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Biomedical subjects

A Bhat

Publications and source records attributed to A Bhat.

At least 19 recordsLinked to original sources
PubMed2004

Shoulder and elbow joint power differ as a general feature of vertical arm movements.

Consistent patterns of joint power underlie coordinated lower extremity behaviors such as running and walking. Recent work found that shoulder and elbow power consistently differed during reaching movements in the horizontal plane. Moreover, joint power during horizontal reaching appears correlated with motor cortical activity. It is not known if the feature of differential joint power extends to vertical plane reaches or to reaches of different movement conditions. The purpose of this study was to test for differential shoulder and elbow power during the acceleratory and deceleratory phases of fast and normal speed vertical reaches in sitting and supine positions. Our results suggest that shoulder and elbow power typically differed both within and across conditions. First, shoulder power values were positive or negative dependent largely on movement direction and movement phase. That is, for each direction and phase, the shoulder either generated or absorbed energy independent of speed or body position. Second, and unexpectedly, reaches of certain condition combinations had similar shoulder power magnitudes across directions. In contrast, elbow power values for each direction varied between positive and negative values depending on phase, speed and position, and no two condition combinations overlapped across directions. Third, as target direction, movement phase and body position varied, shoulder power at fast and normal speeds were linearly correlated, as was shoulder power in sitting and in supine. In contrast, elbow power was linearly correlated only between speeds. These results join other studies to suggest that the neuromotor control of the shoulder may be less complex as compared to the elbow as a general feature of reaching movements. This differential control has important implications for the study of reaching impairments in neurorehabilitation populations, and provides a potentially important variable in the study of cortical firing patterns.

Acceleration↗
PubMed2001

Escape from repeat-induced point mutation of a gene-sized duplication in Neurospora crassa crosses that are heterozygous for a larger chromosome segment duplication.

In Neurospora crassa the ability of an ectopic gene-sized duplication to induce repeat-induced point mutation (RIP) in its target gene was suppressed in crosses that were heterozygous for another larger chromosome segment duplication. Specifically, the frequency of RIP in the erg-3 gene due to a 1.3-kb duplication was reduced if the chromosome segment duplications Dp(IIIR > [I;II]) AR17, Dp(VIR > IIIR) OY329, or Dp(IVR > VII) S1229 were present in either the same or the other parental nucleus of the premeiotic dikaryon. We suggest that the larger duplications act as sinks to titrate the RIP machinery away from the smaller duplication. In contrast, RIP efficiency was relatively unaffected in comparably unproductive interspecies crosses with N. intermedia and N. tetrasperma. These findings offer a novel explanation for the observed persistence of the transposable element Tad in only a subset of Neurospora strains.

Chromosomes, Fungal↗
PubMed2001

Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway.

Alterations in the expression of integrin receptors for extracellular matrix (ECM) proteins are strongly associated with the acquisition of invasive and/or metastatic properties by human cancer cells. Despite this, comparatively little is known of the biochemical mechanisms that regulate the expression of integrin genes in cells. Here we demonstrate that the Ras-activated Raf-MEK-extracellular signal-regulated kinase (ERK) signaling pathway can specifically control the expression of individual integrin subunits in a variety of human and mouse cell lines. Pharmacological inhibition of MEK1 in a number of human melanoma and pancreatic carcinoma cell lines led to reduced cell surface expression of alpha6- and beta3-integrin. Consistent with this, conditional activation of the Raf-MEK-ERK pathway in NIH 3T3 cells led to a 5 to 20-fold induction of cell surface alpha6- and beta3-integrin expression. Induced beta3-integrin was expressed on the cell surface as a heterodimer with alphav-integrin; however, the overall level of alphav-integrin expression was not altered by Ras or Raf. Raf-induced beta3-integrin was observed in primary and established mouse fibroblast lines and in mouse and human endothelial cells. Consistent with previous reports of the ability of the Raf-MEK-ERK signaling pathway to induce beta3-integrin gene transcription in human K-562 erythroleukemia cells, Raf activation in NIH 3T3 cells led to elevated beta3-integrin mRNA. However, unlike immediate-early Raf targets such as heparin binding epidermal growth factor and Mdm2, beta3-integrin mRNA was induced by Raf in a manner that was cycloheximide sensitive. Surprisingly, activation of the Raf-MEK-ERK signaling pathway by growth factors and mitogens had little or no effect on beta3-integrin expression, suggesting that the expression of this gene requires sustained activation of this signaling pathway. In addition, despite the robust induction of cell surface alphavbeta3-integrin expression by Raf in NIH 3T3 cells, such cells display decreased spreading and adhesion, with a loss of focal adhesions and actin stress fibers. These data suggest that oncogene-induced alterations in integrin gene expression may participate in the changes in cell adhesion and migration that accompany the process of oncogenic transformation.

