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.

Molecular background of three lethal fetal syndromes

This study identified the molecular defects underlying three lethal fetal syndromes. Lethal Congenital Contracture Syndrome 1 (LCCS1, MIM 253310) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD, MIM 611890) are fetal motor neuron diseases. They affect the nerve cells that control voluntary muscle movement, and eventually result in severe atrophy of spinal cord motor neurons and fetal immobility. Both LCCS1 and LAAHD are caused by mutations in the GLE1 gene, which encodes for a multifunctional protein involved in posttranscriptional mRNA processing. LCCS2 and LCCS3, two syndromes that are clinically similar to LCCS1, are caused by defective proteins involved in the synthesis of inositol hexakisphosphate (IP6), an essential cofactor of GLE1. This suggests a common mechanism behind these fetal motor neuron diseases, and along with accumulating evidence from genetic studies of more late-onset motor neuron diseases such as Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), implicates mRNA processing as a common mechanism in motor neuron disease pathogenesis. We also studied gle1-/- zebrafish in order to investigate whether they would be a good model for studying the pathogenesis of LCCS1 and LAAHD. Mutant zebrafish exhibit cell death in their central nervous system at two days post fertilization, and the distribution of mRNA within the cells of mutant zebrafish differs from controls, encouraging further studies. The third lethal fetal syndrome is described in this study for the first time. Cocoon syndrome (MIM 613630) was discovered in a Finnish family with two affected individuals. Its hallmarks are the encasement of the limbs under the skin, and severe craniofacial abnormalities, including the lack of skull bones. We showed that Cocoon syndrome is caused by a mutation in the gene encoding the conserved helix-loop-helix ubiquitous kinase CHUK, also known as IκB kinase α (IKKα). The mutation results in the complete lack of CHUK protein expression. CHUK is a subunit of the IκB kinase enzyme that inhibits NF-κB transcription factors, but in addition, it has an essential, independent role in controlling keratinocyte differentiation, as well as informing morphogenetic events such as limb and skeletal patterning. CHUK also acts as a tumor suppressor, and is frequently inactivated in cancer. This study has brought significant new information about the molecular background of these three lethal fetal syndromes, as well as provided knowledge about the prerequisites of normal human development.

Interplay of Virulence Factors in Complement Resistance of Streptococcus pneumoniae

Streptococcus pneumoniae (pneumococcus) is a normal inhabitant of the human nasopharynx. Symptoms occur in only a small proportion of those who become carriers, but the ubiquity of the organism in the human population results in a large burden of disease. S. pneumoniae is the leading bacterial cause of pneumonia, sepsis, and meningitis worldwide, causing the death of a million children each year. Middle-ear infection is the most common clinical manifestation of mucosal pneumococcal infections. In invasive disease, S. pneumoniae gains access to the bloodstream and spreads to normally sterile parts of the body. The progression from asymptomatic colonization to disease depends on factors characteristic of specific pneumococcal strains as well as the status of host defenses. The polysaccharide capsule surrounding the bacterium is considered to be the most important factor affecting the virulence of pneumococci. It protects pneumococci from phagocytosis and also may determine its affinity to the respiratory epithelium. S. pneumoniae as a species comprises more than 90 different capsular serotypes, but not all of them are equally prevalent in human diseases. Invasive serotypes are rarely isolated from healthy carriers, but relatively often cause invasive disease. Serotypes that are carried asymptomatically for a long time behave like opportunistic pathogens, causing disease in patients who have impaired immune defenses. The complement system is a collection of blood and cell surface proteins that act as a major primary defense against invading microbes. Phagocytic cells with receptors for complement proteins can engulf and destroy pneumococcal cells opsonized with these proteins. S. pneumoniae has evolved a number of ways to subvert mechanisms of innate immunity, and this is likely to contribute to its pathogenicity. The capsular serotype, proteins essential for virulence, as well the genotype, may all influence the ability of pneumococcus to resist complement and its potential to cause disease. Immunization with conjugate vaccines produces opsonic antibodies, which enhance complement deposition and clearance of the bacteria. The pneumococcal vaccine included in the Finnish national immunization program in 2010 contains the most common serotypes causing invasive disease. Clinical data suggest that protection from middle-ear infection and possibly also from invasive disease depends largely on the capsular serotype, for reasons hitherto unknown. The general aim of this thesis is to assess the relative roles of the pneumococcal capsule and virulence proteins in complement evasion and subsequent opsonophagocytic killing. The main question is whether differences between serotypes to resist complement explain the different abilities of serotypes to cause disease. The importance of particular virulence factors to the complement resistance of a strain may vary depending on its genotype. Prior studies have evaluated the effect of the capsule and virulence proteins on complement resistance of S. pneumoniae by comparing only a few strains. In this thesis, the role of pneumococcal virulence factors in the complement resistance of the bacterium was studied in several genotypically different strains. The ability of pneumococci to inhibit deposition of the complement protein C3 on the bacterial surface was found to depend on the capsular serotype as well as on other features of the bacteria. The results suggest that pneumococcal histidine triad (Pht) proteins may play a role in complement inhibition, but their contribution depends on the bacterial genotype. The capsular serotype was found to influence complement resistance more than the bacterial genotype. A higher concentration of anticapsular antibodies was required for the opsonophagocytic killing of serotypes resistant to C3 deposition. The invasive serotypes were more resistant to C3 deposition than the opportunistic serotypes, suggesting that the former are better adapted to resist immune mechanisms controlling the development of invasive disease. The different susceptibilities of serotypes to complement deposition, opsonophagocytosis, and resultant antibody-mediated protection should be taken into account when guidelines for serological correlates for vaccine efficacy evaluations are made. The results of this thesis suggest that antibodies in higher quantity or quality are needed for efficient protection against the invasive serotypes.

