Networking Notch : regulation of Notch traffic and signaling crosstalk

Utvecklingen av flercelliga organismer är en mångfacetterad process som kräver kommunikation celler emellan. Under utvecklingen av en organism måste cellerna göra vissa val, vilket bestämmer riktningen för deras fortsatta utveckling. Utgående från dessa val erhåller cellerna egenskaper som är karaktäristiska för olika celltyper. Notch-signalräckan är en viktig reglerare av valet mellan olika cellöden. Notch-signalräckan aktiveras när Notch-receptorer som uttrycks på ytan av en cell binder till Notch-ligander som uttrycks på ytan av en annan närliggande cell. Denna avhandling belyser mekanismerna som reglerar omsättningen av såväl Notch-receptorer som -ligander till och från cellmembranen, samt ökar förståelsen för hur dessa mekanismer påverkar Notch-medierade cellöden i stamceller. Internalisering av Notch receptorer anses nödvändigt för fullständig aktivering av Notch-signalvägen. De bakomliggande molekylära mekanismerna är dock fortfarande oklara. Vi har upptäckt att atypiskt protein kinas Cζ (aPKCζ) reglerar internaliseringen av Notch-receptorer. aPKCζ fosforylerar Notch, vilket leder till receptorns internalisering, men effekten är beroende av receptorns signaleringsstatus. Vi visar att aPKCζ reglerar Notch-signaleringen och styr både neuroners och muskelcellers differentiering. Ytterligare har vi analyserat samspelet mellan cellskelettet och Notch-signalvägen. Våra resultat visar att intermediärfilamenten, en del av cellskelettet, är viktiga reglerare av Notch-signaleringen både under neuronal och vaskulär utveckling. Intermediärfilamenten vimentin och GFAP reglerar uttrycket av Notch-ligander vid cellmembranen i hjärnans stödceller, astrocyterna, och påverkar därmed neuronala stamcellers cellödesbeslut. Vimentin är även viktigt reglerare av Notch-signalräckan vid angiogenesen. Celler som saknar vimentin uppvisar avvikande Notch-signalering emedan möss som saknar vimentin påvisar en fördröjd utveckling av vaskulaturen under embryonalstadiet. ------------------------------------------------- Monisoluisten organismien kehittyminen on monimutkainen prosessi, joka vaatii viestintää solujen välillä. Kehittymisen aikana solut joutuvat tiettyjen valintojen eteen, mitkä tulevat määrittämään niiden erilaistumisen suunnan. Solut omaksuvat solutyypille ominaisia ominaisuuksia näihin valintoihin perustuen Notch-signalointireitti säätelee solujen erilaistumista eri suuntiin. Notch-signalointireitti aktivoituu, kun Notch-reseptori yhden solun pinnalla sitoo Notch-ligandin toisen, viereisen solun solukalvolla. Tutkimukseni lisää tuntemusta Notch-reseptoreiden ja ligandien solun sisäisestä liikennöinnistä ja sitä säätelevistä mekanismeista, sekä tämän säätelyn vaikutuksista kantasulojen erilaistumiseen. Notch-signalointireitin aktivoituminen vaatii reseptoreiden ja ligandien sisäistämisen solukalvolta, mutta taustalla olevat ja sisäistymistä säätelevät mekanismit ovat vielä epäselviä. Tutkimukseni osoittaa, että atyyppinen proteiinikinaasi Cζ (aPKCζ) säätelee Notch-reseptoreiden endosytoosia. Endosytoosin lopputulos riippuu siitä onko reseptori aktivoitunut ligandin välityksellä vai ei. Tuloksemme osoittavat aPKCζ säätelevän Notch-signalointia ja kontrolloivan sekä hermosolujen, että lihassolujen erilaistumista. Analysoimme myös Notch-signaloinnin ja solun tukirangan vuorovaikutuksia. Välikokoiset filamentit, jotka ovat osa tukirankaa, säätelevät Notch-signalointia neuronaalisen erilaistumisen sekä verisuonten uudismuodostumisen aikana. Vimentiini ja GFAP ovat välikokoisia säikeitä, jotka säätelevät Notch-ligandien ekspressiota astrosyyttien, eli aivojen hermotukisolujen solukalvolla. Vimentiini säätelee myös Notch-signalointireittiä angiogeneesin aikana. Vimentiiniä vailla olevilla soluilla ilmenee heikentynyttä Notch-signalointia, joka voidaan liittää hiirillä ilmenevään vimenttiinin puutteesta johtuvaan viivästyneeseen verisuonien kehitykseen.

