2,547 research outputs found
Polymer multimode waveguide optical and electronic PCB manufacturing
No full textThe paper describes the research in the £1.3 million IeMRC Integrated Optical and Electronic Interconnect PCB Manufacturing (OPCB) Flagship Project in which 8 companies and 3 universities carry out collaborative research and which was formed and is technically led by the author. The consortium’s research is aimed at investigating a range of fabrication techniques, some established and some novel, for fabricating polymer multimode waveguides from several polymers, some formulations of which are being developed within the project. The challenge is to develop low cost waveguide manufacturing techniques compatible with commercial PCB manufacturing and to reduce their alignment cost. The project aims to take the first steps in making this hybrid optical waveguide and electrical copper track printed circuit board disruptive technology widely available by establishing and incorporating waveguide design rules into commercial PCB layout software and transferring the technology for fabricating such boards to a commercial PCB manufacturer. To focus the research the project is designing an optical waveguide backplane to tight realistic constraints, using commercial layout software with the new optical design rules, for a demonstrator into which 4 daughter cards are plugged, each carrying an aggregate of 80 Gb/s data so that each waveguide carries 10 Gb/s
Alcohol and lung cancer risk: a pooled analysis using International Lung Cancer Consortium studies
No full textFehringer, G., Brenner, D.R., Zhang, Z.-F., Lee, Y.-C.A., Matsuo, K., Ito, H., Lan, Q., Vineis, P., Johansson, M., Overvad, K., Riboli, E., Trichopoulou, A., Sacerdote, C., Stucker, I., Boffetta, P., Brennan, P., Christiani, D.C., Hong, Y.-C., Landi, M.T., Morgenstern, H., Schwartz, A.G., Wenzlaff, A.S., Rennert, G., McLaughlin, J.R., Harris, C.C., Olivo-Marston, S., Orlow, I., Park, B.J., Zauderer, M., Barros Dios, J.M., Ruano Raviña, A., Siemiatycki, J., Koushik, A., Lazarus, P., Fernández-Somoano, A., Tardon, A., Le Marchand, L., Brenner, H., Saum, K.-U., Duell, E.J., Andrew, A.S., Szeszenia-Dabrowska, N., Lissowska, J., Zaridze, D., Rudnai, P., Fabianova, E., Mates, D., Foretova, L., Janout, V., Bencko, V., Holcatova, I., Pesatori, A.C., Consonni, D., Olsson, A., Straif, K., Hung, R.J
Manual para o tratamento cognitivo-comportamental dos doentes com esquizofrenia nas areas residencial, laboral e de ocupaçao dos tempo-livres (WAF)
No full text
The Chance and Probability Concepts Project
No full textThis article, created by D.R. Green, describes an investigation of what concepts and intuitions concerning random processes are present in the minds of children of varying abilities across the 11-16 age range. The ability to list permutations, combinations and arrangements is also being investigated. The author states, "Over the past two decades the topic of 'Probabilityâ has been brought into the mathematics curriculum but it may be that this is more an empty gesture rather than a sound strategy." This article can help to alleviate many of the struggles in teaching probability concepts. The article is pitched at a more elementary audience, but is still a perfect resource for almost anyone teaching in the field
Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study
No full textThe CAPUA Study, was financed by FIS-FEDER/Spain grant numbers FIS-01/310,FIS-PI03-0365,FIS-PI060604;FICYT/AsturiasgrantnumbersFICYTPB02-67 and FICYTIB09133,the IUOPA,University of Oviedo and the CIBERESP,SpainBrenner, D.R., Fehringer, G., Zhang, Z.-F., Lee, Y.-C.A., Meyers, T., Matsuo, K., Ito, H., Vineis, P., Stucker, I., Boffetta, P., Brennan, P., Christiani, D.C., Diao, N., Hong, Y.-C., Landi, M.T., Morgenstern, H., Schwartz, A.G., Rennert, G., Saliba, W., McLaughlin, J.R., Harris, C.C., Orlow, I., Barros Dios, J.M., Ruano Raviña, A., Siemiatycki, J., Koushik, A., Cote, M., Lazarus, P., Fernandez-Tardon, G., Tardon, A., Le Marchand, L., Brenner, H., Saum, K.-U., Duell, E.J., Andrew, A.S., Consonni, D., Olsson, A., Hung, R.J., Straif, K
Achieving 10 ps coincidence time resolution in TOF-PET is an impossible dream
No full textGreen Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.RST/Radiation, Science and TechnologyRST/Medical Physics & Technolog
Managing issues in risk assessment in auditing process
No full textThe paper intends to present some aspects of evaluating various dimensions of risks as they are necessary to be estimated in the auditing process. The definitions for audit are used to emphasize on the nature of the evidence data and the input information for conducting such an audit. Then, a short characterization of the evaluation of risk and a prioritization procedure are described.auditing process, risk assessment, prioritization procedure
Agrin promotes acetylcholine receptor clustering at the mammalian neuro-muscular junction by PI3K/GSK3ß²-mediated regulation of +TIPs and microtubule capture
No full textNeurotransmission an der neuromuskulären Endplatte von Säugetieren
erfolgt durch Ausschüttung von Acetylcholin (ACh) aus motorischen Nerven
in den synaptischen Spalt und verursacht letztendlich Muskelkontraktion im
angesteuerten Muskel. Der Signalstoff Agrin, welcher ebenfalls vom
Motornerv sekretiert wird, ist hauptverantwortlich für die postsynaptische
Differenzierung der Muskelfasern und bewirkt die räumliche Konzentration
der Rezeptoren für den Neurotransmitter Acetylcholin (AChR) in einem
kleinen - meist zentralen - Areal der Faser unterhalb des Ansatzpunkt der
Motornervendigung. Nach intensiver Beforschung sind die Endeffekte von
Agrin auf Muskelfasern gut dokumentiert und viele involvierte Moleküle
bekannt. Trotzdem ist die Rolle des subsynaptischen Mikrotubuli-Zytoskeletts
beim Transport, bei der Membraninsertion und bei der Konzentrierung von
AChR-Molekülen wenig erforscht und die zugrundeliegenden molekularen
Mechanismen, welche ein Mikrotubuli-Netzwerk unterhalb der Synapse
etablieren, sind grossteils unbekannt. Im Zuge meiner Doktorarbeit
untersuchte ich daher neue Aspekte der agrin-induzierten biochemischen
Signalübertragung im Muskel und deren zellbiologischen Konsequenzen auf
das Mikrotubuli-Zytoskelett.
Gerichteter intrazellulärer Vesikel-Transport erfolgt generell entlang von
polaren Cytoskelettstrukturen, ein grosser Teil davon entlang von Mikrotubuli
- kurzlebige Cytoskelettfilamente, deren dynamischeres „Plus-Ende“
beständig zwischen Wachsen und Schrumpfen wechselt. Bestimmte Stimuli
jedoch können über Signaltransduktions-kaskaden dazu führen, dass die
schnell wachsenden Plus-Enden der Mikrotubuli mithilfe assoziierter Proteine
(+TIP-Proteine) längerfristig an die Innenseite der Zellmembran oder an das
Actinzytoskelett binden und dort verankert werden („Microtubule Capture“).
Dieser Vorgang stabilisiert die betreffenden Mikrotubuli und verlängert ihre
Halbwertszeit – die stabilisierten Microtubuli dienen der Zelle in weiterer
Folge als gerichtete Transportrouten.
In meiner Doktorarbeit konnte ich zeigen, dass die Acetylcholinrezeptorreiche
postsynaptische Zentralregion der Muskelfasern von einem dichten
Netzwerk von Microtubuli umgeben ist, einige dieser Microtubuli sind zudem
durch post-translationale Modifikationen weiter stabilisiert. Weiters konnte
ich demonstrieren, dass der Botenstoff Agrin im Muskel eine biochemische
Signaltransduktions-kaskade auslöst, welche die PI3-Kinase aktiviert und an
deren Ende GSK3β durch Phosphorylierung lokal inaktiviert wird.
Da viele der zuvor erwähnten +TIP-Proteine, zum Beispiel CLASP2, durch
GSK3β negativ reguliert sind, ist eine lokalisierte Inaktivierung von GSK3β
zentrale Voraussetzung dafür, dass +TIP-Proteine an Mikrotubuli Plus-Enden
binden können und somit zur Etablierung von stabilen Mikrotubuli-Filamenten
beitragen. Nach agrin-induzierter Inaktivierung von GSK3β bindet CLASP2 an
Mikrotubuli Plus-Enden und befestigt diese am Zellkortex in der AChR-reichen
Region von Myotuben in Wechselwirkung mit LL5β - welches von PI3K zur
synaptischen Membran rekrutiert wird. Die betreffenden Mikrotubuli werden
dadurch stabilisiert und können der Zelle als intrazelluläre Transportrouten
für postsynaptisches Material wie etwa AChRs und Strukturproteine dienen.
