Mass spectrometry and n-in-one analytics in early drug discovery: Combinatorial chemistry libraries, lipophilicity and absorption screening

This thesis describes current and past n-in-one methods and presents three early experimental studies using mass spectrometry and the triple quadrupole instrument on the application of n-in-one in drug discovery. N-in-one strategy pools and mix samples in drug discovery prior to measurement or analysis. This allows the most promising compounds to be rapidly identified and then analysed. Nowadays properties of drugs are characterised earlier and in parallel with pharmacological efficacy. Studies presented here use in vitro methods as caco-2 cells and immobilized artificial membrane chromatography for drug absorption and lipophilicity measurements. The high sensitivity and selectivity of liquid chromatography mass spectrometry are especially important for new analytical methods using n-in-one. In the first study, the fragmentation patterns of ten nitrophenoxy benzoate compounds, serial homology, were characterised and the presence of the compounds was determined in a combinatorial library. The influence of one or two nitro substituents and the alkyl chain length of methyl to pentyl on collision-induced fragmentation was studied, and interesting structurefragmentation relationships were detected. Two nitro group compounds increased fragmentation compared to one nitro group, whereas less fragmentation was noted in molecules with a longer alkyl chain. The most abundant product ions were nitrophenoxy ions, which were also tested in the precursor ion screening of the combinatorial library. In the second study, the immobilized artificial membrane chromatographic method was transferred from ultraviolet detection to mass spectrometric analysis and a new method was developed. Mass spectra were scanned and the chromatographic retention of compounds was analysed using extract ion chromatograms. When changing detectors and buffers and including n-in-one in the method, the results showed good correlation. Finally, the results demonstrated that mass spectrometric detection with gradient elution can provide a rapid and convenient n-in-one method for ranking the lipophilic properties of several structurally diverse compounds simultaneously. In the final study, a new method was developed for caco-2 samples. Compounds were separated by liquid chromatography and quantified by selected reaction monitoring using mass spectrometry. This method was used for caco-2 samples, where absorption of ten chemically and physiologically different compounds was screened using both single and nin- one approaches. These three studies used mass spectrometry for compound identification, method transfer and quantitation in the area of mixture analysis. Different mass spectrometric scanning modes for the triple quadrupole instrument were used in each method. Early drug discovery with n-in-one is area where mass spectrometric analysis, its possibilities and proper use, is especially important.

Measurement of Zγ production in pp̅ collisions at √s=1.96 TeV

The production rate and kinematics of photons produced in association with Z bosons are studied using 2/fb of p\bar{p} collision data collected at the Collider Detector at Fermilab. The cross section for p\bar{p} -> l^+ l^- gamma + X (where the leptons l are either muons or electrons with dilepton mass M_{ll} > 40 GeV/c^2, and where the photon has transverse energy Et_{gamma} > 7 GeV and is well separated from the leptons) is 4.6 +/- 0.2 (stat) +/- 0.3 (syst) +/- 0.3 (lum) pb, which is consistent with standard model expectations. We use the photon Et distribution from Z-gamma events where the Z has decayed to mu^+ mu^-, e^+ e^-, or nu\bar{nu} to set limits on anomalous (non-standard-model) trilinear couplings between photons and Z bosons.

Alppihiihdon alkutaival : Pujottelu- ja tunturihiihto Suomessa 1920-luvulta 1960-luvulle

The object of study in this thesis is Finnish skiing culture and Alpine skiing in particular from the point of view of ethnology. The objective is to clarify how, when, why and by what routes Alpine skiing found its way to Finland. What other phenomena did it bring forth? The objective is essentially linked to the diffusion of modern sports culture to Finland. The introduction of Alpine skiing to Finland took place at a time when skiing culture was changing: flat terrain skiing was abandoned in favour of cross-country skiing in the early decades of the 20th century, and new techniques and equipment made skiing a much more versatile sport. The time span of the study starts from the late 19th century and ends in the mid-20th century. The spatial focus is in Finland. People and communities formed through their actions are core elements in the study of sports and physical activity. Organizations tend to raise themselves into influential actors in the field of physical culture even if active individuals work in their background. Original archive documents and publications of sports organizations are central source material for this thesis, complemented by newspapers and sports magazines as well as photographs and films on early Alpine skiing in Finland. Ever since their beginning in the late 19th century skiing races in Finland had mostly taken place on flat terrain or sea ice. Skiing in broken cross-country terrain made its breakthrough in the 1920 s, at a time when modern skiing techniques were introduced in instruction manuals. In the late 1920 s the Finnish Women s Physical Education Association (SNLL) developed unconventional forms of pedagogical skiing instruction. They abandoned traditional Finnish flat terrain skiing and boldly looked for influences abroad, which caused friction between the leaders of the women s sports movement and the (male) leaders of the central skiing organization. SNLL was instrumental in launching winter tourism in Finnish Lapland in 1933. The Finnish Tourism Society, the State Railways and sports organizations worked in close co-operation to instigate a boom in tourism, which culminated in the inauguration of a tourist hotel at Pallastunturi hill in the winter of 1938. Following a Swedish model, fell-skiing was developed as a domestic counterpart to Alpine skiing as practiced in Central Europe. The first Finnish skiing resorts were built at sites of major cross-country skiing races. Inspired by the slope at Bad Grankulla health spa, the first slalom skiing races and fell-skiing, slalom enthusiasts began to look for purpose-built sites to practice turn technique. At first they would train in natural slopes but in the late 1930 s new slopes were cleared for slalom races and recreational skiing. The building of slopes and ski lifts and the emergence of organized slalom racing competitions gradually separated Alpine skiing from the old fell-skiing. After the Second World War fell-skiing was transformed into ski trekking on marked courses. At the same time Alpine skiing also parted ways with cross-country skiing to become a sport of its own. In the 1940 s and 1950 s Finnish Alpine skiing was almost exclusively a competitive sport. The specificity of Alpine skiing was enhanced by rapid development of equipment: the new skis, bindings and shoes could only be used going downhill.

