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1.
Vpliv rastnih faktorjev in zaviralcev fibrotičnega tipa celjenja na keratocite v celičnih modelih roženične rane
Tomislav Šarenac, 2018, doktorsko delo/naloga

Opis: Celjenje roženičnih ran je pogosto omejeno s fibrozo in tvorjenjem brazgotin, ki jih lahko povzroča transformni rastni faktor β (angl. transforming growth factor – TGF). Nadzirana fibroza, ki jo lahko usmerimo z inzulinu podobnim rastnim faktorjem – 1 (angl. insulin-like growth factor – IGF) in protifibrotičnimi učinkovinami, bi lahko prispevala k ohranjanju prozornosti roženice med celjenjem. S pomočjo stimulacije primarnih človeških keratocitov s TGF-β v brezserumskem gojitvenem mediju smo ustvarili celični model roženične stromalne rane. S slikovno pretočno citometrijo smo analizirali posamezne celice iz celičnih kultur in določali stopnjo nuklearizacije Smad3 in znotrajcelično fluorescenčno intenziteto obarvanega Smad7 in roženičnega Kristalina – aldehidne dehidrogenaze 3A1. Pri preučevanju izločanja proteoglikanov Biglikana in Keratokana v zunajcelični matriks smo uporabili teste ELISA. Skupaj s stimulacijo s TGF-β smo celice obravnavali samo z IGF-1, s suberoilanilidehidroksiamično kislino (SAHA) ali halouginonom; ločenim populacijam smo poleg protifibrotikov dodali še IGF-1. Pri samostojni obravnavi z IGF-1 smo ugotovili zmanjšano translokacijo Smad3 in zvišano količino Aldehidne dehidrogenaze 3A1 znotraj celic. Poleg tega je bilo izločanje proteoglikanov prav tako ugodno za ustvarjanje pogojev prozornosti. SAHA je povzročila zvišanje Smad7 v celicah in inhibirala translokacijo Smad3 v jedra – tudi v kombinaciji z IGF-1. Imunofluorescenčna mikroskopija je pokazala, da je dodatek IGF-1 in v kombinaciji s protifibrotičnimi učinkovinami zavrl transdiferenciacijo v miofibroblaste in spodbudil nastanek fibroblastov. TGF-β/ Smad signalna pot fibroze in zamotnjenosti roženice je bila inhibirana s strani IGF-1; še posebej ob dodatku SAHA kakor tudi s halofuginonom. Zaključujemo, da bi lahko IGF-1 uspešno dodali k zdravljenju s protifibrotičnimi učinkovinami, kar bi omogočilo boljše celjenje roženične rane in tvorbo bolj prozornega tkiva.
Ključne besede: Roženica, keratocit, miofibroblast, fibroza, celjenje ran, TGF-b, IGF-1, SAHA, halofuginon, Smad, celična kultura, slikovna pretočna citometrija
Objavljeno: 14.01.2019; Ogledov: 646; Prenosov: 83
.pdf Celotno besedilo (69,22 MB)

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Critical and supercritical spatiotemporal calcium dynamics in beta cells
Marko Gosak, Andraž Stožer, Rene Markovič, Jurij Dolenšek, Matjaž Perc, Marjan Rupnik, Marko Marhl, 2017, izvirni znanstveni članek

Opis: A coordinated functioning of beta cells within pancreatic islets is mediated by oscillatory membrane depolarization and subsequent changes in cytoplasmic calcium concentration. While gap junctions allow for intraislet information exchange, beta cells within islets form complex syncytia that are intrinsically nonlinear and highly heterogeneous. To study spatiotemporal calcium dynamics within these syncytia, we make use of computational modeling and confocal high-speed functional multicellular imaging. We show that model predictions are in good agreement with experimental data, especially if a high degree of heterogeneity in the intercellular coupling term is assumed. In particular, during the first few minutes after stimulation, the probability distribution of calcium wave sizes is characterized by a power law, thus indicating critical behavior. After this period, the dynamics changes qualitatively such that the number of global intercellular calcium events increases to the point where the behavior becomes supercritical. To better mimic normal in vivo conditions, we compare the described behavior during supraphysiological non-oscillatory stimulation with the behavior during exposure to a slightly lower and oscillatory glucose challenge. In the case of this protocol, we observe only critical behavior in both experiment and model. Our results indicate that the loss of oscillatory changes, along with the rise in plasma glucose observed in diabetes, could be associated with a switch to supercritical calcium dynamics and loss of beta cell functionality.
Ključne besede: beta cells, islets of Langerhans, self-organized criticality, intercellular dynamics, calcium waves, glucose oscillations, computational model, confocal calcium imaging
Objavljeno: 23.01.2018; Ogledov: 743; Prenosov: 299
.pdf Celotno besedilo (3,43 MB)
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4.
Nove metode za ocenjevanje tveganja za razvoj metaboličnega sindroma pri otrocih
Bernarda Vogrin, 2017, doktorsko delo/naloga