Electrocardiographic parameters of ventricular repolarization : modifiers and the prognostic value

Electric activity of the heart consists of repeated cardiomyocyte depolarizations and repolarizations. Abnormalities in repolarization predispose to ventricular arrhythmias. In body surface electrocardiogram, ventricular repolarization generates the T wave. Several electrocardiographic measures have been developed both for clinical and research purposes to detect repolarization abnormalities. The study aim was to investigate modifiers of ventricular repolarization with the focus on the relationship of the left ventricular mass, antihypertensive drugs, and common gene variants, to electrocardiographic repolarization parameters. The prognostic value of repolarization parameters was also assessed. The study subjects originated from a population of more than 200 middle-aged hypertensive men attending the GENRES hypertension study, and from an epidemiological survey, the Health 2000 Study, including more than 6000 participants. Ventricular repolarization was analysed from digital standard 12-lead resting electrocardiograms with two QT-interval based repolarization parameters (QT interval, T-wave peak to T-wave end interval) and with a set of four T-wave morphology parameters. The results showed that in hypertensive men, a linear change in repolarization parameters is present even in the normal range of left ventricular mass, and that even mild left ventricular hypertrophy is associated with potentially adverse electrocardiographic repolarization changes. In addition, treatments with losartan, bisoprolol, amlodipine, and hydrochlorothiazide have divergent short-term effects on repolarization parameters in hypertensive men. Analyses of the general population sample showed that single nucleotide polymorphisms in KCNH2, KCNE1, and NOS1AP genes are associated with changes in QT-interval based repolarization parameters but not consistently with T-wave morphology parameters. T-wave morphology parameters, but not QT interval or T-wave peak to T-wave end interval, provided independent prognostic information on mortality. The prognostic value was specifically related to cardiovascular mortality. The results indicate that, in hypertension, altered ventricular repolarization is already present in mild left ventricular mass increase, and that commonly used antihypertensive drugs may relatively rapidly and treatment-specifically modify electrocardiographic repolarization parameters. Common variants in cardiac ion channel genes and NOS1AP gene may also modify repolarization-related arrhythmia vulnerability. In the general population, T-wave morphology parameters may be useful in the risk assessment of cardiovascular mortality.

