Cooperation and conflict in conspecific brood parasitism : an alternative reproductive tactic

Interactions among individuals give rise to both cooperation and conflict. Individuals will behave selfishly or altruistically depending on which gives the higher payoff. The reproductive strategies of many animals are flexible and several alternative tactics may be present from which the most suitable one is applied. Generally, alternative reproductive tactics may be defined as a response to competition from individuals of the same sex. These alternative reproductive tactics are means by which individuals may fine-tune their fitness to the reigning circumstances and which are shaped by the environment individuals are occupying as well as by the behaviour of other individuals sharing the environment. By employing such alternative ways of achieving reproductive output, individuals may alleviate competition from others. Conspecific brood parasitism (CBP) is an alternative reproductive strategy found in several egg laying animal groups, and it is especially common among waterfowl. Within this alternative reproductive strategy, four reproductive options can be identified. These four options represent a continuum from low reproductive effort coupled with low fitness returns, to high reproductive effort and consequently high benefits. It may not be evident how individuals should allocate reproductive effort between eggs laid in their own nest vs. in nests of others, however. Limited fecundity will constrain the number of eggs donated by a parasite, but also the tendency for hosts to accept parasitic eggs may affect the allocation decision. Furthermore, kinship, individual quality and the costs of breeding may play a role in complicating the allocation decision. In this thesis, I view the seemingly paradoxical effects of kinship on conflict resolution in the context of alternative reproductive tactics, examining the resulting features of cooperation and conflict. Conspecific brood parasitism sets the stage for investigating these questions. By using both empirical and theoretical approaches, I examine the nature of CBP in a brood parasitic duck, the Barrow's goldeneye (Bucephala islandica). The theoretical chapter of this thesis gives rise to four main conclusions. Firstly, variation in individual quality plays a central role in shaping breeding strategies. Secondly, kinship plays a central role in the evolution of CBP. Thirdly, egg recognition ability may affect the prevalence of parasitism. If egg recognition is perfect, higher relatedness between host and parasite facilitates CBP. Finally, I show that the relative costs of egg laying and post-laying care play a so far underestimated role in determining the prevalence of parasitism. The costs of breeding may outweigh possible inclusive fitness benefits accrued from receiving eggs from relatives. Several of the patterns brought out by the theoretical work are then confirmed empirically in the following chapters. Findings include confirmation of the central role of relatedness in determining the extent of parasitism as well as inducing a counterintuitive host clutch reduction. Furthermore, I demonstrate a cost of CBP inflicted on hosts, as well as results suggesting that host age reflects individual quality, affecting the ability to overcome costs inflicted by CBP. In summary, I demonstrate both theoretically and empirically the presence of cooperation and conflict in the interactions between conspecific parasites and their hosts. The field of CBP research has traditionally been divided, but the first steps have now been taken toward the acceptance of the opposite side of the divide. Especially the theoretical findings of chapter 1 offer the possibility to view seemingly contrasting results of various studies within the same framework, and may direct future research toward more general features underlying differences in the patterns of CBP between populations or species.

The influence of eutrophication on sexual selection in sticklebacks

Jordens ekologiska system undergår för tillfället stora förändringar pga. människans aktiviteter. Ett växande antal studier visar att dessa förändringar påverkar naturliga och sexuella urvalet och därmed evolutiva processer. Målet med detta arbete var att undersöka effekterna av omgivningsförändringar på sexuella urvalet genom att använda den ökade övergödningen inom storpiggen Gasterosteus aculeatus lekområden som modell system. Sexuella urvalet är en viktig evolutiv kraft med följder på populations- och artnivå (Kapitel 1). Avhandlingens olika delar fokuserar på övergödningens effekter på upptäckandet av partners, användningen av visuella- och doftsignaler i partnersval, och fördelningen av parningsframgången mellan bobyggande hanar. I Kapitel II och III simuleras hur grumlighet orsakad av fytoplankton påverkar hastigheten med vilken potentiella partners påträffas, genom effekter på synligheten. Resultaten visar att normala algblomningar i Östersjön har en måttlig effekt på finnandet av potentiella partners. Detta tyder på att algblomningarna troligen inte kommer att minska på selektiva parningen pga. ökade sökkostnader. I Kapitel IV visas att storspiggen ändrar relativa användningen av olika signaler när vattnets grumlighet ökar; visuella signaler minskar i betydelse medan doftsignaler ökar i betydelse. Samtidigt underlättas användandet av doftsignaler av ändringar i vattnets kemiska sammansättning då fotosyntesen intensifieras (Kapitel V). Lek i övergödda vatten kan ändå vara kostsamt både på individ- och populationsnivån, då parasiterade hanar, som troligen är dåligt genetiskt anpassade till sin miljö, lyckas få mer ägg i sina bon än friskare hanar som troligen är av högre genetisk kvalitet (Kapitel VI). Övergödningen påverkar således partnersval och konkurrensen om partners genom att påverka upptäckandet av potentiella partners, evalueringen av partners och fördelningen av partners inom lekområdena. De följder detta kan ha för evolutionen av sexuellt selekterad egenskaper och för populationers dynamik och livskraft är dock oklara. Avhandlingen visar på svårigheten att förutse följderna av omgivningsförändringar för sexuella urvalet och effekterna på individ och populationsnivå.

