PAMAM Dendrimer-Drug Interactions: Effect of pH on the Binding and Release Pattern

Understanding the dendrimer-drug interaction is of great importance to design and optimize the dendrimer-based drug delivery system. Using atomistic molecular dynamics (MD) simulations, we have analyzed the release pattern of four ligands (two soluble drugs, namely, salicylic acid (Sal), L-alanine (Ala), and two insoluble drugs, namely, phenylbutazone (Pbz) and primidone (Prim)), which were initially encapsulated inside the ethylenediamine (EDA) cored polyamidoamine (PAMAM) dendrimer using the docking method. We have computed the potential of mean force (PMF) variation with generation 5 (G5)-PAMAM dendrimer complexed with drug molecules using umbrella sampling. From our calculated PMF values, we observe that soluble drugs (Sal and Ala) have lower energy barriers than insoluble drugs (Pbz and Prim). The order of ease of release pattern for these drugs from G5 protonated PAMAM dendrimer was found to be Ala > Sal > Prim > Pbz. In the case of insoluble drugs (Prim and Pbz), because of larger size, we observe much nonpolar contribution, and thus, their larger energy barriers can be reasoned to van der Waals contribution. From the hydrogen bonding analysis of the four PAMAM drug complexes under study, we found intermolecular hydrogen bonding to show less significant contribution to the free energy barrier. Another interesting feature appears while calculating the PMF profile of G5NP (nonprotonated)-PAMAM Pbz and G5NP (nonprotonated)-PAMAM-Sal complex. The PMF was found to be less when the drug is bound to nonprotonated dendrimer compared to the protonated dendrimer. Our results suggest that encapsulation of the drug molecule into the host PAMAM dendrimer should be carried out at higher pH values (near pH 10). When such complex enters the human body, the pH is around 7.4 and at that physiological pH, the dendrimer holds the drug tightly. Hence the release of drug can occur at a controlled rate into the bloodstream. Thus, our findings provide a microscopic picture of the encapsulation and controlled release of drugs in the case of dendrimer-based host-guest systems.

Scaling analysis: Equivalence of convective and radiative heating of levitated droplet

This letter develops theoretical relationships for equilibrium timescale and temperature scale of a vaporizing droplet in a convective and a radiative environment. The transient temperature normalized by the respective scales exhibits a unified profile for both modes of heating. The analysis allows for the prediction of the required laser flux to show its equivalence in a corresponding heated gas stream. The theoretical equivalence shows good agreement with experiments across a range of droplet sizes. Simple experiments can be conducted in a levitator to extrapolate information in realistic convective environments like combustion and spray drying. (C) 2012 American Institute of Physics. http://dx.doi.org/10.1063/1.4720092]

Is land really a constraint for the utilization of solar energy in India?

This article compares the land use in solar energy technologies with conventional energy sources. This has been done by introducing two parameters called land transformation and land occupation. It has been shown that the land area transformed by solar energy power generation is small compared to hydroelectric power generation, and is comparable with coal and nuclear energy power generation when life-cycle transformations are considered. We estimate that 0.97% of total land area or 3.1% of the total uncultivable land area of India would be required to generate 3400 TWh/yr from solar energy power systems in conjunction with other renewable energy sources.

Monsoon sensitivity to aerosol direct radiative forcing in the community atmosphere model

Aerosol forcing remains a dominant uncertainty in climate studies. The impact of aerosol direct radiative forcing on Indian monsoon is extremely complex and is strongly dependent on the model, aerosol distribution and characteristics specified in the model, modelling strategy employed as well as on spatial and temporal scales. The present study investigates (i) the aerosol direct radiative forcing impact on mean Indian summer monsoon when a combination of quasi-realistic mean annual cycles of scattering and absorbing aerosols derived from an aerosol transport model constrained with satellite observed Aerosol Optical Depth (AOD) is prescribed, (ii) the dominant feedback mechanism behind the simulated impact of all-aerosol direct radiative forcing on monsoon and (iii) the relative impacts of absorbing and scattering aerosols on mean Indian summer monsoon. We have used CAM3, an atmospheric GCM (AGCM) that has a comprehensive treatment of the aerosol-radiation interaction. This AGCM has been used to perform climate simulations with three different representations of aerosol direct radiative forcing due to the total, scattering aerosols and black carbon aerosols. We have also conducted experiments without any aerosol forcing. Aerosol direct impact due to scattering aerosols causes significant reduction in summer monsoon precipitation over India with a tendency for southward shift of Tropical Convergence Zones (TCZs) over the Indian region. Aerosol forcing reduces surface solar absorption over the primary rainbelt region of India and reduces the surface and lower tropospheric temperatures. Concurrent warming of the lower atmosphere over the warm oceanic region in the south reduces the land-ocean temperature contrast and weakens the monsoon overturning circulation and the advection of moisture into the landmass. This increases atmospheric convective stability, and decreases convection, clouds, precipitation and associated latent heat release. Our analysis reveals a defining negative moisture-advection feedback that acts as an internal damping mechanism spinning down the regional hydrological cycle and leading to significant circulation changes in response to external radiative forcing perturbations. When total aerosol loading (both absorbing and scattering aerosols) is prescribed, dust and black carbon aerosols are found to cause significant atmospheric heating over the monsoon region but the aerosol-induced weakening of meridional lower tropospheric temperature gradient (leading to weaker summer monsoon rainfall) more than offsets the increase in summer-time rainfall resulting from the atmospheric heating effect of absorbing aerosols, leading to a net decrease of summer monsoon rainfall. Further, we have carried out climate simulations with globally constant AODs and also with the constant AODs over the extended Indian region replaced by realistic AODs. Regional aerosol radiative forcing perturbations over the Indian region is found to have impact not only over the region of loading but over remote tropical regions as well. This warrants the need to prescribe realistic aerosol properties in strategic regions such as India in order to accurately assess the aerosol impact.

