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  • Heiniö, Raija-Liisa (Helsingin yliopisto, 2003)
  • Tuimala, Jarno (Helsingin yliopisto, 2004)
  • Kuuliala, Krista (Helsingin yliopisto, 2007)
    The pathogenesis of inflammatory rheumatic diseases, including rheumatoid arthritis (RA) and spondyloarthropathies (SpAs) such as reactive arthritis (ReA), is incompletely understood. ReA is a sterile joint inflammation, which may follow a distal infection caused by Gram-negative bacteria that have lipopolysaccharide (LPS) in their outer membrane. The functions of innate immunity that may affect the pathogenesis, prognosis and treatment of these diseases were studied in this thesis. When compared with healthy controls, whole blood monocytes of healthy subjects with previous ReA showed enhanced capacity to produce TNF, an essential proinflammatory cytokine, in response to adherent conditions (mimicking vascular endothelium made adherent by inflammatory signals) and non-specific protein kinase C stimulation. Also, blood neutrophils of these subjects showed high levels of CD11b, an important adhesion molecule, in response to adherence or LPS. Thus, high responsiveness of monocytes and neutrophils when encountering inflammatory stimuli may play a role in the pathogenesis of ReA. The results also suggested that the known risk allele for SpAs, HLA-B27, may be an additive contributor to the observed differences. The promoter polymorphisms TNF 308A and CD14 (gene for an LPS receptor component) 159T were found not to increase the risk of acute arthritis. However, all female patients who developed chronic SpA had 159T and none of them had 308A, possibly reflecting an interplay between hormonal and inflammatory signals in the development of chronic SpA. Among subjects with early RA, those having the polymorphic TLR4 +896G allele (causing the Asp299Gly change in TLR4, another component of LPS receptor) required a combination of disease-modifying antirheumatic drugs to achieve remission. It is known that rapid treatment response is essential in order to maintain the patients work ability. Hence, +896G might be a candidate marker for identifying the patients who need combination treatment. The production of vascular endothelial growth factor (VEGF), which strongly promotes vascular permeability and angiogenesis that takes place e.g. early in rheumatic joints, was induced by LPS and inhibited by interferon (IFN)-alpha in peripheral blood mononuclear cells. These long-living cells might provide a source of VEGF when stimulated by LPS and migrating to inflamed joints, and the effect of IFN-alpha may contribute to the clinical efficacy of this cytokine in inhibiting joint inflammation.
  • Lahti, Katriina (Helsingin yliopisto, 2001)
  • Häärä, Otso (Helsingin yliopisto, 2013)
    The salivary glands and the teeth are organs derived from the embryonic germ layer, ectoderm, and share a common early development. Ectodysplasin (Eda) is a signaling molecule belonging to the tumor necrosis factor (TNF) family and its function has been shown to be vital for the formation of the ectodermal organs in vertebrates from teleost fish to mammals. A mutation in Eda in human causes hypohidrotic ectodermal dysplasia (HED), an X-linked hereditary disease causing reduced salivation and missing or modified teeth, in addition to defects in other ectodermal organs. The spontaneous mutant mouse for Eda, called Tabby, shares similar defects and serves as a good model to study HED. In Tabby, teeth are smaller and modified in shape. While the mechanisms of Eda signaling are well known in teeth, they are not yet understood in salivary gland development. However, it is known that in Tabby, the salivary glands are smaller with reduced branching of the saliva-secreting epithelium. In both organs, beside Eda, other major signaling pathways including Wnt/β-catenin, Hh, BMP and Fgf, also operate simultaneously during development. Eda is thought to interact with these pathways; however, it is not known how Eda is integrated with these other pathways. Here I have analyzed the role of Eda in salivary gland development and showed that branching of the epithelium, required to produce adequate surface area for saliva production, is dependent on Eda. In Tabby, branching of the epithelium and thus, the surface area, was reduced. The effect of Eda was largely mediated by the Hh pathway in the salivary gland. I also showed that the transcription factor NF-B is required for Eda signaling and that the Wnt pathway induced Eda expression in the salivary gland. In tooth, Eda induced the Fgf pathway ligand Fgf20, which I identified as a novel regulator of tooth development. Using an Fgf20-null mouse crossed with either the Eda loss-of-function (Tabby) or the gain-of-function mice (K14-Eda), I showed that Fgf20 mediates many functions of Eda and was required for the regulation of tooth size and shape. Interestingly, loss of Fgf20 in the K14-Eda mouse supported the formation of an extra molar in the place of the ancestral premolar, a structure lost during rodent evolution 45 million years ago. I observed that reducing Fgf20 levels from normal to null in K14-Eda mouse mimics the shift from omnivorous to faunivorous type of rodent dentition, evoking a scenario that Fgf20 and Eda might be genes operating in the microevolution of dentition.
