Multiple roles of charged amino acids in cytoplasmic loop 7 for expression and function of the multidrug and organic anion transporter MRP1 (ABCC1)

Multidrug resistance protein MRP1 mediates the ATP-dependent efflux of many chemotherapeutic agents and organic anions. MRP1 has two nucleotide binding sites (NBSs) and three membrane spanning domains (MSDs) containing 17 transmembrane helices linked by extracellular and cytoplasmic loops (CL). Homology models suggest that CL7 (amino acids 1141-1195) is in a position where it could participate in signaling between the MSDs and NBSs during the transport process. We have individually replaced eight charged residues in CL7 with Ala, and in some cases, an amino acid with the same charge, and then investigated the effects on MRP1 expression, transport activity, and nucleotide and substrate interactions. A triple mutant in which Glu(1169), Glu(1170), and Glu(1172) were all replaced with Ala was also examined. The properties of R1173A and E1184A were comparable with those of wild-type MRP1, whereas the remaining mutants were either poorly expressed (R1166A, D1183A) or exhibited reduced transport of one or more organic anions (E1144A, D1179A, K1181A, (1169)AAQA). Same charge mutant D1183E was also not expressed, whereas expression and activity of R1166K were similar to wild-type MRP1. The moderate substrate-selective changes in transport activity displayed by mutants E1144A, D1179A, K1181A, and (1169)AAQA were accompanied by changes in orthovanadate-induced trapping of [alpha-(32)P]azidoADP by NBS2 indicating changes in ATP hydrolysis or release of ADP. In the case of E1144A, estradiol glucuronide no longer inhibited trapping of azidoADP. Together, our results demonstrate the extreme sensitivity of CL7 to mutation, consistent with its critical and complex dual role in both the proper folding and transport activity of MRP1.

Design of Raman-based nonlinear loop mirror for all-optical 2R regeneration of differential phase-shift-keying transmission

We present a concept for all-optical regeneration of signals modulated in phase-sensitive modulation formats, which is based on a new design of Raman amplified nonlinear optical loop mirror (RA-NOLM). We demonstrate simultaneous amplitude-shape regeneration and phase-noise reduction in high-speed differential phase-shift-keying transmission systems by use of the RA-NOLM combined with spectral filtering.

All-optical nonlinear pulse processing based on normal dispersion fiber-enhanced nonlinear optical loop mirror

A novel simple all-optical nonlinear pulse processing technique using loop mirror intensity filtering and nonlinear broadening in normal dispersion fiber is described. The pulse processor offers reamplification and cleaning up of the optical signals and phase margin improvement. The efficiency of the technique is demonstrated by application to 40-Gb/s return-to-zero optical data streams.

Auto-solitons guided by in-line nonlinear optical loop mirrors in dispersion-managed communication systems

Summary form only given. Both dispersion management and the use of a nonlinear optical loop mirror (NOLM) as a saturable absorber can improve the performance of a soliton-based communication system. Dispersion management gives the benefits of low average dispersion while allowing pulses with higher powers to propagate, which helps to suppress Gordon-Haus timing jitter without sacrificing the signal-to-noise ratio. The NOLM suppresses the buildup of amplifier spontaneous emission noise and background dispersive radiation which, if allowed to interact with the soliton, can lead to its breakup. We examine optical pulse propagation in dispersion-managed (DM) transmission system with periodically inserted in-line NOLMs. To describe basic features of the signal transmission in such lines, we develop a simple theory based on a variational approach involving Gaussian trial functions. It, has already been proved that the variational method is an extremely effective tool for description of DM solitons. In the work we manage to include in the variational description the point action of the NOLM on pulse parameters, assuming that the Gaussian pulse shape is inherently preserved by propagation through the NOLM. The obtained results are verified by direct numerical simulations

All-optical passive regeneration of 40 Gbit/s soliton data stream using dispersion-management and in-line nonlinear optical loop mirrors

We numerically demonstrate for the first time that dispersion management and in-line nonlinear optical loop mirrors can achieve all-optical passive regeneration and distance-unlimited transmission of a soliton data stream at 40 Gbit/s over standard fibre.

Normal dispersion fibre-enhanced nonlinear optical loop mirror for 2R regeneration and phase margin improvement

A novel all-optical regeneration technique using loop-mirror intensity-filtering and nonlinear broadening in normal-dispersion fibre is described. The device offers 2R-regeneration function and phase margin improvement. The technique is applied to 40Gbit/s return-to-zero optical data streams.