Bilingual Notaries in Hellenistic Egypt : A Study of Language Use

The impact of Greek-Egyptian bilingualism on language use and linguistic competence is the key issue in this dissertation. The language use in a corpus of 148 Greek notarial contracts is analyzed on phonological, morphological and syntactic levels. The texts were written by bilingual notaries (agoranomoi) in Upper Egypt in the later Hellenistic period. They present, for the most part, very good administrative Greek. On the other hand, their language contains variation and idiosyncrasies that were earlier condemned as ungrammatical and bad Greek, and were not subjected to closer analysis. In order to reach plausible explanations for those phenomena, a thorough research into the sociohistorical and linguistic context was needed before the linguistic analysis. The general linguistic landscape, the population pattern and the status and frequency of Greek literacy in Ptolemaic Egypt in general, and in Upper Egypt in particular, are presented. Through a detailed examination of the notaries themselves (their names, families and handwriting), it became evident that there were one to three persons at the notarial office writing under the signature of one notary. Often the documents under one notary's name were written in the same hand. We get, therefore, exceptionally close to studying idiolects in written material from antiquity. The qualitative linguistic analysis revealed that the notaries made relatively few orthographic mistakes that reflect the ongoing phonological changes and they mastered the morphological forms. The problems arose at the syntactic level, for example, with the pattern of agreement between the noun groups or a noun with its modifiers. The significant structural differences between Greek and Egyptian can be behind the innovative strategies used by some of the notaries. Moreover, certain syntactic structures were clearly transferred from the notaries first language, Egyptian. This is obvious in the relative clause structure. Transfer can be found in other structures, as well, although, we must not forget the influence of parallel Greek structures. Sometimes these can act simultaneously. The interesting linguistic strategies and transfer features come mostly from the hand of one notary, Hermias. Some other notaries show similar patterns, for example, Hermias' cousin, Ammonios. Hermias' texts reveal that he probably spoke Greek more than his predecessors. It is possible to conclude, then, that the notaries of the later generations were more fluently bilingual; their two languages were partly integrated in their minds as an interlanguage combining elements from both languages. The earlier notaries had the two languages functionally separated and they followed the standardized contract formulae more rigidly.

Monte Carlo simulations of molecular clusters in nucleation

A better understanding of the limiting step in a first order phase transition, the nucleation process, is of major importance to a variety of scientific fields ranging from atmospheric sciences to nanotechnology and even to cosmology. This is due to the fact that in most phase transitions the new phase is separated from the mother phase by a free energy barrier. This barrier is crossed in a process called nucleation. Nowadays it is considered that a significant fraction of all atmospheric particles is produced by vapor-to liquid nucleation. In atmospheric sciences, as well as in other scientific fields, the theoretical treatment of nucleation is mostly based on a theory known as the Classical Nucleation Theory. However, the Classical Nucleation Theory is known to have only a limited success in predicting the rate at which vapor-to-liquid nucleation takes place at given conditions. This thesis studies the unary homogeneous vapor-to-liquid nucleation from a statistical mechanics viewpoint. We apply Monte Carlo simulations of molecular clusters to calculate the free energy barrier separating the vapor and liquid phases and compare our results against the laboratory measurements and Classical Nucleation Theory predictions. According to our results, the work of adding a monomer to a cluster in equilibrium vapour is accurately described by the liquid drop model applied by the Classical Nucleation Theory, once the clusters are larger than some threshold size. The threshold cluster sizes contain only a few or some tens of molecules depending on the interaction potential and temperature. However, the error made in modeling the smallest of clusters as liquid drops results in an erroneous absolute value for the cluster work of formation throughout the size range, as predicted by the McGraw-Laaksonen scaling law. By calculating correction factors to Classical Nucleation Theory predictions for the nucleation barriers of argon and water, we show that the corrected predictions produce nucleation rates that are in good comparison with experiments. For the smallest clusters, the deviation between the simulation results and the liquid drop values are accurately modelled by the low order virial coefficients at modest temperatures and vapour densities, or in other words, in the validity range of the non-interacting cluster theory by Frenkel, Band and Bilj. Our results do not indicate a need for a size dependent replacement free energy correction. The results also indicate that Classical Nucleation Theory predicts the size of the critical cluster correctly. We also presents a new method for the calculation of the equilibrium vapour density, surface tension size dependence and planar surface tension directly from cluster simulations. We also show how the size dependence of the cluster surface tension in equimolar surface is a function of virial coefficients, a result confirmed by our cluster simulations.

