The spindle assembly checkpoint as a drug target - Novel small-molecule inhibitors of Aurora kinases

Cell division (mitosis) is a fundamental process in the life cycle of a cell. Equal distribution of chromosomes between the daughter cells is essential for the viability and well-being of an organism: loss of fidelity of cell division is a contributing factor in human cancer and also gives rise to miscarriages and genetic birth defects. For maintaining the proper chromosome number, a cell must carefully monitor cell division in order to detect and correct mistakes before they are translated into chromosomal imbalance. For this purpose an evolutionarily conserved mechanism termed the spindle assembly checkpoint (SAC) has evolved. The SAC comprises a complex network of proteins that relay and amplify mitosis-regulating signals created by assemblages called kinetochores (KTs). Importantly, minor defects in SAC signaling can cause loss or gain of individual chromosomes (aneuploidy) which promotes tumorigenesis while complete failure of SAC results in cell death. The latter event has raised interest in discovery of low molecular weight (LMW) compounds targeting the SAC that could be developed into new anti-cancer therapeutics. In this study, we performed a cell-based, phenotypic high-throughput screen (HTS) to identify novel LMW compounds that inhibit SAC function and result in loss of cancer cell viability. Altogether, we screened 65 000 compounds and identified eight that forced the cells prematurely out of mitosis. The flavonoids fisetin and eupatorin, as well as the synthetic compounds termed SACi2 and SACi4, were characterized in more detail utilizing versatile cell-based and biochemical assays. To identify the molecular targets of these SAC-suppressing compounds, we investigated the conditions in which SAC activity became abrogated. Eupatorin, SACi2 and SACi4 preferentially abolished the tensionsensitive arm of the SAC, whereas fisetin lowered also the SAC activity evoked by lack of attachments between microtubules (MTs) and KTs. Consistent with the abrogation of SAC in response to low tension, our data indicate that all four compounds inhibited the activity of Aurora B kinase. This essential mitotic protein is required for correction of erratic MT-KT attachments, normal SAC signaling and execution of cytokinesis. Furthermore, eupatorin, SACi2 and SACi4 also inhibited Aurora A kinase that controls the centrosome maturation and separation and formation of the mitotic spindle apparatus. In line with the established profound mitotic roles of Aurora kinases, these small compounds perturbed SAC function, caused spindle abnormalities, such as multi- and monopolarity and fragmentation of centrosomes, and resulted in polyploidy due to defects in cytokinesis. Moreover, the compounds dramatically reduced viability of cancer cells. Taken together, using a cell-based HTS we were able to identify new LMW compounds targeting the SAC. We demonstrated for the first time a novel function for flavonoids as cellular inhibitors of Aurora kinases. Collectively, our data support the concept that loss of mitotic fidelity due to a non-functional SAC can reduce the viability of cancer cells, a phenomenon that may possess therapeutic value and fuel development of new anti-cancer drugs.

Arpajaislain uudistamisprosessi ja uudistusten vaikutukset rahapelien markkinointiin

Tutkielma kuvaa Suomen arpajaislain muutosprosessia ja sen taustalla olevia tekijöitä sekä muutoksen vaikutuksia rahapelien markkinointiin. Tutkielmassa tarkastellaan erityisesti vuoden 2010 arpajaislain uudistusta ja vaikutuksia. Rahapelejä on kohdeltu Europpan Yhteisöjen lainsäädännössä eri tavalla verrattuna muuhun liiketoimintaan eikä siihen ole sovellettu palveluiden vapaan liikkuvuuden periaatetta samassa mittakaavassa kuin muuhun kaupalliseen toimintaan. Rahapelipalveluiden tarjoaminen internetissä on asettanut valtioiden vanhat rahapelimonopolit uusien haasteiden eteen myös lainsäädännöllisesti. Suomessa valtio on lainmuutoksilla pyrkinyt turvaamaan vallitsevan tilanteen, jossa rahapelipalveluiden tarjoamisesta suomalaisille vastaavat tietyt yhtiöt ja yhdistykset yksinoikeudella. Tutkielma pyrkii kuvaamaan tätä prosessia käyden läpi sen syitä ja seurauksia. Erityishuomion kohteeksi on otettu lakimuutosten vaikutukset ulkomaisten rahapeliyhtiöiden mainontaan suomalaisessa mediassa. Lähteinä on käytetty pääasiassa viranomaislähteitä, mutta tutkielmassa on pyritty tuomaan esille myös rahapelialan toimijoiden näkökulmia.

