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Biomedical subjects

N Sinha

Publications and source records attributed to N Sinha.

At least 19 recordsLinked to original sources
PubMed2001

Developmental changes due to long-distance movement of a homeobox fusion transcript in tomato.

Long-distance movement of RNA through the phloem is known to occur, but the functional importance of these transported RNAs has remained unclear. Grafting experiments with a naturally occurring dominant gain-of-function leaf mutation in tomato were used to demonstrate long-distance movement of mutant messenger RNA (mRNA) into wild-type scions. The stock-specific pattern of mRNA expression was graft transmissible, indicating that the mRNA accumulation pattern is inherent to the transcript and not attributable to the promoter. The translocated mRNA caused changes in leaf morphology of the wild-type scions, suggesting that the translocated RNA is functional.

Artificial Gene Fusion↗
PubMed2001

Point mutations and sequence variability in proteins: redistributions of preexisting populations.

Here we study the effect of point mutations in proteins on the redistributions of the conformational substates. We show that regardless of the location of a mutation in the protein structure and of its type, the observed movements of the backbone recur largely at the same positions in the structures. Despite the different interactions that are disrupted and formed by the residue substitution, not only are the conformations very similar, but the regions that move are also the same, regardless of their sequential or spatial distance from the mutation. This observation leads us to conclude that, apart from some extreme cases, the details of the interactions are not critically important in determining the protein conformation or in specifying which parts of the protein would be more prone to take on different local conformations in response to changes in the sequence. This finding further illustrates why proteins manifest a robustness toward many mutational events. This nonuniform distribution of the conformer population is consistently observed in a variety of protein structural types. Topology is critically important in determining folding pathways, kinetics, building block cutting, and anatomy trees. Here we show that topology is also very important in determining which regions of the protein structure will respond to sequence changes, regardless of the sequential or spatial location of the mutation.

Adenylate Kinase↗
PubMed2001

Interdomain interactions in hinge-bending transitions.

BACKGROUND: The mechanisms that allow or constrain protein movement have not been understood. Here we study interdomain interactions in proteins to investigate hinge-bending motions. RESULTS: We find a limited number of salt bridges and hydrogen bonds at the interdomain interface, in both the "closed" and the "open" conformations. Consistently, analysis of 222 salt bridges in an independently selected database indicates that most salt bridges form within rather than between independently folding hydrophobic units. Calculations show that these interdomain salt bridges either destabilize or only marginally stabilize the closed conformation in most proteins. In contrast, the nonpolar buried surface area between the moving parts can be extensive in the closed conformations. However, when the nonpolar buried surface area is large, we find that at the interdomain interface in the open conformation it may be as large or larger than in the closed conformation. Hence, the energetic penalty of opening the closed conformation is overcome. Consistently, a large nonpolar surface area buried in the closed interdomain interface accompanies limited opening of the domains, yielding a larger interface. CONCLUSIONS: Short-range electrostatic interactions are largely absent between moving domains. Interdomain nonpolar buried surface area may be large in the closed conformation, but it is largely offset by the area buried in the open conformation. In such cases the opening of the domains appears to be relatively small. This may allow prediction of the extent of domain opening. Such predictions may have implications for the shape and size of the binding pockets in drug/protein design.

Adenylate Kinase↗
PubMed2001

Effect of endosulfan during fetal gonadal differentiation on spermatogenesis in rats.

Pregnant rats were exposed to endosulfan (1 or 2 mg/kg per day) from day 12 of gestation through parturition. Male neonates were fostered to untreated dams. At 100 days of age, the male offspring were sacrificed. Exposure to endosulfan during fetal gonadal differentiation altered the process of spermatogenesis by affecting testicular lactate dehydrogenase and sorbitol dehydrogenase. Reduction in spermatid count in testis and sperm count in cauda epididymis was observed. Testis, epididymis and seminal vesicle showed significant decrease in weights in both the treated groups while no effect on prostate weight was recorded. Hence it can be suggested that endosulfan interferes in the process of spermatogenesis. The overall toxicity was dose dependent.

Journal Article↗
PubMed2001

Building blocks, hinge-bending motions and protein topology.

