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1.
From isles of Königsberg to islets of Langerhans: examining the function of the endocrine pancreas through network science
Andraž Stožer, Marko Šterk, Eva Paradiž, Rene Markovič, Maša Skelin, Cara E. Ellis, Lidija Križančić Bombek, Jurij Dolenšek, Patrick E. MacDonald, Marko Gosak, 2022, review article

Abstract: Islets of Langerhans are multicellular microorgans located in the pancreas that play a central role in whole-body energy homeostasis. Through secretion of insulin and other hormones they regulate postprandial storage and interprandial usage of energy-rich nutrients. In these clusters of hormone-secreting endocrine cells, intricate cell-cell communication is essential for proper function. Electrical coupling between the insulin-secreting beta cells through gap junctions composed of connexin36 is particularly important, as it provides the required, most important, basis for coordinated responses of the beta cell population. The increasing evidence that gap-junctional communication and its modulation are vital to well-regulated secretion of insulin has stimulated immense interest in how subpopulations of heterogeneous beta cells are functionally arranged throughout the islets and how they mediate intercellular signals. In the last decade, several novel techniques have been proposed to assess cooperation between cells in islets, including the prosperous combination of multicellular imaging and network science. In the present contribution, we review recent advances related to the application of complex network approaches to uncover the functional connectivity patterns among cells within the islets. We first provide an accessible introduction to the basic principles of network theory, enumerating the measures characterizing the intercellular interactions and quantifying the functional integration and segregation of a multicellular system. Then we describe methodological approaches to construct functional beta cell networks, point out possible pitfalls, and specify the functional implications of beta cell network examinations. We continue by highlighting the recent findings obtained through advanced multicellular imaging techniques supported by network-based analyses, giving special emphasis to the current developments in both mouse and human islets, as well as outlining challenges offered by the multilayer network formalism in exploring the collective activity of islet cell populations. Finally, we emphasize that the combination of these imaging techniques and network-based analyses does not only represent an innovative concept that can be used to describe and interpret the physiology of islets, but also provides fertile ground for delineating normal from pathological function and for quantifying the changes in islet communication networks associated with the development of diabetes mellitus.
Keywords: pancreatic islets, beta cells, calcium imaging, intercellular communication, functional networks, multilayer networks
Published in DKUM: 20.12.2024; Views: 0; Downloads: 3
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2.
Network representation of multicellular activity in pancreatic islets : Technical considerations for functional connectivity analysis
Marko Šterk, Yaowen Zhang, Viljem Pohorec, Eva Paradiž, Jurij Dolenšek, Richard K. P. Benninger, Andraž Stožer, Vira Kravets, Marko Gosak, 2024, original scientific article

Abstract: Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect of metabolic homeostasis. Despite the inherent heterogeneity and multimodal activity of individual cells, intercellular coupling acts as a homogenizing force, enabling coordinated responses through the propagation of intercellular waves. Disruptions in this coordination are implicated in irregular insulin secretion, a hallmark of diabetes. Recently, innovative approaches, such as integrating multicellular calcium imaging with network analysis, have emerged for a quantitative assessment of the cellular activity in islets. However, different groups use distinct experimental preparations, microscopic techniques, apply different methods to process the measured signals and use various methods to derive functional connectivity patterns. This makes comparisons between findings and their integration into a bigger picture difficult and has led to disputes in functional connectivity interpretations. To address these issues, we present here a systematic analysis of how different approaches influence the network representation of islet activity. Our findings show that the choice of methods used to construct networks is not crucial, although care is needed when combining data from different islets. Conversely, the conclusions drawn from network analysis can be heavily affected by the pre-processing of the time series, the type of the oscillatory component in the signals, and by the experimental preparation. Our tutorial-like investigation aims to resolve interpretational issues, reconcile conflicting views, advance functional implications, and encourage researchers to adopt connectivity analysis. As we conclude, we outline challenges for future research, emphasizing the broader applicability of our conclusions to other tissues exhibiting complex multicellular dynamics.
Keywords: islets of Langerhans, beta cells, calcium signaling, intercellular communication, functional networks, myosin model
Published in DKUM: 09.12.2024; Views: 0; Downloads: 3
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3.
The role of cAMP in beta cell stimulus-secretion and intercellular coupling
Andraž Stožer, Eva Paradiž, Viljem Pohorec, Jurij Dolenšek, Lidija Križančić Bombek, Marko Gosak, Maša Skelin, 2021, review article

