<p>Mikrokapsule, kao nosači aktivnih supstanci, imaju sve veću primenu u različitim granama industrije, naročito prehrambene i farmaceutske. Inkorporiranje biolo&scaron;ki aktivnih supstanci unutar mikrokapsula omogućava maskiranje neprijatnih mirisa i ukusa, za&scaron;titu osetljivih i lako isparljivih komponenata.<br />Cilj ove doktorske disertacije je dobijanje mikrokapsula za istovremeno inkorporiranje hidrosolubilnih i liposolubilnih aktivnih materija, radi njihove za&scaron;tite i kontrolisanog otpu&scaron;tanja. Mikrokapsule su formirane iz duplih emulzija tipa voda-ulje-voda (V/U/V) metodom koacervacije, odnosno deponovanjem koacervata, koji nastaje u sistemu dva suprotno naelektrisana proteina, želatina i natrijum kazeinata (NaKN), na granicu faza ulje/voda. Kao model supstance za hidrosolubilne i liposolubilne biolo&scaron;ki aktivne materije, kori&scaron;ćeni su vitamini C i E.<br />Najpre su detaljno ispitane interakcije u sistemu želatin/NaKN primenom različitih metoda (merenje zeta potencijala, tenziometrija, viskozimetrija, reolo&scaron;ka ispitivanja). Na osnovu ovih rezultata definisane su promene, kako na granici faza, tako i unutar rastvora, kao i mehanizama formiranja koacervata između ova dva suprotno naelektrisana proteina. Utvrđeno je da se pri masenom odnosu želatin:NaKN od 2:1 dolazi do formiranja nerastvornog koacervata. Ispitan je uticaj interakcija u ovom sistemu na osobine duplih, V/U/V emulzija dobijenih emulgovanjem primarnih voda/ulje (V/U) emulzija u sme&scaron;i želatin/NaKN, pri njihovim odabranim masenim odnosima i zaključeno je da interakcija između proteina u kontinualnoj fazi utiče na<br />osobine emulzija.<br />S obzirom da je prvi korak ka dobijanju stabilne V/U/V emulzije, dobijanje stabilne primarne V/U emulzije, ispitana je mogućnost primene lipofilnih emulgatora, poliglicerol poliricinoleata (PGPR) i poliglicerol estra jestivih masnih kiselina i njihovih sme&scaron;a, za dobijanje 20% V/U emulzija. Ispitivanjem uticaja sastava sme&scaron;e emulgatora i njegove koncentracije na formiranje adsorpcionog sloja na graničnoj povr&scaron;ini ulje/voda i osobine formiranih V/U emulzija odabran je najpogodniji sistem za stabilizaciju primarnih emulzija.<br />Nakon formulisanja stabilnih duplih V/U/V emulzija sa inkorporiranim vitaminima C i E, optimizovani su uslovi za dobijanje mikrokapsula umrežavanjem kompleksa proteina na kapima ulja pomoću genipina, a njihovo izdvajanje iz rastvora ostvareno je primenom Spray drying postupka. Karakterizacijom dobijenih mikrokapsula (ispitivanjem morfologije povr&scaron;ine, efikasnosti inkapsulacije vitamina C i E, kinetike otpu&scaron;tanja vitamina C u in vitro uslovima) zaključeno je da na osobine mikrokapsula utiče koncentracija umreživača, kao i interakcija između želatina i NaKN u kontinualnoj fazi emulzija V/U/V.</p> / <p>Microcapsules, as active substance carriers, have increasing application in different industries, especially in food and pharmaceutical industry. Incorporation of the biologically active substances inside the microcapsules allows masking of unpleasant taste and smell, protection od sensitive and volatile components.<br />The aim of this thesis is preparation of microcapsules for parallel incorporation of water and oil soluble active substances for their protection and controlled release. Microcapsules were formed from double water-oil-water emulsions (W/O/W) by coacervation method, depositing the coacervate formed in the system of two oppositely charged proteins, gelatin and sodium caseinate (NaCN), at the water/oil interface. As a model for water and oil soluble biological active substances, vitamins C and E were used.<br />First of all, interactions in the gelatin/NaCN system were investigated in detail, by using different methods (measuring of zeta potential, tensiometry, vicometry, rheological investigations). Based on these results, changes at the interface and in the bulk of the system, as well as mechanisms of coacervate formation were defined. It has been determined that at gelatin:NaCN mass ratio of 2:1 non soluble coacervate were formed.<br />Influence of the interactions in this system on properties of the W/O/W double emulsions, made by emulsification of primary water/oil (W/O) emulsions in gelatin/NaCN mixtures, at desired mass ratios of proteins, was investigated. It was concluded that interactions between proteins in continuous phase of emulsions have influence on their properties.<br />As the first step in formation of stable W/O/W emulsions is<br />obtaining stable primary W/O emulsion, possibility of using lipophilic emulsifiers, polyglycerol polyricinoleate (PGPR) and polyglycerol esters of edible fatty acids and their mixtures, for 20% W/O emulsions formation were investigated. Results of these investigations showed that composition of emulsifiers mixtures and their concentrations have an influence on adsorption layer, at the water/oil interface, formation, as well as on stability of W/O emulsion, and based on these results the most suitable system of emulsifiers were chosen.<br />After formulation of stable double W/O/W emulsions with incorporated vitamins C and E, conditions for microcapsules formation, by crosslinking of proteins complex at oil droplets with genipin, were optimized, and for their separation from dispersion spray drying method was applied. Characterization of obtained microcapsules (investigation of the surface morphology, efficiency of the vitamins C and E encapsulation, release kinetics of vitamin C under in vitro conditions) showed that concentration of crosslinking agent, as well as interaction between gelatin and NaCN, have an influence on microcapsules properties.</p>