On the use of weather radar for mesoscale applications in northern conditions

Mesoscale weather phenomena, such as the sea breeze circulation or lake effect snow bands, are typically too large to be observed at one point, yet too small to be caught in a traditional network of weather stations. Hence, the weather radar is one of the best tools for observing, analyzing and understanding their behavior and development. A weather radar network is a complex system, which has many structural and technical features to be tuned, from the location of each radar to the number of pulses averaged in the signal processing. These design parameters have no universal optimal values, but their selection depends on the nature of the weather phenomena to be monitored as well as on the applications for which the data will be used. The priorities and critical values are different for forest fire forecasting, aviation weather service or the planning of snow ploughing, to name a few radar-based applications. The main objective of the work performed within this thesis has been to combine knowledge of technical properties of the radar systems and our understanding of weather conditions in order to produce better applications able to efficiently support decision making in service duties for modern society related to weather and safety in northern conditions. When a new application is developed, it must be tested against ground truth . Two new verification approaches for radar-based hail estimates are introduced in this thesis. For mesoscale applications, finding the representative reference can be challenging since these phenomena are by definition difficult to catch with surface observations. Hence, almost any valuable information, which can be distilled from unconventional data sources such as newspapers and holiday shots is welcome. However, as important as getting data is to obtain estimates of data quality, and to judge to what extent the two disparate information sources can be compared. The presented new applications do not rely on radar data alone, but ingest information from auxiliary sources such as temperature fields. The author concludes that in the future the radar will continue to be a key source of data and information especially when used together in an effective way with other meteorological data.

How the development of condensation particle counters is reforming our view on atmospheric nucleation

Aerosol particles deteriorate air quality, atmospheric visibility and our health. They affect the Earth s climate by absorbing and scattering sunlight, forming clouds, and also via several feed-back mechanisms. The net effect on the radiative balance is negative, i.e. cooling, which means that particles counteract the effect of greenhouse gases. However, particles are one of the poorly known pieces in the climate puzzle. Some of the airborne particles are natural, some anthropogenic; some enter the atmosphere in particle form, while others form by gas-to-particle conversion. Unless the sources and dynamical processes shaping the particle population are quantified, they cannot be incorporated into climate models. The molecular level understanding of new particle formation is still inadequate, mainly due to the lack of suitable measurement techniques to detect the smallest particles and their precursors. This thesis has contributed to our ability to measure newly formed particles. Three new condensation particle counter applications for measuring the concentration of nano-particles were developed. The suitability of the methods for detecting both charged and electrically neutral particles and molecular clusters as small as 1 nm in diameter was thoroughly tested both in laboratory and field conditions. It was shown that condensation particle counting has reached the size scale of individual molecules, and besides measuring the concentration they can be used for getting size information. In addition to atmospheric research, the particle counters could have various applications in other fields, especially in nanotechnology. Using the new instruments, the first continuous time series of neutral sub-3 nm particle concentrations were measured at two field sites, which represent two different kinds of environments: the boreal forest and the Atlantic coastline, both of which are known to be hot-spots for new particle formation. The contribution of ions to the total concentrations in this size range was estimated, and it could be concluded that the fraction of ions was usually minor, especially in boreal forest conditions. Since the ionization rate is connected to the amount of cosmic rays entering the atmosphere, the relative contribution of neutral to charged nucleation mechanisms extends beyond academic interest, and links the research directly to current climate debate.

Identification of molecules relevant for the invasiveness of fibrosarcomas and melanomas

