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Vodorazrjedivi premazi za zaštitu brončane kulturne zaštite
No full textObjects of tangible cultural heritage, such as sculptures, are often made of bronze and located outdoors where they are directly exposed to the corrosive effect of precipitation, humidity, sunlight, temperature and airborne contaminants. To protect them organic coatings, varnishes and waxes are used that meet the requirements of the conservation profession. However, in recent decades, legislations were enacted with an aim to restrict the use of coatings with high content of volatile organic compounds due to their toxicity and negative impact on the environment and human health. For this reason, efforts are being made in all branches of industry to replace solventborne with waterborne coatings, in which the content of organic solvents is reduced and replaced by water. However, waterborne coatings still offer weaker protection than solventborne coatings under similar conditions. For that reason, different approaches to improve their performance are examined. The aim of this thesis was to investigate the applicability of industrial waterborne coatings for corrosion protection of bare and patinated bronze surfaces and the possibility of enhancement of their corrosion protection efficiency and adhesion by surface pretreatment with long-chain phosphonic acids. Sculptures made of bronze are artificially patinated before protective coating application and exposure to the outdoor environment. This artificially formed patina is very reactive, so it was necessary to study its behavior before applying the protection. Artificial sulphide patina was formed on various bronze substrates (CuSn12, CuSn6, RG7) used in the production of bronze sculptures. The corrosion behaviour of the patina was investigated by electrochemical methods, in different corrosive environments: artificial urban and acid rain as well as in NO2 rich atmosphere, with alternating wet and dry cycles. The morphology and composition of the samples were analyzed using microscopic (SEM) and spectroscopic (FTIR) techniques. It was found that the patina undergoes transformation when exposed to a corrosive medium, increasing its resistance and corrosion stability. This entire process depended significantly on the duration of wet period and corrosivity of medium, while the bronze substrate composition was less important factor. Since waterborne coatings contain water, which is less volatile than organic solvents, it was necessary to study the influence of temperature and duration of the drying process on coating final properties. In the first step, conducting tests with an industrial coating, containing a corrosion inhibitor, enabled the selection of suitable coating application parameters. Then, additional waterborne coating was selected, which does not contain corrosion inhibitor, and both coatings were applied on differently patinated bronze substrates, as well as on bare bronzes. Although both coatings proved to be effective, the coating containing corrosion inhibitor showed slightly higher level of corrosion protection and was selected for further studies. It is important to emphasize that this coating does not change the visual appearance of the surface either during application or after exposure to a corrosive environment, as required by conservation ethics. In the next step, the possibility of improvement of waterborne coating corrosion protection and adhesion on bare and patinated bronzes was examined. For this purpose surface pre-treatment with long-chain phosphonic acid was applied. The level of corrosion protection of bare and artificially patinated bronze was tested by electrochemical measurements (polarization measurements and electrochemical impedance spectroscopy) under conditions of simulated acid rain (pH 5) or NO2 atmosphere. The adhesion of the coating to the metal substrate was tested using the pull-off method. It was found that 12- aminododecylphosphonic acid, when applied on bronze by immersion in ethanolic solution, can act as a corrosion inhibitor, as well as a coating adhesion promoter. The research was extended to two other phosphonic acids that differ in chain length and terminal group. Furthermore, all three acids were applied by the brush method in addition to the immersion, which would be more suitable in the practice of cultural heritage. It has been shown that certain improvements can be achieved with both methods, which are more pronounced on a bare surface than on a patinated surface, which is quite porous and reactive. The arrangement of the phosphonic acid films was analyzed by goniometry and the correlation between phosphonic film crystallinity and its effect on coating properties was observed. In summary, it has been shown that industrial waterborne acrylic coatings can effectively protect bare and patinated bronzes, even if the level of protection does not reach the level of similar solventborne coatings. It has been shown that pretreatment with appropriate phosphonic acid can improve the protective properties and adhesion of such coating.Objekti materijalne kulturne baštine, poput skulptura, često su izrađeni od bronce i nalaze se na otvorenom gdje su izravno izloženi korozivnom djelovanju oborina, vlage, sunčeve svjetlosti, temperature i onečišćenja iz zraka. Za njihovu zaštitu koriste se organski premazi, lakovi i voskovi koji zadovoljavaju zahtjeve konzervatorske struke. Posljednjih desetljeća doneseni su zakoni kojima se ograničila uporaba premaza s visokim udjelom hlapivih organskih spojeva zbog njihove toksičnosti i negativnog utjecaja na okoliš i zdravlje ljudi. Zbog toga se u svim granama industrije premazi na bazi otapala nastoje zamijeniti premazima na bazi vode u kojima je sadržaj organskih otapala smanjen i zamijenjen vodom. Međutim, premazi na bazi vode i dalje pružaju slabiju zaštitu od premaza na bazi otapala pod sličnim uvjetima. Zbog toga se istražuju pristupi za poboljšanje njihove učinkovitosti. Cilj ovog doktorskog rada bio je istražiti primjenjivost industrijskih vodorazrjedivih premaza u svrhe korozijske zaštite čistih i patiniranih brončanih površina te mogućnost unaprjeđenja učinkovitosti njihove zaštite i adhezije površinskom predobradom dugolančanim fosfonskim kiselinama. Skulpture izrađene od bronce umjetno se patiniraju prije nanošenja zaštitnog premaza i izlaganja vanjskom okolišu. Ova umjetno stvorena patina je vrlo reaktivna te je bilo potrebno proučiti njeno ponašanje prije nanošenja zaštite. Umjetna sulfidna patina formirana je na različitim brončanim podlogama (CuSn12, CuSn6, RG7) koje se koriste u izradi brončanih skulptura. Korozivno ponašanje patine istraženo je elektrokemijskim metodama u različitim korozivnim okolišima: umjetna urbana i kisela kiša, kao i u atmosferi bogatoj NO2 s izmjeničnim vlažnim i suhim ciklusima. Morfologija i sastav uzoraka analizirani su mikroskopskom (SEM) i spektroskopskom (FTIR) tehnikom. Utvrđeno je da se patina transformira kada je izložena korozivnom mediju gdje dolazi do porasta njene otpornosti i korozijske stabilnosti. Cijeli ovaj proces značajno je ovisio o trajanju vlažnog razdoblja i korozivnosti medija dok je sastav brončane podloge bio manje bitan faktor. Budući da vodorazrjedivi premazi sadrže vodu, koja je manje hlapiva od organskih otapala, bilo je potrebno istražiti utjecaj temperature i trajanja procesa sušenja na konačna svojstva premaza. U prvom koraku provođenje testova s industrijskim premazom, koji sadrži inhibitor korozije, omogućilo je odabir odgovarajućih parametara nanošenja premaza. Zatim je odabran dodatni vodorazrjedivi premaz koji ne sadrži inhibitor korozije te su oba premaza nanesena na različito patinirane brončane podloge kao i na gole bronce. Iako su se oba premaza pokazala učinkovitima, premaz koji je sadržavao inhibitor korozije pokazao je nešto višu razinu korozijske zaštite te je odabran za daljnja istraživanja. Važno je naglasiti da ovaj premaz ne mijenja vizualni izgled površine niti tijekom nanošenja niti nakon izlaganja korozivnoj okolini što je u skladu s konzervatorskom etikom. U sljedećem koraku ispitana je mogućnost poboljšanja korozijske zaštite i adhezije vodorazrjedivog premaza na čistoj i patiniranoj bronci. U tu svrhu primijenjena je predobrada površine dugolančanom fosfonskom kiselinom. Razina korozijske zaštite čiste i umjetno patinirane bronce ispitana je elektrokemijskim mjerenjima (polarizacijska mjerenja i elektrokemijska impedancijska spektroskopija) u uvjetima simulirane kisele kiše (pH 5) ili atmosfere NO2. Adhezija premaza na metalnu podlogu ispitana je pull-off testom. Utvrđeno je da 12-aminododecilfosfonska kiselina, kada se nanese na broncu uranjanjem u etanolnu otopinu, može djelovati kao inhibitor korozije te kao promotor adhezije premaza. Istraživanje je prošireno na dvije druge fosfonske kiseline koje se razlikuju po duljini lanca i terminalnoj skupini. Nadalje, sve tri kiseline su uz metodu uranjanja nanesene i metodom kista koja bi bila prikladnija u praksi za kulturnu baštinu. Pokazalo se da se objema metodama mogu postići određena poboljšanja koja su izraženija na čistoj nego na patiniranoj površini budući da je ona dosta porozna i reaktivna. Uređenost filmova fosfonskih kiselina analizirana je goniometrijom te je proučavana korelacija između kristalnosti filma fosfonske kiseline i njezinog učinka na svojstva premaza. U konačnici, pokazalo se da industrijski, vodorazrjedivi akrilni premazi mogu učinkovito zaštititi čistu i patiniranu broncu čak i ako razina zaštite ne doseže razinu zaštite sličnih organskih premaza. Pokazalo se da prethodna obrada odgovarajućom fosfonskom kiselinom može poboljšati zaštitna svojstva i adheziju takvog premaza
