Structural Characterization of the Drug Translocation Path of MRP1/ABCC1

The rapid clearance of drugs from human cells is carried out by MRP1 and other proteins of the ABC transporter superfamily. Selective mutations carried out by DeGorter indicated that replacement of Y324 by phenylalanine (but not by tryptophan or alanine) enhances the capacity of the protein to extrude various drugs. In this study we investigate the effect of mutation on the structure of the isolated transmembrane domain of MRP1 through molecular dynamics simulations of the protein embedded in a POPC membrane. The simulations reveal a persistent tendency of the translocation path to experience a partial constriction, losing ∼50 % of the water inside the conducting path. While the Wt, Y324W and Y324A transporters all experienced the same constriction, the Y324F transporter, the one having a higher clearance rate than the Wt, retains a fully open configuration. The structure of the Y324F mutant reveals an alternate set of stabilizing interactions that force a kink in transmembrane helix 6, which keeps the protein in a fully open outward-facing configuration thus providing a molecular-level account for the higher activity of the mutant. The ability of the simulations to corroborate the experimental observations implies that the homology model of MRP1 is a proper representation of the internal interactions between the residues in the protein, and can be used as a reliable model for studying the human multidrug resistance function of the MRP1 protein.     

Controlling surfaces and interfaces of semiconductors using organic molecules

Control over semiconductor surface energetics can be achieved using different chemisorbed organic molecules with diverse electronic properties. We find evidence of such control over CdTe upon adsorption of dicarboxylic acid derivatives with different substituted phenyl rings. FT-IR measurements show that the dicarboxylic acid derivatives bind as carboxylates to form approximately one monolayer. Such chemisorption modifies both the band bending and the electron affinity (up to 500 and 700 mV, respectively), as measured by contact potential difference WPM Changes in band bending result from a coupling between molecular orbitals and surface states close to the valence band and depend on the withdrawing character of the phenyl substituent. A model is presented to interpret and explain the data.     

Overexpression of adenovirus-encoded transgenes from the cytomegalovirus immediate early promoter in irradiated tumor cells

Efficient expression of therapeutic genes in irradiated tumor cells would facilitate the conversion of a malignant tumor nodule into a cancer vaccine in situ. We reported previously that transgene expression from an adenoviral vector could be markedly enhanced by treating transduced tumor cells with butyrate. In this study, we demonstrated that a similar butyrate effect could be achieved in irradiated tumor cells. In addition, irradiating cells at doses of 2-40 Gy prior to transduction could also amplify recombinant adenoviral transgene products in a cell-type-specific manner. This suggests that adenovirus-mediated gene therapy, radiation therapy, and butyrate-mediated cancer therapy may potentially be formulated into one synergistic protocol for cancer treatment.     

Multi-input/single-output computer-aided control design using the quantitative feedback theory

The quantitative feedback theory is an engineering design technique of uncertain feedback systems having robust stability and robust performance specifications. The crux of the quantitative feedback theory is a transformation of robust stability and robust performance specifications into domains in the complex plane, referred to as bounds, where a nominal loop transmission should lie within. To date, a quantitative feedback theory design is being carried out using manual (i.e. graphical) procedures or search algorithms. This paper shows that there exists a formal map from the uncertain plant and each closed-loop specification to these bounds. In particular, it is shown that each map has a closed form consisting of a quadratic inequality. These maps greatly simplify the computational aspects of the quantitative feedback theory in design of single-loop feedback systems. Based on this new development, a simple-to-implement, efficient computer algorithm is outlined.     

APPLICATION OF MULTIVARIABLE CONTROL DESIGN TO DUAL‐MODE DIGITAL VERSATILE DISC DRIVE

With the ever increasing demand for on storage media with more memory and faster speeds, Digital Versatile Disc (DVD) appears to eclipse Compact Discs (CD). Its denser track pitch and shorter minimum pit length allows for at least eight time more storage memory in the same area. However, smaller tracks increase the performance demands placed on control algorithms. Moreover, to achieve shorter read times, higher disc rotation speed is required, further increasing the demands on the controller. Classical single‐loop control design techniques, the usual approach used in such applications, become less effective for DVDs and may even fail to yield a design for higher disc speeds and with increased coupling in the mechanism's dynamics. For this purpose, we employ the Quantitative Feedback Theory (QFT) and specialized graphical user interface to experimentally demonstrate that new design tools can accomplish the task. Specifically, we show that our multivariable design approach can cope with performance robustness issues and achieve back‐compatibility for dual use (i.e. play both CD and DVD discs) in a single drive. Moreover, since QFT can be used with direct frequency response measurements to represent the dynamics, our control tuning procedure facilitates fast and efficient use in an industrial setting so as to minimize the time it takes to bring new products to market.     

Minimizing Total Flow Time and Total Completion Time with Immediate Dispatching

We consider the problem of scheduling jobs arriving over time in a multiprocessor setting, with immediate dispatching, disallowing job migration. The goal is to minimize both the total flow time (total time in the system) and the total completion time. Previous studies have shown that while preemption (interrupt a job and later continue its execution) is inherent to make a scheduling algorithm efficient, migration (continue the execution on a different machine) is not. Still, the current non-migratory online algorithms suffer from a need for a central queue of unassigned jobs which is a "no option" in large computing systems, such as the Web. We introduce a simple online non-migratory algorithm IMD, which employs immediate dispatching, i.e., it immediately assigns released jobs to one of the machines. We show that the performance of this algorithm is within a logarithmic factor of the optimal migratory offline algorithm, with respect to the total flow time, and within a small constant factor of the optimal migratory offline algorithm, with respect to the total completion time. This solves an open problem suggested by Awerbuch et al. (STOC 99).     

Maximizing throughput in multi-queue switches

We study a basic problem in Multi-Queue switches. A switch connectsm input ports to a single output port. Each input port is equipped with an incoming FIFO queue with bounded capacityB. A switch serves its input queues by transmitting packets arriving at these queues, one packet per time unit. Since the arrival rate can be higher than the transmission rate and each queue has limited capacity, packet loss may occur as a result of insufficient queue space. The goal is to maximize the number of transmitted packets. This general scenario models most current networks (e.g. IP networks) which only support a “best effort” service in which all packet streams are treated equally. A 2-competitive algorithm for this problem was designed in [5] for arbitraryB. Recently, a (17/9 ≈ 1.89)-competitive algorithm was presented forB>1 in [3]. Our main result in this paper shows that forB which is not too small our algorithm can do better than 1.89, and approach a competitive ratio ofe/(e − 1) ≈ 1.58. The research of Yossi Azar was supported in part by the Israeli Ministry of Industry and Trade and by the Israel Science Foundation.