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Biomedical subjects

S Abraham

Publications and source records attributed to S Abraham.

At least 19 recordsLinked to original sources
PubMed1992

Human immunodeficiency virus gp120 binding C'C" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules.

Using site-directed mutagenesis informed by high-resolution CD4 structural data, we have investigated the role of residues of the C'C'' ridge region of human CD4 on class II major histocompatibility complex (MHC) binding. This C'C'' ridge is homologous to the CDR2 loop of an immunoglobulin variable domain and is known to contain the binding site for human immunodeficiency virus (HIV) coat glycoprotein gp120. Here we report that this region is also involved in interaction with class II MHC. Exposed positively charged residues Lys-35, Lys-46, and Arg-59 and the exposed hydrophobic residue Phe-43 contribute significantly to class II MHC binding. Moreover, mutations in the buried residues Trp-62 and Ser-49, which support the top and bottom of the C'C'' ridge, respectively, disrupt class II MHC interaction. The HIV binding region appears to involve a restricted area of the larger class II MHC binding site on CD4. Strategies of drug design aimed at interrupting CD4-HIV interaction will need to consider the extensive overlap between class II MHC and HIV gp120 binding surfaces in this region of CD4.

Animals↗
PubMed1992

The human immunodeficiency virus gp120 binding site on CD4: delineation by quantitative equilibrium and kinetic binding studies of mutants in conjunction with a high-resolution CD4 atomic structure.

The first immunoglobulin V-like domain of CD4 contains the binding site for human immunodeficiency virus gp120. Guided by the atomic structure of a two-domain CD4 fragment, we have examined gp120 interaction with informative CD4 mutants, both by equilibrium and kinetic analysis. The binding site on CD4 appears to be a surface region of about 900 A2 on the C" edge of the domain. It contains an exposed hydrophobic residue, Phe43, on the C" strand and four positively charged residues, Lys29, Lys35, Lys46, and Arg59, on the C, C', C", and D strands, respectively. Replacement of Phe43 with Ala or Ile reduces affinity for gp120 by more than 500-fold; Tyr, Trp, and Leu substitutions have smaller effects. The four positively charged side chains each make significant contributions (7-50-fold). This CD4 site may dock into a conserved hydrophobic pocket bordered by several negatively charged residues in gp120. Class II major histocompatibility complex binding includes the same region on CD4; this overlap needs to be considered in the design of inhibitors of the CD4-gp120 interaction.

Antibodies, Monoclonal↗
PubMed1992

Immunocytochemical demonstration of neural cell adhesion molecule (NCAM) along the migration route of luteinizing hormone-releasing hormone (LHRH) neurons in mice.

Contact between the developing forebrain and the ingrowing central processes of the olfactory, vomeronasal and terminal nerves is preceded by a migration of neural cell adhesion molecule (NCAM)-immunoreactive cells from the epithelium of the olfactory pit and the formation of an NCAM-immunoreactive cellular aggregate in the mesenchyme between the olfactory pit and the forebrain. The axons of the olfactory, vomeronasal, and terminal nerves, also NCAM-immunoreactive, grow into the cellular aggregate, which as development proceeds, becomes continuous with the rostral tip of the forebrain. The lateral and more rostral part of the cellular aggregate receives the ingrowing axons of the olfactory nerves and becomes the olfactory nerve layer of the olfactory bulb. The medial, more caudal part receives the central processes of the vomeronasal and terminal nerves. The vomeronasal nerve ends in the accessory olfactory bulb. The central processes of the terminal nerve end in the medial forebrain. Luteinizing hormone-releasing hormone (LHRH)-immunoreactive neurons, like the vomeronasal and terminal nerves, originate from the medial part of the olfactory pit. These LHRH cells migrate into the brain along and within a scaffolding formed by the NCAM-immunoreactive axons of the vomeronasal and terminal nerves, and they are never seen independent of this NCAM scaffold as they cross the nasal lamina propria. The results suggest that: (1) NCAM is likely to be necessary for scaffold formation, and (2) the scaffold may be essential for the subsequent migration of LHRH neurons into the brain. Because they aggregate, migrating LHRH-immunoreactive neurons, on which we did not detect NCAM immunoreactivity, may interact via other cell adhesion molecules (CAM). Inasmuch as the interaction between the LHRH-immunoreactive neurons and the NCAM-immunoreactive scaffold is heterotypic, the possibility of a heterophilic (NCAM to other CAM) interaction is not ruled out. These findings focus our attention on the functional role of NCAM in this migratory system.

Animals↗
PubMed1992

p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein.

