Molekulaartehnoloogia praktilise meditsiini teenistuses. Antisense-tehnika

Järgnevate aastate jooksul jõuab arvatavasti lõpule inimgenoomi projekt ning kogu DNA järjestus on avatud geenmutatsioonide põhjustatud haiguste uuringuteks. Võimalus efektiivselt kontrollida geeni ekspressiooni on olnud ravimieellaste tootjate vaateväljas juba paarkümmend aastat. Ravimieellased (pro-drugs) on ained, mis omavad teatud bioloogilist efekti ja mille struktuuri täiustatakse temast ravimi väljatöötamise käigus, et suurendada tema spetsiifilisust ja efektiivsust. Üks huvitavamaid ja praeguseks ka kõige kaugemale jõudnumaid teadusharusid sel alal on antisense-tehnoloogia ehk antisense-oligonukleotiidide kasutamine

Ajukestade permeabiliteet akuutse ja kroonilise alkoholismi puhul

Digiteeritud Rahvusarhiivi koordineeritud MKMi rahastatud SF-projekti „Vaba rahvas vabal maal (1920-1940)“ raames OÜ Andmevara Services poolthttps://www.ester.ee/record=b364975

Returned to ‘normality’? Estonian national identity constructions after EU and NATO accession

Estonian identity politics in the 1990s were firmly rooted in the narrative of ‘returning to Europe’ and breaking with the Soviet past – to become a ‘normal’ country again. This narrative underwent a significant change on successful entry to key international organisations such as the EU and NATO. This research is a qualitative in-depth investigation into the complex and multi-layered Estonian national identity constructions evident within Estonian society after it had had nearly a decade to ‘settle into’ this European ‘normality’. Estonia formally validated its ‘return in Europe’ in 2004, but how is ‘Europeanness’ conceptualised by the people on the ground? The thesis demonstrates that the economic crisis which hit Europe in 2008, and had an impact on the defining of ‘Europeanness’, encouraged a new binary of North vs South division in how Europe was perceived. Following interviews with 33 persons from different parts of Estonia, an emergent theme from the empirical findings was, that for many, Estonia was seen as embodying the ‘true’ neoliberal values associated with the understanding of ‘Europe’. The same neoliberal paradigm was at play in helping to shape understandings of Russia, which also frame domestic interethnic relations to a degree. The latter has been the central focus of previous studies to which the current research offers a novel perspective. Themes of security have not lost their relevance in relations with Russia but the pragmatic understanding of reconciling the economic necessity and the more national emotional element has become pertinent nearly a decade after officially ‘returning to Europe’. Another key finding of this research shows a shift from the inter-war period to the early 1990s as a benchmark for Estonian identity-construction, which implies that at the time of conducting this study there was no longer a need to return to ‘Europe’. In addition to the limited research done on Estonian national identity since joining the EU and NATO, there has been minimal attention paid to a grassroots perspective on the issue. By taking a bottom-up perspective through in-depth interviewing and using an innovative visual methodology, this research makes a significant and timely contribution into understanding the ‘normality’ that had settled in Estonia after EU and NATO accession

Canonical sonic Hedgehog signaling in early lung development

The canonical hedgehog (HH) signaling pathway is of major importance during embryonic development. HH is a key regulatory morphogen of numerous cellular processes, namely, cell growth and survival, differentiation, migration, and tissue polarity. Overall, it is able to trigger tissue-specific responses that, ultimately, contribute to the formation of a fully functional organism. Of all three HH proteins, Sonic Hedgehog (SHH) plays an essential role during lung development. In fact, abnormal levels of this secreted protein lead to severe foregut defects and lung hypoplasia. Canonical SHH signal transduction relies on the presence of transmembrane receptors, such as Patched1 and Smoothened, accessory proteins, as Hedgehog-interacting protein 1, and intracellular effector proteins, like GLI transcription factors. Altogether, this complex signaling machinery contributes to conveying SHH response. Pulmonary morphogenesis is deeply dependent on SHH and on its molecular interactions with other signaling pathways. In this review, the role of SHH in early stages of lung development, specifically in lung specification, primary bud formation, and branching morphogenesis is thoroughly reviewed.FEDER funds, through the Competitiveness Factors Operational Program (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038; and by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). The funders had no role in decision to publish or preparation of the manuscriptinfo:eu-repo/semantics/publishedVersio

