La creación y el uso del cuerpo-maquina en las primeras dos décadas del regimen comunista en Bulgaria

The paper analyses the communist treatment of labour in Bulgaria in the first two decades after the establishment of the socialist rule. It examines the figure of the worker as an ideal type of communist person. The article also studies the communist negation of idleness and the relation between idleness, sexual corruption and moral disgrace. The main emphasis is laid on the conceptualization of idleness in terms of anti-communist resistance. Also the concept of “body machine” is introduced to reveal some aspects of this extremely high valuation of labour on the one hand, and of the neglect of pleasure on the other hand. Key-words: discipline, body machine, communist bio-politics, labour camps.En el artículo se analiza el trato del trabajo en las dos primeras décadas después del establecimiento de un Estado comunista en Bulgaria. Se examina la figura del trabajador como modelo de persona comunista. También se estudia la negación de la ociosidad así como la relación entre la ociosidad, la corrupción sexual y la desgracia moral. El énfasis principal está puesto en la conceptualización de la ociosidad en términos de resistencia anticomunista. El concepto de “cuerpomaquina” se introduce para revelar algunos aspectos de esta extremadamente alta valoración del trabajo, por un lado, y de la negligencia del placer por otro lado

Dihydroorotate dehydrogenase : new insights into an old target

Purine and pyrimidine nucleotides are important for both biosynthetic and regulatory pathways in cells. As constituents of the DNA and RNA molecules, the requirements for nucleotides in actively dividing cells are increased. Therefore, the enzymes from the purine and pyrimidine nucleotide synthesis pathways are considered attractive targets for treatment of diseases associated with deregulated cell proliferation, such as cancer. Dihydroorotate dehydrogenase (DHODH), an enzyme from the de novo pyrimidine ribonucleotide synthesis pathway located on the inner mitochondrial membrane, has been intensively studied in the past few years as a target for anti-cancer therapy. As a result, several inhibitors of DHODH are currently in clinical trials for treatment of myeloid malignancies. In a screen for p53 activators, we discovered a novel class of DHODH inhibitors with a tetrahydroindazole core structure (Paper I). The hit compound from the screen, the chiral compound named HZ00, increased p53 translation without increasing p53 mRNA levels or the stability of the protein. Furthermore, treatment with HZ00 accumulated cancer cells in the S-phase of the cell cycle while it led to cell cycle arrest in normal fibroblasts. After screening of commercially available HZ analogues, we discovered the more potent compound HZ05. The active enantiomer of the chiral HZ compound was the (R)-enantiomer, confirmed by the co-crystallization of DHODH with HZ05 where only (R)-HZ05 was bound to the quinone tunnel of DHODH (membrane binding domain). Additionally, both compounds acted synergistically with the MDM2 inhibitor nutlin-3 (which protects p53 from degradation) in different tumor cell lines and in a melanoma xenograft model. Following the discovery of the HZ compounds as inhibitors of DHODH, we investigated the structure and function of DHODH using mass spectrometry and molecular dynamics simulations (Paper II) and afterwards optimized the HZ compounds in a structure activity relationship study (SAR, Paper III). Using non-denaturing mass spectrometry, we established that the interactions between DHODH and its co-factor FMN, the lipids present in the mitochondrial membrane, as well as ligands such as the DHODH inhibitor brequinar, have stabilizing effect on the protein. Furthermore, molecular dynamic stimulations demonstrated the flexibility of the membrane binding domain and the transmembrane helix. We also illustrated that the lipid interactions that stabilize the membrane binding domain may affect the binding of longer ligands, which is important for the design of new inhibitors. The optimization of the HZ-compounds was based on a metabolic soft spot study and the crystal structure of DHODH with (R)-HZ05 obtained in Paper I. The activity of many of the new HZ inhibitors was improved in the in vitro enzymatic assay as well as in cellular assays using a melanoma cell line. Based on in vitro metabolic stability analysis we identified a lead compound in the series, which demonstrated high specificity towards DHODH. The new active HZ-analogues were also able to trigger p53 transcription factor function and affected the cell growth/viability of a melanoma cell line with only a small effect on a normal fibroblast, suggesting a reasonably wide therapeutic window. Supplementation with an excess of uridine ameliorated both, the activation of p53 by the HZ compounds and their effect on cell growth/viability. Under our experimental conditions, the new HZ analogues did not activate DNA damage markers. Additionally, we demonstrated that the ability of DHODH inhibitors to induce apoptosis related g-H2AX was prevented by co-treatment with the pan-caspase inhibitor Z-VAD-FMK. Due to the re-emerging interest in DHODH as a drug target, we investigated the early events triggered after inhibition of this enzyme (Paper IV). For that purpose, we performed RNA sequencing analysis of cells treated with two DHODH inhibitors for up to 4 h. One of the earliest significant changes was the fast downregulation of PNUTS mRNA. This event was observed at the protein level as well. The PNUTS decrease was accompanied by an increase of p53 protein, although the correlation between the two changes requires further investigation. Nevertheless, due to the early decrease in PNUTS we propose that the downregulation of PNUTS mRNA may be a marker for DHODH inhibition