3T3 Cells↗
PubMed2000

Central pulmonary artery anatomy in right ventricular outflow tract obstructions.

We reviewed the cine-angiograms of 190 patients with right ventricular outflow tract (RVOT) obstructions for size and anatomy of pulmonary arteries, patent ductus arteriosus (PDA) and major aorto pulmonary collateral arteries (MAPCAs). Patients were grouped into three, Tetralogy of Fallot (TOF) with pulmonary atresia (group 1, N=86), TOF with pulmonary stenosis (group 2, N=97) and 7 cases of pulmonary atresia with intact interventricular septum (group 3). Out of 86 patients in group 1, 49 had PDA alone, 30 had MAPCAs alone, six had both and one had none. In group 2, 31 patients had persistent PDA and one patient had MAPCAS and PDA. A discrete stenosis (DS) of pulmonary artery was seen significantly more in patients with RVOT obstructions associated with PDA compared to patients without PDA (67/84 vs. 5/96). Out of the 84 cases with ducti, 53 had stenosis of the pulmonary artery at the site of ductus insertion. Thus presence of PDA was an important factor in the development of DS. The likely cause of pulmonary artery stenosis in TOF with PDA may be the opposing flows through RVOT and PDA producing a watershed effect at the ductus-pulmonary artery junction. Diffuse hypoplasia of pulmonary arteries (DH) was seen more significantly in RVOT obstructions associated with MAPCAs, compared to other patient groups (19/36 vs. 14/87). These small pulmonary arteries had no discrete stenosis and this diffuse hypoplasia might be the result of inadequate blood flow during intrauterine life [Harikrishnan S, Tharakan J, Titus T, Bhat A, Sivasankaran S, Bimal F, Syam Sunder KR, James, KJ. Central pulmonary artery anatomy in right ventricular outflow tract obstructions. Indian Heart Journal 1997;49:624 (Abstract)[18]].

Cineangiography↗
PubMed2000

Triacontanol inhibits both enzymatic and nonenzymatic lipid peroxidation.

The effect of the plant growth regulator, triacontanol (TRIA) on lipid peroxidation was studied in three different systems: (i) isolated chloroplasts of spinach (Spinacea oleracea L.) leaves; (ii) egg lecithin liposomes; and (iii) soybean lipoxygenase (LOX) system. The nonenzymatic lipid peroxidation in isolated chloroplasts and egg lecithin liposomes was measured as the amount of thiobarbituric acid reactive substances (TBARS) formed. Inhibition of Fe2+ and/or light-induced lipid peroxidation by TRIA was observed in both isolated chloroplasts and egg lecithin liposomes. The kinetics of soybean lipoxygenase-1 (LOX-1) was studied using linoleic acid as the substrate. The enzyme was competitively inhibited by TRIA. The Ki for TRIA inhibition of the enzyme was estimated to be 3.2-5.0 microM according to different methods of estimation. TRIA has been known to exhibit anti-inflammatory action in animals and this anti-inflammatory effect of TRIA might be mediated through inhibition of lipid peroxidation. Since LOX inhibitors have been extensively used as therapeutic agents, TRIA, being a natural compound has been suggested to be an effective anti-inflammatory drug.

Fatty Alcohols↗
PubMed2000

Abl kinase but not PI3-kinase links to the cytoskeletal defects in Bcr-Abl transformed cells.

