VAP-1 as drug target in inflammation : structural features determining ligand interactions

Vascular adhesion protein-1 (VAP-1), which belongs to the copper amine oxidases (CAOs), is a validated drug target in inflammatory diseases. Inhibition of VAP-1 blocks the leukocyte trafficking to sites of inflammation and alleviates inflammatory reactions. In this study, a novel set of potent pyridazinone inhibitors is presented together with their X-ray structure complexes with VAP-1. The crystal structure of serum VAP-1 (sVAP-1) revealed an imidazole binding site in the active site channel and, analogously, the pyridazinone inhibitors were designed to bind into the channel. This is the first time human VAP-1 has been crystallized with a reversible inhibitor and the structures reveal detailed information of the binding mode on the atomic level. Similarly to some earlier studied inhibitors of human VAP-1, the designed pyridazinone inhibitors bind rodent VAP-1 with a lower affinity than human VAP-1. Therefore, we made homology models of rodent VAP-1 and compared human and rodent enzymes to determine differences that might affect the inhibitor binding. The comparison of the crystal structures of the human VAP-1 and the mouse VAP-1 homology model revealed key differences important for the species specific binding properties. In general, the channel in mouse VAP-1 is more narrow and polar than the channel in human VAP-1, which is wider and more hydrophobic. The differences are located in the channel leading to the active site, as well as, in the entrance to the active site channel. The information obtained from these studies is of great importance for the development and design of drugs blocking the activity of human VAP-1, as rodents are often used for in vivo testing of candidate drugs. In order to gain more insight into the selective binding properties of the different CAOs in one species a comprehensive evolutionary study of mammalian CAOs was performed. We found that CAOs can be classified into sub-families according to the residues X1 and X2 of the Thr/Ser-X1-X2-Asn-Tyr-Asp active site motif. In the phylogenetic tree, CAOs group into diamine oxidase, retina specific amine oxidase and VAP-1/serum amine oxidase clades based on the residue in the position X2. We also found that VAP-1 and SAO can be further differentiated based on the residue in the position X1. This is the first large-scale comparison of CAO sequences, which explains some of the reasons for the unique substrate specificities within the CAO family.

The role of product features on buyer-supplier collaboration in packaging industry

The thesis presents the study relative to the collaboration between suppliers and buyers in packaging industry with the impact of product features. The main purpose of this study is to examine the importance of product characteristics on collaboration to develop better packaging and to figure out how buyer-supplier collaboration in the supply chain perspectives is conducted and managed in packaging industry. The theoretical part reviewed some basic frameworks of collaboration including the scopes and levels of collaboration, risks as well as powers of collaboration, relationship and some key factors for successful collaboration. Followed by the overviews of packaging industry with the main issues related to product characteristics in packaging. By using the qualitative method, secondary data consisting of articles, reports, websites and primary data through interviewing some well-known packaging companies and case companies are collected in the thesis. The empirical result emphasized the importance of product features’ analysis in packaging industry since it plays a central role in the materials, design process, production and innovation with the role of collaboration. Collaboration in packaging is vital for packaging companies to survive and grow in the competitive environment. Finally, some key factors for effective collaboration were summarized based on the perspectives of packaging companies. It is highly recommend building a long-run collaboration with their customers due to undeniable benefits With increasingly importance of collaboration in packaging industry, further studies may be conducted.

English L2 Learners’ Speech – And How the Spoken Language Course Affects Its Lexical Richness

