A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration

Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylationmediated molecular switch comprising deleted in liver cancer 1(DLC1), tensin-3(TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3-DLC1 and PTEN-PI3K complexes into the TNS3-PI3K and PTEN-DLC1 complexes. Subsequently, the TNS3-PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN-DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration

Erratum: A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration

Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylation-mediated molecular switch comprising deleted in liver cancer 1 (DLC1), tensin-3 (TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3–DLC1 and PTEN–PI3K complexes into the TNS3–PI3K and PTEN–DLC1 complexes. Subsequently, the TNS3–PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN–DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration

Recent breakthroughs in carrier depletion based silicon optical modulators

The majority of the most successful optical modulators in silicon demonstrated in recent years operate via the plasma dispersion effect and are more specifically based upon free carrier depletion in a silicon rib waveguide. In this work we overview the different types of free carrier depletion type optical modulators in silicon. A summary of some recent example devices for each configuration is then presented together with the performance that they have achieved. Finally an insight into some current research trends involving silicon based optical modulators is provided including integration, operation in the mid-infrared wavelength range and application in short and long haul data transmission link

Metagenomic study of the viruses of African straw-coloured fruit bats: detection of a chiropteran poxvirus and isolation of a novel adenovirus

Viral emergence as a result of zoonotic transmission constitutes a continuous public health threat. Emerging viruses such as SARS coronavirus, hantaviruses and henipaviruses have wildlife reservoirs. Characterising the viruses of candidate reservoir species in geographical hot spots for viral emergence is a sensible approach to develop tools to predict, prevent, or contain emergence events. Here, we explore the viruses of Eidolon helvum, an Old World fruit bat species widely distributed in Africa that lives in close proximity to humans. We identified a great abundance and diversity of novel herpes and papillomaviruses, described the isolation of a novel adenovirus, and detected, for the first time, sequences of a chiropteran poxvirus closely related with Molluscum contagiosum. In sum, E. helvum display a wide variety of mammalian viruses, some of them genetically similar to known human pathogens, highlighting the possibility of zoonotic transmission

Trace gas/aerosol boundary concentrations and their impacts on continental-scale AQMEII modeling domains

Copyright 2011 Elsevier B.V., All rights reserved.Over twenty modeling groups are participating in the Air Quality Model Evaluation International Initiative (AQMEII) in which a variety of mesoscale photochemical and aerosol air quality modeling systems are being applied to continental-scale domains in North America and Europe for 2006 full-year simulations for model inter-comparisons and evaluations. To better understand the reasons for differences in model results among these participating groups, each group was asked to use the same source of emissions and boundary concentration data for their simulations. This paper describes the development and application of the boundary concentration data for this AQMEII modeling exercise. The European project known as GEMS (Global and regional Earth-system Monitoring using Satellite and in-situ data) has produced global-scale re-analyses of air quality for several years, including 2006 (http://gems.ecmwf.int). The GEMS trace gas and aerosol data were made available at 3-hourly intervals on a regular latitude/longitude grid of approximately 1.9° resolution within 2 "cut-outs" from the global model domain. One cut-out was centered over North America and the other over Europe, covering sufficient spatial domain for each modeling group to extract the necessary time- and space-varying (horizontal and vertical) concentrations for their mesoscale model boundaries. Examples of the impact of these boundary concentrations on the AQMEII continental simulations are presented to quantify the sensitivity of the simulations to boundary concentrations. In addition, some participating groups were not able to use the GEMS data and instead relied upon other sources for their boundary concentration specifications. These are noted, and the contrasting impacts of other data sources for boundary data are presented. How one specifies four-dimensional boundary concentrations for mesoscale air quality simulations can have a profound impact on the model results, and hence, this aspect of data preparation must be performed with considerable care.Peer reviewedFinal Accepted Versio

Neonatal hyperoxia promotes asthma-like features through IL-33–dependent ILC2 responses

Background Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. Objective We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. Methods Mice were exposed to neonatal hyperoxia followed by a period of room air recovery. A group of mice was also intranasally exposed to house dust mite antigen. Assessments were performed at various time points for evaluation of airway hyperresponsiveness, eosinophilia, mucus production, inflammatory gene expression, and TH and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and levels of IL-33 and type 2 cytokines were measured. Results Neonatal hyperoxia induced asthma-like features including airway hyperresponsiveness, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic TH responses to house dust mite exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13 but not IL-4 in preterm infants. Conclusions These data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity

APOE3, but Not APOE4, Bone Marrow Transplantation Mitigates Behavioral and Pathological Changes in a Mouse Model of Alzheimer Disease

Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset Alzheimer disease and confers a proinflammatory, neurotoxic phenotype to microglia. Here, we tested the hypothesis that bone marrow cell APOE genotype modulates pathological progression in experimental Alzheimer disease. We performed bone marrow transplants (BMT) from green fluorescent protein–expressing human APOE3/3 or APOE4/4 donor mice into lethally irradiated 5-month-old APPswe/PS1ΔE9 mice. Eight months later, APOE4/4 BMT–recipient APPswe/PS1ΔE9 mice had significantly impaired spatial working memory and increased detergent-soluble and plaque Aβ compared with APOE3/3 BMT–recipient APPswe/PS1ΔE9 mice. BMT-derived microglia engraftment was significantly reduced in APOE4/4 recipients, who also had correspondingly less cerebral apoE. Gene expression analysis in cerebral cortex of APOE3/3 BMT recipients showed reduced expression of tumor necrosis factor-α and macrophage migration inhibitory factor (both neurotoxic cytokines) and elevated immunomodulatory IL-10 expression in APOE3/3 recipients compared with those that received APOE4/4 bone marrow. This was not due to detectable APOE-specific differences in expression of microglial major histocompatibility complex class II, C-C chemokine receptor (CCR) type 1, CCR2, CX3C chemokine receptor 1 (CX3CR1), or C5a anaphylatoxin chemotactic receptor (C5aR). Together, these findings suggest that BMT-derived APOE3-expressing cells are superior to those that express APOE4 in their ability to mitigate the behavioral and neuropathological changes in experimental Alzheimer disease