Innovation Project Portfolio Management

Companies today are forced to innovate in order to remain within business. Such innovation projects undertaken by the companies are defined in this study as creative ideas which have been managed through “Stage-Gate” innovation process. This process is used to manage innovation projects as they proceed from being newly created to ready for launching/implementing. This has ensured that the companies manage the innovation project right. However, with so many new creative ideas the companies can come up within limited resources, the companies must rely on Innovation Project Portfolio Management (IPPM) to ensure that they are managing only the right innovation projects. Although, there are many tools and techniques available for use within Project Portfolio Management, there is still no consensus on which are the most effective and no standard framework has been established especially for IPPM. Thus, this study proposes a practical framework for which individual innovative organization can follow as a guideline to manage its innovation project portfolio. The study theoretically first addresses the key differences between project portfolio management of innovation projects and other traditional projects - one of which is the stage nature of innovation projects due to their unclear objectives from the beginning compare to clearly established objectives of traditional projects. Secondly, different tools and techniques which can be used are examined based on the three goals of IPPM: (1) Maximizing the Value of Innovation Project Portfolio: Financial Methods, Decision Trees, Scoring Models and Checklists; (2) Balancing Innovation Project Portfolio: Visual Representations; and (3) Aligning Innovation Project Portfolio with Strategy: Bottom-Up (Scoring Models with Strategic Criteria) and Top-Down (Strategic Buckets). Finally, the two approaches in which IPPM can be integrated with Stage-Gate innovation process are discussed: (1) Gates- Dominated; and (2) Portfolio Reviews-Dominated. Practically, this study investigates IPPM of a case organization, and through analysis of the case study results proposes a practical framework for case organization to improve its current management of innovation project portfolio. This framework is then generalized to propose a final practical framework or guideline for which an innovative organization can follow to manage its innovation project portfolio.

Suomalaisen musiikkiteollisuuden murros

Tämä tutkimus on kvalitatiivinen monitapaustutkimus, jossa tutkitaan suomalaisen musiikkiteollisuuden arvoketjun sisältöä ja sen muutoksia vuosituhannen vaihteen jälkeisenä aikana. Tutkimuksen tavoitteena on selvittää millainen on suomalaisen musiikkiteollisuuden arvoketjun sisältö nykyisin ja miten se on muuttunut musiikkiteollisuuden nykyisen murroksen myötä. Nykyinen murrostilanne johtuu pääosin fyysisten äänitteiden myyntimäärien laskusta ja teknologian kehityksestä. Äänitteiden myynnistä saatavien tulovirtojen pienennyttyä monet teollisuudenalan toimijat ovat joutuneet tehostamaan toimintaansa, ja niiden roolit ovat jatkuvan muutoksen alla. Teknologian kehityksen myötä teollisuudenalalle on tullut myös uusia toimijoita, jotka ovat mahdollistaneet uusia toimintatapoja ja ansaintalogiikoita.

The seasonal and ovarian status effects on in vitro production of domestic cat embryos between Equator and Tropic of Capricorn

