The role of the Integrin β3 Adhesome in Angiogenesis

Angiogenesis, the formation of new blood vessels from those that already exist, plays an essential role in development, homeostasis and tumour growth. As such, targeting angiogenesis is seen as crucial in treatment of cardiovascular diseases or cancer. Therapies directed against vascular endothelial growth factor and its major receptor, VEGFR2 (vascular endothelial growth factor receptor 2), whilst effective in a number of cancers, are not without side-effects due to the role this signalling pathway plays in vascular homeostasis. Because of their restricted expression, fibronectin binding endothelial integrins, especially αvβ3- and α5β1-integrins, have emerged as alternative anti-angiogenic targets to neovasculature, particularly in the case of β3. However, neither global nor conditional knockouts of these integrins block tumour angiogenesis beyond acute deletions, and clinical trials of blocking antibodies and peptides directed against these extracellular matrix receptors have been disappointing. To gain novel insight into how αvβ3-integrin regulates outside-in signal transmission, in this thesis we have optimised an enrichment and mass spectrometry workflow to undertake an unbiased analysis of the molecular composition of the mature endothelial adhesome, and profiled changes that occur when β3-integrin function or expression are manipulated. In so doing, we have uncovered β3-integrin dependent changes in microtubule behaviour that affect cell migration and offered some potential explanations as to why current inhibitors have failed clinical trials. β3 negatively regulates microtubule stability/targeting to focal adhesions and these changes are driven by Rcc2 (Regulator of Chromatin Condensation 2) and Anxa2 (Annexin A2) regulation of Rac1 (Ras-related C3 botulinum toxin substrate 1). As a result, cell migration, angiogenesis and tumour growth in the absence of β3 are susceptible to low doses of clinically relevant microtubule inhibitors

Vägen till europeisk toppfotboll - En studie av svenska yrkesverksamma utlandsspelares fotbollsutbildningsbakgrund

Svensk fotboll satsar mer pengar än någonsin för att få fram spelare av så hög kvalite som möjligt och arbetet med talangutveckling går längre och längre ner i åldrarna med bland annat en ny elitförberedande klass i Gothia Cup och Akademicertifiering för U17 och U19 i svenska klubbar. Men vad ger denna satsning för resultat? Denna studie försöker skapa tydlighet kring vilken fotbollsutbildning av bredd och akademi som skapar flest fotbollsspelare som lyckas ta sig till de 20 högst rankade ligorna i Europa. Därefter valdes 101 spelare med olika utbildningsbakgrund ut efter kriterier som innefattar om man har varit i en Akademi samt hur högt man spelat. Data bearbetades i Excel och SPSS och resultatet visade att Akademierna producerar fler spelare till samtliga ligor rankade 1–20 i Europa. Dock visade ett Chi-2 test att det i studiens population inte fanns någon skillnad i procentuell fördelning vad gäller spelare från Akademi och bredd. Man kan diskutera om resultatet visar att Akademierna har missat de spelarna som blivit yrkesverksamma utomlands utan att gå genom en Akademi eller om det handlar mer om talang än om utbildning för spelare att nå till toppen i Europa. Den slutsats som till sist drogs var att båda utbildningarna skapar spelare till liga 1–20 i Europa men att i vår population var spelare med Akademibakgrund överrepresenterade. Mer forskning med en mer kontrollerad och jämt fördelad population skulle vara bra för att få ett tydligare resultat om samband mellan utbildning och hur högt man kan nå som fotbollsspelare

Sulforaphane exerts anti-angiogenesis effects against hepatocellular carcinoma through inhibition of STAT3/HIF-1α/VEGF signalling

Angiogenesis plays an important role in hepatocellular carcinoma (HCC), the inhibition of which is explored for cancer prevention and treatment. The dietary phytochemical sulforaphane (SFN) is known for its anti-cancer properties in vitro and in vivo; but until now, no study has focused on the role of SFN in HCC tumor angiogenesis. In the present study, in vitro cell models using a HCC cell line, HepG2, and human endothelial cells, HUVECs, as well as ex vivo and in vivo models have been used to investigate the anti-tumor and anti-angiogenic effect of SFN. The results showed that SFN decreased HUVEC cell viability, migration and tube formation, all of which are important steps in angiogenesis. More importantly, SFN markedly supressed HepG2-stimulated HUVEC migration, adhesion and tube formation; which may be due to its inhibition on STAT3/HIF-1α/VEGF signalling in HepG2 cells. In addition, SFN significantly reduced HepG2 tumor growth in a modified chick embryo chorioallantoic membrane (CAM) assay, associated with a decrease of HIF-1α and VEGF expression within tumors. Collectively, these findings provide new insights into the inhibitory effect of SFN on HCC tumor angiogenesis as well as tumor growth, and indicate that SFN has potential for the prevention and treatment of HCC

A security perspective on Unikernels

Cloud-based infrastructures have grown in popularity over the last decade leveraging virtualisation, server, storage, compute power and network components to develop flexible applications. The requirements for instantaneous deployment and reduced costs have led the shift from virtual machine deployment to containerisation, increasing the overall flexibility of applications and increasing performances. However, containers require a fully fleshed operating system to execute, increasing the attack surface of an application. Unikernels, on the other hand, provide a lightweight memory footprint, ease of application packaging and reduced start-up times. Moreover, Unikernels reduce the attack surface due to the self-contained environment only enabling low-level features. In this work, we provide an exhaustive description of the unikernel ecosystem; we demonstrate unikernel vulnerabilities and further discuss the security implications of Unikernel-enabled environments through different use-cases

