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Biomedical subjects

S Sinha

Publications and source records attributed to S Sinha.

At least 145 records · Page 8Linked to original sources
PubMed2001

Adenovirus-mediated gene transfer of a secreted transforming growth factor-beta type II receptor inhibits luminal loss and constrictive remodeling after coronary angioplasty and enhances adventitial collagen deposition.

BACKGROUND: Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-beta1 on luminal loss after PTCA. METHODS AND RESULTS: Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-beta type II receptor (Ad5-RIIs), an adenovirus expressing beta-galactosidase (Ad5-lacZ), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs-injected arteries (1.71+/-0.12 mm(2)) than in the Ad5-lacZ (1.33+/-0.13 mm(2)) or vehicle-only (1.08+/-0.17 mm(2); P=0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (P=0.013) and external (P=0.031) elastic laminae in Ad5-RIIs-treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-lacZ and vehicle-only groups (P=0.004). CONCLUSIONS: Adenovirus-mediated antagonism of TGF-beta1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-beta1 stimulates the formation of a dense collagenous adventitia, which prevents constrictive remodeling by acting as an external scaffold. These findings demonstrate the potential of gene therapy-mediated antagonism of TGF-beta1 as prophylactic therapy for restenosis.

Adenoviridae↗
PubMed2001

Dynamic instability of a rotating Bose-Einstein condensate.

We consider a Bose-Einstein condensate subject to a rotating harmonic potential, in connection with recent experiments leading to the formation of vortices. We use the classical hydrodynamic approximation to the nonlinear Schrödinger equation to determine almost analytically the evolution of the condensate. We predict that this evolution can exhibit dynamical instabilities, for the stirring procedure previously demonstrated at ENS and for a new stirring procedure that we put forward. These instabilities take place within the range of stirring frequency and amplitude for which vortices are produced experimentally. They provide therefore an initiating mechanism for vortex nucleation.

Journal Article↗
PubMed2001

Structural remodeling of an A + U-rich RNA element by cation or AUF1 binding.

Association of AUF1 with A + U-rich elements (AREs) induces rapid cytoplasmic degradation of mRNAs containing these sequences, involving the recruitment or assembly of multisubunit trans-acting complexes on the mRNA. Recently, we reported that Mg(2+)-induced conformational changes in the ARE from tumor necrosis factor alpha mRNA inhibited AUF1 binding and oligomerization activities on this substrate (Wilson, G. M., Sutphen, K., Chuang, K., and Brewer, G. (2001) J. Biol. Chem. 276, 8695-8704). In this study, resonance energy transfer was employed to characterize structural changes in RNA substrates in response to cation- and AUF1-binding events. An RNA substrate containing the tumor necrosis factor alpha ARE displayed a weak conformational transition in the absence of added cations but was cooperatively stabilized by Mg(2+). Additional assays demonstrated a strong preference for small, multivalent cations, suggesting that the folded RNA structure was stabilized by counterion neutralization at discrete regions of high negative charge density. Association of AUF1 with cognate RNA substrates also induced formation of condensed RNA structures, although distinct from the folded structure stabilized by multivalent cations. Taken together, these experiments indicate that association of AUF1 with an ARE may function to remodel local RNA structures, which may be a prerequisite for subsequent recruitment of additional trans-acting factors.

Cations↗
PubMed2001

Targeting spatiotemporal patterns in extended systems with multiple coexisting attractors.

We set up adaptive control algorithms which can be used to achieve control to desired attractors in spatially extended systems. Traditional adaptive control methods often fail in such systems due to the presence of multiple coexisting attractors that lead to a high probability of the system getting trapped in an undesired attractor despite the application of control. We use quenching techniques to achieve control in such difficult scenarios. When the control parameter evolves through parameter regions that lead to undesired attractors, the control parameter is changed sufficiently fast so that the system does not get time to get trapped in these attractors, but gets quenched instead to the desirable attractor. The rate of change of the parameter is guided by using variable stiffness of control. We demonstrate the efficacy of our technique in a system of coupled sine-circle maps. Further, such variable stiffness schemes can also be used to step up the efficiency of adaptive control algorithms by making frequent suitable changes in the stiffness of control during the control dynamics. This strategy is very successful in reducing the time required to achieve control, while maintaining the stability of the control dynamics.