From the Tropic of Capricorn to Equator, the seasonality of domestic cat is known to be absent, i.e., these animals are considered non-seasonal breeders at these regions. We hypothesized that this particularity might have some influence on in vitro embryo production. The aim of this experiment was to determine the percentage of cleavage and morulae and blastocyst formation produced from oocytes recovered from queen ovaries of three distinct status - follicular, luteal or inactive - during two different reproductive seasons experienced by cats in southeast of Brazil (22°53'09" S and 48°26'42" W) - non breeding season (NBS), comprehending January to March; and breeding season (BS), August to October. Thirty queens were neutered. Ovaries were classified according to their status and were sliced in PBS for cumulus oocyte complex (COC) releasing. Grade I COC were washed three times in H-MEM supplemented with BSA, glutamine, sodium pyruvate, cysteine, streptomycin and penicillin. Oocytes were incubated in groups of 20-30 in 400µL of DMEM supplemented with FSH, LH, estradiol, IGF-I and basic fibroblast growth factor under mineral oil for 30 or 36 hours at 38°C in humidified environment of 5% de O2, 5% CO2 and 90% N2. COC were fertilized in Ham's F-10 medium supplemented with BSA, cysteine, pyruvate and streptomycin/penicillin (culture medium) with fresh semen selected through swim up technique. Eighteen hours later, the presumptive zygotes were denuded, the percentage of cleavage was determined and every 10 zygotes were transferred to 100mL drops of culture medium for culture during three days. After 72 hours of culture the percentage of morulae formation was evaluated and these structures were transferred to drops of the same culture medium. At the eighth day of culture blastocyst formation was analyzed. During NBS, from a total of 272 (inactive), 162 (luteal) and 134 (follicular) fertilized oocytes, the percentage of cleaved zygotes, morulae and blastocysts derived from inactive ovaries were 24.63, 16.54 and 8.09 respectively; for those derived from luteal ovaries, the percentage was 21.6, 12.96 and 8.64, and for those from follicular ovaries, they were 24.62, 16.41 and 8.21. Considering BS, from a total of 102 (inactive), 198 (luteal) and 86 (follicular) fertilized oocytes, the relative frequency (%) of cleaved zygotes, morulae and blastocysts derived from inactive ovaries were 64.7, 41.17 and 23.53 respectively; for those derived from luteal ovaries, the percentage was 64.14, 40.41 and 23.73, and for those from follicular ovaries, they were 63.95, 39.54 and 24.41. The results of this experiment demonstrate that no statistically significant difference (P<0.05) was verified in the frequency of cleaved embryos and morulae and blastocyst formation when comparing the three ovarian conditions in the same season. However the breeding season presented better results considering cleavage and morulae and blastocyst formation.

Drivers and barriers of mobile travel and tourism service adoption : a study of individual perceptions and business model development in a travel and tourism context