Abstract: Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus-secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca2+ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans.
Keywords: cAMP, beta cells, stimulus-secretion coupling, intercellular coupling, PKA, Epac2A
Published in DKUM: 16.10.2024; Views: 0; Downloads: 4
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4.
In vitro disease models of the endocrine pancreas
Marko Milojević, Jan Rožanc, Jernej Vajda, Laura Činč Ćurić, Eva Paradiž, Andraž Stožer, Uroš Maver, Boštjan Vihar, 2021, review article

Abstract: The ethical constraints and shortcomings of animal models, combined with the demand to study disease pathogenesis under controlled conditions, are giving rise to a new field at the interface of tissue engineering and pathophysiology, which focuses on the development of in vitro models of disease. In vitro models are defined as synthetic experimental systems that contain living human cells and mimic tissue- and organ-level physiology in vitro by taking advantage of recent advances in tissue engineering and microfabrication. This review provides an overview of in vitro models and focuses specifically on in vitro disease models of the endocrine pancreas and diabetes. First, we briefly review the anatomy, physiology, and pathophysiology of the human pancreas, with an emphasis on islets of Langerhans and beta cell dysfunction. We then discuss different types of in vitro models and fundamental elements that should be considered when developing an in vitro disease model. Finally, we review the current state and breakthroughs in the field of pancreatic in vitro models and conclude with some challenges that need to be addressed in the future development of in vitro models.
Keywords: in vitro disease models, pancreas, islet of Langerhans, 3D cell culture, scaffolds, acute tissue slices
Published in DKUM: 01.10.2024; Views: 0; Downloads: 7
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5.
Vpliv inkretinov in njihovih analogov na dinamiko kalcija v celicah beta v svežih rezinah trebušne slinavke
Eva Paradiž Leitgeb, 2024, doctoral dissertation

Abstract: Natančno uravnavanje sklopitve stimulacije in izločanja v celicah beta je ključnega pomena za vzdrževanje normoglikemije. Čeprav glukoza v tem procesu predstavlja primarni dražljaj, inkretini ključno prispevajo k povečanemu izločanju inzulina, delno tudi preko ojačitve znotrajcelične dinamike [Ca2+] ([Ca2+]IC). Podrobnosti o tem, kako inkretini vplivajo na rekrutacijo celic beta v fazi aktivacije, na aktivni čas in funkcionalno povezanost v fazi platoja in kako na njihovo deaktivacijo, še niso pojasnjene. S pomočjo konfokalne mikroskopije smo v svežih tkivnih rezinah trebušne slinavke z visoko resolucijo istočasno zajemali [Ca2+]IC signale v številnih celicah in tako sistematično proučili vpliv agonistov receptorjev GLP-1 (GLP-1RA), eksendina-4 (Ex-4) in GLP-1, na aktivnost sklopljenih celic beta. V nestimulativni koncentraciji glukoze (6 mM) je Ex-4 aktiviral približno četrtino celic beta v otočku. Kostimulacija z Ex-4 in glukozo (10 mM) je skrajšala zamik do aktivacije celic beta in pospešila dinamiko njihove aktivacije. Tako se je čas, ki je bil potreben, da so celice dosegle polovično vrednost maksimalnega aktivnega časa, v prisotnosti Ex-4 prepolovil. Aktivni čas in regularnost oscilacij [Ca2+]IC sta se povečala, zlasti v začetnem delu odziva celic beta. Kasnejše dodajanje Ex-4, ko so bile celice že aktivne, ni privedel do tako izrazitega porasta aktivnosti. Mrežne analize so potrdile povečano povezanost celic med fazo aktivacije in fazo platoja, pri čemer je vloga centralnih celic ostala stabilna tako v kontrolnih poskusih kot ob stimulaciji z Ex-4. Zanimivo je, da smo pri Ex-4 opazili dvojen učinek na deaktivacijo celic beta, tako da se je celična aktivnost pri nizkih koncentracijah podaljšala, pri visokih pa skrajšala. Naši poskusi so dosledno pokazali, da je GLP-1 šibkejši agonist. Kostimulacija z GLP-1RA in glukozo tako povzroči porast [Ca2+]IC med aktivacijo in aktivnostjo celic beta, kar kaže, da je učinek inkretinov v veliki meri mogoče pojasniti z ojačano dinamiko [Ca2+]IC. Predhodna stimulacija z inkretini ne privede do kritičnega podaljšanja aktivnosti celic beta, kar potrjuje njihovo nizko tveganje za razvoj hipoglikemije.
Keywords: celice beta, tkivna rezina, agonisti receptorjev GLP-1, konfokalna mikroskopija, kalcijeve oscilacije
Published in DKUM: 26.03.2024; Views: 215; Downloads: 38
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6.
7.
Biomonitoring rastlin in okolja za trajnostno izvajanje varstva narave
Jasna Paradiž, 2011, original scientific article