  • Palva, J. Matias (Helsingin yliopisto, 2005)
  • Pernu, Tuomas (Helsingin yliopisto, 2013)
    The notion of causal explanation is an essential element of the naturalistic world view. This view is typically interpreted to claim that we are only licensed to postulate entities that make a causal difference , or have causal power . The rest are epiphenomena and hence eliminable from the correct view of reality. The worry that some entities and phenomena that we take for granted mental properties in particular turn out to be epiphenomenal, can be seen as stemming from this sort of naturalistic attitude. This thesis reviews the issue of causal explanation within the context of the naturalistic philosophy of mind. It is argued that there is no single monolithic, unanimously accepted notion of causation that the naturalist should be committed to. Views vary on what this notion amounts to exactly, and fields of science vary with respect to their causal commitments. However, the naturalist can still presume that a scientifically informed philosophical account of causation exists, an account that is fundamentally philosophical, but also sensitive to actual scientific practice and its view of reality. The central issue of the current naturalistic philosophy of mind is the so-called problem of causal exclusion. According to this, the assumption that mental states could have genuine and autonomous effects on the physical world is inconsistent with physical commitments, namely the idea that mental states are necessarily neurally based and the idea that the physical world is causally complete. The causal exclusion argument claims that mental causes must be reduced to physical causes, as there remains no role for independent mental causes. The thesis reviews some central responses to the causal exclusion argument. It is shown that within the context of the interventionist notion of causation, inter-level causation can be ruled out. The causal exclusion argument would thus find support, contrary to what the proponents of the interventionist view typically claim. However, the result is also shown to have the corollary that purely higher-level, mental-to-mental causation is possible. The thesis suggests that this offers a consistent view of mental causation for a naturalist to hold.
  • Sopanen, Sanna (Helsingin yliopisto, 2009)
    The aim of the studies reported in this thesis was to examine the feeding interactions between calanoid copepods and toxic algae in the Baltic Sea. The central questions in this research concerned the feeding, survival and egg production of copepods exposed to toxic algae. Furthermore, the importance of copepods as vectors in toxin transfer was examined. The haptophyte Prymnesium parvum, which produces extracellular toxins, was the only studied species that directly harmed copepods. Beside this, it had allelopathic effects (cell lysis) on non-toxic Rhodomonas salina. Copepods that were exposed to P. parvum filtrates died or became severely impaired, although filtrates were not haemolytic (indicative of toxicity in this study). Monospecific Prymnesium cell suspensions, in turn, were haemolytic and copepods in these treatments became inactive, although no clear effect on mortality was detected. These results suggest that haemolytic activity may not be a good proxy of the harmful effects of P. parvum. In addition, P. parvum deterred feeding, and low egestion and suppressed egg production were consequently observed in monospecific suspensions of Prymnesium. Similarly, ingestion and faecal pellet production rates were suppressed in high concentration P. parvum filtrates and in mixtures of P. parvum and R. salina. These results indicate that the allelopathic effects of P. parvum on other algal species together with lowered viability as well as suppressed production of copepods may contribute to bloom formation and persistence. Furthermore, the availability of food for planktivorous animals may be affected due to reduced copepod productivity. Nodularin produced by Nodularia spumigena was transferred to Eurytemora affinis via grazing on filaments of small N. spumigena and by direct uptake from the dissolved pool. Copepods also acquired nodularin in fractions where N. spumigena filaments were absent. Thus, the importance of microbial food webs in nodularin transfer should be considered. Copepods were able to remove particulate nodularin from the system, but at the same time a large proportion of the nodularin disappeared. This indicates that copepods may possess effective mechanisms to remove toxins from their tissues. The importance of microorganisms, such as bacteria, in the degradation of cyanobacterial toxins could also be substantial. Our results were the first reports of the accumulation of diarrhetic shellfish toxins (DSTs) produced by Dinophysis spp. in copepods. The PTX2 content in copepods after feeding experiments corresponded to the ingestion of <100 Dinophysis spp. cells. However, no DSTs were recorded from field-collected copepods. Dinophysis spp. was not selected by the copepods and consumption remained low. It seems thus likely that copepods are an unimportant link in the transfer of DSTs in the northern Baltic Sea.