The Travel and Tourism field is undergoing changes due to the rapid development of information technology and digital services. Online travel has profoundly changed the way travel and tourism organizations interact with their customers. Mobile technology such as mobile services for pocket devices (e.g. mobile phones) has the potential to take this development even further. Nevertheless, many issues have been highlighted since the early days of mobile services development (e.g. the lack of relevance, ease of use of many services). However, the wide adoption of smartphones and the mobile Internet in many countries as well as the formation of so-called ecosystems between vendors of mobile technology indicate that many of these issues have been overcome. Also when looking at the numbers of downloaded applications related to travel in application stores like Google Play, it seems obvious that mobile travel and tourism services are adopted and used by many individuals. However, as business is expected to start booming in the mobile era, many issues have a tendency to be overlooked. Travelers are generally on the go and thus services that work effectively in mobile settings (e.g. during a trip) are essential. Hence, the individuals’ perceived drivers and barriers to use mobile travel and tourism services in on-site or during trip settings seem particularly valuable to understand; thus this is one primary aim of the thesis. We are, however, also interested in understanding different types of mobile travel service users. Individuals may indeed be very different in their propensity to adopt and use technology based innovations (services). Research is also switching more from investigating issues of mobile service development to understanding individuals’ usage patterns of mobile services. But designing new mobile services may be a complex matter from a service provider perspective. Hence, our secondary aim is to provide insights into drivers and barriers of mobile travel and tourism service development from a holistic business model perspective. To accomplish the research objectives seven different studies have been conducted over a time period from 2002 – 2013. The studies are founded on and contribute to theories within diffusion of innovations, technology acceptance, value creation, user experience and business model development. Several different research methods are utilized: surveys, field and laboratory experiments and action research. The findings suggest that a successful mobile travel and tourism service is a service which supports one or several mobile motives (needs) of individuals such as spontaneous needs, time-critical arrangements, efficiency ambitions, mobility related needs (location features) and entertainment needs. The service could be customized to support travelers’ style of traveling (e.g. organized travel or independent travel) and should be easy to use, especially easy to take into use (access, install and learn) during a trip, without causing security concerns and/or financial risks for the user. In fact, the findings suggest that the most prominent barrier to the use of mobile travel and tourism services during a trip is an individual’s perceived financial cost (entry costs and usage costs). It should, however, be noted that regulations are put in place in the EU regarding data roaming prices between European countries and national telecom operators are starting to see ‘international data subscriptions’ as a sales advantage (e.g. Finnish Sonera provides a data subscription in the Baltic and Nordic region at the same price as in Finland), which will enhance the adoption of mobile travel and tourism services also in international contexts. In order to speed up the adoption rate travel service providers could consider e.g. more local initiatives of free Wi-Fi networks, development of services that can be used, at least to some extent, in an offline mode (do not require costly network access during a trip) and cooperation with telecom operators (e.g. lower usage costs for travelers who use specific mobile services or travel with specific vendors). Furthermore, based on a developed framework for user experience of mobile trip arrangements, the results show that a well-designed mobile site and/or native application, which preferably supports integration with other mobile services, is a must for true mobile presence. In fact, travel service providers who want to build a relationship with their customers need to consider a downloadable native application, but in order to be found through the mobile channel and make contact with potential new customers, a mobile website should be available. Moreover, we have made a first attempt with cluster analysis to identify user categories of mobile services in a travel and tourism context. The following four categories were identified: info-seekers, checkers, bookers and all-rounders. For example “all-rounders”, represented primarily by individuals who use their pocket device for almost any of the investigated mobile travel services, constituted primarily of 23 to 50 year old males with high travel frequency and great online experience. The results also indicate that travel service providers will increasingly become multi-channel providers. To manage multiple online channels, closely integrated and hybrid online platforms for different devices, supporting all steps in a traveler process should be considered. It could be useful for travel service providers to focus more on developing browser-based mobile services (HTML5-solutions) than native applications that work only with specific operating systems and for specific devices. Based on an action research study and utilizing a holistic business model framework called STOF we found that HTML5 as an emerging platform, at least for now, has some limitations regarding the development of the user experience and monetizing the application. In fact, a native application store (e.g. Google Play) may be a key mediator in the adoption of mobile travel and tourism services both from a traveler and a service provider perspective. Moreover, it must be remembered that many device and mobile operating system developers want service providers to specifically create services for their platforms and see native applications as a strategic advantage to sell more devices of a certain kind. The mobile telecom industry has moved into a battle of ecosystems where device makers, developers of operating systems and service developers are to some extent forced to choose their development platforms.

Celioscopic liver biopsy in silver catfish (Rhamdia quelen)

Endosurgery has been used for assessment of fish celomatic cavity, as well as for obtaining biopsies for organic analysis. Such minimally invasive access may also be used for the analysis of environmental impact on biomarkers of pollution. In Brazil, studies and literature regarding the use of celioscopy in fish are sparse. The purpose of the current study was to develop a two-port celioscopy technique to obtain liver biopsy in silver catfish (Rhamdia quelen). Six adult female silver catfish were used. The animals were anesthetized and the inspection of the celomatic cavity were performed using a telescope and celioscopic-guided liver biopsy were taken using laparoscopic Kelly forceps. On the early postoperative period, the animals were released in a confined water reservoir where mortality could be checked. The liver samples were sent for histological assessment. There were no complications during surgery on early postoperative period. It was possible to visualize meticulously several organs (liver, spleen, stomach, pancreas, swim bladder, ovaries, bowel and transverse septum). In conclusion, the surgical technique and the anesthetic protocol proposed were suitable to perform liver biopsies in silver catfish and provided low morbidity.