Journal Article↗
PubMed2001

BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, beta-amyloid peptides (Abetas), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma-secretases. beta-secretase activity cleaves APP to define the N-terminus of the Abeta1-x peptides and, therefore, has been a long- sought therapeutic target for treatment of AD. The gene encoding a beta-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary beta-secretase in mammalian brain nor whether inhibition of beta-secretase might have effects in mammals that would preclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, beta-secretase activity and Abeta production. These mice appeared to develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable beta-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Abeta from APP. The findings that BACE is the primary beta-secretase activity in brain and that loss of beta-secretase activity produces no profound phenotypic defects with a concomitant reduction in beta-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.

Alzheimer Disease↗
PubMed2001

Controlling neuronal spikes.

We propose two control strategies for achieving desired firing patterns in a physiologically realistic model neuron. The techniques are powerful, efficient, and robust, and we have applied them successfully to obtain a range of targeted spiking behaviors. The methods complement each other: one involves the manipulation of only a parameter, the applied soma current, and the other involves the manipulation of only a state variable, the membrane potential. Both techniques have the advantage that they are not measurement-intensive nor do they involve much run-time computation, as knowledge of only the interspike interval is necessary to implement control.

Journal Article↗
PubMed2001

Defibrillation via the elimination of spiral turbulence in a model for ventricular fibrillation.

Ventricular fibrillation, the major reason behind sudden cardiac death, is turbulent cardiac electrical activity in which rapid, irregular disturbances in the spatiotemporal electrical activation of the heart make it incapable of any concerted pumping action. Methods of controlling ventricular fibrillation include electrical defibrillation as well as injected medication. Electrical defibrillation, though widely used, involves subjecting the whole heart to massive, and often counterproductive, electrical shocks. We propose a defibrillation method that uses a very low-amplitude shock (of order mV) applied for a brief duration (of order 100 ms) and over a coarse mesh of lines on our model ventricle.

Defibrillators, Implantable↗
PubMed2001

Retention of the Alzheimer's amyloid precursor fragment C99 in the endoplasmic reticulum prevents formation of amyloid beta-peptide.

gamma-Secretase is a membrane-associated endoprotease that catalyzes the final step in the processing of Alzheimer's beta-amyloid precursor protein (APP), resulting in the release of amyloid beta-peptide (Abeta). The molecular identity of gamma-secretase remains in question, although recent studies have implicated the presenilins, which are membrane-spanning proteins localized predominantly in the endoplasmic reticulum (ER). Based on these observations, we have tested the hypothesis that gamma-secretase cleavage of the membrane-anchored C-terminal stump of APP (i.e. C99) occurs in the ER compartment. When recombinant C99 was expressed in 293 cells, it was localized mainly in the Golgi apparatus and gave rise to abundant amounts of Abeta. Co-expression of C99 with mutant forms of presenilin-1 (PS1) found in familial Alzheimer's disease resulted in a characteristic elevation of the Abeta(42)/Abeta(40) ratio, indicating that the N-terminal exodomain of APP is not required for mutant PS1 to influence the site of gamma-secretase cleavage. Biogenesis of both Abeta(40) and Abeta(42) was almost completely eliminated when C99 was prevented from leaving the ER by addition of a di-lysine retention motif (KKQN) or by co-expression with a dominant-negative mutant of the Rab1B GTPase. These findings indicate that the ER is not a major intracellular site for gamma-secretase cleavage of C99. Thus, by inference, PS1 localized in this compartment does not appear to be active as gamma-secretase. The results suggest that presenilins may acquire the characteristics of gamma-secretase after leaving the ER, possibly by assembling with other proteins in peripheral membranes.