Archaeology of identities in 5th and 6th centuries in late antique Dalmatia and southern Pannonia
No full textOva disertacija predstavlja istraživanje identiteta 5. i 6. stoljeća na prostoru nekadašnjih rimskih provincija (Savia, Sirmiensis, Dalmatia), odnosno istraživanje područja južne Panonije i Dalmacije, s osobitim naglaskom na teritorij Republike Hrvatske. Pitanja identiteta, u velikoj mjeri neistraženih stoljeća turbulentnog razdoblja velike seobe naroda tijekom navedena dva stoljeća, u arheologiji se najčešće baziraju na donošenju mišljenja i zaključaka o etničkim identitetima novodoseljenog stanovništva na teritorij spomenutih rimskih provincija. Disertacija donosi pogled na istraživanje identiteta uopće te se ne ograničava isključivo na etnički identitet već problem sagledava dubinski, prateći sociološke promjene pojedinaca i skupina unutar društva koje se suživotom novodoseljenog i starosjedilačkog stanovništva neminovno mijenja velikom brzinom. Razmatra se pitanje u kojoj mjeri predmeti arheološke materijalne kulture mogu nedvosmisleno svjedočiti identitetu nositelja materijalne kulture. Na taj način, disertacija predstavlja zanimljive društvene fenomene koji mijenjaju etnički, socijalni, ekonomski i gospodarski profil navedenog područja. Interdisciplinarnim pristupom znanstvenom istraživanju nerimskog stanovništva južne Panonije i Dalmacije, mogu se temeljitije promatrati navedeni fenomeni koji se u arheologiji mogu odražavati u materijalnoj kulturi koju je to stanovništvo tijekom 5. i 6. stoljeća ostavilo na obrađivanim područjima. Pojedine, već postojeće, interpretacije arheološkog materijala potrebno je preispitati te iscrpiti maksimum mogućih podataka koji predmet može pružiti s obzirom na navedene kategorije. Pristup istraživanju neminovno je interdisciplinaran te, uz arheologiju, pretpostavlja uključivanje drugih znanstvenih disciplina koje nadopunjuju arheološke zaključke. Posebno se razmatra odnos pisanih izvora naspram istraženih predmeta materijalne kulture, u smislu relevantnih informacija koje dobivamo s jedne i s druge strane da bi se izbjegla česta situacija u prošlosti kada su se pisana vrela uzimala kao činjenice. Detaljno proučavanje te predstavljanja većine istraženih i objavljenih predmeta materijalne kulture nerimskog stanovništva na jednom mjestu, olakšavaju rad istraživača koji će, u budućnosti, interesno zadirati u ovo razdoblje. Interpretacija nalaza kroz tekstualni i slikovni dio rekonstukcija, otvara ovu temu za daljnju raspravu o mogućnostima interpretacije identiteta nerimskog stanovništva južne Panonije i Dalmacije tijekom 5. i 6. stoljeća. Razdoblje navedena dva stoljeća označava turbulencije koje su se u to vrijeme događale na teritoriju Rimskog Carstva, a koje su značile korjenite promjene i temelj uspostave Europe kakvu poznajemo danas.This dissertation represents the research of the identity of the 5th and 6th centuries in the area of the former Roman provinces (Savia, Sirmiensis, Dalmatia), that is, the research of the area of southern Pannonia and Dalmatia, with a special emphasis on the territory of the Republic of Croatia. Questions of identity, largely unexplored during the turbulent period of the great migration of peoples during the aforementioned two centuries, in archeology are most often based on opinions and conclusions about the ethnic identities of the newly settled population in the territory of the mentioned Roman provinces. The dissertation brings a view of identity research in general and is not limited exclusively to ethnic identity, but the problem of looking in-depth, following the sociological changes of individuals and groups within society, which is inevitably changing at a high speed due to the coexistence of the newly settled and indigenous population. The question to what extent objects of archaeological material culture can unequivocally testify to the identity of the bearer of material culture is considered. In this way, the dissertation presents interesting social phenomena that change the ethnic, social, economic and economic profile of the mentioned area. With an interdisciplinary approach to the scientific research of the non-Roman population of southern Pannonia and Dalmatia, the aforementioned phenomena can be more thoroughly observed, which in archeology can be reflected in the material culture that this population left in the cultivated areas during the 5th and 6th centuries. Certain, already existing, interpretations of archaeological material need to be re-examined and the maximum amount of possible data that the subject can provide with regard to the above categories should be exhausted. The research approach is inevitably interdisciplinary and, along with archaeology, it assumes the inclusion of other scientific disciplines that complement the archaeological conclusions. Special consideration is given to the relationship between written sources and researched objects of material culture, in terms of the relevant information we receive from one side and the other. The detailed study and presentation of most of the researched and published objects of the material culture of the non-Roman population in one place facilitate the work of researchers who, in the future, will interestingly delve into this period. The interpretation of the findings through the textual and pictorial part of the reconstruction opens this topic for further discussion about the possibilities of interpreting the identity of the non-Roman population of southern Pannonia and Dalmatia during the 5th and 6th centuries. The period of the mentioned two centuries marks the turbulences that took place at that time in the territory of the Roman Empire, which meant radical changes and the foundation of the establishment of Europe as we know it today
Development of cerebral cortex and neurodegenerative changes in Down syndrome on human cerebral organoids model
No full textCerebralni organoidi uzgojeni od induciranih pluripotentnih matičnih stanica čovjeka su trodimenzionalne strukture koje rastu oko 100 dana u staničnoj kulturi te razvijaju morfološka obilježja specifična za ljudski mozak. Cilj istraživanja bio je iskoristiti model koji je dobiven od iste osobe, mozaika za trisomiju 21 kromosoma, što omogućava usporedbu diferencijacije kore ljudskog mozga u osoba s Downovim sindromom i njegovom izogeničnom kontrolom. Istraživanje je pokazalo kako cerebralni organoidi čovjeka ispoljavaju sve biljege karakteristične za koru velikog mozga, čime se potvrdila vrijednost ovog modela u istraživanju normalne i narušene strukture mozga. Također pokazano je kako izražaj biljega RELN, CTIP2 i TBR1 kasni u trisomičnim organoidima u odnosu na disomične, što upućuje da kod ljudi s ovom kromosopatijom dolazi do kašnjenja u najranijim fazama razvoja tkiva mozga. Također, zamijećen je manji izražaj svih biljega u trisomičnim organoidima u odnosu na disomične, čime se potvrđuje činjenica kako je cjelokupan broj živčanih stanica u mozgu ljudi s DS smanjen. Nadalje, trisomični organoidi imali su izražene biljege neurodegeneracije 6E10, 4G8 i Aßx-40 čime je potvrđena pretpostavka kako cerebralni organoidi s tri kopije 21 kromosoma predstavljaju koristan model u istraživanju neurodegenerativnih bolesti pridruženih Downovu sindromu, kao što je Alzheimerova demencija. Uspoređujući rezultate na organoidima s rezultatima analize mozgova fetusa s Downovim sindromom, starosti 18.