Products of the ras gene family, termed p21ras, are GTP-binding proteins that have been implicated in signal transduction via receptors encoding tyrosine kinase domains. Recent findings have defined a superfamily of hemopoietin receptors that includes receptors for a number of interleukins and colony-stimulating factors. The intracellular portions of these receptors show only restricted homologies, have no tyrosine kinase domain, and provide no clues to the mode of signal transduction. However, in most cases the factors stimulate tyrosine phosphorylation. We demonstrate here that ligand-induced activation of the interleukin (IL)-2, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors resulted in activation of p21ras in various hemopoietic cell lines. The only cytokine tested that binds to a hemopoietin receptor and that did not activate p21ras was IL-4. Activation of p21ras was also observed in response to Steel factor, which stimulates the endogenous tyrosine kinase activity of the c-kit receptor, as well as with phorbol esters, which activate protein kinase C. Experiments with protein kinase inhibitors implicated tyrosine kinase activity, but not protein kinase C activity, as the upstream signal in p21ras activation via these growth factor receptors. Attempts to demonstrate tyrosine phosphorylation of the p21ras GTPase-activating protein (GAP) were negative, suggesting that phosphorylation of GAP may not be the major mechanism for regulation of p21ras activity by tyrosine kinases.

Animals↗
PubMed1992

Phosphorylation of multiple CD3 zeta tyrosine residues leads to formation of pp21 in vitro and in vivo. Structural changes upon T cell receptor stimulation.

T lymphocyte activation resulting from antigen recognition involves a protein tyrosine kinase pathway which triggers phosphorylation of several cellular substrates including the CD3 zeta subunit of the T cell receptor (TCR) to form pp21. The homologous TCR-associated protein, CD3 eta, is an alternatively spliced product of the same gene locus as CD3 zeta. CD3 eta lacks one of six cytoplasmic tyrosine residues (Tyr-132) found in CD3 zeta and is itself not phosphorylated. Site-directed mutagenesis in conjunction with in vitro and in vivo phosphorylation studies herein demonstrates that Tyr-132 is required for the formation of pp21. Moreover, the differential phosphorylation of CD3 zeta versus CD3 eta is not due to a selective association of the known TCR-associated protein tyrosine kinase, p59fyn; p59fyn but not p56lck or p62yes is associated with each of the three TCR isoforms containing CD3 zeta 2, or CD3 eta 2, or CD3 zeta-eta. This association occurs through components of the TCR complex distinct from CD3 zeta or CD3 eta. In addition, we show that pp21 formation is not only dependent on Tyr-132 but results from concomitant phosphorylation of other CD3 zeta residues including Tyr-121. Mutation of Tyr-90, -121, or -132 does not alter primary signal transduction as shown by the ability of individual CD3 zeta Tyr----Phe mutants to produce interleukin-2 upon TCR stimulation. Thus, the substantial structural changes in CD3 zeta upon TCR stimulation as reflected by alteration in its mobility in sodium dodecyl sulfate-polyacrylamide gel electrophoresis may affect subsequent events such as receptor desensitization, receptor movement, and/or protein associations.

Amino Acid Sequence↗
PubMed1992

T cell receptor complexes containing Fc epsilon RI gamma homodimers in lieu of CD3 zeta and CD3 eta components: a novel isoform expressed on large granular lymphocytes.

CD3 zeta and CD3 eta form disulfide-linked homo- or heterodimers important in targeting partially assembled Ti alpha-beta/CD3 gamma delta epsilon T cell receptor (TCR) complexes to the cell surface and transducing stimulatory signals after antigen recognition. Here we identify a new TCR isoform expressed on splenic CD2+, CD3/Ti alpha-beta+, CD4-, CD8-, CD16+, NK1.1+ mouse large granular lymphocytes (LGL), which are devoid of CD3 zeta and CD3 eta proteins. The TCRs of this subset contain homodimers of the gamma subunit of the high affinity receptor for IgE (Fc epsilon RI gamma) in lieu of CD3 zeta and/or CD3 eta proteins. The LGL display natural killer-like activity and are cytotoxic for B cell hybridomas producing anti-CD3 epsilon and anti-CD16 monoclonal antibodies, demonstrating the signaling capacity of both TCR and CD16 in this cell type. These findings provide evidence for an additional level of complexity of TCR signal transduction isoforms in naturally occurring T cell subsets.

Animals↗
PubMed1992

Ischemic but not reperfusion arrhythmias depend upon serum potassium concentration.

The effects of variations in serum concentrations of potassium on the occurrence and severity of ischemia- and reperfusion-induced arrhythmias have been studied in conscious rats. Serum potassium concentrations were modified by maintaining rats on diets which varied in potassium concentration, by treatment with hydrochlorothiazide, amiloride, spironolactone or infusions of potassium chloride. An inverse linear relationship was demonstrated between ischemia-induced arrhythmias and log(e) serum potassium concentration such that a 50% reduction in arrhythmias occur with a 3.8-fold increase in serum potassium concentration. On the other hand, the incidence of reperfusion-induced arrhythmias after 7 min of regional ischemia prior to reperfusion in previously untreated rats were not influenced by elevation of serum potassium concentrations prior to and after reperfusion. Effects on ischemia-induced arrhythmias could not be explained by changes in blood pressure or heart rate. It is speculated that modification of potassium concentration in non-ischemic or border zone ventricular tissue may directly modify arrhythmogenesis due to ischemia but not that due to reperfusion.

