Honey flows through fertile valleys : The cognitive and evolutionary foundations of paradise representations

The aim of the study is to explain how paradise beliefs are born from the viewpoint of mental functions of the human mind. The focus is on the observation that paradise beliefs across the world are mutually more similar than dissimilar. By using recent theories and results from the cognitive and evolutionary study of religion as well as from studies of environmental preferences, I suggest that this is because pan-human unconscious motivations, the architecture of mind, and the way the human mind processes information constrain the possible repertoire of paradise beliefs. The study is divided into two parts, theoretical and empirical. The arguments in the theoretical part are tested with data in the empirical part with two data sets. The first data set was collected using an Internet survey. The second data set was derived from literary sources. The first data test the assumption that intuitive conceptions of an environment of dreams generally follow the outlines set by evolved environmental preferences, but that they can be tweaked by modifying the presence of desirable elements. The second data test the assumption that familiarity is a dominant factor determining the content of paradise beliefs. The results of the study show that in addition to the widely studied belief in supernatural agents, belief in supernatural environments wells from the natural functioning of the human mind attesting the view that religious thinking and ideas are natural for human species and are produced by the same mental mechanisms as other cultural information. The results also help us to understand that the mental structures behind the belief in the supernatural have a wider scope than has been previously acknowledged.

Genomic and functional profiling of gastric cancer

Helicobacter pylori infection is a risk factor for gastric cancer, which is a major health issue worldwide. Gastric cancer has a poor prognosis due to the unnoticeable progression of the disease and surgery is the only available treatment in gastric cancer. Therefore, gastric cancer patients would greatly benefit from identifying biomarker genes that would improve diagnostic and prognostic prediction and provide targets for molecular therapies. DNA copy number amplifications are the hallmarks of cancers in various anatomical locations. Mechanisms of amplification predict that DNA double-strand breaks occur at the margins of the amplified region. The first objective of this thesis was to identify the genes that were differentially expressed in H. pylori infection as well as the transcription factors and signal transduction pathways that were associated with the gene expression changes. The second objective was to identify putative biomarker genes in gastric cancer with correlated expression and copy number, and the last objective was to characterize cancers based on DNA copy number amplifications. DNA microarrays, an in vitro model and real-time polymerase chain reaction were used to measure gene expression changes in H. pylori infected AGS cells. In order to identify the transcription factors and signal transduction pathways that were activated after H. pylori infection, gene expression profiling data from the H. pylori experiments and a bioinformatics approach accompanied by experimental validation were used. Genome-wide expression and copy number microarray analysis of clinical gastric cancer samples and immunohistochemistry on tissue microarray were used to identify putative gastric cancer genes. Data mining and machine learning techniques were applied to study amplifications in a cross-section of cancers. FOS and various stress response genes were regulated by H. pylori infection. H. pylori regulated genes were enriched in the chromosomal regions that are frequently changed in gastric cancer, suggesting that molecular pathways of gastric cancer and premalignant H. pylori infection that induces gastritis are interconnected. 16 transcription factors were identified as being associated with H. pylori infection induced changes in gene expression. NF-κB transcription factor and p50 and p65 subunits were verified using elecrophoretic mobility shift assays. ERBB2 and other genes located in 17q12- q21 were found to be up-regulated in association with copy number amplification in gastric cancer. Cancers with similar cell type and origin clustered together based on the genomic localization of the amplifications. Cancer genes and large genes were co-localized with amplified regions and fragile sites, telomeres, centromeres and light chromosome bands were enriched at the amplification boundaries. H. pylori activated transcription factors and signal transduction pathways function in cellular mechanisms that might be capable of promoting carcinogenesis of the stomach. Intestinal and diffuse type gastric cancers showed distinct molecular genetic profiles. Integration of gene expression and copy number microarray data allowed the identification of genes that might be involved in gastric carcinogenesis and have clinical relevance. Gene amplifications were demonstrated to be non-random genomic instabilities. Cell lineage, properties of precursor stem cells, tissue microenvironment and genomic map localization of specific oncogenes define the site specificity of DNA amplifications, whereas labile genomic features define the structures of amplicons. These conclusions suggest that the definition of genomic changes in cancer is based on the interplay between the cancer cell and the tumor microenvironment.