Comparison between one-dimensional uncoupled and convection-conduction conjugated approaches in finned surface heat transfer

This work studies the forced convection problem in internal flow between concentric annular ducts, with radial fins at the internal tube surface. The finned surface heat transfer is analyzed by two different approaches. In the first one, it is assumed one-dimensional heat conduction along the internal tube wall and fins, with the convection heat transfer coefficient being a known parameter, determined by an uncoupled solution. In the other way, named conjugated approach, the mathematical model (continuity, momentum, energy and K-epsilon equations) applied to tube annuli problem was numerically solved using finite element technique in a coupled formulation. At first time, a comparison was made between results obtained for the conjugated problem and experimental data, showing good agreement. Then, the temperature profiles under these two approaches were compared to each other to analyze the validity of the one-dimensional classical formulation that has been utilized in the heat exchanger design.

Control of a one-legged robot with energy savings

This paper presents a new strategy to control an one-legged robot aiming to reduce the energy expended by the system. To validate this algorithm, a classic method as benchmark was used. This method has been extensively validated by simulations and experimental prototypes in the literature. For simplicity reasons, the work is restricted to the two dimensional case due to simplicity reasons. This new method is compared to the classic one with respect to performance and energy expended by the system. The model consists on a springy leg, a simple body, and an actuated hinge-type hip. The new control strategy is composed of three parts, considering the hopping height, the forward speed, and the body orientation separately. The method exploits the system passive dynamics, defined as non-forced response of the system. In this case, the model is modified adding a spring to the hip. The method defines a desired leg trajectory close to the passive hip swing movement. Simulation results for both methods are analyzed and compared.

Inverse convection problem of simultaneous estimation of two boundary heat fluxes in parallel plate channels

This paper deals with the use of the conjugate gradient method of function estimation for the simultaneous identification of two unknown boundary heat fluxes in parallel plate channels. The fluid flow is assumed to be laminar and hydrodynamically developed. Temperature measurements taken inside the channel are used in the inverse analysis. The accuracy of the present solution approach is examined by using simulated measurements containing random errors, for strict cases involving functional forms with discontinuities and sharp-corners for the unknown functions. Three different types of inverse problems are addressed in the paper, involving the estimation of: (i) Spatially dependent heat fluxes; (ii) Time-dependent heat fluxes; and (iii) Time and spatially dependent heat fluxes.

Chaos and Unpredictability in the Vibration of an Elasto-Plastic Beam

This contribution discusses the nonlinear dynamics of a pin-ended elasto-plastic beam with both kinematic and isotropic hardening. An iterative numerical procedure based on the operator split technique is developed in order to deal with the nonlinearities in the equations of motion. Free and forced responses for harmonic sinusoidal and square wave excitations are investigated. Numerical simulations present many interesting behaviors such as jump phenomena, sensitivity to initial conditions, chaos and transient chaos. These results indicate that there are practical problems in predicting the response of the beam even when periodic steady state response is expected.

On non-ideal and non-linear portal frame dynamics analysis using bogoliubov averaging method

We apply the Bogoliubov Averaging Method to the study of the vibrations of an elastic foundation, forced by a Non-ideal energy source. The considered model consists of a portal plane frame with quadratic nonlinearities, with internal resonance 1:2, supporting a direct current motor with limited power. The non-ideal excitation is in primary resonance in the order of one-half with the second mode frequency. The results of the averaging method, plotted in time evolution curve and phase diagrams are compared to those obtained by numerically integrating of the original differential equations. The presence of the saturation phenomenon is verified by analytical procedures.

The role of potassium in the corrosion of superheater materials in boilers firing biomass