Opis: Uvod. Zaradi epidemije otroške debelosti in metaboličnega sindroma lahko v prihodnosti pri otrocih pričakujemo še večje obremenitve srca in žil, čemur smo priča danes. Zgodnje odkrivanje oseb, ki so nagnjene k metaboličnim motnjam in boleznim srca in žil, lahko bistveno pripomore k načrtovanju preventive in zdravljenju bolezni. Hipoteza. Z merjenjem žilne funkcije, telesne sestave in natančno analizo serumskih lipidov lahko odkrijemo nagnjenost k metaboličnemu sindromu in boleznim srca in žil že v otroštvu, še pred pojavom kliničnih znakov. Metode. V študiji je sodelovalo 81 šolarjev starih 11–16 let. Z anketnim vprašalnikom smo pridobili podatke o njihovem socialnem okolju, prehranskih navadah in učnem uspehu. Z analizo športno vzgojnih kartonov smo ocenili njihovo telesno zmogljivost. Opravili smo meritve telesne konstitucije: telesno višino (TV), telesno težo (TT), obseg pasu (OP) in bokov (OB), kožno gubo na nadlahti (KGN) ter izračunali indeks telesne mase (BMI) in standardni odklon glede na spol in starost (SDS BMI). Telesno sestavo (odstotek maščobe (FAT %)) smo ocenjevali z bioimpedanco. Lastnosti arterijskega sistema smo merili z Arteriografom, z določanjem augmentacijskega indeksa (AIx), hitrosti pulznih valov (PWV) in centralnega sistoličnega arterijskega tlaka (SBPao). V vzorcu venozne krvi smo analizirali glukozo (GLU) in serumske lipide vključno s prostimi maščobnimi kislinami (PMK). Rezultati. AIx je značilno koreliral s TV, učnim uspehom, nekaterimi motoričnimi testi in serumskimi lipidi. PWV je značilno koreliral s TT, TV, BMI, SDS BMI, OP, OB, nekaterimi motoričnimi testi in PMK. SBPao je negativno koreliral z učnim uspehom. FAT % je kazal značilne povezave z GLU, PMK in drugimi lipidi. Pri 5 % oziroma 6 % učencev smo ugotovili zelo visoke vrednosti AIx, SBPao in PWV. Zaključki. AIx, PWV, PMK in FAT % so dobri pokazatelji začetnih žilnih in metaboličnih nepravilnosti pri otrocih in mladostnikih. Zvečana AIx in SBPao sta povezana s slabšimi učnimi in motoričnimi sposobnostmi. PWV je pri otrocih in mladostnikih zelo odvisen od telesne konstitucije.
Ključne besede: Metabolični sindrom, augmentacijski indeks, hitrost pulznih valov, otroci, bioimpedanca
Objavljeno: 29.11.2017; Ogledov: 600; Prenosov: 90
.pdf Celotno besedilo (1,91 MB)

5.
Tkivni inženiring hrustančnega tkiva na biosintetičnem polimernem polyHIPE nosilcu
Jakob Naranđa, 2017, doktorsko delo/naloga

Opis: Tkivni inženiring hrustančnega tkiva še vedno nudi številne možnosti za izboljšavo, navkljub intenzivnim raziskovalnim naporom v zadnjem času. Razvoj umetnih materialov in 3-D celičnih nosilcev ima pomembno vlogo pri regeneraciji hrustančnega tkiva. Zanimiv pristop pri izdelavi celičnih nosilcev predstavlja izgradnja s pomočjo emulzij. Nastali material, imenovan polyHIPE (PHP), je sintetični visoko porozen polimer, ki ga pripravimo s polimerizacijo visokega deleža notranje faze emulzij (HIPEs – high internal phase emulsions). Glavni cilj te doktorske disertacije je raziskati možnosti za tvorbo hrustančnega tkiva znotraj celičnih nosilcev pripravljenih iz PHP materiala. Proizvodnjo PHP nosilcev smo posebej prilagodili tkivnemu inženiringu hrustanca, tako da smo pripravili porozne (85 %) strukture s primarno velikostjo por v območju 50–170 m. Pokazali smo, da je PHP material biokompatibilen s človeškimi sklepnimi hondrociti, kar smo ovrednotili s pomočjo testa za preživetje celic (Live/Dead kit) in histološko analizo. Opazovali smo hondrocite z okroglimi jedri, ki so bili organizirani v večceličnih plasteh na površini PHP nosilca in so rastli približno 300 m v notranjost nosilca. Kopičenje kolagena tipa 2 smo dokazali s pomočjo imunohistokemije, molekularna analiza je pokazala izražanje hrustančno specifičnih genov z ugodnim razmerjem kolagena tipa 2 in tipa 1. Dodatno so bili PHP vzorci biološko razgradljivi, njihove osnovne mehanske lastnosti pa primerljive z nativnim sklepnim hrustancem. Izsledki raziskave dokazujejo, da je zasnovan PHP celični nosilec primeren za nadaljnjo uporabo v tkivnem inženiringu hrustančnega tkiva.
Ključne besede: humani sklepni hrustanec, tkivni inženiring, biokompatibilni celični nosilec, sintetični polimer, polyHIPE, diferenciacija hondrocitov
Objavljeno: 17.10.2017; Ogledov: 1004; Prenosov: 128
.pdf Celotno besedilo (24,38 MB)