  • Voutilainen, Liina (Helsingin yliopisto, 2013)
    Among rodent-borne pathogens, hantaviruses are one of the most important groups concerning human health and economy. Understanding the interactions between hantaviruses and their reservoir host species is crucial for prediction and prevention of human epidemics. In this thesis, I studied the interactions between Puumala hantavirus (PUUV) and its host, the bank vole (Myodes glareolus). The study was conducted in the boreal zone of Europe, where human incidence of nephropathia epidemica (NE, a mild form of haemorrhagic fever with renal syndrome) caused by PUUV is the highest. Endemic pathogens, such as hantaviruses, have been hypothesized to cause no apparent symptoms or fitness costs to their hosts. However, we found PUUV infection to decrease the over-winter survival of wild bank voles. We also found wild bank voles to shed PUUV via urine, faeces, and saliva throughout their life span without any remarkable decline, in contrast to earlier results from laboratory-reared rodent hosts. For the first time, dynamics of PUUV infection were studied during winter, when the majority of NE cases occur in the boreal zone. We found PUUV-infected bank voles to be most abundant in the winters of increase and peak years of the 3-year density cycle. In bank voles, the prevalence of PUUV infection showed a regular, seasonal fluctuation, which resulted from seasonal population turnover and the positive correlation between age and the likelihood of being PUUV infected. However, despite its regular fluctuation, PUUV prevalence in voles is not a good predictor of human NE risk since the periods of high prevalence coincided with low NE incidence in humans. Aggression has been suggested as the key driver for other hantaviruses in their host species, but the rate of PUUV transmission in bank voles was higher outside the breeding season, when bank voles do not show aggressive behaviour, than during the breeding season. The high rate of transmission outside the breeding season may be attributed to subnivean conditions that promote virus stability, lower immune response during cold conditions, and high host density in fall. We also found evidence for the dilution effect hypothesis, which assumes non-host species to reduce virus transmission between hosts: the prevalence of PUUV was low in bank voles when other small mammals were abundant. Male sex bias in infection is a general phenomenon that has also been observed in several hantavirus-host systems. We found a male bias in PUUV infection only in overwintered, breeding bank voles, whereas a female bias was seen in summer-born breeding animals. In non-breeding animals, no sex differences existed. Therefore, the effects of host sex in hantavirus transmission may be more complex than previously thought. Forest habitats disturbed by intensive forest management were associated with a higher likelihood of PUUV infection in bank voles. This finding could be explained by the poorer quality of these habitats, leading to lower condition and higher susceptibility, and also by more favourable environmental conditions for virus survival outside the host. Despite the higher infection prevalence in voles, the total number of PUUV-infected bank voles was 46-64% lower in young, intensively managed than in undisturbed, old forests. Thus, environmental change per se does not automatically lead to relative success of species that serve as reservoirs for zoonotic pathogens, and thereby, to increased human disease risk. The results of this thesis encourage further studies of host-pathogen interactions in natural conditions, and in different host-hantavirus systems. They also provide a framework for risk models aiming at reduction of human hantavirus infections.