Non-coding RNAs in muscle differentiation and musculoskeletal disease

RNA is likely to be the most rediscovered macromolecule in biology. Periodically, new non-canonical functions have been ascribed to RNA, such as the ability to act as a catalytic molecule or to work independently from its coding capacity. Recent annotations show that more than half of the transcriptome encodes for RNA molecules lacking coding activity. Here we illustrate how these transcripts affect skeletal muscle differentiation and related disorders. We discuss the most recent scientific discoveries that have led to the identification of the molecular circuitries that are controlled by RNA during the differentiation process and that, when deregulated, lead to pathogenic events. These findings will provide insights that can aid in the development of new therapeutic interventions for muscle disease

Anti-infectious and anti-inflammatory effects of peptide fragments sequentially derived from the antimicrobial peptide centrocin 1 isolated from the green sea urchin, Strongylocentrotus droebachiensis

Bacterial resistance against antibiotic treatment has become a major threat to public health. Antimicrobial peptides (AMPs) have emerged as promising alternative agents for treatment of infectious diseases. This study characterizes novel synthetic peptides sequentially derived from the AMP centrocin 1, isolated from the green sea urchin, for their applicability as anti-infective agents.The microbicidal effect of centrocin 1 heavy chain (CEN1 HC-Br), its debrominated analogue (CEN1 HC), the C-terminal truncated variants of both peptides, i.e. CEN1 HC-Br (1--20) and CEN1 HC (1--20), as well as the cysteine to serine substituted equivalent CEN1 HC (Ser) was evaluated using minimal microbicidal concentration assay. The anti-inflammatory properties were assessed by measuring the inhibition of secretion of pro-inflammatory cytokines. All the peptides tested exhibited marked microbicidal and anti-inflammatory properties. No difference in efficacy was seen comparing CEN1 HC-Br and CEN1 HC, while the brominated variant had higher cytotoxicity. C-terminal truncation of both peptides reduced salt-tolerability of the microbicidal effect as well as anti-inflammatory actions. Also, serine substitution of cysteine residue decreased the microbicidal effect. Thus, from the peptide variants tested, CEN1 HC showed the best efficacy and safety profile. Further, CEN1 HC significantly reduced bacterial counts in two different animal models of infected wounds, while Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) failed to develop resistance against this peptide under continued selection pressure. In summary, CEN1 HC appears a promising new antimicrobial agent, and clinical studies are warranted to evaluate the applicability of this AMP for local treatment of infections in man

Opposite transcriptional regulation in skeletal muscle of AMP-activated protein kinase gamma3 R225Q transgenic versus knock-out mice

AMP-activated protein kinase (AMPK) is an evolutionarily conserved heterotrimer important for metabolic sensing in all eukaryotes. The muscle-specific isoform of the regulatory gamma-subunit of the kinase, AMPK gamma3, has an important role in glucose uptake, glycogen synthesis, and fat oxidation in white skeletal muscle, as previously demonstrated by physiological characterization of AMPK gamma3 mutant (R225Q) transgenic (TgPrkag3(225Q)) and gamma3 knock-out (Prkag3(-/-)) mice. We determined AMPK gamma3-dependent regulation of gene expression by analyzing global transcription profiles in glycolytic skeletal muscle from gamma3 mutant transgenic and knock-out mice using oligonucleotide microarray technology. Evidence is provided for coordinated and reciprocal regulation of multiple key components in glucose and fat metabolism, as well as skeletal muscle ergogenics in TgPrkag3(225Q) and Prkag3(-/-) mice. The differential gene expression profile was consistent with the physiological differences between the models, providing a molecular mechanism for the observed phenotype. The striking pattern of opposing transcriptional changes between TgPrkag3(225Q) and Prkag3(-/-) mice identifies differentially expressed targets being truly regulated by AMPK and is consistent with the view that R225Q is an activating mutation, in terms of its downstream effects. Additionally, we identified a wide array of novel targets and regulatory pathways for AMPK in skeletal muscle