Cancer is becoming the leading cause of deaths in the world. As 90% of all deaths from cancer are caused by metastasis, discovery of the mechanisms behind cancer cell invasion and metastasis is of utmost importance. Only new effective therapies targeting cancer progression can reduce cancer mortality rates. The aim of this study was to identify molecules that are relevant for tumor cell invasion and spreading in fibrosarcomas and melanomas, and to analyze their potential for cancer biomarkers or therapeutic targets. First, the gene expression changes of normal cells and transformed cells showing high invasiveness, S-adenosylmethionine decarboxylase (AdoMetDC)-transfected murine fibroblasts and human melanoma cells, were studied by microarray analyses. The function of the identified candidate molecules were then studied in detail in these cell lines. Finally, the physiological relevance of the identified changes was studied by immunohistochemical analyses of human sarcoma and melanoma specimens or by a mouse xenograft model. In fibrosarcoma cells, the most remarkable change detected was a dramatic up-regulation of the actin-sequestering molecule thymosin beta 4 (TB4), which was shown to be important for the transformed phenotype of the AdoMetDC-transfected cells (Amdc-s and -as). A sponge toxin latrunculin A, inhibiting the binding of TB4 to actin, was found to selectively inhibit the migration and invasion of these cells. Further, Amdc-s-induced mouse tumors and human high-grade sarcomas were found to show intense TB4 immunostaining. In addition to TB4, integrin subunits alfa 6 and beta 7 (ItgA6 and ItgB7) were found to be up-regulated in Amdc-s and -as cells. ItgA6 was shown to dimerize mainly with ItgB1 in Amdc-s. Inhibition of ItgA6 or ItgB1 function with neutralizing antibodies fully blocked the invasiveness of Amdc-s cells, and importantly also human HT-1080 fibrosarcoma cells, in three-dimensional (3D)-Matrigel mimicking tumor extracellular matrix (ECM). By immunohistochemical analyses, strong staining for ITGA6 was detected in human high-grade fibrosarcomas and other sarcomas, especially at the invasion fronts of the tumors. In the studied melanoma cell lines, the expression levels of the adhesion-related ECM proteins tenascin-C (TN-C), fibronectin (FN), and transforming growth factor beta-induced (TGFBI) were found to be highly up-regulated. By immunohistochemistry, intense TN-C and FN staining was detected in invasive and metastatic melanoma tumors, showing co-localization (together with procollagen-I) in tubular meshworks and channels around the invading melanoma cells. In vitro, TN-C and FN were further found to directly stimulate the migration of melanoma cells in 3D-collagen-I matrix. The third candidate protein, TGFBI, was found to be an anti-adhesive molecule for melanoma cells, and knockdown of its expression in metastatic melanoma cells (TGFBI-KD cells) led to dramatically impaired tumor growth in immunocompromized mice. Interestingly, the control tumors showed intense TGFBI immunostaining in the invasion fronts, showing partial co-localization with the fibrillar FN staining, whereas the small TGFBI-KD cell-induced tumors displayed amorphous, non-fibrillar FN staining. These data suggest an important role for TGFBI in FN fibrillogenesis and melanoma progression. In conclusion, we have identified several invasion-related molecules, which show potential for cancer diagnostic or prognostic markers, or therapeutic targets. Based on our previous and present fibrosarcoma studies, we propose the possibility of using ITGA6 antagonists (affecting tumor cell adhesion) in combination with TB4 inhibitors (affecting tumor cell migration) and cathepsin L inhibitors (affecting the degradation of basement membrane and ECM proteins) for the treatment of fibrosarcomas and other tumors overexpressing these molecules. With melanoma cells, in turn, we point to the importance of three secreted ECM proteins, TN-C, FN, and TGFBI, in melanoma progression. Of these, especially the potential of TN-C as a prognostic melanoma biomarker and TGFBI as a promising therapeutic target molecule are clearly worth additional studies.

Physical Properties of Deep Drill Cores : Implications for Meteorite Impact Effects and Crustal Structures

