Oma maailm

Loov-praktiline lõputöö - kontsert “Oma maailm” - avab läbi muusika ning kontserdiruumi võimaluste autori maailma, mis viimased neli aastat on olnud seotud muusikaõpingutega Viljandis,Tallinnas ja Helsingis. Kõik nii töö- kui eraelus toimuv on mingil hetkel väljundi leidnud muusikas ja tähtsamad tunded tulevad läbi muusikapalade esitusele kontserdil, mis toimus 29. mail 2017 Viljandi Pärimusmuusika Aida suures saalis. Käesolevas lõputöö kirjalikus osas tutvustab autor 1. peatükis õpikogemkontserdi kontseptsiooni ja põhjendab eraldi iga loo valikut. 2. peatükis avab ettevalmistusprotsessi tagamaid, mis hõlmasid proove, videomontaaži, lavakujunduse ning illustratsioonide tegemist. Lõputöö lisades on repertuaari noodid, lavaplaan, kontserdi plakat ning postkaartide pildid.http://www.ester.ee/record=b4683298*es

Immunomodulatory Effects of Engineered Nanomaterials in Healthy and Diseased Lungs and Skin

Nanotechnology is exerting a huge impact on various sectors of everyday life as it has a tremendous potential for revolutionizing a long list of consumer products and industrial applications. The key to success in the nanotechnology field lies in the fact that materials at the nanoscale possess novel and enhanced properties such as greater strength and improved conductivity when compared with their bulk-sized equivalents. The most probable occupational and consumer routes of exposure to engineered nanomaterials (ENM) are via the respiratory tract and skin. Due to their small size, ENM are able to bypass physical and chemical barriers in the human body and come into contact with the immune system which is capable of recognizing foreign structures including ENM. However, the downscaling of the materials also increases their chemical reactivity, which in combination with the small size and other physicochemical properties, means that ENM could influence our immune system exerting possibly beneficial but also adverse effects on our health. The aim of this thesis was to investigate modulatory effects and physiological outcomes of ENM on a healthy and a compromised immune system in the lungs and skin. The main findings of the thesis were that rigid, rod-like but not long and tangled carbon nanotubes (CNT) were able to induce a condition similar to allergic airway inflammation via activation of innate immunity. Although nanofibrillated celluloses triggered acute pulmonary inflammation, their effects subsided within one month and regardless of the material’s biopersistence, their health outcomes differed significantly from the long-term pathologies of rigid, rod-like CNT. Uncoated and functionalized CuO nanomaterials demonstrated an ability to worsen allergic asthma by eliciting pulmonary neutrophilia, however it was found that surface PEGylation significantly suppressed the inflammatory potential of the pristine CuO ENM; this effect was especially evident at the transcriptional level. Topical exposure to nano-sized ZnO in a murine model of atopic dermatitis revealed that the particles were able to pass through mechanically injured allergic skin. This penetration of the material resulted in a local inhibition of pro-inflammatory and allergic reactions and a systemic exacerbation of IgE antibody production. This work provides knowledge of pulmonary and dermal effects of ENM. The results of this thesis demonstrate that ENM with different physicochemical characteristics possess an ability to modulate our immune system. These observations emphasize the diversity and complexity of the materials as well as highlighting their impacts on the immune system and the resulting consequences on health. These data contribute to the safety assessment of ENM as well as information that can be useful in nanomedicine.Nanoteknologialla on suuri vaikutus arkielämän eri osa-alueisiin, koska sillä on valtava potentiaali mullistaa kulutushyödykkeitä ja teollisia sovelluskohteita. Nanoteknologian menestyksen avain perustuu nanokokoisten materiaalien uusiin ja paranneltuihin ominaisuuksia, kuten lujuuteen ja johtokykyyn verrattuna vastaaviin, mikrokokoisiin materiaaleihin. Sekä kuluttajat että työntekijät altistuvat todennäköisimmin teollisesti tuotetuille nanomateriaaleille (ENM, engl. engineered nanomaterials) hengitysteiden ja ihon kautta. ENM:n pienen koon vuoksi ne pystyvät ohittamaan ihmiskehon fysikaaliset ja kemialliset esteet, minkä jälkeen ne joutuvat kosketuksiin immuunijärjestelmän kanssa, joka kykenee tunnistamaan elimistölle vieraita rakenteita, kuten ENM:eja. Materiaalien partikkelikoon pienentäminen lisää myös niiden kemiallista reaktiivisuutta, joka yhdessä pienen koon ja muiden fysikaalis-kemiallisten ominaisuuksien kanssa tarkoittaa, että ENM:t voivat vaikuttaa immuunijärjestelmäämme, ja vaikutukset voivat olla hyödyllistä mutta myös haitallisia terveydellemme. Tämän väitöskirjatyön tarkoituksena oli tutkia ENM:ien vaikutuksia ja fysiologisia seurauksia terveessä ja heikentyneessä immuunijärjestelmässä sekä keuhkoissa että ihossa. Väitöskirjatyön päähavainnot olivat, että jäykät ja sauvamaiset, mutta eivät pitkät ja lankakerämäiset, hiilinanoputket (CNT, engl. carbon nanotubes) pystyivät aktivoimaan luontaisen immuniteetin ja aiheuttamaan samanlaisen tilan kuin allerginen hengitysteiden tulehdus. Vaikka nanofibrillimäiset selluloosat aiheuttivat akuuttia pulmonaarista tulehdusta, niiden vaikutukset vähenivät kuukaudessa ja aineen biopysyvyydestä huolimatta niiden terveysvaikutukset erosivat merkittävästi jäykän, sauvanmuotoisen CNT:n aiheuttamista pitkäaikaisista patologisista vaikutuksista. Sekä päällystämättömät että funktionalisoidut CuO-nanomateriaalit pahensivat allergista astmaa aiheuttamalla keuhkojen neutrofiliaa, mutta partikkelin pinnan PEGylaatio vähensi merkittävästi muokkaamattomien CuO ENM:n tulehdusvaikutuksia, mikä havaittiin erityisen selvästi transkriptionaalisella tasolla. Paikallinen ihoaltistuminen nano-kokoiselle ZnO:lle hiiren atopisen dermatiitin mallissa paljasti, että partikkelit kykenivät kulkemaan allergisen ihon läpi, mikä oli mekaanisesti rikkoutunut. Tämä materiaalin tunkeutuminen johti pro-inflammatoristen ja allergisten reaktioiden paikalliseen vähentymiseen, sekä IgE-vasta-ainetuotannon systeemiseen lisääntymiseen. Tämä työ antaa tietoa ENM:ien vaikutuksista keuhkoissa ja ihossa. Tämän väitöskirjatyön tulokset osoittavat, että ENM:t, joilla on erilaisia fysikaalis-kemiallisia ominaisuuksia, kykenevät moduloimaan immuunijärjestelmäämme. Nämä havainnot korostavat materiaalien moninaisuutta ja monimutkaisuutta, sekä korostavat niiden vaikutuksia immuunijärjestelmään ja sen seurauksia terveydelle. Nämä tiedot edistävät ENM:n turvallisuuden arviointia, ja niistä voi olla hyötyä nanolääketieteessä