Characterization of inhibition of platelet function by paracetamol and its interaction with diclofenac and parecoxib

Aim: To characterize the inhibition of platelet function by paracetamol in vivo and in vitro, and to evaluate the possible interaction of paracetamol and diclofenac or valdecoxib in vivo. To assess the analgesic effect of the drugs in an experimental pain model. Methods: Healthy volunteers received increasing doses of intravenous paracetamol (15, 22.5 and 30 mg/kg), or the combination of paracetamol 1 g and diclofenac 1.1 mg/kg or valdecoxib 40 mg (as the pro-drug parecoxib). Inhibition of platelet function was assessed with photometric aggregometry, the platelet function analyzer (PFA-100), and release of thromboxane B2. Analgesia was assessed with the cold pressor test. The inhibition coefficient of platelet aggregation by paracetamol was determined as well as the nature of interaction between paracetamol and diclofenac by an isobolographic analysis in vitro. Results: Paracetamol inhibited platelet aggregation and TxB2-release dose-dependently in volunteers and concentration-dependently in vitro. The inhibition coefficient was 15.2 mg/L (95% CI 11.8 - 18.6). Paracetamol augmented the platelet inhibition by diclofenac in vivo, and the isobole showed that this interaction is synergistic. Paracetamol showed no interaction with valdecoxib. PFA-100 appeared insensitive in detecting platelet dysfunction by paracetamol, and the cold-pressor test showed no analgesia. Conclusions: Paracetamol inhibits platelet function in vivo and shows synergism when combined with diclofenac. This effect may increase the risk of bleeding in surgical patients with an impaired haemostatic system. The combination of paracetamol and valdecoxib may be useful in patients with low risk for thromboembolism. The PFA-100 seems unsuitable for detection of platelet dysfunction and the cold-pressor test seems unsuitable for detection of analgesia by paracetamol.

Determinants of Coronary and Carotid Atherosclerosis in Finnish Patients with Clinically Suspected Coronary Artery Disease. A Quantitative Angiography and Ultrasound Study

Background. Cardiovascular disease (CVD) remains the most serious threat to life and health in industrialized countries. Atherosclerosis is the main underlying pathology associated with CVD, in particular coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease. Risk factors play an important role in initiating and accelerating the complex process of atherosclerosis. Most studies of risk factors have focused on the presence or absence of clinically defined CVD. Less is known about the determinants of the severity and extent of atherosclerosis in symptomatic patients. Aims. To clarify the association between coronary and carotid artery atherosclerosis, and to study the determinants associated with these abnormalities with special regard to novel cardiovascular risk factors. Subjects and methods. Quantitative coronary angiography (QCA) and B-mode ultrasound were used to assess coronary and carotid artery atherosclerosis in 108 patients with clinically suspected CAD referred for elective coronary angiography. To evaluate anatomic severity and extent of CAD, several QCA parameters were incorporated into indexes. These measurements reflected CAD severity, extent, and overall atheroma burden and were calculated for the entire coronary tree and separately for different coronary segments (i.e., left main, proximal, mid, and distal segments). Maximum and mean intima-media thickness (IMT) values of carotid arteries were measured and expressed as mean aggregate values. Furthermore, the study design included extensive fasting blood samples, oral glucose tolerance test, and an oral fat-load test to be performed in each participant. Results. Maximum and mean IMT values were significantly correlated with CAD severity, extent, and atheroma burden. There was heterogeneity in associations between IMT and CAD indexes according to anatomical location of CAD. Maximum and mean IMT values, respectively, were correlated with QCA indexes for mid and distal segments but not with the proximal segments of coronary vessels. The values of paraoxonase-1 (PON1) activity and concentration, respectively, were lower in subjects with significant CAD and there was a significant relationship between PON1 activity and concentration and coronary atherosclerosis assessed by QCA. PON1 activity was a significant determinant of severity of CAD independently of HDL cholesterol. Neither PON1 activity nor concentration was associated with carotid IMT. The concentration of triglycerides (TGs), triglyceride-rich lipoproteins (TRLs), oxidized LDL (oxLDL), and the cholesterol content of remnant lipoprotein particle (RLP-C) were significantly increased at 6 hours after intake of an oral fatty meal as compared with fasting values. The mean peak size of LDL remained unchanged 6 hours after the test meal. The correlations between total TGs, TRLs, and RLP-C in fasting and postprandial state were highly significant. RLP-C correlated with oxLDL both in fasting and in fed state and inversely with LDL size. In multivariate analysis oxLDL was a determinant of severity and extent of CAD. Neither total TGs, TRLs, oxLDL, nor LDL size were linked to carotid atherosclerosis. Insulin resistance (IR) was associated with an increased severity and extent of coronary atherosclerosis and seemed to be a stronger predictor of coronary atherosclerosis in the distal parts of the coronary tree than in the proximal and mid parts. In the multivariate analysis IR was a significant predictor of the severity of CAD. IR did not correlate with carotid IMT. Maximum and mean carotid IMT were higher in patients with the apoE4 phenotype compared with subjects with the apoE3 phenotype. Likewise, patients with the apoE4 phenotype had a more severe and extensive CAD than individuals with the apoE3 phenotype. Conclusions. 1) There is an association between carotid IMT and the severity and extent of CAD. Carotid IMT seems to be a weaker predictor of coronary atherosclerosis in the proximal parts of the coronary tree than in the mid and distal parts. 2) PON1 activity has an important role in the pathogenesis of coronary atherosclerosis. More importantly, the study illustrates how the protective role of HDL could be modulated by its components such that equivalent serum concentrations of HDL cholesterol may not equate with an equivalent, potential protective capacity. 3) RLP-C in the fasting state is a good marker of postprandial TRLs. Circulating oxLDL increases in CAD patients postprandially. The highly significant positive correlation between postprandial TRLs and postprandial oxLDL suggests that the postprandial state creates oxidative stress. Our findings emphasize the fundamental role of LDL oxidation in the development of atherosclerosis even after inclusion of conventional CAD risk factors. 4) Disturbances in glucose metabolism are crucial in the pathogenesis of coronary atherosclerosis. In fact, subjects with IR are comparable with diabetic subjects in terms of severity and extent of CAD. 5) ApoE polymorphism is involved in the susceptibility to both carotid and coronary atherosclerosis.

