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Tiedostamaton näköinformaation prosessointi on joissain tilanteissa mahdollista. Henkilö ei siis tällaisessa tilanteessa koe näkevänsä mitään, mutta esitetty visuaalinen ärsyke ohjaa silti käyttäytymistä jollain tavalla. Miten suuri osuus tästä prosessointikyvystä riippuu siitä sähkömagneettisesta tilasta missä aivot ovat ennen ärsykkeen esittämistä? Tässä tutkielmassa selvitin missä määrin tiedostamatonta prosessointia voidaan ennustaa ennen ärsykkeen esittämistä mitatusta EEG-datasta. Primaarin näköaivokuoren merkitystä tiedostamattomalle prosessoinnille on tutkittu laajalti, mutta yhtenäistä näkemystä sen roolista ei toistaiseksi ole. Stimuluksen aiheuttamaan aktivaatioon vaikuttaa kuitenkin aina aivojen senhetkinen sähköinen tila, joten tiedostamattomalle prosessoinnillekin voi olla välttämätöntä, että aivot ovat tietyllä tapaa vastaanottavassa tilassa. Analysoin EEG-dataa kahdella koneoppimisalgoritmilla K:n lähimmän naapurin menetelmällä, sekä neuroverkolla. Rakentamani mallit eivät kyenneet sattumaa paremmin ennustamaan prosessoiko koehenkilö hänelle esitetyn ärsykkeen tiedostamattomasti, kun mallin syötteenä on ainoastaan ennen ärsykkeen esittämistä mitattu EEG-signaalin voima takaraivolohkon (näköaivokuoren) alueella.
Maailmalla vallitsevan taloudellisen taantuman myötä, niin suurien kuin pientenkin yritysten vienti on romahtanut radikaalisti joka puolella. Tilanteen paikkaamiseksi Suomi tarvitsee pikaisesti uusia vakavasti kasvuhakuisia yrityksiä, jotka tavoittelevat uusia ulkomaisia markkinoita ja kasvun myötä turvaisivat suomalaisia työpaikkoja. Jotta taantuman kääntyessä markkinoille pääsy olisi helpompaa ja yleensäkin mahdollista tulee Suomen pk-yritysten ryhtyä hyvissä ajoin ajattelemaan toimintaansa kansainvälisesti ja ryhtyä kehittämään omia viennin ja kansainvälistymisen asettamia edellytyksiä. Tämän opinnäytetyön tavoitteena on kehittää suomalaisen pk-yrityksen kansainvälistymisstrategiaa kartoittamalla ja analysoimalla eri vienninedistämiskeinoja. Teoriaosuudessa käsitellään yrityksen kansainvälistymistä yleisellä tasolla, painottaen kansainvälistymisen edellytyksiä ja vaihtoehtoisia operaatiomuotoja. Empiriaosuudessa tutkitaan samoja asioita syvällisemmin ja yksityiskohtaisemmin konepajateollisuuden pk-yrityksen Stairon Oy:n näkökulmasta. Stairon Oy toimii suurten kansainvälisten teknologiateollisuusyritysten järjestelmätoimittajana ja valmistaa asiakastarpeiden mukaisia kokonaisjärjestelmiä ja komponentteja. Yritys on erikoistunut paperikoneiden ilmajärjestelmälaitteiden valmistukseen ja on voimakkaasti halukas siirtymään uusille ulkomaisille markkinoille ja eri toimialoille. Tutkimuksen empiriaosuus perustuu tutkimuksen kohdeyrityksen sisäisten dokumenttien analysointiin, avainhenkilöiden kyselylomakehaastatteluun, avoimeen haastatteluun sekä tutkijan osallistuvaan havainnointiin. Tulokset osoittavat, että yrityksillä on kansainvälistyessään useita eri operaatiomuotoja ja niiden yhdistelmiä, joista valita sopivin. Kansainvälistyminen tuo yrityksille kuitenkin lukuisia uusia edellytyksiä, joihin yritysten tulee löytää riittävästi vahvuuksia, jotta menestyminen olisi mahdollista oli operaatiomuoto mikä tahansa. Suunniteltaessa kansainvälistymistä yritysten tulee kriittisesti ja puolueettomasti arvioida omat resurssinsa ja näin kartoittaa kehitettävät alueet. Usein kaikkia tarvittavia resursseja ei löydy heti yritykseltä itseltään, jolloin erinomaisena ratkaisuna toimii tämän päivän ilmiö verkostoituminen. Verkostoituminen tuo toiminnalle resursseja, laajuutta, kokemusta ja uskottavuutta sekä auttaa erottumaan kilpailijoista kilpailukykyisesti.
