Pharmacokinetics and chemotherapeutic efficacy of adriamycin encapsulated in immunoliposomes against avian myeloblastosis virus infection

Immunoliposomes were prepared using rabbit anti-AMV gp80 IgG for the targeted chemotherapy of avian myeloblastosis virus infection. Adriamycin was encapsulated into immunoliposomes and used for in vivo studies. Comparative pharmacokinetics of free drug, drug encapsulated in free liposomes and of drug encapsulated in immunoliposomes in the virus-infected cells revealed that (i) the drug encapsulated in liposomes was cleared from the plasma slowly, and (ii) the drug encapsulated in immunoliposomes accumulated in the target tissue, the bone marrow, 5- and 8.5-fold more than the drug encapsulated in free liposomes and free drug, respectively. The drug encapsulated in immunoliposomes inactivated the virus and exhibited more chemotherapeutic efficacy as compared to controls when injected up to 24 h post-infection. However, when injected 48 h post-infection the drug encapsulated in immunoliposomes did not offer any protection against the virus infection. There is no detectable antibody response against immunoliposomes in the infected animals.

The Skill of ECMWF Medium-Range Forecasts during the Year of Tropical Convection 2008

This study uses the European Centre for Medium-Range Weather Forecasts (ECMWF) model-generated high-resolution 10-day-long predictions for the Year of Tropical Convection (YOTC) 2008. Precipitation forecast skills of the model over the tropics are evaluated against the Tropical Rainfall Measuring Mission (TRMM) estimates. It has been shown that the model was able to capture the monthly to seasonal mean features of tropical convection reasonably. Northward propagation of convective bands over the Bay of Bengal was also forecasted realistically up to 5 days in advance, including the onset phase of the monsoon during the first half of June 2008. However, large errors exist in the daily datasets especially for longer lead times over smaller domains. For shorter lead times (less than 4-5 days), forecast errors are much smaller over the oceans than over land. Moreover, the rate of increase of errors with lead time is rapid over the oceans and is confined to the regions where observed precipitation shows large day-to-day variability. It has been shown that this rapid growth of errors over the oceans is related to the spatial pattern of near-surface air temperature. This is probably due to the one-way air-sea interaction in the atmosphere-only model used for forecasting. While the prescribed surface temperature over the oceans remain realistic at shorter lead times, the pattern and hence the gradient of the surface temperature is not altered with change in atmospheric parameters at longer lead times. It has also been shown that the ECMWF model had considerable difficulties in forecasting very low and very heavy intensity of precipitation over South Asia. The model has too few grids with ``zero'' precipitation and heavy (>40 mm day(-1)) precipitation. On the other hand, drizzle-like precipitation is too frequent in the model compared to that in the TRMM datasets. Further analysis shows that a major source of error in the ECMWF precipitation forecasts is the diurnal cycle over the South Asian monsoon region. The peak intensity of precipitation in the model forecasts over land (ocean) appear about 6 (9) h earlier than that in the observations. Moreover, the amplitude of the diurnal cycle is much higher in the model forecasts compared to that in the TRMM estimates. It has been seen that the phase error of the diurnal cycle increases with forecast lead time. The error in monthly mean 3-hourly precipitation forecasts is about 2-4 times of the error in the daily mean datasets. Thus, effort should be given to improve the phase and amplitude forecast of the diurnal cycle of precipitation from the model.

The gasification of wood-char spheres in CO2---N2 mixtures: analysis and experiments

The gasification of charcoal spheres in an atmosphere of carbon-dioxide-nitrogen mixture involving diffusion and reactions in the pores is modelled and the results are compared with experiments of Standish and Tanjung and those performed in the laboratory on wood-char spheres to determine the effects of diameter, density, gas composition and flow. The results indicate that the conversion time, t(c) approximately d1.03 for large particles (> 5 mm), departing substantially from the t(c) approximately d2 law valid for diffusion limited conditions. The computational studies indicate that the kinetic limit for the particle is below 100 mum. The conversion time varies inversely as the initial char density as expected in the model. Predictions from the model show that there is no significant change in conversion time up to 60% N2 consistent with the CO2-N2 experiments. The variation of diameter and density with time are predicted. The peculiar dependence of conversion time on flow velocity in the experiments is sought to be explained by opposing free and forced convection heat transfer and the attempt is only partly successful. The studies also indicate that the dependence on the CO concentration with low CO2 is significant, indicating the need for multistep reaction mechanism against the generally accepted single-step reaction.