Arterial stiffness and cardiovascular risk factors

Background: As the human body ages, the arteries gradually lose their elasticity and become stiffer. Although inevitable, this process is influenced by hereditary and environmental factors. Interestingly, many classic cardiovascular risk factors affect the arterial stiffness. During the last decade, accelerated arterial stiffening has been recognized as an important cardiovascular risk factor associated with increased mortality as well as with several chronic disorders. Objectives: This thesis examines the role of arterial stiffness in relation to variations in a physiological feature in healthy individuals. In addition, the effect on arterial stiffness of an acute transitory disease and the effect of a chronic disease are studied. Furthermore, the thesis analyzes the prognostic value of a marker of arterial stiffness in individuals with chronic disease. Finally, a potential method of reducing arterial stiffness is evaluated. Material and study design: The first study examines pulse wave reflection and pulse wave velocity in relation to muscle fibre distribution in healthy middle-aged men. In the second study, pulse wave reflection in women with current or previous preeclampsia is compared to a healthy control group. The effect of aging on the different blood pressure indices in patients with type 1 diabetes is examined in the third study, whereas the fourth paper studies the relation between these blood pressure indices and mortality in type 2 diabetes. The fifth study evaluates how intake of a fermented milk product containing bioactive peptides affects pulse wave reflection in individuals with mild hypertension. Results and conclusions: Muscle fibre type distribution is not an independent determinant of arterial stiffness in middle-aged males. Pulse wave reflection is increased in pregnant women with preeclampsia, but not in previously preeclamptic non-pregnant women. Patients with type 1 diabetes have a higher and more rapidly increasing pulse pressure, which suggests accelerated arterial stiffening. In elderly type 2 diabetic patients, very high and very low levels of pulse pressure are associated with higher mortality. Intake of milk-derived bioactive peptides reduces pulse wave reflection in hypertensive males but not in hypertensive females.

The effect of blood glucose on the vasculature in young patients with type 1 diabetes

