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  • Nummela, Pirjo (Helsingin yliopisto, 2011)
    Cancer is becoming the leading cause of deaths in the world. As 90% of all deaths from cancer are caused by metastasis, discovery of the mechanisms behind cancer cell invasion and metastasis is of utmost importance. Only new effective therapies targeting cancer progression can reduce cancer mortality rates. The aim of this study was to identify molecules that are relevant for tumor cell invasion and spreading in fibrosarcomas and melanomas, and to analyze their potential for cancer biomarkers or therapeutic targets. First, the gene expression changes of normal cells and transformed cells showing high invasiveness, S-adenosylmethionine decarboxylase (AdoMetDC)-transfected murine fibroblasts and human melanoma cells, were studied by microarray analyses. The function of the identified candidate molecules were then studied in detail in these cell lines. Finally, the physiological relevance of the identified changes was studied by immunohistochemical analyses of human sarcoma and melanoma specimens or by a mouse xenograft model. In fibrosarcoma cells, the most remarkable change detected was a dramatic up-regulation of the actin-sequestering molecule thymosin beta 4 (TB4), which was shown to be important for the transformed phenotype of the AdoMetDC-transfected cells (Amdc-s and -as). A sponge toxin latrunculin A, inhibiting the binding of TB4 to actin, was found to selectively inhibit the migration and invasion of these cells. Further, Amdc-s-induced mouse tumors and human high-grade sarcomas were found to show intense TB4 immunostaining. In addition to TB4, integrin subunits alfa 6 and beta 7 (ItgA6 and ItgB7) were found to be up-regulated in Amdc-s and -as cells. ItgA6 was shown to dimerize mainly with ItgB1 in Amdc-s. Inhibition of ItgA6 or ItgB1 function with neutralizing antibodies fully blocked the invasiveness of Amdc-s cells, and importantly also human HT-1080 fibrosarcoma cells, in three-dimensional (3D)-Matrigel mimicking tumor extracellular matrix (ECM). By immunohistochemical analyses, strong staining for ITGA6 was detected in human high-grade fibrosarcomas and other sarcomas, especially at the invasion fronts of the tumors. In the studied melanoma cell lines, the expression levels of the adhesion-related ECM proteins tenascin-C (TN-C), fibronectin (FN), and transforming growth factor beta-induced (TGFBI) were found to be highly up-regulated. By immunohistochemistry, intense TN-C and FN staining was detected in invasive and metastatic melanoma tumors, showing co-localization (together with procollagen-I) in tubular meshworks and channels around the invading melanoma cells. In vitro, TN-C and FN were further found to directly stimulate the migration of melanoma cells in 3D-collagen-I matrix. The third candidate protein, TGFBI, was found to be an anti-adhesive molecule for melanoma cells, and knockdown of its expression in metastatic melanoma cells (TGFBI-KD cells) led to dramatically impaired tumor growth in immunocompromized mice. Interestingly, the control tumors showed intense TGFBI immunostaining in the invasion fronts, showing partial co-localization with the fibrillar FN staining, whereas the small TGFBI-KD cell-induced tumors displayed amorphous, non-fibrillar FN staining. These data suggest an important role for TGFBI in FN fibrillogenesis and melanoma progression. In conclusion, we have identified several invasion-related molecules, which show potential for cancer diagnostic or prognostic markers, or therapeutic targets. Based on our previous and present fibrosarcoma studies, we propose the possibility of using ITGA6 antagonists (affecting tumor cell adhesion) in combination with TB4 inhibitors (affecting tumor cell migration) and cathepsin L inhibitors (affecting the degradation of basement membrane and ECM proteins) for the treatment of fibrosarcomas and other tumors overexpressing these molecules. With melanoma cells, in turn, we point to the importance of three secreted ECM proteins, TN-C, FN, and TGFBI, in melanoma progression. Of these, especially the potential of TN-C as a prognostic melanoma biomarker and TGFBI as a promising therapeutic target molecule are clearly worth additional studies.