Savonlinnaan rakennettiin 2016–2019 välisenä aikana kaksi Suomen suurinta jännitettyä betonista jatkuvaa laattapalkkisiltaa. Silloissa on käytetty useita eri perustamistapoja. Tässä opinnäytetyössä tutkittiin Laitaasalmen pohjoisen betonisillan perustamistapoja. Työn tavoitteena oli selvittää, miten ja miksi kyseisiin ratkaisuihin on päädytty ja mitä vaihtoehtoja olisi ollut. Työn tilaaja on Destia Oy. Opinnäytetyön materiaali on kerätty kirjallisuudesta sekä haastattelemalla hankkeen työmaapäällikkö Aki Loikkasta, Destia Oy, geosuunnittelija Mikko Smuraa, Destia Oy ja siltasuunnittelijoita Juha Litmasta sekä Pekka Lämsää, Sweco Oy. Tutkimuksessa selvisi, että käytetyt perustamistavat ovat optimaalisimmat juuri kyseiseen siltaan, eikä parempia perustamistapoja löytynyt.
Aivovaurio primaarilla näköaivokuorella (V1) aiheuttaa sokeuden siihen osaan näkökenttää, jonka prosessoinnista vaurioitunut aivokuoren osa vastaa. Jotkut tällaisista primaarin näköaivokuoren vauriosta johtuvasta sokeudesta kärsivistä potilaista pystyvät kuitenkin tiedostamattomasti prosessoimaan visuaalisia ärsykkeitä, jotka on esitetty sokealle näkökentälle. Tällaista prosessointia voidaan mitata esimerkiksi pyytämällä koehenkilö esittämään paras arvaus visuaalisen ärsykkeestä, jota hän ei raportoi nähneensä. Mikäli vastaustarkkuus on arvaustodennäköisyyttä parempi, voidaan todeta, että visuaalinen ärsyke vaikutti henkilön käyttäytymiseen tiedostamattomalla tasolla. Tästä ilmiöstä käytetään yleisesti nimeä sokeanäkö. Neurologisilla potilailla tehdyistä havainnoista ei kuitenkaan voida suoraan tehdä päätelmiä, jotka yleistyisivät koskemaan kaikkia ihmisiä. Potilaiden aivoissa tapahtuu plastisiteetin vuoksi muutoksia, jotka voivat selittää näitä säästyneitä visuaalisia kykyjä. Transkraniaalisella magneettistimulaatiolla (TMS) voidaan tutkia neurologisesti terveiden koehenkilöiden aivojen osien funktioita, sillä TMS häiritsee hetkellisesti aivojen normaalia viestinvälitystä. Primaarille näköaivokuorelle kohdistetut TMS-pulssit häiritsevät tietoista näkemistä. Tässä tutkielmassa selvitin, onko tiedostamaton prosessointi mahdollista, kun ärsykkeen tietoista havaintoa on häiritty primaarin näköaivokuoren stimulaatiolla. Tutkimuksissamme havaitsimme, että sekä tietoinen että tiedostamaton näköinformaation prosessointi vaativat primaarin näköaivokuoren toimintaa neurologisesti terveillä. Tiedostamatonta näköinformaation prosessointia havaittiin ainoastaan yksinkertaisimmassa tehtävässä, jossa koehenkilö reagoi ärsykkeen ilmestymiseen. Silloinkin ainoastaan, kun aikaista prosessointia primaarilla näköaivokuorella ei häiritty. Liikkeen ja värin prosessointia mittaavissa kokeissa tiedostamatonta prosessointia V1-stimulaation aikana ei havaittu. Tiedostamaton näköinformaation prosessointi riippuu siis primaarin näköaivokuoren toiminnasta neurologisesti terveillä koehenkilöillä.