-23. gestacijska tjedna, uočeno je kako organoidi mozga mogu vjerodostojno odražavati zbivanja tijekom embrionalnog razvoja čovjeka.Cerebral organoids grown from human induced pluripotent stem cells are three-dimensional structures that grow for approximately 100 days in cell culture and develop morphological features specific to the human brain. This study aimed to use a model derived from the same individual, a mosaic for trisomy 21, which allowed us to compare cortical differentiation in individuals with Down syndrome and their isogenic control. The study showed that human cerebral organoids express all markers characteristic of the cerebral cortex, confirming the value of this model in studying normal and disrupted brain structure. It was also found that the expression of the RELN, CTIP2, and TBR1 is delayed in trisomic organoids compared to disomic ones, indicating a delay in the earliest stages of brain tissue development in individuals with this chromosomal disorder. Additionally, a lower expression of all markers was observed in trisomic organoids compared to disomic ones, confirming that the total number of neurons in the brains of individuals with Down syndrome is reduced. Furthermore, trisomic organoids exhibited neurodegeneration markers 6E10, 4G8, and Aßx-40, confirming the hypothesis that cerebral organoids with three copies of chromosome 21 are a useful model for studying neurodegenerative diseases, such as Alzheimer's dementia. Comparing the results from the organoids with the results from the analysis of brains of fetuses with Down syndrome, aged 18-23 gestational weeks, it was observed that brain organoids can authentically replicate events that occur during human embryonic development
Synthesis and structural characterization of novel benzimidazole and benzothiazole derivatives as potential antiproliferative agents with antioxidative activity
No full textU ovom radu opisana je sinteza nekoliko klasa derivata benzimidazola i benzotiazola kojima je ispitana antiproliferativna i antioksidativna aktivnost. U linearnoj višestupanjskoj sintezi novih konjugata benzazola primijenjeni su klasični sintetski pristupi kao i neke suvremene sintetske metode, uključujući sintezu u ekološki prihvatljivim otapalima ili sintezu potpomognutu mikrovalovima. Novi akrilonitrilni derivati N-supstituiranih derivata benzazola 32‒71 i 77‒107 priređeni su aldolnom kondenzacijom odgovarajućih cijanometilbenzazola s benzaldehidima supstituirani promjenjivim brojem metoksi i hidroksi skupina te 4-N,N-dimetilamino i
4-N,N-dietilamino skupinom. Derivati Schiffovih baza supstituirani benzimidazolom 117‒132 priređeni su kondenzacijom N-supstituiranih 2-aminobenzimidazola 108‒115 s odgovarajućim 4-N,N-dimetilamino i 4-N,N-dietilamino supstituiranim benzaldehidima. Derivati iminokumarina i kumarina 134‒149 te amidino-supstituirani derivati kumarina 164‒175 priređeni su ciklokondenzacijom različito supstituiranih 2-hidroksibenzaldehida s odgovarajućim 2-cijanometilbenzimidazolima, te iz kumarinskih aldehida reakcijom kondenzacije s odgovarajućim 4-amidino-supstituiranim 1,2-fenilendiaminima uz korištenje p-benzokinona kao oksidansa. Amidino-supstituirani benzimidazoli 193‒216 priređeni su kondenzacijom 5-supstituiranih salicilaldehida s odgovarajućim 4-amidino-supstituiranim
1,2-fenilendiaminima. Amidino-supstituirani benzotiazoli 179‒181 i 216‒227 priređeni su iz različito supstituiranih 2-hidroksibenzaldehida i odgovarajućih zwitter iona u ledenoj octenoj kiselini. Metoksi-supstituirani karboksamidi 235‒262 priređeni su kondenzacijom benzoilnih klorida s N-supstituiranim derivatima 2-aminobenzimidazola. Hidroksi-supstituirani amidni derivati N-benzimidazola 263‒268 i 280‒286 priređeni su uklanjanjem zaštitnih metoksi skupina, korištenjem BBr3 na niskim temperaturama, te benzilnih zaštitnih skupina katalitičkim hidrogeniranjem uz Pd/C u metanolu. Amidino-supstituirani derivati benzamida 289‒293 priređeni su kiselo-kataliziranom Pinnerovom reakcijom iz odgovarajućih cijano-supstituiranih polaznih spojeva. Strukture novosintetiziranih spojeva potvrđene su
1H i 13C NMR spektroskopijom, a nekim je spojevima struktura dodatno okarakterizirana i masenom spektrometrijom. Svim priređenim spojevima ispitana je antiproliferativna aktivnost in vitro na niz staničnih linija humanih karcinoma i zdravih stanica, dok je ispitivanje antioksidativne aktivnosti in vitro provedeno primjenom spektroskopskih metoda DPPH, FRAP i ABTS. Amidino-supstituiranim derivatima 164‒175 i 179‒181 ispitana je antiviralna aktivnost in vitro na nekoliko sojeva virusa, te su neki od derivata pokazali jako dobru i selektivnu aktivnost prema pojedinim sojevima virusa. Derivatima Schiffovih baza 117‒132 te amidino-supstituiranim benzazolima 193‒216 i 217‒228 ispitana je i antibakterijska aktivnost prema Gram pozitivnim i Gram negativnim bakterijama. Iz dobivenih rezultata ispitivanja biološke aktivnosti i SAR studije, utvrđeno je da na antioksidativnu aktivnost značajno utječe broj metoksi i hidroksi skupina na fenilnom prstenu, te supstituent na dušikovom atomu benzimidazolne jezgre. Najizraženiji utjecaj na povećanje antiproliferativne aktivnosti pokazuje 4-N,N-dietilamino skupina smještena na položaju 7 kumarinskog prstena i fenilnom prstenu akrilonitrilnih derivata, te izobutilni supstituent na N atomu benzimidazolne jezgre. Nekima od najaktivnijih derivata benzazola dodatno su ispitani mehanizmi biološkog djelovanja, te je tako utvrđeno da neki derivati akrilonitrila i iminokumarina djeluju kao inhibitori polimerizacije tubulina, dok je amidnim derivatima ispitana i antioksidativna aktivnost u stanicama. Dokazano je i da najbolju antivirusnu aktivnost ima kumarinski derivat benzimidazola supstituiran nesupstituiranim amidinom koji inhibira ranu fazu replikacijskog ciklusa virusa, odnosno sintezu virusne RNK.This thesis describes the synthesis of several classes of benzimidazoles and benzothiazoles in order to investigate their antiproliferative and antioxidant activity. By using multi-step linear synthesis of new benzazole conjugates, classical synthetic approaches as well as some modern synthetic methods, including synthesis in environmentally friendly solvents or microwave-assisted synthesis, were applied. New acrylonitrile derivatives of N-substituted benzazoles 32‒71 and 77‒107 were prepared by aldol condensation of the corresponding cyanomethylbenzazoles with benzaldehydes with a variable number of methoxy and hydroxy groups and 4-N,N-dimethylamino and 4-N,N-diethylamino groups. Benzimidazole derived Schiff bases 117‒132 were prepared by condensation of N-substituted 2-aminobenzimidazoles 108‒115 with corresponding 4-N,N-dimethylamino and
4-N,N-diethylamino-substituted benzaldehydes. Iminocoumarin and coumarine derivatives 134‒149 and amidino-substituted coumarine derivatives 164‒175 obtained by cyclocondensation of substituted 2-hydroxybenzaldehydes with corresponding 2-cyanomethylbenzimidazoles as well as from coumarine aldehydes with corresponding 4-amidino-substituted 1,2-phenylenediamines using p-benzoquinone as an oxidant. Amidino-substituted benzimidazoles 193‒216 were synthesized within the condensation of 5-substituted salicylaldehydes with corresponding 4-amidino-substituted