  • Hilditch, Satu (Helsingin yliopisto, 2010)
    Pectin is a natural polymer consisting mainly of D-galacturonic acid monomers. Microorganisms living on decaying plant material can use D-galacturonic acid for growth. Although bacterial pathways for D-galacturonate catabolism had been described previously, no eukaryotic pathway for D-galacturonate catabolism was known at the beginning of this work. The aim of this work was to identify such a pathway. In this thesis the pathway for D-galacturonate catabolism was identified in the filamentous fungus Trichoderma reesei. The pathway consisted of four enzymes: NADPH-dependent D-galacturonate reductase (GAR1), L-galactonate dehydratase (LGD1), L-threo-3-deoxy-hexulosonate aldolase (LGA1) and NADPH-dependent glyceraldehyde reductase (GLD1). In this pathway D-galacturonate was converted to pyruvate and glycerol via L-galactonate, L-threo-3-deoxy-hexulosonate and L-glyceraldehyde. The enzyme activities of GAR1, LGD1 and LGA1 were present in crude mycelial extract only when T. reesei was grown on D-galacturonate. The activity of GLD1 was equally present on all the tested carbon sources. The corresponding genes were identified either by purifying and sequencing the enzyme or by expressing genes with homology to other similar enzymes in a heterologous host and testing the activities. The new genes that were identified were expressed in Saccharomyces cerevisiae and resulted in active enzymes. The GAR1, LGA1 and GLD1 were also produced in S. cerevisiae as active enzymes with a polyhistidine-tag, and purified and characterised. GAR1 and LGA1 catalysed reversible reactions, whereas only the forward reactions were observed for LGD1 and GLD1. When gar1, lgd1 or lga1 was deleted in T. reesei the deletion strain was unable to grow with D-galacturonate as the only carbon source, demonstrating that all the corresponding enzymes were essential for D-galacturonate catabolism and that no alternative D-galacturonate pathway exists in T. reesei. A challenge for biotechnology is to convert cheap raw materials to useful and more valuable products. Filamentous fungi are especially useful for the conversion of pectin, since they are efficient producers of pectinases. Identification of the fungal D-galacturonate pathway is of fundamental importance for the utilisation of pectin and its conversion to useful products.
  • Tiittanen, Minna (Helsingin yliopisto, 2006)
    Type 1 diabetes (T1D) is considered to be an autoimmune disease. The cause of T1D is the destruction of insulin-producing β-cells in the pancreatic islets. The autoimmune nature of T1D is characterized by the presence of autoreactive T-cells and autoantibodies against β-cell molecules. Insulin is the only β-cell-specific autoantigen associated with T1D but the insulin autoantibodies (IAAs) are difficult to measure with proper sensitivity. T-cell assays for detection of autoreactive T-cells, such as insulin-specific T-cells, have also proven to be difficult to perform. The genetic risk of T1D is associated with the HLA gene region but the environmental factors also play an important role. The most studied environmental risk factors of T1D are enteroviruses and cow's milk which both affect the immune system through the gut. One hypothesis is that the insulin-specific immune response develops against bovine insulin in cow's milk during early infancy and later spreads to include human insulin. The aims of this study were to determine whether the separation of immunoglobulin (Ig)G from plasma would improve the sensitivity of the IAA assay and how insulin treatment affects the cellular immune response to insulin in newly diagnosed patients. Furthermore, the effect of insulin concentration in mother's breast milk on the development of antibodies to dietary insulin in the child was examined. Small intestinal biopsies were also obtained from children with T1D to characterize any immunological changes associated with T1D in the gut. The isolation of the IgG fraction from the plasma of T1D patients negative for plasma IAA led to detectable IAA levels that exceeded those in the control children. Thus the isolation of IgG may improve the sensitivity of the IAA assay. The effect of insulin treatment on insulin-specific T-cells was studied by culturing peripheral blood mononuclear cells with insulin. The insulin stimulation induced increased expression of regulatory T-cell markers, such as Foxp3, in those patients treated with insulin than in patients examined before initiating insulin treatment. This finding suggests that insulin treatment in patients with T1D stimulates regulatory T-cells in vivo and this may partly explain the difficulties in measuring autoantigen-specific T-cell responses in recently diagnosed patients. The stimulation of regulatory T-cells by insulin treatment may also explain the remission period often seen after initiating insulin treatment. In the third study we showed that insulin concentration in mother's breast milk correlates inversely with the levels of bovine insulin-specific antibodies in those infants who were exposed to cow's milk proteins in their diet, suggesting that human insulin in breast milk induces tolerance to dietary bovine insulin. However, in infants who later developed T1D-associated autoantibodies, the insulin concentration in their mother's breast milk was increased. This finding may indicate that in those children prone to β-cell autoimmunity, breast milk insulin does not promote tolerance to insulin. In the small intestinal biopsies the presence of several immunological markers were quantified with the RT-PCR. From these markers the expression of the interleukin (IL)-18 cytokine was significantly increased in the gut in patients with T1D compared with children with celiac disease or control children. The increased IL-18 expression lends further support for the hypothesis that the gut immune system is involved in the pathogenesis of T1D.