Immune cells infiltrating the central nervous system (CNS) are involved in the defense against invading microbes as well as in the pathogenesis of neuroinflammatory diseases. In these conditions, the presence of several types of immune and inflammatory cells have been demonstrated. However, some studies have also reported low amounts of immune cells that have been detected in the CNS of healthy individuals, but the cell types present have not been systematically analyzed. To do this, we now used brain samples from The Genotype- Tissue Expression (GTEx) project to analyze the relative abundance of 22 infiltrating leukocyte types using a digital cytometry tool (CIBERSORTx). To characterize cell proportions in different parts of the CNS, samples from 13 different anatomic brain regions were used. The data obtained demonstrated that several leukocyte types were present in the CNS. Six leukocyte types (CD4 memory resting T cells, M0 macrophages, plasma cells, CD8 T cells, CD4 memory activated T cells, and monocytes) were present with a proportion higher than 0.05, i.e. 5%. These six cell types were present in most brain regions with only insignificant variation. A consistent association with age was seen with monocytes, CD8 T cells, and follicular helper T cells. Taken together, these data show that several infiltrating immune cell types are present in the non-diseased CNS tissue and that the proportions of infiltrating cells are affected by age in a manner that is consistent with literature on immunosenecence and inflammaging.
Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the human genome. RNA expression of individual HERVs has frequently been observed in various pathologic conditions, but some activity can also be seen in healthy individuals, e.g. in the blood. To quantitate the basal expression levels of HERVs in the brain, we now used high-throughput sequencing-based metagenomic analysis to characterize the expression profiles of the HERV-K (HML-2) family proviruses in different brain regions of healthy brain tissue. To this end, RNA-seq data from the Genotype-Tissue Expression (GTEx) project was used. The GTEx project is a public resource to study tissue-specific gene expression and regulation, consisting of a large selection of sequenced samples from different tissues. The GTEx data used in this study consisted of 378 samples taken from 13 brain regions from 55 individuals. The data demonstrated that out of 99 intact proviruses in the family 58 were expressed, but the expression profiles were highly divergent and there were no significant differences in the expression profiles between the various anatomic regions of the brain. It is known that the brain contains a variety of infiltrating immune cells, which are probably of great importance both in the normal defense mechanisms as well as in the various pathogenic processes. Digital cytometry (CIBERSORTx) was used to quantify the proportions of the infiltrating immune cells in the same brain samples. Six most abundant (>5 % of the total population) cell types were observed to be CD4 memory resting T cells, M0 macrophages, plasma cells, CD8 T cells, CD4 memory activated T cells, and monocytes. Analysis of the correlations between the individual HERVs and infiltrating cell types indicated that a cluster of 6 HERVs had a notable correlation signature between T cell type infiltrating cell proportions and HERV RNA expression intensity. The correlations between inflammatory type infiltrating cells were negative or weak. Taken together, these data indicate that the expression of HERVs is associated with a T cell type immunity.
Some neurological patients with primary visual cortex (V1) lesions can guide their behavior based on stimuli presented to their blind visual field. One example of this phenomenon is the ability to discriminate colors in the absence of awareness. These so-called patients with blindsight must have a neural pathway that bypasses V1, explaining their ability to unconsciously process stimuli. The pathways that have been most often hypothesized to be the cause of blindsight connect lateral geniculate nucleus (LGN) or superior colliculus (SC) to extrastriate cortex, most likely V5, and parietal areas. To test if similar pathways function in neurologically healthy individuals or if unconscious processing depends on early visual cortex, we disturbed the visibility of a chromatic stimulus with metacontrast masking (Experiment 1) or neuronavigated transcranial magnetic stimulation (TMS) of early visual cortex, exact target being retinotopically mapped V1 (Experiment 2). We measured unconscious processing using the redundant target effect (RTE), which is the speeding up of reaction times in response to dual stimuli compared with one stimulus, when the task is to respond to any number of stimuli. An unconscious chromatic RTE was found when the visibility of the redundant chromatic stimulus was suppressed with a visual mask. When TMS was targeted to the correct retinotopic location of V1, and conscious perception of the redundant chromatic stimulus suppressed, the RTE was eliminated. Whether the elimination of unconscious RTE during TMS was exclusively due to disruption of V1 activity, or whether it was due to the possible interference with processing in V2 or even V3, is discussed. Based on our results and converging evidence from previous studies, we conclude that unconscious processing of chromatic information depends on the early visual cortex, in neurologically healthy participants.
