Structural Basis of Drug Resistance by Genetic Variants of HIV Type 1 Clade C Protease from India

Using computer modeling of three-dimensional structures and structural information available on the crystal structures of HIV-1 protease, we investigated the structural effects of mutations, in treatment-naive and treatment-exposed individuals from India and postulated mechanisms of resistance in clade C variants. A large number of models (14) have been generated by computational mutation of the available crystal structures of drug bound proteases. Localized energy minimization was carried out in and around the sites of mutation in order to optimize the geometry of interactions present. Most of the mutations result in structural differences at the flap that favors the semiopen state of the enzyme. Some of the mutations were also found to confer resistance by affecting the geometry of the active site. The E35D mutation affects the flap structure in clade B strains and E35N and E35K mutation, seen in our modeled strains, have a more profound effect. Common polymorphisms at positions 36 and 63 in clade C also affected flap structure. Apart from a few other residues Gln-58, Asn-83, Asn-88, and Gln-92 and their interactions are important for the transition from the closed to the open state. Development of protease inhibitors by structure-based design requires investigation of mechanisms operative for clade C to improve the efficacy of therapy.

Comparison Of If Estimation Methods For Noise Robustness

Non-stationary signal modeling is a well addressed problem in the literature. Many methods have been proposed to model non-stationary signals such as time varying linear prediction and AM-FM modeling, the later being more popular. Estimation techniques to determine the AM-FM components of narrow-band signal, such as Hilbert transform, DESA1, DESA2, auditory processing approach, ZC approach, etc., are prevalent but their robustness to noise is not clearly addressed in the literature. This is critical for most practical applications, such as in communications. We explore the robustness of different AM-FM estimators in the presence of white Gaussian noise. Also, we have proposed three new methods for IF estimation based on non-uniform samples of the signal and multi-resolution analysis. Experimental results show that ZC based methods give better results than the popular methods such as DESA in clean condition as well as noisy condition.

Estrogen modulation of retinol-binding protein in immature chicks: Comparison with riboflavin carrier protein

The kinetics of estrogen (E) modulation of retinol-binding protein (RBP) production in the liver of immature chicks were compared with those governing de novo induction of riboflavin carrier protein (RCP) in the same tissue. A single dose of E markedly enhanced the plasma levels of RBP without any detectable lag period to reach peak value by 24 h and this was followed by a decline to attain the baseline by 4 days. There was no amplification of the response during secondary stimulation unlike the case with RCP induction. With multiple E administration, the 4-fold increased plasma RBP concentrations were sustained at a steady state during both primary and secondary stimulations, whereas concomitant RCP concentration progressively increased with each hormone administration and this response was further amplified during secondary stimulation. Unlike RCP induction, enhanced RBP accumulation was not strictly E dose dependent although a minimal threshold level of the steroid was required to elicit measurable response. Progesterone (P) could neither modulate nor substitute for E in enhancing plasma levels of either of the 2 proteins while the anti-estrogens, en- and zuclomifene citrate severely suppressed the production of both the proteins. RCP induction was completely inhibited by both α-amanitin and cycloheximide for prolonged periods while E-stimulated RBP production was affected only partially by α-amanitin. Likewise, cycloheximide inhibition of RBP accumulation followed a pattern similar to that of hepatic general protein synthesis.

Structure and Conformation of an Antidepressant Drug, Nitroxazepine Hydrochloride Monohydrate

CIsH20N3Oa+.C1-.H2 O, M r = 395, orthorhombic, Pn21a, a = 7.710 (4), b = 11.455 (3), c -- 21.199 (3)/k, Z = 4, V = 1872.4/k 3, D m = 1.38, D C = 1.403 g cm -3, F(000) = 832, g(Cu Kct) = 20.94 cm -l. Intensities for 1641 reflections were measured on a Nonius CAD-4 diffractometer; of these, 1470 were significant. The structure was solved by direct methods and refined to an R index of 0.045 using a blockdiagonal least-squares procedure. The angle between the least-squares planes through the benzene rings is 125.0 (5) ° and the side chain is folded similarly to one of the independent molecules of imipramine hydrochloride.