<p>Savremene svetske tendencije upućuju na sve &scaron;iru primenu<br />ekstrakata lekovitog i aromatičnog bilja, kako u prehrambenim<br />proizvodima&ndash; funkcionalna hrana, tako i u proizvodima<br />farmaceutske i kozmetičke industrije. Ekstrakti biljnog<br />materijala, dobijeni primenom ugljendioksida pod pritiskom,<br />sadrže termički nepromenjene aktivne komponente, te se<br />poslednjih godina sve vi&scaron;e primenjuju u farmaceutskoj i<br />prehrambenoj industriji.<br />Cilj ove doktorske disertacije je da se ispita mogućnost<br />inkorporiranja ekstrakta nevena (<em>Calendula officinalis</em> L.), kao<br />farmakolo&scaron;ki aktivne materije, u mikrokapsule sa ciljem za&scaron;tite<br />od spolja&scaron;njih uticaja, produžetka njegovog delovanja i<br />pro&scaron;irenja mogućnosti primene.<br />Za dobijanje ekstrakata nevena primenjeni su postupci<br />ekstrakcije ugljendioksidom u tečnom i superkritičnom stanju.<br />Definisani su uslovi pri kojima je moguće dobiti ekstrakat sa<br />visokim sadržajem etarskog ulja, nosiocem gastro-intestinalnog<br />delovanja (200 bar, 40^oC). Totalni ekstrakt dobijen pod ovim<br />uslovima ekstrakcije je odabran za dobijanje mikrokapsula.<br />Ispitivana je mogućnosti primene polimer&ndash;PAM interakcije<br />nejonskih derivata celuloze- hidroksipropilmetil celuloze<br />(HPMC) i anjonske PAM- natrijum dodecilsulfata (SDS), za<br />formiranje omotača mikrokapsula. Primenom konduktometrijske<br />i viskozimetrijske metode, određene su karakteristične<br />koncentracije pri kojima HPMC&ndash;SDS interakcija započinje i<br />zavr&scaron;ava se. Definisan je uticaj osobina molekula HPMC<br />(molekulska masa, stepen supstitucije, vrsta supstituenta) i<br />temperature na &scaron;irinu intervala interakcije i obja&scaron;njeni<br />mehanizmi njihovog povezivanja, sa osvrtom na strukturu i<br />osobine formiranih HPMC/SDS komleksa. Reolo&scaron;kim<br />ispitivanjima pri različitim uslovima definisane su promene u<br />pona&scaron;anju sistema u zavisnosti od HPMC&ndash;SDS interakcije.<br />Ispitivan je uticaj interakcije na osobine 20% emulzija<br />suncokretovog ulja u vodi određivanjem njihovih reolo&scaron;kih<br />osobina, veličina i raspodela veličina kapi i praćenjem<br />stabilnosti. Utvrđeno je da se u oblasti najizraženije HPMC&ndash;SDS interakcije, odnosno kada se na granici faza ulje-voda<br />nalazi umrežen HPMC/SDS kompleks, dobijaju emulzije<br />najveće stabilnosti, sa njajmanjim srednjim prečnikom kapi.<br />Su&scaron;enjem emulzija, primenom spray drying postupka,<br />dobijene su mikrokapsule uljnog sadržaja, stabilizovane<br />kompleksom HPMC/SDS. Najbolje karakteristike mikrokapsula<br />(mehanička otpornost, morfolo&scaron;ke karakteristike, sposobnost<br />redispergovanja, veličina i raspodela veličina čestica i količina<br />inkapsuliranog ulja), dobijene u oblasti najizraženije interakcije.<br />Dodatak odabranog CO₂ ekstrakta nevena u uljnu fazu<br />emulzija ne menja značajno njihove osobine, kao ni osobine iz<br />njih dobijenih mikrokapsula.<br />Ispitivanja sprovedena u ovoj doktorskoj disertaciji<br />pokazala su da se osobine kompleksa polimer/PAM mogu<br />iskoristiti za mikrokapsulaciju ulja kao nosača farmakolo&scaron;ki<br />aktivnih materija.</p> / <p>Contemporary global trends in food- functional food,<br />pharmaceutical and cosmetic industry as well have been<br />focused on a wider medical plants extracts application during<br />the recent decade. Plant extracts obtained by means of carbon<br />dioxide under high pressure contained all unchanged active<br />compounds from plant, so that they have became more<br />popular for application in food and pharmaceuticals recently.<br />The aim of this thesis was to investigate the possibility to<br />incorporate marigold extract (<em>Calendula officinalis</em> L.), as a<br />pharmacologicaly active compound, into microcapsules in<br />order to protect them from surrounding medium, improve<br />their activity and enlarge application.<br />Marigold extracts were obtained by means of carbon<br />dioxide- CO2 under subcritical and supercritical conditions.<br />Extraction conditions under which obtained extract has high<br />content of essential oil, responsible for gastrointestinal<br />activity, were determined (200bar and 40^oC). Total extract<br />obtained under such conditions, was chosen for microcapsule<br />preparation. Application possibility of polymer&ndash;surfactant<br />interaction between non-ionic cellulose derivativehydroxypropylmethyl<br />cellulose (HPMC) and anionic<br />surfactant- sodium dodecylsulfate (SDS) to microcapsule<br />wall formation was investigated. Characteristic<br />concentrations at which interaction starts and ends were<br />determined by means of conductometric and viscometric<br />measurements. The influence of HPMC molecular<br />characteristics (molecular weight, degree of substitution and<br />substituents kind) and temperature on interaction were<br />determined and, considering the structure and characteristics<br />of HPMC/SDS complexes, binding mechanism was<br />explained. The changes in HPMC-SDS system caused by<br />their interaction were defined by rheological investigations<br />that took place under various conditions.