1,2-phenylenediamines. Amidino-substituted benzothiazoles 179‒181 i 216‒227 were prepared by condensation of differently substituted 2-hydroxybenzaldehydes and corresponding zwitter ions in glacial acetic acid. Methoxy-substituted carboxamides 235‒262 were prepared by condensation of benzoyl chlorides with N-substituted 2-aminobenzimidazole derivatives. Hydroxy-substituted amide derivatives of N-benzimidazole 263‒268 and 280‒286 obtained by removing protective methoxy groups, using BBr3 at low temperatures, and benzyl protective groups by catalytic hydrogenation with Pd/C in methanol. Amidino-substituted benzamide derivatives 289‒293 were synthesized via acid-catalyzed Pinner reaction from the corresponding cyano-substituted starting precursors. Structures of all newly prepared compounds were confirmed by 1H and 13C NMR spectroscopy while some of them were additionally characterized by mass spectrometry. All prepared compounds were tested for their antiproliferative activity in vitro on a number of human cancer cell lines as well as normal fibroblasts, while antioxidant activity in vitro was performed using spectroscopic DPPH, FRAP and ABTS methods. Amidino-substituted derivatives 164‒175 and 179‒181 were tested for antiviral activity in vitro on several virus strains, and some compounds have shown pronounced and selective activity against some viruses. Schiff base derived benzazoles 117‒132 and amidino-substituted benzazoles 193‒216 and 217‒228 were tested for antibacterial activity against Gram positive and Gram negative bacteria. Results obtained from evaluation of biological activity and SAR studies, revealed that the antioxidant activity is affected by the number of methoxy and hydroxy groups on the phenyl ring as well as the substituent on the nitrogen atom of the benzimidazole nucleus. The strongest impact on the enhancement of antiproliferative activity was observed by 4-N,N-diethylamino group placed at the position 7 on coumarin ring and phenyl ring of acrylonitrile derivatives. The isobutyl substituent on the N atom of the benzimidazole core has the greatest influence on increasing the activity of the synthesized compounds. Some of the most active benzazole derivatives were additionally evaluated to study their mechanisms of biological action and it was confirmed that some of the acrylonitrile and iminocoumarin derivatives have proven to be tubuline polymerization inhibitors, while for amide derivatives the antioxidative activity was tested also in the cells. It has been proven that the most promising antiviral activity has been possessed by coumarine derived benzimidazole substituted with amidine group, being inhibitor of an early step in the replication cycle of virus, respectively the synthesis of viral RNA
Monometallic and heterobimetallic complexes of N-heterocycles – synthesis, structural characterization and biological evaluation
No full textU okviru disertacije proučavani su N-heterociklički ligandi i njihovi metalni kompleksi. Provedena je sinteza heterocikličkih spojeva, poput derivata piridina, 2,2'-dipiridilamina, benzimidazola i benzotiazola, koji sadrže monodentatne, bidentatne i tridentatne koordinirajuće skupine, te njihovih koordinacijskih kompleksa s prijelaznim metalima. Pripravljeni derivati podijeljeni su u šest klasa. Bidentatni i tridentatni heterociklički ligandi sintetizirani su višestupnjevitom sintezom primjenom konvencionalnih sintetskih metoda i reakcijama „zelene“ kemije potpomognutih mikrovalovima. Strukture ligadana i metalnih kompleksa potvrđene su spetroskopskopijom NMR, IR i UV, te difrakcijom rendgenskog zračenja u jediničnom kristalu, a heterobimetalni kompleksi karakterizirani su voltametrijski te računalnom analizom. Pripravljenim ligandima i metalnim kompleksima ispitano je antiproliferativno djelovanje na niz tumorskih staničnih linija in vitro, kao i na zdrave stanice uz referentne kliničke lijekove. Koordinacija metalom poboljšala je antitumorsku aktivnost i selektivnost u većini slučajeva. Heterobimetalni kompleks konjugata ferocena i
2,2'-dipiridilamina s bakrom(II) [Cu(A8c)2](CF3SO3)2 pokazao je selektivno inhibitorno djelovanje na stanice HeLa, MES-OV, A549 i MDA-MB-231 uz povećanje stanične populacije u fazama staničnog ciklusa S i G2/M. Aktivnost 2,2'-dipiridilaminskih kompleksa poboljšana je koordinacijom s Re(I), pri čemu je najizraženiju aktivnost, bolju u odnosu na cisplatinu, pokazao kompleks [Re(B4a)(CO)3]Cl. Kompleks strukturno fleksibilnijeg
bis(2,2'-pikolil)aminskog liganda i Ni(II), [Ni(C1)2](NO3)2, pokazao je istaknuto antiproliferativno djelovanje ometajući proces replikacije DNK i smanjujući ekspresiju antiapoptotskog markera Bcl-2. Rutenijevi(II) polusendvič kompleksi 2-arilbenzotiazola i 2-pikolila povezani 1,2,3-triazolnom premosnicom imali su antiproliferativno djelovanje u submikromolarnom području, pokazujući selektivnost prema PANC1 stanicama. Konjugati acil-tiourea i benzotiazola te njihovi Ru(II) kompleksi imali su inhibitorno djelovanje u niskom mikromolarnom i nanomolarnom području na stanice H460, MCF-7, SW 620 i HepG2, s izraženim djelovanjem na staničnoj liniji raka dojke (MCF-7). Spojevi su, osim toga, pokazali slabo do umjereno antibakterijsko djelovanje prema E. faecalis. Ligand E5c i kompleksi D4aRu, E4cRu i E5cRu odabrani su za daljnja testiranja mehanizma biološkog djelovanja.In this dissertation, selected N-heterocyclic ligands and their metal complexes were studied. The synthesis of heterocyclic compounds, such as derivatives of pyridine,
2,2'-dipyridylamine, benzimidazole and benzothiazole, containing monodentate, bidentate and tridentate coordinating groups, and their coordination complexes with transition metals was carried out. The prepared derivatives are divided into corresponding six classes. The bidentate and tridentate heterocyclic ligands were synthesized by multi-step synthesis using conventional synthetic methods and „green“ microwave-assisted synthesis. The structures of the ligands and metal complexes were confirmed by NMR, UV and IR-spectroscopy and single-crystal X-ray diffraction. Heterobimetallic complexes were additionally characterized by voltammetry and computational analysis. The prepared ligands and metal complexes were evaluated for their antiproliferative activity in vitro against several tumor cell lines, as well as on normal cells with clinical drugs as references. Generally, metal coordination improved activity and selectivity in most cases. The heterobimetallic complex of ferrocene and
2,2'-dipyridylamine conjugate with copper(II) [Cu(A8c)2](CF3SO3)2 showed a selective inhibitory effect on HeLa, MES-OV, A549 and MDA-MB-231 cells with an increase in cell population in the S and G2/M phase of the cell cycle. The activity of 2,2'-dipyridylamine complexes was improved by coordination with Re(I), where [Re(B4a)(CO)3]Cl showed the most pronounced activity, better than cisplatin. The Ni(II) complex of the more structurally flexible bis(2,2'-picolyl)amine ligand, [Ni(C1)2](NO3)2, showed prominent antiproliferative activity by interfering with the DNA replication process and reducing the expression of the antiapoptotic marker Bcl-2. Ruthenium(II) half-sandwich complexes of 2-arylbenzothiazole and 2-picolyl linked by a 1,2,3-triazole bridge showed antiproliferative activity in the submicromolar range, displaying selectivity towards PANC1 cells. Acyl thiourea and benzothiazole conjugates and their Ru(II) complexes exhibited cytostatic activity in the low micromolar and nanomolar range against H460, MCF-7, SW 620 and HepG2 cells, with prominent activity against the MCF-7 breast cancer cell line. Besides, compounds showed weak to moderate antibacterial activity against E. faecalis. Ligand E5c and complexes D4aRu, E4cRu and E5cRu were selected for further evaluation of their mechanism of biological action
Language identity of popular music lyricists of the Dalmatian regiolect
No full textRazličiti društveno-povijesni čimbenici nastali u razdobljima promjenjivih jezičnih politika, stoljetnih previranja po pitanju tvorbe standardnoga jezika te dugotrajnih i mnogostrukih utjecaja stranih uprava rezultirali su heterogenom slikom hrvatskoga dijalekatskog područja i promjenama u vrijednosnim percepcijama jezičnih varijeteta. Nacionalna popularnost i prestiž dalmatinskoga regiolekta od šezdesetih su godina 20. st. postignuti posredstvom medija, serijalima Velo Misto i Naše malo misto, popularnom glazbom i Festivalom zabavne glazbe Split, a u 21. st. novonastalim Klapskim valom. Tekstopisci popularne glazbe na području dalmatinskoga regiolekta svojim autorskim radom doprinose njegovoj popularizaciji. Međutim, potaknuti različitom motivacijom uz regiolekt u tekstovima koriste i druge jezične varijetete, standardni hrvatski jezik, čakavicu te autorske hibridne jezike. Cilj rada jest izraditi jezične biografije autora iz kojih će se definirati različiti jezični varijeteti kojima se služe iz svoga osobnog repertoara i koji čine njihov jezični identitet. Triangulacijom s podatcima dobivenima iz makroanalize sadržaja narativa, analize idiolekta te analize autorskih jezika istražila se polazišna tezu o kružnom procesu u kojemu se društveno-političke i jezične mijene odražavaju na idiolekte i autorske jezične odabire u glazbenim tekstovima, a koji pak, s druge strane, brzom rasprostranjivosti preko masovnih medija utječu na jezične ideologije te nacionalnu afirmaciju i popularnost regiolekta. Ovo je kvalitativno, interdisciplinarno istraživanje iz područja sociolingvistike, glazbenotekstne lingvistike, dijalektologije i