29 resultados para Epididymis tail
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Post-testicular sperm maturation occurs in the epididymis. The ion concentration and proteins secreted into the epididymal lumen, together with testicular factors, are believed to be responsible for the maturation of spermatozoa. Disruption of the maturation of spermatozoa in the epididymis provides a promising strategy for generating a male contraceptive. However, little is known about the proteins involved. For drug development, it is also essential to have tools to study the function of these proteins in vitro. One approach for screening novel targets is to study the secretory products of the epididymis or the G protein-coupled receptors (GPCRs) that are involved in the maturation process of the spermatozoa. The modified Ca2+ imaging technique to monitor release from PC12 pheochromocytoma cells can also be applied to monitor secretory products involved in the maturational processes of spermatozoa. PC12 pheochromocytoma cells were chosen for evaluation of this technique as they release catecholamines from their cell body, thus behaving like endocrine secretory cells. The results of the study demonstrate that depolarisation of nerve growth factor -differentiated PC12 cells releases factors which activate nearby randomly distributed HEL erythroleukemia cells. Thus, during the release process, the ligands reach concentrations high enough to activate receptors even in cells some distance from the release site. This suggests that communication between randomly dispersed cells is possible even if the actual quantities of transmitter released are extremely small. The development of a novel method to analyse GPCR-dependent Ca2+ signalling in living slices of mouse caput epididymis is an additional tool for screening for drug targets. By this technique it was possible to analyse functional GPCRs in the epithelial cells of the ductus epididymis. The results revealed that, both P2X- and P2Y-type purinergic receptors are responsible for the rapid and transient Ca2+ signal detected in the epithelial cells of caput epididymides. Immunohistochemical and reverse transcriptase-polymerase chain reaction (RTPCR) analyses showed the expression of at least P2X1, P2X2, P2X4 and P2X7, and P2Y1 and P2Y2 receptors in the epididymis. Searching for epididymis-specific promoters for transgene delivery into the epididymis is of key importance for the development of specific models for drug development. We used EGFP as the reporter gene to identify proper promoters to deliver transgenes into the epithelial cells of the mouse epididymis in vivo. Our results revealed that the 5.0 kb murine Glutathione peroxidase 5 (GPX5) promoter can be used to target transgene expression into the epididymis while the 3.8 kb Cysteine-rich secretory protein-1 (CRISP-1) promoter can be used to target transgene expression into the testis. Although the visualisation of EGFP in living cells in culture usually poses few problems, the detection of EGFP in tissue sections can be more difficult because soluble EGFP molecules can be lost if the cell membrane is damaged by freezing, sectioning, or permeabilisation. Furthermore, the fluorescence of EGFP is dependent on its conformation. Therefore, fixation protocols that immobilise EGFP may also destroy its usefulness as a fluorescent reporter. We therefore developed a novel tissue preparation and preservation techniques for EGFP. In addition, fluorescence spectrophotometry with epididymal epithelial cells in suspension revealed the expression of functional purinergic, adrenergic, cholinergic and bradykinin receptors in these cell lines (mE-Cap27 and mE-Cap28). In conclusion, we developed new tools for studying the role of the epididymis in sperm maturation. We developed a new technique to analyse GPCR dependent Ca2+ signalling in living slices of mouse caput epididymis. In addition, we improved the method of detecting reporter gene expression. Furthermore, we characterised two epididymis-specific gene promoters, analysed the expression of GPCRs in epididymal epithelial cells and developed a novel technique for measurement of secretion from cells.
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By an exponential sum of the Fourier coefficients of a holomorphic cusp form we mean the sum which is formed by first taking the Fourier series of the said form,then cutting the beginning and the tail away and considering the remaining sum on the real axis. For simplicity’s sake, typically the coefficients are normalized. However, this isn’t so important as the normalization can be done and removed simply by using partial summation. We improve the approximate functional equation for the exponential sums of the Fourier coefficients of the holomorphic cusp forms by giving an explicit upper bound for the error term appearing in the equation. The approximate functional equation is originally due to Jutila [9] and a crucial tool for transforming sums into shorter sums. This transformation changes the point of the real axis on which the sum is to be considered. We also improve known upper bounds for the size estimates of the exponential sums. For very short sums we do not obtain any better estimates than the very easy estimate obtained by multiplying the upper bound estimate for a Fourier coefficient (they are bounded by the divisor function as Deligne [2] showed) by the number of coefficients. This estimate is extremely rough as no possible cancellation is taken into account. However, with small sums, it is unclear whether there happens any remarkable amounts of cancellation.