Structural and functional roles of KCC2 in developing cortex

Cation chloride cotransporters (CCCs) are critical for controlling intracellular chloride homeostasis. The CCC family is composed of four isoforms of K-Cl cotransporters (KCC1-4), two isoforms of Na-K-2Cl cotransporters (NKCC1-2), one Na-Cl cotransporter (NCC) and two the structurally related proteins with unknown function, CCC8 also known as cation-chloride cotransporter interaction protein, CIP, and CCC9. KCC2 is a neuron-specific isoform, which plays a prominent role in controlling the intracellular Cl- concentration in neurons and is responsible for producing the negative shift of GABAA responses from depolarizing to hyperpolarizing during neuronal maturation. In the present studies we first used in situ hybridization to examine the developmental expression patterns of the cation-chloride cotransporters KCC1-4 and NKCC1. We found that they display complementary expression patterns during embryonic brain development. Most interestingly, KCC2 expression in the embryonic central nervous system strictly follows neuronal maturation. In vitro data obtained from primary and organotypic neuronal cultures support this finding and revealed a temporal correlation between the expression of KCC2 and synaptogenesis. We found that KCC2 is highly expressed in filopodia and mature spines as well as dendritic shaft and investigated the role of KCC2 in spine formation by analyzing KCC2-/- neurons in vitro. Our studies revealed that KCC2 is a key factor in the maturation of dendritic spines. Interestingly, the effect of KCC2 in spine formation is not due to Cl- transport activity, but mediated through the interaction between KCC2 C-terminal and intracellular protein associated with cytoskeleton. The interacting protein we found is protein 4.1N by immunoprecipitation. Our results indicate a structural role for KCC2 in the development of functional glutamatergic synapses and suggest KCC2 as a synchronizer for the functional development of glutamatergic and GABAergic synapses in neuronal network. Studies on the regulatory mechanisms of KCC2 expression during development and plasticity revealed that synaptic activity of both the glutamatergic and GABAergic system is not required for up-regulation of KCC2 during development, whereas in acute mature hippocampal slices which undergo continuous synchronous activity induced by the absence of Mg2+ solution, KCC2 mRNA and protein expression were down-regulated in CA1 pyramidal neurons subsequently leading to a reduced capacity for neuronal Cl- extrusion. This effect is mediated by endogenous BDNF-TrkB down-stream cascades involving both Shc/FRS-2 and PLCγ-CREB signaling. BDNF mediated changes in KCC2 expression indicate that KCC2 is significantly involved in the complex mechanisms of neuronal plasticity during development and pathophysiological conditions.

Structural and Functional Studies on Trimeric Autotransporters

Trimeric autotransporters are a family of secreted outer membrane proteins in Gram-negative bacteria. These obligate homotrimeric proteins share a conserved C-terminal region, termed the translocation unit. This domain consists of an integral membrane β-barrel anchor and associated α-helices which pass through the pore of the barrel. The α-helices link to the extracellular portion of the protein, the passenger domain. Autotransportation refers to the way in which the passenger domain is secreted into the extracellular space. It appears that the translocation unit mediates the transport of the passenger domain across the outer membrane, and no external factors, such as ATP, ion gradients nor other proteins, are required. The passenger domain of autotransporters contains the specific activities of each protein. These are usually related to virulence. In trimeric autotransporters, the main function of the proteins is to act as adhesins. One such protein is the Yersinia adhesin YadA, found in enteropathogenic species of Yersinia. The main activity of YadA from Y. enterocolitica is to bind collagen, and it also mediates adhesion to other molecules of the extracellular matrix. In addition, YadA is involved in serum resistance, phagocytosis resistance, binding to epithelial cells and autoagglutination. YadA is an essential virulence factor of Y. enterocolitica, and removal of this protein from the bacteria leads to avirulence. In this study, I investigated the YadA-collagen interaction by studying the binding of YadA to collagen-mimicking peptides by several biochemical and biophysical methods. YadA bound as tightly to the triple-helical model peptide (Pro-Hyp-Gly)10 as to native collagen type I. However, YadA failed to bind a similar peptide that does not form a collagenous triple helix. As (Pro-Hyp-Gly)10 does not contain a specific sequence, we concluded that a triple-helical conformation is necessary for YadA binding, but no specific sequence is required. To further investigate binding determinants for YadA in collagens, I examined the binding of YadA to a library of collagen-mimicking peptides that span the entire triple-helical sequences of human collagens type II and type III. YadA bound promiscuously to many but not all peptides, indicating that a triple-helical conformation alone is not sufficient for binding. The high-binding peptides did not share a clear binding motif, but these peptides were rich in hydroxyproline residues and contained a low number of charged residues. YadA thus binds collagens without sequence specificity. This strategy of promiscuous binding may be advantageous for pathogenic bacteria. The Eib proteins from Escherichia coli are immunoglobulin (Ig)-binding homologues of YadA. I showed conclusively that recombinant EibA, EibC, EibD and EibF bind to IgG Fc. I crystallised a fragment of the passenger domain of EibD, which binds IgA in addition to IgG. The structure has a YadA-like head domain and an extended coiled-coil stalk. The top half of the coiled-coil is right-handed with hendecad periodicity, whereas the lower half is a canonical left-handed coiled-coil. At the transition from right- to left-handedness, a small β-sheet protrudes from each monomer. I was able to map the binding regions for IgG and IgA using truncations and site-directed mutagenesis to the coiled-coil stalk and identified residues critical for Ig binding.

