Indian company offers low cost AIDS drugs.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
S Kumar
Publications and source records attributed to S Kumar.
Angiogenesis in breast cancer: the role of transforming growth factor beta and CD105.
The progression of breast cancer depends on the establishment of a neovasculature, by a process called angiogenesis. Angiogenesis is an invasive cellular event that requires the co-ordination of numerous molecules including growth factors and their receptors, extracellular proteins, adhesion molecules, and proteolytic enzymes. TGFbeta has emerged to be a major modulator of angiogenesis by regulating endothelial cell proliferation, migration, extracellular matrix (ECM) metabolism, and the expression of adhesion molecules. It is a potent growth inhibitor of normal mammary epithelial cells and a number of breast cancer cell lines. It seems that TGFbeta exerts pleiotropic effects in the oncogenesis of breast cancers in a contextual manner, i.e., it suppresses tumourigenesis at an early stage by direct inhibition of angiogenesis and tumour cell growth. However, over-production of TGFbeta by an advanced tumour may accelerate disease progression through indirect stimulation of angiogenesis and immune suppression. The cell membrane antigen CD105 (endoglin) binds TGFbeta1 and TGFbeta3 and is preferentially expressed in angiogenic vascular endothelial cells. The reduction of CD105 levels in HUVEC leads to in vitro angiogenesis inhibition and massive cell mortality in the presence of TGFbeta1. CD105 null mice die in utero with impaired vasculature, indicating the pivotal role of CD105 in vascular development. The administration of an immunotoxin-conjugate, mab to CD105, induces long-term and complete regression of breast cancer growth in SCID mice. Therefore, CD105 is a promising vascular target for antiangiogenic therapy.
Animals↗
Immobilization of oligodeoxyribonucleotides with multiple anchors to microchips.
Facile modification of oligodeoxyribonucleotides is required for efficient immobilization to a pre-activated glass surface. This report presents an oligodeoxyribonucleotide which contains a hairpin stem-loop structure with multiple phosphorothioate moieties in the loop. These moieties are used to anchor the oligo to glass slides that are pre-activated with bromoacetamidopropylsilane. The efficiency of the attachment reaction was improved by increasing the number of phosphorothioates in the loop, as shown in the remarkable enhancement of template hybridization and single base extension through catalysis by DNA polymerase. The loop and stem presumably serve as lateral spacers between neighboring oligodeoxyribonucleotides and as a linker arm between the glass surface and the single-stranded sequence of interest. The oligodeoxyribonucleotides of this hairpin stem-loop architecture with multiple phosphorothioate moieties have broad application in DNA chip-based gene analysis.
Base Sequence↗
India tries to rebuild 600,000 lives after earthquake.
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Altruism↗
Substituent effects and charge delocalization mode in chrysenium, benzo[c]phenanthrenium, and benzo[g]chrysenium cations: a stable ion and electrophilic substitution study.