Juvenile diversity of tree species in Theobroma cacao L. agroforestry and primary forest – Central Sulawesi, Indonesia

This thesis studies the tree species’ juvenile diversity in cacao (Theobroma cacao L.) based agroforestry and in primary forest in a natural conservation forest environment of Lore Lindu National Park, Sulawesi, Indonesia. Species’ adult composition in Lore Lindu National Park is relatively well studied, less is known about tree species’ diversity in seedling communities particularly in frequently disturbed cacao agroforestry field environment. Cacao production forms a potentially serious thread for maintaining the conservation areas pristine and forested in Sulawesi. The impacts of cacao production on natural environment are directly linked to the diversity and abundance of shade tree usage. The study aims at comparing differences between cacao agroforestry and natural forest in the surrounding area in their species composition in seedling and sapling size categories. The study was carried out in two parts. Biodiversity inventory of seedlings and saplings was combined with social survey with farmer interviews. Aim of the survey was to gain knowledge of the cacao fields, and farmers’ observations and choices regarding tree species associated with cacao. Data was collected in summer 2008. The assessment of the impact of environmental factors of solar radiation, weeding frequency, cacao tree planting density, distance to forest and distance to main park road, and type of habitat on seedling and sapling compositions was done with Non-metric Multidimensional Scaling (NMS). Outlier analysis was used to assess distorting variables for NMS, and Multi-Response Permutation Procedures (MRPP) analysis to differentiate the impact of categorical variables. Sampling success was estimated with rarefaction curves and jackknife estimate of species richness. In the inventory 135 species of trees and shrubs were found. Only some agroforestry related species were dominating. The most species rich were sapling communities in forest habitat. NMS was showing generally low linear correlation between variation of species composition and environmental variables. Solar radiation was having most significance as explaining variable. The most clearly separated in ordination were cacao and forest habitats. The results of seedling and sapling inventory were only partly coinciding with farmers’ knowledge of the tree species occurring on their fields. More research with frequent assessment of seedling cohorts is needed due to natural variability of cohorts and high mortality rate of seedlings.

Ratkaiseeko raha? : Tulospalkkiojärjestelmään ja työympäristöön liittyvien kokemusten yhteys esimiesten työtyytyväisyyteen ja työmotivaatioon

The aim of this study was to investigate the relationship between merit pay system and work environment and foremen´s work satisfaction and work motivation. There has been a lot of investigation on rewarding. Less research has been done on previous surveys among the merit pay systems and motivation investigations. According to former surveys, rewarding systems cannot be released from its context. Therefore this survey expanded to deal with work environment. It was also essential to investigate different dimensions of extrinsic and intrinsic motivation and equity of rewarding. Investigation or work motivation and work satisfaction was challenging because both of these concepts have been investigated under quite traditional frame of reference of work motivation theories. In some surveys, the concepts have not been even separated or they have been used even as synonyms. The data were collected with the 193 foremen working in the profit centers of the different chains of the company in the field of retail trade. The questions were: Are the experiences of merit pay system and work environment related to foremen´s work satisfaction and work motivation? Are the backround variables related to foremen´s work satisfaction and work motivation? The data collection was carried out by an electronic inquiry during May 2010. 137 replied from foremen working under merit pay system. The research material was analyzed with PASW-software. Various analyzing methods were used: factor analyses, regression analyses and group of different parametric and non-parametric analyses. In contrast to theoretical framework in the factor analyses work satisfaction and work motivation clustered into the same dimension. As a main result the atmosphere, possibilities to influence and the atmosphere of leading were strongly positively related to foremen´s work satisfaction and work motivation. According to regression analyses these factors were able to explain 55 % of the foremen´s work satisfaction and work motivation. The best explanatory variable was atmosphere. Instead, the backround variables (age, sex, working years, group of profession, education) were not associated with work satisfaction and work motivation.

