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(2019)It has lately become a common practice among national authorities with macroeconomic mandates to build large Dynamic Stochastic General Equilibrium (DSGE) models to assist in forecasting and policy analysis. The Finnish Ministry of Finance has also developed a small open economy New Keynesian DSGE model, “KOOMA”. As DSGE models try to emulate the key features and dynamics of the economy, the crucial question is, how well do they function in accordance with reality? An answer to this question can be searched by using Structural Vector Autoregression (SVAR) models, which are natural econometric counterparts to DSGE models and are better suited for analyzing data. The aim of this study is to evaluate the calibration of KOOMA with a SVAR model, which is identified with sign restrictions. I compare impulse response functions from the SVAR model, which are found both statistically significant and robust to changes in model specifications, to the equivalent impulse response functions from KOOMA. The findings suggest, that KOOMA generally produce impulse responses with same signs as the SVAR model, but there are some differences in the magnitudes and persistence of the responses.
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(2020)Central counterparties (CCPs) interpose themselves between the counterparties to contracts traded on financial markets, becoming the buyer to every seller and the seller to every buyer. Over the past two decades, CCPs have grown into some of the world’s most interconnected financial market infrastructures clearing financial instruments worth trillions of dollars a day. A possible default of a CCP has been described as an extremely high-impact event and notable academics have considered that a default of a CCP would require a large-scale tax payer bail-out. CCP-related financial stability concerns have grown especially in the European Union (EU) as the United Kingdom (UK) exited the EU on 31 January 2020 (Brexit). Many of the world’s leading CCPs are located in the City of London and Brexit has meant that these CCPs will be no longer authorised and supervised pursuant to the European Market Infrastructure Regulation (EU) No 648/2012 (EMIR). They are moving out of the EU’s jurisdiction and becoming “third country CCPs” from the perspective of the EU regulation. The EU confronts these growing financial stability concerns by revising EMIR with European Market Infrastructure Regulation (EU) 2019/2099 (EMIR 2.2). EMIR 2.2 has entered into force on 1 January 2020 and it introduces an unconventional approach to regulate third country CCPs. This approach includes a requirement for third country CCPs to accept direct regulation and supervision of the EU authorities despite the CCPs being located outside the EU’s jurisdiction. In addition, the regime enables the controversial “location policy”, a mechanism to compel third country CCPs to relocate into the EU. This research examines the tensions in extraterritorial regulation of systemically important CCPs and how EMIR 2.2 succeeds in its objective of reinforcing the overall stability of the Union financial system in relation to third country CCPs. The first part examines extraterritorial regulation and supervision of systemically important CCPs through the financial trilemma, a theory developed in economics and international governance, to discover the underlying tensions. The aim is to arrive at a framework that enables meaningful evaluation of EMIR 2.2. The second part evaluates whether EMIR 2.2 is capable to achieve its objective.
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(2022)Late blight, caused by Phytophthora infestans (Mont.) de Bary, is considered the most devastating disease in potato (Solanum tuberosum L.) production worldwide. Control methods involve mostly the use of fungicides, which are costly and are under political pressure for reduction in Europe. Potatoes from the major potato cultivar in Sweden, King Edward, previously stacked with three resistance (R) genes (RB, Rpi-blb2 and Rpi-vnt1.1) were tested in a local Swedish field, with spontaneous P. infestans infection over three seasons to evaluate the effectiveness and stability of the resistance on leaves. In addition, testing of resistance was done in both in leaves and tubers. Field results demonstrated that the 3R stacked into the cultivar King Edward, showed practically full resistance to infections of P. infestans, with no difference to fungicide use. Moreover, the resistance was effective in both leaves and tubers. The results reveal the 3R potatoes offer a functional field resistance, that could, alone, reduce the total use of fungicides in agriculture by several percent in Sweden, in an event of modifications in the EU legislation.
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(2022)The exploration of mineral resources is a major challenge in a world that seeks sustainable energy, renewable energy, advanced engineering, and new commercial technological devices. The rapid decrease in mineral reserves shifted the focus to under-explored and low accessibility areas that led to the use of on-site portable techniques for mineral mapping purposes, such as near infrared hyperspectral image sensors. The large datasets acquired with these instruments needs data pre-processing, a series of mathematical manipulations that can be achieved using machine learning. The aim of this thesis is to improve an existing method for mineralogy mapping, by focusing on the mineral classification phase. More specifically, a spectral similarity index was utilized to support machine learning classifiers. This was introduced because of the inability of the employed classification models to recognize samples that are not part of a given database; the models always classified samples based on one of the known labels of the database. This could be a problem in hyperspectral images as the pure component found in a sample could correspond to a mineral but also to noise or artefacts due to a variety of reasons, such as baseline correction. The spectral similarity index calculates the similarity between a sample spectrum and its assigned database class spectrum; this happens through the use of a threshold that defines whether the sample belongs to a class or not. The metrics utilized in the spectral similarity index were the spectral angler mapper, the correlation coefficient and five different distances. The machine learning classifiers used to evaluate the spectral similarity index were the decision tree, k-nearest neighbor, and support vector machine. Simulated distortions were also introduced in the dataset to test the robustness of the indexes and to choose the best classifier. The spectral similarity index was assessed with a dataset of nine minerals acquired from the Geological Survey of Finland retrieved from a Specim SWIR camera. The validation of the indexes was assessed with two mine samples obtained with a VTT active hyperspectral sensor prototype. The support vector machine was chosen after the comparison between the three classifiers as it showed higher tolerance to distorted data. With the evaluation of the spectral similarity indexes, was found out that the best performances were achieved with SAM and Chebyshev distance, which maintained high stability with smaller and bigger threshold changes. The best threshold value found is the one that, in the dataset analysed, corresponded to the number of spectra available for each class. As for the validation procedure no reference was available; because of this reason, the results of the mine samples obtained with the spectral similarity index were compared with results that can be obtained through visual interpretation, which were in agreement. The method proposed can be useful to future mineral exploration as it is of great importance to correctly classify minerals found during explorations, regardless the database utilized.
