Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC50 = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography.
- MeSH
- HIV infekce * farmakoterapie MeSH
- HIV reverzní transkriptasa metabolismus MeSH
- HIV-1 * metabolismus MeSH
- inhibitory reverzní transkriptasy MeSH
- látky proti HIV * chemie MeSH
- lidé MeSH
- racionální návrh léčiv MeSH
- rilpivirin terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Hybrid sterility contributes to speciation by preventing gene flow between related taxa. Prdm9, the first and only hybrid male sterility gene known in vertebrates, predetermines the sites of recombination between homologous chromosomes and their synapsis in early meiotic prophase. The asymmetric binding of PRDM9 to heterosubspecific homologs of Mus musculus musculus × Mus musculus domesticus F1 hybrids and increase of PRDM9-independent DNA double-strand break hotspots results indificult- to- repair double-strand breaks, incomplete synapsis of homologous chromosomes, and meiotic arrest at the first meiotic prophase. Here, we show that Prdm9 behaves as a major hybrid male sterility gene in mice outside the Mus musculus musculus × Mus musculus domesticus F1 hybrids, in the genomes composed of Mus musculus castaneus and Mus musculus musculus chromosomes segregating on the Mus musculus domesticus background. The Prdm9cst/dom2 (castaneus/domesticus) allelic combination secures meiotic synapsis, testes weight, and sperm count within physiological limits, while the Prdm9msc1/dom2 (musculus/domesticus) males show a range of fertility impairment. Out of 5 quantitative trait loci contributing to the Prdm9msc1/dom2-related infertility, 4 control either meiotic synapsis or fertility phenotypes and 1 controls both, synapsis, and fertility. Whole-genome genotyping of individual chromosomes showed preferential involvement of nonrecombinant musculus chromosomes in asynapsis in accordance with the chromosomal character of hybrid male sterility. Moreover, we show that the overall asynapsis rate can be estimated solely from the genotype of individual males by scoring the effect of nonrecombinant musculus chromosomes. Prdm9-controlled hybrid male sterility represents an example of genetic architecture of hybrid male sterility consisting of genic and chromosomal components.
- MeSH
- chromozomy MeSH
- histonlysin-N-methyltransferasa genetika metabolismus MeSH
- meióza * genetika MeSH
- mužská infertilita * genetika MeSH
- myši MeSH
- sperma metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Článek se zabývá vznikem, vývojem a současnou pozicí interdisciplinárního vědního podoboru pedagogika sportu. V rámci toho se autoři zaměřují především na historický vývoj podoboru, kdy konstatují, že pedagogika sportu je úzce spjata s osobou P. de Coubertina a myšlenkou olympismu, resp. olympijské výchovy. Článek rovněž ukazuje na řazení pedagogiky sportu do současného systému vědních oborů a vyzdvihuje její, nejen aktuální společenský význam. Součástí práce je i komparace pojetí pedagogiky sportu v České republice a v zahraniční. Cíle práce se orientují na deskripci vzniku a vývoje pedagogiky sportu, ale i na analýzu jejího stávajícího významu v České republice. Metodologické zázemí tvoří obsahová analýza relevantních dokumentů, text je zpracován převážně diachronním postupem. Autoři dochází k závěru, že pedagogika sportu je v současné době předmětem vysoce potřebným, a to jak z širšího společenského hlediska (návaznost na odkaz P. de Coubertina), tak také z praktického hlediska možnosti přípravy budoucích učitelů školní tělesné výchovy, trenérů aj., tomu však neodpovídá její zařazení do kurikula některých významných vzdělávacích institucí.
The paper deals with a formation, a development and a current position of an interdisciplinary scientific subdicipline Pedagogy of Sport. Within above mentioned facts, authors focuse mainly on a historical development of the subdiscipline when they find that Pedagogy of Sport is tightly connected with P. de Coubertin and the idea of Olympism. The paper also works with a placement of Pedagogy of Sport into a current system of scientific disciplines and emphasized its social importance. The paper also includes a comparation of approaches to Pedagogy of Sport in foreign countries. Goals of the paper are oriented on a description of an origin and a development of Pedagogy of Sport and also on an analysis of its importance in Czech Republic. Methodological background is formed by the content analysis of relevant documents. The text is processed mainly by a diachronical procedure. Authors find that Pedagogy of Sport is in current times highly needed scientific subdicipline from a wide social point of view (a continuity of Coubertin ideas) as well as from a practical point of view (preparation of future physical education teachers). Unfortunately, this importance is not always reflected in an inclusion of Pedagogy of Sport into the curriculum of important educational institutions.
