Role of the canonical transient receptor potential channel 2 (TRPC2) in thyroid cell function

Kalciumjonen reglerar flera processer i celler såsom transkribering av gener, celldelning, cellernas rörlighet och celldöd. Därför har cellerna utvecklat många mekanismer för att reglera den intracellulära kalciumkoncentrationen. Kalciumkanaler spelar en viktig roll i denna regleringsprocess. TRPC-kanalerna (eng. canonical transient receptor potential) är en familj av jonkanaler med sju medlemmar (TRPC1-7) vars regleringsmekanismer och fysiologiska roller är varierande. TRPC2-kanalens fysiologiska signifikans, samt hur kanalen regleras, är dåligt karakteriserad. För första gången, rapporterar vi närvaron av TRPC2 kanalen i råttans sköldkörtelceller samt primära sköldkörtelceller från råtta. Hos gnagare har TRPC2 antagits vara exklusivt uttryckt i det vomeronasala organet. För att undersöka den fysiologiska betydelsen av kanalen, har vi utvecklat stabila celler med nedreglerat TRPC2 (shTRPC2) m.h.a. shRNA-teknik. Nedreglering av TRPC2 resulterade i stora skillnader i flera viktiga cellulära funktioner och i regleringen av sköldkörtelcellernas cellsignalering. Nedreglering av TRPC2 orsakade minskad agonist-beroende frigivning av kalcium från det endoplasmatiska nätverket, samt minskat agonist-beroende inflöde av extracellulärt kalcium, men ökade det basala kalciuminflödet. Uttrycket av PKCβ1 och PKCδ, SERCA-aktiviteten och kalciumhalten i det endoplasmatiska nätverket minskade i shTRPC2 celler. Kommunikation mellan kalcium- och cAMP-signalering påvisades vara TRPC2-beroende, vilket visades reglera uttrycket av TSH-receptorn. Vi undersökte också betydelsen av TRPC2 kanalen i reglering av sköldkörtelcellers proliferation, migration, vidhäftning och invasion; processer som alla var dämpade i shTRPC2 celler. Samamnfattningsvis påvisade dessa resultat en ny och viktig fysiologisk betydelse för TRPC2 kanalerna.

Análise interactômica da VDAC (voltage-dependent anion selective channel) nos cérebros aviar, bovino e murino

A VDAC é a proteína mais abundante na membrana mitocondrial externa. Exerce o controle da atividade desta organela através da regulação da troca de metabólitos e tem função crucial no mecanismo de apoptose. Em nosso caso, os estudos dos complexos protéicos, das interações entre a VDAC e outras proteínas presentes no interior do neurônio que auxiliam na manutenção das funções das organelas e da célula, fazem parte da chamada interactômica. O presente estudo determinou o interactoma do complexo protéico Hexoquinase-VDAC-ANT presente em cérebros murino, bovino e aviar. Nosso objetivo foi identificar se as expressões diferenciadas da VDAC1 e VDAC2 verificadas nos cérebros murino, aviar e bovino, estão associadas a diferenças nos interactomas dessas proteínas. Este estudo revelou que as espécies aviar e bovina apresentaram o maior número de complexos protéicos contendo VDACs (5) quando comparadas com os neurônios de rato (1), o que é indicativo de uma cinética diferencial de montagem ou desmontagem do complexo. Além disso, a VDAC mitocondrial neuronal aviar também interage com mais proteínas em relação à VDAC mitocondrial neuronal bovina, o que é resultado de uma composição de subunidades diferenciada. Tais resultados indicam diferenças significativas quanto ao metabolismo energético e apoptótico no cérebro aviar, bovino e murino, existindo interações diferenciais da VDAC no cérebro aviar.