<br />The influence of interaction on the properties of 20%<br />sunflower oil/water emulsion was investigated by rheology<br />measurement, particle size and particle size distribution<br />determination and stability testing. It was provided that<br />emulsions prepared in the region of pronounced HPMC&ndash;SDS<br />interaction, where HPMC/SDS complex is adsorbed at the</p><p>o/w interface, have highest stability and smallest particle<br />mean diameter.<br />Microcapsules were obtained by spray drying of<br />emulsions stabilized with HPMC/SDS complex. The best<br />characteristics (mechanical resistance, morphological<br />characteristics, redispersing ability, particle size and particle<br />size distribution and amount of encapsulated oil) have<br />microcapsules obtained in the region of most pronounced<br />interaction.<br />Addition of marigold CO₂ extract in to the oil phase of<br />emulsions has no significant influence neither on their, nor on<br />corresponding microcapsules characteristics<br />Investigations conducted in this thesis showed that<br />characteristics of polymer/surfactant complexes can be used<br />in microencapsulation of oil as carrier of pharmacologically<br />active compounds</p>

<p>U prvom delu rada ispitana je adsorpcija četiri grupe organskih&nbsp;jedinjenja: (1) nitroaromatičnih (nitrobenzen), (2) nepolarno alifatičnih&nbsp;(heksan), (3)&nbsp; monoaromatičnih (benzen, toluen, 1,2,3- i 1,2,4-trihlorbenzen) i (4) policikličnih aromatičnih ugljovodonika, PAH&nbsp;(naftalen, fenantren, piren i fluoranten) na vi&scaron;eslojnim ugljeničnim&nbsp;nanocevima (od eng. multiwalled carbon nanotubes, MWCNTs). Cilj&nbsp;ovog dela rada bio je pronaći korelaciju između parametara adsorpcije i&nbsp;fizičko-hemijskih karakteristika organskih molekula, kao i parametara&nbsp;<br />adsorpcije i karakteristika adsorbenata. Na osnovu dobijenih korelacija&nbsp;predložiti mehanizam adsorpcije ispitivanih organskih molekula na&nbsp;MWCNT-u.</p><p>U cilju ispitivanja uticaja kiseoničnih funkcionalnih grupa na povr&scaron;ini&nbsp;MWCNT-a odabrane su tri vrste MWCNT-a: originalni, nemodifikovani&nbsp;MWCNT (OMWCNT) i dve vrste funkcionalno modifikovanog&nbsp;MWCNT-a koji su dobijeni tretiranjem sa kiselinom tokom 3 h&nbsp;(FMWCNT3h) i 6 h (FMWCNT6h). Sve adsorpcione izoterme opisane&nbsp;<br />su Freundlich-ovim modelom. Nelinearnost izotermi bila je u opsegu od&nbsp;0,418 do 0,897. Rezultati pokazuju da dobijeni afiniteti adsorpcije (za ravnotežnu koncentraciju 50% rastvorljivosti jedinjenja u vodi, K_d0,5 S_W) za PAH-ove rastu sa povećanjem specifične povr&scaron;ine (SP) adsorbenta. Veći afiniteti adsorpcije dobijeni su za velike molekule kao &scaron;to su PAH-ovi u poređenju sa malim molekulima (benzen, toluen i heksan) &scaron;to može biti posledica veće kontaktne povr&scaron;ine između većih molekula i povr&scaron;ine adsorbenta. Pozitivna korelacija između afiniteta adsorpcije i hidrofobnosti molekula ukazuje da hidrofobne interakcije dominantno kontroli&scaron;u adsorpciju ispitivanih organskih jedinjenja, osim u slučaju nitobenzena. Da bi se ispitao uticaj &pi;-&pi; interakcija,&nbsp; K_d za odabranu ravnotežnu koncentraciju su normalizovane sa hidrofobno&scaron;ću molekula pri čemu su dobijeni odgovarajući&nbsp; K_d/K_OW&nbsp;odnosi. Za sva ispitivana jedinjenja K_d/K_OW<font size="1">&nbsp;</font>odnosi na svim ispitivanim MWCNT rastu u sledećem nizu: nepolarni alifatični &lt; monoaromatični &lt; PAH-ovi &lt; nitrobenzen, &scaron;to ukazuje da &pi;-&pi; interakcije značajno pobolj&scaron;avaju adsorpciju aromatičnih jedinjenja na MWCNT-u. Snažne interakcije između MWCNT-a i nitrobenzena posledica su formiranja &pi;-&pi; elektron donorsko-akceptorskih (EDA) interakcija izemđu nitroaromatičnih molekula (elektron akceptori)i visoko polarizovane ugljenične povr&scaron;ine nanocevi (elektron donori). Na osnovu dobijenih rezultata može se uočiti da se pri adsorpciji ispitivanihorganskih molekula na MWCNT-u istovreme odigrava vi&scaron;e mehanizama.</p><p>U drugom delu rada ispitan je uticaj ugljeničnog nanomaterijala (od eng.&nbsp;carbon based nanomaterial, CNM) natransport odabranih organskih&nbsp;jedinjenja (1,2,3- i 1,2,4-trihlorbenzena, naftalena, fenantrena, pirena i&nbsp;fluorantena) kroz sediment Dunava. Cilj ovog dela rada bio je ispitati&nbsp;mehanizam transporta odabranih organskih jedinjenja u prisustvu i&nbsp;odsustvu CNM. C/C_0&nbsp;vrednosti, dobijene za vreme trajanja eksperimenta&nbsp;<br />(t=96 h), ispitivanog jedinjenja u eluatu kolone napunjene samo&nbsp;sedimentom rastu u sledećem nizu: fluoranten &lt; piren &lt; fenantren &lt;&nbsp;1,2,4-trihlorbenzen &lt; 1,2,3-trihlorbenzen &lt; naftalen. U cilju ispitivanja&nbsp;uticaja hidrofobnosti ispitivanih molekula na sorpciju u neravnotežnim&nbsp;uslovima, dobijene vrednosti C/C₀ ispitivanih molekula su korelirane sa&nbsp;hidrofobno&scaron;ću molekula. Uočena je negativna korelacija &scaron;to ukazuje da&nbsp;hidrofobniji molekuli pokazuju duže vreme zadržavanja na koloni, a time&nbsp;i veću neravnotežnu sorpcijutokom transporta.