Assessment of In-House Natural Product and Synthetic Compound Libraries Based on In vitro Inhibition of Cholinesterases

The first line medication for mild to moderate Alzheimer s disease (AD) is based on cholinesterase inhibitors which prolong the effect of the neurotransmitter acetylcholine in cholinergic nerve synapses which relieves the symptoms of the disease. Implications of cholinesterases involvement in disease modifying processes has increased interest in this research area. The drug discovery and development process is a long and expensive process that takes on average 13.5 years and costs approximately 0.9 billion US dollars. Drug attritions in the clinical phases are common due to several reasons, e.g., poor bioavailability of compounds leading to low efficacy or toxic effects. Thus, improvements in the early drug discovery process are needed to create highly potent non-toxic compounds with predicted drug-like properties. Nature has been a good source for the discovery of new medicines accounting for around half of the new drugs approved to market during the last three decades. These compounds are direct isolates from the nature, their synthetic derivatives or natural mimics. Synthetic chemistry is an alternative way to produce compounds for drug discovery purposes. Both sources have pros and cons. The screening of new bioactive compounds in vitro is based on assaying compound libraries against targets. Assay set-up has to be adapted and validated for each screen to produce high quality data. Depending on the size of the library, miniaturization and automation are often requirements to reduce solvent and compound amounts and fasten the process. In this contribution, natural extract, natural pure compound and synthetic compound libraries were assessed as sources for new bioactive compounds. The libraries were screened primarily for acetylcholinesterase inhibitory effect and secondarily for butyrylcholinesterase inhibitory effect. To be able to screen the libraries, two assays were evaluated as screening tools and adapted to be compatible with special features of each library. The assays were validated to create high quality data. Cholinesterase inhibitors with various potencies and selectivity were found in natural product and synthetic compound libraries which indicates that the two sources complement each other. It is acknowledged that natural compounds differ structurally from compounds in synthetic compound libraries which further support the view of complementation especially if a high diversity of structures is the criterion for selection of compounds in a library.

A Possible and Necessary Consistency Proof

After Gödel's incompleteness theorems and the collapse of Hilbert's programme Gerhard Gentzen continued the quest for consistency proofs of Peano arithmetic. He considered a finitistic or constructive proof still possible and necessary for the foundations of mathematics. For a proof to be meaningful, the principles relied on should be considered more reliable than the doubtful elements of the theory concerned. He worked out a total of four proofs between 1934 and 1939. This thesis examines the consistency proofs for arithmetic by Gentzen from different angles. The consistency of Heyting arithmetic is shown both in a sequent calculus notation and in natural deduction. The former proof includes a cut elimination theorem for the calculus and a syntactical study of the purely arithmetical part of the system. The latter consistency proof in standard natural deduction has been an open problem since the publication of Gentzen's proofs. The solution to this problem for an intuitionistic calculus is based on a normalization proof by Howard. The proof is performed in the manner of Gentzen, by giving a reduction procedure for derivations of falsity. In contrast to Gentzen's proof, the procedure contains a vector assignment. The reduction reduces the first component of the vector and this component can be interpreted as an ordinal less than epsilon_0, thus ordering the derivations by complexity and proving termination of the process.

Pietismin kuva - ikkuna yksityiseen hengellisyyteen : Johann Arndtin opetukset pietistisen embleemin perustana

The image of Pietism a window to personal spirituality. The teachings of Johann Arndt as the basis of Pietist emblems The Pietist effect on spiritual images has to be scrutinised as a continuum initiating from the teachings of Johann Arndt who created a protestant iconography that defended the status of pictures and images as the foundation of divine revelation. Pietist artworks reveal Arndtian part of secret, eternal world, and God. Even though modern scholars do not regarded him as a founding father of Pietism anymore, his works have been essential for the development of iconography, and the themes of the Pietist images are linked with his works. For Arndt, the starting point is in the affecting love for Christ who suffered for the humankind. The reading experience is personal and the words point directly at the reader and thus appear as evidence of the guilt of the reader as well as of the love of God. Arndt uses bounteous and descriptive language which has partially affected promoting and picturing of many themes. Like Arndt, Philipp Jakob Spener also emphasised the heart that believes. The Pietist movement was born to oppose detached faith and the lack of the Holy Ghost. Christians touched by the teachings of Arndt and Spener began to create images out of metaphors presented by Arndt. As those people were part of the intelligentsia, it was natural that the fashionable emblematics of the 17th century was moulded for the personal needs. For Arndt, the human heart is manifested as a symbol of soul, personal faith or unbelief as well as an allegory of the burning love for Jesus. Due to this fact, heart emblems were gradually widely used and linked with the love of Christ. In the Nordic countries, the introduction of emblems emanated from the gentry s connections to the Central Europe where emblems were exploited in order to decorate books, artefacts, interiors, and buildings as well as visual/literal trademarks of the intelligentsia. Emblematic paintings in the churches of the castles of Venngarn (1665) and Läckö (1668), owned by Magnus Gabriel De la Gardie, are one of the most central interior paintings preserved in the Nordic countries, and they emphasise personal righteous life. Nonetheless, it was the books by Arndt and the Poet s Society in Nurnberg that bound the Swedish gentry and the scholars of the Pietist movement together. The Finnish gentry had no castles or castle churches so they supported county churches, both in building and in maintenance. As the churches were not private, their iconography could not be private either. Instead, people used Pietist symbols such as Agnus Dei, Cor ardens, an open book, beams, king David, frankincense, wood themes and Virtues. In the Pietist images made for public spaces, the attention is focused on pedagogical, metaphorical, and meaningful presentation as well as concealed statements.