- Klíčová slova
- olympijské hry,
- MeSH
- dějiny 19. století MeSH
- dějiny 20. století MeSH
- lidé MeSH
- sporty * dějiny výchova MeSH
- vyučování MeSH
- Check Tag
- dějiny 19. století MeSH
- dějiny 20. století MeSH
- lidé MeSH
- Publikační typ
- historické články MeSH
- O autorovi
- Coubertin, Pierre de
Příspěvek se zabývá dalším vzděláváním trenérů individuálních a týmových sportů ve vztahu ke skutečnosti, zda trenérskou činnost vykonávají jako svoji hlavní ekonomickou aktivitu, vedlejší ekonomickou aktivitu či dobrovolnou činnost bez nároku na finanční odměnu. Cílem práce bylo zjistit přístup trenérů k vlastnímu vzdělávání. Hlavní výzkumnou metodou byl dotazník Svobody (1998), v upravené verzi. Získaná data byla zpracována pomocí deskriptivní statistiky, konkrétně kontingenčních tabulek, dále byl využito chí-kvadrát testu, vše pomocí programu NCSS (verze 6.0.21). Našeho šetření se zúčastnilo celkem 511respondentů (z toho bylo 311 mužů a 200 žen) z řad trenérů různých kvalifikačních stupňů. Výběr souboru proběhl záměrným způsobem, kdy byli osloveni frekventanti kurzů trenérských licencí na FTVS UK. Zatímco ke vzdělávání směřujícímu k získání nějakého druhu trenérské licence mají trenéři obecně kladný postoj, zcela odlišně přistupují k vzdělávání mimo obor své trenérské činnosti. Snaha získat trenérskou licenci, resp. stupeň licence, je zřetelně spjata s ekonomickým charakterem trenérské činnosti. Z hlediska rozdílů mezi individuálními a týmovými sporty je rozdíl zejména v oblasti dalšího,nelicenčního zvyšování trenérské odbornosti, a to opět ve vztahu k ekonomickému charakteru činnosti trenéra.
The paper occupies with further education of coaches of individual and team sports with the respect tothe fact, whether coaches carry out their activity as main economic activity, partial economic activityor if they are volunteers (without any right to a salary). The goal of the paper was to investigate theapproach of coaches to their education.As the main research method, we use a questionnaire from Svoboda (1998), which was adjustedwith the respect to current social conditions. The data were processed by using a descriptive statis-tics, namely crossed tables, further we use a chi-square test. All data were processed by statisticalprogramme NCSS (version 6.0.21). The research sample contains 511 coaches with different levels oftraining licence (311 men and 200 women). Respondents were choosed by an intentional selection andresearch sample consists from attenders of coaching licence education in FTVS UK.On one hand, coaches have generally positive attitude to taking part in coaching licence education,one the other hand their attitude to education which is not joined with coaching is prevailinglynegative. Their effort to gain a coaching licence is apparently connected with an economic characterof coaching acitivity. If we assess differences between individual sports and team sports, we can seethem mainly in the area of further proffesional education (but not namely coaching licence), againwith the connection to an economic character of coaching acitivity.We can conclude that sport coaches have a very different approach to different kinds of theireducation and the obvious agent is mainly formalism.
- MeSH
- kontinuální vzdělávání MeSH
- lidé MeSH
- sporty MeSH
- tělesná výchova MeSH
- vzdělávání odborné * MeSH
- Check Tag
- lidé MeSH
F1 hybrids between mouse inbred strains PWD and C57BL/6 represent the most thoroughly genetically defined model of hybrid sterility in vertebrates. Hybrid male sterility can be fully reconstituted from three components of this model, the Prdm9 gene, intersubspecific homeology of Mus musculus musculus and Mus musculus domesticus autosomes, and the X-linked Hstx2 locus. Hstx2 modulates the extent of Prdm9-dependent meiotic arrest and harbors two additional factors responsible for intersubspecific introgression-induced oligospermia (Hstx1) and meiotic recombination rate (Meir1). To facilitate positional cloning and to overcome the recombination suppression within the 4.3 Mb encompassing the Hstx2 locus, we designed Hstx2-CRISPR and SPO11/Cas9 transgenes aimed to induce DNA double-strand breaks specifically within the Hstx2 locus. The resulting recombinant reduced the Hstx2 locus to 2.70 Mb (chromosome X: 66.51-69.21 Mb). The newly defined Hstx2 locus still operates as the major X-linked factor of the F1 hybrid sterility, and controls meiotic chromosome synapsis and meiotic recombination rate. Despite extensive further crosses, the 2.70 Mb Hstx2 interval behaved as a recombination cold spot with reduced PRDM9-mediated H3K4me3 hotspots and absence of DMC1-defined DNA double-strand-break hotspots. To search for structural anomalies as a possible cause of recombination suppression, we used optical mapping and observed high incidence of subspecies-specific structural variants along the X chromosome, with a striking copy number polymorphism of the microRNA Mir465 cluster. This observation together with the absence of a strong sterility phenotype in Fmr1 neighbor (Fmr1nb) null mutants support the role of microRNA as a likely candidate for Hstx2.