Comparison of Elasticity, Shell Core, and Sandwich Shell Theories

The problem of an infinite circular sandwich shell subjected to an a\isymmetric radial line load is investigated using three-dimensional elasticity theory, shell core method, and sandwich shell theory due to Fulton and Schmidt. A comparison of the stresses and displacements with an exact elasticity solution is carried out for various shell parameters in order to clearly bring out the limitations of sandwich shell theories of Fulton and Schmidt as well as the shell core solution.

How Good is the Assumption About Visible Surface Reflectance in MODIS Aerosol Retrieval Over Land? A Comparison With Aircraft Measurements Over an Urban Site in India

In this paper, we discuss the measurements of spectral surface reflectance (rho(s)(lambda)) in the wavelength range 350-2500 nm measured using a spectroradiometer onboard a low-flying aircraft over Bangalore (12.95 degrees N, 77.65 degrees E), an urban site in southern India. The large discrepancies in the retrieval of aerosol propertiesover land by the Moderate-Resolution Imaging Spectroradiometer (MODIS), which could be attributed to the inaccurate estimation of surface reflectance at many sites in India and elsewhere, provided motivation for this paper. The aim of this paper was to verify the surface reflectance relationships assumed by the MODIS aerosol algorithm for the estimation of surface reflectance in the visible channels (470 and 660 nm) from the surface reflectance at 2100 nm for aerosol retrieval over land. The variety of surfaces observed in this paper includes green and dry vegetations, bare land, and urban surfaces. The measuredreflectance data were first corrected for the radiative effects of atmosphere lying between the ground and aircraft using the Second Simulation of Satellite Signal in the Solar Spectrum (6S) radiative transfer code. The corrected surface reflectance in the MODIS's blue (rho(s)(470)), red (rho(s)(660)), and shortwave-infrared (SWIR) channel (rho(s)(2100)) was linearly correlated. We found that the slope of reflectance relationship between 660 and 2100 nm derived from the forward scattering data was 0.53 with an intercept of 0.07, whereas the slope for the relationship between the reflectance at 470 and 660 nm was 0.85. These values are much higher than the slope (similar to 0.49) for either wavelengths assumed by the MODIS aerosol algorithm over this region. The reflectance relationship for the backward scattering data has a slope of 0.39, with an intercept of 0.08 for 660 nm, and 0.65, with an intercept of 0.08 for 470 nm. The large values of the intercept (which is very small in the MODIS reflectance relationships) result in larger values of absolute surface reflectance in the visible channels. The discrepancy between the measured and assumed surface reflectances could lead to error in the aerosol retrieval. The reflectance ratio (rho(s)(660)/rho(s)(2100)) showed a clear dependence on the N D V I-SWIR where the ratio increased from 0.5 to 1 with an increase in N V I-SWIR from 0 to 0.5. The high correlation between the reflectance at SWIR wavelengths (2100, 1640, and 1240 nm) indicated an opportunity to derive the surface reflectance and, possibly, aerosol properties at these wavelengths. We need more experiments to characterize the surface reflectance and associated inhomogeneity of land surfaces, which play a critical role in the remote sensing of aerosols over land.

A comparative study of tbe regulation of cytochrome P-450 and glutathione transferase gene expression in rat liver