Background. Patients with type 1 diabetes are at markedly increased risk of vascular complications. In this respect it is noteworthy that hyperglycaemia that is shown to cause endothelial dysfunction, has clearly been shown to be a risk factor for diabetic microvascular disease. However, the role of hyperglycaemia as a predictor of macrovascular disease is not as clear as for microvascular disease, although type 1 diabetes itself increases the risk of cardiovascular disease substantially. Furthermore, it is not known whether it is the short-term or the long-term hyperglycaemia that confers possible risk. In addition, the role of glucose variability as a predictor of complications is to a large extent unexplored. Interestingly, although hyperglycaemia increases the risk of pre-eclampsia in women with type 1 diabetes, it is unclear whether pre-eclampsia, a condition characterized by endothelial dysfunction, is also a risk factor for microvascular complication, diabetic nephropathy. Aims. This doctoral thesis investigated the role of acute hyperglycaemia and glucose variability on arterial stiffness and cardiac ventricular repolarisation in male patients with type 1 diabetes as well as in healthy male volunteers. The thesis also explored whether acute hyperglycaemia leads to an inflammatory response, endothelial dysfunction and oxidative stress. Finally, the role of pre-eclampsia, as a predictor of diabetic nephropathy in type 1 diabetes was examined. Subjects and methods. In order to study glucose variability and the daily glycaemic control, 22 male patients with type 1 diabetes, without any diabetic complications, were monitored for 72-h with a continuous glucose monitoring system. At the end of the 72-h glucose monitoring period a 2-h hyperglycaemic clamp was performed both in the patients with type 1 diabetes and in the 13 healthy age-matched male volunteers. Blood pressure, arterial stiffness and QT time were measured to detect vascular changes during acute hyperglycaemia. Blood samples were drawn at baseline (normoglycaemia) and during acute hyperglycaemia. In another patient sample, women with type 1 diabetes were followed during their pregnancy and restudied eleven years later to elucidate the role of pre-eclampsia and pregnancy-induced hypertension as potential risk factors for diabetic nephropathy. Results and conclusions. Acute hyperglycaemia increased arterial stiffness as well as caused a disturbance in the myocardial ventricular repolarisation, emphasizing the importance of a strict daily glycaemic control in male patients with type 1 diabetes. An inflammatory response was also observed during acute hyperglycaemia. Furthermore, a high mean daily blood glucose but not glucose variability per se is associated with arterial stiffness. While glucose variability in turn correlated with central blood pressure, the results suggest that the glucose metabolism is closely linked to the haemodynamic changes in male patients with uncomplicated type 1 diabetes. Notably, the results are not directly applicable to females. Finally, a history of a pre-eclamptic pregnancy, but not pregnancy-induced hypertension was associated with increased risk of diabetic nephropathy.

Dynamics of free-running, pump-modulated and coupled semiconductor and solid-state lasers

The output of a laser is a high frequency propagating electromagnetic field with superior coherence and brightness compared to that emitted by thermal sources. A multitude of different types of lasers exist, which also translates into large differences in the properties of their output. Moreover, the characteristics of the electromagnetic field emitted by a laser can be influenced from the outside, e.g., by injecting an external optical field or by optical feedback. In the case of free-running solitary class-B lasers, such as semiconductor and Nd:YVO4 solid-state lasers, the phase space is two-dimensional, the dynamical variables being the population inversion and the amplitude of the electromagnetic field. The two-dimensional structure of the phase space means that no complex dynamics can be found. If a class-B laser is perturbed from its steady state, then the steady state is restored after a short transient. However, as discussed in part (i) of this Thesis, the static properties of class-B lasers, as well as their artificially or noise induced dynamics around the steady state, can be experimentally studied in order to gain insight on laser behaviour, and to determine model parameters that are not known ab initio. In this Thesis particular attention is given to the linewidth enhancement factor, which describes the coupling between the gain and the refractive index in the active material. A highly desirable attribute of an oscillator is stability, both in frequency and amplitude. Nowadays, however, instabilities in coupled lasers have become an active area of research motivated not only by the interesting complex nonlinear dynamics but also by potential applications. In part (ii) of this Thesis the complex dynamics of unidirectionally coupled, i.e., optically injected, class-B lasers is investigated. An injected optical field increases the dimensionality of the phase space to three by turning the phase of the electromagnetic field into an important variable. This has a radical effect on laser behaviour, since very complex dynamics, including chaos, can be found in a nonlinear system with three degrees of freedom. The output of the injected laser can be controlled in experiments by varying the injection rate and the frequency of the injected light. In this Thesis the dynamics of unidirectionally coupled semiconductor and Nd:YVO4 solid-state lasers is studied numerically and experimentally.

Understanding the chemistry of atmospheric aerosol particle formation via observations of physical properties