6.
SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of $Ca^{2+}$ oscillations in $\beta$ cell networks
Teresa Daraio, Lidija Križančić Bombek, Marko Gosak, Ismael Valladolid-Acebes, Maša Skelin, Essam Refai, Per-Olof Berggren, Kerstin Brismar, Marjan Rupnik, Christina Bark, 2017, izvirni znanstveni članek

Opis: SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic $\beta$ cells. The protein exists as two alternatively spliced isoforms, SNAP-25a and SNAP-25b, differing in 9 out of 206 amino acids, yet their specific roles in pancreatic $\beta$ cells remain unclear. We explored the effect of SNAP-25b-deficiency on glucose-stimulated insulin release in islets and found increased secretion both in vivo and in vitro. However, slow photo-release of caged $Ca^{2+}$ in $\beta$ cells within pancreatic slices showed no significant differences in $Ca^{2+}$-sensitivity, amplitude or rate of exocytosis between SNAP-25b-deficient and wild-type littermates. Therefore, we next investigated if $Ca^{2+}$ handling was affected in glucose-stimulated [beta] cells using intracellular $Ca^{2+}$-imaging and found premature activation and delayed termination of [$Ca^{2+}$] i elevations. These findings were accompanied by less synchronized $Ca^{2+}$-oscillations and hence more segregated functional $\beta$ cell networks in SNAP-25b-deficient mice. Islet gross morphology and architecture were maintained in mutant mice, although sex specific compensatory changes were observed. Thus, our study proposes that SNAP-25b in pancreatic [beta] cells, except for participating in the core SNARE complex, is necessary for accurate regulation of $Ca^{2+}$-dynamics.
Ključne besede: insulin secretion, pre-diabetes
Objavljeno: 23.08.2017; Ogledov: 584; Prenosov: 90
.pdf Celotno besedilo (3,80 MB)
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7.
Increased augmentation index and central systolic arterial pressure are associated with lower school and motor performance in young adolescents
Bernarda Vogrin, Marjan Rupnik, Dušanka Mičetić-Turk, 2017, izvirni znanstveni članek

Opis: Objective: In adults, improper arterial function has been linked to cognitive impairment. The pulse wave velocity (PWV), augmentation index (AIx) and other vascular parameters are useful indicators of arterial health. In our study, we monitored arterial properties, body constitution, school success, and motor skills in young adolescents. We hypothesize that reduced cognitive and motor abilities have a vascular origin in children. Methods: We analysed 81 healthy school children aged 11-16 years. Anthropometry central systolic arterial pressure, body mass index (BMI), standard deviation scores (SDS) BMI, general school performance grade, and eight motor tests were assessed. PWV, AIx, and central systolic arterial pressure (SBPao) were measured. Results: AIx and SBPao correlated negatively with school performance grades. Extremely high AIx, PWVand SBPao values were observed in 5% of children and these children had average to low school performance. PWV correlated significantly with weight, height, and waist and hip circumference. AIx, PWV, school success, and BMI correlated strongly with certain motor functions. Conclusions: Increased AIx and SBPao are associated with lower school and motor performance in children. PWV is influenced by the body's constitution.
Ključne besede: augmentation index, pulse wave velocity, school success, motor functions, young adolescents, central systolic arterial pressure, body mass index
Objavljeno: 13.07.2017; Ogledov: 503; Prenosov: 256
.pdf Celotno besedilo (160,29 KB)
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8.
Single-cell analysis reveals IGF-1 potentiation of inhibition of the TGF-ß/Smad pathway of fibrosis in human keratocytes in vitro
Tomislav Šarenac, Martin Trapečar, Lidija Gradišnik, Marjan Rupnik, Dušica Pahor, 2016, izvirni znanstveni članek