A cDNA clone for the Ya subunit of glutathione transferase from rat liver was constructed in E.coli. The clone hybridized to Ya and Yc subunit messenger RNAs. On the basis of experiments involving cell-free translation and hybridization to the cloned probe, it was shown that prototype inducers of cytochrome P-450 such as phenobarbitone and 3-methylcholanthrene as well as inhibitors such as CoCl2 and 3-amino-l,2,4-triazole enhanced the glutathione transferase (Ya+Yc) messenger RNA contents in rat liver. A comparative study with the induction of cytochrome P-450 (b+e) by phenobarbitone revealed that the drug manifested a striking increase in the nuclear pre-messenger RNAs for the cytochrome at 12 hr, but did not significantly affect the same in the case of glutathione transferase (Ya+Yc). 3-Amino-l, 2,4-tnazole and CoCl- blocked the phenobarbitone mediated increase in cytochrome P-450 (b+e) nuclear pre-messenger RNAs. These compounds did not significantly affect the glutathione transferase (Ya+Yc) nuclear pre-messenger RNA levels. The polysomal, poly (A)- containing messenger RNAs for cytochrome P-450 (b+e) increased by 12–15 fold after phenobarbitone administration, reached a maximum around 16hr and then decreased sharply. In comparison, the increase in the case of glutathione transferase (Ya+Yc) mesenger RNAs was sluggish and steady and a value of 3–4 fold was reached around 24 hr. Run-off transcription rates for cytochrome P-450 (b+e) increased by nearly 15 fold in 4 hr after phenobarbitone administration, whereas the increase for glutathione transferase (Ya+Yc) was only 2.0 fold. At 12 hr after the drug administration, the glutathione transferase (Ya+Yc) transcription rates were near normal. Administration of 3-amino-l,2,4-triazole and CoCl2 blocked the phenobarbitone-mediated increase in the transcription of cytochrome P-450 (b+e) messenger RNAs. These compounds at best had only marginal effects on the transcription of glutathione transferase (Ya+Yc) messenger RNAs. The half-life of cytochrome P-450 (b+e) messenger RNA was estimated to be 3–4 hr, whereas that for glutathione transferase (Ya+Yc) was found to be 8-9 hr. Administration of phenobarbitone enhanced the half-life of glutathione transferase (Ya+Yc) messenger RNA by nearly two fold. It is suggested that while transcription activation may play a primary role in the induction of cytochrome P-450 (b+e), the induction of glutathione transferase (Ya+Yc) may essentially involve stabilization of the messenger RNAs.

Hormonal induction of riboflavin carrier protein in the chicken oviduct and liver: a comparison of kinetics and modulation

Estrogen (E) induction of riboflavin carrier protein (RCP) in the chicken oviduct and liver was investigated to compare and contrast the kinetics, hormonal specificity and modulation of its elaboration in the 2 steroid-responsive tissues. During primary stimulation, continued daily E administration to immature female chicks elicited, after an initial lag, rapid growth and RCP content of the oviduct; neither progesterone (P) nor testosterone (T) could substitute for E in this respect. Furthermore, P given along with E curtailed tissue growth and its RCP content, whereas E + T had a synergistic effect on tissue growth only. During secondary stimulation, E administration steeply enhanced both tissue weight and RCP content without any lag. Interestingly, P (but not T) could substitute for E in augmenting magnum RCP concentration to a comparable extent while a concomitant effect on tissue growth was less marked. In contrast, hepatic induction of RCP was absolutely E-specific during both primary and secondary stimulations. Secondary stimulation with either E or P of E-primed birds enhanced the rates of RCP synthesis in the oviduct relative to that of total protein, whereas in the liver only E was effective in this regard. The absolute rate of E-induced RCP synthesis in both the steroid-stimulated tissues was significantly higher than that of general protein elaboration.

Short-window spectral analysis using AMVAR and multitaper methods: a comparison

We compare two popular methods for estimating the power spectrum from short data windows, namely the adaptive multivariate autoregressive (AMVAR) method and the multitaper method. By analyzing a simulated signal (embedded in a background Ornstein-Uhlenbeck noise process) we demonstrate that the AMVAR method performs better at detecting short bursts of oscillations compared to the multitaper method. However, both methods are immune to jitter in the temporal location of the signal. We also show that coherence can still be detected in noisy bivariate time series data by the AMVAR method even if the individual power spectra fail to show any peaks. Finally, using data from two monkeys performing a visuomotor pattern discrimination task, we demonstrate that the AMVAR method is better able to determine the termination of the beta oscillations when compared to the multitaper method.