Profiling Non-Coding RNA Changes Associated with 16 Different Engineered Nanomaterials in a Mouse Airway Exposure Model

Perturbations in cellular molecular events and their associated biological processes provide opportunities for hazard assessment based on toxicogenomic profiling. Long non-coding RNAs (lncRNAs) are transcribed from DNA but are typically not translated into full-length proteins. Via epigenetic regulation, they play important roles in organismal response to environmental stress. The effects of nanoparticles on this important part of the epigenome are understudied. In this study, we investigated changes in lncRNA associated with hazardous inhalatory exposure of mice to 16 engineered nanomaterials (ENM)–4 ENM (copper oxide, multi-walled carbon nanotubes, spherical titanium dioxide, and rod-like titanium dioxide particles) with 4 different surface chemistries (pristine, COOH, NH2, and PEG). Mice were exposed to 10 µg of ENM by oropharyngeal aspiration for 4 consecutive days, followed by cytological analyses and transcriptomic characterization of whole lung tissues. The number of significantly altered non-coding RNA transcripts, suggestive of their degrees of toxicity, was different for each ENM type. Particle surface chemistry and shape also had varying effects on lncRNA expression. NH2 and PEG caused the strongest and weakest responses, respectively. Via correlational analyses to mRNA expression from the same samples, we could deduce that significantly altered lncRNAs are potential regulators of genes involved in mitotic cell division and DNA damage response. This study sheds more light on epigenetic mechanisms of ENM toxicity and also emphasizes the importance of the lncRNA superfamily as toxicogenomic markers of adverse ENM exposure

Profiling Non-Coding RNA Changes Associated with 16 Different Engineered Nanomaterials in a Mouse Airway Exposure Model

