The question of agency in humanitarian intervention: cosmopolitan approaches

The purpose of this dissertation was to explore the question of humanitarian intervention’s agency from the theoretical perspective of cosmopolitanism. Cosmopolitanism is critical about the role of states in protecting individuals’ rights and thus questions whether the world should be organized around sovereign states system. In an ideal cosmopolitan world order without sovereign states, there would be no states and thus no need to intervene. In the non-ideal world, however, human rights violations are still present and thus humanitarian interventions are a necessity. Central to the discussion of this dissertation is the dilemma of applying an ideal theory to the problems of the non-ideal world. This dissertation sets out to identify the theoretical challenges that cosmopolitanism aces when applying its ideal principles to the problem of humanitarian intervention. The major objective of this thesis was to clarify how cosmopolitans approach the issue of right agent for humanitarian intervention. Cosmopolitanism calls for extensive reforms in the global order to handle more effectively the question of large-scale fundamental human rights abuses present in the imperfect world order. Thus the purpose of this thesis is to explore the possible alternatives to the current governance of humanitarian intervention from the perspective of cosmopolitanism, by asking who would be the most legitimate agent to authorize and undertake a humanitarian intervention. With that aim, the thesis identified the premises underlying the cosmopolitan conception of humanitarian intervention, and analyzed the arguments of the leading contemporary cosmopolitan thinkers and weighed them critically against one another. The findings of this dissertation suggest that cosmopolitanism provides normative guidance for the non-ideal world by (1) establishing the ideal global order and (2) offering guidelines to approximate that ideal. As according to cosmopolitanism the agents for humanitarian intervention in the real world lack legitimacy, they propose reforms to create the ideal agents, which would offer a much more effective protection of human rights. However the theoretical exploration conducted in the dissertation suggested that this needs to be approached with caution since there are certain limitations involved when applying the ideal theory to the non-ideal world.http://www.ester.ee/record=b4412331~S77*es

Profileerimise tajumisest internetis gümnaasiumiõpilaste seas

Käesoleva uurimistöö eesmärgiks oli teada saada, millised on gümnaasiumiõpilaste teadmised ja arvamused internetis avaldatud isikuandmete kogumisest ja kasutusest interneti suurkorporatsioonide poolt, millised on nende üldised teadmised big datast, millised on nende teadmised ja kogemused suurkorporatsioonide poolse isikuandmete kogumisega ning kuidas suhtuvad nad personaliseeritud veebisisusse. Teooria peatükis kirjutasin üldisemalt big datast, selle defineerimisvõimalustest ning kuidas big datat kasutada saab, lisaks seletasin, mida tähendab profileerimine interneti kontekstis ning kuidas on see seotud big dataga. Andsin ülevaate ka Facebooki „Like“ nupust kui ühest profileerimise vahendist ning kirjutasin ka personaalsest veebisisust ja andmekaevandamise abil reklaamide pakkumisest. Teema uurimiseks püstitasin neli suuremat uurimisküsimust, mille abil uurisin, millised on gümnaasiumiõpilaste teadmised ja arvamused internetis avaldatud isikuandmete kogumisest ja kasutusest interneti suurkorporatsioonide poolt, milliseid suurandmeid on noorte arvates võimalik koguda isikute Facebooki „meeldib“ nupu kasutamise pinnalt, milliseid kogemusi omavad gümnaasiumiõpilased interneti suurkorporatsioonide poolse isikuandmete kogumisega ning milline on noorte suhtumine personaliseeritud veebisisusse. Andmete saamiseks kasutasin kvalitatiivset meetodit. Seminaritöö raames viisin 2015. aasta detsembris läbi kaks semi-struktureeritud informandi intervjuud, millele lisandus kaheksa 2016. aasta aprillis lõputöö raames läbi viidud intervjuud. Intervjuusid analüüsisin cross-case ehk horisontaalanalüüsi meetodit kasutades. Valimisse kuulus kümme gümnaasiumiastmes õppivat noort. Uuringu tulemustest selgus, et gümnaasiumiõpilaste teadmised big data teemast üldiselt on väga väikesed. Isikuandmete kogumisega oldi kokku puututud ning teatud juhtudel teati ka seda, milleks võidakse isikuandmeid kasutada, kuid täpsemalt sellele, kuidas andmete pinnalt personaliseeritud reklaamid tekivad, ei osatud vastata. Neile personaalselt suunatud reklaame olid märganud vähesed. Kui noored said teada, milleks nende isikuandmeid kasutatakse, siis pigem oli see neile vastumeelne, et keegi nende tegevusi internetis jälgib. Kokkuvõtvalt saab öelda, et kuigi gümnaasiumiõpilased kasutavad internetti igapäevaselt, siis big data on nende jaoks väga võõras teema. Muidugi on ka big dataga seotud mõisted keerulised, mida ei osata seletada. Osatakse pakkuda erinevaid isikuandmeid, mida suurkorporatsioonid meilt koguvad, kuid ei osata aimata, mida nende andmetega teha saab. Tundub, et eriti ei pöörata tähelepanu ka internetis olevatele reklaamidele, sest vähe seostati neid enda varasemate tegevustega internetis. Kui saadi teada, et nende isikuandmeid võidakse ära kasutada, siis see oli intervjueeritavatele vastumeelne, seda, et see võib olla inimestele ka kasulik, ei osatud välja tuua. Mina arvan, et eduka e-riigina tuleks noorte kui ka kõigi teiste inimeste teadlikkust internetis toimuvast tõsta, et ennetada oma isikuandmete sattumist valedesse kätesse.http://www.ester.ee/record=b4576184*es