Managing Customer Issues through a Support Channel Network

The importance of after-sales service or service in general can be seen and experienced by customers every day with industrial as well as other non-industrial services or products. This dissertation, drawing on theory and experience, focuses on practical engineering implications, specifically the management of customer issues in the after-sales phase in the mobile phone arena. The main objective of this doctoral dissertation is to investigate customer after-sales issue management, specifically regarding mobile phones. The case studies focus on issue resolution time and the issue of corrective actions. This dissertation consists of a main body and four peer-reviewed journal articles and one manuscript currently under review by a peer-reviewed journal. The main body of this dissertation examines the elements of customer satisfaction, loyalty, and retention with respect to corrective actions to address customer issues and issue resolution time through literature and empirical studies. The five independent works are case studies supporting the thesis research questions. This study examines four questions: 1) What are the factors affecting corrective actions for customers? 2) How can customer issue resolution time be controlled? 3) What are the factors affecting processes in the service chain? and 4) How can communication be measured in a service chain? In this work, both quantitative and qualitative analysis methods are used. The main body of the thesis reviews the literature regarding the elements that bridge the five case studies. The case studies of the articles and surveys lean more toward the methodology of critical positivism and then apply the interpretive approach in interpreting the results. The case study articles employ various statistical methods to analyze and to interpret the empirical and survey data. The statistical methods were used to create a model that is useful for significantly optimizing issue resolution time. Moreover, it was found that samples for verifying issues provided by the customer neither improve the perceived quality of corrective actions nor the perceived quality of issue resolution time. The term “service” in this work is limited to the technical services that are provided by product manufacturers and after-sales authorized service vendors. On the basis of this research work, it has been observed that corrective actions and issue resolution time are associated with customer satisfaction and hence, according to induction theory, to customer loyalty and retention. This thesis utilizes knowledge of marketing and customer relationships to contribute to the existing body of knowledge concerning information and communication technology for after-sales service recovery of mobile terminals. The established models in the thesis contribute to the existing knowledge of the after-sales process of dealing with customer issues in the field of mobile phones. The findings suggest that process managers could focus more on communication and training provided to the staff as new technology evolves rapidly. The study also suggest the managers formulate strategies for how customers can be kept informed on a regular basis of the status of issues that have been escalated for corrective action. The findings also lay the foundation for the comprehensive objective to control the entire product development process, starting with conceptualization. This implies that robust design should be applied to the new products so that problems affecting customer service quality are not repeated. The objective will be achieved when the entire service chain from product development to the final user can be modeled and this model can be used to support the organization at all levels.

Distribution channel plan for wound care products: Case 3M Finland Ltd.

The aim of this master’s thesis was to make a qualitative marketing research and on the basis of this to develop a distribution plan for the case company Finnish 3M Ltd.’s wound care products. The literature review includes three important parts: distribution channel planning, the buying behavior of seniors, and special characteristics of health care products’ marketing. The empirical part of this thesis comprises two different parts. The first part is a marketing research, in which the buying behavior of wound care products is studied in Espoo. The research aim was to examine, in which distribution channels the wound care patients under home care would most preferably buy wound care products during the time period, when municipalities will not yet provide the products for free. The data was collected through semi-structured phone interviews and regular interviews, and was treated qualitatively and anonymously. The study revealed that the recommendations of nurses and doctors influenced most the buying behavior of wound care customers. In the second part of the thesis a distribution channel plan for wound care products was made for the case company 3M Finland Ltd. based on the results. 3M Finland Ltd. should focus on pharmacies, online-stores and municipal health centers as their main distributors.

Vasorelaxant effects of the potassium channel opener SR 47063 on the isolated human saphenous vein and rat aorta

The vasorelaxant effects of SR 47063 (4-(2-cyanimino-1,2-dihydropyrid-1-yl)-2,2-dimethyl-6-nitrochromene), a new K+-channel opener structurally related to levcromakalim, were examined in isolated human saphenous vein (HSV) and rat aorta (RA). HSV or RA rings were precontracted with either KCl or noradrenaline and cumulative relaxant concentration-response curves were obtained for SR 47063 (0.1 nM to 1 µM) in the presence or absence of 3 µM glibenclamide. SR 47063 potently relaxed HSV and RA precontracted with 20 mM (but not 60 mM) KCl or 10 µM noradrenaline in a concentration-dependent manner, showing slightly greater activity in the aorta. The potency of the effect of SR 47063 on HSV and RA was 12- and 58-fold greater, respectively, than that reported for the structurally related K+-channel opener levcromakalim. The vasorelaxant action of SR 47063 in both blood vessels was strongly inhibited by 3 µM glibenclamide, consistent with a mechanism of action involving ATP-dependent K+-channels.

ClC-5 chloride channel and kidney stones: what is the link?

