"Alternative" endocytic mechanisms exploited by pathogens: new avenues for therapeutic delivery?

Some pathogens utilize unique routes to enter cells that may evade the intracellular barriers encountered by the typical clathrin-mediated endocytic pathway. Retrograde transport and caveolar uptake are among the better characterized pathways, as alternatives to clathrin-mediated endocytosis, that are known to facilitate entry of pathogens and potential delivery agents. Recent characterization of the trafficking mechanisms of prion proteins and certain bacteria may present new paradigms for strategizing improvements in therapeutic spread and retention of therapy. This review will provide an overview of such endocytic pathways, and discuss current and future possibilities in using these routes as a means to improve therapeutic delivery

What's Neoliberalism Got to Do With It? Towards a Political Economy of Punishment in Greece

SAGE copyright policy clearly states that the co-authors 'may not post the final version of the article as published by SAGE or the SAGE–created PDF – ‘version 3’. Thus we cannot achieve the submitted (SAGE.pdf) version

Potential applications of simulation modelling techniques in healthcare: lessons learned from aerospace and military

The Aerospace and Military areas are to do with complex missions and situations. Modelling and Simulation (M&S) has been applied in many areas of defence ranging from space sciences, satellite engineering to multi-warfare (air warfare, undersea warfare), air & missile defence, acquisition, tactical military trainings & exercises, national security analysis and strategic decision making & planning, etc. The application of simulation modelling techniques in healthcare would improve the provision of healthcare services; however, their application has been much relatively feeble in the healthcare sector as compared to the defence sector. This paper presents results from a systematic literature survey on applications of modelling simulation techniques in the Aerospace & Military. The knowledge gained or lessons learned from the survey were finally used to analyze the potential applications of the simulation modelling techniques to the healthcare sector. Results show that in the defence sector, Distributed Simulation has now become a widely adopted technique. However, System Dynamics (SD) and Discrete Event Simulation (DSE) have also gained relative attention. From this survey it becomes clear that various simulation modelling techniques are useful for specific purposes and have potential applications in the healthcare sector

The onset and association of CMEs with sigmoidal active regions

Previous studies of active regions characterised by Soft X-ray S or inverse-S morphology [Canfield et al., 1999], have found these regions to possess a higher probability of eruption. In such cases, CME launch has been inferred using X-ray proxies to indicate eruption. Active regions observed during 1997, previously categorised as both sigmoidal and eruptive [Canfield, 1999], have been selected for further study, incorporating SoHO-LASCO, SoHO-EIT and ground based H-alpha data. Our results allow re-classification into three main categories; sigmoidal, non-sigmoidal and active regions appearing sigmoidal due to the projection of many loops. Although the reduced dataset size prevents a statistical measure of significance, we note that regions comprising a single S (or inverse-S) shaped structure are more frequently associated with a CME than those classed as non-sigmoidal. This motivates the study of a larger dataset and highlights the need for a quantitative observational definition of the term "sigmoid"

Robust sliding mode control for discrete stochastic systems with mixed time delays, randomly occurring uncertainties, and randomly occurring nonlinearities

This is the post-print version of the paper. The official published version can be accessed from the link below - Copyright @ 2012 IEEEThis paper investigates the robust sliding mode control (SMC) problem for a class of uncertain nonlinear stochastic systems with mixed time delays. Both the sectorlike nonlinearities and the norm-bounded uncertainties enter into the system in random ways, and such randomly occurring uncertainties and randomly occurring nonlinearities obey certain mutually uncorrelated Bernoulli distributed white noise sequences. The mixed time delays consist of both the discrete and the distributed delays. The time-varying delays are allowed in state. By employing the idea of delay fractioning and constructing a new Lyapunov–Krasovskii functional, sufficient conditions are established to ensure the stability of the system dynamics in the specified sliding surface by solving a certain semidefinite programming problem. A full-state feedback SMC law is designed to guarantee the reaching condition. A simulation example is given to demonstrate the effectiveness of the proposed SMC scheme.This work was supported in part by the National Natural Science Foundation of China under Grants 61028008, 60825303 and 60834003, National 973 Project under Grant 2009CB320600, the Fok Ying Tung Education Fund under Grant 111064, the Special Fund for the Author of National Excellent Doctoral Dissertation of China under Grant 2007B4, the Key Laboratory of Integrated Automation for the Process Industry Northeastern University) from the Ministry of Education of China, the Engineering and Physical Sciences Research Council (EPSRC) of the U.K. under Grant GR/S27658/01, the Royal Society of the U.K., and the Alexander von Humboldt Foundation of Germany

