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Biomedical subjects

S Srinivasan

Publications and source records attributed to S Srinivasan.

At least 19 recordsLinked to original sources
PubMed1992

Cloning of human and bovine homologs of SNF2/SWI2: a global activator of transcription in yeast S. cerevisiae.

We performed positional cloning of genes carried on yeast artificial chromosomes that span a human translocation breakpoint associated with a human disease and isolated by chance human and bovine genes with strong homology to the S. cerevisiae genes, SNF2/SWI2 and STH1, and the D. melanogaster gene brahma. We report here sequence analysis, expression data, and functional studies for this human SNF2-like gene (hSNF2L) and its bovine homolog (bovSNF2L). Despite strong homology at the amino acid level, hSNF2L is not capable of complementing the yeast mutations snf2 or sth1 in S. cerevisiae. Furthermore, in contrast to SNF2 itself, a fusion protein consisting of the DNA binding domain of LexA and hSNF2L did not transactivate a reporter gene downstream of LexA binding sites in a yeast expression system. The strong similarity between hSNF2L and these yeast and drosophila genes suggest that the mammalian genes are part of an evolutionarily conserved family that has been implicated as global activators of transcription in yeast and fruitflies but whose function in mammals remains unknown.

Adenosine Triphosphatases↗
PubMed1992

Resistance to tamoxifen with persisting sensitivity to estrogen: possible mediation by excessive antiestrogen binding site activity.

The growth of a large proportion of estrogen receptor-positive breast tumors is stimulated by estrogen and can often be controlled through antiestrogen therapy. Resistance to antiestrogen (AE) therapy can occur while tumors retain the expression of estrogen receptors (ERc) and remain functionally responsive to estrogens. The ability of specific antiestrogen binding sites (AEBS) to prevent AE from interacting with ERc has been examined as a possible mechanism through which this appropriation of AE could interfere with antiestrogen action. Comparisons were performed between uterine preparations where ERc activity exceeded AEBS binding and liver preparations where AEBS binding predominated. Identical estimates of ERc activity were obtained in uterine preparations using either [3H]estradiol or [3H]-4OH-tamoxifen and radioinert diethylstilbestrol (alpha,alpha'-diethyl-4,4'-stilbenediol) to estimate nonspecific binding. AEBS binding was observed only when [3H]-4OH-tamoxifen was used, while binding to Type II sites was resolved only with [3H]estradiol. When excess AEBS activity predominated, analyses with radiolabeled estrogen and antiestrogen present simultaneously showed that virtually all of the antagonist was bound to AEBS with little of the antagonist available to associate with ERc. In an effort to relate these observations to AE resistance per se, ERc and AEBS were measured in MCF-7 human breast cancer cells (ERc-positive, responsive to estrogens and antiestrogens) and in variant AE-insensitive LY-2 human breast cancer cells (ERc-positive, responsive only to estrogens). In AE-resistant LY-2 cells, the ratio of AEBS:ERc was approximately three times greater than in MCF-7 cells. Examination of 128 human breast carcinomas revealed that AEBS activity was present and could exceed ERc activity. Importantly, the partition of significant AE away from ERc was observed in human specimens. These observations identify a biochemical mechanism for antiestrogen resistance through which AE access to ERc can be totally incapacitated while sensitivity to estrogens continues. These observations indicate that AEBS activity, in addition to ERc activity, may provide helpful information for predicting the response of certain cancers to hormonal therapy.

Animals↗
PubMed1992

Effects of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on hepatic cellular antioxidants and lipid peroxidation in rats.

The purpose of this study was to determine if hepatic cellular antioxidants and indices of oxidative damage are altered by administration of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA). Rats were fed 0.01% ciprofibrate in the diet or were injected with PFDA (0.5 or 5.0 mg/kg, i.p.) every 4 weeks for 6, 14, 30, 54, and 78 weeks. Peroxisomal fatty acyl-CoA oxidase and catalase activities were increased by both ciprofibrate and PFDA throughout the study. Neither ciprofibrate nor PFDA increased the levels of malonaldehyde or conjugated dienes, but ciprofibrate decreased these indices at early time points. Ciprofibrate decreased the following cellular antioxidants or antioxidant enzymes: vitamin C, vitamin D, DT-diaphorase, glutathione peroxidase, glutathione-S-transferase, and glutathione reductase; superoxide dismutase and glutathione were not affected. PFDA decreased DT-diaphorase and increased superoxide dismutase, but did not affect other cellular antioxidants. This study shows that administration of the peroxisome proliferators ciprofibrate and PFDA did not increase indices of lipid peroxidation, but that cellular antioxidant defenses were inhibited for a prolonged period of time by the peroxisome proliferator ciprofibrate.

Acyl-CoA Oxidase↗
PubMed1992

An approach to computer-aided inhibitor design: application to cathepsin L.