Here we show that the locations of molecular hinges in protein structures fall between building block elements. Building blocks are fragments of the protein chain which constitute local minima. These elements fold first. In the next step they associate through a combinatorial assembly process. While chain-linked building blocks may be expected to trial-associate first, if unstable, alternate more stable associations will take place. Hence, we would expect that molecular hinges will be at such inter-building block locations, or at the less stable, unassigned regions. On the other hand, hinge-bending motions are well known to be critical for protein function. Hence, protein folding and protein function are evolutionarily related. Further, the pathways through which proteins attain their three dimensional folds are determined by protein topology. However, at the same time the locations of the hinges, and hinge-bending motions are also an outcome of protein topology. Thus, protein folding and function appear coupled, and relate to protein topology. Here we provide some results illustrating such a relationship.

Amino Acid Sequence↗
PubMed2001

A proposed structural model for amyloid fibril elongation: domain swapping forms an interdigitating beta-structure polymer.

We propose a model illustrating how proteins, which differ in their overall sequences and structures, can form the propagating, twisted beta-sheet conformations, characteristic of amyloids. Some cases of amyloid formation can be explained through a "domain swapping" event, where the swapped segment is either a beta-hairpin or an unstable conformation which can partially unfold and assume a beta-hairpin structure. As in domain swapping, here the swapped beta-hairpin is at the edge of the structure, has few (if any) salt bridges and hydrogen bonds connecting it to the remainder of the structure and variable extents of buried non-polar surface areas. Additionally, in both cases the swapped piece constitutes a transient "building block" of the structure, with a high population time. Whereas in domain swapping the swapped fragment has been shown to be an alpha-helix, loop, strand or an entire domain, but so far not a beta-hairpin, despite the large number of cases in which it was already detected, here swapping may involve such a structural motif. We show how the swapping of beta-hairpins would form an interdigitated, twisted beta-sheet conformation, explaining the remarkable high stability of the protofibril in vitro. Such a swapping mechanism is attractive as it involves a universal mechanism in proteins, critical for their function, namely hinge-bending motions. Our proposal is consistent with structural superpositioning of mutational variants. While the overall r.m.s.d.s of the wild-type and mutants are small, the proposed hinge-bending region consistently shows larger deviations. These larger deviations illustrate that this region is more prone to respond to the mutational changes, regardless of their location in the sequence or in the structure. Nevertheless, above all, we stress that this proposition is hypothetical, since it is based on assumptions lacking definitive experimental support.

Amyloid↗
PubMed2001

Sucrose export defective1 encodes a novel protein implicated in chloroplast-to-nucleus signaling.

The Sucrose export defective1 (Sxd1) gene of maize was cloned and shown to encode a novel protein conserved between plants and cyanobacteria. The structure of the Sxd1 locus was determined in wild-type plants and two independent sxd1 alleles. Expression analysis demonstrated that the gene was transcribed in all green tissues, with highest levels in maturing leaf blades. In situ hybridization studies revealed high levels of Sxd1 mRNA in bundle sheath cells, with lower levels within the mesophyll. The SXD1 protein was localized to chloroplasts, in both bundle sheath and mesophyll cells. Levels of sucrose, glucose, and fructose were compared between wild-type and sxd1 plants. Mutant plants were fully capable of producing sucrose and accumulated all three sugars at concentrations above those measured in wild-type plants. Despite these increased sugar concentrations, photosynthetic gene expression was not significantly downregulated in affected areas of sxd1 leaf blades. These results are consistent with photosynthate being trapped within anthocyanin-accumulating regions of sxd1 leaves due to plasmodesmal occlusion at the bundle sheath-vascular parenchyma boundary of the minor veins. A model for SXD1 function is proposed in which the protein is involved in a chloroplast-to-nucleus signaling pathway necessary for proper late-stage differentiation of maize bundle sheath cells, including the developmentally regulated modification of plasmodesmata.

Amino Acid Sequence↗
PubMed2001

Beneficial effects of nicorandil versus enalapril in chronic rheumatic severe mitral regurgitation: six months follow up echocardiographic study.

