1,721,052 research outputs found
Prediction of endocrine activity of colours permitted to use in comsetic products with in silico method
No full textDynamical model of a type II DNA topoisomerase and in silico design of novel catalytic inhibitors as potential chemotherapeutics
No full textDNA topoizomeraze tipa II so biološki molekulski motorji, ki katalizirajo topološke spremembe v molekuli DNA in so pomembne tarče protirakavih zdravil. S pomočjo molekulskih simulacij in eksperimentalnih podatkov smo razvili dinamičen model različnih konfiguracij topoizomeraze IIA v njenem katalitičnem ciklu. Simulacije so pokazale, da sta rotacijsko gibanje dimera in drsno gibanje znotraj DNA-vrat inherentni dinamični lastnosti encima. Ugotovili smo tudi, da ATP ključno prispeva k stabilizaciji T-segmenta, saj hidroliza ATP povečuje konformacijsko aktivnost N-vrat.
Načrtovali smo katalitične zaviralce človeške topoizomeraze II?, ki ciljajo na vezavno mesto za ATP, da bi obšli omejitve obstoječih topoizomeraznih strupov, ki se uporabljajo v kemoterapiji. Z uporabo molekulskih simulacij in umetne inteligence smo optimizirali zaviralce iz skupine 4,6-substituiranih-1,3,5-triazin-2(1H)-onov, pri čemer so uvedeni biciklični substituenti na mestu 6 ohranili zaviralno aktivnost in nekoliko izboljšali fizikalno-kemijske lastnosti spojin. Razvili smo tudi novo metodo načrtovanja učinkovin s pomočjo dinamičnih farmakofornih modelov. Za validacijo metode smo uporabili vezavno mesto za ATP človeške DNA topoizomeraze II? ter odkrili nove katalitične zaviralce naravnega izvora. Z uporabo tako razvitega farmakofornega modela smo odkrili substituirane 3-(imidazol-2-il) morfoline, ki selektivno zavirajo topoizomerazo II? in se vežejo na ATPazno domeno. Te spojine so tudi citotoksične preko mehanizma, ki je drugačen kot pri topoizomeraznih strupih.Type II DNA topoisomerases are biological molecular motors that catalyze topological changes in DNA molecules and are considered important targets for anticancer drugs. Using molecular simulations and experimental data, we developed a dynamic model of various configurations of topoisomerase IIA in its catalytic cycle. The simulations revealed that both the rotational movement of the dimer and the sliding motion within the DNA gates are inherent dynamic properties of the enzyme. Furthermore, ATP could play a crucial role in the stabilization of the T-segment, as ATP hydrolysis increased the conformational activity of the N-gate.
To overcome the limitations of current topoisomerase poisons used in chemotherapy catalytic inhibitors of human topoisomerase IIα that target the ATP binding site were developed. By utilizing molecular simulations and artificial intelligence, we optimized inhibitors from the group of 4,6-substituted-1,3,5-triazine-2(1H)-ones, where the introduced bicyclic substituents at position 6 maintained inhibitory activity and somewhat improved the physicochemical properties of the compounds. In addition, a novel approach for designing compounds was developed using dynamic pharmacophore models. To validate this method, the ATP binding site of human DNA topoisomerase IIα was examined, and new catalytic inhibitors of natural origin were identified. The derived pharmacophore model was then used to identify a class of substituted 3-(imidazol-2-yl) morpholines which selectively inhibit topoisomerase IIα and bind to its ATPase domain. These compounds also exhibit cytotoxic properties through a mechanism that is different from that of topoisomerase poisons
Dictionary of New Slovenian Words - SNB (ELEXIS)
No full textSlovar novejšega besedja slovenskega jezika.
Dictionary of New Slovenian Words represents a basic new lexical supplement to the Slovar slovenskega knjižnega jezika (Dictionary of the Slovenian Standard Language). It contains 6399 new words and phrases that appeared in Slovenian or gained ground after 1991 as well as new meanings of previously standardised lexis. Two important new features of the dictionary are a corpus-driven analysis of new words that are in actual language use and etymological explanations of the included words.