Alone among herpesviruses, persistent Cytomegalovirus (CMV) markedly alters the numbers and proportions of peripheral immune cells in infected-vs-uninfected people. Because the rate of CMV infection increases with age in most countries, it has been suggested that it drives or at least exacerbates “immunosenescence”. This contention remains controversial and was the primary subject of the Third International Workshop on CMV & Immunosenescence which was held in Cordoba, Spain, 15-16th March, 2012. Discussions focused on several main themes including the effects of CMV on adaptive immunity and immunosenescence, characterization of CMV-specific T cells, impact of CMV infection and ageing on innate immunity, and finally, most important, the clinical implications of immunosenescence and CMV infection. Here we summarize the major findings of this workshop.
Aging is associated with alterations in the content and patterns of DNA methylation virtually throughout the entire human lifespan. Reasons for these variations are not well understood. However, several lines of evidence suggest that the epigenetic instability in aging may be traced back to the alteration of the expression of DNA methyltransferases. Here, the association of the expression of DNA methyltransferases DNMT1 and DNMT3B with age has been analysed in the context of the MARK-AGE study, a large-scale cross-sectional study of the European general population. Using peripheral blood mononuclear cells, we assessed the variation of DNMT1 and DNMT3B gene expression in more than two thousand age-stratified women and men (35-75 years) recruited across eight European countries. Significant age-related changes were detected for both transcripts. The level of DNMT1 gradually dropped with aging but this was only observed up to the age of 64 years. By contrast, the expression of DNMT3B decreased linearly with increasing age and this association was particularly evident in females. We next attempted to trace the age-related changes of both transcripts to the influence of different variables that have an impact on changes of their expression in the population, including demographics, dietary and health habits, and clinical parameters. Our results indicate that age affects the expression of DNMT1 and DNMT3B as an almost independent variable in respect of all other variables evaluated.
Background: As we age, the functioning of the human immune system declines. The results of this are increases in morbidity and mortality associated with infectious diseases, cancer, cardiovascular disease, and neurodegenerative disease in elderly individuals, as well as a weakened vaccination response. The aging of the immune system is thought to affect and be affected by the human virome, the collection of all viruses present in an individual. Persistent viral infections, such as those caused by certain herpesviruses, can be present in an individual for long periods of time without any overt pathology, yet are associated with disease in states of compromised immune function. To better understand the effects on human health of such persistent viral infections, we must first understand how the human virome changes with age. We have now analyzed the composition of the whole blood virome of 317 individuals, 21–70 years old, using a metatranscriptomic approach. Use of RNA sequencing data allows for the unbiased detection of RNA viruses and active DNA viruses. Results: The data obtained showed that Epstein-Barr virus (EBV) was the most frequently expressed virus, with other detected viruses being herpes simplex virus 1, human cytomegalovirus, torque teno viruses, and papillomaviruses. Of the 317 studied blood samples, 68 (21%) had EBV expression, whereas the other detected viruses were only detected in at most 6 samples (2%). We therefore focused on EBV in our further analyses. Frequency of EBV detection, relative EBV RNA abundance and the genetic diversity of EBV was not significantly different between age groups (21–59 and 60–70 years old). No significant correlation was seen between EBV RNA abundance and age. Deconvolution analysis revealed a significant difference in proportions of activated dendritic cells, macrophages M1, and activated mast cells between EBV expression positive and negative individuals. Conclusions: As it is likely that the EBV RNA quantified in this work is derived from reactivation of the latent EBV virus, these data suggest that age does not affect the rate of reactivation nor the genetic landscape of EBV. These findings offer new insight on the genetic diversity of a persistent EBV infection in the long-term.
Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently completed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3200 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation.
Background Old age is associated with increased levels of circulating pro-inflammatory cytokines, a phenomenon termed inflamm-aging. Elevated levels of pro-inflammatory cytokines have been associated with several age-associated diseases and with a shortened lifespan. Indoleamine 2,3-dioxygenase (IDO) has immunomodulatory properties and its activity is elevated in inflammation, autoimmune disorders and malignancies. We have previously shown that IDO activity is increased in nonagenarians compared to young individuals and that high IDO activity is associated with mortality at old age. Findings In this study our aim was to assess whether this difference in IDO activity in the plasma was due to the differential expression of either the IDO1 or IDO2 gene in peripheral blood mononuclear cells. Our results show that IDO1 and IDO2 are not differently expressed in nonagenarians compared to controls and that the expression of IDO genes is not associated with the level of IDO activity in the plasma. Conclusion The level of IDO activity in the plasma is not regulated through the expression of IDO1 or IDO2 in the peripheral blood mononuclear cells.
Background Prediction models for old-age mortality have generally relied upon conventional markers such as plasma-based factors and biophysiological characteristics. However, it is unknown whether the existing markers are able to provide the most relevant information in terms of old-age survival or whether predictions could be improved through the integration of whole-genome expression profiles. Methods We assessed the predictive abilities of survival models containing only conventional markers, only gene expression data or both types of data together in a Vitality 90+ study cohort consisting of n = 151 nonagenarians. The all-cause death rate was 32.5% (49 of 151 individuals), and the median follow-up time was 2.55 years. Results Three different feature selection models, the penalized Lasso and Ridge regressions and the C-index boosting algorithm, were used to test the genomic data. The Ridge regression model incorporating both the conventional markers and transcripts outperformed the other models. The multivariate Cox regression model was used to adjust for the conventional mortality prediction markers, i.e., the body mass index, frailty index and cell-free DNA level, revealing that 331 transcripts were independently associated with survival. The final mortality-predicting transcriptomic signature derived from the Ridge regression model was mapped to a network that identified nuclear factor kappa beta (NF-κB) as a central node. Conclusions Together with the loss of physiological reserves, the transcriptomic predictors centered around NF-κB underscored the role of immunoinflammatory signaling, the control of the DNA damage response and cell cycle, and mitochondrial functions as the key determinants of old-age mortality.
Infection with human cytomegalovirus (CMV) affects the function and composition of the immune system during ageing. In addition to the presence of the pathogen, the strength of the immune response, as measured by the anti-CMV IgG titre, has a significant effect on age-related pathogenesis. High anti-CMV IgG titres have been associated with increased mortality and functional impairment in the elderly. In this study, we were interested in identifying the molecular mechanisms that are associated with the strength of the anti-CMV response by examining the gene expression profiles that are associated with the level of the anti-CMV IgG titre. Results The level of the anti-CMV IgG titre is associated with the expression level of 663 transcripts in nonagenarians. These transcripts and their corresponding pathways are, for the most part, associated with metabolic functions, cell development and proliferation and other basic cellular functions. However, no prominent associations with the immune system were found, and no associated transcripts were found in young controls. Conclusions The lack of defence pathways associated with the strength of the anti-CMV response can indicate that the compromised immune system can no longer defend itself against the CMV infection. Our data imply that the association between high anti-CMV IgG titres and increased mortality and frailty is mediated by basic cellular processes.