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Integrins are heterodimeric adhesion receptors mediating adhesion to extracellular matrix proteins and to other cells. Integrins are important in embryonic development, structural integrity of connective tissue, blood thrombus formation, and immune defense system. Integrins are transmembrane proteins whose ligand binding capacity (activity) is regulated by large conformational changes. Extracellular ligand binding or intracellular effector binding to integrin cytoplasmic face regulate integrin activity. Integrins are thus able to mediate bi-directional signaling. Integrin function is also regulated by intracellular location. Integrins are constantly recycled from endocytic vesicles to plasma membrane, and this has been shown to be important for cell migration and invasion as well. Deregulation of integrin functionality can lead to deleterious illnesses, such as bleeding or inflammatory disorders. It is also evident that integrin deregulation is associated with cancer progression. In this study, a novel Beta1 integrin associating protein, Rab21, was characterized. Rab21 binding to integrin cytoplasmic tail was shown to be important for Beta1 integrin endo- and exocytosis – intracellular trafficking. It was furher shown that this interaction has an important role in cell adhesion, migration, as well as in the final step of cell division, cytokinesis. This work showed that abrogation of Rab21 function or β1 integrin endocytic traffic, can lead to defects in cell division and results in formation of multinucleated cells. Multinucleation and especially tetraploidy can be a transient pathway to aneuploidy and tumorigenesis. This work characterized chromosomal deletions in rab21 locus in ovarian and prostate cancer samples and showed that a cell line with rab21 deletion also had impairment in cell division, which could be rescued by Rab21 re-expression. The work demonstrates an important role for Rab21 and Beta1 integrin traffic regulation in cell adhesion and division, and suggests a probable associaton with tumorigenesis. In this study, Beta1 integrin activity regulation was also addressed. A novel cell array platform for genome-scale RNAi screenings was characterized here. More than 4500 genes were knocked-down in prostate cancer cells using siRNA-mediated silencing. The effects on Beta1 integrin activity were analyzed upon knock-downs. The screen identified more that 400 putative regulators of Beta1 integrin activity in prostate cancer. In conclusion, this work will help us to understand complex regulatory pathways involved in cancer cell adhesion and migration.
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Metastases are the major cause of cancer deaths. Tumor cell dissemination from the primary tumor utilizes dysregulated cellular adhesion and upregulated proteolytic degradation of the extracellular matrix for progeny formation in distant organs. Integrins are transmembrane adhesive receptors mediating cellcell and cellmatrix interactions that are crucial for regulating cell migration, invasion, proliferation, and survival. Consequently, increased integrin activity is associated with augmented migration and invasion capacity in several cancer types. Heterodimeric integrins consist of an alpha - and beta-subunit that are held together in a bent conformation when the receptor is inactive, but extension and separation of subdomains is observed during receptor activation. Either inside-out or outside-in activation of receptors is possible through the intracellular molecule binding to an integrin cytoplasmic domain or extracellular ligand association with an integrin ectodomain, respectively. Several regulatory binding partners have been characterized for integrin cytoplasmic beta-domains, but the regulators interacting with the cytoplasmic alpha-domains have remained elusive. In this study, we performed yeast two-hybrid screens to identify novel binding partners for the cytoplasmic integrin alpha-domains. Further examination of two plausible candidates revealed a significant coregulatory role of an integrin alpha-subunit for cellular signaling processes. T-cell protein tyrosine phosphatase (TCPTP) showed a specific interaction with the cytoplasmic tail of integrin alpha1. This association stimulated TCPTP phosphatase activity, leading to negative regulation of epidermal growth factor receptor (EGFR) signaling and diminished anchorage-independent growth. Another candidate, mammary-derived growth inhibitor (MDGI), exhibited binding to several different integrin cytoplasmic alpha-tails through a conserved GFFKR sequence. MDGI overexpression in breast cancer cells altered EGFR trafficking and caused a remarkable accumulation of EGFR in the cytoplasm. We further demonstrated in vivo that MDGI expression induced a novel form of anti-EGFR therapy resistance. Moreover, MDGI binding to α-tails retained integrin in an inactive conformation attenuating integrin-mediated adhesion, migration, and invasion. In agreement with these results, sustained MDGI expression in breast cancer patients correlated with an increased 10-year distant disease-free survival. Taken together, the integrin signaling network is far from a complete view and future work will doubtless broaden our understanding further.