  • Kailanto, Sanna (Helsingin yliopisto, 2010)
    It has been hypothesized that abuse of supra-therapeutic doses of anabolic androgenic steroids (AASs) can lead to dependence and function as a gateway to abuse of other drugs. This is supported by behavioral studies on animal models and psychiatric evaluations of human subjects, although their neurochemical effects remain largely unknown. A large body of evidence suggests that the ability of the drugs to induce a strong elevation of extracellular dopamine (DA) levels in the nucleus accumbens (NAc), especially, plays a crucial role in their reinforcing effects. -- This study had four main aims. The first was to explore the effects of nandrolone decanoate on dopaminergic and serotonergic activities in the brains of rats. The second aim was to assess whether or not nandrolone pre-exposure modulates the acute neurochemical and behavioral effects of psychostimulant drugs in experimental animals. The third was to investigate if the AAS-pre-treatment induced changes in brain reward circuitry are reversible. And the fourth main goal was to evaluate the role of androgen and estrogen receptors in the modulation of the dopaminergic and serotonergic effects of acute injections of stimulant drugs by sub-chronic nandrolone treatment. The results showed that nandrolone decanoate at doses, high enough to induce erythropoiesis, significantly increased the levels of DOPAC and 5-HT in the cerebral cortex. Co-administration of AAS and psychostimulant drugs showed that the increase in extracellular DA and 5-HT concentration evoked by amphetamine, MDMA and cocaine in the NAc was attenuated dose-dependently by pretreatment with nandrolone. Nandrolone pre-exposure also attenuated the ability of stimulants to cause increased stereotyped behavior and locomotor activity. Despite the significant decrease in nandrolone concentration in blood, the attenuation of cocaine’s effects remained unchanged after a fairly long period without nandrolone, suggesting that nandrolone effects could be long lasting. Blockade of androgen receptors with flutamide abolished the attenuating effect of nandrolone pretreatment on amphetamine-induced elevation of extracellular DA concentration. --- In conclusion, the results show that AAS-pretreatment is able to inhibit the reward-related neurochemical and behavioral effects of amphetamine, MDMA and cocaine in experimental animals. Furthermore, it seems that these effects could be long lasting and it appears that the ability of nandrolone to modulate reward-related effects of stimulants is dependent on activation of androgen receptors.
  • Aranko, A. Sesilja (Helsingin yliopisto, 2014)
    Inteins are selfish but harmless autocatalytic proteins that perform a post-translational modification, termed protein splicing. In protein splicing an intein excises itself off from the precursor protein and simultaneously ligates the flanking proteins together with a peptide bond. Inteins are found sporadically distributed in unicellular organisms, but their biological functions remain obscure. Importanly, inteins that are split into two can remain active and perform protein ligation by protein trans-splicing (PTS). In principle, PTS allows ligation of any two protein-sequences, with the only requirement being Ser, Thr, or Cys as the first residue downstream of the intein. This has inspired development of numerous biotechnological applications including protein semisynthesis, segmental isotopic labeling, and cyclization. Protein ligation by split inteins is, however, limited by the lengths, substrate specificity, orthogonality, and the reaction yields of the split inteins. The objective of this thesis was to advance the development of protein splicing as a protein-ligation tool. First, the split site of a natively split DnaE intein was shifted in order to engineer a split intein with shorter C-intein that could be easily chemically synthetized. The newly engineered split intein could perform protein ligation in high yields and was demonstrated to be in certain cases even better than the natively split intein. Encouraged by this, 21 more split inteins were engineered starting from four different inteins, guided by the three dimensional structures of these inteins. Split inteins were systematically tested for activity and orthogonality to evaluate their potential for biotechnological applications. Next, the scope was widened to bacterial intein-like (BIL) domains. BIL domains belong to the same superfamily with inteins but are distinct by their distribution and functions and have a wider variety of residues at the downstream junction. The first structure of a BIL domain was solved. It highlighted their homology to inteins as well as allowed engineering of split BIL domains. The split BIL domains could perform protein ligation also with Ala at the downstream splicing junction, although in minute yields, which could be the first step towards nucleophile-free protein ligation. Finally, discovery of a previously not reported intermolecular protein-splicing reaction, termed intein-mediated protein alternative splicing (iPAS), was described. Structural studies revealed that three-dimensional domain swapping is the underlying mechanisms of iPAS. iPAS makes it possible to increase diversity at protein level, without altering the genetic code, and could be used to control protein functions in concentration and expression-order dependent manner. Discovery of this new phenomenon could allow protein interference and is opening new insights into the possible biological functions of inteins.