Korkeakoulupolitiikan dynamiikat Suomessa

The study scrutinizes the dynamics of the Finnish higher education political system. Dynamics is understood as the regularity of interaction between actors. By actors is meant the central institutions in the system. The theoretical framework of the study draws on earlier research in political science and higher education political studies. The theoretical model for analysis is built on agenda-setting theories. The theoretical model separates two dimensions of dynamics, namely the political situation and political possibilities. A political situation can be either favourable or contradictory to change. If the institutional framework within the higher education system is not compatible with the external factors of the system, the political situation is contradictory to change. To change the situation into a favourable one, one needs either to change the institutional structure or wait for external factors to change. Then again, the political possibilities can be either settled or politicized. Politicization means that new possibilities for action are found. Settled possibilities refer to routine actions performed according to old practices. The research tasks based on the theoretical model are: 1. To empirically analyse the political situation and the possibilities from the actors point of view. 2. To theoretically construct and empirically test a model for analysis of dynamics in the Finnish higher education politics. The research material consists of 25 thematic interviews with key persons in the higher education political system in 2008. In addition, there are also documents from different actors since the 1980s and statistical data. The material is analysed in four phases. In the first phase the emphasis is on trying to understand the interviewees and actors points of view. In the second phase the different types of research material are related to each other. In the third phase the findings are related to the theoretical model, which is constructed over the course of the analysis. In the fourth phase the interpretation is tested. The research distinguishes three historical periods in the Finnish higher education system and focuses on the last one. This is the era of the complex system beginning in the 1980s 1990s. Based on the interviews, four policy threads are identified and analysed in their historical context. Each of the policy threads represents one of the four possible dynamics identified in the theoretical model. The research policy thread functions according to reform dynamics. A coalition of innovation politics is able to use the politicized possibilities due to the political situation created by the conception of the national innovation system. The regional policy thread is in a gridlock dynamics. The combination of a political system based on provincial representation, a regional higher education institutional framework and outside pressure to streamline the higher education structure created a contradictory political situation. Because of this situation, the politicized possibilities in the so-called "regional development plan" do not have much effect. In the international policy thread, a consensual change dynamics is found. Through changes in the institutional framework, the higher education political system is moulded into a favourable situation. However, the possibilities are settled: a pragmatic national gaze prevailed. A dynamics of friction is found in the governance policy thread. A political situation where political-strategic and budgetary decision-making are separated is not favourable for change. In addition, as governance policy functions according to settled possibilities, the situation seems unchangeable. There are five central findings. First, the dynamics are different depending on the policy thread under scrutiny. Second, the settled possibilities in a policy thread seemed to influence other threads the most. Third, dynamics are much related to changes external to the higher education political system, the changing positions of the actors in different policy threads and the unexpected nature of the dynamics. Fourth, it is fruitful to analyse the dynamics with the theoretical model. Fifth, but only hypothetically and thus left for further research, it seems that the Finnish higher education politics is reactive and weak at politicization.

Contamination routes and control of Listeria monocytogenes in Food Production

Listeria monocytogenes is the causative agent of the severe foodborne infection listeriosis. The number of listeriosis cases in recent years has increased in many European countries, including Finland. Contamination of the pathogen needs to be minimized and growth to high numbers in foods prevented in order to reduce the incidence of human cases. The aim of this study was to evaluate contamination routes of L. monocytogenes in the food chain and to investigate methods for control of the pathogen in food processing. L. monocytogenes was commonly found in wild birds, the pig production chain and in pork production plants. It was found most frequently in birds feeding at landfill site, organic farms, tonsil samples, and sites associated with brining. L. monococytogenes in birds, farms, food processing plant or foods did not form distinct genetic groups, but populations overlapped. The majority of genotypes recovered from birds were also detected in foods, food processing environments and other animal species and birds may disseminate L. monocytogenes into food chain. Similar genotypes were found in different pigs on the same farm, as well as in pigs on farms and later in the slaughterhouse. L. monocytogenes contamination spreads at farm level and may be a contamination source into slaughterhouses and further into meat. Incoming raw pork in the processing plant was frequently contaminated with L. monocytogenes and genotypes in raw meat were also found in processing environment and in RTE products. Thus, raw material seems to be a considerable source of contamination into processing facilities. In the pork processing plant, the prevalence of L. monocytogenes increased in the brining area, showing that the brining was an important contamination site. Recovery of the inoculated L. monocytogenes strains showed that there were strain-specific differences in the ability to survive in lettuce and dry sausage. The ability of some L. monocytogenes strains to survive well in food production raises a challenge for industry, because these strains can be especially difficult to remove from the products and raises a need to use an appropriate hurdle concept to control most resistant strains. Control of L. monocytogenes can be implemented throughout the food chain. Farm-specific factors affected the prevalence of L. monocytogenes and good farm-level practices can therefore be utilized to reduce the prevalence of this pathogen on the farm and possibly further in the food chain. Well separated areas in a pork production plant had low prevalences of L. monocytogenes, thus showing that compartmentalization controls the pathogen in the processing line. The food processing plant, especially the brining area, should be subjected to disassembling, extensive cleaning and disinfection to eliminate persistent contamination by L. monocytogenes, and replacing brining with dry-salting should be considered. All of the evaluated washing solutions decreased the populations of L. monocytogenes on precut lettuce, but did not eliminate the pathogen. Thus, the safety of fresh-cut produce cannot rely on washing with disinfectants, and high-quality raw material and good manufacturing practices remain important. L. monocytogenes was detected in higher levels in sausages without the protective culture than in sausages with this protective strain, although numbers of L. monocytogenes by the end of the ripening decreased to the level of < 100 MPN/g in all sausages. Protective starter cultures provide an appealing hurdle in dry sausage processing and assist in the control of L. monocytogenes.