jezične biografistike čiji inovativan metodološki okvir obuhvaća jezičnobiografski intervju, kvalitativnu analizu sadržaja, metode tekstne lingvistike, dodirnog jezikoslovlja i analize diskursa koja otkriva kojim diskursnim strategijama pozicioniraju varijetete te konstruiraju individualne i društvene identitete. Autorskim radom nastaju pjesme s kojima se slušatelji poistovjećuju pa je u radu predstavljen inovativan, novoosmišljeni model pjevanog diskursa u kojemu se iskazuju, izgrađuju te prenose (višestruki) identiteti. Analizom zabilježenog govora potvrđeno je da se primarni i sekundarni jezični utjecaji ogledaju u idiolektima ispitanika. Tekstna analiza pjesama potvrdila je polazišnu tezu da su jezična politika restandardizacije hrvatskoga jezika u svrhu izgradnje nacionalnog identiteta te utjecaj američke rock kulture i razvoj urbane splitske scene devedesetih godina 20. stoljeća utjecali na autore i rezultirali češćom uporabom standardnoga jezika u njihovim tadašnjim autorskim tekstovima. Također, jačanje regiolekata u 21. stoljeću, kao i osobno sazrijevanje nekih autora, rezultiralo je češćom uporabom regiolekta u tekstovima ranih dvije tisućitih godina do danas. Triangulacijom podataka svih analiza dobiveni su vrijedni odgovori na istraživačka pitanja: autori iskazuju snažan lokalni identitet; koriste više jezičnih varijeteta potaknuti različitom motivacijom; u školama se uporaba dijalektalnog govora branila ili poticala ovisno o društveno-povijesnim prilikama određenog razdoblja; posvjedočili su popularnosti dalmatinskog regiolekta u drugim krajevima Hrvatske i susjednih zemalja; osnovni motivi za njegovu uporabu u tekstovima jesu melodioznost, emotivnost i autentičnost, a istraživanje je otkrilo i promjenu u pristupu medija prema dalmatinskom regiolektu od 1960-ih do danas.Različiti društveno-povijesni čimbenici nastali u razdobljima promjenjivih jezičnih
politika, stoljetnih previranja po pitanju tvorbe standardnoga jezika te dugotrajnih i mnogostrukih
utjecaja stranih uprava rezultirali su heterogenom slikom hrvatskoga dijalekatskog područja i
promjenama u vrijednosnim percepcijama jezičnih varijeteta. Nacionalna popularnost i prestiž
dalmatinskoga regiolekta od šezdesetih su godina 20. st. postignuti posredstvom medija, serijalima
Velo Misto i Naše malo misto, popularnom glazbom i Festivalom zabavne glazbe Split, a u 21. st.
novonastalim Klapskim valom. Tekstopisci popularne glazbe na području dalmatinskoga
regiolekta svojim autorskim radom doprinose njegovoj popularizaciji. Međutim, potaknuti
različitom motivacijom uz regiolekt u tekstovima koriste i druge jezične varijetete, standardni
hrvatski jezik, čakavicu te autorske hibridne jezike. Cilj rada jest izraditi jezične biografije autora
iz kojih će se definirati različiti jezični varijeteti kojima se služe iz svoga osobnog repertoara i koji
čine njihov jezični identitet. Triangulacijom s podatcima dobivenima iz makroanalize sadržaja
narativa, analize idiolekta te analize autorskih jezika istražila se polazišna tezu o kružnom procesu
u kojemu se društveno-političke i jezične mijene odražavaju na idiolekte i autorske jezične odabire
u glazbenim tekstovima, a koji pak, s druge strane, brzom rasprostranjivosti preko masovnih
medija utječu na jezične ideologije te nacionalnu afirmaciju i popularnost regiolekta. Ovo je
kvalitativno, interdisciplinarno istraživanje iz područja sociolingvistike, glazbenotekstne
lingvistike, dijalektologije i jezične biografistike čiji inovativan metodološki okvir obuhvaća
jezičnobiografski intervju, kvalitativnu analizu sadržaja, metode tekstne lingvistike, dodirnog
jezikoslovlja i analize diskursa koja otkriva kojim diskursnim strategijama pozicioniraju varijetete
te konstruiraju individualne i društvene identitete. Autorskim radom nastaju pjesme s kojima se
slušatelji poistovjećuju pa je u radu predstavljen inovativan, novoosmišljeni model pjevanog
diskursa u kojemu se iskazuju, izgrađuju te prenose (višestruki) identiteti. Analizom zabilježenog
govora potvrđeno je da se primarni i sekundarni jezični utjecaji ogledaju u idiolektima ispitanika.
Tekstna analiza pjesama potvrdila je polazišnu tezu da su jezična politika restandardizacije
hrvatskoga jezika u svrhu izgradnje nacionalnog identiteta te utjecaj američke rock kulture i razvoj
urbane splitske scene devedesetih godina 20. stoljeća utjecali na autore i rezultirali češćom uporabom standardnoga jezika u njihovim tadašnjim autorskim tekstovima. Također, jačanje
regiolekata u 21. stoljeću, kao i osobno sazrijevanje nekih autora, rezultiralo je češćom uporabom
regiolekta u tekstovima ranih dvije tisućitih godina do danas. Triangulacijom podataka svih analiza
dobiveni su vrijedni odgovori na istraživačka pitanja: autori iskazuju snažan lokalni identitet;
koriste više jezičnih varijeteta potaknuti različitom motivacijom; u školama se uporaba
dijalektalnog govora branila ili poticala ovisno o društveno-povijesnim prilikama određenog
razdoblja; posvjedočili su popularnosti dalmatinskog regiolekta u drugim krajevima Hrvatske i
susjednih zemalja; osnovni motivi za njegovu uporabu u tekstovima jesu melodioznost, emotivnost
i autentičnost, a istraživanje je otkrilo i promjenu u pristupu medija prema dalmatinskom
regiolektu od 1960-ih do danas.1. Introduction In Croatia there is a rich history of research of its three dialects, the turbulent processes of language standardization and the status of language varieties. The specific internal variety dynamics is also reflected in language practices of popular music songwriters from the 1960s to the present day, with special notice that there was a tendency of writing lyrics in standard Croatian during the nineties. It was a war and post-war period during which political and linguistic tendencies were designed to strengthen national unity and identity. The aim of the research is to investigate the circular process in which socio-political and linguistic circumstances are reflected in author’s language choices in musical texts, which in turn through rapid media widespread influence language ideologies, national affirmation of the Dalmatian regiolect and supra-regional language norms at the lexical and phraseological level. The theoretical framework of this interdisciplinary research consists of language biographical studies, text linguistics and contact linguistics, dialectology and musical text linguistics. It uses sociolinguistic terminology, and where the research results require, Croatian dialectological terminology is applied. The research is based on the qualitative analysis of narrative interviews with ten most popular authors selected because they write in the Dalmatian regiolect and standard Croatian, in periods of significant change in language policies. The formal-functional structure of the narrative, discourse strategies used by the informants to express positioning and the construction of individual and collective identities are analysed. Furthermore, by analysing their musical texts (lyrics) it is determined whether they write in standard Croatian during the nineties and to what extent do the narrative statements about their linguistic tendencies match their actual authorial language practice. The analysis of their idiolect, recorded in the interview, determined which language variant they speak and if it matches their authorial language. All the data is then combined in order to recreate the picture of certain language ideologies in the last seventy years and to reconstruct language biographies of the most important songwriters in the Dalmatian regiolect area. 2. Theoretical framework and previous research According to Ivo Žanić (2016), the beginning of sociolinguistics in Croatia is considered to be the 1952 article by Slavko Pavešić which presented language practices of Croatian speakers as a specific dialectal situation. In 1997 Dalibor Brozović pointed out that the three dialects essentially define Croatian language and enrich it with a built-in heritage. However, such an affirmative attitude towards dialects was not viewed favourably by language purists in certain years and regional varieties were usually stigmatized and corrected as wrong within the educational system. This influenced the public perception and status of Croatian dialects and other language varieties. In the first half of the 20th century, the Adriatic area was not integrated into the national identity narrative and Katičić (2004: 14) asserted that the Dalmatian regiolect was unfairly neglected