  • Makkonen, Maarit (Helsingin yliopisto, 2013)
    The ability of actin to form dynamic networks is crucial for processes including cell migration, endocytosis and cell division. Furthermore, in sarcomeres of muscle cells, actin and myosin form interdigitating networks responsible for muscle contraction. Actin is found from all eukaryotic cells where it exists as monomeric and filamentous forms, which are in balance and strictly regulated by plethora of actin binding proteins. Among the most central actin binding proteins are cyclase-associated protein (CAP), cofilin, profilin and twinfilin, which are under investigation in this study. CAP is known to bind actin monomers and accelerate actin turnover together with cofilin. Furthermore, CAP has been shown to accelerate nucleotide exchange on actin monomers. Also profilin catalyzes nucleotide exchange and CAP is known to interact with profilin, but the exact mechanism how these proteins work together is not understood. This study reveals that interactions with actin monomers, cofilin and profilin are conserved in CAPs from yeast to mammals. Unexpectedly, mammalian CAP was observed to have a higher affinity for ATP-actin than yeast CAP, and mammalian CAP was found to have two independent profilin binding sites whereas yeast CAP has only one. This study also demonstrates a novel function for the mini-CAP from apicomplexan parasite as a nucleotide exchange promoting factor. The malaria parasite CAP comprises only the C-terminal ADP-actin binding site suggesting that this domain harbors the most conserved function of CAPs. The unpublished data of this study reveals that CAP, twinfilin and ADP-actin form a ternary complex. Many actin-binding proteins have muscle-specific isoforms in addition to nonmuscle ones. The muscle-specific cofilin-2 was studied here and levels of cofilin-2 were shown to increase during sarcomere maturation while cofilin-1 amounts remained constant. Also, cofilin-2 showed higher affinity for ATP-actin than cofilin-1 through a specific cluster of residues on its surface. Therefore, a specific cofilin isoform with high affinity for ATP-actin evolved to regulate actin dynamics in thin filaments of sarcomeres. The roles of other muscle-specific proteins are under particular interest and subject of future research. In summary, the findings of this study reveal the mechanisms by which CAP regulates actin dynamics together with cofilin, profilin and twinfilin. Furthermore, this study elucidates yet rather unknown actin regulation by muscle-specific cofilin-2.
  • Pekkonen, Minna (Helsingin yliopisto, 2013)
    Organisms interact continuously with their environment. They change the quality of the environment by consuming the resources or otherwise modifying the conditions. Changes in environmental conditions in turn affect fundamentally the dynamics of populations and communities. This two-directional interaction between organisms and environment can also be an important evolutionary force. In my thesis I have studied how changes in environmental conditions affect organisms on different levels of biological hierarchy ranging from individuals to communities. I have focused on the ecological and evolutionary effects of temporal changes in resource availability. Intermediate resource fluctuations are predicted to promote community diversity. Furthermore, rare fluctuations in resource availability together with inter- or intraspecific competition can shape the evolution of life-history traits. The questions of my thesis were addressed using experimental evolution techniques and heterotrophic bacteria. The results of my thesis exemplify a system where the interaction between organisms and their environment is dynamic, changing, and reciprocal. I found support for the view that temporal environmental variation promotes diversity within communities. However, also other factors contributed to the species coexistence such as spatial heterogeneity due to bacterial growth as biofilms, and evolutionary changes in life-history traits. I monitored the evolution of fitness related traits (mortality, growth rate, biomass and biofilm production) over hundreds of bacterial generations. When bacteria experienced rare, seasonal changes in their resource availability, the evolutionary response was decreased mortality during resource scarcity. The growth rate increased over evolutionary time in one of my study species, when it experienced interspecific competition and resource fluctuations. In addition, my results show that bacteria modify their habitat, and these changes alter the between species interaction from antagonistic to positive. The temporal changes in species interaction type can partly explain the long-term coexistence of the study species. Altogether, the results of my thesis show that biological interactions can be complex even in a relatively simple system. Changes in environmental conditions affect population dynamics and coexistence of species, and in turn, the activity of organisms changes the environmental conditions and evolution adds complexity in these dynamics.