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(2019)Modern high energy physics describes natural phenomena in terms of quantum field theories (QFTs). The relevant calculations in QFTs aim at the evaluation of physical quantities, which often leads to the application of perturbation theory. In non-thermal theories these quantities emerge from, for example, scattering amplitudes. In high-temperature theories thermodynamical quantities, such as pressure, arise from the free energy of the system. The actual computations are often performed with Feynman diagrams, which visually illustrate multi-dimensional momentum (or coordinate) space integrals. In essence, master integrals are integral structures (within these diagrams) that can not be reduced to more concise or simpler integral representations. They are crucial in performing perturbative corrections to any system described by (any) QFT, as the diagrammatic structures reduce to linear combinations of master integrals. Traditional zero-temperature QFT relates the corresponding master integrals to multi-loop vacuum diagrams, which leads in practice to the evaluation of $d$-dimensional regularized momentum integrals. Upon transitioning to thermal field theory (TFT), the corresponding master integrals become multi-loop sum-integrals. Both the thermal and non-thermal master integral structures are explored at length, using $\overline{MS}$-scheme (Modified Minimal Subtraction) in the calculations. Throughout this thesis, a self-consistent methodology is presented for the evaluation of both types of master integrals, while limiting the calculations to one- and two-loop diagrams. However, the methods are easily generalized to more complex systems. The physical background of master integrals is introduced through a derivation of Feynman rules and diagrams for $\phi^4$ scalar field theory. Afterwards, the traditional $d$-dimensional master integral structures are considered, up to general two-loop structures with massive propagators. The evaluation strategies involve e.g. the Feynman parametrization and the Mellin-Barnes transform. The application of these results is demonstrated through the evaluation of three different diagrams appearing in the two-loop effective potential of the dimensionally reduced variant of the Standard model. The relevant thermal one-loop integral structures are introduced through the high-temperature expansion of a massive one-loop sum-integral (with a single massive propagator). The thermal multi-loop computations are predominantly considered with a methodology that decomposes the integrals into finite and infinite elements. Specifically, we demonstrate the removal of both the ultraviolet and infrared (UV and IR) divergences, and evaluate the remaining finite integral using the Fourier transform from momentum space back to coordinate space. The strategies are applied to multiple non-trivial diagrammatic structures arising from the Standard model.
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(2021)Large graphs often have labels only for a subset of nodes. Node classification is a semi-supervised learning task where unlabeled nodes are assigned labels utilizing the known information of the graph. In this thesis, three node classification methods are evaluated based on two metrics: computational speed and node classification accuracy. The three methods that are evaluated are label propagation, harmonic functions with Gaussian fields, and Graph Convolutional Neural Network (GCNN). Each method is tested on five citation networks of different sizes extracted from a large scientific publication graph, MAG240M-LSC. For each graph, the task is to predict the subject areas of scientific publications, e.g., cs.LG (Machine Learning). The motivation of the experiments is to give insight on whether the methods would be suitable for automatic labeling of scientific publications. The results show that label propagation and harmonic functions with Gaussian fields reach mediocre accuracy in the node classification task, while GCNN had a low accuracy. Label propagation was computationally slow compared to the other methods, whereas harmonic functions were exceptionally fast. Training of the GCNN took a long time compared to harmonic functions, but computational speed was acceptable. However, none of the methods reached a high enough classification accuracy to be utilized in automatic labeling of scientific publications.
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(2023)Immune checkpoint inhibitor (ICI) therapy aims to enhance the endogenous immune response against tumour cells, and it has become a potent treatment option for various types of cancers. Despite the promise of ICIs, most patients do not respond to the treatment. The primary limitation of ICI therapy is the immunosuppressive tumour microenvironment (TME), which is characterised by the lack of tumour- infiltrating cytotoxic T cells (CTLs) and the presence of immunosuppressive cells, such as tumour- associated macrophages (TAMs). A promising immunotherapeutic strategy that can promote antitumor immunity is oncolytic virus (OV) therapy. OVs can selectively replicate in and kill cancer cells, leading to the release of immunostimulatory molecules. These molecules can induce local inflammation and prime and recruit CTLs to the tumour site. In addition, OVs can also be used as a delivery platform for immunostimulatory transgenes that can further enhance the activation of anti-tumour immune response and help to overcome the immunosuppressive TME. Another strategy used to support anti-tumour immune responses and overcome immunosuppressive TME is epigenetic therapy. Epigenetic therapy can reprogram both cancer and immune cells towards a less immunosuppressive phenotype, thus helping to overcome the limitation of immune checkpoint therapy. The aim of this study was to generate a novel oncolytic adenovirus armed with epigenetic modifying transgene (EpiCRAd) to overcome the immunosuppressive TME and enhance the anti-tumour immune response. We tested its efficacy and immunogenicity in vitro and in vivo using a murine triple-negative breast cancer model. We demonstrated that EpiCRAd was able to modulate the epigenome of cancer cells without affecting viruses’ infectivity. Upon examining the potential effect of EpiCRAd on cancer cells, we observed that epigenetic regulation did not notably influence the expression of MHC class I and PD- L1 proteins, both of which play a role in the immune evasion mechanism of tumour cells. In addition, the in vivo experiments show that EpiCRAd controls tumour growth the best, especially together with an immune checkpoint inhibitor, suggesting that the virus was able to create an immune microenvironment more favourable for anti-tumour response. Interestingly, the TAM infiltration in the TME seems to reduce after treatment with EpiCRAd. Overall, the combination of epigenetic therapy with oncolytic virotherapy has shown promising results in converting immunotherapy-resistant tumours into immunotherapy-responsive tumours. Our findings provide valuable insights into the effect of EpiCRAd on cancer and immune cells. This study encourages exploring the use of epigenetic cancer remodelling and oncolytic viruses for cancer immunotherapy.