&nbsp;</p><p>U prisustvu FMWCNT3h u koloni kojaje napunjena sedimentom može&nbsp;se uočiti da su koncentracije ispitivanih jedinjenja u eluatu manje za 2-3&nbsp;puta. Pri datim uslovima procenat detektovane koncentracije ispitivanog&nbsp;jedinjenja u eluatu raste u sledećem nizu: fluoranten &lt; fenantren &lt; piren &lt; naftalen &lt; 1,2,4-trihlorbenzena &lt; 1,2,3-trihlorbenzen. Predloženi mehanizam je sledeći: na eksperimentalnoj pH (pH=6,5) karboksilne grupe na FMWCNT3h su negativno naelekrisane, s druge strane tačka nultog naelektrisanja sedimenta Dunav je 4, &scaron;to ukazuje da je ukupna povr&scaron;ina pri pH=6,5 negativno naelektrisana. Međutim, metalni oksidi i hidroksidi gvožđa, aluminijuma i nikla na povr&scaron;ini sedimenta uzrokuju pozitivno naelektrisane centre &scaron;to dovodi do depozicije FMWCNT3h kao posledica elektrostatičkog privlačenja. Pri transportu organskih jedinjenja kroz sediment Dunava u prisustvu FMWCNT3h dolazi do simultane sorpcije organskih jedinjenja na organskom ugljeniku sedimenta i do adsorpcije na FMWCNT3h. Kada se pH vrednost poveća smanjuje se pozitivno naelekrisanje metalnih&nbsp; oksida i hidroksida na povr&scaron;ini sedimenta &scaron;to dovodi do povećane mobilnosti FMWCNT3h, a time i organskih jedinjenja adsorbovanih na njima. Svi rezultati ukazuju da pH vrednost ima veoma značajnu ulogu i može povećati &nbsp;transport funkcionalizovanog MWCNT-a, a time i transport organskih molekula adsorbovanih na njima.</p> / <p>The first part of the thesis investigates the adsorption of four&nbsp;groups of organic compounds (OCs): (1) nitroaromatics (nitrobenzene),&nbsp;(2) nonpolar aliphatics (hexane), (3) monoaromatics (benzene, toluene,&nbsp;1,2,3- and 1,2,4-trichlorobenzene) and (4) polycyclic aromatic&nbsp;hydrocarbons (PAHs, napthalene,&nbsp; phenanthrene, pyrene and&nbsp;fluoranthene) on multiwalled carbon nanotubes (MWCNTs). This part of&nbsp;the work aimed to find a correlationbetween the adsorption parameters&nbsp;and physical-chemical properties of the organic molecules, as well as the&nbsp;parameters of adsorption and the characteristics of the adsorbents. On the&nbsp;basis of the obtained correlations the adsorption mechanism was&nbsp;proposed. In order to investigate the influence which oxygen containing&nbsp;functional groups exert on the adsorption process, three MWCNTs were&nbsp;used: the pristine (original, as-received) MWCNTs (OMWCNT) and two&nbsp;<br />MWCNTs functionally modified by acid treatment of OMWCNT over 3&nbsp;h and 6 h (FMWCNT3h, FMWCNT6h). All adsorption isotherms well&nbsp;fitted with the Freundlich model. The nonlinearity of the isotherms&nbsp;ranged from 0.418 to 0.897. The results show that K_d&nbsp;values for PAHs&nbsp;increased with increasing specific surface areas (SSAs). The adsorption&nbsp;affinities of the larger molecular size OCs (PAHs) were higher &nbsp;than those of the smaller size OCs (benzene, toluene and hexane) which is probably due to their large contact area with the surface of the adsorbent. Adsorption of OCs on MWCNTs was mainly controlled by hydrophobic interactions, except for the nitroaromatic compound, as shown by the increasing adsorption affinities with the compound&rsquo;s hydrophobicity. K_OW-normalized adsorption coefficients (K_d/K_OW) for all the investigated compounds on all the MWCNTs followed the order: nonpolar aliphatic &lt; monoaromatics &lt; PAHs &lt; nitroaromatic, implying that &pi;-&pi; interactions enhanced the adsorption of aromatics on the MWCNTs. It can be concluded that the strong adsorptiveinteractions between the MWCNTs and nitroaromatics was due to the &pi;-&pi; electron-donor&ndash;acceptor (EDA) interaction between nitroaromatic molecules (electron acceptors) and the highly polarisable graphene sheets(electron donors) of the carbon nanotubes. Based on the obtained results, it can be concluded that multiple mechanisms control the adsorption of organic compounds on MWCNTs.</p><p>In the second part, the influence of carbon based nanomaterials CNM on&nbsp;transport of selected organic compounds (1,2,3 - and 1,2,4-trichlorobenzene, naphthalene, phenanthrene, pyrene and fluoranthene)&nbsp;through sediment Danube was investigated. &nbsp;The aim of this part of the&nbsp;work was to investigate the transport mechanism of selected organic&nbsp;compounds in the presence and absence of CNM. The C/C_0&nbsp;values for the&nbsp;tested compounds in the eluate of the column filled with sediment only&nbsp;increased in the following order: fluoranthene &lt;pyrene &lt;phenanthrene&nbsp;&lt;1,2,4-trichlorobenzene &lt;1,2,3-trichlorobenzene &lt;naphthalene. In order&nbsp;to investigate the influence of&nbsp; hydrophobicity of the investigated&nbsp;compounds on the nonequilibrium sorption, the obtained C/C_0&nbsp;values (for&nbsp;the duration of the experiment, t = 96 h) for these molecules were&nbsp;correlated with the hydrophobicity of the molecules. There was a&nbsp;negative correlation, indicating that more hydrophobic molecules show&nbsp;long residence times in the column, and thus had higher non-equilibrium&nbsp;sorption during transport. In the presence of FMWCNT3h in the column&nbsp;filled with sediment, it can be observed that the concentrations of&nbsp;compounds in the column eluate decreased by factors of 2-3. C/C_0&nbsp;values&nbsp;for the investigated compounds in the eluate increased in the following&nbsp;order: fluoranthene &lt;phenanthrene &lt;pyrene &lt;naphthalene &lt;1,2,4-trichlorobenzene &lt;1,2,3-trichlorobenzene. The proposed mechanism is as&nbsp;follows: under the experimental pH (pH = 6.5), carboxyl groups are&nbsp;negatively charged on the surface of FMWCNT3h and the point of zero&nbsp;charge of the Danube