The cytokine tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 have a neuroprotective effect in the central nervous system

<p>Abstract</p> <p>Background</p> <p>Cerebral cortical neurons have a high vulnerability to the harmful effects of hypoxia. However, the brain has the ability to detect and accommodate to hypoxic conditions. This phenomenon, known as preconditioning, is a natural adaptive process highly preserved among species whereby exposure to sub-lethal hypoxia promotes the acquisition of tolerance to a subsequent lethal hypoxic injury. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are found in neurons and their expression is induced by exposure to sub-lethal hypoxia. Accordingly, in this work we tested the hypothesis that the interaction between TWEAK and Fn14 induces tolerance to lethal hypoxic and ischemic conditions.</p> <p>Methods</p> <p>Here we used <it>in vitro </it>and <it>in vivo </it>models of hypoxic and ischemic preconditioning, an animal model of transient middle cerebral artery occlusion and mice and neurons genetically deficient in TWEAK, Fn14, or tumor necrosis factor alpha (TNF-α) to investigate whether treatment with recombinant TWEAK or an increase in the expression of endogenous TWEAK renders neurons tolerant to lethal hypoxia. We used enzyme-linked immunosorbent assay to study the effect of TWEAK on the expression of neuronal TNF-α, Western blot analysis to investigate whether the effect of TWEAK was mediated by activation of mitogen-activated protein kinases and immunohistochemical techniques and quantitative real-time polymerase chain reaction analysis to study the effect of TWEAK on apoptotic cell death.</p> <p>Results</p> <p>We found that either treatment with recombinant TWEAK or an increase in the expression of TWEAK and Fn14 induce hypoxic and ischemic tolerance <it>in vivo </it>and <it>in vitro</it>. This protective effect is mediated by neuronal TNF-α and activation of the extracellular signal-regulated kinases 1 and 2 pathway via phosphorylation and inactivation of the B-cell lymphoma 2-associated death promoter protein.</p> <p>Conclusions</p> <p>Our work indicate that the interaction between TWEAK and Fn14 triggers the activation of a cell signaling pathway that results in the induction of tolerance to lethal hypoxia and ischemia. These data indicate that TWEAK may be a potential therapeutic strategy to protect the brain from the devastating effects of an ischemic injury.</p

The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility

Deubiquitinating enzymes are now emerging as potential therapeutic targets that control many cellular processes, but few have been demonstrated to control cell motility. Here, we show that ubiquitin-specific protease 17 (USP17) is rapidly and transiently induced in response to chemokines SDF-1/CXCL12 and IL-8/CXCL8 in both primary cells and cell lines, and that its depletion completely blocks chemokine-induced cell migration and cytoskeletal rearrangements. Using live cell imaging, we demonstrate that USP17 is required for both elongated and amoeboid motility, in addition to chemotaxis. USP17 has previously been reported to disrupt Ras localization and we now find that USP17 depletion blocks chemokine-induced subcellular relocalization of GTPases Cdc42, Rac and RhoA, which are GTPases essential for cell motility. Collectively, these results demonstrate that USP17 has a critical role in cell migration and may be a useful drug target for both inflammatory and metastatic disease

No Evidence of Persisting Unrepaired Nuclear DNA Single Strand Breaks in Distinct Types of Cells in the Brain, Kidney, and Liver of Adult Mice after Continuous Eight-Week 50 Hz Magnetic Field Exposure with Flux Density of 0.1 mT or 1.0 mT

BACKGROUND: It has been hypothesized in the literature that exposure to extremely low frequency electromagnetic fields (50 or 60 Hz) may lead to human health effects such as childhood leukemia or brain tumors. In a previous study investigating multiple types of cells from brain and kidney of the mouse (Acta Neuropathologica 2004; 107: 257-264), we found increased unrepaired nuclear DNA single strand breaks (nDNA SSB) only in epithelial cells of the choroid plexus in the brain using autoradiographic methods after a continuous eight-week 50 Hz magnetic field (MF) exposure of adult mice with flux density of 1.5 mT. METHODS: In the present study we tested the hypothesis that MF exposure with lower flux densities (0.1 mT, i.e., the actual exposure limit for the population in most European countries, and 1.0 mT) shows similar results to those in the previous study. Experiments and data analysis were carried out in a similar way as in our previous study. RESULTS: Continuous eight-week 50 Hz MF exposure with 0.1 mT or 1.0 mT did not result in increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice. MF exposure with 1.0 mT led to reduced unscheduled DNA synthesis (UDS) in epithelial cells in the choroid plexus of the fourth ventricle in the brain (EC-CP) and epithelial cells of the cortical collecting duct in the kidney, as well as to reduced mtDNA synthesis in neurons of the caudate nucleus in the brain and in EC-CP. CONCLUSION: No evidence was found for increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice after continuous eight-week 50 Hz magnetic field exposure with flux density of 0.1 mT or 1.0 mT

The DNA of winning ideas : a network perspective of success in new product development.