Abstract Some patients with a visual field loss due to a lesion in the primary visual cortex (V1) can shift their gaze to stimuli presented in their blind visual field. The extent to which a similar “blindsight” capacity is present in neurologically healthy individuals remains unknown. Using retinotopically navigated transcranial magnetic stimulation (TMS) of V1 (Experiment 1) and metacontrast masking (Experiment 2) to suppress conscious vision, we examined neurologically healthy humans’ ability to make saccadic eye movements toward visual targets that they reported not seeing. In the TMS experiment, the participants were more likely to initiate a saccade when a stimulus was presented, and they reported not seeing it, than in trials which no stimulus was presented. However, this happened only in a very small proportion (∼8%) of unseen trials, suggesting that saccadic reactions were largely based on conscious perception. In both experiments, saccade landing location was influenced by unconscious information: When the participants denied seeing the target but made a saccade, the saccade was made toward the correct location (TMS: 68%, metacontrast: 63%) more often than predicted by chance. Signal detection theoretic measures suggested that in the TMS experiment, saccades toward unseen targets may have been based on weak conscious experiences. In both experiments, reduced visibility of the target stimulus was associated with slower and less precise gaze shifts. These results suggest that saccades made by neurologically healthy humans may be influenced by unconscious information, although the initiation of saccades is largely based on conscious vision.
The increased paternal age at conception (PAC) has been associated with autism spectrum disorder (ASD), schizophrenia and other neurodevelopmental disorders, thus raising questions that imply, potential health concerns in the offspring. As opposed to female oogonia, the male germ cells undergo hundreds of cell divisions during the fertile years. Thus, the advanced paternal age is associated with increase of point mutations in the male spermatogonia DNA, implying that this could be the major driving mechanism behind the paternal age effect observed in the offspring. In addition to replication errors, DNA replication fidelity and inefficient DNA repair machinery in the spermatogonia also contribute to the mutagenic load. Our study population consisted of 38 nonagenarians, participants in the Vitality 90+ Study, born in the year 1920 (women n = 25, men n = 13), for whom the parental birth dates were available. The gene expression profile of the study subjects was determined with HumanHT-12 v4 Expression BeadChip from peripheral blood mononuclear cells. We used Spearman's rank correlation to look for the associations of gene expression with paternal age at conception. Associated transcripts were further analyzed with GOrilla and IPA to determine enriched cellular processes and pathways. PAC was associated with the expression levels of 648 transcripts in nonagenarian subjects. These transcripts belonged to the process of mitochondrial translational termination and the canonical pathway of Mitochondrial dysfunction, more specifically of Oxidative phosphorylation. The observed systematic down-regulation of several mitochondrial respiratory chain components implies compromised function in oxidative phosphorylation and thus in the production of chemical energy.
Background: Low socioeconomic status (SES) is associated both with poorer functioning and elevated levels of inflammatory and cardiometabolic biomarkers, however knowledge of such relations for the oldest old is limited. Our aim was to study whether education is associated with cardiometabolic (cholesterol levels, BMI and leptin) and inflammatory (CRP, IL-6, IL-1Ra) biomarkers for the 90-year-olds who participated in the Vitality 90+ study. In addition, we investigated whether these biomarkers explain educational inequalities in functioning. Methods: All persons in Tampere, Finland, who were born in 1909 or 1910, were invited to participate, irrespective of their health status or dwelling place. The sample consisted of 262 participants who went through the home interview and blood tests. The SES indicator used was the highest education, and physical functioning was assessed using the Barthel index. The association of education with individual and combined biomarker scores, and with functioning, was analyzed cross-sectionally applying generalized linear models. Results: The low- and mid-level-educated participants had greater odds of belonging to the high risk group in cardiometabolic biomarkers than did the high-educated. Differences were statistically significant in three individual biomarkers (HDL-cholesterol, leptin, BMI) and in a cardiometabolic score. There were no educational differences in inflammatory biomarkers. When all biomarkers were combined, they mediated educational differences in functioning on an average of 23%. After controlling for smoking, alcohol use and diseases, biomarkers mediated part of the differences between the mid-level- and high-educated. Conclusions: High education was associated with better cardiometabolic biomarkers and functioning among the 90-year-olds. In part, educational inequalities in functioning were explained by cardiometabolic biomarkers