as a result of national linguistic standardization which was "performed in the light of inappropriate linguistic ideology". However, the integration of the regiolect into the national cultural and linguistic framework took place in the 1960s mainly through media, especially TV series Malo and Velo Misto, popular music and the Split Festival. A natural absorption occurred of the Mediterranean sociocultural lexicon into the Novoštokavian, standard language norm (Žanić, 2016: 195). Thus, one can say that popular music "actually corrects what the educational system often fails to set in elementary school" (Žanić, 2015a). Based on the Bourdieu's 1992 theoretical model, standard language tends to acquire a hegemonic position and prestige in relation to other varieties through the mediation of schools and through its connection with elite groups, but it seems that this is not the case in Croatia (Žanić, 2015b). The first Croatian research on the status of varieties conducted in 1988 showed that high school students actually attribute prestige to the Split and Zagreb vernaculars, as idioms of the most important urban national centres, and not to the standard language which has a reduced status (Jakovčević, 1988). More recent research (Sujoldžić, 2009; Šimičić and Sujoldžić, 2013) also show a rather low status of the standard, which "is not surprising given the frequent perception of this variant as artificial and formalized" (Sujoldžić, 2009: 101). Based on research of the role of varieties in popular music in Croatia, sociolinguist Ivo Žanić confirms that the three dialects or regional varieties – Kajkavian, South Chakavian and North Chakavian – are recognized in popular music genres. The sociolinguistic role of popular music and festivals in the emancipation of dialects and their speakers was highlighted in 1972 by linguist Ljudevit Jonke who claimed that dialects are vital thanks to music and that they transcend their local area reach. The aforementioned role of the festival was also apostrophized by Stjepko Težak (1997: 21) and Dubravka Sesar who pointed out that through the mediation of popular music and festivals dialects do not disappear but "consolidate and achieve a certain degree of autonomy" (2004: 74). The widespread of the Dalmatian regiolect started in the sixties through media and popular music and gained full national recognition in the former state of Jugoslavija during the eighties, also called the Golden period of Split Festival. A crucial historic overturn happened in 1990 when Jugoslavija started fragmentizing and the Croatian War of Independence changed political and linguistic circumstances. In Croatia the 1990s were largely characterized by linguistic purism and prescriptivism intended to distinguish Croatian from Serbian (Kapović, 2013: 392) and patriotic songs sung in Croatian by means of which politicians and linguists were empowering national identity through Croatian language independence and purity. On the other hand, it was during the late eighties and nineties when a strong urban music scene developed in Split under the influence of American and British pop and rock bands. It is notable that under both circumstances authors of popular music in the area of Dalmatian regiolect started writing lyrics in the standard Croatian variety more often than in the regiolect. Only in the region of Istria did the northern Chakavian dialect become stronger through the "Ča wave" music genre whose authors were influenced by the linguistic policy of deliberate preservation of dialects (Žanić, 2015a). In the 21st century the ideas of nation, language, and identity started being questioned under the influence of neoliberalism, globalization, and economic and political conditions that lead countries into post-nationalism (Heller, 2011). At the turn of the millennium, the three original dialects in Croatia transformed into a trinity combined of standard – Zagreb vernacular –Split vernacular (or Dalmatian regiolect), and the standard's "functional and thematic comprehensiveness was challenged", especially in media and popular music (Žanić, 2010). Various language varieties and dialects started to be heard more often in popular TV shows on national and private TV, so there seems to be more liberty in using one’s idiolect freely in media discourse and thus in music lyrics as well. Today new authors are open to linguistic innovations and use idioms creatively (Žanić, 2015a). However, their idiom is no longer an "authentic dialect" but a hybridized slang dialect (Berruto, 1994) in which the dominant distinguishing features of the Chakavian dialect are eliminated (Vranić and Zubčić, 2015: 53) and anglicisms give it a modern touch and prestige. Choosing a non-standard language variety in lyrics is thus an act of identification which enables authors to escape into linguistic anarchism and individualism (Robertson, 1994). Through their linguistic choices they position themselves in the world and define the groups they consider to be members of and those they want to distinguish themselves from (Novak, 2012: 147–199). However, Peti-Stantić and Langston (2013: 3) conclude that it is usually not possible to completely objectively describe the relations between language communities and language varieties by means of theoretically accepted classifications of languages and dialects, but it is necessary to take into account various sociolinguistic factors. Because we are reconstructing biographies in this research we are dealing with all notions of identities, individual, collective, local, regional, national, and authorial. In contemporary linguistics, researches of the connection between language and identity began with variationist sociolinguistics in the 1970s which presented results statistically. In the last few decades, under the influence of poststructuralist thought, the essentialist notion of an unchanging and permanent identity has been rejected so identities are viewed as dynamic, fluid, changing and often contradictory processes (De Fina et al., 2006; Benwell and Stokoe, 2006) and are investigated in qualitative studies. Kalogjera (2007: 261) pointed out that identity is most clearly expressed in discourse, in communicative interaction, "when a communicatively competent individual chooses expressions from one’s language repertoire by means of which one builds and expresses identity, that is, the identity of belonging to a certain group". So, when describing a speaker's identity and social roles, later approaches such as interactionist sociolinguistics started taking into account the situational context and social and discourse conventions of language use (Bamberg et al., 2007). Identity is thus expressed and built through narrative, which was defined as the oral transmission of personal experiences by Labov and Waletzki in 1967. Labov later set theoretical guidelines for the sociolinguistic analysis of narratives and Schiffrin (1996) also emphasized that the central function of the narrative is the sociolinguistic construction of identity. With the development of sociolinguistics, the narrator as the bearer of cultural and social norms, the functional characteristics of the narrative, the situational context and narrative expression of identity started being studied. In this study we adopt the concept of identity as it is determined in Western, postmodern societies, as a fragmented and plural concept and as a reflection of socio-historical circumstances (Lucius-Hoene and Deppermann, 2004), and determine in which ways and by which discourse means the authors/informants express and build their identities. Because the informants produce lyrics, which are texts intended to be sung and are thus research material in musical discourse, we adopted analytical methods of musical text analysis which determined how musical discourse is used to express identity and how it can be used as a tool for social change (Pavlovova, 2013). Sociolinguist Ivo Žanić set the framework of musical text sociolinguistics in Croatia and expanded the terminological dichotomy of two types of language discourse – spoken and written – into a triadic division by introducing the so-called sung discourse, as part of the broader musical discourse theory. In this paper we took a step forward and integrated notions from identity theories into musical discourse theory and presented a newly designed model of sung discourse with the implementation of concepts of author’s identity (Ahonen, 2007). (...)