See also: http://hdl.handle.net/11356/1091
This dictionary was published as a printed book:
Bizjak Končar, Aleksandra, Snoj, Marko, Gložančev, Alenka, Kern, Boris, Kostanjevec, Polona, Krvina, Domen, Ledinek, Nina, Michelizza, Mija, Perdih, Andrej, Petric, Špela, Šircelj-Žnidaršič, Ivanka, Žele, Andreja, Mirtič, Tanja, Gliha Komac, Nataša, Klemenčič, Simona. Slovar novejšega besedja slovenskega jezika. Ljubljana : Založba ZRC, ZRC SAZU, 2012
Application of molecular modeling methods in design and optimization of inhibitors of the human DNA topoisomerase II[alpha]
No full textDictionary of New Slovenian Words
No full textSlovar novejšega besedja slovenskega jezika (Dictionary of New Slovenian Words) represents a basic new lexical supplement to the Slovar slovenskega knjižnega jezika (Dictionary of the Slovenian Standard Language). It contains 6399 new words and phrases that appeared in Slovenian or gained ground after 1991 as well as new meanings of previously standardised lexis. Two important new features of the dictionary are a corpus-driven analysis of new words that are in actual language use and etymological explanations of the included words.
This dictionary was published as a printed book:
Bizjak Končar, Aleksandra, Snoj, Marko, Gložančev, Alenka, Kern, Boris, Kostanjevec, Polona, Krvina, Domen, Ledinek, Nina, Michelizza, Mija, Perdih, Andrej, Petric, Špela, Šircelj-Žnidaršič, Ivanka, Žele, Andreja, Mirtič, Tanja, Gliha Komac, Nataša, Klemenčič, Simona. Slovar novejšega besedja slovenskega jezika. Ljubljana : Založba ZRC, ZRC SAZU, 2012. ISBN 978-961-254-413-3
Design and optimization of catalytic inhibitors of the human DNA topoisomerase IIα as potential anticancer agents
No full textDNA topoisomerases are a diverse family of enzymes, that work as molecular motors and enable topological changes of the DNA molecule. While there are several subgroups of topoisomerases, the subject of our research was the human DNA topoisomerase II[alpha], which is a validated and established anticancer target, as its concentration is higher in rapidly dividing cells compared to normal cells. Type II topoisomerases act via a complex catalytic cycle that offers multiple points for its modulation and consequently drug design. Clinically used inhibitors of this enzyme, topoisomerase II poisons, act by stabilizing a short-lived complex between the DNA and the enzyme turning it into a cellular toxin. However, they at the same time also damage the DNA molecule, and this can lead to serious side effects, such as cardiotoxicity and the onset of secondary forms of cancer. Therefore, in recent years, research has focused on the development of catalytic topo II inhibitors that do not cause DNA damage. In our research outlined by four research hypotheses, we investigated the identification, optimization, and evaluation of new catalytic inhibitors of human topoisomerase II[alpha] that bind to its ATP binding site. In our first study substituted 4,5%-bitiazoles, known inhibitors of the bacterial topoisomerase type II DNA gyrase were used as a design starting point. By comparing the ATP binding sites of both enzymes, we pinpointed their key differences and similarities that were used in a virtual screening of a targeted chemical library to identify inhibitors that would better bind to the topoisomerase II[alpha] ATP binding site. For selected compounds, we demonstrated at the in vitro level that they act as catalytic ATP-competitive inhibitors of topoisomerase II[alpha] and bind to its isolated ATPase domain. The compounds were also effective at the cellular level, as some of them exhibited cytotoxicity on the HepG2 and MFC-7 cell lines in the same range as clinically used anticancer drug etoposide. The substituted 4,5%-bitiazoles stopped the cell cycle in the G1 phase, affected the cell proliferation, and did not cause the occurrence of DNA double-strand breaks, a further evidence that these compounds exhibit a different mode of action at the cellular level compared to topoisomerase II poisons. Our second study dealt with the optimization of position 4 of the 4,6-disubstituted 1,3,5 triazin-2(1H)-ones, for which previous studies have shown they act as catalytic topoisomerase II[alpha] inhibitors and bind to the ATPase domain. Using a developed docking binding model, we screened a focused virtual library of possible analogues with different substituents at the position 4 of the 1,3,5-triazine ring that could form additional interactions with the ATP binding site. After screening, selected in silico optimized analogues were synthesized and were shown to be more potent catalytic inhibitors than the parent compounds. 