Physical properties provide valuable information about the nature and behavior of rocks and minerals. The changes in rock physical properties generate petrophysical contrasts between various lithologies, for example, between shocked and unshocked rocks in meteorite impact structures or between various lithologies in the crust. These contrasts may cause distinct geophysical anomalies, which are often diagnostic to their primary cause (impact, tectonism, etc). This information is vital to understand the fundamental Earth processes, such as impact cratering and associated crustal deformations. However, most of the present day knowledge of changes in rock physical properties is limited due to a lack of petrophysical data of subsurface samples, especially for meteorite impact structures, since they are often buried under post-impact lithologies or eroded. In order to explore the uppermost crust, deep drillings are required. This dissertation is based on the deep drill core data from three impact structures: (i) the Bosumtwi impact structure (diameter 10.5 km, 1.07 Ma age; Ghana), (ii) the Chesapeake Bay impact structure (85 km, 35 Ma; Virginia, U.S.A.), and (iii) the Chicxulub impact structure (180 km, 65 Ma; Mexico). These drill cores have yielded all basic lithologies associated with impact craters such as post-impact lithologies, impact rocks including suevites and breccias, as well as fractured and unfractured target rocks. The fourth study case of this dissertation deals with the data of the Paleoproterozoic Outokumpu area (Finland), as a non-impact crustal case, where a deep drilling through an economically important ophiolite complex was carried out. The focus in all four cases was to combine results of basic petrophysical studies of relevant rocks of these crustal structures in order to identify and characterize various lithologies by their physical properties and, in this way, to provide new input data for geophysical modellings. Furthermore, the rock magnetic and paleomagnetic properties of three impact structures, combined with basic petrophysics, were used to acquire insight into the impact generated changes in rocks and their magnetic minerals, in order to better understand the influence of impact. The obtained petrophysical data outline the various lithologies and divide rocks into four domains. Based on target lithology the physical properties of the unshocked target rocks are controlled by mineral composition or fabric, particularly porosity in sedimentary rocks, while sediments result from diverse sedimentation and diagenesis processes. The impact rocks, such as breccias and suevites, strongly reflect the impact formation mechanism and are distinguishable from the other lithologies by their density, porosity and magnetic properties. The numerous shock features resulting from melting, brecciation and fracturing of the target rocks, can be seen in the changes of physical properties. These features include an increase in porosity and subsequent decrease in density in impact derived units, either an increase or a decrease in magnetic properties (depending on a specific case), as well as large heterogeneity in physical properties. In few cases a slight gradual downward decrease in porosity, as a shock-induced fracturing, was observed. Coupled with rock magnetic studies, the impact generated changes in magnetic fraction the shock-induced magnetic grain size reduction, hydrothermal- or melting-related magnetic mineral alteration, shock demagnetization and shock- or temperature-related remagnetization can be seen. The Outokumpu drill core shows varying velocities throughout the drill core depending on the microcracking and sample conditions. This is similar to observations by Kern et al., (2009), who also reported the velocity dependence on anisotropy. The physical properties are also used to explain the distinct crustal reflectors as observed in seismic reflection studies in the Outokumpu area. According to the seismic velocity data, the interfaces between the diopside-tremolite skarn layer and either serpentinite, mica schist or black schist are causing the strong seismic reflectivities.

Geochemistry and petrology of the ferropicrite dikes and associated rocks of Vestfjella, western Dronning Maud Land, Antarctica

This study provides insights into the composition and origin of ferropicrite dikes (FeOtot = 13 17 wt. %; MgO = 13 19 wt. %) and associated meimechite, picrite, picrobasalt, and basalt dikes found at Vestfjella, western Dronning Maud Land, Antarctica. The dikes crosscut Jurassic Karoo continental flood basalts (CFB) that were emplaced during the early stages of the breakup of the Gondwana supercontinent ~180 Ma ago. Selected samples (31 overall from at least eleven dikes) were analyzed for their mineral chemical, major element, trace element, and Sr, Nd, Pb, and Os isotopic compositions. The studied samples can be divided into two geochemically distinct types: (1) The depleted type (24 samples from at least nine dikes) is relatively depleted in the most incompatible elements and exhibits isotopic characteristics (e.g., initial εNd of +4.8 to +8.3 and initial 187Os/188Os of 0.1256 0.1277 at 180 Ma) similar to those of mid-ocean ridge basalts (MORB); (2) The enriched type (7 samples from at least two dikes) exhibits relatively enriched incompatible element and isotopic characteristics (e.g., initial εNd of +1.8 to +3.6 and initial 187Os/188Os of 0.1401 0.1425 at 180 Ma) similar to those of oceanic island basalts. Both magma types have escaped significant contamination by the continental crust. The depleted type is related to the main phase of Karoo magmatism and originated as highly magnesian (MgO up to 25 wt. %) partial melts at high temperatures (mantle potential temperature >1600 °C) and pressures (~5 6 GPa) from a sublithospheric, water-bearing, depleted peridotite mantle source. The enriched type sampled pyroxene-bearing heterogeneities that can be traced down to either recycled oceanic crust or melt-metasomatized portions of the sublithospheric or lithospheric mantle. The source of the depleted type represents a sublithospheric end-member source for many Karoo lavas and has subsequently been sampled by the MORBs of the Indian Ocean. These observations, together with the purported high temperatures, indicate that the Karoo CFBs were formed in an extensive melting episode caused mainly by internal heating of the upper mantle beneath the Gondwana supercontinent. My research supports the view that ferropicritic melts can be generated in several ways: the relative Fe-enrichment of mantle partial melts is most readily achieved by (1) relatively low degree of partial melting, (2) high pressure of partial melting, and (3) melting of enriched source components (e.g., pyroxenite and metasomatized peridotite). Ferropicritic whole-rock compositions could also result from accumulation, secondary alteration, and fractional crystallization, however, and caution is required when addressing the parental magma composition.

