Негативна утопія в рецепції німецького літературознавства (NEGATIVE UTOPIA IN RECEPTION OF THE GERMAN LITERARY CRITICISM)

Стаття присвячена вивченню негативної утопії в німецькому літературознавстві. Розглядаються концепції «чорної утопії» Р. Зааґе, дослідження повоєнної антиутопічної літератури Й. Ябвковської, наукові розвідки Г. У. Зеебера, А. Гайєра, Ш. Майєра та ін. Прослідковуються причини появи негативної утопії та її бурхливого розвитку у ХХ столітті. Приділяється увага термінологічним проблемам, зокрема питанню диференціації понять «антиутопія» та «дистопія». Аналізуються структурні ознаки, тематичні та мотивні зміни жанру. (The article deals with the anti-utopian genre. It is based upon the scientific researches of the German literary critics. The conception of the R. Saage’s «black utopia», J. Jabłkowska’s investigations of the post-war anti-utopian literature, scientific studies of H.U. Seeber, A. Heyer, S. Meyer and other. There are retraced reasons of the appearance of negative utopia. There are several grounds of its tremendous up growth in XX century such as critic of human progress based only on scientific and technological advance, inability to bear responsibility for new capabilities, word war, Russian revolution and socialism. The objects of the study are also terminological problems, particularly the differentiation of the concepts of «anti-utopia» and «dystopia». Anti-utopia is directed intentionally against utopia, it denies utopian thought fundamentally. Dystopia is the opposite of utopia, depicting fictional societies in which the living is bad and imperfect caused by human misery, poverty, tyranny and terrorism. Creators of dystopian fictions explore worst possible scenario, highlighting sense of fear in order to show that a perfect society is not possible. Structural elements, thematical and motif changes of the time of stage are examined in the paper. Early negative utopias derided the impossibility of the utopian visions, the modern dystopias critic internal conflicts of utopia realization.

Motivation as a factor that affects astivity of the staff

Background Cisplatin is used for treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) but treatment with cisplatin often leads to acquired resistance to cisplatin, resulting in poor patient survival. Globotriaosylceramide (Gb3) and multidrug resistance protein 1 (MDR1) have been associated with cisplatin resistance. Gb3 serves as a receptor for verotoxin-1 (VT-1), which induces apoptosis, and has been shown to have a functional dependency to MDR1 and heat shock protein 70 (HSP7o). The Bcl-2 family of proteins and inhibitors of apoptosis (IAPs) are key regulators of apoptosis. BH3-mimetics mimic pro-apoptotic BH3-only proteins, while Smac mimetics mimic the IAP-binding protein Smac/Diablo. These drugs have shown great promise in reversing cisplatin resistance. Exosomes are small bio-nanoparticles secreted and taken up by both cancer cells and normal cells. They have the ability to transfer properties between cells and have been shown to confer resistance to cisplatin. Methods In this thesis, NSCLC cell line H1299 and MPM cell line P31 were studied using western blot, flow cytometry, proteome profilers, confocal microscopy and gene expression arrays to investigate changes in protein and gene expression after acquisition of cisplatin resistance (P31res and H1299res) or after incubation with exosomes or drugs that target these. The cytotoxic and apoptotic effects were studied using fluorometric cytotoxicity assay (FMCA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results This thesis confirms that Gb3 is a potential target for cisplatin resistance reversal. Incubation with glycosphingolipid production inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) and VT-1 led to reduced Gb3 cell surface expression and increased cytotoxic effect of cisplatin in all cell lines. Gb3 and MDR1 was not co-localized in any studied cell line, but Gb3 and HSP70 were co-localized on the cell surface and PPMP and VT-1 led to a decrease of both Gb3 and HSP70. Both BH3-mimetic obatoclax and Smac mimetic AT-406 had an additive effect on cisplatin-induced cytotoxicity and apoptosis in P31 and a synergistic effect in P31res. Results indicate that exosomes from cisplatin-resistant cell lines can transfer HSP70 to the surface of cells. Conclusion Cell surface Gb3 and HSP70, the Bcl-2/IAP-family proteins and exosomal transfer of cisplatin resistance characteristics are potential targets in combatting cisplatin resistance that show therapeutic promise and warrant further research

Structural Insights into the Incorporation of the Mo Cofactor into Sulfite Oxidase from Site-Directed Spin Labeling