ATP release and autocrine signaling through P2X4 receptors regulate gamma delta T cell activation

Purinergic signaling plays a key role in a variety of physiological functions, including regulation of immune responses. Conventional alpha beta T cells release ATP upon TCR cross-linking; ATP binds to purinergic receptors expressed by these cells and triggers T cell activation in an autocrine and paracrine manner. Here, we studied whether similar purinergic signaling pathways also operate in the ``unconventional'' gamma delta T lymphocytes. We observed that gamma delta T cells purified from peripheral human blood rapidly release ATP upon in vitro stimulation with anti-CD3/CD28-coated beads or IPP. Pretreatment of gamma delta T cells with (10)panx-1, CBX, or Bf A reversed the stimulation-induced increase in extracellular ATP concentration, indicating that panx-1, connexin hemichannels, and vesicular exocytosis contribute to the controlled release of cellular ATP. Blockade of ATP release with (10)panx-1 inhibited Ca2+ signaling in response to TCR stimulation. qPCR revealed that gamma delta T cells predominantly express purinergic receptor subtypes A2a, P2X1, P2X4, P2X7, and P2Y11. We found that pharmacological inhibition of P2X4 receptors with TNP-ATP inhibited transcriptional up-regulation of TNF-alpha and IFN-gamma in gamma delta T cells stimulated with anti-CD3/CD28-coated beads or IPP. Our data thus indicate that purinergic signaling via P2X4 receptors plays an important role in orchestrating the functional response of circulating human gamma delta T cells. J. Leukoc. Biol. 92: 787-794; 2012.

Premixed flame response to equivalence ratio fluctuations: Comparison between reduced order modeling and detailed computations

Combustion instability events in lean premixed combustion systems can cause spatio-temporal variations in unburnt mixture fuel/air ratio. This provides a driving mechanism for heat-release oscillations when they interact with the flame. Several Reduced Order Modelling (ROM) approaches to predict the characteristics of these oscillations have been developed in the past. The present paper compares results for flame describing function characteristics determined from a ROM approach based on the level-set method, with corresponding results from detailed, fully compressible reacting flow computations for the same two dimensional slot flame configuration. The comparison between these results is seen to be sensitive to small geometric differences in the shape of the nominally steady flame used in the two computations. When the results are corrected to account for these differences, describing function magnitudes are well predicted for frequencies lesser than and greater than a lower and upper cutoff respectively due to amplification of flame surface wrinkling by the convective Darrieus-Landau (DL) instability. However, good agreement in describing function phase predictions is seen as the ROM captures the transit time of wrinkles through the flame correctly. Also, good agreement is seen for both magnitude and phase of the flame response, for large forcing amplitudes, at frequencies where the DL instability has a minimal influence. Thus, the present ROM can predict flame response as long as the DL instability, caused by gas expansion at the flame front, does not significantly alter flame front perturbation amplitudes as they traverse the flame. (C) 2012 The Combustion Institute. Published by Elsevier Inc. All rights reserved.

