Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility

The ability of low-frequency ultrasound (LFUS) to release encapsulated drugs from sterically stabilized liposomes in a controlled manner was demonstrated. Three liposomal formulations having identical lipid bilayer compositions and a similar size ( approximately 100 nm) but differing in their encapsulated drugs and methods of drug loading have been tested. Two of the drugs, doxorubicin and methylpredinisolone hemisuccinate, were remote loaded by transmembrane gradients (ammonium sulfate and calcium acetate, respectively). The third drug, cisplatin, was loaded passively into the liposomes. For all three formulations, a short exposure to LFUS (<3 min) released nearly 80% of the drug. The magnitude of drug release was a function of LFUS amplitude and actual exposure time, irrespective of whether irradiation was pulsed or continuous. Furthermore, no change in liposome size distribution or in the chemical properties of the lipids or of the released drugs occurred due to exposure to LFUS. Based on our results, we propose that the mechanism of release is a transient introduction of porelike defects in the liposome membrane, which occurs only during exposure to LFUS, after which the membrane reseals. This explains the observed uptake of the membrane-impermeable fluorophore pyranine from the extraliposomal medium during exposure to LFUS. The implications of these findings for clinical applications of controlled drug release from liposomes are discussed.     

Superpolynomial Lower Bounds for Monotone Span Programs

monotone span programs computing explicit functions. The best previous lower bound was by Beimel, Gál, Paterson [7]; our proof exploits a general combinatorial lower bound criterion from that paper. Our lower bounds are based on an analysis of Paley-type bipartite graphs via Weil's character sum estimates. We prove an lower bound for the size of monotone span programs for the clique problem. Our results give the first superpolynomial lower bounds for linear secret sharing schemes. We demonstrate the surprising power of monotone span programs by exhibiting a function computable in this model in linear size while requiring superpolynomial size monotone circuits and exponential size monotone formulae. We also show that the perfect matching function can be computed by polynomial size (non-monotone) span programs over arbitrary fields. Received: August 1, 1996     

Expanders That Beat the Eigenvalue Bound: Explicit Construction and Applications

n and 0 < δ < 1, we construct graphs on n nodes such that every two sets of size share an edge, having essentially optimal maximum degree . Using known and new reductions from these graphs, we derive new explicit constructions of: 1.  A k round sorting algorithm using comparisons. 2.  A k round selection algorithm using comparisons. 3.  A depth 2 superconcentrator of size . 4.  A depth k wide-sense nonblocking generalized connector of size . All of these results improve on previous constructions by factors of , and are optimal to within factors of . These results are based on an improvement to the extractor construction of Nisan & Zuckerman: our algorithm extracts an asymptotically optimal number of random bits from a defective random source using a small additional number of truly random bits. Received: June 13, 1995/Revised: Revised October 23, 1998     

Tiny families of functions with random properties: A quality-size trade-off for hashing

We present three explicit constructions of hash functions, which exhibit a trade-off between the size of the family (and hence the number of random bits needed to generate a member of the family), and the quality (or error parameter) of the pseudorandom property it achieves. Unlike previous constructions, most notably universal hashing, the size of our families is essentially independent of the size of the domain on which the functions operate. The first construction is for the mixing property—mapping a proportional part of any subset of the domain to any other subset. The other two are for the extraction property—mapping any subset of the domain almost uniformly into a range smaller than it. The second and third constructions handle, respectively, the extreme situations when the range is very large or very small. We provide lower bounds showing that our constructions are nearly optimal, and mention some applications of the new constructions. © 1997 John Wiley & Sons, Inc. Random Struct. Alg., 11 , 315–343 (1997)     

Signatures of a Concentration‐Dependent Flory χ Parameter: Swelling and Collapse of Coils and Brushes

The quality of solvents of polymers is often described in terms of the Flory χ parameter typically assumed to depend only on the temperature, T. In certain polymer‐solvent systems fitting the experimental data enforces the replacement of (χT) by a concentration‐dependent χ_eff. In turn, this modifies the swelling and collapse behavior. These effects are studied, in the framework of a mean‐field theory, for isolated coils and for planar brushes. The ϕ dependence of χ_eff gives rise to three main consequences: (i) shift in the cross‐over between Gaussian and self‐avoidance regimes; (ii) a possibility of first‐order collapse transition for isolated flexible coils; (iii) the possibility of a first‐order phase transition leading to a vertical phase separation within the brush. The discussion relates these effects directly to thermodynamic measurements and does not involve a specific microscopic model. The implementation for the case of poly(N‐isopropylamide) (PNIPAM) brushes is discussed.