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(2018)Uusien lääkkeiden sydäntoksisuus ilmenee yleensä sydämen sähköisen toiminnan häiriöinä (rytmihäiriöt) ja supistustoiminnan heikkenemisenä. Tällä hetkellä uusien lääkemolekyylien sydänturvallisuutta arvioidaan lähinnä tutkimalla yhdisteen vaikutusta hERG-ionikanavan aktiivisuuteen sekä tutkimalla molekyylin vaikutusta aktiopotentiaalin kestoon. Nykymenetelmät perustuvat yksittäisiin solumalleissa tehtäviin ionikanavatutkimuksiin ja patch clamp-mittauksiin sekä koe-eläimillä tehtäviin toksisuustutkimuksiin. Nykymenetelmät ovat työläitä ja saadut tulokset eivät aina ennusta luotettavasti lääkeaineen sydänturvallisuutta ihmisen elimistössä. Optogenetiikka on optiikkaan ja geenimuokkaukseen perustuva menetelmä, joka mahdollistaa kohdesolujen tutkimisen ja hallitsemisen valon avulla. Menetelmässä hyödynnetään valoherkkiä proteiineja, opsiineja. Kun opsiineja koodaavat geenit on siirretty kohdesoluihin, voidaan solujen toimintaa arvioida ja ohjata valolla eri aallonpituuksia hyödyntäen. Optogeneettinen menetelmä soveltuu hyvin myös sydänlihassolujen sähköisen toiminnan tutkimiseen ja sydänlihassolujen tahdistamiseen. Sydänlihassolujen sähköfysiologisilla mittauksilla voidaan havaita esimerkiksi lääkeaineiden rytmihäiriövaikutuksia. Sydänlihassolujen tahdistamismahdollisuus kokeiden aikana on tärkeää, koska osa lääkkeen rytmihäiriövaikutuksista ilmaantuu vain normaalia korkeammilla syketaajuuksilla. Tämän tutkimuksen tavoitteena oli pystyttää ja validoida uusi optogeneettinen menetelmä lääkkeiden sydäntoksisuuden arvioimiseen. Valoherkät opsiinit Optopatch ja CaViar vietiin lentivirustransduktiolla ihmisen kantasoluperäisiin (induced pluripotent stem cell, iPSC) sydänlihassoluihin. Transdusoituja sydänlihassoluja tahdistettiin sinisen laservalon avulla. Sydänlihassolujen sähköistä toimintaa arvioitiin mittaamalla aktiopotentiaaleja sekä solunsisäistä kalsiumvirtausta optogeneettisen fluoresenssi- videomikroskopian avulla. Kuvantamisdatan käsittelyyn kehitettiin Matlab-pohjainen automaattinen analyysiohjelmisto. Videomikroskopiadatasta analysoitiin ohjelmiston avulla sähköfysiologisia muuttujia, kuten sydänlihassolujen syketaajuus, aktiopotentiaalien kesto (action potential duration, APD) ja amplitudi (APA) sekä kalsiumvirtauksen kesto (calcium transient duration, CTD). Optogeneettiseen menetelmään yhdistettiin myös videomikroskopia, jonka avulla voitiin arvioida solujen supistuvuutta. Optogeneettisellä menetelmällä saatuja tuloksia verrattiin patch clamp- menetelmällä saatuihin tuloksiin. Lentivirustransduktiot eivät olleet soluille toksisia, eikä virusten todettu aiheuttavan tilastollisesti merkitsevä muutoksia sydänlihassolujen sähköisessä toiminnassa. Optogeneettisella menetelmällä rekisteröidyt sähköfysiologiset muuttujat (syketaajuus, APD, APA) eivät eronneet tilastollisesti merkitsevästi patch clamp- mittauksilla saaduista tuloksista. Tutkimustulostemme perusteella voidaan optogeneettista menetelmää pitää yhtä luotettavana kuin perinteistä patch clamp-menetelmää. Lääkeainekokeissa sydänlihassolut altistettiin E-4031:lle (hERG kaliumkanavan salpaaja). Lääkkeen annosvasteiset tutkimukset tehtiin sekä spontaanisykkeellä että 1 Hz:n ja 2 Hz:n taajuuteen tahdistetuilla rytmeillä. E-4031 pidensi pienillä pitoisuuksilla aktiopotentiaalin kestoa, jota seurasivat suurilla pitoisuuksilla havaitut varhaiset jälkipolarisaatiot (early afterdepolarization, EAD) ja lopuksi sykkeen loppuminen. Patch clamp- ja supistuvuusmittauksissa saatiin esille samanlaiset vasteet E-4031 lääkealtistuksille. Samankaltainen, mutta E-4031:a vaatimattomampi lääkeainevaste saatiin esiin, kun solut altistettiin JNJ-303:lle (IKs kaliumkanavan salpaaja). Sydänlihassolujen optogeneettinen menetelmä soveltuu korvaamaan ja täydentämään perinteistä patch clamp-menetelmää uusien lääkkeiden sydäntoksisuustutkimuksissa. Yksittäisiin ionikanavatutkimuksiin soveltuu edelleen parhaiten patch clamp-menetelmä. Nopeutensa vuoksi optogeneettinen kuvantaminen soveltuu erityisesti lääkeaineaihioiden teho- ja turvallisuusseulontaan. Ei-invasiivisena menetelmänä optogenetiikka mahdollistaa myös pitkäaikaiset lääkeainealtistuskokeet.