sediment is 4, which indicates thatthe total surface of the Danube sediment at pH 6.5 isnegatively charged. However, metal oxides and hydroxides of iron, aluminum and nickel on the surface of the sediment cause a positively charged centre that leads to the deposition of FMWCNT3h as a result of electrostatic attraction. Transport of organic compounds through the Danube sediment in the presence FMWCNT3h leads to the simultaneous &nbsp;sorption oforganic compounds on the sediment organic carbon and the adsorption of &nbsp;FMWCNT3h. When the pH increased, the positive charge of metal oxides and hydroxides on the sediment surface decreased, which leads to increased FMWCNT3h mobility and thus the organic compounds adsorbed on them. All results indicate that the pH value plays animportant role and can increase the transport of functionally modified MWCNT&#39;s, and thus the transport of organic molecules adsorbed on them.&nbsp;</p>

<p>U ovom radu kori&scaron;cen je spektroskopski, teorijski i hemometrijski pristup<br />proucavanju N-HO i N-H&middot;&middot;&middot; vodonicne veze koja se uspostavlja izmedu<br />amidnog protona i etarskog kiseonika tj aromaticnog sistema. U ovom radu<br />odredeni su parametri N-HO i N-H vodonicne veze za &scaron;esnaest Nsupstituisanih<br />amida sa tetrahidrofuranom i toluenom. Vecina ispitivanih amida do<br />sada nije bila izucavana sa stanovi&scaron;ta vodonicne veze. Uspostavljene su korelacije<br />izmedu spektorsopskih i teorijskih parametara. Izvr&scaron;eno je poredenje medu<br />osobinama vodonicno vezanih kompleksa za razlicite amide kao proton donore.<br />Svih 32 ispitivanih vodonicno vezanih kompleksa okarakterisano je<br />hemometrijskim metodama: Klaster analizom i analizom glavne komponente, na<br />osnovu spektroskopskih, teorijskih i Taftovih parametara</p> / <p> In this PhD thesis, N-H&times;&times;&times;O and N-H&middot;&middot;&middot; hydrogen bond beetwen the amide<br /> proton with ether oxygen and aromatic system has been investigated using the<br /> spectroscopic and theoretical approach. The study included sixteen N-substituted<br /> amides (formamides, acetamides, caproamides and benzamides) as well as<br /> tetrahydrofuran and toluene. The possibility of using chemometric methods was<br /> investigated in order to characterise N-H...O and N-H&middot;&middot;&middot; hydrgen bonded<br /> complexes. Hierarchial clustering and Principal Component Analysis (PCA) have<br /> been applied on infrared spectroscopic, PM3 theoretical and Taft parameters of 32 Nsubstituted<br /> amide complexes with tetrahydrofuran and toluene</p>

<p>U doktorskoj disertaciji posmatrani su Rimanovi problemi kod strogo i slabo hiperboličnih&nbsp;nelinearnih sistema PDJ. U uvodu je predstavljena jednačina zakona održanja u jednoj prostornoj&nbsp;dimenziji i definisani su Ko&scaron;ijevi i Rimanovi problemi. U drugoj glavi, date su osnovne osobine&nbsp;nelinearnih hiperboličnih zakona održanja, uvedeni supojmovi stroge hiperboličnosti i slabog re&scaron;enja&nbsp;zakona održanja. Definisani su Rankin-Igono i entropijski uslovi kao i op&scaron;te re&scaron;enje Rimanovog problema&nbsp;(za dovoljno male početne uslove). U trećoj glavi detaljno je obja&scaron;njena Glimova diferencna &nbsp;&scaron;ema. Metod&nbsp;praćenja talasa predstavljen je u četvrtoj glavi. Pokazano je da se ovom metodom, za dovoljno male&nbsp;početne uslove, dobija stabilno i jedinstveno re&scaron;enje koje u svakom vremenu ima ograničenu totalnu&nbsp;varijaciju. U petoj glavi, posmatrana je jednačina protoka izentropnog gasa u Lagranžovim koordinatama.&nbsp;Uz pretpostavku da je početni uslov ograničen i da ima ograničenu totalnu varijaciju, pokazano je da&nbsp;Ko&scaron;ijev problem ima jedinstveno slabo re&scaron;enje ako je totalna varijacija početnog uslova pomnožena sa &nbsp;0&lt;&epsilon;&lt;&lt; 1 dovoljno mala. Slabo re&scaron;enjedobijeno je metodom praćenja talasa. U glavi &scaron;est ispitana je&nbsp;interakcija dva delta talasa koji su posmatrani kao specijalna vrsta shadowtalasa. U glavi sedam,&nbsp;pokazano je da za proizvoljno velike početne uslove, re&scaron;enje Rimanovog problema jednodimenzionalnog&nbsp;Ojlerovog zakona održanja gasne dinamikepostoji, daje jedinstveno i entropijski dopustivo, uz drugačiju<br />ocenu snaga elementarnih talasa. Data je numerička verifikacija interakcije dva delta talasa kori&scaron;ćenjem&nbsp;metode praćenja talasa.</p> / <p>In this doctoral thesis, Riemann problems for strictly and weakly nonlinear hyperbolic PDE&nbsp;systems were observed. In the introduction, conservation laws in one spatial dimension were presented&nbsp;and the Cauchy and Riemann problems were defined. In the second chapter, the basic properties of&nbsp;nonlinear hyperbolic conservation laws were intorduced, as well as the terms such as strictly hyperbolic&nbsp;system and weak solution of conservation law. Also, Rankine -Hugoniot and entropy conditions were<br />introduced and the general solution to the Riemann problem (for sufficiently small initial conditions) were&nbsp;defined. Glimm&rsquo;s difference scheme was explained in the third chapter. The wave front tracking method&nbsp;was introduced in the fourth chapter. It was shown that, using this method, for sufficiently small initial&nbsp;conditions, it could be obtained a unique solution with bounded total variation for t &ge;0. In the fifth&nbsp;chapter, the Euler equations for isentropic