Inhibition of global warming has become one of the major goals for the coming decades. A key strategy is to replace fossil fuels with more sustainable fuels, which has generated growing interest in the use of waste-derived fuels and of biomass fuels. However, from the chemical point of view, biomass is an inhomogeneous fuel, usually with a high concentration of water and considerable amounts of potassium and chlorine, all of which are known to affect the durability of superheater tubes. To slow down or reduce corrosion, power plants using biomass as fuel have been forced to operate at lower steam temperatures as compared to fossil fuel power plants. This reduces power production efficiency: every 10°C rise in the steam temperature results in an approximate increase of 2% in power production efficiency. More efficient ways to prevent corrosion are needed so that power plants using biomass and waste-derived fuels can operate at higher steam temperatures. The aim of this work was to shed more light on the alkali-induced corrosion of superheater steels at elevated temperatures, focusing on potassium chloride, the alkali salt most frequently encountered in biomass combustion, and on potassium carbonate, another potassium salt occasionally found in fly ash. The mechanisms of the reactions between various corrosive compounds and steels were investigated. Based on the results, the potassium-induced accelerated oxidation of chromia protected steels appears to occur in two consecutive stages. In the first, the protective chromium oxide layer is destroyed through a reaction with potassium leading to the formation of intermediates such as potassium chromate (K2CrO4) and depleting the chromium in the protective oxide layer. As the chromium is depleted, chromium from the bulk steel diffuses into the oxide layer to replenish it. In this stage, the ability of the material to withstand corrosion depends on the chromium content (which affects how long it takes the chromium in the oxide layer to be depleted) and on external factors such as temperature (which affects how fast the chromium diffuses into the protective oxide from the bulk steel). For accelerated oxidation to continue, the presence of chloride appears to be essential.

Taloushallinnon tehostaminen – tapaustutkimus ostolaskuprosessin tehostamisesta

Kasvava kilpailu ja alati globalisoituvat markkinat ovat pakottaneet yrityksiä hakemaan tehokkuutta myös taloushallinnon kaltaisista prosesseista, joiden tehokkuuteen ei aikaisemmin kiinnitetty juurikaan huomiota. Tutkielman ensimmäisenä keskeisenä tavoitteena on lisätä tietoa taloushallinnon tehostamisesta peilaamalla sitä tutkielman teoreettisen viitekehyksen kolmen keskeisen elementin – liiketoimintaprosessien tehostamisen, sähköisen taloushallinnon innovaatioiden ja taloushallinnon rajat ylittävän ulkoistamisen – kautta. Tutkimuksen toisena keskeisenä tavoitteena on syventää tätä teoreettista tietoa ja analysoida taloushallinnon tehostamiseksi kehitettyjen menetelmien toimivuutta Suomessa toimivan yrityksen ostolaskuprosessin osalta. Tutkielmassa pystyttiin selkeästi tuomaan esiin taloushallinnon tehostumiseen vaikuttaneita tekijöitä ja osoittamaan näiden ostolaskuprosessia tehostava vaikutus. Analysoitaessa eri menetelmien keskinäistä tehokkuutta voidaan suomalaisen yrityksen näkökulmasta perustellusti olettaa, että rajat ylittävät ulkoistamiset ovat vain välivaihe matkalla mahdollisimman pitkälle automatisoituun prosessiin – kun laskut vastaanotetaan sähköisinä verkkolaskuina ja täsmäytetään automaattisesti sähköisiin ostotilauksiin, voidaankin kysyä mitä ostolaskuprosessista voitaisiin ylipäänsä ulkoistaa.

Violations of children's rights in armed conflicts : international treaties, observations by peacekeepers and crisis management training in Finland

Ninety-nine Finnish peacekeepers, who had been serving in 15 different operations around the world, participated in the study (8 women, 27-52 years old, m = 37.4, SD = 8.9; and 91 men, 21-69 years old, m = 41.4, SD = 10.2). Three military crisis management trainers from the Finnish Defence Forces International Centre also participated in the study. The data was collected with two webbased questionnaires. In addition two interviews were made with specialists of civilian crisis management in Finland. The study also provides an overview of international treaties concerning children’s rights in armed conflict. The results show that 48.7 % of dangers for children in conflicts reported by the peacekeepers were related to physical injury (e.g. landmines and traffic), and 27.4 % were related to social problems (e.g. poverty, child soldiers, and trafficking). 24.1 % of the peacekeepers had made observations of children’s rights violations either often or very often during peacekeeping operations. 49.6 % of the observations were related to social problems (e.g. child labour or being forced to beg), and 33.0 % were related to physical injury (e.g. assault). Frequency of observation of children’s rights violations was not associated with either sex or military degree of the peacekeepers; instead it was significantly correlated with the peacekeepers’ degree of knowledge of EU’s child protection guidelines. On the basis of the results, it is recommended that knowledge about children’s rights and protection should be included in the training of Finnish crisis management personnel to a much higher degree than at the present.