The first series of persistent carbocations derived from mono- and disubstituted chrysenes Ch (5- methyl- 3, 2-methoxy- 19, 2-methoxy-11-methyl- 20, 2-methoxy-5-methyl- 21, and 9-methyl-4H-cyclopenta[def]chrysene 22), monosubstituted benzo[c]phenanthrenes BcPh (3-methoxy- 23, 3-hydroxy- 24), and monosubstituted benzo[g]chrysenes BgCh (12-methoxy- 25; 12-hydroxy- 26) were generated in FSO3H/SO2ClF or FSO3H-SbF5 (4:1)/SO2ClF and studied by low-temperature NMR at 500 MHz. The methoxy and methyl substituents direct the protonation to their respective ortho positions. Whereas parent Ch 1 is protonated at C-6/C-12, 3 is protonated at C-6 (3aH+) and at C-12 (3bH+) with the latter being the thermodynamic cation. The 2-methoxy-Ch 19 is protonated at C-1 to give two conformationally distinct carboxonium ions (19aH+/19bH+). In the disubstituted Ch derivatives 20 and 21, the 2-methoxy overrides the 5-methyl and the predominant carbocations formed are via attack ortho to methoxy. For the methano derivative 22 (Me at C-9), a 3:1 mixture of 22aH+/22bH+ is formed. For parent BcPh 13, nitration and benzoylation are directed to C-5. With 3-methoxy-BcPh 23, the site of attack moves to C-4, thus producing two conformationally distinct carboxonium ions (23aH+/23bH+), whereas conventional nitration gave a 2:1 mixture of 23aNO2 and 23bNO2. In 3-hydroxy-BcPh 24, the carboxonium ion 24H+ is exclusively formed. For parent BgCh 16, protonation, nitration, and benzoylation are all directed to C-10 (16H+, 16NO2, 16COPh), but presence of OMe or OH substituent at C-12 changes the site of attack to C-11. Charge delocalization mode is probed based on magnitude of delta delta 13Cs and conformational aspects via NOED experiments. Complete NMR data are also reported for several benzoylation/nitration products. Using ab initio/GIAO (and NICS), the NMR chemical shifts (and aromaticity) in model carbocations A-D were evaluated. This work represents the first direct study of the carbocations derived from the methyl-, methoxy-/hydroxy-derivatives of three important classes of bay-region and fjord-region PAHs whose diol-epoxides extensively bind to DNA. It also extends the available data on electrophilic chemistry of BcPh and BgCh.
Chrysenes↗
Authorities overstretched as earthquake death toll increases.
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Disasters↗
Roles of the C termini of alpha -, beta -, and gamma -subunits of epithelial Na+ channels (ENaC) in regulating ENaC and mediating its inhibition by cytosolic Na+.
The amiloride-sensitive epithelial Na(+) channels (ENaC) in the intralobular duct cells of mouse mandibular glands are inhibited by the ubiquitin-protein ligase, Nedd4, which is activated by increased intracellular Na(+). In this study we have used whole-cell patch clamp methods in mouse mandibular duct cells to investigate the role of the C termini of the alpha-, beta-, and gamma-subunits of ENaC in mediating this inhibition. We found that peptides corresponding to the C termini of the beta- and gamma-subunits, but not the alpha-subunit, inhibited the activity of the Na(+) channels. This mechanism did not involve Nedd4 and probably resulted from the exogenous C termini interfering competitively with the protein-protein interactions that keep the channels active. In the case of the C terminus of mouse beta-ENaC, the interacting motif included betaSer(631), betaAsp(632), and betaSer(633). In the C terminus of mouse gamma-ENaC, it included gammaSer(640). Once these motifs were deleted, we were able to use the C termini of beta- and gamma-ENaC to prevent Nedd4-mediated down-regulation of Na(+) channel activity. The C terminus of the alpha-subunit, on the contrary, did not prevent Nedd4-mediated inhibition of the Na(+) channels. We conclude that mouse Nedd4 interacts with the beta- and gamma-subunits of ENaC.
Amiloride↗
The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel.
The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPxY, motif which is believed to be important for interaction with the WW domains of the ubiquitin-protein ligase, Nedd4. Disruption of this interaction, as in Liddle's syndrome, where mutations delete or alter the PPxY motif of either the beta or gamma subunits, has been proposed to result in increased ENaC activity. Here we present evidence that KIAA0439 protein, a close relative of Nedd4, is also a potential regulator of ENaC. We demonstrate that KIAA0439 WW domains bind all three ENaC subunits. We show that a recombinant KIAA0439 WW domain protein acts as a dominant negative mutant that can interfere with the Na(+)-dependent feedback inhibition of ENaC in whole-cell patch clamp experiments. We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC regulation or function in a tissue- and/or signal-specific manner to down-regulate ENaC.
Animals↗
Theories of musculoskeletal injury causation.