MED25 roll hariliku müürlooga õhulõhede regulatsioonis ja arengus

Taimelehtede ja varte pinnal olevad õhulõhed on väikesed poorid atmosfääri süsihappegaasi ammutamiseks, kaasneva mõjuna kaotab taim õhulõhede kaudu ka vett. Õhulõhed on võimelised reageerima mitmetele keskkonnatingimustele oma suuruse muutmise läbi, mis aitab taimel näiteks põuatingimustes elutähtsat vett säästa. Taimede õhulõhede regulatsiooni täpsem mõistmine on seetõttu väga vajalik selleks, et tulevikus luua muutuvate keskkonnatingimustega paremini toime tulevaid taimi. Praegusel hetkel on õhulõhede regulatsioonist punases valguses vähe teada ja olemasolevad teooriad on vastuolulised. Seetõttu uuriti käesolevas töös MED25 kui võimaliku õhulõhede punase valguse regulatsiooni komponendi rolli õhulõhede regulatsioonis ja arengus metsiktüüpi hariliku müürlooga (Arabidopsis thaliana) Col-0 ökotüüpi taimede ja MED25 katkestusega mutantide abil. Töö tulemustest selgus, et MED25 omab olulist rolli õhulõhede avanemises ja sulgumises ning nende arengu

Erineva lainepikkusega valguse mõju süsihappegaasi kontsentratsiooni muutustest tingitud õhulõ-hede sulgumisele ja avanemisele

Õhulõhed on poorid taime lehtede ja varte pinnal, mis reguleerivad taimede veevahetust. Taimede õhulõhede avanemis- ja sulgumismehhanismide mõistmine on oluline, sest sooje-neva kliima, CO2 kontsentratsiooni tõusu ja kahanevate veevarudega võib tulevikus kujuneda eluliselt tähtsaks taimede veekasutuse efektiivsuse suurendamine. Seetõttu uuriti käesole-vas töös valguse mõju süsihappegaasi kontsentratsiooni muutuse poolt algatatud õhulõhede reaktsioonidele. Selleks teostati gaasivahetuseksperimendid hariliku müürlooga (Arabidopsis thaliana) kahe ökotüübi ja vääristubakaga (Nicotiana tabacum). Katsete tulemustest selgus, et eri lainepikkusega valgus omab mõju õhulõhede reageerimisele ja see tundub olevat liigiti varieeruv

