Improved synthesis of [18F] fallypride and characterization of a Huntington’s disease mouse model, zQ175DN KI, using longitudinal PET imaging of D2/D3 receptors

Dopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington’s disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [18F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [18F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD.Peer reviewe

Liiketoimintasuunnitelma pienyritykselle

Tässä toiminnallisessa opinnäytetyössä toteutettiin toimeksiantona liiketoimintasuunnitelma. Toimeksiantajana toimi Itä-Suomessa toimiva pienyritys, joka työllistää pääasiassa vain yrittäjän. Tavoitteena oli laatia uusi liiketoimintasuunnitelma yrityksen kehittämistä varten tilanteessa, jossa yrityksen oli joko laajennettava liiketoimintaansa tai kehitettävä uutta olemassa olevan rinnalle. Uuden liiketoimintasuunnitelman tavoitteena oli olla helposti yrittäjän itsensä päivitettävissä myös tulevaisuudessa. Toteutettu liiketoimintasuunnitelma on salainen. Opinnäytetyöraportissa perehdyttiin liiketoimintasuunnitelman teoriaan yleisesti ja sitä käsiteltiin myös toimeksiantajayrityksen näkökulmasta. Toimeksiantajayrityksen liiketoimintasuunnitelmassa painottuivat yrityksen strategia ja tulevaisuuden tavoitteet sekä yrityksen talous ja riskienhallinta, mitkä huomioitiin myös laajemmin tässä raportissa. Opinnäytetyön lähteinä käytettiin sekä alan kirjallisuutta että internetsivustoja. Lisäksi tietoa saatiin toimeksiantajayrittäjältä. Opinnäytetyönä syntyi pienyritykselle liiketoimintasuunnitelma ja kehitysideoita yritystoiminnan tehostamiseksi ja laajentamiseksi. Lisäksi opinnäytetyön yhteydessä tehtiin toimeksiantajayrityksen kehitystä tukevat työkalut talouden seuraamista ja toiminnan suunnittelua vartenAbstract The purpose of this study was to create a business plan for a small-sized company. The company mainly employs the entrepreneur himself and is located in Eastern Finland. The objective was to develop a new business plan for the client in case of need to expand the current business or innovate new services. The aim of the thesis was to make a such business plan that can easily be updated by the entrepreneur himself in the future. The business plan is confidential. The study report focus on the theory of business plans in general. The theory was processed in the client's perspective. The business plan emphasizes the company's strategy and visions for the future. The financial and risk management of the company were also observed in the report. Moreover, the entrepreneur’s interview, various literature sources and websites were used as sources of information in the study. The thesis provides a business plan for a small-sized company as well as ideas for expanding and strengthening business operations. In addition, tools for business plan and finance management were carried out for the client company

Palvelumuotoilun ja lahjoittajakeskeisyyden vahvistaminen nonprofit-organisaation varainhankintatoiminnassa