It is widely accepted that the global climate is heating up due to human activities, such as burning of fossil fuels. Therefore we find ourselves forced to make decisions on what measures, if any, need to be taken to decrease our warming effect on the planet before any irrevocable damage occurs. Research is being conducted in a variety of fields to better understand all relevant processes governing Earth s climate, and to assess the relative roles of anthropogenic and biogenic emissions into the atmosphere. One of the least well quantified problems is the impact of small aerosol particles (both of anthropogenic and biogenic origin) on climate, through reflecting solar radiation and their ability to act as condensation nuclei for cloud droplets. In this thesis, the compounds driving the biogenic formation of new particles in the atmosphere have been examined through detailed measurements. As directly measuring the composition of these newly formed particles is extremely difficult, the approach was to indirectly study their different characteristics by measuring the hygroscopicity (water uptake) and volatility (evaporation) of particles between 10 and 50 nm. To study the first steps of the formation process in the sub-3 nm range, the nucleation of gaseous precursors to small clusters, the chemical composition of ambient naturally charged ions were measured. The ion measurements were performed with a newly developed mass spectrometer, which was first characterized in the laboratory before being deployed at a boreal forest measurement site. It was also successfully compared to similar, low-resolution instruments. The ambient measurements showed that sulfuric acid clusters dominate the negative ion spectrum during new particle formation events. Sulfuric acid/ammonia clusters were detected in ambient air for the first time in this work. Even though sulfuric acid is believed to be the most important gas phase precursor driving the initial cluster formation, measurements of the hygroscopicity and volatility of growing 10-50 nm particles in Hyytiälä showed an increasing role of organic vapors of a variety of oxidation levels. This work has provided additional insights into the compounds participating both in the initial formation and subsequent growth of atmospheric new aerosol particles. It will hopefully prove an important step in understanding atmospheric gas-to-particle conversion, which, by influencing cloud properties, can have important climate impacts. All available knowledge needs to be constantly updated, summarized, and brought to the attention of our decision-makers. Only by increasing our understanding of all the relevant processes can we build reliable models to predict the long-term effects of decisions made today.

Computer simulation of H and He effects in fusion reactor materials

Fusion power is an appealing source of clean and abundant energy. The radiation resistance of reactor materials is one of the greatest obstacles on the path towards commercial fusion power. These materials are subject to a harsh radiation environment, and cannot fail mechanically or contaminate the fusion plasma. Moreover, for a power plant to be economically viable, the reactor materials must withstand long operation times, with little maintenance. The fusion reactor materials will contain hydrogen and helium, due to deposition from the plasma and nuclear reactions because of energetic neutron irradiation. The first wall divertor materials, carbon and tungsten in existing and planned test reactors, will be subject to intense bombardment of low energy deuterium and helium, which erodes and modifies the surface. All reactor materials, including the structural steel, will suffer irradiation of high energy neutrons, causing displacement cascade damage. Molecular dynamics simulation is a valuable tool for studying irradiation phenomena, such as surface bombardment and the onset of primary damage due to displacement cascades. The governing mechanisms are on the atomic level, and hence not easily studied experimentally. In order to model materials, interatomic potentials are needed to describe the interaction between the atoms. In this thesis, new interatomic potentials were developed for the tungsten-carbon-hydrogen system and for iron-helium and chromium-helium. Thus, the study of previously inaccessible systems was made possible, in particular the effect of H and He on radiation damage. The potentials were based on experimental and ab initio data from the literature, as well as density-functional theory calculations performed in this work. As a model for ferritic steel, iron-chromium with 10% Cr was studied. The difference between Fe and FeCr was shown to be negligible for threshold displacement energies. The properties of small He and He-vacancy clusters in Fe and FeCr were also investigated. The clusters were found to be more mobile and dissociate more rapidly than previously assumed, and the effect of Cr was small. The primary damage formed by displacement cascades was found to be heavily influenced by the presence of He, both in FeCr and W. Many important issues with fusion reactor materials remain poorly understood, and will require a huge effort by the international community. The development of potential models for new materials and the simulations performed in this thesis reveal many interesting features, but also serve as a platform for further studies.

Diversitet och tillväxtfrämjande egenskaper hos Stenotrophomonas-endofyter isolerade från Calliandra calothyrsus Meisn. rotknölar

The bacterial genus Stenotrophomonas comprises 12 species. They are widely found throughout the environment and particularly S. maltophilia, S. rhizophila and S. pavanii are closely associated with plants. Strains of the most common Stenotrophomonas species, S. maltophilia, promote plant growth and health, degrade natural and man-made pollutants and produce biomolecules of biotechnological and economical value. Many S. maltophilia –strains are also multidrug resistant and can act as opportunistic human pathogens. During an INCO-project (1998-2002) rhizobia were collected from root nodules of the tropical leguminous tree Calliandra calothyrsus Meisn. from several countries in Central America, Africa and New Caledonia. The strains were identified by the N2-group (Helsinki university) and some strains turned out to be members of the genus Stenotrophomonas. Several Stenotrophomonas strains induced white tumor- or nodule-like structures on Calliandra?s roots in plant experiments. The strains could, besides from root nodules, also be isolated from surface sterilized roots and stems. The purpose of my work was to investigate if the Stenotrophomonas strains i) belong to a new Stenotrophomonas species, ii) have the same origin, iii) if there are other differences than colony morphology between phase variations of the same strain, iv) have plant growth-promoting (PGP) activity or other advantageous effects on plants, and v) like rhizobia have ability to induce root nodule formation. The genetic diversity and clustering of the Stenotrophomonas strains were analyzed with AFLP fingerprinting to get indications about their geographical origin. Differences in enzymatic properties and ability to use different carbon and energy sources were tested between the two phases of each strain with commercial API tests for bacterial identification. The ability to infect root hairs and induce root nodule formation was investigated both using plant tests with the host plant Calliandra and PCR amplification of nodA and nodC genes for nodulation. The PGP activity of the strains was tested in vitro mainly with plate methods. The impact on growth, nitrogen content and nodulation in vivo was investigated through greenhouse experiments with the legumes Phaseolus vulgaris and Galega orientalis. Both the genetic and phenotypic diversity among the Stenotrophomonas strains was small, which proposes that they have the same origin. The strains brought about changes on the root hairs of Calliandra and they also increased the amount of root hairs. However, no root nodules were detected. The strains produced IAA, protease and lipase in vitro. They also showed plant a growth-promoting effect on G. orientalis, both alone and together with R. galegae HAMBI 540, and also activated nodulation among efficient rhizobia on P. vulgaris in greenhouse. It requires further research to get a better picture about the mechanisms behind the positive effects. The results in this thesis, however, confirm earlier studies concerning Stenotrophomonas positive impact on plants.

