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131.
Weinstock DS Narayanan C Baum J Levy RM 《Protein science : a publication of the Protein Society》2008,17(5):950-954
Replica exchange molecular dynamics simulations are used to generate three ensembles of an S-peptide analog (AETAAAKFLREHMDS). Percent helicity of the peptide ensembles calculated using STRIDE is compared to percent helicity calculated from (13)C(alpha) chemical shift deviations (CSD) from random coil in order to test the assumption that CSD can be correlated to percent helicity. The two estimates of helicity, one based on structure and the other on CSD, are in close to quantitative agreement, except at the edges of helical stretches where disagreements of as much as 50% can be found. These disagreements can occur by CSDs both as an under- and an overestimate of peptide helicity. We show that underestimation arises due to ensemble averaging of positive CSDs from conformers with torsion angles in the helical region of Ramachandran space with negative CSDs corresponding to conformers of the peptide in the extended region. In contrast, overestimation comes about due to the fact that a large number of conformations with torsion angles in the helical region are not counted as helical by STRIDE due to a lack of correlated helical torsion angles in neighboring residues. 相似文献
132.
Structure of the mammalian 80S ribosome at 8.7 A resolution 总被引:1,自引:0,他引:1
Chandramouli P Topf M Ménétret JF Eswar N Cannone JJ Gutell RR Sali A Akey CW 《Structure (London, England : 1993)》2008,16(4):535-548
In this paper, we present a structure of the mammalian ribosome determined at approximately 8.7 A resolution by electron cryomicroscopy and single-particle methods. A model of the ribosome was created by docking homology models of subunit rRNAs and conserved proteins into the density map. We then modeled expansion segments in the subunit rRNAs and found unclaimed density for approximately 20 proteins. In general, many conserved proteins and novel proteins interact with expansion segments to form an integrated framework that may stabilize the mature ribosome. Our structure provides a snapshot of the mammalian ribosome at the beginning of translation and lends support to current models in which large movements of the small subunit and L1 stalk occur during tRNA translocation. Finally, details are presented for intersubunit bridges that are specific to the eukaryotic ribosome. We suggest that these bridges may help reset the conformation of the ribosome to prepare for the next cycle of chain elongation. 相似文献
133.
Libusha Kelly Ursula Pieper Narayanan Eswar Franklin A. Hays Min Li Zygy Roe-Zurz Deanna L. Kroetz Kathleen M. Giacomini Robert M. Stroud Andrej Sali 《Journal of structural and functional genomics》2009,10(4):269-280
Membrane proteins serve as cellular gatekeepers, regulators, and sensors. Prior studies have explored the functional breadth
and evolution of proteins and families of particular interest, such as the diversity of transport-associated membrane protein
families in prokaryotes and eukaryotes, the composition of integral membrane proteins, and family classification of all human
G-protein coupled receptors. However, a comprehensive analysis of the content and evolutionary associations between membrane
proteins and families in a diverse set of genomes is lacking. Here, a membrane protein annotation pipeline was developed to
define the integral membrane genome and associations between 21,379 proteins from 34 genomes; most, but not all of these proteins
belong to 598 defined families. The pipeline was used to provide target input for a structural genomics project that successfully
cloned, expressed, and purified 61 of our first 96 selected targets in yeast. Furthermore, the methodology was applied (1)
to explore the evolutionary history of the substrate-binding transmembrane domains of the human ABC transporter superfamily,
(2) to identify the multidrug resistance-associated membrane proteins in whole genomes, and (3) to identify putative new membrane
protein families. 相似文献
134.
Narayanan H Arruda EM Grosh K Garikipati K 《Biomechanics and modeling in mechanobiology》2009,8(3):167-181
In this paper, we address some modelling issues related to biological growth. Our treatment is based on a formulation for
growth that was proposed within the context of mixture theory (J Mech Phys Solids 52:1595–1625, 2004). We aim to make this
treatment more appropriate for the physics of porous soft tissues, paying particular attention to the nature of fluid transport,
and mechanics of fluid and solid phases. The interactions between transport and mechanics have significant implications for
growth and swelling. We also reformulate the governing differential equations for reaction-transport of solutes to represent
the incompressibility constraint on the fluid phase of the tissue. This revision enables a straightforward implementation
of numerical stabilisation for the advection-dominated limit of these equations. A finite element implementation with operator
splitting is used to solve the coupled, non-linear partial differential equations that arise from the theory. We carry out
a numerical and analytic study of the convergence of the operator splitting scheme subject to strain- and stress-homogenisation
of the mechanics of fluid–solid interactions. A few computations are presented to demonstrate aspects of the physical mechanisms,
and the numerical performance of the formulation. 相似文献
135.