OBJECTIVE: The purpose of this study was to investigate the contribution of Abl kinase and phosphatidylinositol 3-kinase (PI3-kinase) to the altered adhesive properties and cytoskeletal defects in a Bcr-Abl transformed fibroblast cell model. MATERIALS ANID METHODS: Two fibroblast cell lines stably transfected with Bcr-Abl were compared to their parental counterparts for alterations in their adhesive properties in an attachment assay and for abnormalities in their cytoskeletal architecture by immunofluorescence microscopy. Cells then were treated with specific inhibitors of either the Abl kinase CGP57148 or the PI3-kinase LY294002 to determine whether these treatments would restore normal cytoarchitecture and adhesion. RESULTS: [corrected] Significant defects in cytoskeletal architecture were observed using this fibroblast model of Bcr-Abl expression. Specific changes include loss of stress fibers and focal adhesions, which correlated with an adhesive defect. [corrected] Treatment of Bcr-Abl expressing cells with CGP57148, but not LY294002, resulted in reversion of cells to a near-normal phenotype, as assessed by immunofluorescence and attachment of Bcr-Abl transformed fibroblasts. CONCLUSIONS: Our studies demonstrate that Bcr-Abl tyrosine kinase but not PI3- kinase activity is required for maintenance of cytoskeletal rearrangements resulting from Bcr-AbI expression. Further, inhibition of Abl kinase restored normal adhesive properties to the Bcr-Abl-expressing cells, demonstrating the contribution of Bcr-Abl kinase activity to abnormal cytoskeletal function.

3T3 Cells↗
PubMed1999

Analysis of complex traits using neural networks.

A recently developed approach that employs artificial neural networks (ANNs) was applied to the simulated data set to identify sets of marker loci involved in disease etiology. In this implementation, ANNs are trained to predict the disease state (output) from the given genetic marker data (input). A contribution value (CV) for each locus is calculated from the weights that represent the strength of the connections for the trained ANN; a higher CV indicates a higher probability of linkage. The highest CV values were chosen as the most likely candidate regions involved in the disease.

Computer Simulation↗
PubMed1999

Linkage analysis in heterogeneous and complex traits.

Linkage analysis is generally carried out under single-gene models, while complex traits are thought to be under the control of multiple interacting genes. Current issues related to linkage analysis for complex traits are discussed. It is argued that linkage analyses should be carried out for sub-phenotypes, in addition to classical "affected-unaffected" phenotypes. Correlations for phenotypes among family members are often computed on the basis of extreme phenotypes of a proband, which results in biased estimates. Methods for ascertainment corrections are recommended. A generalized version of heterogeneity analysis is introduced and are shown to provide an effective single-locus analysis for complex traits.

Adult↗
PubMed1999

Heterogeneity for multiple disease loci in linkage analysis.

Many mendelian traits show heterogeneity; that is, the disease phenotype in different families may be caused by genes at different locations. In linkage analysis, this admixture type of heterogeneity (locus heterogeneity) has often been accommodated with one of the HOMOG programs, which thus far have been restricted to at most two disease gene locations. Here, an extension to an arbitrary number of disease locations is described. It has been implemented in a computer program, HOMOGM. This approach is also suitable as an approximation to the situation of complex traits, in which multiple disease genes may occur in the same family.

Algorithms↗
PubMed1999

CRKL binding to BCR-ABL and BCR-ABL transformation.

The SH2-SH3 domain-containing adaptor protein CRKL is the predominant tyrosine phosphorylated protein in chronic myelogenous leukemia (CML) neutrophils and BCR-ABL-expressing cell lines. The amino terminal CRKL SH3 domain binds directly to a proline-rich region in the C-terminus of BCR-ABL. BCR-ABL mutants with deletions of this region were constructed to assess biologic effects of eliminating the CRKL binding site. Yeast two-hybrid analysis and gel overlay assays show eradication of the direct interaction of CRKL with BCR-ABL in the proline deletion mutants. However, these BCR-ABL mutants transform myeloid cells to growth factor independence, and in these cells CRKL is tyrosine phosphorylated and associates with BCR-ABL. These findings suggest both direct and indirect interactions of CRKL with BCR-ABL. Thus, disruption of the direct interaction with BCR-ABL has not excluded a role for CRKL in BCR-ABL-mediated transformation.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Interactions of p62(dok) with p210(bcr-abl) and Bcr-Abl-associated proteins.