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(2020)There are significant inter-individual differences in the effects of drugs. These differences can be caused by, for example, other diseases, adherence to treatment, or drug-drug interactions. A drug-drug interaction can lead to an increase in the concentration of the active substance in the circulation (pharmacokinetic interactions) or a change in the effect of the drug without changes in plasma concentration (pharmacodynamic interactions). A drug-drug interaction can change the efficacy of a drug or affect the adverse drug reaction profile. The individual’s genetic background, such as diversity in drug-modifying enzymes (polymorphism), also has an effect on the efficacy and the risk for adverse drug reactions of some drugs. A pharmacogenetic test can be used to study how genetic factors affect drug treatments. The aim of this master's thesis was to examine the possibilities of personalized migraine pharmacotherapy from the perspective of pharmacogenomics and drug-drug interactions. Four online drug-drug interaction databases available in Finland were compared. Inxbase is the most widely used interaction database by physicians in Finland and it is also integrated into Finnish pharmacy systems. Other databases used in this study were the international professional database Micromedex as well as Medscape Drug Interaction Checker and Drugs.com Drug Interactions Checker. The latter two are open-access databases available for healthcare professionals and patients. Interaction searches were conducted in the selected databases between acute and prophylactic drugs used for the treatment of migraine (e.g. bisoprolol-sumatriptan). Fourteen acute and 12 prophylactic drugs were selected for this study based on the Current Care Guidelines in Finland (Käypä hoito), and the data were collected in Excel spreadsheets. The first search was completed in December 2019 and the second search in March 2020. In this study, many potential interactions were found between acute and prophylactic drugs used to treat migraine in Finland. For more than half of the drug pairs studied, a potential interaction was found in at least one of the databases. There were significant differences between the interaction databases regarding which interactions the database contains and how the severity of the interactions was classified. Of the interactions found, only 45% were found in all four databases, and each database contained interactions that were not found in the other databases. Even very serious interactions or drug pairs classified as contraindicated were not found to be consistently presented across all four databases. When selecting drug treatment for a migraine patient, potential drug-drug interactions between acute and prophylactic drugs as well as the patient's genetic background should be considered. Individualizing migraine treatment to achieve the best efficacy and to reduce the risk for adverse drug reactions is important because migraine as a disease causes a heavy burden on individuals, healthcare, and society. Pharmacogenetic tests particularly developed to help choosing migraine treatment are not yet available, but tests are available for few other indications in both public and private healthcare. The use of these tests in clinical practice will increase as physicians’ pharmacogenetic knowledge and scientific evidence on pharmacogenetic tests increase. Utilization of pharmacogenetic data requires that test results are stored in electronic health records so that they are available in the future, when changes are made to drug treatment of individuals. More studies are warranted to better understand the clinical impact of pharmacogenomics and drug-drug interactions in migraine care.
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(2023)Parkinson’s disease is a progressive neurodegenerative disorder which is commonly treated with Levodopa (L-dopa) and Dopa Decarboxylase (DDC)/ Catechol-O-methyltransferase (COMT) inhibitors. The main problem with this treatment is the intestinal conversion of L-dopa to dopamine despite DDC and COMT inhibition which probably occurs by the Tyrosine Decarboxylase (TyrDC) of intestinal bacteria. This study aims to find new inhibitor molecules that would have dual inhibitory effects towards both DDC and TyrDC enzymes. Currently, available DDC inhibitors cannot inhibit the bacterial TyrDC enzyme. A recently found TyrDC inhibitor (S)-α-Fluoromethyltyrosine (AFMT) is not able to inhibit the human DDC enzyme, respectively. The dual inhibition of both decarboxylases could reduce the dosing frequency and side effects related to L-dopa. In addition, the object of this study is to produce the human DDC enzyme by DNA recombinant technique as well as develop and optimize a biochemical DDC inhibition assay to study the effect of selected small molecule compounds towards inhibition of DDC and L-dopa conversion in E. faecalis model by previously developed cell-based assay. The human DDC was successfully produced in a TB medium with a yield of 1.8 mg/mL. The Km value of DDC for L-dopa was found to be 34 μM which indicates a high affinity for L-dopa. In the optimization of the DDC inhibition assay, the sample volume of 80 μL and incubation time of 3 h with detection reagent was found to give the highest fluorometric signal with sufficient robustness. In the initial screening of test compounds, 14 % of the compounds (n=59) were classified as active towards human DDC, while 31 % of the compounds were active towards L-dopa conversion in the E. faecalis model. Of those compounds, five were having dose-dependent dual inhibitory effects, but the IC50 values of them were higher compared to either carbidopa or AFMT. The most effective compounds were 8009-2501 (IC50 37 μM in E. faecalis model and 19 % inhibition at 1000 μM towards DDC enzyme) and 8012-3386 (IC50 248 μM in E. faecalis model and 37 % inhibition at 1000 μM towards DDC enzyme). However, this study confirms the possibility to find dual decarboxylase inhibitors. By optimizing the structures as well as investigating the mechanism of action, selectivity, and structure-activity relationships of the most active compounds, it is possible to find more effective dual inhibitors in the future.
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(2015)Cereal β-glucan is a water-soluble cell wall polysaccharide, which has positive health effects on humans. Oxidative Degradation of β-glucan may occur during food processing, leading to the loss in physiological functionality of β-glucan. Oxidative degradation can result in cleavages of polysaccharide chain, the formation of oxidised functional groups (e.g. carbonyls) along the chain or the release of carboxylic acids (e.g. formic acid). In the case of β-glucan, chain scission and the formation of oxidised functional groups due to hydroxyl-radical induced oxidation has been shown, but the identification of released carboxylic acids has not been done. The aim was therefore to study the oxidation pathway of β-glucan, by analysing its degradation products. The focus was the release of carboxylic acids, especially formic acid. The change in molecular structure of β-glucan after the release of formic acid was also analysed. Barley β-glucan water solutions were oxidised with H2O2 and ascorbic acid at different concentrations (5, 10, 40, 70 mM), in the presence of 1 mM FeSO4·7H2O. Samples were collected on 1, 2 and 4 days and formic acid was analysed using formic acid assay kit. To evaluate the structure of oxidised β-glucan, part of the samples underwent reduction to convert any carbonyl groups back to hydroxyl groups. The oligosaccharide composition and monosaccharide composition of samples were then analysed. Results showed that formic acid was formed in H2O2 treated β-glucan and its content was positively correlated with H2O2 concentration in the presence of Fe2+. Formic acid was also formed in ascorbic acid treated β-glucan but an obvious increase in formic acid content at increased ascorbic acid concentration was not observed. Formic acid accumulated in β-glucan solution over time. Monosaccharide composition showed that samples were mainly composed of glucose. In H2O2 treated β-glucan, however, an additional component was observed which was identified to be arabinose. Arabinose was reduced by reducing agent, indicating that arabinose was formed at the reducing end of oxidised β-glucan. The content of arabinose increased with increasing H2O2 concentration, which was concomitant with a decreasing glucose content. Arabinose content decreased from oxidation day 1 to day 4. Oxidative degradation of β-glucan is proposed to proceed progressively, with random chain scission and degradation of the reducing ends. Formic acid was released due to oxidation and arabinose was formed at the reducing end. As oxidation proceeded, we suggest that the reducing end unit was degraded stepwise to release formic acid. Formic acid is demonstrated to be the oxidation product of β-glucan for the first time. The released formic acid was well related to the degree of oxidation induced by H2O2 and Fe2+. Therefore, formic acid can be used as an indicator for the oxidation of β-glucan induced by H2O2 and Fe2+.