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Maailman energian kulutuksen lisääntymisen ja ilmastonmuutoksen myötä energiantuotannossa joudutaan jatkuvasti sopeutumaan muuttuviin tilanteisiin ja haasteisiin. Polttoteknillisiä haasteita aiheuttavat pelto- ja kierrätyspolttoaineet ovat lisäämässä osuuttaan uusiutuvien polttoaineiden joukossa. Jotta kyseisiä haasteellisia polttoaineita pystytään hyödyntämään, täytyy niiden aiheuttamat ongelmat tuntea ja laitevalmistajien kehittää niiden hyödyntämiseen sopivaa tekniikkaa. Tässä diplomityössä käydään läpi tulevaisuudessa käytettävät polttoaineet, nykyiset päästörajat, kiinteiden polttoaineiden poltto- ja kaasutustekniikat sekä likaantumis-, kuonaantumis- ja korroosiomekanismit voimalaitoskattiloissa. Työssä tutkitaan, onko haasteellisten polttoaineiden käyttöön investoiminen järkevää ja mikä nykypäivän tekniikoista on kannattavin. Myös välitulistuksen, lauhdeperän ja apujäähdyttimen kannattavuuksia vertaillaan sähkön ja lämmön yhteistuotannossa. Tuloksiksi saatiin, että edullisten peltobiomassojen ja kierrätyspolttoaineiden käyttäminen, joko perinteisten polttoaineiden seassa tai pääpolttoaineena, on nykyhinnoilla perinteisiin polttoaineisiin verrattuna kannattavaa. Investoiminen kierrätyspolttoaineiden valmistuslaitteisiin maksimoi kierrätyspolttoaineista saatavaa hyötyä. Välitulistuksen todettiin soveltuvan huonosti vastapaineprosessiin, sillä siitä saatava sähköntuotannon lisäys on hyvin pieni. Lauhdeperän ja apujäähdyttimen vertailuissa huomattiin, että lauhdeperä on kannattava investointi, jos sähkön ja lämmön hintaero pysyy tarpeeksi suurena. Haasteellisilla polttoaineilla pystytään pienentämään kasvihuonepäästöjä ja korvaamaan fossiilisten polttoaineiden käyttöä.
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The purpose of this study is to examine how well risk parity works in terms of risk, return and diversification relative to more traditional minimum variance, 1/N and 60/40 portfolios. Risk parity portfolios were constituted of five risk sources; three common asset classes and two alternative beta investment strategies. The three common asset classes were equities, bonds and commodities, and the alternative beta investment strategies were carry trade and trend following. Risk parity portfolios were constructed using five different risk measures of which four were tail risk measures. The risk measures were standard deviation, Value-at-Risk, Expected Shortfall, modified Value-at-Risk and modified Expected Shortfall. We studied also how sensitive risk parity is to the choice of risk measure. The hypothesis is that risk parity portfolios provide better return with the same amount of risk and are better diversified than the benchmark portfolios. We used two data sets, monthly and weekly data. The monthly data was from the years 1989-2011 and the weekly data was from the years 2000-2011. Empirical studies showed that risk parity portfolios provide better diversification since the diversification is made at the risk level. Risk based portfolios provided superior return compared to the asset based portfolios. Using tail risk measures in risk parity portfolios do not necessarily provide better hedge from tail events than standard deviation.