H ∞ sliding mode observer design for a class of nonlinear discrete time-delay systems: A delay-fractioning approach

Copyright @ 2012 John Wiley & SonsIn this paper, the H ∞  sliding mode observer (SMO) design problem is investigated for a class of nonlinear discrete time-delay systems. The nonlinear descriptions quantify the maximum possible derivations from a linear model, and the system states are allowed to be immeasurable. Attention is focused on the design of a discrete-time SMO such that the asymptotic stability as well as the H ∞  performance requirement of the error dynamics can be guaranteed in the presence of nonlinearities, time delay and external disturbances. Firstly, a discrete-time discontinuous switched term is proposed to make sure that the reaching condition holds. Then, by constructing a new Lyapunov–Krasovskii functional based on the idea of ‘delay fractioning’ and by introducing some appropriate free-weighting matrices, a sufficient condition is established to guarantee the desired performance of the error dynamics in the specified sliding mode surface by solving a minimization problem. Finally, an illustrative example is given to show the effectiveness of the designed SMO design scheme

A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem.

Potassium channels catalyse the permeation of K+ ions across cellular membranes and are identified by a common structural motif, a highly conserved signature sequence of eight amino acids in the P domain of each channel's pore-forming alpha-subunit. Here we describe a novel K+ channel (TOK1) from Saccharomyces cerevisiae that contains two P domains within one continuous polypeptide. Xenopus laevis oocytes expressing the channel exhibit a unique, outwardly rectifying, K(+)-selective current. The channel is permeable to outward flow of ions at membrane potentials above the K+ equilibrium potential; its conduction-voltage relationship is thus sensitive to extracellular K+ ion concentration. In excised membrane patches, external divalent cations block the channel in a voltage-dependent manner, and their removal in this configuration allows inward channel current. These attributes are similar to those described for inwardly rectifying K+ channels, but in the opposite direction, a previously unrecognized channel behaviour. Our results identify a new class of K+ channel which is distinctive in both its primary structure and functional properties. Structural homologues of the channel are present in the genome of Caenorhabditis elegans

Short-term variability in the sedimentary BIT index of Lake Challa, East Africa over the past 2200 years : validating the precipitation proxy

Abstract. The branched vs. isoprenoid index of tetraethers (BIT index) in Lake Challa sediments has been applied as a monsoon precipitation proxy on the assumption that the primary source of branched tetraether lipids (brGDGTs) was soil washed in from the lake's catchment. However, water column production has since been identified as the primary source of brGDGTs in Lake Challa, meaning that there is no longer a clear mechanism linking BIT index variation and precipitation. Here we investigate BIT index variation and GDGT concentrations at a decadal resolution over the past 2200 years, in combination with GDGT data from profundal surface sediments and 45 months of sediment-trap deployment. The 2200 year record reveals high-frequency variability in GDGT concentrations, and therefore the BIT index. Also surface sediments collected in January 2010 show a distinct shift in GDGT composition relative to those collected in August 2007. Increased bulk flux of settling particles with high Ti / Al ratios during March–April 2008 reflect an event of high detrital input to Lake Challa, concurrent with intense precipitation at the onset of the principal rain season that year. Although brGDGT distributions in the settling material are initially unaffected, this soil erosion event is succeeded by a large diatom bloom in July–August 2008 and a concurrent increase in GDGT-0 fluxes. Near-zero crenarchaeol fluxes indicate that no thaumarchaeotal bloom developed during the subsequent austral summer season; instead a peak in brGDGT fluxes is observed in December 2008. We suggest that increased nutrient availability, derived from eroded soil washed into the lake, stimulated both diatom productivity and the GDGT-0 producing archaea which help decompose dead diatoms passing through the suboxic zone of the water column. This disadvantaged the Thaumarchaeota that normally prosper during the following austral summer. Instead, a bloom of supposedly heterotrophic brGDGT-producing bacteria occurred. Episodic recurrence of such high soil-erosion events, integrated over multi-decadal and longer timescales and possibly enhanced by other mechanisms generating low BIT index values in dry years, can explain the positive relationship between the sedimentary BIT index and monsoon precipitation at Lake Challa. However, application elsewhere requires ascertaining the local situation of lacustrine brGDGT production and of variables affecting the productivity of Thaumarchaeota. </jats:p