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(2018)Auctions are in the core on the field of dynamic pricing. Prices alter as a function of time, by either ascending or descending, and the objective of this kind of pricing mechanism is to allocate the good for the one who is willing to pay the winning price. Northwestern University has used a pricing mechanism (Purple Pricing) combining characteristics of descending auction and dynamic pricing for several years in order to sell tickets to the university’s basketball teams’ home matches. The aim of this thesis is to examine and evaluate the functioning of this kind of mechanism. The main sources for the material and content for this literary survey can be categorized to three branches. Models and main theoretic results were provided by using related economic literature, practical model of Purple Pricing was taken as a research topic separately, and some of key facts regarding functioning of the pricing mechanism were gathered through enquiry. Main results were that Purple Pricing can be modelled by using Bellman equation and characterised as a descending auction where agents (the university and the spectators) interact with both sides having own separate maximization problems. The agents can be distinguished into seller and bidders. With certain assumptions regarding the agents, model can be solved. The solution in itself provides optimality conditions which maximize the allocation (and revenue maximization) problem of the organizer (the university). The functioning of the model has caused result concerning both ticket allocation, but also real life side effects. Besides being socially efficient in allocating the tickets, its merits have been likes of the disclosure of demand curve and abolishment of black market. Although due to its special pricing policy it was not able to reach optimum (maximum) revenue, increase in revenue did occur. Similar pricing mechanisms with context-related adjustments have potential to be used in Finnish football.
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(2016)Myyräkuume on Puumala-viruksen aiheuttama munuaisoireinen verenvuotokuume, jonka oirekuva vaihtelee lievästä vakavaan. Puumala-virus kuuluu jyrsijöiden, hyönteissyöjien ja lepakoiden levittämiin hantaviruksiin, jotka aiheuttavat munuaisoireista verenvuotokuumetta Euroopassa ja Aasiassa ja hantavirus-sydän-keuhko-oireyhtymää Amerikan mantereella. Puumala on Euroopan yleisin hantavirus ja sitä tavataan Pohjois-, Keski- ja Itä-Euroopassa ja Venäjällä. Sen kantajana toimii metsämyyrä (Myodes glareolus), jonka kannan vaihteluita myyräkuumeinsidenssi seuraa ollen noin 560–3800 vuosittain. Suomalaisista noin 5 % on Puumala-seropositiivisia, joskin luku on jopa 11 % Itä-Suomessa. Myyräkuumeen itämisaika on noin kahdesta neljään viikkoa. Tauti alkaa äkillisesti kuumeella ja päänsäryllä, joita seuraavat vatsa- ja selkäkivut, pahoinvointi ja oliguria. Taudin alussa noin kolmasosalla esiintyy myopiaa, joka on patognomonista myyräkuumeelle. Verenkuvassa näkyvät kohonnut CRP ja leukosyytit sekä trombosytopenia. 0,1 % potilaista menehtyy ja kuolinsyynä on useimmiten verenvuotoshokki tai aivolisäkkeen verenvuoto. 5 % potilaista päätyy dialyysiin ja jotkut kärsivät useamman vuoden ajan taudin sairastamisen jälkeen kohonneista verenpainearvoista. Myyräkuumeen laboratoriodiagnostiikka perustuu tällä hetkellä IgM-luokan vasta-aineiden osoittamiseen verestä. Potilaat serokonvertoituvat jo taudin ensimmäisinä päivänä, joten serologia on varsin käyttökelpoinen diagnostisena menetelmänä. Halusimme kuitenkin selvittää, onko myyräkuumetta mahdollista diagnosoida reaaliaikaisella PCR-testillä, joka osoittaisi Puumala-viruksen RNA:ta ja viremian potilaan verestä jo aivan taudin alkuvaiheessa. Keräsimme yhteensä 238 seeruminäytettä, jotka oli lähetetty HUSLAB-laboratorioon eri sairaaloista ja terveyskeskuksista rutiininomaista myyräkuumediagnostiikkaa varten. Lisäksi tutkittiin muille hantaviruksille positiiviset näytteet (Saaremaa, Tula, Tobografov, Dobrava ja Hantaan) sekä 20 negatiivista kontrollinäytettä. Näytteet tutkittiin rutiininomaisen IgM-testin lisäksi sekä kehittämällämme reaaliaikaisella qRT-PCR-menetelmällä (PUUV-qRT-PCR) että kaksivaiheisella RT-nested-PCR-menetelmällä, josta positiiviset näytteet lähetettiin eteenpäin sekvensoitaviksi. qRT-PCR-menetelmässä standardinäytteenä toimi Sotkamo-kannan RNA:n S-juoste. Diagnostiikassa positiivisiksi osoittautui 31 näytettä. Näistä 30 oli positiivisia serologisella menetelmällä. Yksi näyte jäi siis positiiviseksi ainoastaan PUUV-qRT-PCR:ssä. 30 IgM-positiivisesta näytteestä 28 oli positiivisia PUUV-qRT-PCR-menetelmällä. Diagnostinen