Structure and conformation of an anti-depressant drug, nitroxazepine hydrochloride monohydrate

CIsH20N3Oa+.C1-.H2 O, M r = 395, orthorhombic, Pn21a, a = 7.710 (4), b = 11.455 (3), c -- 21.199 (3)/k, Z = 4, V = 1872.4/k 3, D m = 1.38, D C = 1.403 g cm -3, F(000) = 832, g(Cu Kct) = 20.94 cm -l. Intensities for 1641 reflections were measured on a Nonius CAD-4 diffractometer; of these, 1470 were significant. The structure was solved by direct methods and refined to an R index of 0.045 using a blockdiagonal least-squares procedure. The angle between the least-squares planes through the benzene rings is 125.0 (5) ° and the side chain is folded similarly to one of the independent molecules of imipramine hydrochloride.

Biochemical effects of the porphyrinogenic drug allylisopropylacetamide. A comparative study with phenobarbital

Successive administrations of allylisopropylacetamide, a potent porphyrinogenic drug, increase liver weight, microsomal protein and phospholipid contents. There is an increase in the rate of microsomal protein synthesis in vivo and in vitro. The drug decreases microsomal ribonuclease activity and increases NADPH–cytochrome c reductase activity. Phenobarbital, which has been reported to exhibit all these changes mentioned, is a weaker inducer of δ-aminolaevulinate synthetase and increases the rate of haem synthesis only after a considerable time-lag in fed female rats, when compared with the effects observed with allylisopropylacetamide. Again, phenobarbital does not share the property of allylisopropylacetamide in causing an initial decrease in cytochrome P-450 content. Haematin does not counteract most of the biochemical effects caused by allylisopropylacetamide, although it is quite effective in the case of phenobarbital. Haematin does not inhibit the uptake of [2-14C]allylisopropylacetamide by any of the liver subcellular fractions.

The non-planar peptide unit II. Comparison of theory with crystal structure datastar, open

The theoretical results derived in Part I (Ramachandran, G.N., Lakshminarayan, A.V. and Kolaskar, A.S. (1973) Biochim. Biophys. Acta 303, 8–13) that the three bonds of the peptide unit meeting at N can have a pyramidal structure is confirmed by an analysis of 14 published crystal structures of small peptides. It is shown that the dihedral angles θN and Δω are correlated, while θC, is small and is uncorrelated with Δω, showing that the non-planar distortion at C′ is generally small.

Einstein relation in n-i-p-i and microstructures of nonlinear optical, optoelectronic and related materials: Simplified theory, relative comparison and suggestions for an experimental determination

We investigate the Einstein relation for the diffusivity-mobility ratio (DMR) for n-i-p-i and the microstructures of nonlinear optical compounds on the basis of a newly formulated electron dispersion law. The corresponding results for III-V, ternary and quaternary materials form a special case of our generalized analysis. The respective DMRs for II-VI, IV-VI and stressed materials have been studied. It has been found that taking CdGeAs2, Cd3As2, InAs, InSb, Hg1−xCdxTe, In1−xGaxAsyP1−y lattices matched to InP, CdS, PbTe, PbSnTe and Pb1−xSnxSe and stressed InSb as examples that the DMR increases with increasing electron concentration in various manners with different numerical magnitudes which reflect the different signatures of the n-i-p-i systems and the corresponding microstructures. We have suggested an experimental method of determining the DMR in this case and the present simplified analysis is in agreement with the suggested relationship. In addition, our results find three applications in the field of quantum effect devices.

Dual Drug Delivery Microcapsules via Layer-by-Layer Self-Assembly

The integration of hydrophobic and hydrophilic drugs in the polymer microcapsule offers the possibility of developing a new drug delivery system that combines the best features of these two distinct classes of material. Recently, we have reported the encapsulation of an uncharged water-insoluble drug in the polymer membrane. The hydrophobic drug is deposited using a layer-by-layer (LbL) technique, which is based on the sequential adsorption of oppositely charged polyelectrolytes onto a charged substrate. In this paper, we report the encapsulation of two different drugs, which are invariably different in structure and in their solubility in water. We have characterized these dual drug vehicular capsules by confocal laser scanning microscopy, atomic force microscopy, visible microscopy, and transmission electron microscopy. The growth of a thin film on a flat substrate by LbL was monitored by UV−vis spectra. The desorption kinetics of two drugs from the thin film was modeled by a second-order rate model.