Mononuclear molybdoenzymes catalyze a broad range of redox reactions and are highly conserved in all kingdoms of life. This study addresses the question of how the Mo cofactor (Moco) is incorporated into the apo form of human sulfite oxidase (hSO) by using site-directed spin labeling to determine intramolecular distances in the nanometer range. Comparative measurements of the holo and apo forms of hSO enabled the localization of the corresponding structural changes, which are localized to a short loop (residues 263–273) of the Moco-containing domain. A flap-like movement of the loop provides access to the Moco binding- pocket in the apo form of the protein and explains the earlier studies on the in vitro reconstitution of apo-hSO with Moco. Remarkably, the loop motif can be found in a variety of structurally similar molybdoenzymes among various organisms, thus suggesting a common mechanism of Moco incorporation

Comparison of the functional properties of trimeric and monomeric CaiT of Escherichia coli

Secondary transporters exist as monomers, dimers or higher state oligomers. The significance of the oligomeric state is only partially understood. Here, the significance of the trimeric state of the L-carnitine/gamma-butyrobetaine antiporter CaiT of Escherichia coli was investigated. Amino acids important for trimer stability were identified and experimentally verified. Among others, CaiT-D288A and -D288R proved to be mostly monomeric in detergent solution and after reconstitution into proteoliposomes, as shown by blue native gel electrophoresis, gel filtration, and determination of intermolecular distances. CaiT-D288A was fully functional with kinetic parameters similar to the trimeric wild-type. Significant differences in amount and stability in the cell membrane between monomeric and trimeric CaiT were not observed. Contrary to trimeric CaiT, addition of substrate had no or only a minor effect on the tryptophan fluorescence of monomeric CaiT. The results suggest that physical contacts between protomers are important for the substrate-induced changes in protein fluorescence and the underlying conformational alterations

Modelling multi-protein complexes using PELDOR distance measurements for rigid body minimisation experiments using XPLOR-NIH

Crystallographic and NMR approaches have provided a wealth of structural information about protein domains. However, often these domains are found as components of larger multi domain polypeptides or complexes. Orienting domains within such contexts can provide powerful new insight into their function. The combination of site specific spin labelling and Pulsed Electron Double Resonance (PELDOR) provide a means of obtaining structural measurements that can be used to generate models describing how such domains are oriented. Here we describe a pipeline for modelling the location of thio-reactive nitroxyl spin locations to engineered sties on the histone chaperone Vps75. We then use a combination of experimentally determined measurements and symmetry constraints to model the orientation in which homodimers of Vps75 associate to form homotetramers using the XPLOR-NIH platform. This provides a working example of how PELDOR measurements can be used to generate a structural model

Синдром втомлюваності після перенесеної вірусної хвороби. Постковідна екзантема інфікована. Іхтіоз шкіри ніг. (Клінічний випадок)

Пандемія COVID-19 поставила багато викликів перед медичною спільнотою, низка з яких залишиться і в найближчому майбутньому. Аналіз клінічних випадків допомагає визначати проблеми, планувати майбутні дослідження, що може змінити розуміння наслідків хвороби. У міру віддалення від першого року цієї пандемії з’являється краще розуміння патофізіології вірусу та різноманітних результатів візуалізації COVID-19 в уражених органах, що має вирішальне значення для покращення лікування цієї складної хвороби та поліпшення здоров’я. Описано клінічний випадок екзантеми в пацієнта 11-річного віку після перенесеного COVID-19. Застосовано клінічні та імунологічні методи дослідження. Стан дитини був середньої тяжкості, обумовлений шкірним і астено-вегетативним синдромами. Дитині встановлено діагноз COVID-19; синдром втомлюваності після перенесеної вірусної хвороби; постковідну екзантему інфіковану; іхтіоз шкіри ніг. Особливість наведеного випадку полягає у виникненні екзантеми на шкірі в дитини після перенесеного COVID-19. У таких випадках слід підвищувати обізнаність лікарів-педіатрів для підвищення рівня знань про правильний діагностичний алгоритм. Дослідження виконано відповідно до принципів Гельсінської декларації. На проведення досліджень отримано інформовану згоду батьків дитини. Автори заявляють про відсутність конфлікту інтересів

Accurate extraction of nanometer distances in multimers by pulse EPR

B.E.B. is grateful for funding from the European Union (REA 334496). This work was supported by the EPSRC (EP/M024660/1), the Wellcome Trust [099149/Z/12/Z], and the Royal Society (RG140723).Pulse electron paramagnetic resonance (EPR) is gaining increasing importance in structural biology. The PELDOR (pulsed electron-electron double resonance) method allows extracting distance information on the nanometer scale. Here, we demonstrate the efficient extraction of distances from multimeric systems such as membrane embedded ion channels where data analysis is commonly hindered by multi-spin effects.Publisher PDFPeer reviewe

Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications

ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented