Nitric oxide synthesis and biological functions of nitric oxide released from ruthenium compounds

During three decades, an enormous number of studies have demonstrated the critical role of nitric oxide (NO) as a second messenger engaged in the activation of many systems including vascular smooth muscle relaxation. The underlying cellular mechanisms involved in vasodilatation are essentially due to soluble guanylyl-cyclase (sGC) modulation in the cytoplasm of vascular smooth cells. sGC activation culminates in cyclic GMP (cGMP) production, which in turn leads to protein kinase G (PKG) activation. NO binds to the sGC heme moiety, thereby activating this enzyme. Activation of the NO-sGC-cGMP-PKG pathway entails Ca2+ signaling reduction and vasodilatation. Endothelium dysfunction leads to decreased production or bioavailability of endogenous NO that could contribute to vascular diseases. Nitrosyl ruthenium complexes have been studied as a new class of NO donors with potential therapeutic use in order to supply the NO deficiency. In this context, this article shall provide a brief review of the effects exerted by the NO that is enzymatically produced via endothelial NO-synthase (eNOS) activation and by the NO released from NO donor compounds in the vascular smooth muscle cells on both conduit and resistance arteries, as well as veins. In addition, the involvement of the nitrite molecule as an endogenous NO reservoir engaged in vasodilatation will be described.

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Hypoxia inducible factor-1α (HIF-1α) is an important transcription factor, which plays a critical role in the formation of solid tumor and its microenviroment. The objective of the present study was to evaluate the expression and function of HIF-1α in human leukemia bone marrow stromal cells (BMSCs) and to identify the downstream targets of HIF-1α. HIF-1α expression was detected at both the RNA and protein levels using real-time PCR and immunohistochemistry, respectively. Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) were detected in stromal cells by enzyme-linked immunosorbent assay. HIF-1α was blocked by constructing the lentiviral RNAi vector system and infecting the BMSCs. The Jurkat cell/BMSC co-cultured system was constructed by putting the two cells into the same suitable cultured media and conditions. Cell adhesion and secretion functions of stromal cells were evaluated after transfection with the lentiviral RNAi vector of HIF-1α. Increased HIF-1α mRNA and protein was detected in the nucleus of the acute myeloblastic and acute lymphoblastic leukemia compared with normal BMSCs. The lentiviral RANi vector for HIF-1α was successfully constructed and was applied to block the expression of HIF-1α. When HIF-1α of BMSCs was blocked, the expression of VEGF and SDF-1 secreted by stromal cells were decreased. When HIF-1α was blocked, the co-cultured Jurkat cell’s adhesion and migration functions were also decreased. Taken together, these results suggest that HIF-1α acts as an important transcription factor and can significantly affect the secretion and adhesion functions of leukemia BMSCs.

Relative performance of the two hands in simple and choice reaction time tasks

There is evidence that the left hemisphere is more competent for motor control than the right hemisphere. This study investigated whether this hemispheric asymmetry is expressed in the latency/duration of sequential responses performed by the left and/or right hands. Thirty-two right-handed young adults (16 males, 16 females; 18-25 years old) were tested in a simple or choice reaction time task. They responded to a left and/or right visual target by moving their left and/or right middle fingers between two keys on each side of the midline. Right hand reaction time did not differ from left hand reaction time. Submovement times were longer for the right hand than the left hand when the response was bilateral. Pause times were shorter for the right hand than the left hand, both when the responses were unilateral or bilateral. Reaction time results indicate that the putatively more efficient response preparation by the left hemisphere motor mechanisms is not expressed behaviorally. Submovement time and pause time results indicate that the putatively more efficient response execution by the left hemisphere motor mechanisms is expressed behaviorally. In the case of the submovements, the less efficient motor control of the left hand would be compensated by a more intense attention to this hand.