We have developed an approach to search for molecules that can be used as lead compounds in designing an inhibitor for a given proteolytic enzyme when the 3D structure of a homologous protein is known. This approach is based on taking the cast of the binding pocket of the protease and comparing its dimensions with that of the dimensions of small molecules. Herein the 3D structure of papain is used to model cathepsin L using the comparative modeling technique. The cast of the binding pocket is computed using the crystal structure of papain because the structures of papain and the model of cathepsin L are found to be similar at the binding site. The dimensions of the cast of the binding site of papain are used to screen for molecules from the Cambridge Structural Database (CSD) of small molecules. Twenty molecules out of the 80,000 small molecules in the CSD are found to have dimensions that are accommodated by the papain binding pocket. Visual comparison of the shapes of the cast and the 20 screened molecules resulted in identifying brevotoxin b, a toxin isolated from the 'red tide' dinoflagellate Ptycho brevis (previously classified as Gymonodium breve), as the structure that best fits the binding pocket of papain. We tested the proteolytic activity of papain and cathepsin L in the presence of brevotoxin b and found inhibition of papain and cathepsin L with Kis of 25 microM and 0.6 microM, respectively. We also compare our method with a more elaborate method in the literature, by presenting our results on the computer search for inhibitors of the HIV-1 protease.

Binding Sites↗
PubMed1992

Intrauterine perineal tear: a rare birth injury.

A rare case of birth injury having intrauterine complete perineal tear is presented. Defunctioning sigmoid colostomy was undertaken because of bad perineal condition. The baby died of Pseudomonas septicemia on the 15th day before definitive surgical procedure could be undertaken.

Birth Injuries↗
PubMed1992

A movement pattern generator model using artificial neural networks.

Artificial neural networks (ANN's) allow a new approach to biological modeling. The main applications of ANN's have been geared towards the modeling of the association and learning mechanisms of the brain; only a few researchers have explored them for motor control. The fact that ANN's are based on biological systems indicates their potential application for a biological act such as locomotion. Towards this goal, we have developed a "movement pattern generator," using an ANN for generating periodic movement trajectories. This model is based on the concept of "central pattern generators." Jordan's sequential network, which is capable of learning sequences of patterns, was modified and used to generate several bipedal trajectories (or gaits), coded in task space, at different frequencies. The network model successfully learned all of the trajectories presented to it. The model has many attractive properties such as limit cycle behavior, generalization of trajectories and frequencies, phase maintenance, and fault tolerance. The movement pattern generator model is potentially applicable for improved understanding of animal locomotion and for use in legged robots and rehabilitation medicine.

Animals↗
PubMed1992

Structural basis of C3b binding by glycoprotein C of herpes simplex virus.

Glycoproteins C (gC) from herpes simplex virus type 1 (HSV-1) and HSV-2, gC-1 and gC-2, bind the human complement fragment C3b, although the two glycoproteins differ in their abilities to act as C3b receptors on infected cells and in their effects on the alternative complement pathway. Previously, we identified three regions of gC-2 (I, II, and III) which are important for C3b binding. In this study, our goal was to identify C3b-binding sites on gC-1 and to continue our analysis of gC-2. We constructed a large panel of mutants by using the cloned gC-1 and gC-2 genes. Most of the mutant proteins were transported to the surface of transiently transfected L cells and reacted with one or more monoclonal antibodies to discontinuous epitopes. By using 31 linker insertion mutants spread across the coding region of gC-1, we identified four regions in the ectodomain of gC-1 which are important for C3b binding, three of which are similar in position to C3b-binding regions I, II, and III of gC-2. Region III shares some similarities with the short consensus repeat found in CR1, the human complement receptor. These were, in part, the targets for construction of 20 single amino acid changes in region III of gC-1 and gC-2. These mutants identified similarities and differences in the C3b-binding properties of gC-1 and gC-2 and suggest that the amino half of region III is more important for C3b binding. However, our results do not support the concept of a structural relationship between the short consensus repeat of CR1 and gC, since mutations of some of the conserved residues, including three of four cysteines in region III, had no effect on C3b binding. Finally, we constructed four deletion mutants of gC-1, including one which lacked residues 33 to 123, as well as residues 367 to 449. This severely truncated molecule, lacking four cysteines and five potential N-linked glycosylation sites, was transported to the cell surface and retained its ability to bind monoclonal antibodies as well as C3b. Thus, the four distinct C3b-binding regions of gC-1 and several epitopes within two different antigenic sites are localized within residues 124 to 366.

Amino Acid Sequence↗
PubMed1992

C9 conformation of N-(N alpha-[(tert.-butyloxy)-carbonyl]-L-alanyl)-N,N'-dicyclohexylu rea in solid and solution.