Based on the scientific evidence in published literature about precipitation of musculoskeletal injuries in the workplace, four theories have been proposed to explain these afflictions. Central to all theories is the presupposition that all occupational musculoskeletal injuries are biomechanical in nature. Disruption of mechanical order of a biological system is dependent on the individual components and their mechanical properties. These common denominators will be causally affected by the individual's genetic endowment, morphological characteristics and psychosocial makeup, and by the occupational biomechanical hazards. This phenomenon is explained by the Multivariate Interaction Theory. Differential Fatigue Theory accounts for unbalanced and asymmetric occupational activities creating differential fatigue and thereby a kinetic and kinematic imbalance resulting in injury precipitation. Cumulative Load Theory suggests a threshold range of load and repetition product beyond which injury precipitates, as all material substances have a finite life. Finally, Overexertion Theory claims that exertion exceeding the tolerance limit precipitates occupational musculoskeletal injury. It is also suggested that while these theories may explain the immediate mechanism of precipitation of injuries, they all operate simultaneously and interact to modulate injuries to varying degrees in different cases.
Biomechanical Phenomena↗
Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia.
Mitogen-activated protein kinases (MAPKs) are involved in many cellular processes. The stress-activated MAPK, p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Here, we demonstrate focal ischemic stroke-induced p38 enzyme activation (i.e., phosphorylation) in the brain. The second generation p38 MAPK inhibitor SB 239063 was identified to exhibit increased kinase selectivity and improved cellular and in vivo activity profiles, and thus was selected for evaluation in two rat models of permanent focal ischemic stroke. SB 239063 was administered orally pre- and post-stroke and intravenously post-stroke. Plasma concentration levels were achieved in excess of those that effectively inhibit p38 activity. In both moderate and severe stroke, SB 239063 reduced infarct size by 28-41%, and neurological deficits by 25-35%. In addition, neuroprotective plasma concentrations of SB 239063 that reduced p38 activity following stroke also reduced the stroke-induced expression of IL-1beta and TNFalpha (i.e., cytokines known to contribute to stroke-induced brain injury). SB 239063 also provided direct protection of cultured brain tissue to in vitro ischemia. This robust SB 239063-induced neuroprotection emphasizes a significant opportunity for targeting MAPK pathways in ischemic stroke injury, and also suggests that p38 inhibition be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.
Animals↗
Sesamin a potent antifeedant principle from Piper mullesua.
Sesamin, a major lignan of Piper mullesua of Manipur origin, exhibited significant antifeedant activity and moderate growth inhibition towards 4th instar larvae of Spilarctia obliqua. No larval toxicity of sesamin could be established in topical bioassay experiments. Its effective dose for 50% feeding deterrence (ED(50)) and growth inhibition (GI(50)) were found to be 3856 and 6212 ppm, respectively.
Animals↗
IL-1- and TNF-induced bone resorption is mediated by p38 mitogen activated protein kinase.
We have previously shown that p38 mitogen-activated protein kinase (MAPK) inhibitors, which block the production and action of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), are effective in models of bone and cartilage degradation. To further investigate the role of p38 MAPK, we have studied its activation in osteoblasts and chondrocytes, following treatment with a panel of proinflammatory and osteotropic agents. In osteoblasts, significant activation of p38 MAPK was observed following treatment with IL-1 and TNF, but not parathyroid hormone, transforming growth factor-beta (TGF-beta), 1,25(OH)(2)D(3), insulin-like growth factor-1 (IGF-1), or IGF-II. Similar results were obtained using primary bovine chondrocytes and an SV40-immortalized human chondrocyte cell line, T/C28A4. SB 203580, a selective inhibitor of p38 MAPK, inhibited IL-1 and TNF-induced p38 MAPK activity and IL-6 production (IC(50)s 0.3--0.5 microM) in osteoblasts and chondrocytes. In addition, IL-1 and TNF also activated p38 MAPK in fetal rat long bones and p38 MAPK inhibitors inhibited IL-1- and TNF-stimulated bone resorption in vitro in a dose-dependent manner (IC(50)s 0.3--1 microM). These data support the contention that p38 MAPK plays a central role in regulating the production of, and responsiveness to, proinflammatory cytokines in bone and cartilage. Furthermore, the strong correlation between inhibition of kinase activity and IL-1 and TNF-stimulated biological responses indicates that selective inhibition of the p38 MAPK pathway may have therapeutic utility in joint diseases such as rheumatoid arthritis (RA).