Formulation development and evaluation of lamivudine controlled release tablets using cross-linked sago starch

Objectives: Modified starches based polymeric substances find utmost applicability in pharmaceutical formulation development. Cross-linked starches showed very promising results in drug delivery application. The present investigation concerns with the development of controlled release tablets of lamivudine using cross-linked sago starch. Methods: The cross-linked derivative was synthesized with phosphorous oxychloride and native sago starch in basic pH medium. The cross-linked sago starch was tested for acute toxicity and drug-excipient compatibility study. The formulated tablets were evaluated for various physical characteristics, in vitro dissolution release study and in vivo pharmacokinetic study in rabbit model. Results: In vitro release study showed that the optimized formulation exhibited highest correlation (R) in case of zero order kinetic model and the release mechanism followed a combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (T-max, C-max, AUC, V-d, T-1/2, and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir (R). Conclusion: The cross-linked starch showed promising results in terms of controlling the release behavior of the active drug from the matrix. The hydrophilic matrix synthesized by cross-linking could be used with a variety of active pharmaceutical ingredients for making their controlled/sustained release formulations.

Exploiting the Structure of the Constraint Graph for Efficient Points-to Analysis

Points-to analysis is a key compiler analysis. Several memory related optimizations use points-to information to improve their effectiveness. Points-to analysis is performed by building a constraint graph of pointer variables and dynamically updating it to propagate more and more points-to information across its subset edges. So far, the structure of the constraint graph has been only trivially exploited for efficient propagation of information, e.g., in identifying cyclic components or to propagate information in topological order. We perform a careful study of its structure and propose a new inclusion-based flow-insensitive context-sensitive points-to analysis algorithm based on the notion of dominant pointers. We also propose a new kind of pointer-equivalence based on dominant pointers which provides significantly more opportunities for reducing the number of pointers tracked during the analysis. Based on this hitherto unexplored form of pointer-equivalence, we develop a new context-sensitive flow-insensitive points-to analysis algorithm which uses incremental dominator update to efficiently compute points-to information. Using a large suite of programs consisting of SPEC 2000 benchmarks and five large open source programs we show that our points-to analysis is 88% faster than BDD-based Lazy Cycle Detection and 2x faster than Deep Propagation. We argue that our approach of detecting dominator-based pointer-equivalence is a key to improve points-to analysis efficiency.

Advanced multifunctional inorganic nanostructured oxides for controlled release and sensing

ADVANCED MULTIFUNCTIONAL INORGANIC NANOSTRUCTURED OXIDES FOR CONTROLLED RELEASE AND SENSING. We demonstrate here certain examples of multifunctional nanostructured oxidematerials for biotechnological and environmental applications.Various in-house synthesized homogeneous nanostructured viz.mesoporous and nanotubes silica and titania have been employed for controlled drug delivery and electrochemical biosensing applications. Confinement of macromolecules such as proteins studied via electrochemical, thermal and spectroscopic methods showed no detrimental effect on native protein structure and function, thus suggesting effective utility of oxide nanostructures as bio-encapsulators. Multi-functionalitywas demonstrated via employing similar nanostructures for sensing organic water pollutants e.g. textile dyes.

Prioritizing constraint evaluation for efficient points-to analysis

Pervasive use of pointers in large-scale real-world applications continues to make points-to analysis an important optimization-enabler. Rapid growth of software systems demands a scalable pointer analysis algorithm. A typical inclusion-based points-to analysis iteratively evaluates constraints and computes a points-to solution until a fixpoint. In each iteration, (i) points-to information is propagated across directed edges in a constraint graph G and (ii) more edges are added by processing the points-to constraints. We observe that prioritizing the order in which the information is processed within each of the above two steps can lead to efficient execution of the points-to analysis. While earlier work in the literature focuses only on the propagation order, we argue that the other dimension, that is, prioritizing the constraint processing, can lead to even higher improvements on how fast the fixpoint of the points-to algorithm is reached. This becomes especially important as we prove that finding an optimal sequence for processing the points-to constraints is NP-Complete. The prioritization scheme proposed in this paper is general enough to be applied to any of the existing points-to analyses. Using the prioritization framework developed in this paper, we implement prioritized versions of Andersen's analysis, Deep Propagation, Hardekopf and Lin's Lazy Cycle Detection and Bloom Filter based points-to analysis. In each case, we report significant improvements in the analysis times (33%, 47%, 44%, 20% respectively) as well as the memory requirements for a large suite of programs, including SPEC 2000 benchmarks and five large open source programs.

Size independent fracture energy from fracture energy release rate in plain concrete beams

Size independent fracture energy and size effect on fracture energy are the key concerns for characterization of concrete fracture. Although there have been inconsistencies in results, a consensual fact is that the fracture energy from a large specimen is size independent. The fracture energy is proportional to the size of the fracture process zone (FPZ). FPZ size increases with size of the specimen, but the rate of increase of FPZ size decreases with increase in specimen size 1] implying that rate of increase of fracture energy decreases with increase in specimen size, more appropriately with increase in un-cracked ligament length. The ratio of fracture energy to the un-cracked ligament length almost becomes a constant at larger un-cracked ligament lengths. In the present study an attempt is made to obtain size independent fracture energy from fracture energy release rate. (C) 2012 Elsevier Ltd. All rights reserved.