Volitional mood in South Slavic with a focus on Bulgarian: a paradigmatic view

In this paper we survey some of the inflected and periphrastic volitional mood paradigms in South Slavic with a focus on Bulgarian data. Our review confirms typological observations in the literature that volitional mood paradigms tend to ‘fracture’, in that the cross-categorisation with different person/number features leads to systematic associations with different meanings and, typologically, frequent associations with different forms. This makes it difficult to argue that non-existent inflected forms are gaps in the inflected paradigm. Because of this periphrastic volitional mood forms that exist alongside inflected forms have to be seen as independent (syntactic) paradigms, rather than forms that fill missing cells in inflected paradigms, i.e. the product of feature intersection. Like more canonical periphrases, however, syntactic volitional mood forms are non-compositional and exhibit an organisation akin to the content-form paradigm organisation of inflected paradigms developed in certain inferentialrealizational approaches to morphology. Following some recent formalisations, we suggest a tentative analysis of the most productive periphrastic volitional mood forms in Bulgarian based on the assumption that their properties are constrained partially by the morphology and partially in the syntax

Constructions, grammatical status and morphologization

This paper critically explores the question of what it means for a construction to be grammatical. The paper engages with some of the observations made in the grammaticalisation literature that elements in grammatical constructions undergo morphologization, and aims to show that grammatical status and morphologization need not be aligned. A number of parameters along which the grammatical status of a multiword expressions can vary are proposed and data illustrating different aspects of these parameters are discussed in detail. The data are used to argue that grammatical status is complex and multifaceted and linked not only to the formal properties of a construction, but also to its semantics and the relationship it has with other grammatical forms (e.g. inflected forms) in a given language

Bulgarian Evidential Forms and Wierzbicka’s NSM

Our focus in this paper is on the semantics of a particular grammatical category of Bulgarian, namely evidentiality. Our starting point is the account of evidentiality in Macedonian and Bulgarian in Wierzbicka (in Semantics: Primes and Universals. Oxford: 1996). We elaborate and expand on this proposal by suggesting semantic formulae for the renarrative, dubitative, inferential, and mirative forms, incorporating Wierzbicka’s universal semantic primitives know and think. Our aim is to provide a stepping stone towards precise intra- and inter-linguistic comparisons

English Compounds with ing-form heads

This paper investigates the properties of compounds with right-hand elements that have the form of present-participles, i.e. ing-forms. After a survey of the recent literature on argumental relations in compounds in which the ing-form is an event nominalisation, the paper looks at compounds embedded before another noun. Evidence from attested patterns is used to argue that argumental relations in such sequences can be explained via the embedding of different constructions