fluid inLagrangian coordinates were observed. Under the&nbsp;assumption that the initial condition was bounded and had bounded total variation, it was shown that the&nbsp;Cauchy problem had a weak unique solution, provided that the total variation of initial condition&nbsp;multiplied by 0&lt;&epsilon;&lt;&lt;1 was sufficiently &nbsp;small. Weak solution was obtained by applying the wave front&nbsp;tracking method. In the sixth chapter, the interaction of two delta shock waves were examined. Delta&nbsp;shock waves were regarded as special kind of shadowwaves. In the chapter seven, it was shown that for&nbsp;arbitrarily large initial conditions, solution to the Riemann problem of one-dimensional Euler&nbsp;conservation laws of gas dynamics existed, it was unique and admissible. New bounds on the strength of&nbsp;elementary waves in the wave front tracking algorithm were given. The numerical verification of two&nbsp;delta shock waves interaction via wave front tracking method was given at the end of the thesis.</p>

<p>Metadon je sintetski agonist opijatnih receptora koji se primenjuje u sklopu supstitucione terapije opijatnih zavisnika metadonom (STM) i u terapiji hroničnog bola. Dugoročna primena STM je praćena blagim, uglavnom prolaznim, neželjenim delovanjima. Međutim, metadon pripada grupi lekova koji mogu da prouzrokuju prolongaciju korigovanog QT intervala (QTc) u elektrokardiogramu (EKG-u) i povećaju rizik za nastanak potencijalno fatalnih aritmija tipa torsades de pointes. Opijatni zavisnici metadon najče&scaron;će koriste u kombinaciji sa benzodiazepinima, i ova kombinacija lekova predstavlja faktor rizika za nastanak smrtnog ishoda. Iako je najveći broj lekara upoznat sa rizikom za razvoj respiratorne depresije prilikom primene opijata u kombinacji sa benzodiazepinima, velika studija otkriva da su ventrikularne aritmije i srčani zastoj najče&scaron;će prijavljivana neželjena delovanja metadona, primenjenog u kombinaciji sa benzodiazepinima. Ciljevi ovoga radu su da se analizom smrtnih slučajeva povezanih sa upotrebom metadona (MRDs) tokom desetogodi&scaron;njeg perioda na teritoriji Vojvodine i sprovođenjem kliničkog ispitivanja kod opijatnih zavisnika na STM proceni kardiolo&scaron;ka bezbednost primene metadona, posebno u kombinaciji sa benzodiazepinima. Sprovedena je retrospektivna studija za određivanje karakteristika MRDs na teritoriji Vojvodine, kao i kliničko ispitivanje u kome su učestvovali opijatni zavisnici koji počinju sa STM. Snimanje EKG-a (za izračunavanje QTc intervala) i uzorkovanje krvi (za određivanje koncentracije metadona i diazepama i vrednosti troponina) je sprovedeno kod svih učesnika istraživanja u 5 vremenskih tačaka (pre početka primene STM, 8. i 15. dana i nakon 1. i 6. meseca primene STM). Koncentracije metadona i diazepama u serumu su određivane metodom tečne hromatografije sa masenom spektrometrijom (LC-MS). U Vojvodini je zapažena rastuća tendencija MRDs, ali ni jedan od umrlih nije bio na STM, i najverovatnije su samoinicijativno koristili metadon i benzodiazepine. Patohistolo&scaron;ki nalaz na srcu može govoriti u prilog kardiotoksičnosti metadona i njegove kombinacije sa benzodiazepinima, pogotovo kod slučajeva sa pronađenim akutnim miokardijalnim o&scaron;tećenjem. &Scaron;to se tiče hroničnih promena na srcu, ne postoji mogućnosti da se potvrdi niti opovrgne uloga psihostimulanasa. Detektovane koncentracije metadona i diazepama kod MRDs su bile u opsegu terapijskih (&lt;1 &mu;g/ml). Poredeći socio-demografske karakteristike opijatnih zavisnika koji su počeli sa STM u ovom istraživanju sa podacima iz sličnih studija sprovedenih &scaron;irom sveta, zapažena je sličnost u pogledu velikog broja karakteristika. Srednje doze metadona 8., 15. dana i nakon 1. i 6. meseca primene STM su bile 40,23&plusmn;17,11 mg, 47,11&plusmn;16,79 mg, 50,00&plusmn;17,55 mg i 78,63&plusmn;18,14 mg, dok su srednje doze diazepama u istim vremenskim tačkama bile 35,92&plusmn;10,47 mg, 33,89&plusmn;9,23 mg, 28,33&plusmn;11,55 mg i 28,12&plusmn;11,67 mg. Srednje koncentracije metadona su u posmatranim tačkama ispitivanja iznosile 153,44&plusmn;111,51 ng/ml, 157,43&plusmn;112,39 ng/ml, 176,77&plusmn;118,56 ng/ml i 342,86&plusmn;181,54 ng/ml, dok su srednje koncentracije diazepama bile 923,00&plusmn;537,89 ng/ml, 923,76&plusmn;739,96 ng/ml, 560,74&plusmn;436,72 ng/ml i 1045,32&plusmn;932,72 ng/ml. Dužina QTc intervala pre primene STM je bila 411,87&plusmn;27,22 ms, tj. 414,64&plusmn;29,38 ms 8. dana STM, 416,97&plusmn;26,39 15. dana, i 425,20&plusmn;17,71 ms nakon 1. meseca tj. 423,50&plusmn;14,72 ms nakon 6. meseca primene STM. Pokazan je statistički značajan porast dužine QTc intervala nakon 1. i nakon 6. meseca primene STM u odnosu na vrednost pre primene STM, kako u grupi svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Pokazano je postojanje statistički značajne korelacije između koncentracije metadona i dužine QTc intervala nakon 15. dana, 1. i 6. meseca primene STM, kako kod svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Ova korelacija ostaje statistički značajna i ukoliko se uključe i drugi faktori &ndash; koncentracija diazepama i dužina perioda upotrebe heroina, kod svih ispitanika i u podgrupi mu&scaron;kog pola nakon 15 dana i mesec dana primene STM, kao i u podgrupi mu&scaron;kog pola nakon 6. meseca STM. Iako nijedan pacijent nije prijavio neko neželjeno delovanje metadona na nivou kardiovaskularnog sistema, najveći broj pacijenata oba pola se nakon prvog meseca primene STM žalio na pojačano znojenje i opstipaciju. Koncentracije metadona i diazepama u uzorcima krvi kod MRDs se nalaze u rasponu koncentracija ovih lekova u krvi ispitanika koji su učestvovali u prospektivnoj studiji. Trećina umrlih je imala samo znake akutnog o&scaron;tećenja srca, dok do porasta troponina i vrednosti QTc intervala preko 500 ms nije do&scaron;lo ni kod jednog ispitanika iz prospektivne studije. Potrebno je sprovesti dalja istraživanja sa ciljem razja&scaron;njenja moguće uloge benzodiazepina u povećanju kardiotoksičnosti metadona kod opijatnih zavisnika na STM.