Nephrolithiasis is one of the most common diseases in the Western world. The disease manifests itself with intensive pain, sporadic infections, and, sometimes, renal failure. The symptoms are due to the appearance of urinary stones (calculi) which are formed mainly by calcium salts. These calcium salts precipitate in the renal papillae and/or within the collecting ducts. Inherited forms of nephrolithiasis related to chromosome X (X-linked hypercalciuric nephrolithiasis or XLN) have been recently described. Hypercalciuria, nephrocalcinosis, and male predominance are the major characteristics of these diseases. The gene responsible for the XLN forms of kidney stones was cloned and characterized as a chloride channel called ClC-5. The ClC-5 chloride channel belongs to a superfamily of voltage-gated chloride channels, whose physiological roles are not completely understood. The objective of the present review is to identify recent advances in the molecular pathology of nephrolithiasis, with emphasis on XLN. We also try to establish a link between a chloride channel like ClC-5, hypercalciuria, failure in urine acidification and protein endocytosis, which could explain the symptoms exhibited by XLN patients.

An acid-sensing ion channel that detects ischemic pain

Ischemic pain occurs when there is insufficient blood flow for the metabolic needs of an organ. The pain of a heart attack is the prototypical example. Multiple compounds released from ischemic muscle likely contribute to this pain by acting on sensory neurons that innervate muscle. One such compound is lactic acid. Here, we show that ASIC3 (acid-sensing ion channel #3) has the appropriate expression pattern and physical properties to be the detector of this lactic acid. In rats, it is expressed only in sensory neurons and then only on a minority (~40%) of these. Nevertheless, it is expressed at extremely high levels on virtually all dorsal root ganglion sensory neurons that innervate the heart. It is extraordinarily sensitive to protons (Hill slope 4, half-activating pH 6.7), allowing it to readily respond to the small changes in extracellular pH (from 7.4 to 7.0) that occur during muscle ischemia. Moreover, both extracellular lactate and extracellular ATP increase the sensitivity of ASIC3 to protons. This final property makes ASIC3 a "coincidence detector" of three molecules that appear during ischemia, thereby allowing it to better detect acidosis caused by ischemia than other forms of systemic acidosis such as hypercapnia.

Down-regulation of the cardiac sarcoplasmic reticulum ryanodine channel in severely food-restricted rats

We have shown that myocardial dysfunction induced by food restriction is related to calcium handling. Although cardiac function is depressed in food-restricted animals, there is limited information about the molecular mechanisms that lead to this abnormality. The present study evaluated the effects of food restriction on calcium cycling, focusing on sarcoplasmic Ca2+-ATPase (SERCA2), phospholamban (PLB), and ryanodine channel (RYR2) mRNA expressions in rat myocardium. Male Wistar-Kyoto rats, 60 days old, were submitted to ad libitum feeding (control rats) or 50% diet restriction for 90 days. The levels of left ventricle SERCA2, PLB, and RYR2 were measured using semi-quantitative RT-PCR. Body and ventricular weights were reduced in 50% food-restricted animals. RYR2 mRNA was significantly decreased in the left ventricle of the food-restricted group (control = 5.92 ± 0.48 vs food-restricted group = 4.84 ± 0.33, P < 0.01). The levels of SERCA2 and PLB mRNA were similar between groups (control = 8.38 ± 0.44 vs food-restricted group = 7.96 ± 0.45, and control = 1.52 ± 0.06 vs food-restricted group = 1.53 ± 0.10, respectively). Down-regulation of RYR2 mRNA expressions suggests that chronic food restriction promotes abnormalities in sarcoplasmic reticulum Ca2+ release.

Involvement of the TRPV1 channel in the modulation of spontaneous locomotor activity, physical performance and physical exercise-induced physiological responses

Physical exercise triggers coordinated physiological responses to meet the augmented metabolic demand of contracting muscles. To provide adequate responses, the brain must receive sensory information about the physiological status of peripheral tissues and organs, such as changes in osmolality, temperature and pH. Most of the receptors involved in these afferent pathways express ion channels, including transient receptor potential (TRP) channels, which are usually activated by more than one type of stimulus and are therefore considered polymodal receptors. Among these TRP channels, the TRPV1 channel (transient receptor potential vanilloid type 1 or capsaicin receptor) has well-documented functions in the modulation of pain sensation and thermoregulatory responses. However, the TRPV1 channel is also expressed in non-neural tissues, suggesting that this channel may perform a broad range of functions. In this review, we first present a brief overview of the available tools for studying the physiological roles of the TRPV1 channel. Then, we present the relationship between the TRPV1 channel and spontaneous locomotor activity, physical performance, and modulation of several physiological responses, including water and electrolyte balance, muscle hypertrophy, and metabolic, cardiovascular, gastrointestinal, and inflammatory responses. Altogether, the data presented herein indicate that the TPRV1 channel modulates many physiological functions other than nociception and thermoregulation. In addition, these data open new possibilities for investigating the role of this channel in the acute effects induced by a single bout of physical exercise and in the chronic effects induced by physical training.