Coolability of porous core debris beds : Effects of bed geometry and multi-dimensional flooding

This thesis addresses the coolability of porous debris beds in the context of severe accident management of nuclear power reactors. In a hypothetical severe accident at a Nordic-type boiling water reactor, the lower drywell of the containment is flooded, for the purpose of cooling the core melt discharged from the reactor pressure vessel in a water pool. The melt is fragmented and solidified in the pool, ultimately forming a porous debris bed that generates decay heat. The properties of the bed determine the limiting value for the heat flux that can be removed from the debris to the surrounding water without the risk of re-melting. The coolability of porous debris beds has been investigated experimentally by measuring the dryout power in electrically heated test beds that have different geometries. The geometries represent the debris bed shapes that may form in an accident scenario. The focus is especially on heap-like, realistic geometries which facilitate the multi-dimensional infiltration (flooding) of coolant into the bed. Spherical and irregular particles have been used to simulate the debris. The experiments have been modeled using 2D and 3D simulation codes applicable to fluid flow and heat transfer in porous media. Based on the experimental and simulation results, an interpretation of the dryout behavior in complex debris bed geometries is presented, and the validity of the codes and models for dryout predictions is evaluated. According to the experimental and simulation results, the coolability of the debris bed depends on both the flooding mode and the height of the bed. In the experiments, it was found that multi-dimensional flooding increases the dryout heat flux and coolability in a heap-shaped debris bed by 47–58% compared to the dryout heat flux of a classical, top-flooded bed of the same height. However, heap-like beds are higher than flat, top-flooded beds, which results in the formation of larger steam flux at the top of the bed. This counteracts the effect of the multi-dimensional flooding. Based on the measured dryout heat fluxes, the maximum height of a heap-like bed can only be about 1.5 times the height of a top-flooded, cylindrical bed in order to preserve the direct benefit from the multi-dimensional flooding. In addition, studies were conducted to evaluate the hydrodynamically representative effective particle diameter, which is applied in simulation models to describe debris beds that consist of irregular particles with considerable size variation. The results suggest that the effective diameter is small, closest to the mean diameter based on the number or length of particles.

Utilization of multi-branding in business to business markets

Case company utilizes multi-branding strategy (or house of brands strategy) in its product portfolio. In practice the company has multiple brands – one main brand and four acquired brands – which all utilize one single product platform. The objective of this research is to analyze case company’s multi-branding strategy and its benefits and challenges. Moreover, the purpose is to clarify that how could a company in B2B markets utilize multi-branding strategy more efficiently and profitably. The theoretical part of this thesis consists of aspects of branding strategies; different brand name architectures, benefits and challenges of different strategies and different ways of utilize branding strategies in mergers and acquisitions. The empirical part, on the other hand, includes the description of the case company’s branding strategy and the employees’ perspective on the benefits and challenges of multi-branding strategy, and how to utilize it more efficiently and profitably. This study shows, that the major benefits of utilizing multi-branding are lower production costs, ability to reach wider market coverage, possibility to utilize common sales tools, synergies in R&D and shared resources. On the other hand, the major challenges are lack of product differentiation, internal competition, branding issues in production and deliveries, pricing issues and conflicts, and compromises in product compatibility and suitability. Based on the results, several ways to utilize multi-branding strategy more efficiently and profitably were found; by putting more effort on brand image and product differentiation, by having more co-operation among the brands and by focusing on more precise customer and market segmentation.

Control of multi-actuator system by an electrically driven hydraulic pump-motor

The awareness and concern of our environment together with legislation have set more and more tightening demands for energy efficiency of non-road mobile machinery (NRMM). Integrated electro-hydraulic energy converter (IEHEC) has been developed in Lappeenranta University of Technology (LUT). The elimination of resistance flow, and the recuperation of energy makes it very efficient alternative. The difficulties of IEHEC machine to step to the market has been the requirement of one IEHEC machine per one actuator. The idea is to switch IEHEC between two actuators of log crane using fast on/off valves. The control system architecture is introduced. The system has been simulated in co-simulation using two different software. The simulated responses of pump-controlled system is compared to the responses of the conventional valve-controlled system.