4 Moreover, two of them also exhibited promising cytotoxicity on the HepG2 cancer cell line. In addition, this chemical class did not induce the formation of DNA double-strand breaks at the cellular level. In our final study, we started from the inactive compounds from the class of 3,5-disubstituted 1,2,4-oxadiazoles, which were originally designed as DNA gyrase inhibitors. We added more rigid moieties to the core structure along with functional groups, which could enable stronger interactions with the ATP binding pocket. In addition to the synthesized compounds, several commercially available substituted oxadiazoles were included in the evaluation of topo II% inhibition. The assays identified several 3,5-disubstituted 1,2,4-oxadiazoles with introduced rigid structures which possessed human topoisomerase II[alpha] inhibition activity. These compounds acted via a catalytic inhibition mechanism and were able to bind to the isolated ATPase domain. They further displayed a cytotoxic potential on the MCF-7 cancer cell line and did not lead to DNA double-strand breaks. During our research we were able to confirm all four research hypotheses. In addition, the discovered lead compounds could via proper optimization lead to preclinical candidates with comparable efficacy as clinically used topoisomerase II poisons, and decreased incidence of serious side effects associated with this group of anticancer agents.DNA topoizomeraze so družina encimov, ki delujejo kot molekulski motorji in omogočajo topološke spremembe v molekuli DNA ter s tem mnoge procese v celici. V naših raziskavah smo se osredotočili na človeško DNA topoizomerazo II[alfa], ki je validirana in uveljavljena protirakava tarča, saj je njena koncentracija višja v hitro delečih se celicah v primerjavi z normalnimi. Topoizomeraze tipa II delujejo preko kompleksnega katalitičnega cikla, ki ponuja več prijemališč za načrtovanje zdravilnih učinkovin. Klasični zaviralci tega encima, topoizomerazni II strupi, stabilizirajo kovalentni kompleks med DNA in encimom ter ga spremenijo v celični strup. Pri tem tudi poškodujejo DNA molekulo in lahko povzročajo resne neželene učinke, kot sta kardiotoksičnost in nastanek sekundarnih oblik raka. Zato so se v zadnjih letih raziskave usmerile v razvoj katalitičnih zaviralcev, ki ne povzročijo poškodb DNA. V okviru doktorske disertacije smo želeli preko štirih raziskovalnih hipotez identificirati in ovrednotiti nove katalitične zaviralce topoizomeraze II[alfa] ter tudi optimizirati obstoječe katalitične zaviralce, ki se vežejo v vezavno mesto za ATP. V prvi raziskavi smo kot izhodiščno točko načrtovanja uporabili poznane zaviralce bakterijske topoizomeraze tipa II, substituirane 4,5%-bitiazole. S primerjavo vezavnih mest za ATP bakterijske DNA giraze in človeške topoizomeraze II[alfa] smo določili ključne razlike in podobnosti v vezavnih mestih, ki so omogočile virtualno rešetanje usmerjene kemijske knjižnice za identifikacijo zaviralcev, ki bi se bolje vezali na človeško topoizomerazo II[alfa]. Spojine tega razreda delujejo kot katalitični ATP kompetitivni zaviralci človeške DNA topoizomeraze II[alfa] in se vežejo na izolirano ATPazno domeno. Spojine so bile učinkovite tudi na celičnem nivoju, saj so nekatere izmed njih izkazovale citotoksičnost na HepG2 in MFC-7 celični linijah v enakem obsegu kot uveljavljena protirakava zdravilna učinkovina etopozid. Za izbrano spojino smo ugotovili, da ustavi celični cikel v G1 fazi, vpliva na proliferacijo celic ter dokazali, da ne povzroča dvojnih prelomov DNA, kar je dodatni dokaz, da spojine tega razreda tudi na celičnem nivoju delujejo drugače kot topoizomerazni II strupi. V drugi raziskavi smo se osredotočili na optimizacijo mesta substitucije 4 kemijskega razreda 4,6-disubstituiranih 1,3,5-triazin-2(1H)-onov, za katere so v prejšnjih študijah pokazali, da so katalitični zaviralci človeške topoizomeraze II[alfa] in se vežejo na ATPazno domeno, kjer se nahaja ATP vezavno mesto. S pomočjo in silico vezavnega modela smo zgradili in rešetali usmerjeno kemijsko knjižnico možnih analogov z različnimi substituenti na mestu 4 1,3,5-triazinskega obroča, da bi tako spojini omogočili dodatne interakcije z vezavnim mestom za ATP. Po načrtovanju so bili sintetizirani novi analogi, ki so se izkazali kot boljši katalitični zaviralci človeške topoizomeraze II[alfa] kot izhodne spojine. 