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This study presents a review of theories of the so-called post-industrial society, and proposes that the concept of post-industrial society can be used to understand the recent developments of the World Wide Web, often described as Web 2.0 or social Web. The study combines theories ranging from post-war management science and cultural studies to software development, and tries to build a holistic view of the development of the post-industrial society, and especially the Internet. The discourse on the emergence of a post-industrial society after the World Wars has addressed the ways in which the growing importance of information, and innovations in digital communications technology, are changing our society. It is furthermore deeply connected with the discourse on the postmodern society, which emphasizes cultural fragmentation, intertextuality, and pluralism. The Internet age is characterized by increasing masses of information that are managed through various technologies. While 1990s Internet technologies often used the network as a traditional broadcasting channel with added interactivity, Web 2.0 technologies are specifically designed to utilize the network model by facilitating communication between various services and devices, and analyzing the relationships between users and objects in order to produce intelligent insight. The wide adoption of the Internet, and recently of Internet-enabled mobile devices, is furthermore continuously producing new ways of communicating, consuming, and producing. Applications of the social Web, such as social media or social networking services, are permanently changing our traditional social, cultural, and economic practices. The study first presents an overview of the post-industrial society, the Internet, and the concept of Web 2.0. Then the concept of social Web is described with an analysis of the term social media, the brief histories of the interactive Web and social networking services, and a description of the concept ―long tail‖, used to represent the masses of information available in the Web that do not receive mainstream attention. Finally, methods for retrieving and filtering information, modeling social and cultural relationships, and communicating with customers, are presented.
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Tämän tutkimuksen tavoitteena oli nykyisin tuotantokäytössä olevan rullaoikaisukoneen automatisointi ja uuden oikaisukonekokonaisuuden mitoitus tulevaisuuden materiaaliominaisuuksien perusteella. Automatisoinnilla on tarkoitus nykyisessä käytössä helpottaa nauhahitsaajan työtä ja lähitulevaisuudessa optimoida romutustarvetta kelojen keula- ja häntäalueilla. Uuden oikaisukonekokonaisuuden osalta työssä on määritetty rullaoikaisukoneen rullakoot, rullien keskiöetäisyys, vaadittava moottoriteho ja rullien tuennan tarve sekä erillisen hilseenmurskaimen/rullavenytysoikaisukoneen tarve peittauslinjan toiminnassa. Rullaoikaisukoneen asetusarvojen laskeminen toteutettiin ympyräkaarimenetelmää ja seurantatutkimusta käyttäen. Ensimmäisen ylärullan asetteluarvot on laskettu suorilla kaavasovelluksilla. Toisen ylärullan kohdalla oli tarpeellista tehdä laajempaa seurantatutkimusta, jotta löydettiin sellainen tapa, jolla myös sen arvot saataisiin riippuvaiseksi ensimmäisen ylärullan asetteluarvoista ja ympyränkaarimenetelmästä. Uutta oikaisukonekokonaisuutta varten suoritettujen laskelmien perusteella rullaoikaisukoneen telakokoa ja keskiöetäisyyttä on pienennettävä, moottoritehoa on kasvatettava ja työrullien tuentaa on parannettava verrattuna nykyiseen tuotantokoneeseen. Esioikaisukonetyyppisen rullaoikaisukoneen rajoittuneesta oikaisutuloksesta ja tietyillä kelalaaduilla esiintyvä erittäin luja wüstiittihilse puoltaa vahvasti erillisen hilseenmurskaimen lisäämistä peittauslinjan konekantaan.
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Fibroblast growth factors (FGFs) are involved in the development and homeostasis of the prostate and other reproductive organs. FGF signaling is altered in prostate cancer. Fibroblast growth factor 8 (FGF8) is a mitogenic growth factor and its expression is elevated in prostate cancer and in premalignant prostatic intraepithelial neoplasia (PIN) lesions. FGF8b is the most transforming isoform of FGF8. Experimental models show that FGF8b promotes several phases of prostate tumorigenesis - including cancer initiation, tumor growth, angiogenesis, invasion and development of bone metastasis. The mechanisms activated by FGF8b in the prostate are unclear. In the present study, to examine the tumorigenic effects of FGF8b on the prostate and other FGF8b expressing organs, an FGF8b transgenic (TG) mouse model was generated. The effect of estrogen receptor beta (ERβ) deficiency on FGF8binduced prostate tumorigenesis was studied by breeding FGF8b-TG mice with ERβ knockout mice (BERKOFVB). Overexpression of FGF8b caused progressive histological and morphological changes in the prostate, epididymis and testis of FGF8b-TG-mice. In the prostate, hyperplastic, preneoplastic and neoplastic changes, including mouse PIN (mPIN) lesions, adenocarcinomas, sarcomas and carcinosarcomas were present in the epithelium and stroma. In the epididymis, a highly cancer-resistant tissue, the epithelium contained dysplasias and the stroma had neoplasias and hyperplasias with atypical cells. Besides similar histological changes in the prostate and epididymis, overexpression of FGF8b induced similar changes in the expression of genes such as osteopontin (Spp1), connective tissue growth factor (Ctgf) and FGF receptors (Fgfrs) in these two tissues. In the testes of the FGF8b-TG mice, the seminiferous epithelium was frequently degenerative and the number of spermatids was decreased. A portion of the FGF8b-TG male mice was infertile. Deficiency of ERβ did not accelerate prostate tumorigenesis in the FGF8b-TG mice, but increased significantly the frequency of mucinous metaplasia and slightly the frequency of inflammation in the prostate. This suggests putative differentiation promoting and anti-inflammatory roles for ERβ. In summary, these results underscore the importance of FGF signaling in male reproductive organs and provide novel evidence for a role of FGF8b in stromal activation and prostate tumorigenesis.