Alzheimer Disease↗
PubMed2001

Identification and dissection of an enhancer controlling epithelial gene expression in skin.

Keratins 14 and 5 are the structural hallmarks of the basal keratinocytes of the epidermis and outer root sheath (ORS) of the hair follicle. Their genes are controlled in a tissue-specific manner and thus serve as useful tools to elucidate the regulatory mechanisms involved in keratinocyte-specific transcription. Previously we identified several keratinocyte-specific DNase I hypersensitive sites (HSs) in the 5' regulatory sequences of the K14 gene and showed that a 700-bp regulatory domain encompassing HSs II and III can confer epidermal and ORS-specific gene expression in transgenic mice in vivo. Although HS II harbored much of the transactivation activity in vitro, it was not sufficient to restrict expression to keratinocytes in vivo. We now explore the HS III regulatory element. Surprisingly, this element on its own confers gene expression to the keratinocytes of the inner root sheath (IRS) of the hair follicle, whereas a 275-bp DNA fragment containing both HSs II and III shifts the expression from the IRS to the basal keratinocytes and ORS in vivo. Electrophoretic mobility-shift assays and mutational studies of HSs III reveal a role for CACCC-box binding proteins, Sp1 family members, and other factors adding to the list of previously described factors that are involved in keratinocyte-specific gene expression. These studies highlight a cooperative interaction of the two HSs domains and strengthen the importance of combinatorial play of transcription factors that govern keratinocyte-specific gene regulation.

Animals↗
PubMed2001

Using thresholding at varying intervals to obtain different temporal patterns.

We show how stroboscopic threshold mechanisms can be effectively employed to obtain a wide range of stable cyclic behavior from chaotic systems, by simply varying the frequency of control. We demonstrate the success of the scheme in a prototypical one-dimensional map, as well as in a three-dimensional system modeling lasers where the threshold action is implemented on any one of the variables. It is evident that thresholding is capable of yielding exact limit cycles of varying periods and geometries when implemented at different intervals (even when very infrequent). This suggests a simple and potent mechanism for selecting different regular temporal patterns from chaotic dynamics.

Journal Article↗
PubMed2001

Studies on the hypoglycaemic activity of Punica granatum seed in streptozotocin induced diabetic rats.

The hypoglycaemic activity of Punica granatum Linn. (Family Punicaceae) seed extract on rats made diabetic by streptozotocin (STZ) was investigated. The methanol extract of the seed at doses of 300 and 600 mg/kg, and chlorpropamide 200 mg/kg was administered to STZ diabetic rats. The seed extract (150, 300 and 600 mg/kg, orally) caused a significant reduction of blood glucose levels in STZ induced diabetic rats by 47% and 52%, respectively, at the end of 12 h.

Administration, Oral↗
PubMed2001

Genetic heterogeneity and alterations in chromosome 9 loci in a localized region of a functional pituitary adenoma.

The molecular alterations reported in pituitary adenomas include mutations at the G(s)alpha in somatotrophinomas, and hypermethylation of the p16 tumor suppressor gene. There are, however, no reports of genomic instability or intratumor genetic heterogeneity in pituitary adenomas. We have studied the microsatellite loci on the short arm of chromosome 9 (9p) and the DNA fingerprinting pattern, of adjacent compartments, about 2 mm across, in a functional chromophobe pituitary adenoma secreting growth hormone and prolactin. The microsatellite loci were studied by PCR amplification using locus specific primers, while the DNA fingerprinting pattern was studied by randomly amplified polymorphic DNA (RAPD) analysis. Normal leukocyte DNA was taken as control. Only one compartment (Ta) showed alterations in several of the microsatellite loci and in the RAPD pattern vis a vis corresponding normal DNA and also the other two compartments of the tumor. This provides evidence for the localized nature of genomic instability in this tumor.