Opinnäytetyössä tarkastellaan lahjoittajakeskeisyyden vahvistamista Suomen Sydänliitto ry:n varainhankintatoiminnassa. Tavoitteena on palvelumuotoilun keinoin tunnistaa kasvun mahdollistavat toimenpiteet ja vaikuttamiskeinot. Lahjoittamiskäyttäytyminen on tällä hetkellä voimakkaassa muutoksessa, kun ihmisten osallistuminen on muuttumassa enemmän kertaluontoiseksi. Nonprofit-organisaatioiden rooli huolehtia ihmisten ja yhteiskunnan hyvinvoinnista tulee kuitenkin tulevaisuudessa kasvamaan, ja sillä on suora vaikutus myös varainhankintatoiminnan kasvu- ja kehittämistarpeeseen voittoa tavoittelemattomien organisaatioiden toiminnassa. Teoreettisessa viitekehyksessä lahjoittajakeskeisyyttä on tarkastelu asiakasymmärryksen, arvotekijöiden, palvelumuotoilun ja vaikuttamismuotoilun kautta. Tutkimuksellinen osuus on kuvattu palvelumuotoiluprosessin vaiheiden mukaisesti keskittyen kolmeen ensimmäiseen: määrittelyyn, tutkimukseen ja suunnitteluun. Tutkimuksessa käytetään laadullisen tutkimuksen aineistonkeruumenetelmiä ja hyödynnetään palvelumuotoilun menetelmiä tulosten kuvaamisessa. Tutkimusaineiston muodostavat sekundääriaineistona käytetyt asiakas- ja markkinatutkimukset, puhelinhaastatteluaineisto sekä työpajatoiminnan kautta saatu tutkimusaineisto. Keskeisenä tekijänä tutkimuksen tuotoksissa on asiakasymmärryksen syventäminen kohdeorganisaation toiminnassa. Kehittämisehdotuksena on esitetty palvelumuotoilun yhteiskehittämisen ja palveluiden jatkuvan arvioinnin juurruttamista osaksi organisaation toimintaa. Tutkimuksen tuloksena on kuvattu lahjoittamisen Service Blueprint –malli ja luotu organisaatiolle ehdotukset lahjoittajapersoonista, joiden tarkoituksena on syventää asiakasymmärrystä organisaatiossa sekä luoda polku aidosti lahjoittajalähtöiseen toimintaan.The thesis studies how donor centred thinking benefits a non-profit organization’s fundraising. The case organization of this thesis is the Finnish Heart Association. This thesis aims at finding growth possibilities in the case organization’s fundraising by using service design methods and influence communications. At the moment charity giving is undergoing major changes in Finland. The way people participate in non-profit organizations’ activities has recently changed to a more ad hoc way. However, in the future the role of non-profit organization in taking care of people’s well-being in society will get stronger. This also creates new and growing needs for fundraising in all non-profit organizations. The theoretical framework of this thesis considers donor centred thinking through customer understanding, customer value, service design thinking and influence communications. The research part of the thesis has been described through the service design process, focusing especially on the first three part: definition, research and design. The thesis has been implemented by using qualitative research methods. Service design methods have been used for describing the results. The material has been collected by analysing customer surveys and market research, by telephone interviews and by arranging an internal workshop at the case organization. The results of the thesis are the Service Blueprint of the donation process and donor personas. The aim is to deepen customer understanding in the organization and create a path to truly donor centred fundraising actions. The key factor for using the Service Blueprint and the personas is to adopt customer oriented service thinking and co-creation methods as a part of organizational behaviour in the future. This has been mentioned as a development proposal for the case organization in the final conclusion

Modeling of Charge Transfer at Dye-Semiconductor Interfaces in p-Type Solar Cells

Dye-sensitized solar cells are composed of cheap and recyclable materials. These colorful and flexible cells convert sunlight into renewable energy. However, dye-sensitized solar cells are inefficient due to their low-charge current. The goal of this thesis is thus to create better understanding of the various components of these cells in order to improve their efficiencies. The main focus of dye-sensitized solar energy research lies in charge-transfer reactions between three main components: dye molecule; semiconductor surface, and electrolyte. In dye-sensitized solar cells, the charge is transferred from the excited dye molecule to the semiconductor surface. The charge is then transported to the electrode to create the electric current.The studied components are derivatives of boron-dipyrromethene, perylene monoimide, and trisphenyl amine as dye molecules. Nickel oxide and titanium dioxide are used as semiconductor surfaces. The studied anchoring groups are carboxylate, 1,2-diol, and pyridine. These are studied in isolation, and then, their interactions in contact are investigated. In this study theoretical modeling is used, which includes the hybrid functional B3LYP and CRYSTAL09 software. The hybrid functional, B3LYP, is not widely used in studies within periodic boundary conditions such as dye-semiconductor interfaces. Thus, the mentioned systems have not been studied earlier at this level of theory.In the first part of the study, the isolated systems, namely derivatives borondipyrromethene and titanium dioxide, are investigated. Results with BODIPY show that i) the vinylene group makes no difference for the electron transition nor orbital localization of orbitals, ii) phosphonate draws the most and carboxyl the least amount of the electron localization from the anchor, iii) methyl groups block completely the electron localization from the anchoring group, and iv) the absence of donor decreases the energy of HOMO level. BODIPY with vinylene and methyl groups were chosen for the synthesis, because the methyl groups increase the life-time of electron–hole pair. Doping with nitrogen shows that the amount of nitrogen atoms makes difference for electronic structure, yet do not distort the lattice. The electronic structure changes due to the created empty gaps states that enhance electron conductivity.In the second part of this study, derivates of perylenemonoimide based dye molecules trisphenyl amine based anchoring groups on the NiO(100) surface and their interactions are investigated. The study with complete dye molecules on the nickel oxide surface is straightforward: the dyes’ highest occupied molecular orbital is above nickel oxide’s valence band maximum, thus, the spontaneous charge transfer is hard to obtain. Next it is shown that the anchoring group impacts the energy level alignment because of created dipole moment of the system that creates a shift within an electrostatic potential. Due to the shift, the highest occupied molecular orbitals of the dye molecule are either above (in case of carboxylate) or below (in the cases of pyridine and 1,2-diol) valence band maximum. In the case of complete molecules, which have the carboxylate as an anchoring group, HOMOs are above the VBM.The results and analysis of the study show the importance of the size of the molecule and the anchoring group. The smaller the dye molecule, the smaller the distances are inside the interacting system, and shorter distances to transfer the charge. In the case of complete molecules, which have the carboxylate as an anchoring group, HOMOs are above the VBM. In conclusion, the largest effect is caused by the anchoring group inside the interacting system

