Mechanism of transport of saquinavir-loaded nanostructured lipid carriers across the intestinal barrier

[EN] The aims of this work were (i) to evaluate the potential of nanostructured lipid carriers (NLCs) as a tool to 24 enhance the oral bioavailability of poorly soluble compounds using saquinavir (SQV), a BCS class IV drug 25 and P-gp substrate as a model drug, and (ii) to study NLC transport mechanisms across the intestinal barrier. 26 Three different NLC formulations were evaluated. SQV transport across Caco-2 monolayers was enhanced up 27 to 3.5-fold by NLCs compared to SQV suspension. M cells did not enhance the transport of NLCs loaded with 28 SQV. The size and amount of surfactant in the NLCs influenced SQV's permeability, the transcytosis pathway 29 and the efflux of SQV by P-gp. An NLC of size 247 nm and 1.5% (w/v) surfactant content circumvented P-gp 30 efflux and used both caveolae- and clathrin-mediated transcytosis, in contrast to the other NLC formulations, 31 which used only caveolae-mediated transcytosis. By modifying critical physicochemical parameters of the 32 NLC formulation, we were thus able to overcome the P-gp drug efflux and alter the transcytosis mechanism 33 of the nanoparticles. These findings support the use of NLCs approaches for oral delivery of poorly 34 water-soluble P-gp substrates.

The cross layer RMPA handover: a reliable mobility pattern aware handover strategy for broadband wireless communication in a high-speed railway domain

Enhancing the handover process in broadband wireless communication deployment has traditionally motivated many research initiatives. In a high-speed railway domain, the challenge is even greater. Owing to the long distances covered, the mobile node gets involved in a compulsory sequence of handover processes. Consequently, poor performance during the execution of these handover processes significantly degrades the global end-to-end performance. This article proposes a new handover strategy for the railway domain: the RMPA handover, a Reliable Mobility Pattern Aware IEEE 802.16 handover strategy "customized" for a high-speed mobility scenario. The stringent high mobility feature is balanced with three other positive features in a high-speed context: mobility pattern awareness, different sources for location discovery techniques, and a previously known traffic data profile. To the best of the authors' knowledge, there is no IEEE 802.16 handover scheme that simultaneously covers the optimization of the handover process itself and the efficient timing of the handover process. Our strategy covers both areas of research while providing a cost-effective and standards-based solution. To schedule the handover process efficiently, the RMPA strategy makes use of a context aware handover policy; that is, a handover policy based on the mobile node mobility pattern, the time required to perform the handover, the neighboring network conditions, the data traffic profile, the received power signal, and current location and speed information of the train. Our proposal merges all these variables in a cross layer interaction in the handover policy engine. It also enhances the handover process itself by establishing the values for the set of handover configuration parameters and mechanisms of the handover process. RMPA is a cost-effective strategy because compatibility with standards-based equipment is guaranteed. The major contributions of the RMPA handover are in areas that have been left open to the handover designer's discretion. Our simulation analysis validates the RMPA handover decision rules and design choices. Our results supporting a high-demand video application in the uplink stream show a significant improvement in the end-to-end quality of service parameters, including end-to-end delay (22%) and jitter (80%), when compared with a policy based on signal-to-noise-ratio information.

Trends in Income and Price Elasticities of Transport Demand (1850-2010)

40 p.

Charge and spin transport in graphene devices

170 p.

Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.