Synthesis of Short Oligonucleotides on a Soluble Support by the Phosphoramidite Method

In the last decades, the chemical synthesis of short oligonucleotides has become an important aspect of study due to the discovery of new functions for nucleic acids such as antisense oligonucleotides (ASOs), aptamers, DNAzymes, microRNA (miRNA) and small interfering RNA (siRNA). The applications in modern therapies and fundamental medicine on the treatment of different cancer diseases, viral infections and genetic disorders has established the necessity to develop scalable methods for their cheaper and easier industrial manufacture. While small scale solid-phase oligonucleotide synthesis is the method of choice in the field, various challenges still remain associated with the production of short DNA and RNA-oligomers in very large quantities. On the other hand, solution phase synthesis of oligonucleotides offers a more predictable scaling-up of the synthesis and is amenable to standard industrial manufacture techniques. In the present thesis, various protocols for the synthesis of short DNA and RNA oligomers have been studied on a peracetylated and methylated β-cyclodextrin, and also on a pentaerythritol-derived support. On using the peracetylated and methylated β-cyclodextrin soluble supports, the coupling cycle was simplified by replacement of the typical 5′-O-(4,4′-dimethoxytrityl) protecting group with an acid-labile acetal-protected 5′-O-(1-methoxy-1-methylethyl) group, which upon acid-catalyzed methanolysis released easily removable volatile products. For this reason monomeric building blocks 5′-O-(1-methoxy-1-methylethyl) 3′-(2-cyano-ethyl-N,N-diisopropylphosphoramidite) were synthesized. Alternatively, on using the precipitative pentaerythritol support, novel 2´-O-(2-cyanoethyl)-5´-O-(1-methoxy-1-methylethyl) protected phosphoramidite building blocks for RNA synthesis have been prepared and their applicability by the synthesis of a pentamer was demonstrated. Similarly, a method for the preparation of short RNAs from commercially available 5´-O-(4,4´-dimethoxytrityl)-2´-O-(tert-butyldimethyl-silyl)ribonucleoside 3´-(2-cyanoethyl-N,N-diisopropylphosphoramidite) building blocks has been developed

Roadmap for Service Charging Development

Corporate support functions are increasingly being concentrated into service centers. Service Management principles guide companies in the transition. Service Financial Management is an integral part in supporting the strategic positioning of the service center. The main goal of this thesis is to create a step-by-step plan to improve and automate the service charging processes for the finance service function of the case company. Automating the service transaction data collection for reporting is expected to improve efficiency, reliability and transparency. Interviews with finance service managers are held to define current processes and areas for improvement. These create the basis for the creation of a development roadmap that takes place in two phases. The first phase is to create an environment where automation is possible, and the second phase is the automation of each finance service. Benchmarking interviews are held with the service centers in three other companies to discover best practices. The service charging processes between the studied companies are found incompatible, and suggestions for process automation cannot be inferred. Some implications of Service Financial Management decisions to the strategy of the service center are identified. The bundling of services and charging them inside or outside of the goal-setting frame of the business unit can be used to support the strategic choice and customer acceptance of the service center.