Mid-urethral slings for treatment of stress urinary incontinence : long- and mid-term follow-up

Urinary incontinence is a common problem, affecting one third of the women at least at some time during their lives. The prevalence of urinary incontinence increases with advancing age, and the everyday impact of incontinence on women and on health services is enormous. Urinary incontinence is usually divided into three different subtypes, of which stress urinary incontinence (SUI) is the most common. Surgical treatment is often needed to cure SUI, and modern mid-urethral sling procedures give the possibility to cure this condition with a low risk of adverse events, a problem often associated with the so-called traditional incontinence operations. Life expectancy among women in Western countries has grown beyond 80 years of age. Long-term efficacy of treatment options for urinary incontinence therefore becomes an important issue in a world with limited eco-nomic resources. The purpose of the present study was to prospectively evaluate the long-term efficacy and safety of the first minimally invasive mid-urethral tape procedure, the Tension-free Vaginal Tape (TVT) procedure. The long-term (5-year) follow-up results of the TVT procedure as a repeat operation af-ter an unsuccessful mid-urethral tape operation were studied and the reasons for failure of the first operation were analyzed. Another purpose was to compare the original TVT procedure with a newer modification, the Tension-free Vaginal Tape Obturator (TVT-O) procedure within a multi-centre, randomized context in order to find out possible differences between these procedures re-garding efficacy and complications and the effects on symptoms of urgency. The first study of the present thesis is a prospective, Nordic, three-centre follow-up study of 90 women suffering from SUI, who were treated by means of the TVT procedure. The mean follow-up time was more than eleven years, and the study is the first to be published in connection with more than ten years of follow-up. The second study is a retrospective analysis of 26 women who were treated with a repeat TVT procedure after an unsuccessful primary mid-urethral tape procedure. The third and fourth studies concern 273 women in seven centres in Finland who were ran-domly assigned to the TVT and TVT-O procedures, the 3-year follow-up results of which are pre-sented in this thesis. After eleven years of follow-up, 90% of the women had a negative cough stress test result and a negative 24-h pad test result. The subjective cure rate measured as the women s global impression of cure was 77%, the rate of improvement 20%, and only 3% thought that the treatment had failed. No late-onset adverse effects were found. The repeat TVT procedure was successful in 75% of the cases when women who were cured and women who were significantly improved were included. The reasons for failure of the first operation could be separated into four different groups: tape material-related, operation technique-related, concomitant illness-related and a group with no identifiable reason. There were no intra-operative complications during the repeat operation. In the randomized trial comparing the TVT with the TVT-O procedure a cough stress test results were negative in 94.6% and 89.5% of the women in the two groups, respectively, after a 3-year follow-up period. There were no statistical differences in the cure rate or the rate of complications be-tween the two procedures. Symptoms of urgency were analyzed more closely and the main finding was that the prevalence of urgency symptoms decreased significantly after both mid-urethral sling procedures. The TVT operation was found to be an effective and safe procedure even after eleven years of follow-up. Long-term follow-up after a repeat TVT procedure revealed that the TVT procedure can well be considered after an unsuccessful mid-urethra tape procedure, because 75% of the patients showed significantly improvement of their incontinence. The TVT and TVT-O procedures showed no statistically significant differences in efficacy and rate of complications after three years of follow-up. In most cases these procedures alleviate preoperative symptoms of urgency and the risk of developing de novo urgency is low.

