Evidence that distinct states of the integrin alpha6beta1 interact with laminin and an ADAM

Integrins can exist in different functional states with low or high binding capacity for particular ligands. We previously provided evidence that the integrin alpha6beta1, on mouse eggs and on alpha6-transfected cells, interacted with the disintegrin domain of the sperm surface protein ADAM 2 (fertilin beta). In the present study we tested the hypothesis that different states of alpha6beta1 interact with fertilin and laminin, an extracellular matrix ligand for alpha6beta1. Using alpha6-transfected cells we found that treatments (e.g., with phorbol myristate acetate or MnCl2) that increased adhesion to laminin inhibited sperm binding. Conversely, treatments that inhibited laminin adhesion increased sperm binding. Next, we compared the ability of fluorescent beads coated with either fertilin beta or with the laminin E8 fragment to bind to eggs. In Ca2+-containing media, fertilin beta beads bound to eggs via an interaction mediated by the disintegrin loop of fertilin beta and by the alpha6 integrin subunit. In Ca2+-containing media, laminin E8 beads did not bind to eggs. Treatment of eggs with phorbol myristate acetate or with the actin disrupting agent, latrunculin A, inhibited fertilin bead binding, but did not induce laminin E8 bead binding. Treatment of eggs with Mn2+ dramatically increased laminin E8 bead binding, and inhibited fertilin bead binding. Our results provide the first evidence that different states of an integrin (alpha6beta1) can interact with an extracellular matrix ligand (laminin) or a membrane-anchored cell surface ligand (ADAM 2)

TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer

Transforming growth factor β (TGFβ) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGFβ binding to type II and type I serine/threonine kinase receptors (TβRII and TβRI) causes activation of different intracellular signaling pathways. TβRI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGFβ, via TRAF6, causes Lys63-linked polyubiquitination of TβRI, promoting cleavage of TβRI by TNF-alpha converting enzyme (TACE), in a PKCζ-dependent manner. The liberated intracellular domain (ICD) of TβRI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGFβ-induced invasion of cancer cells is TACE- and PKCζ- dependent and the TβRI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for TβRI in TGFβ mediated tumour invasion

Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

The multifunctional signaling protein p75 neurotrophin receptor (p75NTR) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75NTR is required for p75NTR-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75NTR or treatment of animals bearing p75NTR-positive intracranial tumors with clinically applicable γ-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75NTR was observed in p75NTR-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75NTR as a therapeutic target, suggesting that γ-secretase inhibitors may have direct clinical application for the treatment of malignant glioma

Key performance indicators for the indoor environment

editorial reviewe

State of the Art Analysis of Wireless Mesh Technologies

Wireless mesh networks are a recent architecture for multihop wireless networks. Also, standards for realizing mesh networks are being actively developed, especially in the IEEE working groups. In contrast with mobile ad hoc networks, mesh networks consist of static nodes communicating with each other over wireless links. The static nodes are essentially wireless routers. Such networks can be used, for example to provide a cost effective alternative to a wireline Internet access network. As opposed to the nodes in mobile ad hoc networks, the nodes in mesh networks are not energy constrained and node mobility is not a concern in protocol scalability. Instead, the main technical problems relate to achieving high user data rates over multihop wireless paths by using advanced MAC/routing layer solutions. This report presents a state-of-the-art analysis of wireless mesh networks, both from the point of view of standardization and academic research activities. In the standardization, we focus on the recent developments on defining new physical layer and MAC layer standards for mesh network in the IEEE 802.11 and 802.16 working groups. At the IP layer, in addition to routing, mobility management is a key issue, and these are reviewed from the point of view of recent IETF activities in the field. In academic research, the emphasis has been on identifying feasible mechanisms that can be used to mitigate the impact of interferenc

Indoor performance and sustainability

Perfection (Performance Indicators for Health, Comfort and Safety of the Indoor Environment, 2009-11) is a European Coordination Action under EC's 7th Framework Programme. It aims to help enabling the application of new building design and technologies that improve the impact of the indoor built environment on health and comfort, feeling of safety and positive stimulation integrated within a sustainable built environment. Perfection project consists of the following components · the inventory of current standards, regulations, technologies, and ongoing and recent research activities and policies related to the optimal indoor environment · an analysis of current indicators for health and comfort, safety and accessibility, positive stimulation, adaptability and usability positioned within a generic framework to assess their impacts to sustainability · experiences from pilot cases exploiting the key indoor performance indicators in different building types. This paper presents the findings from applicable design technologies and potential Key Indoor Performance Indicators (KIPIs) representing health and comfort, accessibility safety and positive stimulation, usability and adaptability in relation with their impacts to sustainable buildings