Software business expansion through distribution channel : Case M-Files - Denmark

The purpose of this study was to find out how a software company can successfully expand business to the Danish software market through distribution channel. The study was commissioned by a Finnish software company and it was conducted using a qualitative research method by analyzing external and internal business environment, and interviewing Danish ICT organizations and M-Files personnel. Interviews were semi-structured interviews, which were designed to collect comprehensive information on the existing ICT and software market in Denmark. The research used three external and internal analyzing frameworks; PEST analysis (market level), Porter´s Five Force analysis (industry level competition) and SWOT analysis (company level). Distribution channels theory was a base to understand why and what kind of distribution channels the case company uses, and what kind of channels target markets companies’ uses. Channel strategy and design were integrated to the industry level analysis. The empirical findings revealed that Denmark has very business friendly ICT environment. Several organizations have ranked Denmark´s information and communication technology as the best in the world. Denmark’s ICT and software market are relatively small, compared to many other countries in Europe. Danish software market is centralized. Largest software clusters are in the largest cities; Copenhagen, Aarhus, Odense and Aalborg. From these clusters, software companies can most likely find suitable resellers. The following growing trends are clearly seen in the software market: mobile and wireless applications, outsourcing, security solutions, cloud computing, social business solutions and e-business solutions. When expanding software business to the Danish market, it is important to take into account these trends. In Denmark distribution channels varies depending on the product or service. For many, a natural distribution channel is a local partner or internet. In the public sector solutions are purchased through a public procurement process. In the private sector the buying process is more straight forwarded. Danish companies are buying software from reliable suppliers. This means that they usually buy software direct from big software vendors or local partners. Some customers prefer to use professional consulting companies. These consulting companies can strongly influence on the selection of the supplier and products, and in this light, consulting companies can be important partners for software companies. Even though the competition is fierce in ECM and DMS solutions, Danish market offers opportunities for foreign companies. Penetration to the Danish market through reseller channel requires advanced solutions and objective selection criteria for channel partners. Based on the findings, Danish companies are interested in advanced and efficient software solutions. Interest towards M-Files solutions was clearly seen and the company has excellent opportunity to expand business to the Danish market through reseller channel. Since the research explored the Danish ICT and software market, the results of the study may offer valuable information also to the other software companies which are expanding their business to the Danish market.

The new era of customer experience in the omni-channel environment of a communication service provider

This study discusses the evolution of an omni-channel model in managing customer experience. The purpose of this thesis is to expand the current academic literature available on omni-channel and offer suggestions for omni-channel creation. This is done by studying the features of an omni-channel approach into engaging with customers and through the sub-objectives of describing the process behind its initiation as well as the special features communication service providers need to take in consideration. Theories used as a background for this study are related to customer experience, channel management, omni-channel and finally change management. The empirical study of this thesis consists of seven expert interviews conducted in a case company. The interviews were held between March and November 2014. One of the interviewees is the manager of an omni-channel development team, whilst the rest were in charge of the management of the various customer channels of the company. The organization and analysis of the interview data was conducted topically. The use of themes related to major theories on the subject was utilized to create linkages between theory and practice. The responses were also organized in two groups based on the viewpoint to map responses related to the company perspective as well as the customers´ perspective. The findings in this study are that omni-channel is among the best tools for companies to respond to the challenge induced by changing customer needs and preferences, as well as intensifying competitive environment. The omni-channel model was found to promote excellent customer experience and thus to be a source of competition advantage and increasing financial returns by creating an omni-experience for the customer. Through omniexperience customers see all of the transactions with a company presenting one brand and providing ease and effortlessness in every encounter. The processes behind omni-channel formulation were identified as customer experience proclaimed as the most important strategic goal, mapping and establishing a unified brand experience in all (service) channels and empowering the first line personnel as the gate keepers of omniexperience. Further the tools, measurement and supporting strategies were to be in accordance with the omni-channel strategy and the customer needs to become a partner in a two way transaction with the firm. Based on these findings a model for omni-channel creation is offered. Future research is needed to firstly, further test these findings and expand the theoretical framework on omni-channel, as it is quite scarce to date and secondly, to increase the generalizability of the model suggested.