Pratap S. Jadon Virendra Gajbhiye Rajesh S. Jadon Kavita R. Gajbhiye Narayanan Ganesh 《AAPS PharmSciTech》2009,10(4):1186-1192
The aim of the present report was to develop nonionic surfactant vesicles (niosomes) to improve poor and variable oral bioavailability
of griseofulvin. Niosomes were prepared by using different nonionic surfactants span 20, span 40, and span 60. The lipid mixture
consisted of surfactant, cholesterol, and dicetyl phosphate in the molar ratio of 125:25:1.5, 100:50:1.5, and 75:75:1.5, respectively.
The niosomal formulations were prepared by thin film method and ether injection method. The influence of different formulation
variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for size distribution
and entrapment efficiency for both methods. Result indicated that the niosomes prepared by thin film method with span 60 provided
higher entrapment efficiency. The niosomal formulation exhibited significantly retarded in vitro release as compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of griseofulvin in albino rats
after a single oral dose. The maximum concentration (C
max) achieved in case of niosomal formulation was approximately double (2.98 μg/ml) as compared to free drug (1.54 μg/ml). Plasma
drug profile also suggested that the developed niosomal system also has the potential of maintaining therapeutic level of
griseofulvin for a longer period of time as compared to free griseofulvin. The niosomal formulation showed significant increase
in area under the curve0-24 (AUC; 41.56 μg/ml h) as compared to free griseofulvin (22.36 μg/ml h) reflecting sustained release characteristics. In conclusion,
the niosomal formulation could be one of the promising delivery system for griseofulvin with improved oral bioavailability
and prolonged drug release profiles. 相似文献
136.
137.
Open reading frame (ORF) 45 of Kaposi''s sarcoma-associated herpesvirus (KSHV) is a tegument protein. A genetic analysis with a null mutant suggested a possible role for this protein in the events leading to viral egress. In this study, ORF45 was found to interact with KIF3A, a kinesin-2 motor protein that transports cargoes along microtubules to cell periphery in a yeast two-hybrid screen. The association was confirmed by both co-immunoprecipitation and immunoflorescence approaches in primary effusion lymphoma cells following virus reactivation. ORF45 principally mediated the docking of entire viral capsid-tegument complexes onto the cargo-binding domain of KIF3A. Microtubules served as the major highways for transportation of these complexes as evidenced by drastically reduced viral titers upon treatment of cells with a microtubule depolymerizer, nocodazole. Confocal microscopic images further revealed close association of viral particles with microtubules. Inhibition of KIF3A–ORF45 interaction either by the use of a headless dominant negative (DN) mutant of KIF3A or through shRNA-mediated silencing of endogenous KIF3A expression noticeably decreased KSHV egress reflecting as appreciable reductions in the release of extracellular virions. Both these approaches, however, failed to impact HSV-1 egress, demonstrating the specificity of KIF3A in KSHV transportation. This study thus reports on transportation of KSHV viral complexes on microtubules by KIF3A, a kinesin motor thus far not implicated in virus transportation. All these findings shed light on the understudied but significant events in the KSHV life cycle, delineating a crucial role of a KSHV tegument protein in cellular transport of viral particles. 相似文献
138.
139.
Hall LM Moran CN Milne GR Wilson J MacFarlane NG Forouhi NG Hariharan N Salt IP Sattar N Gill JM 《PloS one》2010,5(12):e14197
Background
South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures.Methodology/Principal Findings
Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4±5.7 ml.kg−1.min−1, p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg.kg−1.min−1 at 55% VO2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg.kg−1.min−1 at 25 ml O2.kg−1.min−1, p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10–13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity.Conclusions/Significance
These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes. 相似文献140.
Harder DR Narayanan J Gebremedhin D 《American journal of physiology. Heart and circulatory physiology》2011,300(5):H1557-H1565
While myogenic force in response to a changing arterial pressure has been described early in the 20th century, it was not until 1984 that the effect of a sequential increase in intraluminal pressure on cannulated cerebral arterial preparations was found to result in pressure-dependent membrane depolarization associated with spike generation and reduction in lumen diameter. Despite a great deal of effort by different laboratories and investigators, the identification of the existence of a mediator of the pressure-induced myogenic constriction in arterial muscle remained a challenge. It was the original finding by our laboratory that demonstrated the capacity of cerebral arterial muscle cells to express the cytochrome P-450 4A enzyme that catalyzes the formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid, the production of which in cerebral arterial muscle cells increases with the elevation in intravascular pressure. 20-HETE activates protein kinase C and causes the inhibition of Ca(2+)-activated K(+) channels, depolarizes arterial muscle cell membrane, and activates L-type Ca(2+) channel to increase intracellular Ca(2+) levels and evoke vasoconstriction. The inhibition of 20-HETE formation attenuates pressure-induced arterial myogenic constriction in vitro and blunts the autoregulation of cerebral blood flow in vivo. We suggest that the formation and action of cytochrome P-450-derived 20-HETE in cerebral arterial muscle could play a critically important role in the control of cerebral arterial tone and the autoregulation of cerebral blood flow under physiological conditions. 相似文献