Citations

MRP1 (multidrug resistance protein 1) couples ATP binding/hydrolysis at its two non-equivalent NBDs (nucleotide-binding domains) with solute transport. Some of the NBD1 mutants, such as W653C, decreased affinity for ATP at the mutated site, but increased the rate of ATP-dependent solute transport. In contrast, other NBD1 mutants, such as K684L, had decreased ATP binding and rate of solute transport. We now report that mutations of the Walker A lysine residue, K684L and K1333L, significantly alter the tertiary structure of the protein. Due to elimination of the positively charged group and conformational alterations, the K684L mutation greatly decreases the affinity for ATP at the mutated NBD1 and affects ATP binding at the unmutated NBD2. Although K684L-mutated NBD1 can bind ATP at higher concentrations, the bound nucleotide at that site is not efficiently hydrolysed. All these alterations result in decreased ATP-dependent solute transport to approx. 40% of the wild-type. In contrast, the K1333L mutation affects ATP binding and hydrolysis at the mutated NBD2 only, leading to decreased ATP-dependent solute transport to approx. 11% of the wild-type. Consistent with their relative transport activities, the amount of vincristine accumulated in cells is in the order of K1333L≥CFTR (cystic fibrosis transmembrane conductance regulator)>K684L⋙wild-type MRP1. Although these mutants retain partial solute transport activities, the cells expressing them are not multidrug-resistant owing to inefficient export of the anticancer drugs by these mutants. This indicates that even partial inhibition of transport activity of MRP1 can reverse the multidrug resistance caused by this drug transporter.

An orally bioavailable and blood–brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.

It has previously been shown that acoustic ray paths in range-dependent ocean models exhibit chaotic behavior. Most of the investigations into the ray chaos phenomenon have been primarily numerical in nature. The objective of this report is to study theoretically the existence of ray chaos in a parabolic ray system with an analytically prescribed sound-speed model consisting of a double-channel profile perturbed by a typical periodic range-dependent disturbance. The perturbed Hamiltonian ray system is studied analytically via Melnikov’s method. It is shown that, under certain conditions, ray trajectories in some regions of the Poincaré section are equivalent to trajectories of the horseshoe map no matter how small the corresponding perturbation is. These conditions are sufficient for ray chaos and easily satisfied, thus explaining why double-channel propagation is very likely to exhibit chaotic behavior. [Work supported by CA43920 NIH.]

Earlier studies [P. J. Westervelt, J. Acoust. Soc. Am. 29, 199–203, 934–935 (1957)] of the mutual nonlinear interaction of two plane waves of sound with each other are extended to include the viscous effect. The viscous effect is considered both from the equations of motion and the equation of state of the medium. An analytical solution to the lowest order scattering process is obtained if the viscous effect of second order and higher can be neglected. In fact, it is shown that the scattered density ρs of two interacting plane waves having the frequencies ω1 and ω2, respectively, satisfies the following equation: ⧠2vρs=⧠2v{c0−2E12+[(2cosθ +B/A)/2ω1ω2 (1−cosθ)]∇2W12 +[DB(c20ω1ω2)−1 / 4A ×(1−cosθ)2]∇2(∂W12/∂t)+[DB(3+cosθ)/2Ac40 (1−cosθ)](∂V12/∂t)}, where E12, V12, and W12 are, respectively, the total, potential, and special defined energy densities, D is the sound diffusivity, B and A are nonlinearity parameters, θ is the intersecting angle, and ⧠2v is a modified d’Alembertian operator. [Work supported by CA43920 NIH.]

Earlier studies [P. J. Westervelt, J. Acoust. Soc. Am. 29, 199–203, 934–935 (1957)] of the mutual nonlinear interaction of two plane waves of sound with each other are extended to include the viscous effect. The viscous effect is considered both from the equations of motion and the equation of state of the medium. An analytical solution to the lowest-order scattering process is obtained if the viscous effect of second order and higher can be neglected.

Acoustic radiation pressure exerted by an arbitrary acoustic wave in a three-dimensional lossy medium is calculated by extending an indirect approach developed by Chu and Apfel [B-T. Chu and R. E. Apfel, ‘‘Acoustic radiation pressure produced by a beam of sound,’’ J. Acoust. Soc. Am. 72, 1673–1687 (1982)]. Without appealing to the detailed solutions of equations governing fluid motion, a general analytic expression for the radiation pressure in lossy media with arbitrary waves is obtained. When an infinite lossy medium is considered, the expression states that the radiation pressure, to the lowest order of approximation (i.e., second order), is equal to corresponding total energy density. For a special class of confined spaces, the expression leads to a rather general formula for the radiation pressure, in which the radiation pressure is given in terms of various energy densities in the field. Furthermore, a relationship among these energy densities is generalized to the case of lossy media, which enables one to compute the radiation pressure in the class of spaces with the knowledge of the first-order perturbation solution only.

Theories on acoustic radiation pressure associated with plane acoustic waves and lossless media have been examined extensively. The radiation pressure produced by a non-plane wave in a lossy unbounded medium was analyzed. The distinction between Lagrangian and Eulerian pressure was used to clarify the understanding of radiation pressure. The radiation pressure exerted on a perfectly absorbing pointwise target by an arbitrary acoustic wave in an unbounded lossy medium was then considered. By using an indirect approach developed in Chu and Apfel [B.-T. Chu and R. E. Apfel, 1673–1687 (1982)], the radiation pressure was analyzed without appealing to the detailed solutions of the governing fluid dynamic equations. It was shown that even in lossy media with arbitrary waves, the radiation pressure experienced by a pointwise target is equal to the Langevin pressure which is the time average energy density at that point. The radiation pressure exerted on a specific target by an arbitrary acoustic wave in an infinite lossy medium was studied and a concise theoretical result was obtained. [The work was supported by grants CA 43920 and HL 41046 from the National Institutes of Health.]

Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.