Animals↗
Early changes in neuropeptide mRNA expression in the striatum following reserpine treatment.
Chronic dopamine depletion produces neurochemical changes within the striatum as well as enhanced behavioral and metabolic responses to dopamine agonists. Changes in striatal neuropeptides have been consistently described, including increased expression of preproenkephalin mRNA and decreased expression of preprotachykinin and prodynorphin mRNA. Acute dopamine depletion following treatment with reserpine also produces enhanced behavioral and metabolic responses to agonist treatment which develop rapidly. In the present study, we used in situ hybridization histochemistry to investigate whether acute neurochemical changes occur following reserpine treatment. We evaluated neuropeptide mRNA expression in the striatum and nucleus accumbens at several time points from 6 to 120 h following single doses of reserpine and AMPT. The aim of these studies was to determine if changes in neuropeptide mRNA expression occur following acute dopamine depletion and whether such changes are specific to the striatum. Changes in striatal neuropeptide mRNA expression developed rapidly. Preproenkephalin mRNA expression by striatopallidal neurons was unchanged at 48 h, but increased by 44% at 120 h. Preprotachykinin mRNA expression in striatonigral neurons was increased at 6 h and then fell, with a maximal decrease of 45% at 48 h and partial recovery by 120 h. Prodynorphin mRNA expression was unchanged. Expression of preproenkephalin and preprotachykinin mRNA was also examined in subregions of the striatum and the nucleus accumbens. Expression of preproenkephalin mRNA was uniform in the striatum and higher in the core than the shell of the nucleus accumbens. Preprotachykinin mRNA expression in the striatum was higher in the lateral quadrants and was higher in the shell than in the core of the nucleus accumbens. The changes in neuropeptide mRNA following treatment with reserpine were only found in the striatum. These data provide further evidence for early alterations in neuronal function in the striatum following acute dopamine depletion and suggest that neuropeptide expression by striatonigral neurons may be more rapidly regulated in response to changes in dopamine levels.
Adrenergic Uptake Inhibitors↗
Role of LLD, a new locus for leaflet/pinna morphogenesis in Pisum sativum.
Properties of a mutant at the LLD (LEAF-LET DEVELOPMENT) locus in pea Pisum sativum L. are reported in this paper. Plants homozygous for the Mendelian recessive mutation lld bear leaves in which a few to many leaflets are incompletely developed. Opposite pinnae of rachis nodes often formed fused incompletely developed leaflets. The lld mutation was observed to abort pinna development at almost all morphogenetic stages. The lld mutation demonstrated high penetrance and low expressivity. The phenotypes of lld plants in tl, tac, tl tac, tl af and tl af tac backgrounds suggested that LLD function is involved in the separation of lateral adjacent blastozones differentiated on primary, secondary and tertiary rachides and lamina development in leaflets. The aborted development of tendrils and leaflets in lld mutants was related to deficiency in vascular tissue growth. The morphological and anatomical features of the leaflets formed on a tl lld double mutant permitted a model of basipetal leaflet development. The key steps of leaflet morphogenesis include origin of the lamina by splitting of a radially symmetrical growing pinna having abaxial outer surface, opposite to the vascular cylinder, through an invaginational groove, differentiation of adaxial surface along the outer boundary of split tissue in the groove and expansion of the lamina ridges so formed into lamina spans.
Genes, Plant↗
Pleiotropic morphological and abiotic stress resistance phenotypes of the hyper-abscisic acid producing Abo- mutant in the periwinkle Catharanthus roseus.