Genetic polymorphisms and laboratory variables as predictors of blood pressure response to antihypertensive drugs

Hypertension is one of the major risk factors for cardiovascular morbidity. The advantages of antihypertensive therapy have been clearly demonstrated, but only about 30% of hypertensive patients have their blood pressure (BP) controlled by such treatment. One of the reasons for this poor BP control may lie in the difficulty in predicting BP response to antihypertensive treatment. The average BP reduction achieved is similar for each drug in the main classes of antihypertensive agents, but there is a marked individual variation in BP responses to any given drug. The purpose of the present study was to examine BP response to four different antihypertensive monotherapies with regard to demographic characteristics, laboratory test results and common genetic polymorphisms. The subjects of the present study are participants in the pharmacogenetic GENRES Study. A total of 208 subjects completed the whole study protocol including four drug treatment periods of four weeks, separated by four-week placebo periods. The study drugs were amlodipine, bisoprolol, hydrochlorothiazide and losartan. Both office (OBP) and 24-hour ambulatory blood pressure (ABP) measurements were carried out. BP response to study drugs were related to basic clinical characteristics, pretreatment laboratory test results and common polymorphisms in genes coding for components of the renin-angiotensin system, alpha-adducin (ADD1), beta1-adrenergic receptor (ADRB1) and beta2-adrenergic receptor (ADRB2). Age was positively correlated with BP responses to amlodipine and with OBP and systolic ABP responses to hydrochlorothiazide, while body mass index was negatively correlated with ABP responses to amlodipine. Of the laboratory test results, plasma renin activity (PRA) correlated positively with BP responses to losartan, with ABP responses to bisoprolol, and negatively with ABP responses to hydrochlorothiazide. Uniquely to this study, it was found that serum total calcium level was negatively correlated with BP responses to amlodipine, whilst serum total cholesterol level was negatively correlated with ABP responses to amlodipine. There were no significant associations of angiotensin II type I receptor 1166A/C, angiotensin converting enzyme I/D, angiotensinogen Met235Thr, ADD1 Gly460Trp, ADRB1 Ser49Gly and Gly389Arg and ADRB2 Arg16Gly and Gln27Glu polymorphisms with BP responses to the study drugs. In conclusion, this study confirmed the relationship between pretreatment PRA levels and response to three classes of antihypertensive drugs. This study is the first to note a significant inverse relation between serum calcium level and responsiveness to a calcium channel blocker. However, this study could not replicate the observations that common polymorphisms in angiotensin II type I receptor, angiotensin converting enzyme, angiotensinogen, ADD1, ADRB1, or ADRB2 genes can predict BP response to antihypertensive drugs.

Individuals' Responsibility in Corporations

I discuss role responsibly, individual responsibility and collective responsibility in corporate multinational setting. My case study is about minerals used in electronics that come from the Democratic Republic of Congo. What I try to show throughout the thesis is how many things need to be taken into consideration when we discuss the responsibility of individuals in corporations. No easy and simple answers are available. Instead, we must keep in mind the complexity of the situation at all times, judging cases on individual basis, emphasizing the importance of individual judgement and virtue, as well as the responsibility we all share as members of groups and the wider society. I begin by discussing the demands that are placed on us as employees. There is always a potential for a conflict between our different roles and also the wider demands placed on us. Role demands are usually much more specific than the wider question of how we should act as human beings. The terminology of roles can also be misleading as it can create illusions about our work selves being somehow radically separated from our everyday, true selves. The nature of collective decision-making and its implications for responsibility is important too. When discussing the moral responsibility of an employee in a corporate setting, one must take into account arguments from individual and collective responsibility, as well as role ethics. Individual responsibility is not a separate or competing notion from that of collective responsibility. Rather, the two are interlinked. Individuals' responsibilities in collective settings combine both individual responsibility and collective responsibility (which is different from aggregate individual responsibility). In the majority of cases, both will apply in various degrees. Some members might have individual responsibility in addition to the collective responsibility, while others just the collective responsibility. There are also times when no-one bears individual moral responsibility but the members are still responsible for the collective part. My intuition is that collective moral responsibility is strongly linked to the way the collective setting affects individual judgements and moulds the decisions, and how the individuals use the collective setting to further their own ends. Individuals remain the moral agents but responsibility is collective if the actions in question are collective in character. I also explore the impacts of bureaucratic ethic and its influence on the individual. Bureaucracies can compartmentalize work to such a degree that individual human action is reduced to mere behaviour. Responsibility is diffused and the people working in the bureaucracy can come to view their actions to be outside the normal human realm where they would be responsible for what they do. Language games and rules, anonymity, internal power struggles, and the fragmentation of information are just some of the reasons responsibility and morality can get blurry in big institutional settings. Throughout the thesis I defend the following theses: ● People act differently depending on their roles. This is necessary for our society to function, but the more specific role demands should always be kept in check by the wider requirements of being a good human being. ● Acts in corporations (and other large collectives) are not reducible to individual actions, and cannot be explained fully by the behaviour of individual employees. ● Individuals are responsible for the actions that they undertake in the collective as role occupiers and are very rarely off the hook. Hiding behind role demands is usually only an excuse and shows a lack of virtue. ● Individuals in roles can be responsible even when the collective is not. This depends on if the act they performed was corporate in nature or not. ● Bureaucratic structure affects individual thinking and is not always a healthy environment to work in. ● Individual members can share responsibility with the collective and our share of the collective responsibility is strongly linked to our relations. ● Corporations and other collectives can be responsible for harm even when no individual is at fault. The structure and the policies of the collective are crucial. ● Socialization plays an important role in our morality at both work and outside it. We are all responsible for the kind of moral context we create. ● When accepting a role or a position in a collective, we are attaching ourselves with the values of that collective. ● Ethical theories should put more emphasis on good judgement and decision-making instead of vague generalisations. My conclusion is that the individual person is always in the centre when it comes to responsibility, and not so easily off the hook as we sometimes think. What we do, and especially who we choose to associate ourselves with, does matter and we should be more careful when we choose who we work for. Individuals within corporations are responsible for choosing that the corporation they associate with is one that they can ascribe to morally, if not fully, then at least for the most part. Individuals are also inclusively responsible to a varying degree for the collective activities they contribute to, even in overdetermined contexts. We all are responsible for the kind of corporations we choose to support through our actions as consumers, investors and citizens.