On the charging state of atmospheric aerosols and ion-induced nucleation

Floating in the air that surrounds us is a number of small particles, invisible to the human eye. The mixture of air and particles, liquid or solid, is called an aerosol. Aerosols have significant effects on air quality, visibility and health, and on the Earth's climate. Their effect on the Earth's climate is the least understood of climatically relevant effects. They can scatter the incoming radiation from the Sun, or they can act as seeds onto which cloud droplets are formed. Aerosol particles are created directly, by human activity or natural reasons such as breaking ocean waves or sandstorms. They can also be created indirectly as vapors or very small particles are emitted into the atmosphere and they combine to form small particles that later grow to reach climatically or health relevant sizes. The mechanisms through which those particles are formed is still under scientific discussion, even though this knowledge is crucial to make air quality or climate predictions, or to understand how aerosols will influence and will be influenced by the climate's feedback loops. One of the proposed mechanisms responsible for new particle formation is ion-induced nucleation. This mechanism is based on the idea that newly formed particles were ultimately formed around an electric charge. The amount of available charges in the atmosphere varies depending on radon concentrations in the soil and in the air, as well as incoming ionizing radiation from outer space. In this thesis, ion-induced nucleation is investigated through long-term measurements in two different environments: in the background site of Hyytiälä and in the urban site that is Helsinki. The main conclusion of this thesis is that ion-induced nucleation generally plays a minor role in new particle formation. The fraction of particles formed varies from day to day and from place to place. The relative importance of ion-induced nucleation, i.e. the fraction of particles formed through ion-induced nucleation, is bigger in cleaner areas where the absolute number of particles formed is smaller. Moreover, ion-induced nucleation contributes to a bigger fraction of particles on warmer days, when the sulfuric acid and water vapor saturation ratios are lower. This analysis will help to understand the feedbacks associated with climate change.

On formation, growth and concentrations of air ions

Aerosol particles have effect on climate, visibility, air quality and human health. However, the strength of which aerosol particles affect our everyday life is not well described or entirely understood. Therefore, investigations of different processes and phenomena including e.g. primary particle sources, initial steps of secondary particle formation and growth, significance of charged particles in particle formation, as well as redistribution mechanisms in the atmosphere are required. In this work sources, sinks and concentrations of air ions (charged molecules, cluster and particles) were investigated directly by measuring air molecule ionising components (i.e. radon activity concentrations and external radiation dose rates) and charged particle size distributions, as well as based on literature review. The obtained results gave comprehensive and valuable picture of the spatial and temporal variation of the air ion sources, sinks and concentrations to use as input parameters in local and global scale climate models. Newly developed air ion spectrometers (Airel Ltd.) offered a possibility to investigate atmospheric (charged) particle formation and growth at sub-3 nm sizes. Therefore, new visual classification schemes for charged particle formation events were developed, and a newly developed particle growth rate method was tested with over one year dataset. These data analysis methods have been widely utilised by other researchers since introducing them. This thesis resulted interesting characteristics of atmospheric particle formation and growth: e.g. particle growth may sometimes be suppressed before detection limit (~ 3 nm) of traditional aerosol instruments, particle formation may take place during daytime as well as in the evening, growth rates of sub-3 nm particles were quite constant throughout the year while growth rates of larger particles (3-20 nm in diameter) were higher during summer compared to winter. These observations were thought to be a consequence of availability of condensing vapours. The observations of this thesis offered new understanding of the particle formation in the atmosphere. However, the role of ions in particle formation, which is not well understood with current knowledge, requires further research in future.