Nature tourism development possibilities on the island of Hiiumaa

Töö eesmärk on analüüsida Hiiumaa loodusturismi olukorda ja tuua välja kitsaskohad ning teha ettepanekuid ja soovitusi loodusturismi arendamiseks. Peamised probleemid on loodusturismi hooajalisus ja loodusturismile spetsialiseerunud kohalike ettevõtete puudumine. Töö käigus uuriti, mis seisus on Hiiumaa loodusturismi objektid ja kuidas saaks ne id paremini turismis rakendada. Selleks viidi läbi teiseste andmete uuring, selgitamaks välja loodusturismi objektid, mida pakutakse turismiportaalide kaudu, tutvustatakse Hiiumaa turismikaartidel ja mujal avalikus meedias. Valiti välja 49 Hiiumaa olulisimat loodusturismi objekti või sihtkohta ja neid, mille kohta puudus kaasaegne info, külastati. Uuringu põhjal võib järeldada, et Hiiumaal on loodusturismi potentsiaal suures osas ära kasutamata. Üksnes vähesed loodusobjektid kuuluvad turismipakettidesse või moodustavad vaid osa turismimarsruudist.The purpose of current thesis is to analyze the present status of the nature tourism on the island of Hiiumaa and to bring out the shortages, as well as to make some possible suggestions and recommendations. The problem of the nature tourism in Hiiumaa is its seasonality and the lack of the enterprises offering direct nature tourism services. The condition of the nature tourism objects in Hiiumaa has been studied and their improvement and development possibilities have been outlined. 49 nature tourism objects, advertised via Visitestonia.com, Hiiumaa tourism maps and other media were selected for research and those, lacking the contemporary information, were visited. Based on collected information and field visits, the evaluations were made and suggestions given. As a result of the study we can conclude that in Hiiumaa the potential of the nature tourism is mostly unused: only a few nature objects belong to some tourist packages or constitute a part of certain routes

Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson\u27s disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells

Kinetic and structural characterization of NUDT15 and NUDT18 as catalysts of isoprene pyrophosphate hydrolysis

Isoprene pyrophosphates play a crucial role in the synthesis of a diverse array of essential nonsterol and sterol biomolecules and serve as substrates for posttranslational isoprenylation of proteins, enabling specific anchoring to cellular membranes. Hydrolysis of isoprene pyrophosphates would be a means to modulate their levels, downstream products, and protein isoprenylation. While NUDIX hydrolases from plants have been described to catalyze the hydrolysis of isoprene pyrophosphates, homologous enzymes with this function in animals have not yet been reported. In this study, we screened an extensive panel of human NUDIX hydrolases for activity in hydrolyzing isoprene pyrophosphates. We found that human nucleotide triphosphate diphosphatase NUDT15 and 8-oxo-dGDP phosphatase NUDT18 efficiently catalyze the hydrolysis of several physiologically relevant isoprene pyrophosphates. Notably, we demonstrate that geranyl pyrophosphate is an excellent substrate for NUDT18, with a catalytic efficiency of 2.1 × 105 m−1·s−1, thus making it the best substrate identified for NUDT18 to date. Similarly, geranyl pyrophosphate proved to be the best isoprene pyrophosphate substrate for NUDT15, with a catalytic efficiency of 4.0 × 104 M−1·s−1. LC–MS analysis of NUDT15 and NUDT18 catalyzed isoprene pyrophosphate hydrolysis revealed the generation of the corresponding monophosphates and inorganic phosphate. Furthermore, we solved the crystal structure of NUDT15 in complex with the hydrolysis product geranyl phosphate at a resolution of 1.70 Å. This structure revealed that the active site nicely accommodates the hydrophobic isoprenoid moiety and helped identify key binding residues. Our findings imply that isoprene pyrophosphates are endogenous substrates of NUDT15 and NUDT18, suggesting they are involved in animal isoprene pyrophosphate metabolism

A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine

Synthesis of substituted indazole acetic acids by N−N bond forming reactions

Herein, we report on the discovery and development of novel cascade N−N bond forming reactions for the synthesis of rare indazole acetic acid scaffolds. This approach allows for convenient synthesis of three distinct indazole acetic acid derivatives (unsubstituted, hydroxy, and alkoxy) by heating 3-amino-3-(2-nitroaryl)propanoic acids with an appropriate nucleophile/solvent under basic conditions. The reaction tolerates a range of functional groups and electronic effects and, in total, 23 novel indazole acetic acids were synthesized and characterized. This work offers a valuable strategy for the synthesis of useful scaffolds for drug discovery programs