Deviations of Governance In IT Multi-Sourcing: A Case Study

IT outsourcing (ITO) refers to the shift of IT/IS activities from internal to external of an organization. In prior research, the governance of ITO is recognized with persistent strategic importance for practice, because it is tightly related to ITO success. Under the rapid transformation of global market, the evolving practice of ITO requires updated knowledge on effective governance. However, research on ITO governance is still under developed due to the lack of integrated theoretical frameworks and the variety of empirical settings besides dyadic client-vendor relationships. Especially, as multi-sourcing has become an increasingly common practice in ITO, its new governance challenges must be attended by both ITO researchers and practitioners. To address this research gap, this study aims to understand multi-sourcing governance with an integrated theoretical framework incorporating both governance structure and governance mechanisms. The focus is on the emerging deviations among formal, perceived and practiced governance. With an interpretive perspective, a single case study is conducted with mixed methods of Social Network Analysis (SNA) and qualitative inquiries. The empirical setting embraces one client firm and its two IT suppliers for IT infrastructure services. The empirical material is analyzed at three levels: within one supplier firm, between the client and one supplier, and among all three firms. Empirical evidences, at all levels, illustrate various deviations in governance mechanisms, with which emerging governance structures are shaped. This dissertation contributes to the understanding of ITO governance in three domains: the governance of ITO in general, the governance of multi-sourcing in particular, and research methodology. For ITO governance in general, this study has identified two research strands of governance structure and governance mechanisms, and integrated both concepts under a unified framework. The composition of four research papers contributes to multi-sourcing research by illustrating the benefits of zooming in and out across the multilateral relationships with different aspects and scopes. Methodologically, the viability and benefit of mixed-method is illustrated and confirmed for both researchers and practitioners.

26-8-20, circuit de la Sarthe, Duverne sur Rudge Multi : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 60729

Cartilla Networking

Desarrollo empresarial y creación de empresa

Six-month outcomes of a multi-campus smoking cessation contest

Background: Up to 40% of North American post-secondary students smoke at least occasionally, and most want to quit. Given students' preferences for free, easy-to-access, self-directed, convenient cessation methods, a motivational, incentive-based cessation contest may be an effective way to assist students to quit. The current study describes 3- and 6-month outcomes experienced by post-secondary student smokers who entered the 'Let's Make A Deal!' contest. Methodology: Contestants from five university campuses who chose to quit completely ('Quit For Good') or reduce their tobacco consumption by 50% ('Keep The Count') were invited to participate in a study of the contest. Three and six months after registration, participants were contacted by phone to assess their smoking and quitting behaviours. Qualitative and quantitative measures were collected, including weekly tobacco consumption, efficacy to resist temptations to smoke, use of quitting aids, and strategies to cope with withdrawal. Quitting was assessed using 7-day point prevalence and continuous abstinence. Results: Seventy-four (64.9%) of the 114 participants recruited for the study completed the follow-ups. Over 31 % of participants who entered Quit For Good and 23.5% of participants who entered Keep The Count were identified as quitters at the 6-month follow-up. Among the quitters, 45.5% experienced sustained abstinence from smoking for the 6-month duration of the study. Keep The Count contestants reduced their tobacco consumption by 57.2% at 3-month follow-up and sustained some of this reduction through to the 6-month follow-up. Qualitative data provides insights into how quitters coped with withdrawal and what hampered continuing smokers' efforts to quit. Significance: A motivational, incentive-based contest for post-secondary students can facilitate both smoking cessation and harm reduction. The contest environment, incentives, resources, and "buddies" provide positive structural and social supports to help smokers overcome potential barriers to quitting, successfully stop smoking, and manage potential triggers to relapse. The contest cessation rates are higher than the typical 5-7% associated with unassisted quitting.

On the anharmonic, multi-phonon, Debye-Waller contributions to the phonon-limited resistivity of metals : applications to Na and K

The anharmonic, multi-phonon (MP), and Oebye-Waller factor (OW) contributions to the phonon limited resistivity (;0) of metals derived by Shukla and Muller (1979) by the doubletime temperature dependent Green function method have been numerically evaluated for Na and K in the high temperature limit. The anharmonic contributions arise from the cubic and quartic shift of phonons (CS, QS), and phonon width (W) and the interference term (1). The QS, MP and OW contributions to I' are also derived by the matrix element method and the results are in agreement with those of Shukla and Muller (1979). In the high temperature limit, the contributions to;O from each of the above mentioned terms are of the type BT2 For numerical calculations suitable expressions are derived for the anharmonic contributions to ~ in terms of the third and fourth rank tensors obtained by the Ewald procedure. The numerical calculation of the contributions to;O from the OW, MP term and the QS have been done exactly and from the CS, Wand I terms only approximately in the partial and total Einstein approximations (PEA, TEA), using a first principle approach (Shukla and Taylor (1976)). The results obtained indicate that there is a strong pairwise cancellation between the: OW and MP terms, the QS and CS and the Wand I terms. The sum total of these contributions to;O for Na and K amounts to 4 to 11% and 2 to 7%, respectively, in the PEA while in the TEA they amount to 3 to 7% and 1 to 4%, respectively, in the temperature range.