The role of inflammation and matrix proteins in airway remodelling

Asthma is a chronic inflammatory disorder of the airways. Remodelling in asthma is defined as the structural changes seen in the airways of asthmatics in comparison to healthy controls. Progressive loss of lung function also seen in asthma might be caused by remodelling. The research aims of this thesis were to investigate inflammation and remodelling in the airways of different types of asthmatics and smokers. The association between inflammation and remodelling was also examined in a mouse model of allergic airway inflammation. Healthy smokers showed increased numbers of macrophages in the BAL with no changes in the inflammatory cells in biopsies. Macrophages seemed to be quite quiescent, since mRNA expression for a wide variety of inflammatory mediators, especially chemokines CCL3, CCL4, CCL5 and CCL20, secreted by macrophages was significantly lower than in healthy non-smokers. Attenuated macrophage activity in the airway lumen may render smokers more susceptible to airway infections and have an impact on the development of other airway pathology. Patients with diisocyanate-induced asthma (DIA) on inhaled corticosteroids (ICS) who still had non-specific bronchial hyperreactivity (NSBHR) at the end of the follow-up showed increased expression of TNF-α, IL-6 and IL-15 mRNA in BAL cells compared to those without NSBHR. In addition to being markers for poor prognosis and possible slight glucocorticoid resistance, these cytokines might aid in guiding the treatment of DIA. The increase in the thickness of tenascin-C layer in the bronchial basement membrane (BM) was much less than usually seen in other types of asthma, which might not make tenascin-C a good marker for DIA. OVA-induced tenascin-C expression in the lung was attenuated in STAT4-/- mice with impaired Th1-type immunity compared to WT mice. Interestingly, STAT6-/- mice with impaired Th2-type immunity showed tenascin-C expression levels similar to those of WT mice. The clearest difference between these two knockout strains in response to OVA was that STAT4-/- mice exhibited no upregulation of IFN-γ and TNF-α mRNA expression. Thus, tenascin-C expression was unexpectedly more related to Th1 type reactions. In vitro studies confirmed the results. Human fibroblasts stimulated by TNF-α and IFN-γ showed increased expression of tenascin-C. Patients with newly diagnosed asthma showed increased expression of laminin α2 in the bronchial BM in comparison to patients with asthma symptoms only and healthy controls. Both patients with asthma and those with only asthma symptoms showed increased expression of the laminin β2 chain in comparison to controls. Thus, laminin α2 expression differentiated patients with clinical asthma from patients with symptoms only. Furthermore, the expression of laminin α2 and β2 was associated with NSBHR, linking very specific remodelling events to clinical findings.

The prehistory of Suomussalmi, eastern Finland; the first billion years as revealed by isotopes and the composition of granitoid suites

The four papers summarized in this thesis deal with the Archean and earliest Paleoproterozoic granitoid suites observed in the Suomussalmi district, eastern Finland. Geologically, the area belongs to the Kianta Complex of the Western Karelian Terrane in the Karelian Province of the Fennoscandian shield. The inherited zircons up to 3440 Ma old together with Sm Nd and Pb Pb data confirm the existence of previously anticipated Paleoarchean protocrust in Suomussalmi. The general timeline of granitoid magmatism is similar to that of the surrounding areas. TTG magmatism occurred in three distinct phases: ca 2.95 Ga, 2.83 2.78 Ga and 2.76 2.74 Ga. In Suomussalmi the TTGs sensu stricto (K2O/Na2O less than 0.5) belong to the low-HREE type and are interpreted as partial melts of garnet amphibolites, which did not significantly interact with mantle peridotites. Transitional TTGs (K2O/Na2O more than 0.5), present in Suomussalmi and absent from surrounding areas, display higher LILE concentrations, but otherwise closely resemble the TTGs sensu stricto and indicate that recycling of felsic crust commenced in Suomussalmi 200 Ma earlier than in surrounding areas. The youngest TTG phase was coeval with the intrusion of the Likamännikkö quartz alkali feldspar syenite (2741 ± 2 Ma) complex. The complex contains angular fragments of ultrabasic rock, which display considerable compositional heterogeneity and are interpreted as cumulates containing clinopyroxene (generally altered to actinolite), apatite, allanite, epidote, and albite. The quartz alkali feldspar syenite cannot be regarded as alkaline sensu stricto, despite clear alkaline affinities. Within Likamännikkö there are also calcite carbonatite patches, which display mantle-like O- and C-isotope values, as well as trace element characteristics consistent with a magmatic origin, and could thus be among the oldest known carbonatites in the world. Sanukitoid (2.73 2.71 Ga) and quartz diorite suites (2.70 Ga) overlap within error margins and display compositional similarities, but can be differentiated from each other on the basis of higher Ba, K2O and LREE contents of the sanukitoids. The Likamännikkö complex, sanukitoids and quartz diorites are interpreted as originating from the metasomatized mantle and mark the diversification of the granitoid clan after 200 Ma of evolution dominated by the TTG suite. Widespread migmatization and the intrusion of anatectic leucogranitoids as dykes and intrusions of varying size took place at 2.70 2.69 Ga, following collisional thickening of the crust. The leucogranitoids and leucosomes of migmatized TTGs are compositionally alike and characterized by high silica contents and a leucocratic appearance. Due to compositional overlap, definitive discrimination between leucogranitoids and transitional TTGs requires isotope datings and/or knowledge of field relationships. Leucogranitoids represent partial melts of the local TTGs, both the sensu stricto and transitional types, mostly derived under water fluxed conditions, with possible fluid sources being late sanukitoids and quartz diorites as well as dehydrating lower crust. The Paleoproterozoic 2.44 2.39 Ga A-type granitoids of the Kianta Complex emplaced in an extensional environment are linked to the coeval and more widespread mafic intrusions and dykes observed over most of the Archean nucleus of the Fennoscandian shield. The A-type intrusions in the Suomussalmi area are interpreted as partial melts of the Archean lower crust and display differences in composition and magnetite content, which indicate differences in the composition and oxidation state of the source.