Funktionsverändernde Mutationen beteiligter Moleküle sowie
pharmakologische Eingriffe in den PI3K/GSK3β-Signalweg zeigten allesamt
Effekte auf die lokale Konzentrierung von AChRs, die mit oben angeführter
Kausalkette konsistent sind: Die Depolymerisierung von Microtubuli, die
Hemmung der PI3-Kinase, der Verlust des Clasp2-Gens, die shRNAvermittelte
Unterdrückung der LL5β-Expression sowie die Hyperaktivierung
von GSK3β führten jeweils zu reduzierter Grösse der AChR-Ansammlungen,
während die Hemmung von GSK3β die Grösse der AChR-Ansammlungen
erhöhte. Zusammengefasst trägt agrin-induzierte und +TIP-vermittelte
Befestigung von Mikrotubuli an der subsynaptischen Membran zur fokalen
Insertion und zum lokalen Konzentration von AChRs bei.
Abstract
Neurotransmission at the neuromuscular synapse of mammals occurs after
secretion of acetylcholine (ACh) from the motor nerve into the synaptic cleft
and ultimately results in contraction of the target muscle. The signaling
molecule agrin, which is also secreted by the motoneuron, is the main
organizer of postsynaptic differentiation and induces the clustering of
receptors for the neurotransmitter acetylcholine (AChR) in a small – mostly
central – area of the myofiber directly underneath the motoneuron terminal
bouton. After intense research, the end results of agrin-induced
differentiation are well documented and many involved molecules are known.
Nevertheless, the role of the subsynaptic microtubule (MT) cytoskeleton in
the process of AChR transport, insertion and clustering and the molecular
mechanisms of the establishment of such a microtubule network are poorly
defined. During my thesis, I analyzed new aspects of agrin-induced
biochemical signaling and the cell biological consequences for the
microtubule cytoskeleton.
Targeted intracellular transport of vesicles generally occurs along polar
cytoskeletal structures, a major part along microtubules – cytoskeletal
filaments that are normally short-lived with a highly dynamic “plus-end”,
which alternates between periods of growing and shrinking. However, certain
stimuli induce signal transduction cascades which result in the “capture” of
microtubule plus-ends at the cell cortex by interaction of plus-end binding
proteins (+TIPS) with factors that localize to the cortex or the actin
cytoskeleton. This event stabilizes microtubules and can drastically increase
their lifetime – affected microtubule then serve the cell as stable, directional
transport tracks.
During my thesis, I could show that the AChR-rich postsynaptic membrane
encompasses a dense subsynaptic MT network, with some MTs further
stabilized by post-translational modifications. In addition, I could
demonstrate that agrin induces PI3 kinase signaling in muscle, which
ultimately inactivates GSK3β by phosphorylation.
Since many of the former mentioned +TIP proteins are negatively regulated
by GSK3β, localized inactivation of GSK3β is crucial to enable +TIP-mediated
microtubule capture and establishment of stable transport tracks at sites with
elevated protein requirements such as the postsynaptic membrane. +TIP
proteins, in particular Clasp2, then capture MTs at the cell cortex within
AChR-rich sites by interacting with the membrane PIP3-sensor LL5β and thus
establish intracellular transport routes for focal transport of postsynaptic
material like AChRs and structural proteins towards the synapse.
Mutants of involved molecules as well as pharmacologic manipulation of the
PI3K/GSK3β-axis displayed effects on the clustering of AChRs, which are fully
consistent with the aforementioned chain of events: Microtubule
depolymerization, inhibition of PI3K, loss of the clasp2 gene, shRNAmediated
repression of LL5β expression and hyper-activation of GSK3β lead
to reduced AChR clustering, while inhibition of GSK3β elevates AChR
clustering. Taken together, agrin-induced and +TIP-mediated MT capture at
the subsynaptic muscle membrane contributes to focal insertion and
clustering of AChRs at the neuromuscular junction
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