Protein Kinase C and Anaplastic Lymphoma Kinase Targeted Compounds

The protein kinases (PKs) belong to the largest single family of enzymes, phosphotransferases, which catalyze the phosphorylation of other enzymes and proteins and function primarily in signal transduction. Consequently, PKs regulate cell mechanisms such as growth, differentiation, and proliferation. Dysfunction of these cellular mechanisms may lead to cancer, a major predicament in health care. Even though there is a range of clinically available cancer-fighting drugs, increasing number of cancer cases and setbacks such as drug resistance, constantly keep cancer research active. At the commencement of this study an isophthalic acid derivative had been suggested to bind to the regulatory domain of protein kinase C (PKC). In order to investigate the biological effects and structure-activity relationships (SARs) of this new chemical entity, a library of compounds was synthesized. The best compounds induced apoptosis in human leukemia HL-60 cells and were not cytotoxic in Swiss 3T3 fibroblasts. In addition, the best apoptosis inducers were neither cytotoxic nor mutagenic. Furthermore, results from binding affinity assays of PKC isoforms revealed the pharmacophores of these isophthalic acid derivatives. The best inhibition constants of the tested compounds were measured to 210 nM for PKCα and to 530 nM for PKCδ. Among natural compounds targeting the regulatory domain of PKC, the target of bistramide A has been a matter of debate. It was initially found to activate PKCδ; however, actin was recently reported as the main target. In order to clarify and to further study the biological effects of bistramide A, the total syntheses of the natural compound and two isomers were performed. Biological assays of the compounds revealed accumulation of 4n polyploid cells as the primary mode of action and the compounds showed similar overall antiproliferative activities. However, each compound showed a distinct distribution of antimitotic effect presumably via actin binding, proapoptotic effect presumably via PKCδ, and pro-differentiation effect as evidenced by CD11b expression. Furthermore, it was shown that the antimitotic and proapoptotic effects of bistramide A were not secondary effects of actin binding but independent effects. The third aim in this study was to synthesize a library of a new class of urea-based type II inhibitors targeted at the kinase domain of anaplastic lymphoma kinase (ALK). The best compounds in this library showed IC50 values as low as 390 nM for ALK while the initial low cellular activities were successfully increased even by more than 70 times for NPM-ALK- positive BaF3 cells. More importantly, selective antiproliferative activity on ALK-positive cell lines was achieved; while the best compound affected the BaF3 and SU-DHL-1 cells with IC50 values of 0.5 and 0.8 μM, respectively, they were less toxic to the NPM-ALK-negative human leukemic cells U937 (IC50 = 3.2 μM) and BaF3 parental cells (IC50 = 5.4 μM). Furthermore, SAR studies of the synthesized compounds revealed functional groups and positions of the scaffold, which enhanced the enzymatic and cellular activities.