An X-ray diffraction study was carried out on a single crystal of N-(N alpha-[(tert.-butyloxy)-carbonyl]-L-alanyl)-N,N'-dicyclohexylur ea belonging to the tetragonal space group P4(1)2(1)2, having cell dimensions a = b = 10.102(3) A, c = 46.067(7) A, V = 4701.2 A3, Z = 8. The crystal structure was solved by direct methods and refined to an R value of 0.056 for 1602 unique reflections with I greater than 2.5 sigma(I). Crystal structure analysis shows the presence of an intramolecular N-H ... O=C H-bond stabilizing the molecule in a folded form similar to that of a beta turn, forming a nine-membered ring. IR and 1H-NMR studies in CDCl3 solution confirm the stable folded conformation found in the crystalline state, as well as the existence of N-H ... O=C H-bonds in the title compound, as in peptides.

Alanine↗
PubMed1992

Multiply resistant Haemophilus influenzae type b causing meningitis.

The isolation from patients of meningitis, of two multidrug resistant strains of H. influenzae is of relevance to the empirical treatment of meningitis patients. The isolates produced beta lactamase and had higher MICs as compared to the four H. influenzae strains sensitive to the drugs commonly used for the treatment of meningitis. The cephalosporins and gentamicin were found to be effective antibiotic agents. The occurrence of resistance to ampicillin, chloramphenicol, cloxacillin, cotrimoxazole, tetracycline, penicillin and erythromycin is of concern.

Anti-Bacterial Agents↗
PubMed1992

Loose stools in the early neonatal period.

During a two-year period, the various factors associated with loose stools in the early neonatal period were studied among hospital born babies. Low birth weight babies had a lower incidence of non-infective loose stools when compared to neonates with a birth weight of more than 2500 g (p < 0.001). Newborns delivered by Cesarean section (p < 0.001) and those born to women with more than two children (p < 0.02) had a greater frequency of loose stools. Initiation of supplementary feeding and administration of antibiotics were important factors in causing loose stools. Bacterial etiology could be found only in 9.3% of newborns having loose stools. A later onset of loose stools was noted in those, whose stool culture grew bacterial organisms. Only nine newborns with loose stools required antibiotic therapy. Although loose stools were less common among low birth weight babies, they often required treatment with antimicrobials. None of them developed any complications. Since majority of them are non-bacterial and non-infective, great caution must be exercised before administering antibiotics to newborns with loose stools.

Anti-Bacterial Agents↗
PubMed1992

Multidrug resistant enteric fever.

Multidrug resistant typhoid fever (MDRT) is becoming an alarming public health problem in and around Pondicherry, South India. A retrospective review of the multidrug resistant typhoid fever cases admitted to the paediatrics ward of JIPMER Hospital, Pondicherry (India) during 1990 is presented. Prolonged pyrexia, chills and rigors, toxaemia, and tender hepatomegaly often more than 3 cm below the costal margin (often without splenomegaly) were striking features of MDRT cases. The incidence of complications was also greater. Positive blood cultures were observed even after weeks of antibiotic therapy, indicating persistent bacteraemia; resistance was almost always observed for multiple drugs (two or more). The fluoroquinolone group of drugs such as ciprofloxacin have been found to be the best for MDRT in terms of rapid response and cost effectiveness. Cefotaxime has moderate efficacy.

Anti-Bacterial Agents↗
PubMed1991

Experimental and theoretical studies of the three-dimensional structure of human interleukin-4.

The structure of human interleukin 4 (IL-4) was predicted utilizing a series of experimental and theoretical techniques. Circular Dichroism (CD) spectroscopy indicated that IL-4 belonged to the all alpha-helix class of protein structures. Secondary structure prediction, site-directed mutagenesis, and CD spectroscopy suggested a predominantly alpha-helical structure, consistent with a four-helix bundle structural motif. A human/mouse IL-4 chimera was constructed to qualitatively evaluate alternative secondary structure predictions. The four predicted helices were assembled into tertiary structures using established algorithms. The mapping of three disulfide bridges in IL-4 provided additional constraints on possible tertiary structures. Using accessible surface contact area as a criterion, the most suitable structures were right handed all antiparallel four-helix bundles with two overhand loop connections. Successful loop closure and incorporation of the three disulfide constraints were possible while maintaining the expected shape, solvent accessibility, and steric interactions between loops and helices. Lastly, energy minimization was used to regularize the chain.

Amino Acid Sequence↗
PubMed1991

A profile of pyogenic meningitis in children.

Clinical profile of pyogenic meningitis was studied in 256 cases over a period of 8 years. The male to female ratio was 1.46: 1 and 83.6% of the patients were less than 3 years of age. Fever, altered sensorium, refusal to feed, convulsions and vomiting were the common presenting symptoms. Six (2.3%) of them had subnormal temperature and the sensorium was normal in 12.5% of cases. Cerebrospinal fluid was clear in 9.4%, cell count was less than 100/cmm in 8.2%, sugar was more than 40 mg% in 24.2% and protein was less than 50 mg% in 12.5% of cases. Diplococcus pneumoniae was the commonest causative agent. The overall mortality was 30.5%. It is concluded that young children suffering from this disease may not have the typical features and one should have the highest suspicion to make an early diagnosis so that the morbidity and mortality from this condition can be reduced.

Child, Preschool↗