  • Piha, Henna (Helsingin yliopisto, 2006)
    Agriculture-mediated habitat loss and degradation together with climate change are among the greatest global threats to species, communities, and ecosystem functioning. During the last century, more than 50% of the world's wetlands have been lost and agricultural activities have subjected wetland species to increased isolation and decreased quality of habitats. Likewise, as a part of agricultural intensification, the use of pesticides has increased notably, and pesticide residues occur frequently in wetlands making the exposure of wetland organisms to pesticides highly probable. In this thesis, a set of ecotoxicological and landscape ecological studies were carried out to investigate pesticide-effects on tadpoles, and species-habitat relationships of amphibians in agricultural landscapes. The results show that the fitness of R. temporaria tadpoles can be negatively affected by sublethal pesticide concentrations, and that pesticides may increase the costs of response to natural environmental stressors. However, tadpoles may also be able to compensate for some of the negative effects of pesticides. The results further demonstrate that both historic and current-day agricultural land use can negatively impact amphibians, but that in some cases the costs of living in agricultural habitats may only become apparent when amphibians face other environmental stressors, such as drought. Habitat heterogeneity may, however, increase the persistence of amphibians in agricultural landscapes. Hence, the results suggest that amphibians are likely to be affected by agricultural processes that operate at several spatial and temporal scales, and that it is probable that various processes related to current-day agriculture will affect both larval and adult amphibians. The results imply that maintaining dense wetland patterns could enhance persistence of amphibian populations in agricultural habitats, and indicate that heterogeneous landscapes may lower the risk of regional amphibian population declines under extreme weather perturbations.
  • Örmälä-Odegrip, Anni-Maria (Helsingin yliopisto, 2015)
    Bacterial viruses (i.e. phages) are ubiquitous intracellular parasites of bacteria, that along with protist grazers account for majority of bacterial mortality in nature. Phages impose strong selection for bacterial phage-resistance, which is often coupled with fitness costs on bacterial traits such as growth ability, virulence or motility. Traditionally phage-host interactions have been studied with two species systems in the laboratory, neglecting the complex web of interactions present in natural communities. The ability of phages to selectively kill bacteria has ignited an interest on phages as alternative antibacterials. However, in order to develop phage therapy, understanding of phage-host interactions in the eco-evolutionary context is essential. In this thesis I studied the implications of lytic phages on opportunistic pathogenic bacteria, as opportunists often have the ability reproduce and reside in outside-host environments, where they are predisposed to a variety of selection pressures. The role of phages in top-down control of bacterial biomass and the evolution of bacterial phage-resistance were studied in the presence of protist predators with differing feeding modes, in low-resource systems mimicking natural pond environment. Hypothesis of coincidental evolution suggests that virulence is a by-product of selection for traits that maximize bacterial fitness in environmental reservoirs. Yet, disease outbreaks by opportunists are relatively rare, suggesting that something constrains the selection for virulence. To assess the role of lytic phages on the evolution of virulence, bacteria were cultured in low-resource environment, accompanied with changes in temperature regime or changes in composition of the community of interacting bacterial enemy species, and the virulence of bacteria was measured in vivo. To study whether the potential phage-resistant bacteria surviving phage therapy would be coupled with lowered virulence, due to costs associated with phage-resistance, a clinical bacterial isolate was exposed to phage cocktails and the virulence of the phage-resistant bacteria was measured in vivo. given the strong selection for phage- resistance, the prospects of phage therapy depend a great deal on whether new phages infecting pathogenic bacteria can be readily isolated from environment. To address this, an attempt was made to isolate phages against clinical bacterial isolates harboring resistance genes to multiple antibiotics. A single lytic phage was shown to be a non- efficient top-down regulator of bacterial biomass. Rapidly emerging phage-resistant bacteria took over the bacterial populations after initial lysis by phages and protist grazers accounted for most of the long-term negative trophic effects on bacterial biomass. The presence of protist predators selected for bacteria that were less susceptible to infection by lytic phages, which suggests an overlap in the bacterial defense against a parasite and predatory protists. In general, the presence of lytic phages selected for lowered virulence in bacteria. High temperature selected for more virulent and more motile bacteria, but this was constrained by the presence of a lytic phage. In the multispecies communities the presence of all bacterial enemies led to decreased virulence in vivo. Altogether, these results contrast the hypothesis of coincidental evolution, and suggest that the presence of phages in natural reservoirs constrains the evolution of virulence, most likely through fitness costs associated with phage-resistance. Exposure to phage cocktails was also shown to be associated with decreased bacterial virulence in the phage-resistant bacteria. However, exposure to some individual phages resulted in more virulent bacteria, suggesting that the outcome of therapy could depend on the identity of the phage cocktail. Finally, a phage cocktail lysing a wide range of clinical strains was isolated from sewage. This, along with geographical patterns of phage infections suggest that new phages are available in environmental reservoirs for therapy, and the emergence of phage-resistance should not hinder the prospects of phage therapy in the global perspective.