Comparative and functional genome analysis of fungi for development of the protein production host Trichoderma reesei

Filamentous fungi of the subphylum Pezizomycotina are well known as protein and secondary metabolite producers. Various industries take advantage of these capabilities. However, the molecular biology of yeasts, i.e. Saccharomycotina and especially that of Saccharomyces cerevisiae, the baker's yeast, is much better known. In an effort to explain fungal phenotypes through their genotypes we have compared protein coding gene contents of Pezizomycotina and Saccharomycotina. Only biomass degradation and secondary metabolism related protein families seem to have expanded recently in Pezizomycotina. Of the protein families clearly diverged between Pezizomycotina and Saccharomycotina, those related to mitochondrial functions emerge as the most prominent. However, the primary metabolism as described in S. cerevisiae is largely conserved in all fungi. Apart from the known secondary metabolism, Pezizomycotina have pathways that could link secondary metabolism to primary metabolism and a wealth of undescribed enzymes. Previous studies of individual Pezizomycotina genomes have shown that regardless of the difference in production efficiency and diversity of secreted proteins, the content of the known secretion machinery genes in Pezizomycotina and Saccharomycotina appears very similar. Genome wide analysis of gene products is therefore needed to better understand the efficient secretion of Pezizomycotina. We have developed methods applicable to transcriptome analysis of non-sequenced organisms. TRAC (Transcriptional profiling with the aid of affinity capture) has been previously developed at VTT for fast, focused transcription analysis. We introduce a version of TRAC that allows more powerful signal amplification and multiplexing. We also present computational optimisations of transcriptome analysis of non-sequenced organism and TRAC analysis in general. Trichoderma reesei is one of the most commonly used Pezizomycotina in the protein production industry. In order to understand its secretion system better and find clues for improvement of its industrial performance, we have analysed its transcriptomic response to protein secretion stress conditions. In comparison to S. cerevisiae, the response of T. reesei appears different, but still impacts on the same cellular functions. We also discovered in T. reesei interesting similarities to mammalian protein secretion stress response. Together these findings highlight targets for more detailed studies.

University Students' Approaches to Learning, Self-Regulation, and Cognitive and Attributional Strategies : Connections with Well-Being and Academic Success