ϕ vs. z plots, for brushes with N = 300, σ/a² = 18 (σ/R = 0.019) characterized by different χ_eff.     

Techniques for bounding the convergence rate of genetic algorithms

The main purpose of the present paper is the study of computational aspects, and primarily the convergence rate, of genetic algorithms (GAs). Despite the fact that such algorithms are widely used in practice, little is known so far about their theoretical properties, and in particular about their long‐term behavior. This situation is perhaps not too surprising, given the inherent hardness of analyzing nonlinear dynamical systems, and the complexity of the problems to which GAs are usually applied. In the present paper we concentrate on a number of very simple and natural systems of this sort, and show that at least for these systems the analysis can be properly carried out. Various properties and tight quantitative bounds on the long‐term behavior of such systems are established. It is our hope that the techniques developed for analyzing these simple systems prove to be applicable to a wider range of genetic algorithms, and contribute to the development of the mathematical foundations of this promising optimization method. ©1999 John Wiley & Sons, Inc. Random Struct. Alg., 14, 111–138, 1999     

The effect of annealing ambient on carrier recombination in boron implanted silicon

The selection of either an oxidising or inert ambient during high temperature annealing is shown to affect dopant activation and electron–hole recombination in boron implanted silicon samples. Samples implanted with B at fluence between 3 × 10¹⁴ cm^–2 to 3 × 10¹⁵ cm^–2 are shown to have lower dopant activation after oxidation at 1000 °C compared to an equivalent anneal in an inert ambient. In addition, emitter recombination is shown to be up to 15 times higher after oxidation compared with an inert anneal for samples with equivalent passivation from deposited Al₂O₃ films. The observed increase in recombination for oxidised samples is attributed to the enhanced formation of boron‐interstitial defect clusters and dislocation loops under oxidising conditions. It is also shown that an inert anneal for 10 minutes at 1000 °C prior to oxidation has no significant impact on sheet resistance or recombination compared with a standard oxidation process.

     

Accelerating CFD–DEM simulation of processes with wide particle size distributions

Size-reduction systems have been extensively used in industry for many years. Nevertheless, reliable engineering tools to be used to predict the comminution of particles are scarce. Computational fluid dynamics(CFD)–discrete element model(DEM) numerical simulation may be used to predict such a complex phenomenon and therefore establish a proper design and optimization model for comminution systems.They may also be used to predict attrition in systems where particle attrition is significant. Therefore,empirical comminution functions(which are applicable for any attrition/comminution process), such as:strength distribution, selection, equivalence, breakage, and fatigue, have been integrated into the threedimensional CFD–DEM simulation tool. The main drawback of such a design tool is the long computational time required owing to the large number of particles and the minute time-step required to maintain a steady solution while simulating the flow of particulate materials with very fine particles.The present study developed several methods to accelerate CFD–DEM simulations: reducing the number of operations carried out at the single-particle level, constructing a DEM grid detached from the CFD grid enabling a no binary search, generating a sub-grid within the DEM grid to enable a no binary search for fine particles, and increasing the computational time-step and eliminating the finest particles in the simulation while still tracking their contribution to the process.The total speedup of the simulation process without the elimination of the finest particles was a factor of about 17. The elimination of the finest particles gave additional speedup of a factor of at least 18.Therefore, the simulation of a grinding process can run at least 300 times faster than the conventional method in which a standard no binary search is employed and the smallest particles are tracked.     

RNA encapsidation by SV40-derived nanoparticles follows a rapid two-state mechanism

Remarkably, uniform virus-like particles self-assemble in a process that appears to follow a rapid kinetic mechanism. The mechanisms by which spherical viruses assemble from hundreds of capsid proteins around nucleic acid, however, are yet unresolved. Using time-resolved small-angle X-ray scattering (TR-SAXS), we have been able to directly visualize SV40 VP1 pentamers encapsidating short RNA molecules (500mers). This assembly process yields T = 1 icosahedral particles comprised of 12 pentamers and one RNA molecule. The reaction is nearly one-third complete within 35 ms, following a two-state kinetic process with no detectable intermediates. Theoretical analysis of kinetics, using a master equation, shows that the assembly process nucleates at the RNA and continues by a cascade of elongation reactions in which one VP1 pentamer is added at a time, with a rate of approximately 10(9) M(-1) s(-1). The reaction is highly robust and faster than the predicted diffusion limit. The emerging molecular mechanism, which appears to be general to viruses that assemble around nucleic acids, implicates long-ranged electrostatic interactions. The model proposes that the growing nucleo-protein complex acts as an electrostatic antenna that attracts other capsid subunits for the encapsidation process.