sensitiivisyys oli 93.3% (95% CI: 77.93%-99.18%). Tutkimme positiivisen näytteen antaneiden potilaiden tiedot HUSLAB:n potilastietokannasta. Kävi ilmi, että vasta-ainenegatiivisesta, PUUV-qRT-PCR-positiivisen näytteen antaneesta potilaasta oli otettu näyte jo aivan taudin alkuvaiheissa, jolloin viremia on korkealla tasolla, mutta IgM-luokan vasta-aineet eivät ole vielä nousseet. Kyseisestä potilaasta otettiin vielä myöhemmin toinen näyte, joka oli positiivinen sekä IgM-testillä että PUUV-qRT-PCR-menetelmällä. Kaksi PUUV-qRT-PCR-menetelmällä negatiiviseksi jäänyttä IgM-positiivista potilasta oli puolestaan tutkittu 1-2 viikkoa oireiden alusta, jolloin viremia oli jo näin ollen ehtinyt laskea. Kaksivaiheisella RT-nested-PCR-menetelmällä tutkittuna 25 näytteestä oli osoitettavissa Puumala-viruksen RNA:ta. Nämä näytteet sekvensoitiin ja kannat järjestettiin fylogeeniseen puuhun eri suomalaisten kantojen oheen, mikä osoitti PCR-menetelmän löytävän varsin laajasti suomalaisia Puumala-viruskantoja. Negatiiviset kontrollinäytteet ja muille hantaviruksille positiiviset näytteet jäivät PCR-menetelmillä negatiivisiksi, joten menetelmän spesifisyys oli 100 %. Reaaliaikainen qRT-PCR-testi osoittautui sekä herkäksi että tarkaksi ja voisi toimia diagnostiikassa täydentävänä tutkimuksena serologisten menetelmien ohella. Se voisi joissain tapauksissa osittaa taudin jo ennen vasta-aineiden ilmaantumista. Haasteita viruksen RNA:n osoittamiselle diagnostiikassa asettaa Puumalan varsin suuri geneettinen varianssi. Todennäköisesti testimme on varsin spesifinen suomalaisille kannoille, mutta tutkimuksia erilaisilla Puumala-kannoilla tarvitaan vielä. Vastaavia tuloksia on saatu kahdessa ruotsalaistutkimuksessa, jossa reaaliaikainen PCR-testi osoittautui herkäksi ja tarkaksi, mutta varsin spesifiseksi ruotsalaisille kannoille.
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(2016)Ihmisten eliniän odotus on lisääntynyt laajasti ympäri maapalloa. Samaan aikaan on suun terveyden yhteyden merkitys yleisterveyteen lisääntynyt. Myös hammaslääketieteelliset hoidot ovat kehittyneet ja useampi hammas saadaan säästettyä johtaen siihen, että yksilöiden omien hampaiden lukumäärät ovat lisääntyneet. Nämä hampaat voivat kuitenkin toimia mahdollisina infektion lähteinä. Usein hammasinfektiot ovat luonteeltaan kroonisia sekä myös vähäoireisia. Nämä infektiot voivat aiheuttaa yleisinfektion, kuten sydänläppätulehduksen tai aivopaiseen. Suussa infektion voi muodostaa limakalvon (mukosiitti, ientulehdus) sekä hampaan kiinnityskudoksen tulehdukset (juuren kärjen tulehdus, luutulehdus, kystat sekä osittain puhjenneet viisauden hampaat. Karies ja parodontiitti ovat yleisimmät suun infektiofokukset. Parodontiitin pääriskitekijöiksi tiedetään huono suuhygienia, diabetes ja miessukupuoli kun taas karieksen riskitekijöksi tiedetään elämäntavat, kuten runsas sokerin syönti, runsas alkoholin nauttiminen sekä myös huono suuhygienia. Myös tupakka tiedetään liittyvän riskitekijänä parodontiittiin ja kariekseen, tosin karieksen suhteen on myös päinvastaista tutkimustietoa. Tutkimuksessa selvitettiin yhden vuoden kaikki HYKS:n suu ja leukasairauksien klinikkaan suun infektiofokusselvitykseen lähetetyt potilaat. Sisäänottakriteerinä oli vähintään 18 vuoden ikä ja epäily tai poissulku suun infektiofokuksesta. Potilaista kerättiin kaikki suun löydökset. Suun infektiofokus määriteltiin olevan parodontiitti, syvä karies tai jäännösjuuri, juurenkärjentulehdus, osittain puhjennut viisaudenhammas, osteomyeliitti, alveolaarinen osteiitti, mukosiitti, kysta tai traumaattinen löydös. Potilasta kerättiin kliiniset tiedot mukaan lukien käyttäytymistiedot kuten tupakointi, alkoholin käyttö sekä hammashoitohistoria. Vuoden aikana potilaita lähetettiin 2807 joista 408 suun infektiofokusselvityksiin. Näistä muodostui varsinainen tutkimusaineisto. 314 (77%) potilaalla todettiin suun infektiofokus. Suurimman ryhmän muodostivat syöpähoitoihin tulevat potilaat, ja toiseksi suurimman ryhmän immuunipuutteiset, syöpää sairastamattomat potilaat. Kolmanneksi suurimman ryhmän muodostivat bakteriellia etäinfektiota (endokardiitti, sepsis) tai autoimmuunisairautta sairastavat potilaat. Keski-ikä oli 58 vuotta ja suurin osa (69%) oli miehiä. Tupakointi, epäsäännöllinen hammaslääkärissä käynti, miessukupuoli sekä runsas alkoholin käyttö lisäsivät merkittävästi suun infektiofokusten esiintymistä. Monimuuttajamallissa tupakka lisäsi itsenäisenä riskitekijänä suun infektiofokusten esiintymistä. Tupakoitsijoilla oli myös merkitsevästi enemmän erilaisia suun infektiofokuksia, verrattuna tupakoimattomiin. Tilastollisesti merkitsevästi tupakoitsijoilla oli enemmän kariesta ja parodontiitia.