This dissertation empirically explores the relations among three theoretical perspectives: university students approaches to learning, self-regulated learning, as well as cognitive and attributional strategies. The relations were quantitatively studied from both variable- and person-centered perspectives. In addition, the meaning that students gave to their disciplinary choices was examined. The general research questions of the study were: 1) What kinds of relationships exist among approaches to learning, regulation of learning, and cognitive and attributional strategies? What kinds of cognitive-motivational profiles can be identified among university students, and how are such profiles related to study success and well-being? 3) How do university students explain their disciplinary choices? Four empirical studies addressed these questions. Studies I, II, and III were quantitative, applying self-report questionnaires, and Study IV was qualitative in nature. Study I explored relations among cognitive strategies, approaches to learning, regulation of learning, and study success by using correlations and a K-means cluster analysis. The participants were 366 students from various faculties at different phases of their studies. The results showed that all the measured constructs were logically related to each other in both variable- and person-centered approaches. Study II further examined what kinds of cognitive-motivational profiles could be identified among first-year university students (n=436) in arts, law, and agriculture and forestry. Differences in terms of study success, exhaustion, and stress among students with differing profiles were also looked at. By using a latent class cluster analysis (LCCA), three groups of students were identified: non-academic (34%), self-directed (35%), and helpless students (31%). Helpless students reported the highest levels of stress and exhaustion. Self-directed students received the highest grades. In Study III, cognitive-motivational profiles were identified among novice teacher students (n=213) using LCCA. Well-being, epistemological beliefs, and study success were looked at in relation to the profiles. Three groups of students were found: non-regulating (50%), self-directed (35%), and non-reflective (22%). Self-directed students again received the best grades. Non-regulating students reported the highest levels of stress and exhaustion, the lowest level of interest, and showed the strongest preference for certain and practical knowledge. Study IV, which was qualitative in nature, explored how first-year students (n = 536 ) in three fields of studies, arts, law, and veterinary medicine explained their disciplinary choices. Content analyses showed that interest appeared to be a common concept in students description of their choices across the three faculties. However, the objects of interest of the freshmen appeared rather unspecified. Veterinary medicine and law students most often referred to future work or a profession, whereas only one-fifth of the arts students did so. The dissertation showed that combining different theoretical perspectives and methodologies enabled us to build a rich picture of university students cognitive and motivational predispositions towards studying and learning. Further, cognitive-emotional aspects played a significant role in studying, not only in relation to study success, but also in terms of well-being. Keywords: approaches to learning, self-regulation, cognitive and attributional strategies, university students

Determinants of institutional care at older ages in Finland

Väitöskirjassa selvitettiin ikäihmisten laitoshoitoon siirtymisen todennäköisyyttä ja sen taustoja kansainvälisesti ainutlaatuisen rekisteriaineiston avulla. Selvitettäviä asioita olivat eri sairauksien, sosioekonomisten tekijöiden, puolison olemassaolon ja leskeksi jäämisen yhteys laitoshoitoon siirtymiseen yli 65-vuotiailla suomalaisilla. Tutkimuksessa havaittiin, että dementia, Parkinsonin tauti, aivohalvaus, masennusoireet ja muut mielenterveysongelmat, lonkkamurtuma sekä diabetes lisäsivät ikäihmisten todennäköisyyttä siirtyä laitoshoitoon yli 50 prosentilla, kun muut sairaudet ja sosiodemografiset tekijät oli otettu huomioon. Korkeat tulot vähensivät laitoshoidon todennäköisyyttä, kun taas puutteellinen asuminen (ilman peseytymistiloja tai keskus- tai sähkölämmitystä) sekä erittäin puutteellinen asuminen (ilman lämmintä vettä, vesijohtoa, viemäriä tai vesivessaa) lisäsivät todennäkösyyttä, kun muut sosiodemografiset tekijät, sairaudet ja asuinalue oli huomioitu. Kerrostalon hissittömyys ei ollut yhteydessä laitoshoidon todennäköisyyteen. Todennäköisyys siirtyä laitoshoitoon oli jostain syystä korkeampaa niillä ikäihmisillä, jotka asuivat vuokralla ja matalampaa omakotitalossa asuvilla ja niillä, joilla oli auto. Puolison olemassaolo vähensi ja leskeksi jääminen lisäsi laitoshoidon todennäköisyyttä huomattavasti. Todennäköisyys oli erityisen suuri, yli kolminkertainen, kun puolison kuolemasta oli kulunut enintään kuukausi verrattuna niihin, joiden puoliso oli elossa. Todennäköisyys laski, kun puolison kuolemasta kului aikaa. Miesten ja naisten tulokset olivat samansuuntaisia. Korkeat tulot tai koulutus eivät suojanneet riskiltä joutua laitoshoitoon puolison kuoltua. Puolison kuolema näyttää lisäävän hoidon tarvetta, kun kotona ei ole enää puolisoa tukemassa ja huolehtimassa kodin askareista. Laitoshoidon tarve vähenee, jos ja kun lesket ajan kuluessa oppivat elämään yksin. Toisaalta tutkimustulokset saattavat viitata myös siihen, että kaikkein huonokuntoisimmat lesket, jotka eivät pärjää yksin asuessaan, siirtyvät laitoshoitoon hyvin nopeasti puolison kuoltua. Tutkimuksessa oli mukana yhteensä yli 280 000 yli 65-vuotiasta henkilöä, joiden pitkäaikaiseen laitoshoitoon siirtymistä seurattiin tammikuusta 1998 syyskuuhun 2003. Laitoshoidoksi määriteltiin terveyskeskuksissa, sairaaloissa ja vanhainkodeissa tai vastaavissa yksiköissä tapahtuva pitkäaikainen hoito, joka kesti yli 90 vuorokautta tai oli vahvistettu pitkäaikaishoidon päätöksellä. Tutkimuksessa käytetty aineisto koottiin väestörekistereistä, sosiaali- ja terveydenhuollon rekistereistä ja lääkerekistereistä.

