A role for SNX5 in the regulation of macropinocytosis

Background: The mechanisms and components that regulate macropinocytosis are poorly understood. Here we have investigated the role of sorting nexin 5 (SNX5) in the regulation of macropinocytic activity

Minimal Work Principle and its Limits for Classical Systems

The minimal work principle asserts that work done on a thermally isolated equilibrium system, is minimal for the slowest (adiabatic) realization of a given process. This principle, one of the formulations of the second law, is operationally well-defined for any finite (few particle) Hamiltonian system. Within classical Hamiltonian mechanics, we show that the principle is valid for a system of which the observable of work is an ergodic function. For non-ergodic systems the principle may or may not hold, depending on additional conditions. Examples displaying the limits of the principle are presented and their direct experimental realizations are discussed.Comment: 4 + epsilon pages, 1 figure, revte

Coulomb induced positive current-current correlations in normal conductors

In the white-noise limit current correlations measured at different contacts of a mesoscopic conductor are negative due to the antisymmetry of the wave function (Pauli principle). We show that current fluctuations at capacitive contacts induced via the long range Coulomb interaction as consequence of charge fluctuations in the mesoscopic sample can be {\it positively} correlated. The positive correlations are a consequence of the extension of the wave-functions into areas near both contacts. As an example we investigate in detail a quantum point contact in a high magnetic field under conditions in which transport is along an edge state.Comment: Revtex, 4 pages includes 2 figure

Quantum shot-noise at local tunneling contacts on mesoscopic multiprobe conductors

New experiments that measure the low-frequency shot-noise spectrum at local tunneling contacts on mesoscopic structures are proposed. The current fluctuation spectrum at a single tunneling tip is determined by local partial densities of states. The current-correlation spectrum between two tunneling tips is sensitive to non-diagonal density of states elements which are expressed in terms of products of scattering states of the conductor. Thus such an experiment permits to investigate correlations of electronic wave functions. We present specific results for a clean wire with a single barrier and for metallic diffusive conductors.Comment: 4 pages REVTeX, 2 figure

The osmotic pressure of charged colloidal suspensions: A unified approach to linearized Poisson-Boltzmann theory

We study theoretically the osmotic pressure of a suspension of charged objects (e.g., colloids, polyelectrolytes, clay platelets, etc.) dialyzed against an electrolyte solution using the cell model and linear Poisson-Boltzmann (PB) theory. From the volume derivative of the grand potential functional of linear theory we obtain two novel expressions for the osmotic pressure in terms of the potential- or ion-profiles, neither of which coincides with the expression known from nonlinear PB theory, namely, the density of microions at the cell boundary. We show that the range of validity of linearization depends strongly on the linearization point and proof that expansion about the selfconsistently determined average potential is optimal in several respects. For instance, screening inside the suspension is automatically described by the actual ionic strength, resulting in the correct asymptotics at high colloid concentration. Together with the analytical solution of the linear PB equation for cell models of arbitrary dimension and electrolyte composition explicit and very general formulas for the osmotic pressure ensue. A comparison with nonlinear PB theory is provided. Our analysis also shows that whether or not linear theory predicts a phase separation depends crucially on the precise definition of the pressure, showing that an improper choice could predict an artificial phase separation in systems as important as DNA in physiological salt solution.Comment: 16 pages, 5 figures, REVTeX4 styl

Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis.

Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies ("humming bird") compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Integration of decision support systems to improve decision support performance

Decision support system (DSS) is a well-established research and development area. Traditional isolated, stand-alone DSS has been recently facing new challenges. In order to improve the performance of DSS to meet the challenges, research has been actively carried out to develop integrated decision support systems (IDSS). This paper reviews the current research efforts with regard to the development of IDSS. The focus of the paper is on the integration aspect for IDSS through multiple perspectives, and the technologies that support this integration. More than 100 papers and software systems are discussed. Current research efforts and the development status of IDSS are explained, compared and classified. In addition, future trends and challenges in integration are outlined. The paper concludes that by addressing integration, better support will be provided to decision makers, with the expectation of both better decisions and improved decision making processes

Statistical and visual differentiation of subcellular imaging

<p>Abstract</p> <p>Background</p> <p>Automated microscopy technologies have led to a rapid growth in imaging data on a scale comparable to that of the genomic revolution. High throughput screens are now being performed to determine the localisation of all of proteins in a proteome. Closer to the bench, large image sets of proteins in treated and untreated cells are being captured on a daily basis to determine function and interactions. Hence there is a need for new methodologies and protocols to test for difference in subcellular imaging both to remove bias and enable throughput. Here we introduce a novel method of statistical testing, and supporting software, to give a rigorous test for difference in imaging. We also outline the key questions and steps in establishing an analysis pipeline.</p> <p>Results</p> <p>The methodology is tested on a high throughput set of images of 10 subcellular localisations, and it is shown that the localisations may be distinguished to a statistically significant degree with as few as 12 images of each. Further, subtle changes in a protein's distribution between nocodazole treated and control experiments are shown to be detectable. The effect of outlier images is also examined and it is shown that while the significance of the test may be reduced by outliers this may be compensated for by utilising more images. Finally, the test is compared to previous work and shown to be more sensitive in detecting difference. The methodology has been implemented within the iCluster system for visualising and clustering bio-image sets.</p> <p>Conclusion</p> <p>The aim here is to establish a methodology and protocol for testing for difference in subcellular imaging, and to provide tools to do so. While iCluster is applicable to moderate (<1000) size image sets, the statistical test is simple to implement and will readily be adapted to high throughput pipelines to provide more sensitive discrimination of difference.</p