A note on the choice of interfacial friction angle

Estimates of interfacial friction angle (delta) are necessary for the design of retaining structures and deep foundations, Recommendations in the literature regarding delta values are often contradictory and are therefore not easy to apply in geotechnical design, A critical examination of past studies in terms of data generation techniques used and conclusions drawn indicates that two distinctly different test procedures/techniques have been evolved. The interfacial situation in practice can also be categorized into two broad types, These two types of interface problems in geotechnical engineering are (a) the structure is placed on the free surface of prepared fill (type A situation) and (b) the fill is placed against the material surface which functions as a confined boundary (type B situation), The friction angle delta depends on the surface roughness of the construction material, But in the type A situation, it is independent of density and its limiting maximum value (delta(lim)) is the critical state friction angle phi(cv). In the type B situation, it is dependent on density of the fill and its limiting maximum value is the peak angle of internal friction phi(p) of the fill.

Stochastic fluctuations of the solar dynamo

Attempts in the past to model the irregularities of the solar cycle (such as the Maunder minimum) were based on studies of the nonlinear feedback of magnetic fields on the dynamo source terms. Since the alpha-coefficient is obtained by averaging over the turbulence, it is expected to have stochastic fluctuations, and we show that these fluctuations can explain the irregularities of the solar cycle in a more satisfactory way. We solve the dynamo equations in a slab with a single mode, taking the alpha-coefficient to be constant in space but fluctuating stochastically in time with some given amplitude and given correlation time. The same level of percentile fluctuations (about 10 %) produces no effect on an alpha-omega dynamo, but makes an alpha-2 dynamo completely chaotic. The level of irregularities in an alpha-2-omega dynamo qualitatively agrees with the solar behavior, reinforcing the conclusion of Choudhuri (1990a) that the solar dynamo is of the alpha-2-omega-type. The irregularities are found to increase on increasing either the amplitude or the correlation time of the stochastic fluctuations. The alpha-quenching mechanism tends to make the system stable against the irregularities and hence it is inferred that the alpha-quenching should not be too strong so that the irregularities are not completely suppressed. We also present a simple-minded analysis to understand why the stochastic fluctuations in the alpha-omega, alpha-2-omega and alpha-2 regimes have such different outcomes.

Distributed intrusion detection in the presence of correlated sensor readings: Signal-space and communication-complexity view-point

The problem of sensor-network-based distributed intrusion detection in the presence of clutter is considered. It is argued that sensing is best regarded as a local phenomenon in that only sensors in the immediate vicinity of an intruder are triggered. In such a setting, lack of knowledge of intruder location gives rise to correlated sensor readings. A signal-space view-point is introduced in which the noise-free sensor readings associated to intruder and clutter appear as surfaces f(s) and f(g) and the problem reduces to one of determining in distributed fashion, whether the current noisy sensor reading is best classified as intruder or clutter. Two approaches to distributed detection are pursued. In the first, a decision surface separating f(s) and f(g) is identified using Neyman-Pearson criteria. Thereafter, the individual sensor nodes interactively exchange bits to determine whether the sensor readings are on one side or the other of the decision surface. Bounds on the number of bits needed to be exchanged are derived, based on communication-complexity (CC) theory. A lower bound derived for the two-party average case CC of general functions is compared against the performance of a greedy algorithm. Extensions to the multi-party case is straightforward and is briefly discussed. The average case CC of the relevant greaterthan (CT) function is characterized within two bits. Under the second approach, each sensor node broadcasts a single bit arising from appropriate two-level quantization of its own sensor reading, keeping in mind the fusion rule to be subsequently applied at a local fusion center. The optimality of a threshold test as a quantization rule is proved under simplifying assumptions. Finally, results from a QualNet simulation of the algorithms are presented that include intruder tracking using a naive polynomial-regression algorithm. 2010 Elsevier B.V. All rights reserved.

The Wiener-Hopf solution of a class of mixed boundary value problems arising in surface water wave phenomena

Two mixed boundary value problems associated with two-dimensional Laplace equation, arising in the study of scattering of surface waves in deep water (or interface waves in two superposed fluids) in the linearised set up, by discontinuities in the surface (or interface) boundary conditions, are handled for solution by the aid of the Weiner-Hopf technique applied to a slightly more general differential equation to be solved under general boundary conditions and passing on to the limit in a manner so as to finally give rise to the solutions of the original problems. The first problem involves one discontinuity while the second problem involves two discontinuities. The reflection coefficient is obtained in closed form for the first problem and approximately for the second. The behaviour of the reflection coefficient for both the problems involving deep water against the incident wave number is depicted in a number of figures. It is observed that while the reflection coefficient for the first problem steadily increases with the wave number, that for the second problem exhibits oscillatory behaviour and vanishes at some discrete values of the wave number. Thus, there exist incident wave numbers for which total transmission takes place for the second problem. (C) 1999 Elsevier Science B.V. All rights reserved.