Sleep deprivation and brain energy metabolism : in vivo studies in rats and humans

Sleep deprivation leads to increased subsequent sleep length and depth and to deficits in cognitive performance in humans. In animals extreme sleep deprivation is eventually fatal. The cellular and molecular mechanisms causing the symptoms of sleep deprivation are unclear. This thesis was inspired by the hypothesis that during wakefulness brain energy stores would be depleted, and they would be replenished during sleep. The aim of this thesis was to elucidate the energy metabolic processes taking place in the brain during sleep deprivation. Endogenous brain energy metabolite levels were assessed in vivo in rats and in humans in four separate studies (Studies I-IV). In the first part (Study I) the effects of local energy depletion on brain energy metabolism and sleep were studied in rats with the use of in vivo microdialysis combined with high performance liquid chromatography. Energy depletion induced by 2,4-dinitrophenol infusion into the basal forebrain was comparable to the effects of sleep deprivation: both increased extracellular concentrations of adenosine, lactate, and pyruvate, and elevated subsequent sleep. This result supports the hypothesis of a connection between brain energy metabolism and sleep. The second part involved healthy human subjects (Studies II-IV). Study II aimed to assess the feasibility of applying proton magnetic resonance spectroscopy (1H MRS) to study brain lactate levels during cognitive stimulation. Cognitive stimulation induced an increase in lactate levels in the left inferior frontal gyrus, showing that metabolic imaging of neuronal activity related to cognition is possible with 1H MRS. Study III examined the effects of sleep deprivation and aging on the brain lactate response to cognitive stimulation. No physiologic, cognitive stimulation-induced lactate response appeared in the sleep-deprived and in the aging subjects, which can be interpreted as a sign of malfunctioning of brain energy metabolism. This malfunctioning may contribute to the functional impairment of the frontal cortex both during aging and sleep deprivation. Finally (Study IV), 1H MRS major metabolite levels in the occipital cortex were assessed during sleep deprivation and during photic stimulation. N-acetyl-aspartate (NAA/H2O) decreased during sleep deprivation, supporting the hypothesis of sleep deprivation-induced disturbance in brain energy metabolism. Choline containing compounds (Cho/H2O) decreased during sleep deprivation and recovered to alert levels during photic stimulation, pointing towards changes in membrane metabolism, and giving support to earlier observations of altered brain response to stimulation during sleep deprivation. Based on these findings, it can be concluded that sleep deprivation alters brain energy metabolism. However, the effects of sleep deprivation on brain energy metabolism may vary from one brain area to another. Although an effect of sleep deprivation might not in all cases be detectable in the non-stimulated baseline state, a challenge imposed by cognitive or photic stimulation can reveal significant changes. It can be hypothesized that brain energy metabolism during sleep deprivation is more vulnerable than in the alert state. Changes in brain energy metabolism may participate in the homeostatic regulation of sleep and contribute to the deficits in cognitive performance during sleep deprivation.