Rätt som argument : Leo Mechelin och finska frågan 1886-1912

Right as an Argument. Leo Mechelin and the Finnish Question 1886-1912 At the turn of the 20th century the Finnish Question rose up as a political and juridical issue at the international arena. The vaguely précised position of Finland in the Russian empire led to diverse conclusions concerning the correctness of the February manifesto of 1899. It was predominantly among a European elite of politicians, cultural workers and academics the issue rose some interest. Finns were active making propaganda for their cause, and they put an emphasis on the claim that the right was on the Finnish side. In the study Elisabeth Stubb compare the Finnish, Russian and European statements about the Finnish Question and analyse their use of right as an argument. The Finnish Question offers at the same time a case study of a national entity which possesses a political sphere of life but is not fully independent, and its possibilities to drive its interests in an international context. Leo Mechelin (1839-1914), the leader of the Finnish propaganda organization abroad, is used as a point of departure. The biographical stance is formed into a triangle, where Leo Mechelin, the idea of right and the Finnish Question abroad are the three cornerstones. The treatment of one cornerstone sheds a ligth on the two others. The metaphor of triangulation also worked as a method to reach "a third stance" in a scinetific and political issue that usually is polarised into two opposite alternatives. An adherence to a strict legal right could not in the end offer a complete, unquestionable and satisfactory solution to the Finnsih Question, it was dependent on "the right of state wisdom and sound insight". The Finnish propaganda abroad used almost completely alternative ways of making politics. The propaganda did not have a decisive effect on countries' official politics, but gained unofficial support, especially in the public opinion and in academic statements. Mechelin claimed that the political field was dependent on public opinion and scientific research. Together with the official politics these two fields formed a triangle that shared the task of balancing the political arena and preventing it from making unwise decisions of taking an unjust turn. The international sphere worked as a balancing part in the Finnish Question. Mechelin tried by claiming the status of state for Finland's part to secure the country a place at the official international arena. At the same time, and especially when the claim was not fully adopted, he emphasised, and in a European context worked for, that right would become the guiding light not only for international relations, but also for the policy making in the inner life of the state.

Hypertension, kardiotoxicitet och njursvikt i samband med tyrosinkinashämmaren sunitinib

Nybildning av blodkärl från tidigare existerande kärl, angiogenes, är ett väsentligt skede vid tumörtillväxt. Denna process regleras av bland annat tillväxtfaktorer, var av den vaskulära endoteliala tillväxtfaktorn har en central roll. Hämning av angiogenes kan ske antingen extracellulärt med hjälp av humaniserade monoklonala antikroppar eller intracellulärt med hjälp av småmolekylära hämmaren. Sunitinib är en småmolekylär multikinashämmare och inhiberar flera tyrosinkinasreceptorer som påverkar tumörtillväxten och metastasutvecklingen vid cancer. Sunitinibs främsta indikationer är gastrointestinala stromacellstumörer, metastaserad njurcellscancer och neuroendokrina tumörer i bukspottskörteln. Behandling med tyrosinkinashämmare orsakar biverkningar som hypertension, kardiotoxicitet och njursvikt, vilka antas bero på de hämmande effekterna på mål som inte är väsentliga för anti-cancer-aktiviteten (”off-target” biverkningar). Bland annat AMP-aktiverat proteinkinas (AMPK), ett kinas som upprätthåller metabolisk homeostas i hjärtat, inhiberas av sunitinib och antas framkalla kardiovaskulära biverkningar. För att reducera ”off-target” biverkningar strävar man till att hitta alternativ som minskar de skadliga effekterna utan att den terapeutiska aktiviteten försvagas. Bland annat ett begränsat kaloriintag har uppvisat skyddande effekt på hjärtat via mekanismer sammankopplade till ökad resistens mot oxidativ stress, inflammation och mitokondriell dysfunktion, samt avtagande apoptos och autofagi. Detta sker delvis genom aktivering av enzymet Sirt1. Syftet med den här studien var att undersöka ifall kaloribegränsning skyddar mot kardiovaskulära och renala biverkningar inducerade av sunitinib hos råttor. Dessutom studerades vilka signalkedjor i cellen som medverkar. I studien användes 40 spontant hypertensiva råttor samt 10 normotensiva Wistar-Kyoto råttor. Försöksdjuren delades in i fem grupper beroende på behandling; I WKY kontroll, II SHR kontroll, III SHR + kaloribegränsning 70 %, IV SHR + sunitinib 3 mg/kg och V SHR + sunitinib 3 mg/kg + kaloribegränsning 70 %. Behandlingsperioden var åtta veckor. Blodtrycket mättes varje vecka med svansmanchett, urinutsöndringen undersöktes vecka 4 och vecka 8 med metabolismburar, ultraljudsundersökning av hjärtat utfördes sista veckan och blodkärlens respons till acetylkolin och natriumnitroprussid studerades i samband med avlivning. Proteinerna Sirt1 och AMPK analyserades i hjärtat med Western blotting samt förekomsten av makrofagmarkören ED1 i njurarna med immunhistokemi. Studien visade att sunitinibdosen 3 mg/kg är mycket väl tolererbar hos råttor eftersom sunitinib inte orsakade högre blodtryck, kraftigare hypertrofi eller mer omfattande njurskada jämfört med obehandlade SHR- grupper. Utgående från resultaten kan man också konstatera att kaloribegränsningen har positiva kardiovaskulära effekter.