GyrI: a counter-defensive strategy against proteinaceous inhibitors of DNA gyrase

DNA gyrase is the target of two plasmid-encoded toxins CcdB and microcin B17, which ensure plasmid maintenance. These proteins stabilize gyrase-DNA covalent complexes leading to double-strand breaks in the genome. In contrast, the physiological role of chromosomally encoded inhibitor of DNA gyrase (Gyrl) in Escherichia coli is unclear and its mechanism of inhibition has not been established. We demonstrate that the mode of inhibition of GyrI is distinct from all other gyrase inhibitors. It inhibits DNA gyrase prior to, or at the step of, binding of DNA by the enzyme. Gyrl reduces intrinsic as well as toxin-stabilized gyrase-DNA covalent complexes. Furthermore, Gyri reduces microcin B17-mediated double-strand breaks in vivo, imparting protection to the cells against the toxin, substantiating the in vitro results. Thus, Gyrl is an antidote to DNA gyrase-specific proteinaceous poisons encoded by plasmid addiction systems.

A waveguide problem involving a thick iris in the theory of electromagnetism

The problem of electromagnetic wave propagation in a rectangular waveguide containing a thick iris is considered for its complete solution by reducing it to two suitable integral equations, one of which is of the first kind and the other is of the second kind. These integral equations are solved approximately, by using truncated Fourier series for the unknown functions. The reflection coefficient is computed numerically from the two integral equation approaches, and almost the same numerical results are obtained. This is also depicted graphically against the wave number and compared with thin iris results, which are computed by using complementary formulations coupled with Galerkin approximations. While the reflection coefficient for a thin iris steadily increases with the wave number, for a thick iris it fluctuates and zero reflection occurs. The number of zeros of the reflection coefficient for a thick iris increases with the thickness. Thus a thick iris becomes completely transparent for some discrete wave numbers. This phenomenon may be significant in the modelling of rectangular waveguides.

Progressively More Prolate Dark Matter Halo In the Outer Galaxy As Traced by Flaring Hi gas

A galactic disk in a spiral galaxy is generally believed to be embedded in an extended dark matter halo, which dominates its dynamics in the outer parts. However, the shape of the halo is not clearly understood. Here we show that the dark matter halo in the Milky Way is prolate in shape. Further, it is increasingly more prolate at larger radii, with the vertical-to-planar axis ratio monotonically increasing to 2.0 at 24 kpc. This is obtained by modeling the observed steeply flaring atomic hydrogen gas layer in the outer Galactic disk, where the gas is supported by pressure against the net gravitational field of the disk and the halo. The resulting prolate-shaped halo can explain several long-standing puzzles in galactic dynamics, for example, it permits long-lived warps thus explaining their ubiquitous nature.

Seismic reliability assessment of internal stability of reinforced soil walls using the pseudo-dynamic method

The study focuses on probabilistic assessment of the internal seismic stability of reinforced soil structures (RSS) subjected to earthquake loading in the framework of the pseudo-dynamic method. In the literature, the pseudo-static approach has been used to compute reliability indices against the tension and pullout failure modes, and the real dynamic nature of earthquake accelerations cannot be considered. The work presented in this paper makes use of the horizontal and vertical sinusoidal accelerations, amplification of vibrations, shear wave and primary wave velocities and time period. This approach is applied to quantify the influence of the backfill properties, geosynthetic reinforcement and characteristics of earthquake ground motions on reliability indices in relation to the tension and pullout failure modes. Seismic reliability indices at different levels of geosynthetic layers are determined for different magnitudes of seismic acceleration, soil amplification, shear wave and primary wave velocities. The results are compared with the pseudo-static method, and the significance of the present methodology for designing reinforced soil structures is discussed.

A Unique Modification of the Eukaryotic Initiation Factor 5A Shows the Presence of the Complete Hypusine Pathway in Leishmania donovani

Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post-translational synthesis of an unusual amino acid hypusine (N-(sic)-(4-amino-2-hydroxybutyl) lysine), which is present on only one cellular protein, eukaryotic initiation factor 5A (eIF5A). We present here the molecular and structural basis of the function of DOHH from the protozoan parasite, Leishmania donovani, which causes visceral leishmaniasis. The L. donovani DOHH gene is 981 bp and encodes a putative polypeptide of 326 amino acids. DOHH is a HEAT-repeat protein with eight tandem repeats of alpha-helical pairs. Four conserved histidine-glutamate sequences have been identified that may act as metal coordination sites. A similar to 42 kDa recombinant protein with a His-tag was obtained by heterologous expression of DOHH in Escherichia coli. Purified recombinant DOHH effectively catalyzed the hydroxylation of the intermediate, eIF5A-deoxyhypusine (eIF5A-Dhp), in vitro. L. donovani DOHH (LdDOHH) showed similar to 40.6% sequence identity with its human homolog. The alignment of L. donovani DOHH with the human homolog shows that there are two significant insertions in the former, corresponding to the alignment positions 159-162 (four amino acid residues) and 174-183 (ten amino acid residues) which are present in the variable loop connecting the N- and C-terminal halves of the protein, the latter being present near the substrate binding site. Deletion of the ten-amino-acid-long insertion decreased LdDOHH activity to 14% of the wild type recombinant LdDOHH. Metal chelators like ciclopirox olamine (CPX) and mimosine significantly inhibited the growth of L. donovani and DOHH activity in vitro. These inhibitors were more effective against the parasite enzyme than the human enzyme. This report, for the first time, confirms the presence of a complete hypusine pathway in a kinetoplastid unlike eubacteria and archaea. The structural differences between the L. donovani DOHH and the human homolog may be exploited for structure based design of selective inhibitors against the parasite.