Color Confinement, Quark Pair Creation and Dynamical Chiral-Symmetry Breaking in the Dual Ginzburg-Landau Theory

We study the color confinement, the $q$-$\bar q$ pair creation and the dynamical chiral-symmetry breaking of nonperturbative QCD by using the dual Ginzburg-Landau theory, where QCD-monopole condensation plays an essential role on the nonperturbative dynamics in the infrared region. As a result of the dual Meissner effect, the linear static quark potential, which characterizes the quark confinement, is obtained in the long distance within the quenched approximation. We obtain a simple expression for the string tension similar to the energy per unit length of a vortex in the superconductivity physics. The dynamical effect of light quarks on the quark confining potential is investigated in terms of the infrared screening effect due to the $q$-$\bar q$ pair creation or the cut of the hadronic string. The screening length of the potential is estimated by using the Schwinger formula for the $q$-$\bar q$ pair creation. We introduce the corresponding infrared cutoff to the strong long-range correlation factor in the gluon propagator as a dynamical effect of light quarks, and obtain a compact formula of the quark potential including the screening effect in the infrared region. We investigate the dynamical chiral-symmetry breaking by using the Schwinger-Dyson equation, where the gluon propagator includes the nonperturbative effect related toComment: 37 pages, plain TeX (using `phyzzx' macro), (( 8 figures - available on request from [email protected] )

NRP2 as an Emerging Angiogenic Player; Promoting Endothelial Cell Adhesion and Migration by Regulating Recycling of α5 Integrin.

Angiogenesis relies on the ability of endothelial cells (ECs) to migrate over the extracellular matrix via integrin receptors to respond to an angiogenic stimulus. Of the two neuropilin (NRP) orthologs to be identified, both have been reported to be expressed on normal blood and lymphatic ECs, and to play roles in the formation of blood and lymphatic vascular networks during angiogenesis. Whilst the role of NRP1 and its interactions with integrins during angiogenesis has been widely studied, the role of NRP2 in ECs is poorly understood. Here we demonstrate that NRP2 promotes Rac-1 mediated EC adhesion and migration over fibronectin (FN) matrices in a mechanistically distinct fashion to NRP1, showing no dependence on β3 integrin (ITGB3) expression, or VEGF stimulation. Furthermore, we highlight evidence of a regulatory crosstalk between NRP2 and α5 integrin (ITGA5) in ECs, with NRP2 depletion eliciting an upregulation of ITGA5 expression and disruptions in ITGA5 cellular organization. Finally, we propose a mechanism whereby NRP2 promotes ITGA5 recycling in ECs; NRP2 depleted ECs were found to exhibit reduced levels of total ITGA5 subunit recycling compared to wild-type (WT) ECs. Our findings expose NRP2 as a novel angiogenic player by promoting ITGA5-mediated EC adhesion and migration on FN

Stress induced by constrained sintering of 3YSZ films measured by substrate creep

3YSZ green layers approximately 10 μm thick were screen printed onto 3YSZ substrates up to 300 μm in thickness. The stress induced by constrained sintering of the film (between 1150° and 1350°C) was measured by monitoring the bending displacement of vertical strips of bilayers using a long-distance microscope. In order to deduce the stress it was first necessary to measure the creep properties of the substrates by monitoring the bending of horizontal beams under gravity. The creep strain rate of the 3YSZ substrates was linearly dependent on applied stress at the low stresses and strains involved in the present work. The creep viscosity appeared to increase with strain (time), which might be due to changes in grain-boundary composition, and had higher activation energy at temperatures above approximately 1250°C. The magnitudes of the creep viscosities are in reasonable agreement with other creep data in the literature for 3YSZ. The in-plane stress induced during constrained sintering of the 3YSZ films had a maximum value of approximately 3 MPa at 1200°C. This behavior is consistent with literature results reported for constrained sintering of bulk alumina. The stress induced by the constraint is of a similar order to the estimated sintering potential

Deep cultural ancestry and human development indicators across nation states

How historical connections, events and cultural proximity can influence human development is being increasingly recognized. One aspect of history that has only recently begun to be examined is deep cultural ancestry, i.e. the vertical relationships of descent between cultures, which can be represented by a phylogenetic tree of descent. Here, we test whether deep cultural ancestry predicts the United Nations Human Development Index (HDI) for 44 Eurasian countries, using language ancestry as a proxy for cultural relatedness and controlling for three additional factors—geographical proximity, religion and former communism. While cultural ancestry alone predicts HDI and its subcomponents (income, health and education indices), when geographical proximity is included only income and health indices remain significant and the effect is small. When communism and religion variables are included, cultural ancestry is no longer a significant predictor; communism significantly negatively predicts HDI, income and health indices, and Muslim percentage of the population significantly negatively predicts education index, although the latter result may not be robust. These findings indicate that geographical proximity and recent cultural history—especially communism—are more important than deep cultural factors in current human development and suggest the efficacy of modern policy initiatives is not tightly constrained by cultural ancestry.</jats:p