Perturbations in cellular molecular events and their associated biological processes provide opportunities for hazard assessment based on toxicogenomic profiling. Long non-coding RNAs (lncRNAs) are transcribed from DNA but are typically not translated into full-length proteins. Via epigenetic regulation, they play important roles in organismal response to environmental stress. The effects of nanoparticles on this important part of the epigenome are understudied. In this study, we investigated changes in lncRNA associated with hazardous inhalatory exposure of mice to 16 engineered nanomaterials (ENM)–4 ENM (copper oxide, multi-walled carbon nanotubes, spherical titanium dioxide, and rod-like titanium dioxide particles) with 4 different surface chemistries (pristine, COOH, NH2, and PEG). Mice were exposed to 10 µg of ENM by oropharyngeal aspiration for 4 consecutive days, followed by cytological analyses and transcriptomic characterization of whole lung tissues. The number of significantly altered non-coding RNA transcripts, suggestive of their degrees of toxicity, was different for each ENM type. Particle surface chemistry and shape also had varying effects on lncRNA expression. NH2 and PEG caused the strongest and weakest responses, respectively. Via correlational analyses to mRNA expression from the same samples, we could deduce that significantly altered lncRNAs are potential regulators of genes involved in mitotic cell division and DNA damage response. This study sheds more light on epigenetic mechanisms of ENM toxicity and also emphasizes the importance of the lncRNA superfamily as toxicogenomic markers of adverse ENM exposure

Profiling Non-Coding RNA Changes Associated with 16 Different Engineered Nanomaterials in a Mouse Airway Exposure Model

Perturbations in cellular molecular events and their associated biological processes provide opportunities for hazard assessment based on toxicogenomic profiling. Long non-coding RNAs (lncRNAs) are transcribed from DNA but are typically not translated into full-length proteins. Via epigenetic regulation, they play important roles in organismal response to environmental stress. The effects of nanoparticles on this important part of the epigenome are understudied. In this study, we investigated changes in lncRNA associated with hazardous inhalatory exposure of mice to 16 engineered nanomaterials (ENM)-4 ENM (copper oxide, multi-walled carbon nanotubes, spherical titanium dioxide, and rod-like titanium dioxide particles) with 4 different surface chemistries (pristine, COOH, NH2, and PEG). Mice were exposed to 10 mu g of ENM by oropharyngeal aspiration for 4 consecutive days, followed by cytological analyses and transcriptomic characterization of whole lung tissues. The number of significantly altered non-coding RNA transcripts, suggestive of their degrees of toxicity, was different for each ENM type. Particle surface chemistry and shape also had varying effects on lncRNA expression. NH2 and PEG caused the strongest and weakest responses, respectively. Via correlational analyses to mRNA expression from the same samples, we could deduce that significantly altered lncRNAs are potential regulators of genes involved in mitotic cell division and DNA damage response. This study sheds more light on epigenetic mechanisms of ENM toxicity and also emphasizes the importance of the lncRNA superfamily as toxicogenomic markers of adverse ENM exposure.Peer reviewe

Skin microbiota of oxazolone-induced contact hypersensitivity mouse model

Funding Information: K.M. received personal funding from Instrumentarium Science Foundation. The study was supported by grants from the Academy of Finland (decisions 307768 and 333178) admitted to P.K. and H.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors wish to acknowledge Prof. Otso Ovaskainen for providing help with HMSC, and CSC–IT Center for Science, Finland, for computational resources. The DNA sequencing service was provided by the Institute of Molecular Medicine Finland (FIMM) at the Helsinki Institute of Life Science and Biocenter Finland at the University of Helsinki. Publisher Copyright: © 2022 Mäenpää et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Contact allergy is a common skin allergy, which can be studied utilising contact hypersensitivity (CHS) animal model. However, it is not clear, whether CHS is a suitable model to investigate skin microbiota interactions. We characterised the effect of contact dermatitis on the skin microbiota and studied the biological effects of oxazolone (OXA) -induced inflammation on skin thickness, immune cell numbers and changes of the microbiota in CHS mouse model (n = 72) for 28 days. Through 16S rRNA gene sequencing we defined the composition of bacterial communities and associations of bacteria with inflammation. We observed that the vehicle solution of acetone and olive oil induced bacterial community changes on day 1, and OXA-induced changes were observed mainly on day 7. Many of the notably enriched bacteria present in the OXA-challenged positive group represented the genus Faecalibaculum which were most likely derived from the cage environment. Additionally, skin inflammation correlated negatively with Streptococcus, which is considered a native skin bacterium, and positively with Muribacter muris, which is typical in oral environment. Skin inflammation favoured colonisation of cage-derived faecal bacteria, and additionally mouse grooming transferred oral bacteria on the skin. Due to the observed changes, we conclude that CHS model could be used for certain skin microbiome-related research set-ups. However, since vehicle exposure can alter the skin microbiome as such, future studies should include considerations such as careful control sampling and statistical tests to account for potential confounding factors.Peer reviewe

Transcriptomic Profiling the Effects of Airway Exposure of Zinc Oxide and Silver Nanoparticles in Mouse Lungs