The pleiotropic properties of a abo abo (Abo-) gamma-ray induced mutant of Catharanthus roseus cv. Nirmal, selected among the M2 generation seeds for ability to germinate at 45 degrees C, are described. The mutant produced seeds possessing tricotyledonous embryos, unlike the typically dicotyledonous embryos present in the wild type Abo+ seeds. In comparison to Abo+ adults, the mutant plants had short stature and lanceolate leaves. The vascular bundles in the leaves and stem were poorly developed. Leaf surfaces were highly trichomatous, epidermal, cortex and mesophyll cells were small sized and a large majority of stomata were closed. Besides high temperature, the mutant was salinity and water-stress tolerant. The abscisic acid (ABA) content in the leaves was about 500-fold higher. The genetic lesion abo responsible for the above pleiotropy was recessive and inherited in Mendelian fashion. The seedlings and adult plants of the mutant accumulated higher proline than Abo+ plants. The phenotypes of abo abo mutants permitted the conclusions that (i) the mutant synthesizes ABA constitutively, (ii) both ABA-dependent and ABA independent pathways for proline and betaine accumulation are functional in the mutant, and (iii) cell division, elongation and differentiation processes in embryo and adult plant stages are affected in the mutant
Abscisic Acid↗
Epidemiology of undernutrition.
OBJECTIVE: The present study was undertaken to find out the magnitude of the problem of under nutrition among the children under 5 years of age and also to identify the important factors influencing the nutritional status of the children. METHODS: 30 cluster sampling technique had been applied in the study. A total of 600 children below five years of age were covered. Twenty under five children from each cluster were chosen for the study which was carried out during January to February '97. As per IAP criteria a total of 60.29% children were undernourished and 3.92% were severely undernourished. According to NCHS standard 46.57% & 6.86% children had weight below-2SD and -3SD respectively. RESULTS: A statistically significant relationship was found between the different age groups and nutritional status of under 5 children. Severe degree of malnutrition had highest prevalence under two years of age. The influence of variables like age, sex, religion, literacy status of parents and morbidity of the children were significantly associated with malnutrition. CONCLUSION: Practice of exclusive breast feeding, introduction of timely complementary feeding, education for maintaining personal hygiene, proper implementation of UIP immunization, periodic deworming, standard case management of diarrhoea and ARI as well as continuation of feeding during illness may reduce malnutrition of under-five children.
Age Distribution↗
Fetal gastrointestinal malformations.
In an audit to evaluate fetal gastrointestinal (GIT) malformations, case sheets of all mothers who gave birth to newborns with GIT malformations were analysed regarding the maternal history, prenatal ultrasound and the postnatal structural malformations and perinatal management. In 1999, eleven babies were born with gastrointestinal malformations, one was a still birth. Nine had associated malformations of other systems, two had trisomy 21. Eight babies were operated in the immediate newborn period, 5 survived. Ultrasound was not very accurate in the diagnosis of GIT anomaly in this series. In view of associated chromosomal and structural anomaly a fetal ECHO and genetic amniocentesis is warranted. Most of these babies require immediate surgery after birth, so they need to be delivered in a centre which is equipped with good neonatal and pediatric surgery care.
Adult↗
How do thermophilic proteins deal with heat?
Recent years have witnessed an explosion of sequence and structural information for proteins from hyperthermophilic and thermophilic organisms. Complete genome sequences are available for many hyperthermophilic archaeons. Here, we review some recent studies on protein thermostability along with work from our laboratory. A large number of sequence and structural factors are thought to contribute toward higher intrinsic thermal stability of proteins from these organisms. The most consistent are surface loop deletion, increased occurrence of hydrophobic residues with branched side chains and an increased proportion of charged residues at the expense of uncharged polar residues. The energetic contribution of electrostatic interactions such as salt bridges and their networks toward protein stability can be stabilizing or destabilizing. For hyperthermophilic proteins, the contribution is mostly stabilizing. Macroscopically, improvement in electrostatic interactions and strengthening of hydrophobic cores by branched apolar residues increase the enthalpy change between the folded and unfolded states of a thermophilic protein. At the same time, surface loop deletion contributes to decreased conformational entropy and decreased heat capacity change between the folded and unfolded states of the protein.
Archaea↗