</p> / <p>Methadone is a synthetic agonist of opioid receptors which is used in methadone maintenance tratment (MMT) of opiate addicts as well as in the treatment of chronic pain. A long-term use of MMT is followed by mild, mostly transient, adverse effects. However, methadone belongs to a group of medicines which can provoke a prolongation of QTc (corrected QT) interval in electrocardiogram (ECG) and thus increase the risk from the development of potentially fatal arrhythmias &ndash; torsades de pointes. Moreover, methadone is widely associated with benzodiazepines use in heroin addicts, and this combination is considered as a risk factor for lethal outcome. Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines co-administration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine co-medication. The aim of this study is to assess cardiac safety of methadone use, especially in combination with benzodiazepines, by analyzing characteristics of methadone-related deaths (MRDs) during 10-year period as well as by conducting a clinical trial among opiate addicts in MMT. A retrospective study to determine the characteristics of MRDs in Vojvodina, as well as a clinical trial in which participated opiate addicts at the start of MMT were performed. ECG (to calculate QTc interval) and blood sampling (to determine methadone and diazepam concentrations and troponin values) were performed in all study participants at five time points (before the introduction of MMT, on 8th, on 15th day, after 1 and 6 months of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). An increasing tendency of MRDs was observed in the region of Vojvodina, but none of the victims were under healthcare professionals&rsquo; control, and, most commonly, they used methadone and benzodiazepines, on their own initiative. Pathohistological findings in the heart in MRDs might support cardiac adverse effects of methadone and its combination with benzodiazepines, especially in cases with acute myocardial damage. As for the chronic heart changes, we can neither confirm nor exclude the role of psychostimulants. Detected concentrations of methadone and diazepam were in therapeutic range (&lt;1 &mu;g/ml). Comparing socio-demographic characteristics of opiate addicts who started with MMT in this study with data from similar studies conducted worldwide, the similarity in terms of large number of features was observed. The mean methadone dose on the 8th, 15th days, and after 1 and 6 months of MMT was 40.23&plusmn;17.11 mg, 47.11&plusmn;16.79 mg, 50.00&plusmn;17.55 mg and 78.63&plusmn;18.14 mg, respectively, while the mean diazepam dose at the same time points was 35.92&plusmn;10.47 mg, 33.89&plusmn;9.23 mg, 28.33&plusmn;11.55 mg and 28.12&plusmn;11.67 mg, respectively. The mean methadone concentration at observed time points was 153.44&plusmn;111.51 ng/ml, 157.43&plusmn;112.39 ng/ml, 176.77&plusmn;118.56 ng/ml and 342.86&plusmn;181.54 ng/ml, respectively, while the mean diazepam concentration was 923.00&plusmn;537.89 ng/ml, 923.76&plusmn;739.96 ng/ml, 560.74&plusmn;436.72 ng/ml and 1045.32&plusmn;932.72 ng/ml, respectively. The length of QTc interval before the introduction of MMT was 411.87&plusmn;27.22 ms, 414.64&plusmn;29.38 ms on the 8th day of MMT, 416.97&plusmn;26.39 on the 15th day of MMT, after 1 month of MMT 425.20&plusmn;17.71 ms and after 6 months of MMT 423.50&plusmn;14.72 ms. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT, within the whole group of patients and in the subgroup of men. A statistically significant correlation between the concentration of methadone and QTc interval length after 15 days, 1 and 6 months of MMT, both in the whole group and in the subroup of men was observed. The correlation remained statistically significant if the other factors, such as concentration of diazepam and the length of heroin use, were included, in all patients and in the subgroup of men after 15 days and one month of MMT as well as in the subgroup of men after 6 months of MMT. Although none of the patients reported any cardiac adverse effect of methadone, the majority of them complained of sweating and constipation after the first month of MMT. Concentrations of methadone and diazepam in blood samples in MRDs were within the range of concentrations of these drugs in blood of patients who participated in the prospective study. In one third of MRDs only signs of acute myocardial damage were detected, while an increase in troponin values and the length of QTc interval over 500 ms did not occur in any patient in the prospective study. Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT.</p>