Adenoma↗
PubMed2001

Suppression of apoptosis and granulocyte colony-stimulating factor-induced differentiation by an oncogenic form of Cbl.

OBJECTIVE: The retroviral oncogene v-Cbl causes pre-B cell lymphomas and myeloid leukemias in mice, and its Drosophila homologue is oncogenic, causing enhanced receptor tyrosine kinase signaling. The human Cbl gene resides at 11q23. The aim of this study is to determine the effect of oncogenic Cbl on growth-regulating responses. MATERIALS AND METHODS: The oncogenic mutant of Cbl (CblDelta1-357) was transfected into factor-dependent 32Dcl3 myeloid cells. Consequently, cell survival and differentiation were measured. Lyn, Syk, MAP kinase, and phosphatidylinositol 3'(PI3')-kinase activities, protein phosphorylation, Bcl-2 promoter activity, ubiquitination, and levels of Bcl-2, Bax, Bad, and Bcl-x(L) were determined. In addition, the effect of v-Cbl on TF-1 cell survival upon granulocyte-macrophage colony-stimulating factor withdrawal was studied. RESULTS: 32Dcl3 and TF-1 cells expressing v-Cbl showed resistance to apoptosis upon growth factor withdrawal, and 32Dcl3 cells completely failed to respond to granulocyte colony-stimulating factor's induction of differentiation. Basal activities of Lyn, Syk, and PI3'-kinase were elevated in the v-Cbl line. There was neither enhanced tyrosine phosphorylation of cellular protein content, Cbl, or Jak2, nor serine phosphorylation of MAP kinase or Akt. After factor withdrawal, the level of Bcl-2 was greater in v-Cbl cells than in control cells. CONCLUSIONS: Neither increased Bcl-2 promoter activity nor decreased ubiquitination of Bcl-2 could account for increased Bcl-2 levels. v-Cbl-expressing 32Dcl3 cells were resistant to differentiation. v-Cbl suppresses apoptosis and differentiation, possibly through enhancement of Lyn, Syk, and PI3'-kinase activities and Bcl-2.

Animals↗
PubMed2001

Distribution of metals in aquatic edible plants: Trapa natans (Roxb.) Makino and Ipomoea aquatica Forsk.

Most of the water bodies being used for the cultivation of edible aquatic plants (Trapa natans and Ipomoea aquatica) in Lucknow district, U.P., India, were found to be contaminated with a variety of toxic metals (Fe, Cu, Cr, Mn and Pb). The concentration of metals Cr, Pb and Fe in water was much higher than recommended permissible limits of WHO (1995). The edible parts of these plants bioconcentrated metals from their surrounding water significantly. Therefore, the present study was planned to assess the metal concentration in edible part of plants which was collected from various water bodies used for cultivation of these crops. Despite varying levels of metals found in various fruit parts of T. natans, the metal accumulation in kernel was alarming. However, metal content decreased significantly in various parts after boiling the fruit. Similarly, I. aquatica also accumulated significantly higher amounts of these metals in leaves, however the metal accumulating potential varied considerably depending upon level of metal contamination in the water body in which they were growing. The importance of these findings in the exploitation of these aquatic crops to meet the demand of food and health perspectives for human beings is highlighted.

Cooking↗
PubMed2001

Use of olanzapine for elderly patients with psychotic disorders: a review.

The number of elderly persons with psychosis will increase with the increasing geriatric population. Olanzapine is one of the newer atypical antipsychotics with efficacy for positive and negative symptoms and safer side effect profile compared to conventional antipsychotics. The manuscript describes the pharmacology, efficacy and tolerability studies, adverse effects and dosing considerations in the elderly. Further studies are needed to fully assess the efficacy and safety of olanzapine in the elderly. Current research supports a role for olanzapine in treating elderly patients with schizophrenia, schizoaffective disorder and behavioral and psychological symptoms of dementia.

Aged↗