Noncommutative Quantum Field Theory : Problem of Time and Some Applications

In this thesis the current status and some open problems of noncommutative quantum field theory are reviewed. The introduction aims to put these theories in their proper context as a part of the larger program to model the properties of quantized space-time. Throughout the thesis, special focus is put on the role of noncommutative time and how its nonlocal nature presents us with problems. Applications in scalar field theories as well as in gauge field theories are presented. The infinite nonlocality of space-time introduced by the noncommutative coordinate operators leads to interesting structure and new physics. High energy and low energy scales are mixed, causality and unitarity are threatened and in gauge theory the tools for model building are drastically reduced. As a case study in noncommutative gauge theory, the Dirac quantization condition of magnetic monopoles is examined with the conclusion that, at least in perturbation theory, it cannot be fulfilled in noncommutative space.

Nanoscale studies of materials using x-ray synchrotron radiation and mesoscopic modelling

X-ray synchrotron radiation was used to study the nanostructure of cellulose in Norway spruce stem wood and powders of cobalt nanoparticles in cellulose support. Furthermore, the growth of metallic clusters was modelled and simulated in the mesoscopic size scale. Norway spruce was characterized with x-ray microanalysis at beamline ID18F of the European Synchrotron Radiation Facility in Grenoble. The average dimensions and the orientation of cellulose crystallites was determined using x-ray microdiffraction. In addition, the nutrient element content was determined using x-ray fluorescence spectroscopy. Diffraction patterns and fluorescence spectra were simultaneously acquired. Cobalt nanoparticles in cellulose support were characterized with x-ray absorption spectroscopy at beamline X1 of the Deutsches Elektronen-Synchrotron in Hamburg, complemented by home lab experiments including x-ray diffraction, electron microscopy and measurement of magnetic properties with a vibrating sample magnetometer. Extended x-ray absorption fine structure spectroscopy (EXAFS) and x-ray diffraction were used to solve the atomic arrangement of the cobalt nanoparticles. Scanning- and transmission electron microscopy were used to image the surfaces of the cellulose fibrils, where the growth of nanoparticles takes place. The EXAFS experiment was complemented by computational coordination number calculations on ideal spherical nanocrystals. The growth process of metallic nanoclusters on cellulose matrix is assumed to be rather complicated, affected not only by the properties of the clusters themselves, but essentially depending on the cluster-fiber interfaces as well as the morphology of the fiber surfaces. The final favored average size for nanoclusters, if such exists, is most probably a consequence of these two competing tendencies towards size selection, one governed by pore sizes, the other by the cluster properties. In this thesis, a mesoscopic model for the growth of metallic nanoclusters on porous cellulose fiber (or inorganic) surfaces is developed. The first step in modelling was to evaluate the special case of how the growth proceeds on flat or wedged surfaces.