Consumers and manufacturers are exposed to nanosized zinc oxide (nZnO) and silver particles (nAg) via airways, but their biological effects are still not fully elucidated. To understand the immune effects, we exposed mice to 2, 10, or 50 μg of nZnO or nAg by oropharyngeal aspiration and analyzed the global gene expression profiles and immunopathological changes in the lungs after 1, 7, or 28 days. Our results show that the kinetics of responses varied in the lungs. Exposure to nZnO resulted in the highest accumulation of F4/80- and CD3-positive cells, and the largest number of differentially expressed genes (DEGs) were identified after day 1, while exposure to nAg caused peak responses at day 7. Additionally, nZnO mainly activated the innate immune responses leading to acute inflammation, whereas the nAg activated both innate and adaptive immune pathways, with long-lasting effects. This kinetic-profiling study provides an important data source to understand the cellular and molecular processes underlying nZnO- and nAg-induced transcriptomic changes, which lead to the characterization of the corresponding biological and toxicological effects of nZnO and nAg in the lungs. These findings could improve science-based hazard and risk assessment and the development of safe applications of engineered nanomaterials (ENMs), e.g., in biomedical applications

Molecular Signature of Asthma-Enhanced Sensitivity to CuO Nanoparticle Aerosols from 3D Cell Model

More than 5% of any population suffers from asthma, and there are indications that these individuals are more sensitive to nanoparticle aerosols than the healthy population. We used an air-liquid interface model of inhalation exposure to investigate global transcriptomic responses in reconstituted three-dimensional airway epithelia of healthy and asthmatic subjects exposed to pristine (nCuO) and carboxylated (nCuO(COOH)) copper oxide nanoparticle aerosols. A dose-dependent increase in cytotoxicity (highest in asthmatic donor cells) and pro-inflammatory signaling within 24 h confirmed the reliability and sensitivity of the system to detect acute inhalation toxicity. Gene expression changes between nanoparticle-exposed versus air-exposed cells were investigated. Hierarchical clustering based on the expression profiles of all differentially expressed genes (DEGs), cell-death-associated DEGs (567 genes), or a subset of 48 highly overlapping DEGs categorized all samples according to "exposure severity", wherein nanoparticle surface chemistry and asthma are incorporated into the dose-response axis. For example, asthmatics exposed to low and medium dose nCuO clustered with healthy donor cells exposed to medium and high dose nCuO, respectively. Of note, a set of genes with high relevance to mucociliary clearance were observed to distinctly differentiate asthmatic and healthy donor cells. These genes also responded differently to nCuO and nCuO(COOH) nanoparticles. Additionally, because response to transition-metal nanoparticles was a highly enriched Gene Ontology term (FDR 8 X 10(-13)) from the subset of 48 highly overlapping DEGs, these genes may represent biomarkers to a potentially large variety of metal/metal oxide nanoparticles.Peer reviewe

Toxicogenomic Profiling of 28 Nanomaterials in Mouse Airways

Toxicogenomics opens novel opportunities for hazard assessment by utilizing computational methods to map molecular events and biological processes. In this study, the transcriptomic and immunopathological changes associated with airway exposure to a total of 28 engineered nanomaterials (ENM) are investigated. The ENM are selected to have different core (Ag, Au, TiO2, CuO, nanodiamond, and multiwalled carbon nanotubes) and surface chemistries (COOH, NH2, or polyethylene glycosylation (PEG)). Additionally, ENM with variations in either size (Au) or shape (TiO2) are included. Mice are exposed to 10 mu g of ENM by oropharyngeal aspiration for 4 consecutive days, followed by extensive histological/cytological analyses and transcriptomic characterization of lung tissue. The results demonstrate that transcriptomic alterations are correlated with the inflammatory cell infiltrate in the lungs. Surface modification has varying effects on the airways with amination rendering the strongest inflammatory response, while PEGylation suppresses toxicity. However, toxicological responses are also dependent on ENM core chemistry. In addition to ENM-specific transcriptional changes, a subset of 50 shared differentially expressed genes is also highlighted that cluster these ENM according to their toxicity. This study provides the largest in vivo data set currently available and as such provides valuable information to be utilized in developing predictive models for ENM toxicity.Peer reviewe

Hiilinanoputkien aiheuttamien terveysvaikutusten karakterisointi systeemitoksikologian avulla

Hiilinanoputket ovat monikäyttöisiä teollisia nanomateriaaleja, jotka soveltuvat lukuisiin teollisuusaloihin. Hiilinanoputkien asbestin kaltainen muoto on kuitenkin nostanut esiin kysymyksiä niiden turvallisuudesta.1