Animals↗
PubMed1992

The 9-kDa hydrophobic protein encoded at the 3' end of the porcine transmissible gastroenteritis coronavirus genome is membrane-associated.

The open reading frame potentially encoding a 78 amino acid, 9101 Da hydrophobic protein (HP) and, mapping at the 3' end of the porcine transmissible gastroenteritis coronavirus (TGEV) genome, was shown to be expressed during virus replication. The cloned HP gene was placed in a plasmid under control of the T7 RNA polymerase promoter and in vitro translation of transcripts generated in vitro yielded a 9.1-kDa protein that was immunoprecipitable with porcine hyperimmune anti-TGEV serum. Antiserum raised in rabbits against a 31 amino acid synthetic polypeptide that represented the central hydrophilic region of HP specifically immunoprecipitated HP from TGEV-infected cells. HP was further shown to become associated with microsomal membranes during synthesis in vitro and was found to be closely associated with the endoplasmic reticulum and cell surface membranes in infected cells. The intracellular location of HP suggests that it may play a role in the membrane association of replication complexes or in virion assembly.

Amino Acid Sequence↗
PubMed1992

Gene expression: nutrient control of pre- and posttranscriptional events.

Regulation of gene expression by specific nutrients has become a major frontier for the next generation of nutrition scientists. The techniques of molecular biology allow us to define nutrient needs, as well as the outcomes of nutrient excesses, in terms of events that govern gene transcription, mRNA processing, mRNA stability, and mRNA translation. Evidence is presented showing that dietary constituents specifically modulate the nuclear events governing gene transcription and transcript processing. For example, fatty acid synthase gene transcription is inhibited by specific polyunsaturated fatty acids; S14 and pyruvate kinase genes contain a specific carbohydrate response element; and editing of apo B-100 to apo B-48 is enhanced by dietary carbohydrate. Nutrients such as iron and glucose are shown to control mRNA stability and translational rates of certain transcripts by regulating the interaction of cytosolic proteins with specific nucleotide sequences. The data of this review clearly demonstrate that nutrients play an active and specific role in governing the expression of select genes.

Animals↗
PubMed1992

The teaching of behavioural sciences.

Medical science over the last few decades has undergone vast changes. Technologically it has advanced at a rapid pace. There has been a realization as well that the behaviour of individuals and communities also influences the occurrence of disease. Medical schools around the globe have realized the need for incorporating behavioural sciences as an integral part of the basic sciences taught to medical students. This paper presents the experience of Christian Medical College, Vellore in teaching behavioural sciences. Students are taught sociology, psychology and medical anthropology through a community-based, problem-oriented teaching programme. The students have first-hand experience of living in a community and learn by observation and interaction. Pre- and post-assessment has shown a significant improvement of their knowledge and attitude. Feedback from students also indicates that they find this programme relevant and interesting.

Behavioral Sciences↗
PubMed1992

Extracellular matrix in aged human ciliary body: an immunoelectron microscope study.

Tissue from nine human eyes (ages 52-78 yr) was used to investigate the fine structural distribution of collagens I-VI and laminin in the ciliary body using the immunogold antibody labeling technique. The anterior segments of the specimens were normal, and the eyes were removed in treatment of choroidal melanoma. The basement membranes of the ciliary epithelium contained collagens I, III, and IV. Laminin was in greater concentration in the outer part of the nonpigmented epithelial basement membrane, and the distribution suggested a washout effect. The zonular apparatus labeled intensely with laminin. In contrast, laminin was not present in the basement membrane of the myocytes in the ciliary body. These cells were sheathed in a basement membrane that contained types I, III, and IV collagen. Plaque-like structures of slightly different morphology (a, filamentous; b, granular; c, amorphous) were found in the tendinous insertions, and subtypes a and b were strongly labeled with laminin. The basement membranes of the vessels contained types I and IV collagen, but laminin labeling was inconclusive. The major finding was that the lamina densa in the basement membranes of various sites labeled for collagens I, III, and IV. Striated collagen fibrils in the stroma were labeled for types I and III. Collagen subtypes V and VI were not identified in significant quantity in any of the regions examined.

Aged↗
PubMed1991

Metabolism of meadowfoam oil fatty acids in mice.