BACKGROUND AND AIM OF THE STUDY: It is possible that vasodilator therapy may retard left ventricular (LV) dilatation and functional deterioration in chronic mitral regurgitation (MR). The study objectives were to evaluate comparatively the efficacy of nicorandil (a new, balanced vasodilator) and enalapril therapy on LV volume, mass and function in mildly symptomatic, chronic rheumatic severe MR. METHODS: Eighty-seven mildly symptomatic rheumatic patients with severe MR were enrolled in this prospective, randomized study. All patients underwent serial echocardiography study at entry, and again at six months. Eighty patients completed the study. RESULTS: At six months, the nicorandil and enalapril patient groups each had a significant reduction in LV end-systolic volume index (57.4 +/- 24.8 versus 43.2 +/- 20.7 ml/m2, p = 0.003; 50.0 +/- 19.0 versus 40.4 +/- 14.2 ml/m2, p = 0.006, respectively) and LV mass index (218.0 +/- 88.0 versus 188.0 +/- 76.0 g/m2, p = 0.05; 217.2 +/- 48.0 versus 186.2 +/- 45.0 g/m2, p = 0.002 respectively). Both nicorandil and enalapril caused significant improvement in ejection fraction (63.8 +/- 7.0 versus 71.0 +/- 6.7%, p <0.0001; 63.2 +/- 6.9 versus 67.5 +/- 6.4%, p = 0.002, respectively) and a reduction in LV end-systolic stress (152.9 +/- 29.0 versus 126.0 +/- 25.0 dyne/cm2, p = 0.001; 150.0 +/- 30.2 versus 138.0 +/- 29.0 dyne/cm2, p = 0.002, respectively). However, nicorandil caused a greater reduction in absolute LV end-systolic volume index (13.3 +/- 10.1 versus 9.6 +/- 5.9 ml/m2, p = 0.02), and a greater improvement in absolute ejection fraction (7.2 +/- 4.7 versus 4.2 +/- 2.6%, p = 0.0005) than enalapril. CONCLUSION: It is concluded that nicorandil is equivalent to enalapril in improving LV volume, mass, end-systolic stress and ejection fraction in mildly symptomatic chronic rheumatic severe mitral regurgitation over a period of six months.

Adolescent↗
PubMed2001

Complement and cell mediated cytotoxicity by antiendothelial cell antibodies in Takayasu's arteritis.

OBJECTIVE: To study complement and cell mediated cytotoxicity by antiendothelial cell antibodies (AECA) in Takayasu's arteritis (TA). METHODS: Complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC) of AECA positive/negative TA sera were investigated by colorimetric MTT and 51Cr release assays, respectively, using human umbilical vein endothelial cells (HUVEC) as targets. RESULTS: Seven of 12 (58%) sera positive for IgG and/or IgM AECA exhibited CDC in comparison to none of the 13 AECA negative sera (p = 0.0052). The median value of CDC of the AECA positive group was 14% (range 13-21%) and that of the AECA negative group was 1% (p = 0.0012). Interleukin 1beta (10 U/ml) treatment of HUVEC resulted in enhancement in CDC of 6 of the 7 AECA positive cytotoxic sera, the median enhancement being 17% (range 7-29%). Tumor necrosis factor-alpha (100 U/ml) treatment of the targets resulted in a median enhancement by 36% (range 25-55%) in the CDC of 3 of these 7 sera. No sera exhibited ADCC at any of the effector:target ratios tested (10:1 to 100:1). CONCLUSION: AECA in TA mediate CDC against endothelial cells and may have a pathogenic role in the perpetuation of vascular damage in this disease.

Antibodies↗
PubMed2000

Extracting weak phase information from B-->V1V2 decays

We describe a new method for extracting weak, CP-violating &Dmacr;phase information, with no hadronic uncertainties, from an angular analysis of B-->V1V2 decays, where V1 and V2 are vector mesons. The quantity sin (2)(2beta+gamma) can be cleanly obtained from the study of decays such as B(0)(d)(t)-->D*+/-rho(-/+), D(*+/-)a(-/+)(1), D(;) *0K(;) (*0), etc. Similarly, one can use B(0)(s)(t)-->D(*+/-)(s)K*-/+ to extract sin (2)gamma. There are no penguin contributions to these decays. It is possible that sin (2)(2beta+gamma) will be the second function of CP phases, after sin2beta, to be measured at B factories.

Journal Article↗
PubMed2000

Effect of lead on Sertoli-germ cell coculture of rat.

Mixed cultures of Sertoli and germ cells were prepared from rat testes and their response to lead (Pb) was studied. Cultures consisted of a monolayer of Sertoli cells to which clusters of germ cells were attached. The effect of Pb added as lead acetate was tested at 0.0, 0.4, 4.0 and 40.0 microM for 24 and 48 h intervals. Addition of Pb to the culture medium caused germ cells to progressively detach from the Sertoli cell monolayer into the medium in a concentration and duration dependent manner Viability of the detached cells as judged by trypan blue exclusion test showed a decrease with increase in time and concentration of Pb. Significant leakage of lactate dehydrogenase (LDH) was recorded in the culture media only at the higher concentrations of 4.0 and 40.0 microM. Thus Pb at the doses tested induced cytotoxicity in rat Sertoli-germ cell coculture.