A 62-kDa Ras GTPase-activating protein (RasGAP)-associated protein is tyrosine-phosphorylated under a variety of circumstances including growth factor stimulation and in cells transformed by activated tyrosine kinases. A cDNA for p62(dok), reported to be the RasGAP-associated 62-kDa protein, was recently cloned from Abl-transformed cells. In this study, the interactions of p62(dok) with Bcr-Abl and associated proteins were examined. In 32D myeloid cells and Rat-1 fibroblasts transformed by p210(bcr-abl), p62(dok) is tyrosine-phosphorylated and co-immunoprecipitates with Bcr-Abl, RasGAP, and CrkL, a Src homology 2 (SH2) and SH3 domain-containing adaptor protein. Tyrosine-phosphorylated p62(dok) from cells expressing p210(bcr-abl) bound directly to the SH2 domains of Abl and CrkL in a gel overlay assay. Previous work has shown that an SH2 domain deletion mutant of Bcr-Abl is defective in transforming fibroblasts but remains capable of inducing myeloid growth factor independence. In both fibroblasts and myeloid cells expressing this mutant, p62(dok) is underphosphorylated as compared with cells expressing full-length p210(bcr-abl) but remains capable of associating with Bcr-Abl. However, in a gel overlay assay, p62(dok) from cells expressing the SH2 domain deletion was incapable of associating directly with SH2 domains of Abl and CrkL. Interestingly, no direct binding between Bcr-Abl and p62(dok) could be demonstrated in a yeast two-hybrid assay. These data suggest that indirect interactions mediate the interaction between Bcr-Abl and p62(dok) and that the SH2 domain of Bcr-Abl is required for hyperphosphorylation of p62(dok). Further, hyperphosphorylation of p62(dok) correlates with the ability of Bcr-Abl to transform fibroblasts but not with the induction of growth factor independence in myeloid cells.

Animals↗
PubMed1998

1,4-dihydro-2,3-quinoxalinediones as potential flavin metabolites and excitatory amino acid receptor ligands. Part 1: Synthesis and pharmacological evaluation of the benzylic oxidation series of 1,4-dihydro-6,7-dimethyl-2,3-quinoxalinedione.

A series of five 6,7-disubstituted 1,4-dihydro-2,3-quinoxalinediones was prepared, two of which are known microbial flavin metabolites and three of which are potential flavin metabolites. Four of the five compounds inhibited specific binding of [3H]-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid ([3H]AMPA), [3H]kainic acid, and [3H]6-cyano-1,4-dihydro-7-nitro-2,3-quinoxalinedione ([3H]CNQX) in rat brain homogenate fractions, with IC50 values in the low micromolar range (the fifth compound competed only with [3H]CNQX). Two of the compounds were moderately potent AMPA antagonists in an in vitro functional test.

Animals↗
PubMed1997

Percutaneous transvenous mitral commissurotomy using an Inoue balloon in children with rheumatic mitral stenosis.

Percutaneous transvenous mitral commissurotomy (PTMC) using the Inoue technique was performed in 557 patients with rheumatic mitral stenosis. Of these, 107 were children aged 10-18 years (mean +/- SD 14.5 +/- 2.3). All patients were symptomatic New York Heart Association (NYHA) Class II (n = 78) and Class III (n = 29). All were in sinus rhythm. Following PTMC, the mitral valve area (MVA) increased from 0.73 +/- 0.18 to 1.7 +/- 0.53 cm2 (P < 0.001). There was a significant fall in mean transmitral gradient from 15.6 +/- 5.2 to 5.1 +/- 2.3 mmHg, and in mean pulmonary artery pressure from 41 +/- 15 to 28.4 +/- 10 (P < 0.001). Cardiac tamponade developed in one patient. One patient developed severe mitral regurgitation requiring emergency mitral valve replacement. Five patients (4.7%) developed moderate mitral regurgitation. There was no mortality or cerebral embolism in any of the children. Four patients (3.7%) had oximetry evidence of atrial septal defect. Mean mitral valve area and transmitral gradient at 14 months mean follow up was 1.68 +/- 0.4 cm2 and 6 +/- 3.5 mmHg, respectively, and were comparable to the immediate post-PTMC results. Two patients (1.8%) developed restenosis. The immediate haemodynamic results in children were compared to 450 adult patients who underwent PTMC in the same period. The outcome was similar in both groups. Children were found to have significantly higher pulmonary artery pressure compared to adults. We found that PTMC using an Inoue balloon is very effective and safe in children, and consider that it should be the procedure of choice for young patients with symptomatic rheumatic mitral stenosis.

Adolescent↗