The extant literature suggests that the composition of the idea itself may play an important role in explaining its success. However, there is a relative paucity of innovation and marketing research further investigating the nature of the idea. We address this gap with two main contributions. First, we develop a configurational theory about the idea itself (i.e., the “idea DNA”), which suggests that an idea’s compositional features and their configuration may be strong predictors of success. Second, we develop a new network-based methodology that aims to extract the DNA of successful ideas, thereby providing an opportunity to identify further promising ideas in a given domain. We validate this methodology using a dataset from an idea competition in the consumer goods sector. The evidence suggests that an idea’s features and meta- features derived from network analysis can be strong predictors of success

Improving and Sustaining ICT Skills of Health Researchers in Kenya Through a Three-Tiered Approach of Online Learning, Hands-On Workshops, and Personalized Mentoring

Despite the recent growth in health informatics, the use of information, communication and technology (ICT) by health researchers in resource-limited settings has been slow and inequitable. Further, many local institutions that have excellent ICT capacity do not routinely provide such services to the health researchers. innovative delivery of ICT skills to health researchers may improve the quality and impact of research outcomes

Wissenschaftliches Mess- und Evaluierungsprogramm (WMEP) zum Breitentest '250 MW Wind'. Phase 1. Abschlussbericht. Bd. 1

The presented Final Report (3 volumes) describes the works carried out during Phase I (01.01.1990-30.06.1992) of the Scientific Measurement and Evaluation Programme in the '250 MW Wind' Programme and their results. In the middle of the year 1992, WMEP included approx. 550 WEC's representing an installed capacity of approx. 91 MW. At the end of this project phase the essential building-up works could be finished. The achieved status of the remote measurement network now allows for handling essential topics of the WMEP basic evaluation (e.g. local/regional wind conditions). At the end of the project phase furthermore the data achieved in WMEP were made accessible for external users, e.g. manufacturers, WEC owners, utilities and research institutes. The so far achieved project results were already published in 'Annual Reports' 1990 and 1991; the 'Annual report' 1992 respectively, which is to be published by middle of 1993. (orig.)Der vorliegende Abschlussbericht (3 Baende) beschreibt die ausgefuehrten Arbeiten und Ergebnisse der 1. Durchfuehrungsphase (01.01.1990-30.06.1992) des Wissenschaftlichen Mess- und Evaluierungsprogramms (WMEP) zur Foerdermassnahme '250 MW-Wind'. Zur Jahresmitte 1992 erreichte das WMEP einen Umfang von ca. 550 WKA mit ca. 91 MW installierter Leistung. Mit Ende dieser Projektphase konnten die wesentlichen Aufbauarbeiten im WMEP abgeschlossen werden. Mit dem bereits erreichten Ausbaugrad des Fernmessnetzes koennen nunmehr wichtige Themenbereiche der WMEP-Basisauswertung bearbeitet (lokale/regionale Windverhaeltnisse) bzw. in wesentlichen Punkten ergaenzt werden. Zum Ende der Projektphase wurde weiterhin damit begonnen, die im WMEP gewonnenen Daten ueber eine spezielle Benutzerdatenbank auch externen Nutzern, z.B. WKA-Herstellern, -Betreibern, EVU und anderen Forschungseinrichtungen, zugaenglich zu machen. Die bisherigen Projektergebnisse wurden mit den 'Jahresauswertungen' 1990 und 1991 bereits veroeffentlicht bzw. werden mit der 'Jahresauswertung' 1992 bis Mitte 1993 vorliegen. (orig.)Published in three separate volumesSIGLEAvailable from TIB Hannover: F97B159+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman

Wissenschaftliches Mess- und Evaluierungsprogramm (WMEP) zum Breitentest '250 MW Wind'. Phase 2. Bd. 1 Abschlussbericht

SIGLEAvailable from TIB Hannover: F96B1905+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Results of the autoradiographic analyses.

<p>The graphs show mean and standard error of the mean (SEM) of grain numbers representing UDS (<b>A</b>, <b>D</b>, <b>G</b>, <b>J</b>), unrepaired nDNA SSB/ISNT (<b>B</b>, <b>E</b>, <b>H</b>, <b>K</b>) and mtDNA synthesis (<b>C</b>, <b>F</b>, <b>I</b>, <b>L</b>) of neurons in the caudate nucleus in the brain (<b>A–C</b>), epithelial cells in the choroid plexus of the fourth ventricle in the brain (<b>D–F</b>), epithelial cells of the cortical collecting duct in the kidney (<b>G–I</b>), and pericentral hepatocytes in the liver (<b>J–L</b>) after sham-exposure (open bars), MF exposure with 0.1 mT for eight weeks (gray bars), or MF exposure with 1.0 mT for eight weeks (closed bars). For a detailed description of the generation of these grain numbers and grain densities see Section “Evaluation of Autoradiographs” in the main text. Statistically significant differences between groups are indicated.</p

Experimental set-up of the 50 Hz MF exposure of the present study.

<p>Details are provided in the main text.</p