Animals↗
PubMed2000

Primary congenital anomalies of the coronary arteries: a coronary: arteriographic study.

Geographic variations in the incidence of different congenital coronary anomalies are well known, but infrequently studied in the Indian population. Among 4,100 adult patients who underwent diagnostic coronary arteriography, 39 (0.95%) patients (34 males, 5 females) had one or more anomalous coronary arteries. Their mean age was 46.4 +/- 8.2 years (range, 26-68 years). Thirty-five (89.74%) had anomalies of origin and distribution, while the remaining four (10.25%) had coronary artery fistulae. Right coronary artery was the commonest anomalous vessel, involved in 19 (48.74%) patients. It was originating from the left sinus of Valsalva in 15 and from the non-facing aortic sinus in four patients. Anomalous left circumflex artery was the second commonest anomaly, seen in 14 (35.89%) patients. Anomalous left anterior descending artery and anomalous left coronary artery from pulmonary artery were seen in one patient each. Among patients with coronary fistulae, two had fistulae between the left anterior descending artery and the main pulmonary artery, one between the conal artery and the right atrium, while the fourth patient had fistulae from the right coronary as well as from the left anterior descending artery to the left atrium. Atherosclerotic plaques in the anomalous arteries were seen in only 13 (33.33%) patients, much less than the overall incidence of coronary artery disease in patients with congenital coronary anomalies in this series (66.66%). In four (10.25%) patients, only the anomalous vessels were involved in coronary artery disease. Thus, in a small subgroup there does not appear to be an increased risk for development of atherosclerotic coronary artery disease in anomalous coronary arteries. Recognition of coronary anomalies is important in patients undergoing coronary arteriography, coronary interventions and cardiac surgery. Variations in the frequency of primary congenital coronary anomalies may possibly have a genetic background.

Adult↗
PubMed2000

Is axillary temperature an appropriate surrogate for core temperature?

The ideal technique for measuring temperature should be rapid, painless, reproducible and accurately reflect the core temperature. While axillary temperature is commonly used because of convenience and safety, there are conflicting reports about its accuracy. To determine whether axillary temperature can act as a surrogate for oral/rectal temperatures, a prospective comparative study was conducted. The axillary and rectal temperatures (Group 1: infants < 1 year age) and axillary and oral temperatures (Group 2: children 6-14 years age) were compared using mercury-in-glass thermometers. Various tests of agreement were applied to the data obtained. Rectal and axillary temperatures for infants agreed well; the mean difference (95% limits of agreement) between the two being 0.6 degree C (-0.3 degree C, 1.4 degrees C). Similarly, the mean difference (95% limits of agreement) between oral and axillary measurements for children aged 6-14 years was observed to be 0.6 degree C (-0.4 degree C, 1.4 degrees C). Axillary temperature appears to be an acceptable alternative to rectal/oral temperature measurements in children.

Adolescent↗
PubMed2000

Folding and binding cascades: dynamic landscapes and population shifts.

Whereas previously we have successfully utilized the folding funnels concept to rationalize binding mechanisms (Ma B, Kumar S, Tsai CJ, Nussinov R, 1999, Protein Eng 12:713-720) and to describe binding (Tsai CJ, Kumar S, Ma B, Nussinov R, 1999, Protein Sci 8:1181-1190), here we further extend the concept of folding funnels, illustrating its utility in explaining enzyme pathways, multimolecular associations, and allostery. This extension is based on the recognition that funnels are not stationary; rather, they are dynamic, depending on the physical or binding conditions (Tsai CJ, Ma B, Nussinov R, 1999, Proc Natl Acad Sci USA 96:9970-9972). Different binding states change the surrounding environment of proteins. The changed environment is in turn expressed in shifted energy landscapes, with different shapes and distributions of populations of conformers. Hence, the function of a protein and its properties are not only decided by the static folded three-dimensional structure; they are determined by the distribution of its conformational substates, and in particular, by the redistributions of the populations under different environments. That is, protein function derives from its dynamic energy landscape, caused by changes in its surroundings.

Models, Molecular↗