DMT of parallel-path and layered networks under the half-duplex constraint

In this paper, we study the diversity-multiplexing-gain tradeoff (DMT) of wireless relay networks under the half-duplex constraint. It is often unclear what penalty if any, is imposed by the half-duplex constraint on the DMT of such networks. We study two classes of networks; the first class, called KPP(I) networks, is the class of networks with the relays organized in K parallel paths between the source and the destination. While we assume that there is no direct source-destination path, the K relaying paths can interfere with each other. The second class, termed as layered networks, is comprised of relays organized in layers, where links exist only between adjacent layers. We present a communication scheme based on static schedules and amplify-and-forward relaying for these networks. We also show that for KPP(I) networks with K >= 3, the proposed schemes can achieve full-duplex DMT performance, thus demonstrating that there is no performance hit on the DMT due to the half-duplex constraint. We also show that, for layered networks, a linear DMT of d(max)(1 - r)(+) between the maximum diversity d(max) and the maximum MG, r(max) = 1 is achievable. We adapt existing DMT optimal coding schemes to these networks, thus specifying the end-to-end communication strategy explicitly.

Role of Fly Ash Pozzolanic Reactions in Controlling Fluoride Release from Phosphogypsum

Phosphogypsum is added to building materials to accelerate fly ash pozzolanic reaction and contributes to early strength development of concrete. The release of unacceptable fluoride levels by phoshogypsum on contact with water is a major impediment in its usage to manufacture building products because excess fluoride consumption causes dental and skeletal fluorosis. This paper examines the efficacy of fly ash pozzolanic reactions in controlling fluoride release by phosphogypsum. Fly ash (FA), sand (S), lime (L), and phosphogypsum (G) (FA-S-L-G) slurries are cured for various periods, and the fluoride released by the mix is monitored as a function of time. A substantial reduction in fluoride release was observed and is attributed to entrapment of phosphogypsum particles in a cementious matrix formed by fly ash-lime pozzolanic reactions coupled with consumption of fluoride in formation of insoluble compounds. The compressive strength developed by compacted FA-S-L-G specimens with time was observed to be a three-stage process; maximum strength mobilization occurred during 14 and 28days of curing at room temperature. Exposure of the compacted FA-S-L-G specimens to acidic and alkaline environments for 9 days did not impact their compressive strengths. (C) 2013 American Society of Civil Engineers.

Cryogenically cured hydroxyapatite-gelatin nanobiocomposite for bovine serum albumin protein adsorption and release

This research paper presents the first results on the protein adsorption and release kinetics and in vitro biodegradability of cryogenically cured hydroxyapatite-gelatin based micro/macroporous scaffolds (CHAMPS). While the adsorption and release of bovine serum albumin (BSA) protein exhibits steady state behavior over an incubation period of up to 10 days, Fourier transform infrared (FT-IR) analysis importantly confirms the absence of any change in the secondary structure of BSA proteins due to interaction with the CHAMPS scaffold. The compression properties of the CHAMPS scaffold with interconnected porosity (pore size similar to 50-200 mm) is characterized by a non-linear stress-strain response with a strength close to 5 MPa and a maximum strain of up to 24%. The slow but systematic increase in weight loss over a period of 7 days as well as apatite layer formation indicates its good bioactivity. The extensive micro-computed tomography (micro-CT) analysis establishes cancellous bone-like highly interconnected and complex porous architecture of the CHAMPS scaffold. Importantly, the excellent adsorption (up to 50%) and release (up to 60% of adsorbed protein) of BSA has been uniquely attributed to the inherent porous microstructure of the CHAMPS scaffold. Overall, the present study provides an assessment of the interaction of protein with the gelatin-hydroxyapatite macroporous scaffold in vitro, as well as reporting for the first time the efficacy of such scaffolds to release 60% of BSA loaded onto the scaffold in vitro, which is significantly higher than earlier literature reports.

Evaluation of microwave assisted grafted sago starch as controlled release polymeric carrier

In the present investigation an attempt has been made to develop a new co-polymeric material for controlled release tablet formulations. The acrylamide grafting was successfully performed on the backbone of sago starch. The modified starch was tested for acute toxicity and drug-excipient compatibility study. The grafted material was used in making of controlled release tablets of lamivudine. The formulations were evaluated for physical characteristics such as hardness, friability, %drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi model and the release mechanism of the optimized formulation predominantly exhibited combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (T-max, C-max, AUC, V-d, T-1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir (R) was observed. The pharmacokinetics parameters were showed controlled pattern and better bioavailability. The optimized formulation exhibited good stability and release profile at the accelerated stability conditions. (c) 2013 Elsevier B.V. All rights reserved.