the dimer, resulting in apparent increases in dimer stability and decreases in ligand binding affinity. Sedimentation equilibrium studies were also carried out on several drug-resistant HIV-1 protease mutants: V82F, V82F/I84V, V82T/I84V, and L90M. All four mutants exhibited reduced dimer stability relative to the autolysis-resistant mutant at pH 7.0. Our results indicate that reductions in drug affinity may be due to the combined effects of mutations on both dimer stability and inhibitor binding.

Circular Dichroism↗
PubMed1999

Transport of fluid by lens epithelium.

We report for the first time that cultured lens epithelial cell layers and rabbit lenses in vitro transport fluid. Layers of the alphaTN4 mouse cell line and bovine cell cultures were grown to confluence on permeable membrane inserts. Fluid movement across cultured layers and excised rabbit lenses was determined by volume clamp (37 degrees C). Cultured layers transported fluid from their basal to their apical sides against a pressure head of 3 cmH2O. Rates were (in microliter. h-1. cm-2) 3.3 +/- 0.3 for alphaTN4 cells (n = 27) and 4.7 +/- 1.0 for bovine layers (n = 6). Quinidine, a blocker of K+ channels, and p-chloromercuribenzenesulfonate and HgCl2, inhibitors of aquaporins, inhibited fluid transport. Rabbit lenses transported fluid from their anterior to their posterior sides against a 2.5-cmH2O pressure head at 10.3 +/- 0.62 microliter. h-1. lens-1 (n = 5) and along the same pressure head at 12.5 +/- 1.1 microliter. h-1. lens-1 (n = 6). We calculate that this flow could wash the lens extracellular space by convection about once every 2 h and therefore might contribute to lens homeostasis and transparency.

4-Chloromercuribenzenesulfonate↗
PubMed1999

Mobilization of GLUT-4 from intracellular vesicles by insulin and K(+) depolarization in cultured H9c2 myotubes.

The insulin-responsive glucose transporter, GLUT-4, moves from an intracellular compartment to the cell surface in response to insulin and/or muscle contraction. Treatment of H9c2 myotubes with insulin significantly increased uptake of 2-deoxyglucose. Depolarization of the myotubes by increasing extracellular [K(+)], which mimics the initial phases of excitation-contraction coupling, also increased 2-deoxyglucose uptake. The K(+)- but not insulin-evoked increase was blocked by dantrolene, an inhibitor of Ca(2+) release from the sarcoplasmic reticulum. In contrast, wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked insulin- but not K(+)-stimulated 2-deoxyglucose uptake. Increased glucose uptake in response to insulin or K(+) depolarization was associated with increased GLUT-4 in plasma membranes and depletion of a population of small intracellular GLUT-4-containing vesicles. Similarly, in H9c2 cells transfected with c-myc-tagged GLUT-4, translocation of c-myc GLUT-4 to the cell surface was increased after stimulation with insulin or K(+) depolarization. Taken together, these data demonstrate that insulin and K(+) depolarization increase glucose uptake by recruiting GLUT-4 from intracellular vesicles to the plasma membrane of H9c2 myotubes via distinct signaling mechanisms.

Androstadienes↗
PubMed1999

Different subtypes of GABAB receptors are present at pre- and postsynaptic sites within the rat dorsolateral septal nucleus.

GABAB receptor activation modulates neuronal activity mediated by multiple CNS transmitters and can occur at pre- and postsynaptic sites. In low concentrations, baclofen acts presynaptically to diminish transmitter release via both hetero- and autoreceptors, whereas at increasing concentrations, the same compound alters postsynaptic membrane excitability by inducing a membrane hyperpolarization. We have utilized electrophysiological techniques in vitro to focus on the possibility that pharmacologically different subtypes of GABAB receptors are present on presynaptic sites of glutamatergic terminals when compared with GABAB receptors on postsynaptic sites within the dorsolateral septal nucleus (DLSN). The glutamatergic terminal within the DLSN originates from a pyramidal cell body located within the hippocampus and most likely terminates on a GABAergic neuron from which recordings were made. Whole cell patch voltage-clamp methods were employed to record pharmacologically isolated excitatory postsynaptic currents (EPSCs) from DLSN neurons as an index of glutamatergic transmission. Using a modified internal pipette solution containing QX-314 and in which CsGluconate and GDPbetaS replaced Kgluconate and GTP, respectively, we recorded isolated monosynaptic EPSCs. The GABAA receptor antagonists bicuculline and picrotoxin were included in the external standard superfusion solution. Application of the GABAB receptor agonists, (+/-)-baclofen, CGP44533, and CGP35024 (10 nM to 10 microM) depressed glutamate-mediated EPSCs in a concentration-dependent manner. With the use of this combination of solutions, CGP44533 did not produce postsynaptic membrane property changes. Under these conditions, both (+/-)-baclofen and CGP35024 still induced increases of postsynaptic membrane conductance associated with an outward current. The GABAB receptor antagonist CGP55845A (1 microM) blocked the presynaptic CGP44533-mediated depressant effects of EPSCs, whereas CGP35348 (100 microM) or barium (2 mM) was ineffective. Furthermore, both CGP35348 (100 microM) and CGP55845A (1 microM) were effective in blocking the postsynaptic conductance changes associated with baclofen and CGP35024, whereas barium was ineffective. Our results demonstrate a distinct pharmacology for GABAB agonists acting at putative subtypes of GABAB receptors located on presynaptic sites of a glutamatergic terminal versus GABAB receptors on postsynaptic sites of a DLSN neuron. Furthermore, our results also suggest a different pharmacology and/or coupling of a GABAB receptor to different effectors at postsynaptic sites within the DLSN. Thus there may be three or more pharmacologically distinct GABAB receptors or receptor complexes associated with DLSN neurons: at least one pre- and two postsynaptic. If this distinct pharmacology and GABAB receptor distribution also extends to other CNS structures, such differences could provide development of selective drugs to act at these multiple sites.