Gibbs Energy of Formation of Ca3Ti8Al12O37 and Phase Relations and Chemical Potentials in the System Al2O3-TiO2-CaO

The quaternary oxide in the system Al2O3-CaO-TiO2 is found to have the composition Ca3Ti8Al12O37 rather than CaTi3Al8O19 as reported in the literature. The standard Gibbs energy of formation of Ca3Ti8Al12O37 from component binary oxides is measured in the temperature range from 900 to 1250 K using a solid-state electrochemical cell incorporating single crystal CaF2 as the solid electrolyte. The results can be represented by the equation: delta G(f(0x))(0) (+/- 70)/J mol(-1) = -248474 - 15.706(T/K). Combining this information with thermodynamic data on calcium aluminates and titanates available in the literature, subsolidus phase relations in the pseudo-ternary system Al2O3-CaO-TiO2 are computed and presented as isothermal sections. The evolution of phase relations with temperature is highlighted. Chemical potential diagrams are computed at 1200 K, showing the stability domains of the various phases in the chemical potential-composition space. In each chemical potential diagram, chemical potential of one component is plotted against the cationic fraction of the other two components. The diagrams are valid at relatively high oxygen potentials where Ti is present in its four-valent state in all the oxide phases.

The Hinge Region of Human Thyroid-Stimulating Hormone (TSH) Receptor Operates as a Tunable Switch between Hormone Binding and Receptor Activation

The mechanism by which the hinge regions of glycoprotein hormone receptors couple hormone binding to activation of downstream effecters is not clearly understood. In the present study, agonistic (311.62) and antagonistic (311.87) monoclonal antibodies (MAbs) directed against the TSH receptor extracellular domain were used to elucidate role of the hinge region in receptor activation. MAb 311.62 which identifies the LRR/Cb-2 junction (aa 265-275), increased the affinity of TSHR for the hormone while concomitantly decreasing its efficacy, whereas MAb 311.87 recognizing LRR 7-9 (aa 201-259) acted as a non-competitive inhibitor of Thyroid stimulating hormone (TSH) binding. Binding of MAbs was sensitive to the conformational changes caused by the activating and inactivating mutations and exhibited differential effects on hormone binding and response of these mutants. By studying the effects of these MAbs on truncation and chimeric mutants of thyroid stimulating hormone receptor (TSHR), this study confirms the tethered inverse agonistic role played by the hinge region and maps the interactions between TSHR hinge region and exoloops responsible for maintenance of the receptor in its basal state. Mechanistic studies on the antibody-receptor interactions suggest that MAb 311.87 is an allosteric insurmountable antagonist and inhibits initiation of the hormone induced conformational changes in the hinge region, whereas MAb 311.62 acts as a partial agonist that recognizes a conformational epitope critical for coupling of hormone binding to receptor activation. The hinge region, probably in close proximity with the alpha-subunit in the hormone-receptor complex, acts as a tunable switch between hormone binding and receptor activation.

Involvement of the Global Regulator H-NS in the Survival of Escherichia coli in Stationary Phase

Long-term batch cultures of Escherichia coli grown in nutrient-rich medium accumulate mutations that provide a growth advantage in the stationary phase (GASP). We have examined the survivors of prolonged stationary phase to identify loci involved in conferring a growth advantage and show that a mutation in the hns gene causing reduced activity of the global regulator H-NS confers a GASP phenotype under specific conditions. The hns-66 allele bears a point mutation within the termination codon of the H-NS open reading frame, resulting in a longer protein that is partially functional. Although isolated from a long-term stationary-phase culture of the parent carrying the rpoS819 allele that results in reduced RpoS activity, the hns-66 survivor showed a growth disadvantage in the early stationary phase (24 to 48 h) when competed against the parent. The hns-66 mutant is also unstable and reverts at a high frequency in the early stationary phase by accumulating second-site suppressor mutations within the ssrA gene involved in targeting aberrant proteins for proteolysis. The mutant was more stable and showed a moderate growth advantage in combination with the rpoS819 allele when competed against a 21-day-old parent. These studies show that H-NS is a target for mutations conferring fitness gain that depends on the genetic background as well as on the stage of the stationary phase.