Working with benchmark datasets in the Cuby framework

The development and benchmarking of computational chemistry methods relies on comparison with benchmark data. More and larger benchmark datasets are becoming available, and working efficiently with them is a necessity. The Cuby framework provides rich functionality for working with datasets, comes with many ready-to-use predefined benchmark sets, and interfaces with a wide range of computational chemistry software. Here we review the tools Cuby provides for working with datasets and provide examples of more advanced workflows, such as handling large numbers of computations on HPC resources and reusing previously computed data. Cuby has also been extended recently to include two important benchmark databases, NCIAtlas and GMTKN55

Functional panchromatic BODIPY dyes with near-infrared absorption: design, synthesis, characterization and use in dye-sensitized solar cells

International audienc

Early retinal function deficit without prominent morphological changes in the R6/2 mouse model of huntington’s disease

Huntington’s disease (HD) is an inherited neurodegenerative disorder that primarily affects the medium-size GABAergic neurons of striatum. The R6/2 mouse line is one of the most widely used animal models of HD. Previously the hallmarks of HDrelated pathology have been detected in photoreceptors and interneurons of R6/2 mouse retina. Here we aimed to explore the survival of retinal ganglion cells (RGCs) and functional integrity of distinct retinal cell populations in R6/2 mice. The pattern electroretinography (PERG) signal was lost at the age of 8 weeks in R6/2 mice in contrast to the situation in wild-type (WT) littermates. This defect may be attributable to a major reduction in photopic ERG responses in R6/2 mice which was more evident in b- than a-wave amplitudes. At the age of 4 weeks R6/2 mice had predominantly the soluble form of mutant huntingtin protein (mHtt) in the RGC layer cells, whereas the aggregated form of mHtt was found in the majority of those cells from the 12-week-old R6/2 mice and onwards. Retinal astrocytes did not contain mHtt deposits. The total numbers of RGC layer cells, retinal astrocytes as well as optic nerve axons did not differ between 18-week-old R6/2 mice and their WT controls. Our data indicate that mHtt deposition does not cause RGC degeneration or retinal astrocyte loss in R6/2 mice even at a late stage of HDrelated pathology. However, due to functional deficits in the rod- and conepathways, the R6/2 mice suffer progressive deficits in visual capabilities starting as early as 4 weeks; at 8 weeks there is severe impairment. This should be taken into account in any behavioral testing conducted in R6/2 mice

The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain.

The aim of these studies was to demonstrate the therapeutic capacity of an antisense oligonucleotide with the sequence (CUG)7 targeting the expanded CAG repeat in huntingtin (HTT) mRNA in vivo in the R6/2 N-terminal fragment and Q175 knock-in Huntington's disease (HD) mouse models. In a first study, R6/2 mice received six weekly intracerebroventricular infusions with a low and high dose of (CUG)7 and were sacrificed 2 weeks later. A 15-60% reduction of both soluble and aggregated mutant HTT protein was observed in striatum, hippocampus and cortex of (CUG)7-treated mice. This correction at the molecular level resulted in an improvement of performance in multiple motor tasks, increased whole brain and cortical volume, reduced levels of the gliosis marker myo-inositol, increased levels of the neuronal integrity marker N-aceyl aspartate and increased mRNA levels of the striatal marker Darpp-32. These neuroanatomical and neurochemical changes, together with the improved motor performance, suggest that treatment with (CUG)7 ameliorates basal ganglia dysfunction. The HTT-lowering was confirmed by an independent study in Q175 mice using a similar (CUG)7 AON dosing regimen, further demonstrating a lasting reduction of mutant HTT protein in striatum, hippocampus and cortex for up to 18 weeks post last infusion along with an increase in motor activity. Based on these encouraging results, (CUG)7 may thus offer an interesting alternative HTT-lowering strategy for HD