The many ways to delimit species: hairs, genes and surface chemistry

Species identification forms the basis for understanding the diversity of the living world, but it is also a prerequisite for understanding many evolutionary patterns and processes. The most promising approach for correctly delimiting and identifying species is to integrate many types of information in the same study. Our aim was to test how cuticular hydro- carbons, traditional morphometrics, genetic polymorphisms in nuclear markers (allozymes and DNA microsatellites) and DNA barcoding (partial mitochondrial COI gene) perform in delimiting species. As an example, we used two closely related Formica ants, F. fusca and F. lemani, sampled from a sympatric population in the northern part of their distribu- tion. Morphological characters vary and overlap in different parts of their distribution areas, but cuticular hydrocarbons include a strong taxonomic signal and our aim is to test the degree to which morphological and genetic data correspond to the chemical data. In the morphological analysis, species were best separated by the combined number of hairs on pro- notum and mesonotum, but individual workers overlapped in hair numbers, as previously noted by several authors. Nests of the two species were separated but not clustered according to species in a Principal Component Analysis made on nuclear genetic data. However, model-based Bayesian clustering resulted in perfect separation of the species and gave no indication of hybridization. Furthermore, F. lemani and F. fusca did not share any mitochondrial haplotypes, and the species were perfectly separated in a phylogenetic tree. We conclude that F. fusca and F. lemani are valid species that can be separated in our study area relatively well with all methods employed. However, the unusually small genetic differen- tiation in nuclear markers (FST = 0.12) shows that they are closely related, and occasional hybridization between F. fusca and F. lemani cannot be ruled out.

Jakojuuriviljelyn vaikutus kasvihuonekurkun (Cucumis sativus L.) kasvuun ja kehitykseen

Kasvit ottavat vettä parhaiten kasteluravinneliuoksesta, jonka ravinnepitoisuus on pieni. Intensiivisessä kasvihuonetuotannossa käytetään silti kastelulannoituksessa usein korkeita ravinnepitoisuuksia ravinnepuutosten ja satotappioiden välttämiseksi. Jakojuuriviljelyssä kasvin juuriston annetaan kasvaa kahteen erilliseen kasvualustaosioon. Tällöin toiselle puolelle annetaan johtokyvyltään väkevää ja toiselle puolelle laimeaa ravinneliuosta. Erityisesti kasvihuonekurkun, joka on herkkä kasvualustan suolaisuuden aiheuttamille vedensaantiongelmille, on todettu hyötyvän tästä tekniikasta, mikä näkyy kasvaneina satoina. Tämän MTT Piikkiössä toteutetun kasvihuonekurkun jakojuuriviljelytutkimuksen tavoitteena oli tarkentaa tekniikkaa erityisesti kasteluliuosten johtokyvyn osalta. Yhtenäisjuuriviljelyn ja perinteisen jakojuuriviljelyn lisäksi kokeessa oli kaksi jakojuuriviljelykäsittelyä, joissa ravinneliuosväkevyyksiä vaihdettiin väliajoin juuriston toimintakyvyn parantamiseksi. Erillisessä osakokeessa tutkittiin erilaisten johtokyky-yhdistelmien vaikutusta kasvihuonekurkun vegetatiiviseen kasvuun maanpäällisten ja -alaisten kasvinosien välillä sekä juurten morfologiaan ja anatomiaan. Tulokset osoittivat, että jakojuuriviljely lisäsi kasvihuonekurkun sadontuottoa jopa 16 %, mutta ei vaikuttanut koko viljelykauden veden tai ravinteiden ottoon. Yhtenäisjuuriviljelyssä muodostui eniten piikkikärkisiä hedelmiä, mikä viittaa vedensaantiongelmiin haihdutustarpeen ollessa suurin. Viljelytekniikalla ei ollut vaikutusta kasvien vegetatiiviseen kasvuun tai kasvuston rakenteeseen. Lehtiruodeista tehdyt nitraatti- ja kaliummittaukset osoittivat, ettei kasteluliuosten ravinnepitoisuuksilla ollut vaikutusta juurten ravinteiden ottoon. Erilaisilla johtokyky-yhdistelmillä oli huomattavampi vaikutus kasvihuonekurkun juurten painoon kuin verson painoon tai varren pituuskasvuun. Lehtiruotianalyysit viittasivat ravinteiden erilaiseen allokointiin eri johtokyky-yhdistelmissä. Korkeiden johtokykyjen aiheuttama osmoottinen stressi johti muutoksiin juurten morfologiassa ja anatomiassa. Tulosten perusteella jakojuuriviljely paransi kehittyvien hedelmien kohdevahvuutta suhteessa muihin kohteisiin vaikuttamatta vegetatiiviseen kasvuun. Kun laimean ja väkevän ravinneliuoksen puolia vaihdettiin, juuristo otti joustavasti vettä ja ravinteita olosuhteiden määräämästä edullisemmasta johtokyvystä, jolloin kasvihuonekurkun viljelyssä saavutettiin merkittävä satoetu. Juuriston jakaminen vaikuttanee kasvien hormoniaineenvaihduntaan ja voi heikentää juuriston kasvua heikentämättä sen toimintakykyä, jolloin yhteyttämistuotteita kohdennetaan tehokkaammin maanpäällisten osien kasvuun.