  • Gu, Yuexi (Helsingin yliopisto, 2015)
    Women with germline mutations of BRCA1 gene are predisposed to the development of basal-like breast cancer, which is characterized by the absence of the hormonal and growth factor receptors, ER, PR and HER2. Mutation of BRCA1 predicts increased sensitivity to certain DNA-damaging agents, e.g. PARP inhibitors and cisplatin. Yet in clinical trials, some BRCA1-mutant breast tumors show resistance to these drugs. Therefore, it is necessary to understand the molecular mechanisms of the acquired resistance and identify novel therapeutic targets for the treatment of those tumors. In order to better understand the biology of breast cancers caused by BRCA1 mutations, we collected and characterized four BRCA1-mutant breast cancer cell lines as surrogates of BRCA1-mutant tumors. Together with several cell lines expressing wildtype BRCA1, we tested their sensitivities to a panel of DNA-damaging agents. We also carried out a high-throughput chemical compound screen on the BRCA1-mutant and BRCA1-wildtype cell lines, and performed a proteome profiling assay to test the kinase activities of those cell lines. Our results reveal extensive heterogeneity among the BRCA1-mutant breast cancer cell lines, which showed resistance to DNA-damaging agents. Then we created isogenic MDA-MB-231 cells with or without BRCA1 depletion by siRNA transfection, and carried out a high-throughput chemical compound screen on the pair of cells in order to identify potential targets that are synthetically lethal with BRCA1 deficiency. Two proteasome inhibitors, bortezomib and carfilzomib, were found to be able to selectively kill BRCA1-depleted cells. Further studies on mechanisms demonstrate that the proteasome inhibitor bortezomib does not induce DNA damage; rather it inactivates G1 cell cycle checkpoint in BRCA1-deficient cells and leads to the accumulation of these cells at G2/M phase. This is caused by inactivation of the retinoblastoma protein (Rb) through its hyperphosphorylation, which in turn activates its downstream transcription factor E2F1. In addition, bortezomib causes compromised G2/M cell cycle checkpoint in BRCA1-deficient cells, which drives cells to enter mitosis and leads to apoptosis due to uncontrolled cell division. In order to investigate the mechanisms underlying the consistent basal-like phenotype of breast tumors associated with BRCA1 mutations, we established an in vitro assay to study the transition of mouse mammary epithelial cells from luminal to basal lineages. Our results showed that loss of BRCA1 promotes basal-like differentiation by sustaining ΔNp63 activity. In luminal cells, ΔNp63 is not expressed or remains inactive through localization in nucleoli. Depletion of BRCA1 leads to translocation of ΔNp63 into nucleoplasm and promotes transition of luminal cells into a basal state. This study provides a potential link between BRCA1 loss and the basal-like differentiation, which may help to explain why BRCA1-mutant breast cancer tends to bear a basal-like phenotype.