Urana työllistyminen

Tutkimuksen tarkoituksena on ollut selvittää pitkään työttömänä olleiden ammatinvaihtajien ammatinvaihdon ja työllistymisen etenemistä. Tämän lisäksi tutkimuksessa on tarkasteltu kohderyhmän mielikuvaa ohjaavasta koulutuksesta. Pitkittäistutkimus on toteutettu seurannalla, jonka välietappina on ollut kohderyhmän osallistuminen ohjaavaan koulutukseen. Työvoimapoliittinen ohjaava koulutus edusti erityisesti vaikeasti työllistettäville kohdistettavaa interventiota, jolla pyrittiin puuttumaan työttömyyskierteeseen ja ehkäisemään syrjäytymiskehityksen jatkuminen. Tutkimuksen kohderyhmäksi valitut ihmiset (51) ovat suoranaisessa keskiössä tutkittaessa työelämästä syrjäytymistä. Heikentyneet työelämävalmiudet ja työmarkkinakelpoisuus ovat tehneet heistä vaikeasti työllistettäviä. Heidän valintansa kohderyhmäksi, työhallinnon tekemän kurssiosoituksen kriteereinä olevien pitkäaikaistyöttömyyden sekä epäonnistuneen ammatinvaihdon perusteella, osoittaa heidän olevan erityisen ohjauksen ja tuen tarpeessa. On kuitenkin huomattava, että heidät on valittu kohderyhmäksi paitsi kurssiosoituksen saaneina pitkäaikaistyöttöminä myös ammatinvaihtajina, jotka itse haluavat vaihtaa ammattiaan. Tutkimusaineistona ovat olleet työhallinnon asiakasrekisteritiedot ja seurantatutkimuksen perusteella muodostetuista ryhmistä valittujen neljän tapaushenkilön teemahaastatteluaineistot. Tutkimusaineistoa on käsitelty laadullisesti, koska tutkimus kuuluu laadullisen tutkimuksen piiriin sekä tutkimuksen kohteena olevan ilmiön, tutkimuskysymysten ja -aineistojen että tarkoituksensa perusteella. Tutkimuksessa on kuvattu pitkäaikaistyöttömien henkilöiden ammatinvaihtoa ja työllistymistä. Kuvatuissa tapauksissa ammatinvaihtotarve perustuu suurimmalla osalla terveydellisiin rajoitteisiin, joiden vuoksi aikaisemmassa työssä toimiminen on mahdotonta. Useimmiten vajaakuntoisuus on merkittävästi pitkittänyt heidän työttömyyttään. Tämän vuoksi seurantatutkimuksessa on keskitytty tarkastelemaan ammatinvaihtoprosessin etenemistä. Muun muassa työttömyyttä laajasti tutkineet Aho ja Vähätalo ovat todenneet vajaakuntoisuuden olevan merkittävä työttömyyden pitkittymiseen vaikuttava tekijä. Ahon mukaan vajaakuntoisiksi diagnosoituja on jopa viidennes kroonisesti pitkäaikaistyöttömistä työhallinnon asiakasrekisteriin kirjatuista henkilöistä. Monen tekijän summana pitkään työttömänä olleet henkilöt ovat vaarassa ajautua tilanteeseen, jossa he eivät enää kykene omin avuin löytämään ulospääsyä työttömyydestä Tämän seurantatutkimuksen perusteella vain hyvin harvalla kohderyhmään kuuluvista on ammatinvaihdossa ja työllistymisessä tapahtunut merkittävää edistymistä huolimatta useiden vuosien yrittämisestä. Ammatinvaihdon ja työllistymisen edistymistä on tarkasteltu sen perusteella, miten työelämään ja/tai koulutukseen sijoittumiset tai muut toiminnot ovat edesauttaneet tavoitteen toteutumista. Seurantatutkimuksessa on muodostettu neljä tyyppiryhmää ammatinvaihdon ja työllistymisen etenemisen perusteella. Ryhmät ovat: Ammatinvaihdossa onnistuneet (5), ammatinvaihdossa edistyneet (19), pitkäaikaistyöttömäksi jääneet (12) ja epätarkoituksenmukaisesti sijoittuneet (15). Ammatinvaihdossa onnistuneet ovat toteuttaneet ammatinvaihtonsa siirtymällä suoraan työelämään uudelle alalle, työllistymällä koulutusta vastaavaan työhön uudelleenkoulutuksen jälkeen tai kouluttautumalla uuteen ammattiin työllistymättä. Kuitenkin vain kolme heistä on sijoittunut seurannan päättyessä pysyväisluonteiseen terveydelleen soveltuvaan työhön muiden ollessa edelleen työttömänä. Ammatinvaihdossa edistyneet ovat suurimmaksi osaksi edistyneet ammatinvaihdossaan soveltuvien tukitöiden avulla. Työttömyys on kuitenkin jatkunut valtaosalla ja vain yksi heistä on sijoittuneena työelämään seurannan päättyessä. Tämä sijoittuminen ei ole kuitenkaan edistänyt ammatinvaihtoa. Pitkäaikaistyöttömäksi jääneet ovat olleet yhtäjaksoisesti työttömänä kokoseurantajakson ajan. Epätarkoituksenmukaisesti sijoittuneet ovat enimmäkseen sijoittuneet terveytensä kannalta haitallisiin ja/tai ammatinvaihtosuunnitelmilleen soveltumattomiin sijoitustöihin ja määräaikaisuuksiin. Seurannan päättyessä heovat joko työttömänä tai toimivat ammatinvaihtotavoitteensa kannalta haitallisissa työtehtävissä. Tämä on vahvistanut mielikuvaa, joka usealle heille on muodostunut ohjaavasta koulutuksesta työttömille suunnattuna sanktiona, joka ei edistä työllistymistä. Ohjaavassa koulutuksessa suurin osa heistä on kokenut hyötyneensä työharjoittelujaksosta, joka on antanut käyttökelpoista tietoa ammatinvalintaa varten. Lukuun ottamatta kolmea henkilöä, jotka ovat seurannan päättyessä pysyväisluonteisessa työssä terveydelleen soveltuvassa ammatissa, ovat kaikki muut kohderyhmään kuuluvat edelleen erityisen ohjauksen ja tuen tarpeessa johtuen ammatinvaihdon keskeneräisyydestä ja/tai työttömyyden jatkumisesta. Yhdistävänä tekijänä ammatinvaihdossa onnistuneilla vaikuttaa olleen tulevaisuususkon säilyminen pitkäaikaistyöttömyydessä. Sekä ammatinvaihdossa onnistuneet että edistyneet ovat kokeneet työttömyyteen katkoksia tuoneet työt merkityksellisinä riippumatta siitä, ovatko työtehtävät edistäneet ammatinvaihtoa.