Diplomatian historiapolitiikka: Historia-argumenttien käyttö Kosovon kysymyksessä 1998-2010

Tutkielmassa tarkastellaan yhtä kansainvälisten suhteiden ja diplomatian lähihistorian pulmallisinta haastetta, kysymystä Kosovon asemasta vuosina 1998–2010. Se oli yksi keskeisimmistä 1990-luvun Jugoslavian hajoamissotien solmukohdista ja suhtautuminen siihen jakaa edelleen kansainvälisen yhteisön rivejä maailmanlaajuisesti. Tapaus on erityisen mielenkiintoinen myös nationalismin ja historiapolitiikan kannalta, sillä Kosovo on sekä albaanien että serbien kansallisen identiteetin ydinaluetta. Varhaishistorian myytit ja etnohistorialliset kertomukset ovat olleet tärkeässä asemassa lukuisissa aluetta koetelleissa konflikteissa. Tutkimuksen lähtökohtana on historiapolitiikan lähestymistavan välttämättömyys kansainvälisesti politisoituneen ”Kosovon kysymyksen” ymmärtämisessä. Historiapolitiikan teoreettisen viitekehyksen soveltuvuuden koettelu diplomatian argumentaation ja kansainvälisten suhteiden analysoinnissa on olennainen osa tutkimuksen tehtävänasettelua, sillä varsinkaan Suomessa ei vastaavaa tutkimusta ole ennen tehty. Samalla tutkimuksen tavoitteena on luokitella, analysoida ja vertailla eri valtioiden diplomaattisten historia-argumenttien käyttöä Kosovon kysymyksen yhteydessä sekä tarkastella näiden argumenttien kautta suhtautumista kansallisiin etnohistorian tulkintoihin ja niiden käyttöön 1990-luvun retoriikassa. Tutkielman tärkeimpiä alkuperäislähteitä ovat YK:n turvallisuusneuvoston Kosovoa käsittelevien istuntojen pöytäkirjat vuosilta 1998–2010 sekä huhti- ja heinäkuussa 2009 YK:n kansainväliselle tuomioistuimelle (ICJ) toimitetut, Kosovon itsenäisyysjulistuksen lainmukaisuutta käsittelevät, kirjalliset lausunnot ja kommentit. Tutkimuskirjallisuuden osalta tutkielman tärkeimpiä lähteitä ovat muun muassa Oliver Jens Schmittin, Marc Wellerin ja Pekka Visurin teokset sekä monet albaanien ja serbien kansallisia historiakäsityksiä ilmentävät teokset. Tutkielman metodologisena apuvälineenä on sovellettu suomalaisessa tutkimuksessa aikaisemmin hyvin vähän käytettyä Karl-Georg Faberin mallia historian poliitisen käytön kategorisoimiseksi. Faberin mallia käytetään paitsi historia-argumenttien luokittelun kehikkona, myös ajattelua ohjaavana historianfilosofisena kolmitasoisena mallina. Sitä on täydennytty Chaïm Perelmanin ja Lucie Olbrechts-Tytecan retoriikan tutkimuksen teorialla. Tutkimuksen tärkeimpiä johtopäätöksiä on historiapolitiikan näkökulman ja Faberin mallin hedelmällisyyden toteaminen diplomatian argumentaation analysoinnissa. Samalla tutkimus osoittaa, että historia-argumenteilla oli (ja on edelleen) Kosovon kysymyksessä oma erityinen roolinsa, joka vaihteli ajallisesti ja teemoittain. Toisaalta kansalliset historiakäsitykset, kuten käsitys omasta kansasta uhrina, näkyivät argumenteissa selvästi, toisaalta pyrkimyksenä oli vältellä nationalistiseksi tulkittavia historia-argumentteja. Lisäksi monissa argumenteissa vaaditiin väkivaltaisen historian jättämistä taakse eurooppalaisen tulevaisuuden toivossa.