Meadowfoam oil is unusual because over 95% of the fatty acids are 20- and 22-carbon aliphatic acids with cis double bonds located principally at the 5- and/or 13-position. Since little information is available on the metabolism of the 5c-20:1 and 5c,13c-22:2 fatty acids, an exploratory study in mice was conducted to investigate the metabolism of purified samples of the free fatty acids isolated from meadowfoam oil, and to determine the effect of meadowfoam oil on weight gain and tissue lipid composition. Mice fed diets containing 5% by wt of the purified 5c-20:1 or 5c,13c-22:2 for 6 days exhibited no apparent physiological problems. Total liver lipids from mice fed the purified fatty acid diets contained mean values of 2.0% 5c-20:1 and 2.1% 5c,13c-22:2; total heart lipids contained 1.7% 5c-20:1 and 10.7% 5c,13c-22:2. Liver total phospholipids from mice fed a 5% meadowfoam oil diet for 19 wk contained 1.4% 5c-20:1 and 1.9% 5c,13c-22:2. There was no evidence of desaturation, elongation or retroconversion. Weight gain for mice fed the meadowfoam oil diet for 19 wk was similar to mice fed corn oil, and was higher than for mice fed hydrogenated cottonseed oil. Considering the high 5c-20:1 and 5c,13c-22:2 content of the diets, the percentages of these fatty acids in mouse tissue lipids from both the short- and long-term studies were low. Weight gain was surprisingly good since the meadowfoam oil diet was essential fatty acid-deficient. Results of this initial investigation suggest that the 5c-20:1 and 5c,13c-22:2 fatty acids were utilized primarily for energy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker.

1. Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion-induced arrhythmias in conscious animals. 2. The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo. 3. Tedisamil (1-4 mg kg-1, i.v.) caused bradycardia, elevated blood pressure and dose-dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia-associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil-induced bradycardia was prevented by electrically-pacing the left ventricle. 4. Tedisamil dose-dependently lengthened the effective refractory period and prevented electrically-induced VF. In vivo, tedisamil (0.5-4 mg kg-1, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%. 5. Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.

Action Potentials↗
PubMed1991

Attenuation of mammary duct development by menhaden oil in BALB/c mice.

The predominant polyunsaturated fatty acids of the n-6 family found in corn oil (CO) are crucial for normal mammary duct formation when fed to animals. However, as shown here, not all polyunsaturated fatty acids are equally effective in stimulating mammary gland development. The n-3 fatty acids in a 10% menhaden oil (MO) diet fed to mice effectively reduced both the diameter and the length of the growing mammary ducts. Previously, we demonstrated a similar reduction in duct growth by feeding a 10% fat diet high in those saturated fats found in hydrogenated cotton seed oil. The inhibited rate of duct maturation caused by hydrogenated cotton seed oil was reversed when the mice were allowed to mature on a diet containing n-6 fatty acids prior to feeding the saturated fat diet. The addition of 1% CO to a 9% hydrogenated cotton seed oil diet fed to immature mice was also sufficient to restore duct growth. Mice fed menhaden oil diets, on the other hand, continued to show impaired ductal growth well into adulthood. Examination of the ovaries from MO-fed mice as compared with CO-fed mice revealed significantly fewer corpora lutea. When exogenous progesterone was given to MO-fed mice, ductal growth was partially restored, but not to the extent seen in mice fed corn oil diets. Investigation of the fatty acid contents of livers of these mice revealed reduced amounts of arachidonate (20:4) in MO-fed mice when compared with CO-fed animals. The addition of 1% CO to the 9% MO diets did not alter the arachidonate content, indicating a block in the conversion of linoleate (18:2) to 20:4 by the n-3 fatty acids. Hence, dietary n-6 fatty acids are essential for normal mammary ductal development when fed prior to maturation. Although saturated rats are ineffective, n-3 fatty acids can partially substitute for the required n-6 fatty acids in both ductal and ovarian development.

Animals↗
PubMed1990

Recovery after childbirth: a preliminary prospective study.

This prospective study examined the time for 93 women to cease to feel discomfort in their perineal areas after the births of their first babies. Sixty-two of the women had experienced a spontaneous delivery that did not require forceps assistance. In 58 patients, an episiotomy was performed. Of the 35 women in whom an episiotomy was not performed, 24 women required sutures and only four women did not suffer any perineal damage. The median time for perineal comfort in general (including walking and sitting) was one month (range, zero to six months); 20% of women took more than two months to achieve general perineal comfort. For comfort during sexual intercourse, the median time was three months (range, one to more than 12 months); 20% of women took longer than six months to achieve comfort during sexual intercourse. Factors that were associated with discomfort for longer than the median time were delivery by forceps; spontaneous vaginal (not perineal) tears; and, in the three to four days after the birth, oedema and the breakdown of muscle or skin sutures. There was no significant difference in these times between patients who did not undergo an episiotomy and those who underwent an episiotomy without a forceps delivery.

Adolescent↗