  • Gonda, Abigél (Helsingin yliopisto, 2011)
    Brain size and architecture exhibit great evolutionary and ontogenetic variation. Yet, studies on population variation (within a single species) in brain size and architecture, or in brain plasticity induced by ecologically relevant biotic factors have been largely overlooked. Here, I address the following questions: (i) do locally adapted populations differ in brain size and architecture, (ii) can the biotic environment induce brain plasticity, and (iii) do locally adapted populations differ in levels of brain plasticity? In the first two chapters I report large variation in both absolute and relative brain size, as well as in the relative sizes of brain parts, among divergent nine-spined stickleback (Pungitius pungitius) populations. Some traits show habitat-dependent divergence, implying natural selection being responsible for the observed patterns. Namely, marine sticklebacks have relatively larger bulbi olfactorii (chemosensory centre) and telencephala (involved in learning) than pond sticklebacks. Further, I demonstrate the importance of common garden studies in drawing firm evolutionary conclusions. In the following three chapters I show how the social environment and perceived predation risk shapes brain development. In common frog (Rana temporaria) tadpoles, I demonstrate that under the highest per capita predation risk, tadpoles develop smaller brains than in less risky situations, while high tadpole density results in enlarged tectum opticum (visual brain centre). Visual contact with conspecifics induces enlarged tecta optica in nine-spined sticklebacks, whereas when only olfactory cues from conspecifics are available, bulbus olfactorius become enlarged.Perceived predation risk results in smaller hypothalami (complex function) in sticklebacks. Further, group-living has a negative effect on relative brain size in the competition-adapted pond sticklebacks, but not in the predation-adapted marine sticklebacks. Perceived predation risk induces enlargement of bulbus olfactorius in pond sticklebacks, but not in marine sticklebacks who have larger bulbi olfactorii than pond fish regardless of predation. In sum, my studies demonstrate how applying a microevolutionary approach can help us to understand the enormous variation observed in the brains of wild animals a point-of-view which I high-light in the closing review chapter of my thesis.
  • Välimäki, Kaisa (Helsingin yliopisto, 2012)
    Understanding the causes and consequences of phenotypic divergence among natural populations is one of the fundamental goals of evolutionary biology. Phenotypic differentiation among populations can arise through divergent selection leading to local adaptation, phenotypic plasticity, or a combination thereof. Selection can also influence the expression of plasticity in different environments resulting in divergence in phenotypic plasticity. It is therefore essential to know how plasticity evolves under divergent ecological conditions when aiming to understand the mechanisms that underlie phenotypic differentiation. In this thesis I have explored the extent of variation in phenotypic plasticity across a range of locally adapted nine-spined stickleback (Pungitius pungitius) populations from different habitats. Pond and marine populations have diverged in a suite of morphological, life-history and behavioural traits. This divergence has been thought to stem from the absence of piscine predators and interspecific competitors combined with the high intraspecific competition in pond habitats. My aims were to establish if and how predator cues and variation in resource levels induce phenotypic plasticity in the nine-spined stickleback, and whether phenotypic plasticity has also diverged as a response to divergent selective pressures in different environments and between sexes. I quantified phenotypic plasticity in a set of traits that form a continuum from very labile to developmentally fixed ones. The results show that plasticity was induced by both predator presence and food availability. Fish responded to perceived predation risk with reduced growth rates, decreased body condition and by behavioural changes. Food restriction resulted in slower growth and reduced investment in energy storage, but increased feeding activity and risk-taking. The results were largely in accordance with my predictions of increasing plasticity from morphology through life history traits to behaviour. The results also show that population divergence in phenotypic plasticity is habitat dependent. Pond populations responded more strongly to food treatment in terms of behaviour and growth, while marine fish exhibited stronger responses to predation treatment. However, in the case of brain size and lateral line system, predation-induced plastic responses were detected only in pond fish that had evolved in the absence of piscine predation. I also detected strong sexual dimorphism in both trait means and phenotypic plasticity, uncovering a very important determinant of within population variation in phenotypic plasticity. Taken together, the results of my thesis demonstrate how natural and sexual selection do not only affect phenotypic traits themselves, but also the plasticity of the traits. The resultant adaptive variation in phenotypic plasticity is present both between and within populations. In some traits, plasticity was greater whenever the selective pressure was stronger, while in other traits the increased plasticity was coupled with relaxed selection due to the lack of piscine predation in ponds. My thesis demonstrates that the response of phenotypic plasticity to natural selection is context dependent. The results also work to advance our knowledge on the maintenance of phenotypic variation.