Opis: Corneal wound healing is often affected by TGF-β–mediated fibrosis and scar formation. Guided fibrosis with IGF-1 and antifibrotic substances might maintain corneal transparency. Primary human corneal keratocytes under serum-free conditions were used as a model of corneal stromal wounding, with markers of corneal fibrosis and opacity studied under TGF-β2 stimulation. Single-cell imaging flow cytometry was used to determine nuclearization of Smad3, and intracellular fluorescence intensity of Smad7 and the corneal crystallin aldehyde dehydrogenase 3A1. Extracellular matrix proteoglycans keratocan and biglycan were quantified using ELISAs. On the TGF-β2 background, the keratocytes were treated with IGF-1, and suberoylanilidehydroxamic acid (SAHA) or halofuginone ± IGF-1. IGF-1 alone decreased Smad3 nuclearization and increased aldehyde dehydrogenase 3A1 expression, with favorable extracellular matrix proteoglycan composition. SAHA induced higher Smad7 levels and inhibited translocation of Smad3 to the nucleus, also when combined with IGF-1. Immunofluorescence showed that myofibroblast transdifferentiation is attenuated and appearance of fibroblasts is favored by IGF-1 alone and in combination with the antifibrotic substances. The TGF-β/Smad pathway of fibrosis and opacity was inhibited by IGF-1, and further with SAHA in particular, and with halofuginone. IGF-1 is thus a valid aid to antifibrotic treatment, with potential for effective and transparent corneal wound healing.
Ključne besede: cornea, wounds, treatment, antifibrotic treatment, keratocytes
Objavljeno: 23.06.2017; Ogledov: 692; Prenosov: 109
.pdf Celotno besedilo (1,89 MB)
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9.
Progressive glucose stimulation of islet beta cells reveals a transition from segregated to integrated modular functional connectivity patterns
Rene Markovič, Andraž Stožer, Marko Gosak, Jurij Dolenšek, Marko Marhl, Marjan Rupnik, 2015, izvirni znanstveni članek

Opis: Collective beta cell activity in islets of Langerhans is critical for the supply of insulin within an organism. Even though individual beta cells are intrinsically heterogeneous, the presence of intercellular coupling mechanisms ensures coordinated activity and a well-regulated exocytosis of insulin. In order to get a detailed insight into the functional organization of the syncytium, we applied advanced analytical tools from the realm of complex network theory to uncover the functional connectivity pattern among cells composing the intact islet. The procedure is based on the determination of correlations between long temporal traces obtained from confocal functional multicellular calcium imaging of beta cells stimulated in a stepwise manner with a range of physiological glucose concentrations. Our results revealed that the extracted connectivity networks are sparse for low glucose concentrations, whereas for higher stimulatory levels they become more densely connected. Most importantly, for all ranges of glucose concentration beta cells within the islets form locally clustered functional sub-compartments, thereby indicating that their collective activity profiles exhibit a modular nature. Moreover, we show that the observed non-linear functional relationship between different network metrics and glucose concentration represents a well-balanced setup that parallels physiological insulin release.
Ključne besede: endocrinology, computational biophysics, calcium signalling, biological physics
Objavljeno: 23.06.2017; Ogledov: 709; Prenosov: 244
.pdf Celotno besedilo (957,14 KB)
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10.
Polyester type polyHIPE scaffolds with an interconnected porous structure for cartilage regeneration
Jakob Naranđa, Maja Sušec, Uroš Maver, Lidija Gradišnik, Mario Gorenjak, Andreja Vukasović, Alan Ivković, Marjan Rupnik, Matjaž Vogrin, Peter Krajnc, 2016, izvirni znanstveni članek

Opis: Development of artificial materials for the facilitation of cartilage regeneration remains an important challenge in orthopedic practice. Our study investigates the potential for neocartilage formation within a synthetic polyester scaffold based on the polymerization of high internal phase emulsions. The fabrication of polyHIPE polymer (PHP) was specifically tailored to produce a highly porous (85%) structure with the primary pore size in the range of 50–170 μm for cartilage tissue engineering. The resulting PHP scaffold was proven biocompatible with human articular chondrocytes and viable cells were observed within the materials as evaluated using the Live/Dead assay and histological analysis. Chondrocytes with round nuclei were organized into multicellular layers on the PHP surface and were observed to grow approximately 300 μm into the scaffold interior. The accumulation of collagen type 2 was detected using immunohistochemistry and chondrogenic specific genes were expressed with favorable collagen type 2 to 1 ratio. In addition, PHP samples are biodegradable and their baseline mechanical properties are similar to those of native cartilage, which enhance chondrocyte cell growth and proliferation.
Ključne besede: polyester, polymerization, polyHIPE
Objavljeno: 23.06.2017; Ogledov: 978; Prenosov: 316
.pdf Celotno besedilo (1,24 MB)
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