- MeSH
- chromozom X genetika MeSH
- histonlysin-N-methyltransferasa genetika MeSH
- homologní rekombinace MeSH
- meióza MeSH
- mikro RNA genetika MeSH
- modifikátorové geny * MeSH
- mužská infertilita genetika MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- polymorfismus genetický * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Orderly segregation of chromosomes during meiosis requires that crossovers form between homologous chromosomes by recombination. Programmed DNA double-strand breaks (DSBs) initiate meiotic recombination. We identify ANKRD31 as a key component of complexes of DSB-promoting proteins that assemble on meiotic chromosome axes. Genome-wide, ANKRD31 deficiency causes delayed recombination initiation. In addition, loss of ANKRD31 alters DSB distribution because of reduced selectivity for sites that normally attract DSBs. Strikingly, ANKRD31 deficiency also abolishes uniquely high rates of recombination that normally characterize pseudoautosomal regions (PARs) of X and Y chromosomes. Consequently, sex chromosomes do not form crossovers, leading to chromosome segregation failure in ANKRD31-deficient spermatocytes. These defects co-occur with a genome-wide delay in assembling DSB-promoting proteins on autosome axes and loss of a specialized PAR-axis domain that is highly enriched for DSB-promoting proteins in wild type. Thus, we propose a model for spatiotemporal patterning of recombination by ANKRD31-dependent control of axis-associated DSB-promoting proteins.
- MeSH
- chromozom X genetika MeSH
- chromozom Y genetika MeSH
- dvouřetězcové zlomy DNA * MeSH
- homologní rekombinace genetika MeSH
- meióza genetika MeSH
- myši MeSH
- pseudoautozomální oblasti genetika MeSH
- segregace chromozomů genetika MeSH
- spermatocyty růst a vývoj metabolismus MeSH
- transportní proteiny chemie genetika MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o, o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o, o-difluoro- p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.
- Publikační typ
- časopisecké články MeSH
V článku uvádíme posouzení stavu denního režimu a životosprávy učitelů středních škol (bez aprobace z tělesné výchovy), dále pak některé jejich názory a postoje na pohybové aktivity a sport, které jsme získali dotazníkovou metodou. Respondenti působili v době šetření, tedy ve školním roce 2016/2017 na různých typech škol (gym-názia, střední odborné školy a střední odborná učiliště s maturitou). Výsledky prezentujeme především podle pohlaví, kdy celkový počet respondentů činil 709 osob (309 mužů a 400 žen).Za pozitivní zjištění považujeme, že většina učitelů podporuje přiměřené pohybové aktivity a sport a pravidelně se stravuje, za negativní pak, že se přibližná třetina dotazovaných učitelů při své práci potýká s každodenním stresem a ti, kteří jsou kuřáci, zpravidla také pravidelně pijí alkohol. Podrobnější informace uvádíme v textu.
In paper we mention the evaluation of a daily regime and regimen of secondary school teachers' (without PE teaching qualification), further their opinions and attitudes towards motion activities and sport. The data were gained by a method of questionnaire.Within the time of survey (school year 2016/2017) interviewed teachers were employed in different types of secondary school (grammar school and vocational school with GCSE exam). The results we present from the viewpoint of gender. The number of repondents was 709 individuals (309 men and 400 women).We consider as a positive findings that majority of teachers supports adequate motion activities and sport and takes their meals regularly. The negative findnings are that aproximately one third of research sample get stressed because of their work daily and those who are smokers regularly drink alcohol as a rule. More detailed informations we present in the text of our paper.
A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 μm in HEK293 cell-based assays.
- MeSH
- adenin analogy a deriváty chemická syntéza chemie farmakologie MeSH
- adenylátcyklasy metabolismus MeSH
- Bacillus anthracis enzymologie MeSH
- Bordetella pertussis enzymologie MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- organofosfonáty chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
As a part of a broader structure-activity relationship study of substituted 2-aminopyrimidines, the influence of the C-5 substitution on inhibition of prostaglandin E2 (PGE2) production was studied. Thirty compounds were prepared starting from the corresponding 2-amino-4,6-dichloropyrimidines using Suzuki cross-coupling. It was shown previously that 2-amino-4,6-dichloropyrimidines with smaller C-5 substituent (hydrogen and methyl) were devoid of significant activity, while 5-butyl derivatives exhibited prominent potency. In this study, on the other hand, both monoaryl- and bisarylpyrimidines were potent inhibitors of PGE2 production regardless the length of the C-5 substituent (hydrogen, methyl, n-butyl). Moreover, the shorter the C-5 substituent the higher potency to inhibit PGE2 production was observed. 2-Amino-4,6-diphenylpyrimidine was the best inhibitor of PGE2 production with IC50 = 3 nM and no cytotoxicity. The most potent inhibitors deserve further preclinical evaluation as potential anti-inflammatory agents.
- MeSH
- antiflogistika nesteroidní chemická syntéza chemie farmakologie MeSH
- biosyntetické dráhy účinky léků MeSH
- dinoproston antagonisté a inhibitory metabolismus MeSH
- kultivované buňky MeSH
- myši inbrední C57BL MeSH
- pyrimidiny chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