Animals↗
PubMed1999

Morphological and biochemical analysis of anti-nuclear matrix protein antibodies in human sera.

Autoimmune sera have been used in the diagnosis of autoimmune diseases as well as the analysis of nuclear substructures. In an attempt to study the biological characteristics of the nuclear matrix, we screened human sera using immunofluorescent staining and immunoblot. We detected antibodies against nuclear matrix (NM), a remnant nonchromatin protein compartment after the treatment of detergent, salt and nuclease, in 212 out of 284 tested sera (74.6%) by immunoblot. Peptides with molecular weights of 70 kDa, 50 kDa and 25 kDa were detected in the order of frequency. Clinical informations of 198 out of 212 cases were available and went as follows: 38 cases were autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis; 132 non-autoimmune and non-neoplastic diseases; 16 neoplastic diseases and 12 cases unclassified. The immunofluorescent staining intensity by anti-nuclear matrix protein (NMP) antibodies decreased variably, but fibrillogranular, speckled and nucleolar immunolocalization patterns were retained after in situ fractionation. Ku70 and La protein were detected by anti-NMP antibodies. Immunolocalization by anti-NMP antibodies indicates that the NMPs constitute a variety of characteristic nuclear substructures and may serve as autoantigens in diverse human diseases. In addition, the presence of Ku70 and La protein as NMPs suggests that the NM can be functionally active in association with DNA or RNA.

Antigens, Nuclear↗
PubMed1998

Unsymmetric nonpeptidic HIV protease inhibitors containing anthranilamide as a P2' ligand.

A series of novel unsymmetrical anthranilamide-containing HIV protease inhibitors was designed. The structure-activity studies revealed a series of potent P2-P3' inhibitors that incorporate an anthranilamide group at the P2' position. A reduction in molecular weight and lipophilicity is achieved by a judicious choice of P2 ligands (i.e., aromatic, heteroaromatic, carbamate, and peptidic). A systematic investigation led to the 5-thiazolyl carbamate analog 8 m, which exhibited a favorable Cmax/EC50 ratio (> 30), plasma half-life (> 8 h), and potent in vitro antiviral activity (EC50 = 0.2 microM).

Amides↗
PubMed1998

Interaction of the xanthine nucleotide binding Goalpha mutant with G protein-coupled receptors.

We constructed a double mutant version of the alpha subunit of Go that was regulated by xanthine nucleotides instead of guanine nucleotides (GoalphaX). We investigated the interaction between GoalphaX and G protein-coupled receptors in vitro. First, we found that the activated m2 muscarinic cholinergic receptor (MAChR) could facilitate the exchange of XTPgammaS for XDP in the GoalphaXbetagamma heterotrimer. Second, the GoalphaXbetagamma complex was able to induce the high affinity ligand-binding state in the N-formyl peptide receptor (NFPR). These experiments demonstrated that GoalphaX was able to interact effectively with G protein-coupled receptors. Third, we found that the empty form of GoalphaX, lacking a bound nucleotide and betagamma, formed a stable complex with the m2 muscarinic cholingeric receptor associated with the plasma membrane. Finally, we investigated the interaction of GoalphaX with receptor in COS-7 cells. The empty form of GoalphaX bound tightly to the receptor and was not activated because XTP was not available intracellularly. We tested the ability of GoalphaX to inhibit the activities of several different G protein-coupled receptors in transfected COS-7 cells and found that GoalphaX specifically inhibited Go-coupled receptors. Thus the modified G proteins may act as dominant-negative mutants to trap and inactivate specific subsets of receptors.

Animals↗