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(2022)To evaluate whether CMIP6 models provide good simulation in Arctic sea-ice extent, thickness, and motion, selected 6 CMIP6 models are EC-Earth3, ACCESS-CM2, BCC-CSM2-MR, GFDL-ESM4, MPI-ESM1-2-HR, NORESM2-LM. For CMIP6 models and observations, seasonal cycle and the annual variation from 1979-2014 of sea-ice extent were studied, for sea-ice thickness and sea-ice motion, the Arctic is separated into three regions, geographical distribution, inter-annual variation from 1979-2014, seasonal cycle, and trend were studied. Then student t-test is used to evaluate whether the model output has a significant difference from observation, to select the best model(s). For sea-ice extent, EC-Earth3 is overestimating sea-ice extent, especially in winter, BCC-CSM2-MR model underestimates sea-ice extent, ACCESS-CM2, MPI-ESM1-2-HR, NorESM2-LM models perform the best. For sea-ice thickness, BCC-CSM2-MR underestimates sea-ice thickness, EC-Earth3, ACCESS-CM2, and NORESM2-LM models are overestimating sea-ice thickness. GFDL-ESM4 and MPI-ESM1-2-HR have the best performance at sea-ice thickness simulation. For sea-ice motion, the MPI-ESM1-2-HR model overestimates sea-ice drifting speed all year round, ACCESS-CM2 model tends to overestimate sea-ice drifting speed in summer for region1 and region2, in region3 ACCESS-CM2 model mostly overestimate sea-ice motion except winter months. NorESM2-LM model has the best performance overall, and ACCESS-CM2 has the second-best simulation for region1 and region2. EC-Earth3 also has a satisfactory simulation for sea-ice motion. Models and observation also agree on common results for sea-ice properties: Maximum sea-ice extent occurs in March, and minimum sea-ice extent occurs in September. There's a decreasing trend of sea-ice extent. The Central Arctic and Canadian Archipelago always have the thickest sea ice, followed by the East Siberian Sea, Laptev Sea, and Chukchi Sea, Beaufort Sea. East Greenland Sea, Barents Sea, Buffin Bay, and the Kara Sea always have the thinnest sea ice. There's a decreasing trend for sea-ice thickness according to models, sea-ice is thicker in the Chukchi Sea and the Beaufort Sea than in Laptev and East Siberian seas. Winter sea-ice thickness is higher than in summer, and sea-ice thickness has a more rapid decreasing rate in summer than in winter. Laptev and the East Siberian Sea have the most rapidly sea-ice thinning process. Sea-ice thickness has seasonal cycle that maximum usually occurs in May, and minimum sea-ice thickness happens in October. For sea-ice motion, there's an increasing trend of sea-ice motion, and summer sea-ice motion has faster sea-ice motion than winter, Chukchi Sea, and the Beaufort Sea has faster sea-ice motion than Laptev and the East Siberian Sea. Corresponding with the comparatively faster-thinning in the Laptev and the East Siberian Seas simulated by models, there's also a faster increasing rate in the Laptev and the East Siberian Sea.
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(2016)Oncolytic viruses have been extensively studied for the treatment of cancer. They are genetically engineered viruses, which are able to selectively infect and kill the cancer cells causing no harm to normal cells. Adenoviruses are the most commonly used viruses in the gene therapy field and their oncolytic variants are currently under evaluation in many clinical trials. The cell killing properties of oncolytic adenoviruses against the cancer cells have been known for a long time. In addition, it is known that they can activate immune system. To achieve more selective and effective antitumor effects several modifications of oncolytic adenoviruses have been studied. During my internship I worked on the development of a new cancer vaccine platform based on peptide-coated conditionally replicating adenovirus (PeptiCRAd). The PeptiCRAd technology consists of a serotype 5 adenoviruses which are coated with tumorderived peptides. The aim of the thesis was to evaluate the antitumor efficacy of the PeptiCRAd. The cytopathic effects of the PeptiCRAd were studied in vitro using human adenocarcinoma cell line, A549. In this experiment three different treatments were used to study the cytopathic effects of the PeptiCRAd and Ad5Δ24-CpG- virus or polyK-SIINFEKL- peptide alone. The cell viability was assayed using MTS reagent and quantified by spectrophotometer. The antitumor effects were also studied in vivo using immunocompetent C57BL/6 mice bearing B16-OVA melanoma tumors. Tumor-bearing mice were treated with Ad5Δ24-CpG- virus, SIINFEKL- peptide or the PeptiCRAd. To evaluate the antitumor effects, tumor volume was observed after the treatments. In this study, I show that PeptiCRAd and Ad5Δ24-CpG- virus both have oncolytic effects in vitro against A549 cells. In vitro Ad5Δ24-CpG- virus showed significantly better cytopathic effects at high concentration compared to PeptiCRAd. In vivo the PeptiCRAd showed strongest antitumor effect on the growth of established tumors. At the end of the experiment the volume of the tumor was significantly smallest in the PeptiCRAd group.
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(2023)Background: The Finnish registry for Inflammatory Bowel Diseases (IBDs) was established in 2016. Currently it covers approximately 25 % of IBD patients in Finland. Aim: To review the Finnish IBD registry, compare it to existing IBD registries and to evaluate the reliability of the registry in clinical and research settings. Methods: A cohort of 921 patients was selected to evaluate the feasibility of the registry in research use. The cohort was analyzed to determine the relationship between clinical activity and fecal calprotectin (fCal), a surrogate biomarker of inflammation in the gut. Results: The strengths of the Finnish IBD registry include automatic transfer of parameters from electronic health records to the registry, possibility to use in daily clinical practice, and various parameters which can be utilized in quality control and research. However, there are several challenges for the future, notably the inaccuracy of data in registry parameters, most prominently in medications. In our cohort study, most patients had good disease control based on symptoms and fCal, including patients on either conventional or advanced therapies. Moreover, patients with a high fCal (≥ 100 µg/g) had significantly (p < 0.001) worse symptom control than those with a normal fCal (< 100 µg/g). This indicates the symptom questionnaire used was suggestive of disease activity in our cohort.