In approaching the narrative experience, the most commonly used method is the linguistic biographical method. It was mentioned for the first time as a method of contact linguistics in the 1991 manual of German linguists Bechert and Wildgen. It is an adaptation of the biographical method firstly used in sociology and applied in analysis of sociolinguistic and contact linguistic issues (Piškorec, 2007: 457). It provides a differentiated perspective on language acquisition processes and language use enabling a direct insight into how individual experience is connected to social context (Piškorec and Zelić, 2006: 278). In European tradition, language biographies are collected through biographical interviews of informants in order to reconstruct their linguistic biographical trajectories (Nekvapil, 2000; Franceschini, 2003). Narrative data are then often triangulated e.g. combined with socio-historical and socio-political data (Abramac, 2014: 96). In Croatian linguistics some papers deal with linguistic construction of ethnic identity (Starčević, 2014; Abramac, 2014; Ščukanec, 2017; Grgić, 2018), certain aspects of personal identity construction (Bertoša and Novak, 2014; Podboj, 2019) and narrative identity reconstruction in linguistic biographical narratives (Piškorec, 2007). This interdisciplinary research will implement the language biographical method within a theoretical framework based on sociolinguistics, dialectology and musical text linguistics. 3. Research objective and hypotheses. The aim of this work is to recreate language biographies of popular music lyricists from the Dalmatian regiolect area and thus define their linguistic identities. The fractal identity theory was researched by determining primary language influences, in the family, and secondary influences of education, peers, and socio-historic linguistic circumstances, which combined result in the creation of one's personal language repertoires, idiolects, language ideologies, and authorial languages, i.e. one's language identity. The first thesis is the existence of a circular process in which firstly socio-historic, linguistic circumstances and language ideologies are directly reflected in authorial languages, with emphasis on the reflection of standardization policies and national identity of the newly formed state of Croatia as well as the influence of rock’n’roll urban culture in the 1990s. Secondly, due to a massive, widespread reach through rapid media dissemination those authorial language choices in popular lyrics influence national language ideologies, the perception and status of the regiolect, and also influence the standard Croatian language norm. The second thesis is rooted in the postmodern notion that a person’s identity is of a fractal nature. Thus, language identity consists of various language varieties that are part of a person’s language repertoire from which the speaker consciously or unconsciously selects language items depending on the speaking situation, topic, location or interlocutor. The repertoire of each person is like a collage gradually built from birth, under t
Coumarin derivatives of 1,2,4-triazole - synthesis and biological activity related to plant protection application
No full textU okviru doktorskog rada sintetizirani su kumarinski 1,2,4-triazoli s mogućim višestrukim biološkim učincima vezanim za primjenu u zaštiti bilja. Sinteza je provedena kao one-pot reakcija kumarinskih hidrazida (1 – 3) i različito supstituiranih izotiocijanata u niskotemperaturnom eutektičkom otapalu kolin-klorid : urea (molni omjer 1 : 2), miješanjem na magnetskoj miješalici pri 80 °C. Rezultat su tri serije spojeva: prva, u kojoj je
1,2,4-triazolni prsten povezan -CH2- poveznicom na položaju 4, a hidroksilna je skupina na položaju 7 kumarina (1a – k), te druga serija derivata s 1,2,4-triazolnim prstenom povezanim eterskom poveznicom na položaju 7 kumarina i metilnom skupinom na položaju 4 kumarina (2a – o). Treća, dodatna serija derivata od druge se razlikuje po nedostatku metilne skupine na položaju 4 kumarina (3a – h). Korištenje niskotemperaturnog eutektičkog otapala omogućilo je provođenje reakcije u jednom stupnju, bez primjene katalizatora i organskih otapala štetnih za okoliš. Zbog pojednostavljene izolacije i pročišćavanja produkata, skraćeno je vrijeme trajanja postupka u odnosu na konvencionalnu i druge objavljene metode. Derivati kumarinskih 1,2,4-triazola su dobiveni u prinosima od 25 do 91 %, a njihove su strukture potvrđene masenom spektrometrijom te 1H i 13C NMR spektroskopijom. Svim priređenim spojevima računalno je procijenjena sličnost s pesticidima te toksičnost za čovjeka i okoliš. Utvrđeno je kako većina spojeva ima povoljan toksikološki profil u odnosu na komercijalne triazolne pesticide. Antifungalno djelovanje in vitro ispitano je na četiri fitopatogene gljive, a antibakterijsko djelovanje na dvije fitopatogene i dvije zemljišno-korisne bakterije. Kumarinski 1,2,4-triazoli uspješno su inhibirali rast micelija gljiva, s izraženim antifungalnim djelovanjem druge serije derivata na Sclerotinia sclerotiorum i Fusarium oxysporum. Sintetizirani spojevi nisu imali antibakterijski učinak ni na patogene ni na zemljišno-korisne bakterije. Na temelju rezultata antifungalnog djelovanja provedena je analiza kvantitativnog odnosa strukture i aktivnosti (QSAR) spojeva. Model za djelovanje na S. sclerotiorum razvijen je pomoću tri deskriptora (nR=Ct, RDF095m i HATS1e) i može objasniti 79 % inhibitornog djelovanja kumarinskih 1,2,4-triazola. Model za djelovanje na F. oxysporum razvijen je pomoću četiri deskriptora (R4u+, nAROR, RDF080e i Mor11u), a može objasniti 77 % inhibitornog djelovanja spojeva. Pouzdanost razvijenih modela potvrđena je metodama unutarnje i vanjske procjene valjanosti. Potencijalni mehanizam antifungalnog djelovanja istražen je metodom molekulskog uklapanja spojeva u enzime važne za rast micelija (sterol 14α-demetilazu, hitinaze A i B, N-miristoil transferazu) te enzime potrebne za razaranje stanične stijenke domaćina (proteinazu K, endoglukanazu I te endopoligalakturonaze I i II). Spojevi su se dobro uklopili u aktivna mjesta demetilaze, hitinaza A i B, proteinaze K te endopoligalakturonaza I i II. Unatoč dobrim energijama uklapanja, spojevi nisu uspjeli ostvariti interakcije u aktivnim mjestima N-miristoiltransferaze i endoglukanaze. Iz dobivenih rezultata može se zaključiti kako su derivati druge serije kumarinskih triazola potencijalni inhibitori demetilaze, obje hitinaze ili proteinaze K, dok su derivati prve serije spojeva inhibitori endopoligalakturonaza. Spoj 2j ističe se svojim antifungalnim djelovanjem i procjenjenom niskom toksičnosti, što ga čini dobrim kandidatom za razvoj novog aktivnog sastojka sredstava za zaštitu bilja.In this doctoral thesis, coumarin 1,2,4-triazoles with potential multiple biological effects related to application in plant protection were synthesized. The synthesis was carried out as a one-pot reaction of coumarin hydrazides (1 – 3) and differently substituted isothiocyanates in a deep eutectic solvent, choline chloride : urea (molar ratio 1 : 2), by stirring with a magnetic stirrer at 80 °C. The result is three series of compounds: the first in which the 1,2,4-triazole ring is connected by a -CH2- linker at position 4 and the hydroxyl group is at position 7 of the coumarin (1a – k), and the second series of derivatives with a 1,2,4-triazole ring connected by an ether linker at position 7 of the coumarin and a methyl group at position 4 of the coumarin (2a – o). The third, additional series of derivatives, differs from the second by the absence of a methyl group at position 4 of coumarin (3a – h). The use of a deep eutectic solvent enabled to carry out the reaction in one step without the need to use catalysts and environmentally harmful organic solvents. The simplified isolation and purification of the products shortened the duration of the process compared to conventional and other published methods. The derivatives of coumarin 1,2,4-triazoles were obtained in yields of 25 to 91 %, and their structures were confirmed by mass spectrometry and 1H and 13C NMR spectroscopy. All prepared compounds were evaluated in silico for their similarity to pesticides and their toxicity to humans and the environment. Most of the compounds were found to have a favorable toxicological profile compared to commercial triazole pesticides. The antifungal activity was tested in vitro on four phytopathogenic fungi, and the antibacterial activity on two phytopathogenic and two soil-beneficial bacteria. Coumarin 1,2,4-triazoles successfully inhibited the growth of fungal mycelia, with the second series of derivatives showing pronounced antifungal activity on Sclerotinia sclerotiorum and Fusarium oxysporum. The synthesized compounds did not show antibacterial activity, neither on the pathogens nor on the soil-beneficial bacteria. Based on the results of antifungal activity, a quantitative structure-activity relationship (QSAR) analysis of the compounds was performed. The model for the effect on S. sclerotiorum was developed using three descriptors (nR=Ct, RDF095m and HATS1e) and can explain 79 % of the inhibitory effect of coumarin 1,2,4-triazoles. The model for the effect on F. oxysporum was developed using four descriptors (R4u+, nAROR, RDF080e and Mor11u) and can explain 77 % of the inhibitory effect of the compounds. The reliability of the developed models was confirmed by internal and external validation methods. The potential mechanism of antifungal activity was investigated by means of molecular docking of the compounds to the enzymes important for mycelial growth (sterol 14α-demethylase, chitinases A and B, N-myristoyltransferase) and enzymes necessary for host cell wall destruction (proteinase K, endoglucanase I and endopolygalacturonase I and II). The compounds fit well into the active sites of demethylase, chitinases A and B, proteinase K, and endopolygalacturonase I and II. Despite good fitting energies, the compounds failed to achieve interactions in the active sites of N-myristoyltransferase and endoglucanase. From the obtained results, it can be concluded that the derivatives of the second series of coumarin triazoles are potential inhibitors of demethylase, chitinases or proteinase K, while the derivatives of the first series of compounds are inhibitors of endopolygalacturonases. Compound 2j stands out for its antifungal activity and its estimated low toxicity, which emphasized it as a good candidate for the development of a new active ingredient for plant protection products