2 Dve izmed njih sta izkazovala tudi obetavno citotoksičnost na HepG2 rakavi celični liniji. Na celičnem nivoju tudi ta kemijski razred ne povzroča nastanka dvojnih prelomov DNA molekule. V tretji raziskavi smo se lotili optimizacije neaktivnih spojin iz razreda 3,5-disubstituiranih 1,2,4-oksadiazolov, prvotno načrtovanih kot zaviralcev DNA giraze. V molekule smo uvedli rigidnejše fragmente, da bi s tem omogočili stabilnejše interakcije v fosfatnem delu ATP žepa. Poleg sintetiziranih spojin smo ovrednotili tudi nekaj komercialno dostopnih substituiranih oksadiazolov. Identificirali smo več aktivnih spojin, ki nakazujejo, da rigidnejše strukture omogočajo zaviralno aktivnost človeške topoizomeraze II[alfa] preko katalitičnega mehanizma zaviranja ter vezave na ATPazno domeno. Spojine so bile citotoksične na MCF-7 rakavi celični liniji ter niso vodile do nastanka dvojnih prelomov DNA. Tekom raziskav doktorske disertacije smo uspeli potrditi vse štiri izhodiščne raziskovalne hipoteze. Odkrite spojine vodnice so primerne za nadaljnjo optimizacijo do predkliničnih kandidatov, ki bi izkazovali primerljivo učinkovitost kot klinično uporabni topoizomerazni II strupi ter imeli sočasno manjšo pojavnost neželenih učinkov kot ta skupina protirakavih učinkovin
Homology modeling and molecular simulations of the camelid nanobodies as therapeutic tools in the treatment of sarcoma
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Splošni razlagalni slovarji slovanskih jezikov
Full text linkThe monograph ('General Monolingual Dictionaries of the Slavic Languages') provides an overview of the more prominent dictionary typologies, and an overview of general monolingual Slavic language dictionaries created from 1945 untill the present. The analysis presents how dictionary elements of selected dictionaries are treated at the macrostructural and microstructural level. For selected elements (homonymy and homography, multi-word headwords, sub-entries, grammatical information, referential definition type, multi-word lexical units and etymological information), suggestions for further lexicographical practice are given. The standpoint of these suggestions is that a dictionary serves as a representation of a lexicon and as a practical tool, which should effectively and transparently deliver reliable and relevant linguistic data and to a lesser extent non-linguistic data. The suggestions also take into account the completed transition from the initial print dictionary to the initial electronic dictionary, which to a certain extent requires reallocation of the data and to a lesser extent reorganization of data hierarchy.Monografija prinaša pregled vidnejših slovarskih tipologij, pregled splošnih enojezičnih slovanskih slovarjev, nastalih od 1945 do danes. Analiza prikazuje obravnavo slovarskih prvin na makrostrukturni in mikrostrukturni ravni. Za izbrane elemente (homonimija in homografija, večbesedne iztočnice, podgesla, slovnični podatki, sklicevalni tip razlage, večbesedne leksikalne enote in etimološki podatki) so podani predlogi za nadaljnjo slovaropisno prakso. Izhodišče teh predlogov je slovar kot jezikovni opis besedja in kot praktični pripomoček, ki naj kar se da učinkovito in pregledno prinaša zanesljive in relevantne jezikovne in, v manjši meri, tudi nejezikovne podatke, pri predlogih pa je upoštevan tudi zaključen prehod od izhodiščno knjižne podobe slovarja k izhodiščno digitalni podobi slovarja, kar do določene mere zahteva prerazporeditev slovarskih podatkov, v manjši meri pa tudi preureditev njihove hierarhije
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