  • Penttilä, Tuula (Helsingin yliopisto, 2004)
  • Heiniö, Raija-Liisa (Helsingin yliopisto, 2003)
  • Anastasina, Maria (Helsingin yliopisto, 2015)
    Viruses infect all domains of life. They establish complex interactions with their host cells to subvert and hijack multiple cellular processes and warrant their own replication. Understanding virus-host interactions is critical to control spread of pathogenic viruses, develop vaccines and search for antivirals. Besides that, understanding virus-host interactions allows deciphering complex cellular processes and provides useful tools for biotechnology. My research is dedicated to influenza A virus, an important pathogen that infects humans worldwide, represents a constant health care threat and elicits continuous efforts to control the human spread of the disease. Influenza A expresses a non-structural protein NS1 that is a key regulator of viral interactions with the host cell and an important virulence factor. Versatile functions of NS1 modulate multiple cellular functions to secure viral replication. This work addresses several aspects of NS1-mediated modulation of core cellular processes. We discovered that NS1 binds to dsDNA and inhibits transcription of cellular genes, thus limiting antiviral responses. We found that NS1 secures general protein synthesis and mapped several residues within NS1 that are essential for this function. Further, we showed that the length of C-terminal ``tail'' of NS1 is essential for control of cellular antiviral responses and virus pathogenicity. The presented results increase the understanding of influenza A virus-host interactions and can be further utilized in the search for antivirals and vaccine development. In addition, this work provides a biotechnological application of influenza A NS1 protein for improvement of cell-free translation system.
  • 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.
  • Xu, Enjun (Helsingin yliopisto, 2015)
    Regulation of cellular homeostasis is crucial for proper development, survival, defense responses, programmed cell death and ultimately survival. Maintaining cellular homeostasis requires tight regulation of multiple highly interactive signaling pathways. The apoplast lies at the frontier between the cell and the environment, where the plant perceives environmental cues. Since the apoplast is also a site for cell-to-cell communication, it has an important role in mediating plant-environment interactions. Reactive oxygen species (ROS) are known as both toxic agents and indispensable signaling molecules in all aerobic organisms. A ROS burst in the apoplast is one of the first measurable events produced in response to different biotic and abiotic stresses, eventually leading to the initiation of signal transduction pathways and altered gene expression. Apoplastic ROS signaling is well known to dynamically coordinate multiple signaling pathways in the activation of defense responses in plants. Dissection of the signaling crosstalk within such a signaling network could therefore reveal the molecular mechanisms underlying defense responses. Treatments with ozone (O3) have been adopted as an efficient tool to study apoplastic ROS signaling. Plants exposed to O3 trigger a ROS burst in the apoplast and induce extensive changes in gene expression and alteration of defense hormones, such as salicylic acid (SA), jasmonic acid (JA), and ethylene. Genetic variation in O3 sensitivity among Arabidopsis thaliana accessions or mutants highlights the complex genetic architecture of plant responses to ROS. To gain insight into the genetic basis of apoplastic ROS signaling, a recombinant inbred line (RIL) population from a reciprocal cross between two Arabidopsis accessions C24 (O3 tolerant) and Tenela (O3 sensitive) was used for quantitative trait loci (QTL) mapping. Through a combination of QTL mapping and transcriptomic analyses in the response to apoplastic-ROS treatment, three QTL regions containing several potential candidate genes were identified in this study. In addition, multiple mutants with varying O3-sensitivities were employed to dissect the signaling components involved in the early apoplastic ROS signaling and O3-triggered cell death. A combination of global and targeted gene expression profiling, genetic analysis, and cell death assays was performed to dissect the contribution of hormone signaling and various transcription factors to the regulation of apoplastic ROS-triggered gene expression and cell death. The contributions of SA, JA and ethylene were assessed through analysis of mutants deficient in these hormones, mutants with constitutively activated hormone signaling and the exogenous application of hormones. Plants with elevated SA levels were found to be associated with an attenuated O3 response, whereas simultaneous elimination of SA-dependent and SA- independent signaling components enhanced the response to apoplastic ROS treatment. JA could act as both a positive and negative modifier of apoplastic ROS signaling, which was enhanced when ethylene signaling was also impaired. However, transcriptome analysis of a triple mutant deficient in SA, JA and ethylene revealed that these hormones signaling only contributed part (about 30%) of early-apoplastic ROS-triggered changes in gene expression, suggesting multiple signaling pathways could be required to regulate the apoplastic ROS response via combinatorial or overlapping mechanisms.
  • 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.