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(2019)Extracellular vesicles (EVs) are a diverse set of cell-derived membranous vesicles which have exosomes or small EVs (40 -200nm) ,large EVs (>200 nm) and larger apoptotic bodies/oncosomes (>1000 nm). They are present in most biological fluids, such as blood, sweat, and urine etc. EVs are expressed by almost all cells.Recent evidence suggests that EVs are a form of cellular communication, resulting in an intensive investigation of their role in different biological processes and also due to their biomarker potential. Ultracentrifugation (UC) is the standard method used for the isolation of EVs from different biological fluids. UC has some limitations related to laborious operation and scalability issues. Hence, there is a need for new methods for the isolation of EVs.Nanocellulose(NC) is a biopolymer obtained from wood biomass and has the ability to be functionalised with various chemical groups on its surface. The chemical groups alter the surface properties of NC for usability in different applications. Currently, It finds extensive use in different biomedical applications due to its unique physicochemical properties. The aim of the thesis is to evaluate the use of functionalised nanocellulose (FNC) as a novel alternative compared to the standard method of ultracentrifugation in the isolation of EVs from conditioned cell culture media. Cancer cell lines and mesenchymal stromal cells (MSCs) were grown in EV-depleted cell culture media after expansion in cell culture media. The EV-depleted media was collected from the cells after 48 hours and further processed by filtration to obtain the necessary conditioned cell culture media for EV isolation. Extracellular vesicles were isolated from the conditioned cell culture media by using UC and FNC. The isolated EVs from both methods were characterised and evaluated based on their different parameters using Bicinchoninic Acid (BCA) assay, Transmission Electron Microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and Western Blot. The EVs isolated by FNC were smaller in size with few vesicle-like structures around 20-40 nm compared to EVs isolated by UC 60-200nm. Most EVs isolated by UC had a higher particle-to-protein ratio which indicated more purity and reduced levels of non-vesicular contaminants in the EV isolations. The EVs isolated by FNC for many samples had a low particle-to-protein ratio indicating potentially higher levels of non-vesicular contaminants being present. Hsp70, a surface marker of EVs and soluble stress protein was observed in EVs obtained from a primary MSC and another cancer cell line among all the isolation methods. No contamination from Endoplasmic reticulum(ER) components was observed in any of the samples. The EVs isolated by FNC could not be analysed more thoroughly by some of the characterisation methods due to issues such as lack of standardised sample preparation protocols, possible interference from isolation components and sample variations. The isolation method will really benefit from further optimisation of sample preparation steps and the adoption of alternative characterisation methods for evaluation. A narrower research question with focus on FNC-EDA isolation of EVs from HOS-143B and AT-MSC will be an excellent starting point for more detailed investigations.The availability of different surface modifications, faster processing and more research on the isolation mechanism will make this novel method a great alternative to UC for isolation of EVs.
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(2021)Parkinson’s disease (PD) is a progressive chronic neurodegenerative disorder, which results in the selective loss of dopaminergic neurons in the substantia nigra (SN). The loss of these neurons results in the dysfunction of the nigrostriatal pathway bringing forth the characteristic motor symptoms seen in PD: postural instability, rigidity, slowness of movement and resting tremors. Non-motor symptoms, such as cognitive deficits, depression and impaired olfaction, typically emerge before motor symptoms. Currently available treatments only provide symptomatic relief with diminishing returns over time and no improvements on the overall outcome of the disease. Neurotrophic factors (NTF) have been of particular interest as a possible curative treatment for PD due to their potential for neuroprotection and neurorestoration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an NTF that has shown promising results in numerous in vitro and in vivo studies of PD. However, therapy with MANF and other NTFs involves surgical intervention for local administration, as NTFs cannot cross the blood-brain barrier (BBB). Therefore, the therapeutic potential of a systemically administered NTF would be tremendous, as it would lead to a significantly more favorable risk-benefit ratio for the patient. The aim of the current investigation is to evaluate the efficacy of a next generation variant of MANF in the 6-hydroxydopamine toxin-induced unilateral lesion rat model of PD. Prior in vivo results suggested that subcutaneously injected MANF variant is able to penetrate the BBB. Amphetamine-induced rotational behavior (AMPH-ROTO) was used to evaluate the severity of the unilateral lesions during the experiment every other week until the end of the experiment at week eight. Animals were divided into treatment groups during week two based on their AMPH-ROTO results. Animals received MANF variant either subcutaneously through an implanted osmotic minipump at two different dosages or as a single dose divided into three separate intrastriatal injections. Tyrosine hydroxylase (TH) immunohistochemical staining was performed on brain sections collected from the striatum and SN for data analysis. In addition to AMPH-ROTO results, the efficacy of treatment was determined via the optical density of TH-positive striatal fibers and the number of TH-positive cells in the SN. Statistically significant differences (defined by p < 0.05 and a non-zero mean difference at a 95 % confidence interval) were observed only in the number of TH-positive cells in the SN favoring intrastriatal MANF variant treatment over both intrastriatal MANF and the vehicle treatment. The main concern regarding the validity of the results was related to the heterogeneous lesion sizes in different treatment groups possibly resulting in unsuccessful randomization due to excessive baseline differences. The inadvertent negative effects of this was further exacerbated by low a priori statistical power, which in the end had likely caused inflated effect sizes. Thus, assessment of the definitions of the used statistical parameters and the limitations of the experimental design suggest that presently, the efficacy of the MANF variant could not be evaluated reliably, in spite of the statistically significant result.
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(2017)As sequencing costs decline and an increasing amount of genetic data without reference genome is produced there is a need for new reference-free methods for detecting genetic variation. This thesis defines the biological problem of variant detection, introduces some of the tools previously used for solving the issue, and takes an in-depth look at the new reference-free method DiscoSnp. Several test cases were run to assess the programs performance with different input variables.
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