Die Nutzung des Gefällt mir-Buttons auf Organisationsprofilen : eine quantitative Studie zur Erfassung der Nutzungsmotive und des Verlaufs von Gefällt mir-Verknüpfungen zwischen Usern und Organisationen im Online-Netzwerk Facebook

Die Nutzung des Like-Buttons wurde bisher nur oberflächlich und vor allem auf den US-Raum begrenzt erforscht. Dabei lag der Fokus ausschließlich auf wirtschaftlich orientierten Unternehmen und dem monetären Wert, den ein Fan für dieses hat. In der vorliegenden Untersuchung wird eine erweiterte Perspektive gewählt. Aus Sicht deutschsprachiger Nutzer wird erforscht, welche Motive und Bedürfnisse eine Person dazu veranlassen, sich freiwillig per Gefällt-mir zu verknüpfen. Hierzu wird der Uses and Gratifications-Ansatz herangezogen. Es stehen nicht Unternehmen, sondern generell alle Formen von Organisationen im Fokus. Gleichzeitig wird untersucht, wie diese Beziehungen verlaufen: Welche Erwartungen stellen Fans? Welche Handlungen nehmen sie wie häufig vor und welchen Effekt hat eine Fanbeziehung auf die Einstellung eines Nutzers gegenüber einer Organisation? Die Motive hinter der Nutzung des Gefällt mir-Buttons sind umfangreicher, als es bisherige Forschung vermuten ließ. Fans wollen informiert werden, sie wollen ihr Gefallen schnell und einfach bekunden und sich durch die Verknüpfung selbst darstellen. Weniger wichtig, aber dennoch von Relevanz sind die Motive der Partizipation und Unterstützung, der Empfehlung, der Vorteilssuche, der Unterhaltung sowie der Netzwerkerweiterung und Gruppenzugehörigkeit. Die Verwendung des Like-Buttons dient somit der Befriedigung einer ganzen Reihe von Nutzungsbedürfnissen. Der Verlauf der Beziehungen zwischen Organisationen und Usern ist eher von Passivität geprägt. Fans wollen zwar informiert werden und stellen konkrete Ansprüche an die Art und Form von Organisationsmeldungen, sie wollen aber nur selten wirklich direkt mit einem Unternehmen, einem Verein o.ä. interagieren. Langweilen die Meldungen einer Organisation, werden zu viele oder nicht relevante Informationen an die Fans weitergeben, zögern diese nicht, eine Verknüpfung zu beenden. Ein Effekt der Fanschaft auf die Einstellung von Nutzern gegenüber der jeweiligen Organisation konnte nur bedingt festgestellt werden. Letztere zieht einen Gewinn nicht aus einer erhöhten Ausgabebereitschaft seiner Fans, sondern aus deren stärkerer Aufmerksamkeit gegenüber Organisationsmeldungen.

Tanztherapie in der Psychoonkologie : Auswirkungen der Intervention auf die gesundheitsbezogene Lebensqualität

Das Ziel der vorliegenden Arbeit ist es zu prüfen, ob Tanztherapie einen Effekt auf dieLebensqualität bei Brustkrebspatientinnen hat. Brustkrebs ist die häufigste Krebserkrankungbei Frauen in Deutschland. Verbesserte Behandlungsformen und Früherkennungsmaßnahmenführen zu einem Anstieg der Überlebensrate. Dennoch bedingen ein langerBehandlungsweg und Unsicherheit über den Verlauf der Krankheit hohe Belastungen undUnsicherheiten. Nebenwirkungen und Langzeitfolgen der Interventionen beeinflussen zudemdie gesundheitsbezogene Lebensqualität. Körper und Psyche werden stark beansprucht undleiden. Die Psychoonkologie stellt dabei einen Teil des Behandlungsweges dar. Sie bildetesich aus der Erkenntnis heraus, dass die Krebserkrankung nicht nur den Körper beeinflusst,sondern den gesamten Menschen mit seiner seelischen und geistigen Verfassung. DieTanztherapie ist eine Maßnahme im Kanon der psychoonkologischen Betreuung. Sie vereintkörperliche Betätigung und kreative Ausdrucksmöglichkeiten. Psyche und Körper werden beidieser Therapieform angesprochen. Im Gruppensetting fließt zudem die soziale Komponentemit ein. Die These lautet demnach, dass Tanztherapie positive Auswirkungen auf diegesundheitsbezogenen Lebensqualität hat. Denn Körper, Psyche und soziales Umfeld sindTeile der Lebensqualität. Das methodische Vorgehen dieser Arbeit setzte sich aus demRecherchieren von relevanten Studien, Reviews und Metaanalysen zusammen. Es wurdendie Datenbanken Google Scholar, PubMed, PsyCONTENT und Springer Link bis zum Jahre2014 durchsucht. Schlüsselworte waren dabei Tanztherapie, Psychoonkologie, Krebspatient,Lebensqualität, gesundheitsbezogene Lebensqualität, künstlerische Therapie,dance/movement therapy, cancer patient, quality of life, health related quality of life.