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Poster at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014
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In the framework of the biorefinery concept researchers aspire to optimize the utilization of plant materials, such as agricultural wastes and wood. For most of the known processes, the first steps in the valorisation of biomass are the extraction and purification of the individual components. The obtained raw products by means of a controlled separation can consecutively be modified to result in biofuels or biogas for energy production, but also in value-added products such as additives and important building blocks for the chemical and material industries. Considerable efforts are undertaken in order to substitute the use of oil-based starting materials or at least minimize their processing for the production of everyday goods. Wood is one of the raw materials, which have gained large attention in the last decades and its composition has been studied in detail. Nowadays, the extraction of water-soluble hemicelluloses from wood is well known and so for example xylan can be obtained from hardwoods and O-acetyl galactoglucomannans (GGMs) from softwoods. The aim of this work was to develop water-soluble amphiphilic materials of GGM and to assess their potential use as additives. Furthermore, GGM was also applied as a crosslinker in the synthesis of functional hydrogels for the removal of toxic metals and metalloid ions from aqueous solutions. The distinguished products were obtained by several chemical approaches and analysed by nuclear magnetic resonance spectroscopy (NMR), Fourier transform infrared spectroscopy (FTIR), size exclusion chromatography (SEC), thermal gravimetric analysis (TGA), scanning electron microscope SEM, among others. Bio-based surfactants were produced by applying GGM and different fatty acids as starting materials. On one hand, GGM-grafted-fatty acids were prepared by esterification and on the other hand, well-defined GGM-block-fatty acid derivatives were obtained by linking amino-functional fatty acids to the reducing end of GGM. The reaction conditions for the syntheses were optimized and the resultant amphiphilic GGM derivatives were evaluated concerning their ability to reduce the surface tension of water as surfactants. Furthermore, the block-structured derivatives were tested in respect to their applicability as additives for the surface modification of cellulosic materials. Besides the GGM surfactants with a bio-based hydrophilic and a bio-based hydrophobic part, also GGM block-structured derivatives with a synthetic hydrophobic tail, consisting of a polydimethylsiloxane chain, were prepared and assessed for the hydrophobization of surface of nanofibrillated cellulose films. In order to generate GGM block-structured derivatives containing a synthetic tail with distinguished physical and chemical properties, as well as a tailored chain length, a controlled polymerization method was used. Therefore, firstly an initiator group was introduced at the reducing end of the GGM and consecutively single electron transfer-living radical polymerization (SET-LRP) was performed by applying three different monomers in individual reactions. For the accomplishment of the synthesis and the analysis of the products, challenges related to the solubility of the reactants had to be overcome. Overall, a synthesis route for the production of GGM block-copolymers bearing different synthetic polymer chains was developed and several derivatives were obtained. Moreover, GGM with different molar masses were, after modification, used as a crosslinker in the synthesis of functional hydrogels. Hereby, a cationic monomer was used during the free radical polymerization and the resultant hydrogels were successfully tested for the removal of chromium and arsenic ions from aqueous solutions. The hydrogel synthesis was tailored and materials with distinguished physical properties, such as the swelling rate, were obtained after purification. The results generated in this work underline the potential of bio-based products and the urge to continue carrying out research in order to be able to use more green chemicals for the manufacturing of biorenewable and biodegradable daily products.