Kymmenen teollisesti merkittävän puulajin kuoriuutteiden mahdollisuudet tuholaistorjunnassa

Metsäteollisuudesta kertyy vuosittain suuria määriä ylijäämämateriaalia, kuten puun kuorta ja oksia.Ylimääräinen aines käytetään pääasiassa energiantuotantoon, mutta uusia soveltamismahdollisuuksia kaivataan. Kuoren on havaittu olevan potentiaalinen lähde monille bioaktiivisille yhdisteille, joille olisi käyttöä esimerkiksi lääke- ja kemianteollisuudessa sekä maa-, metsä- ja puutarhatuotannon tuholaistorjunnassa. Tutkimus on osa Euroopan Unionin rahoittamaa ForestSpeCs-projektia, jonka tarkoituksena on selvittää metsäteollisuuden ylijäämämateriaalien vaihtoehtoisia käyttötapoja. Valittujen kymmenen teollisesti merkittävän pohjoisen puulajin (Abies nephrolepis, Betula pendula, Larix decidua, L. gmelinii, L. sibirica, Picea abies, P. ajanensis, P. pumila, Pinus sylvestris, Populus tremula) kuoresta uutettujen aineiden soveltuvuutta syönninestoaineeksi testattiin kaaliperhosen (Pieris brassicae L.) ja krysanteemiyökkösen (Spodoptera littoralis Boisduval) toukilla sekä osittain sinappikuoriaisella (Phaedon cochloreae Fabricius) ja idänlehtikuoriaisella (Agelastica alni L.). Uutteet valmistettiin yhteistyössä projektin ryhmien avulla tai itsenäisesti erilaisin menetelmin. Testaukset tehtiin laboratorio-oloissa käyttäen lehtikiekkojen valintabiotestiä sekä karkeilla uutteilla että niistä erotelluilla yksittäisillä yhdisteillä. Tehdyistä mittauksista laskettiin syönninestoindeksit (FDI). Tulosten perusteella lähes kaikki testatut uutteet vaikuttivat ainakin jossain määrin kohdehyönteisen syöntikäyttäytymiseen. Hieman yli puolet kaaliperhosella testatuista 46 uutteesta aiheuttivat yli 50 % syönnineston eli kaaliperhonen suosi kontrollilehtiä uutteella käsiteltyjä todennäköisemmin. Krysanteemiyökkösellä yli 50 %:n syönnineston aiheuttivat vain seitsemän testatuista 56 uutteesta. Lisäksi kolme uutetta lisäsi käsiteltyjen kiekkojen syöntiä merkittävästi. Idänlehtikuoriaistoukat ja -aikuiset karttoivat erityisesti abietiinihapolla käsiteltyjä lehtiä. Sinappikuoriaisella testatut uutteet toimivat myös lupaavasti. Testattujen puulajien kuoresta on mahdollista uuttaa biologisesti aktiivisia yhdisteitä, mutta tuholaistorjunnan kannalta oikeiden pitoisuuksien ja tehokkaiden uuttomenetelmien löytäminen vaatii jatkotutkimuksia. Kuoren sisältämien yhdisteiden laatu ja määrä vaihtelevat monien tekijöiden, kuten ympäristön ja genetiikan vaikutuksesta. Hyönteisten sietokyky vaihtelee myös paljon lajeittain ja yksilöidenkin välillä on eroja. Uutteista valmistettavia torjunta-aineita olisi kuitenkin mahdollista sisällyttää esimerkiksi integroituun torjuntaan muiden menetelmien rinnalle tulevaisuudessa.