Tässä sivuaineen tutkielmassa tarkasteltiin englannin kielen sanaston kehitystä lukion vieraan kielen syventävän suullisen kurssin aikana. Tutkimuksessa selvitettiin, miten oppilaiden sanastollinen rikkaus muuttuu puhutussa kielessä. Sanastollista rikkautta analysoitiin sanastollisen variaation ja sanastollisen tiheyden mittareilla. Työssä hyödynnettiin pitkittäistutkimusasetelmaa eli verrattiin yhden oppilasryhmän puhetta sekä ennen lukion englannin kielen suullista kurssia että sen jälkeen. Osanottajia oli yhteensä yhdeksän, jotka kaikki olivat lukion toisella vuosikurssilla. Osallistujien tekemät suulliset testit olivat osa Turun yliopiston keräämää tutkimuskäyttöön tarkoitettua materiaalia. Äänitteistä tehdyt transkriptiot muokattiin tätä tutkimusta varten sopiviksi, jonka jälkeen niistä mitattiin sanastollista rikkautta erilaisilla mittareilla. Aineistoa tutkittiin määrällisin menetelmin. Tulokset osoittavat, että keskimääräisesti sekä puheen sanastollinen variaatio että sanastollinen tiheys kehittyivät kurssin aikana hiukan. Toisin sanoen oppilaat käyttivät kurssin jälkeen tehdyssä testissä aavistuksen verran monipuolisempaa sanastoa, ja sisältösanojen osuus kieliopillisiin sanoihin nähden oli hieman suurempi kuin ennen kurssia. Kurssin aikana oppilaiden aktiivisessa sanavarastossa tapahtunut kehitys ei kuitenkaan ollut tilastollisesti merkitsevää. Lisäksi tutkimus osoitti, että osallistujien väliset erot olivat suuria, mutta erot tasoittuivat jonkin verran kurssin jälkeen. Tutkimustulosten perusteella voidaan olettaa englannin kielen suullisen kurssin sekä lisänneen oppilaiden sanastollista rikkautta että tasoittaneen yksilöllisiä eroja, yhdessä monien muiden mahdollisten tekijöiden kanssa. Tutkimusotoksen pienuuden vuoksi tuloksia ei kuitenkaan voida yleistää. Jatkossa olisi mielenkiintoista laajentaa tutkimusnäkökulmaa koskemaan muitakin sanastollisen rikkauden osa-alueita kuten sanastollista sofistikaatiota. Olisi myös mielenkiintoista sisällyttää tutkimukseen oppilaiden passsiivisen sanavaraston mittaaminen ja mahdollisesti tutkia englannin kielen suullisen kurssin vaikutuksia oppilaiden suullisen kielitaidon kehittymiseen laajemminkin kuin vain sanavaraston osalta.

Central auditory processing and the acquisition of phonology in 2-year-old children with recurrent acute otitis media

Middle ear infections (acute otitis media, AOM) are among the most common infectious diseases in childhood, their incidence being greatest at the age of 6–12 months. Approximately 10–30% of children undergo repetitive periods of AOM, referred to as recurrent acute otitis media (RAOM). Middle ear fluid during an AOM episode causes, on average, 20–30 dB of hearing loss lasting from a few days to as much as a couple of months. It is well known that even a mild permanent hearing loss has an effect on language development but so far there is no consensus regarding the consequences of RAOM on childhood language acquisition. The results of studies on middle ear infections and language development have been partly discrepant and the exact effects of RAOM on the developing central auditory nervous system are as yet unknown. This thesis aims to examine central auditory processing and speech production among 2-year-old children with RAOM. Event-related potentials (ERPs) extracted from electroencephalography can be used to objectively investigate the functioning of the central auditory nervous system. For the first time this thesis has utilized auditory ERPs to study sound encoding and preattentive auditory discrimination of speech stimuli, and neural mechanisms of involuntary auditory attention in children with RAOM. Furthermore, the level of phonological development was studied by investigating the number and the quality of consonants produced by these children. Acquisition of consonant phonemes, which are harder to hear than vowels, is a good indicator of the ability to form accurate memory representations of ambient language and has not been studied previously in Finnish-speaking children with RAOM. The results showed that the cortical sound encoding was intact but the preattentive auditory discrimination of multiple speech sound features was atypical in those children with RAOM. Furthermore, their neural mechanisms of auditory attention differed from those of their peers, thus indicating that children with RAOM are atypically sensitive to novel but meaningless sounds. The children with RAOM also produced fewer consonants than their controls. Noticeably, they had a delay in the acquisition of word-medial consonants and the Finnish phoneme /s/, which is acoustically challenging to perceive compared to the other Finnish phonemes. The findings indicate the immaturity of central auditory processing in the children with RAOM, and this might also emerge in speech production. This thesis also showed that the effects of RAOM on central auditory processing are long-lasting because the children had healthy ears at the time of the study. An effective neural network for speech sound processing is a basic requisite of language acquisition, and RAOM in early childhood should be considered as a risk factor for language development.

Publication Statistics Speech recordings 1995-

Vapaakappalekartuntaan perustuva tilasto Suomessa julkaistuista puheäänitteistä vuodesta 1995 lähtien