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Mammalian spermatozoa gain their fertilizing ability during maturation in the epididymis. Proteins and lipids secreted into the epididymal lumen remodel the sperm membrane, thereby providing the structure necessary for progressive motility and oocyte interaction. In the current study, genetically modified mouse models were utilized to determine the role of novel genes and regulatory systems in the postnatal development and function of the epididymis. Ablation of the mouse β-defensin, Defb41, altered the flagellar movements of sperm and reduced the ability of sperm to bind to the oocyte in vitro. The Defb41-deficient iCre knock-in mouse model was furthermore utilized to generate Dicer1 conditional knock-out (cKO) mice. DICER1 is required for production of mature microRNAs in the regulation of gene expression by RNA interference. Dicer1 cKO gave rise to dedifferentiation of the epididymal epithelium and an altered expression of genes involved in lipid synthesis. As a consequence, the cholesterol:polyunsaturated fatty acid ratio of the Dicer1 cKO sperm membrane was increased, which resulted in membrane instability and infertility. In conclusion, the results of the Defb41 study further support the important role of β-defensin family members in sperm maturation. The regulatory role of Dicer1 was also shown to be required for epididymal development. In addition, the study is the first to show a clear connection between lipid homeostasis in the epididymis and sperm membrane integrity. Taken together, the results give important new evidence on the regulatory system guiding epididymal development and function
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Epithelial ovarian cancer (EOC) is usually diagnosed in an advanced stage. The prognosis depends highly on the amount of the residual tumor in surgery. In patients with extensive disease, neoadjuvant chemotherapy (NACT) is used to diminish the tumor load before debulking surgery. New non-invasive methods are needed to preoperatively evaluate the disease dissemination and operability. [18F] FDG PET/CT (Positron emission tomography/computed tomography) is a promising method for cancer diagnostics and staging. The biomarker profiles during treatment can predict patient’s outcome. This prospective study included 41 EOC patients, 21 treated with primary surgery and 20 with NACT and interval surgery. The performances of preoperative contrast enhanced PET/CT (PET/ceCT) and diagnostic CT (ceCT) were compared. Perioperative visual estimation of tumor spread was studied in primary and interval surgery. The profile of the serum marker HE4 (Human epididymis 4) during primary chemotherapy was evaluated. In primary surgery, surgical findings were found to form an adequate reference standard for imaging studies. After NACT, the sensitivity for visual estimation of cancer dissemination was significantly worse. Preoperative PET/ceCT was more effective than ceCT alone in detecting extra-abdominal disease spread. The high number of supradiaphragmatic lymph node metastases detected by PET/ceCT at the time of diagnosis brings new insight in EOC spread patterns. The sensitivity of both PET/CT and ceCT remained modest in intra-abdominal areas important to operability. The HE4 profile was in concordance with the CA125 profile during primary chemotherapy. Its role in the evaluation of EOC chemotherapy response will be clarified in further studies.
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For my Licentiate thesis, I conducted research on risk measures. Continuing with this research, I now focus on capital allocation. In the proportional capital allocation principle, the choice of risk measure plays a very important part. In the chapters Introduction and Basic concepts, we introduce three definitions of economic capital, discuss the purpose of capital allocation, give different viewpoints of capital allocation and present an overview of relevant literature. Risk measures are defined and the concept of coherent risk measure is introduced. Examples of important risk measures are given, e. g., Value at Risk (VaR), Tail Value at Risk (TVaR). We also discuss the implications of dependence and review some important distributions. In the following chapter on Capital allocation we introduce different principles for allocating capital. We prefer to work with the proportional allocation method. In the following chapter, Capital allocation based on tails, we focus on insurance business lines with heavy-tailed loss distribution. To emphasize capital allocation based on tails, we define the following risk measures: Conditional Expectation, Upper Tail Covariance and Tail Covariance Premium Adjusted (TCPA). In the final chapter, called Illustrative case study, we simulate two sets of data with five insurance business lines using Normal copulas and Cauchy copulas. The proportional capital allocation is calculated using TCPA as risk measure. It is compared with the result when VaR is used as risk measure and with covariance capital allocation. In this thesis, it is emphasized that no single allocation principle is perfect for all purposes. When focusing on the tail of losses, the allocation based on TCPA is a good one, since TCPA in a sense includes features of TVaR and Tail covariance.