Models to study intermediate filament dynamics and functions

Intermediate filaments are part of the cytoskeleton and nucleoskeleton; they provide cells with structure and have important roles in cell signalling. The IFs are a large protein family with more than 70 members; each tightly regulated and expressed in a cell type-specific manner. Although the IFs have been known and studied for decades, our knowledge about their specific functions is still limited, despite the fact that mutations in IF genes cause numerous severe human diseases. In this work, three IF proteins are examined more closely; the nuclear lamin A/C and the cytoplasmic nestin and vimentin. In particular the regulation of lamin A/C dynamics, the role of nestin in muscle and body homeostasis as well as the functions and evolutionary aspects of vimentin are investigated. Together this data highlights some less well understood functions of these IFs. We used mass-spectrometry to identify inter-phase specific phosphorylation sites on lamin A. With the use of genetically engineered lamin A protein in combination with high resolution microscopy and biochemical methods we discovered novel roles for this phosphorylation in regulation of lamin dynamics. More specifically, our data suggests that the phosphorylation of certain amino acids in lamin A determines the localization and dynamics of the protein. In addition, we present results demonstrating that lamin A regulates Cdk5-activity. In the second study we use mice lacking nestin to gain more knowledge of this seldom studied protein. Our results show that nestin is essential for muscle regeneration; mice lacking nestin recover more slowly from muscle injury and show signs of spontaneous muscle regeneration, indicating that their muscles are more sensitive to stresses and injury. The absence of nestin also leads to decreased over-all muscle mass and slower body growth. Furthermore, nestin has a role in controlling testicle homeostasis as nestin-/- male mice show a greater variation in testicle size. The common fruit fly Drosophila melanogaster lacks cytoplasmic IFs as most insects do. By creating a fly that expresses human vimentin we establish a new research platform for vimentin studies, as well as provide a new tool for the studies of IF evolution.

Entry mode choice of Finnish startups entering Chinese market in tablet industry

Since the implement of opening policy, the overall economy of China has maintained rapid and stable development, which has now makes China become the world's second largest economy. China, it is to become the largest overseas market for many large global enterprises from various industries, this naturally also includes the Tablet PC industry that raised in recent years. The purpose of this thesis is to analyze different internal and external factors that influence the entry mode choices of Finnish SMEs in tablet industry entering Chinese market. The goal is to find out the suitable entry modes for the Finnish tablet or other relevant SMEs entering Chinese market. Qualitative analysis is the main research method in empirical part of this study. The interviews were carried out with the case company and other two Finnish business organizations in China. The result of the study indicated that the internal resource and external business environment affect the entry modes choices much more than other factors for SMES. The exporting mode and sales subsidiary could be a better choice for SMEs entering Chinese market. Furthermore, firms should fully learn the Chinese market combine with its own background before making decisions.

Freedom of choice and bounded rationality: a brief appraisal of behavioral economists' plea for light paternalism

Behavioral economics has addressed interesting positive and normative questions underlying the standard rational choice theory. More recently, it suggests that, in a real world of boundedly rational agents, economists could help people to improve the quality of their choices without any harm to autonomy and freedom of choice. This paper aims to scrutinize available arguments for and against current proposals of light paternalistic interventions mainly in the domain of intertemporal choice. It argues that incorporating the notion of bounded rationality in economic analysis and empirical findings of cognitive biases and self-control problems cannot make an indisputable case for paternalism.

Nature of the state economic expanded functions in the Brazilian economy*

ABSTRACT The paper discusses the dynamics of capital accumulation in Latin America economies. The hypothesis is that in these economies the role of the State is comparatively broader than in the economies of the centers of the capitalism by structural reasons. The argument is mainly based on Marx and Kalecki, besides historical elements of Latin America economies, particularly the Brazilian economy. Then the paper explores the dynamics consequences of this nature at the national levels, concluding that this condition gives a higher degree of instability.