Ljudski genom sadrži milijune regulatornih elemenata - enhancera - koji kvantitativno reguliraju ekspresiju gena. Unatoč ogromnom napretku u razumijevanju načina na koji enhanceri reguliraju ekspresiju gena, području još uvijek nedostaje pristup koji je sustavan, integrativan i dostupan za otkrivanje i dokumentiranje cis-regulatornih odnosa u cijelom genomu. Razvili smo novu računalnu metodu - reg2gene - koja modelira i integrira aktivnost enhancera~ekspresije gena. reg2gene sastoji se od tri glavna koraka: 1) kvantifikacija podataka, 2) modeliranje podataka i procjena značaja, i 3) integracija podataka prikupljenih u reg2gene R paketu. Kao rezultat toga, identificirali smo dva skupa enhancer-gen interakcija (EGA): fleksibilni skup od ~ 230K EGA (flexibleC) i strogi skup od ~ 60K EGA (stringentC). Utvrdili smo velike razlike u prethodno objavljenim računalnim modelima enhancer-gen interakcija; uglavnom u lokaciji, broju i svojstvima definiranih enhancera i EGA. Izveli smo detaljno mjerenje performansi sedam skupova računalno modeliranih EGA-a, ali smo pokazali da se niti jedan od trenutno dostupnih skupova referentnih podataka ne može koristiti kao referentni skup podataka "zlatnI standard". Definirali smo dodatni referentni skup pozitivnih i negativnih EGA -a pomoću kojih smo pokazali da stringentC ima najveću pozitivnu prediktivnu vrijednost (PPV). Pokazali smo potencijal EGA-a za identifikaciju genskih meta nekodirajucih SNP-ova. Proveli smo funkcionalnu analizu kako bismo otkrili nove genske mete, pleiotropiju enhancera i mehanizme aktivnosti enhancera. Ovaj rad poboljšava naše razumijevanje regulacije ekspresije gena posredovane enhancerima. / Das menschliche Genom enthält Millionen von regulatorischen Elementen - Enhancern -, die die Genexpression quantitativ regulieren. Trotz des enormen Fortschritts beim Verständnis, wie Enhancer die Genexpression steuern, fehlt es in diesem Bereich immer noch an einem systematischen, integrativen und zugänglichen Ansatz zur Entdeckung und Dokumentation von cis-regulatorischen Beziehungen im gesamten Genom. Wir haben eine neuartige Methode - reg2gene - entwickelt, die Genexpression~Enhancer-Aktivität modelliert und integriert. reg2gene besteht aus drei Hauptschritten: 1) Datenquantifizierung, 2) Datenmodellierung und Signifikanzbewertung und 3) Datenintegration, die in dem R-Paket reg2gene zusammengefasst sind. Als Ergebnis haben wir zwei Sätze von Enhancer-Gen-Assoziationen (EGAs) identifiziert: den flexiblen Satz von ~230K EGAs (flexibleC) und den stringenten Satz von ~60K EGAs (stringentC). Wir haben große Unterschiede zwischen den bisher veröffentlichten Berechnungsmodellen für Enhancer-Gene-Assoziationen festgestellt, vor allem in Bezug auf die Lage, die Anzahl und die Eigenschaften der definierten Enhancer-Regionen und EGAs. Wir führten ein detailliertes Benchmarking von sieben Sets von rechnerisch modellierten EGAs durch, zeigten jedoch, dass keiner der derzeit verfügbaren Benchmark-Datensätze als "goldener Standard" verwendet werden kann. Wir definierten einen zusätzlichen Benchmark-Datensatz mit positiven und negativen EGAs, mit dem wir zeigten, dass das stringentC-Modell den höchsten positiven Vorhersagewert (PPV) hatte. Wir haben das Potenzial von EGAs zur Identifizierung von Genzielen von nicht-kodierenden SNP-Gene-Assoziationen nachgewiesen. Schließlich führten wir eine funktionelle Analyse durch, um neue Genziele, Enhancer-Pleiotropie und Mechanismen der Enhancer-Aktivität zu ermitteln. Insgesamt bringt diese Arbeit unser Verständnis der durch Enhancer vermittelten Regulierung der Genexpression in Gesundheit und Krankheit voran. / Human genome contains millions of regulatory elements - enhancers - that quantitatively regulate gene expression. Multiple experimental and computational approaches were developed to associate enhancers with their gene targets. Despite the tremendous progress in understanding how enhancers tune gene expression, the field still lacks an approach that is systematic, integrative and accessible for discovering and documenting cis-regulatory relationships across the genome. We developed a novel computational approach - reg2gene- that models and integrates gene expression ~ enhancer activity. reg2gene consists of three main steps: 1) data quantification, 2) data modelling and significance assessment, and 3) data integration gathered in the reg2gene R package. As a result we identified two sets of enhancer-gene associations (EGAs): the flexible set of ~230K EGAs (flexibleC), and the stringent set of ~60K EGAs (stringentC). We identified major differences across previously published computational models of enhancer-gene associations; mostly in the location, number and properties of defined enhancer regions and EGAs. We performed detailed benchmarking of seven sets of computationally modelled EGAs, but showed that none of the currently available benchmark datasets could be used as a “golden-standard” benchmark dataset. To account for that observation, we defined an additional benchmark set of positive and negative EGAs with which we showed that the stringentC model had the highest positive predictive value (PPV) across all analyzed computational models. We reviewed the influence of EGA sets on the functional analysis of risk SNPs and demonstrated the potential of EGAs to identify gene targets of non-coding SNP-gene associations. Lastly, we performed a functional analysis to detect novel gene targets, enhancer pleiotropy, and mechanisms of enhancer activity. Altogether, this work advances our understanding of enhancer-mediated gene expression regulation in health and disease.