Determining planar multiple sound-soft obstacles from scattered acoustic fields

An inverse problem is considered where the structure of multiple sound-soft planar obstacles is to be determined given the direction of the incoming acoustic field and knowledge of the corresponding total field on a curve located outside the obstacles. A local uniqueness result is given for this inverse problem suggesting that the reconstruction can be achieved by a single incident wave. A numerical procedure based on the concept of the topological derivative of an associated cost functional is used to produce images of the obstacles. No a priori assumption about the number of obstacles present is needed. Numerical results are included showing that accurate reconstructions can be obtained and that the proposed method is capable of finding both the shapes and the number of obstacles with one or a few incident waves.

An alternating potential based approach for a Cauchy problem for the Laplace equation in a planar domain with a cut

We consider a Cauchy problem for the Laplace equation in a bounded region containing a cut, where the region is formed by removing a sufficiently smooth arc (the cut) from a bounded simply connected domain D. The aim is to reconstruct the solution on the cut from the values of the solution and its normal derivative on the boundary of the domain D. We propose an alternating iterative method which involves solving direct mixed problems for the Laplace operator in the same region. These mixed problems have either a Dirichlet or a Neumann boundary condition imposed on the cut and are solved by a potential approach. Each of these mixed problems is reduced to a system of integral equations of the first kind with logarithmic and hypersingular kernels and at most a square root singularity in the densities at the endpoints of the cut. The full discretization of the direct problems is realized by a trigonometric quadrature method which has super-algebraic convergence. The numerical examples presented illustrate the feasibility of the proposed method.

Recovering boundary data in planar heat conduction using boundary integral equation method

We consider a Cauchy problem for the heat equation, where the temperature field is to be reconstructed from the temperature and heat flux given on a part of the boundary of the solution domain. We employ a Landweber type method proposed in [2], where a sequence of mixed well-posed problems are solved at each iteration step to obtain a stable approximation to the original Cauchy problem. We develop an efficient boundary integral equation method for the numerical solution of these mixed problems, based on the method of Rothe. Numerical examples are presented both with exact and noisy data, showing the efficiency and stability of the proposed procedure and approximations.

Cholecystokinin (CCK) and CCK receptor expression by human gliomas:evidence for an autocrine/paracrine stimulatory loop

Cholecystokinin (CCK) is a gut-brain peptide has been described to be able to induce mitosis according to recent studies. Additionally, conflicting data has been published on whether tumours of the central and peripheral nervous system in general, and gliomas in particular, express CCK receptors. In the present in vitro study we employed reverse transcription followed by the polymerase chain reaction (RT-PCR) to investigate whether mRNA for CCK-A and CCK-B receptors as well as CCK peptide itself is present in primary human gliomas and the U-87 MG GBM cell line. The data show that 14/14 (100%) of the primary gliomas exhibited mRNA expression for the CCK peptide gene and the B receptor including the U-87 MG cells, whereas, only 2/14 (14%) showed presence of the CCK-A receptor. The presence of CCK receptors together with CCK peptide expression itself suggests presence of an autocrine loop controlling glioma cell growth. In support of this conclusion, a neutralizing antibody against the CCK peptide exhibited a dose dependent inhibition of cell growth whereas, antagonists to CCK caused a dose depend inhibition of exogenous stimulated glioma cell growth in vitro, via the CCK-B receptor which is PKC activated. Assessment of apoptosis and proteasome activity were undertaken and we report that treatment with CCK antagonists decreased proteasome and increased caspase-3 activity. These data indicate that CCK peptide and CCK-B are abundant in human gliomas and they act to stimulate cell growth in an autocrine manner, primarily via the high affinity CCK-B receptor, which was blocked by antagonists to CCK, perhaps via apoptosis.

Transition of planar Couette flow at infinite Reynolds numbers

An outline of the state space of planar Couette flow at high Reynolds numbers (Re<105) is investigated via a variety of efficient numerical techniques. It is verified from nonlinear analysis that the lower branch of the hairpin vortex state (HVS) asymptotically approaches the primary (laminar) state with increasing Re. It is also predicted that the lower branch of the HVS at high Re belongs to the stability boundary that initiates a transition to turbulence, and that one of the unstable manifolds of the lower branch of HVS lies on the boundary. These facts suggest HVS may provide a criterion to estimate a minimum perturbation arising transition to turbulent states at the infinite Re limit. © 2013 American Physical Society.