Funkcionalna analiza gena povezanih s glikozilacijom imunoglobulina G
No full textImmunoglobulin G (IgG) is a key player in the human immune system. Pletohora of its roles is determined by its alternative N-glycosylation of Fc region, which has a role in defining its pro- or antiinflamatory character. Except Fc region, 20-25% of IgG molecules are glycosylated on the Fab region. Genome-wide association studies (GWAS) showed that IgG glycosylation is regulated by a complex gene network including genes with roles in immune cell development and immune response. However, role of these genes in IgG glycosylation is unknown. Therefore, twenty-three of GWAS hits were selected for functional validation in a model system FreeStyle™ 293-F with VPR-dSaCas9 and KRAB-dSpCas9 stably integrated in the genome. This system was modified for simultaneous analysis of Fab and Fc glycosylation followed by gene manipulation. Ten genes were functionally proven to be relevant for Fab and/or Fc glycosylation: KIF3C, MANBA, TNFRSF13B, EEF1A1, HIVEP2, TBX21, SPPL3, DERL2, RRBP1, and KDELR2.Imunoglobulin G (IgG) jedan je od ključnih igrača u imunom sustavu čovjeka s velikim brojem različih uloga koje su određene altrernativnom N-glikozilacijom njegove Fc regije, uključujući njegovo proupalno ili protuupalno djelovanje. Izuzev regije Fc, 20-25% molekula IgG je glikozilirano na regiji Fab. Cjelogenomske studije povezanosti (engl. genome wide association studies, GWAS) su otkrile da je glikozilacija IgG-a regulirana kompleksnom mrežom gena koja uključuje gene s ulogom u razvoju imunoloških stanica i imunološkim odgovorima, čija uloga u IgG glikozilaciji nije poznata. Dvadesettri gena otkrivenih studijama GWAS odabrano je za funkcionalnu validaciju u staničnom modelu FreeStyle™ 293-F sa stabilno ugrađenim fuzijama VPR-dSaCas9 i KRAB-dSpCas9 za manipulaciju gena, a koji je modificiran u svrhu istovremene analize glikozilacije regija Fab i Fc. Rezultat ovog istraživanja otkriva deset gena (identificiranih studijama GWAS) s ulogom u Fab i/ili Fc glikozilacijskom putu: KIF3C, MANBA, TNFRSF13B, EEF1A1, HIVEP2, TBX21, SPPL3, DERL2, RRBP1 i KDELR2
The Relationship Between the Strategic Role of the Supervisory Board and the Integration of Sustainability Goals
No full textIstraživački problem predmetne disertacije odnosi se na ispitivanje povezanosti načina preuzimanja strateške uloge nadzornog odbora i integracije ciljeva održivosti u poslovanje poduzeća. Nadalje, disertacija ispituje moderacijski efekt veličine i određenih obilježja sastava nadzornog odbora na navedenu povezanost. Na koncu, ispituje se signifikantnost određenih procesa grupne dinamike u nadzornom odboru kao antecedenata razine uključenosti nadzornog odbora u strateška pitanja poduzeća. Rezultati empirijskog istraživanja koje je provedeno među-metodnom triangulacijom potvrđuju povezanost strateške uloge nadzornog odbora i integracije ciljeva održivosti. Pritom je moderacijski efekt na navedenu povezanost potvrđen samo za raznolikost znanja i vještina u nadzornom odboru. Na koncu, rezultati potvrđuju utjecaj kognitivnog konflikta, normi truda te primjene znanja i vještina u nadzornom odboru na razinu strateške uključenosti nadzornog odbora. Mapirajući znanstveni prostor na sjecištu korporativnog upravljanja i korporativne održivosti, uz navedeni empirijski doprinos, disertacija kroz bibliometrijsko istraživanje ostvaruje i znanstveni doprinos. Disertacija na temelju empirijskog doprinosa pruža i niz preporuka za unaprjeđenje zakonskog i regulatornog okvira čime ostvaruje i važan aplikativni doprinos.This doctoral thesis is grounded in theoretical assumptions of stakeholder theory and investigates the relationship between the level of supervisory board involvement in the company's strategy and the integration of sustainability goals. Also, this dissertation aims to examine the moderating effects of board size and certain board composition characteristics on the aforementioned relationship. Finally, this thesis aims to determine if certain group dynamics processes influence the level of supervisory board involvement in strategic issues.
Therefore, this thesis is based on three major hypotheses: (H1) group dynamics in the supervisory board is positively related to the strategic role of the supervisory board; (H2) strategic role of the supervisory board is positively related to the integration of sustainability goals, and (H3) size and composition of the supervisory board positively moderate the relationship between the strategic involvement of the supervisory board and the integration of sustainability goals. In order to investigate these assumption, a mixed-method triangulation empirical study is conducted.
The results of this empirical research largely corroborate the initial assumptions. Both quantitative and qualitative research phases confirm the existance of significant positive relationship between the level of supervisory board involvement in the company's strategy and the integration of sustainability goals, thereby confirming H2. This relationship is however only moderated by the diversity in knowledge and experience of board members, while quantitative data failed to establish such an effect for both board independence and gender diversity, and qualitative data failed to confirm initial quantitative research finding for board size. Therefore, H3 was only partially supported. Finally, empirical research confirmed the positive effects of cognitive conflict, effort norms and the use of knowledge and experience of board members on the level of board inveolvement in strategic issues, fully confirming H1.
The scientific contribution of this doctoral thesis encompasses also the bibliometric analysis of the research space at the nexus of corporate sustainability and corporate governance. Finally, the applicative contribution of the dissertation consists of several legislative and regulatory proposals aimed to increase the contributions of corporate governance to corporate sustainability adoption
Epigenetic status and expression of SALL4 in normal and impaired testicular development
No full textUloga gena SALL4, koji kontrolira razvoj spermatogonija, nije dovoljno istražena u razvoju sjemenika sisavaca, a u neplodnosti čovjeka je potpuno neistražena. Cilj disertacije bio je analizirati izražaj Sall4/SALL4 u razvoju sjemenika štakora in vivo i in vitro te u ljudskim sjemenicima s različitim dijagnozama neopstruktivne azoospermije (NOA) in vivo, kao i njegov metilacijski status u in vivo uzorcima. Pirosekvenciranjem je pokazano da je SALL4/Sall4 uvijek hipometiliran u sjemeniku. qRT-PCR-om je pokazan značajno veći izražaj Sall4 mRNA u fetalnom štakorskom sjemeniku nego u postnatalnom; a u ljudskim sjemenicima sa sindromom samo Sertolijevih stanica (SCOS) SALL4 mRNA je snižena u odnosu na hipospermatogenezu (HS) i zastoj u sazrijevanju (MA). Osim u spermatogonijama, poboljšanim IHC i IF protokolima je po prvi put pokazan SALL4 u XY tjelešcu primarnih spermatocita. Također, pokazan je pojačan izražaj SALL4 u pre-pahitenskim spermatocitama i citoplazmi intersticijskih stanica u neplodnom sjemeniku u odnosu na zdravi i HS sjemenik čovjeka. Nadalje, uspostavljen je novi 3D in vitro sustav za uzgoj tkiva sjemenika štakora, a primjena siRNA snizila je izražaj Sall4 na mRNA (za 42 %) i proteinskoj razini uzrokujući smanjeni rast i narušenu histologiju. Ovi rezultati ukazuju na SALL4 kao novi potencijalni biljeg u dijagnostici NOA te podrobnije rasvjetljavaju njegovu ulogu u procesu spermatogeneze.The role of the SALL4 gene which controls the development of spermatogonia, has been insufficiently investigated in the development of the mammalian testis, and is completely unexplored in human infertility. The doctoral thesis aimed to analyze the expression of Sall4/SALL4 in the rat testis development in vivo and in vitro as well as in the human testis with a different diagnosis of nonobstructive azoospermia (NOA) and its DNA methylation status. The pyrosequencing showed that SALL4/Sall4 is always hypomethylated in the testis. The qRT-PCR has shown significantly higher expression of the Sall4 mRNA in fetal rat testis than in postnatal; while SALL4 mRNA was lower in human testis with Sertoli cell only syndrome (SCOS) than in hypospermatogenesis (HS) and maturation arrest (MA). Except in spermatogonia, improved IHC and IF protocols showed the expression of the SALL4 protein in the XY body of primary spermatocytes of human testes. Also, increased expression of SALL4 in pre-pachytene spermatocytes and cytoplasm of interstitial cells in infertile compared to healthy human testis was demonstrated. Furthermore, an original 3D in vitro system for the cultivation of rat testis tissue was established, and the application of siRNA decreased Sall4 at the mRNA (by 42 %) and protein levels, causing reduced growth and impaired histology. These results indicate SALL4 as a new potential marker in the diagnosis of NOA and shed more light on its role in the process of spermatogenesis