Abstract: Tekom desetletnega biomonitoringa rastlin na Ljubljanskem barju smo preučili populacijsko dinamiko pri vrsti Fritillaria meleagris in Solidago canadensis. Izvedli smo tudi bioteste za oceno ogroženosti mokriščnih rastlin zaradi onesnaževanja okolja. Podatki s topografskih kart so pokazali zmanjšanje gostote populacij ogrožene vrste F. meleagris na opazovanih mestih, medtem ko se je razširjenost S. canadensis povečala na celem območju. Na osnovi rezultatov citogenetske analize različnih vrst je ugotovljena povečana stopnja genotoksične ogroženosti rastlin na Ljubljanskem barju v primerjavi z drugimi lokalitetami. Biomonitoring rastlin se priporoča za zgodnje odkrivanje škodljivih učinkov onesnaževanja, in ob ekoremediacijah služi za trajnostno izvajanje varstva rastlin v naravnih habitatih.
Keywords: mokrišča, populacijska dinamika rastlin, citogenetska ogroženost, varstvo narave
Published in DKUM: 04.04.2018; Views: 1359; Downloads: 101
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8.
Povezanost učnega uspeha in gibalne učinkovitosti dečkov in deklic v obdobju zgodnje adolescence
Estera Paradiž, 2017, master's thesis

Abstract: Namen raziskave je bil ugotoviti, kakšna je povezava učne uspešnosti in gibalne učinkovitosti dečkov in deklic v obdobju poznega otroštva in zgodnje adolescence. Raziskava je bila opravljena na neslučajnostnem priložnostnem vzorcu 426 učencev drugega vzgojno-izobraževalnega obdobja iz OŠ Podčetrtek, OŠ Rogaška Slatina, OŠ Lovrenc na Pohorju, OŠ Starše, OŠ Toneta Čufarja Maribor, OŠ Franc Rozman Stane Maribor, OŠ Šentilj in OŠ Mala Nedelja. Podatki so bili zbrani s pomočjo testne baterije »Eurofit«, ki meri gibalne sposobnosti učencev. Merjenci so bili na podlagi učnih ocen pri matematiki, ki so jih posredovali njihovi učitelji, razdeljeni na tri skupine: učno zelo uspešni, uspešni ter učno manj uspešni. Zbrani podatki so bili obdelani z računalniškim programom SPSS Statistic 21.00 za Windows. Razlike v gibalni učinkovitosti glede na učno uspešnost pri matematiki ločeno po spolu smo ugotavljali z analizo variance (ANOVA). Ugotavljanje statistično značilnih razlik je potekalo na ravni tveganja p<0,05. Za še natančnejšo opredelitev predhodno ugotovljenih statistično značilnih razlik smo opravili tudi Post-Hoc preizkus (Scheffe). Rezultati so pokazali, da obstajajo statistično pomembne razlike med učno zelo uspešnimi, uspešnimi in učno manj uspešnimi dečki pri testih, ki merijo hitrost izmeničnih gibov in hitrost teka, eksplozivno, repetitivno in statično moč, koordinacijo gibanja ter vzdržljivost. Statistično značilna razlika med učno zelo uspešnimi, uspešnimi in manj uspešnimi dekleti se je pokazala pri testih, ki merijo ravnotežje, vzdržljivost, hitrost alternativnih gibov in hitrost teka, gibljivost, repetitivno in eksplozivno moč ter koordinacijo telesa. Ugotovitve kažejo, da je učna uspešnost tesno povezana z gibalno učinkovitostjo tako pri dečkih kot tudi pri deklicah. Učno zelo uspešni otroci so prav tako gibalno bolj učinkoviti.
Keywords: gibalne kompetence, motorične sposobnosti, kognitivni razvoj, ocena iz matematike
Published in DKUM: 07.03.2017; Views: 2477; Downloads: 365
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9.
TEHNIKE VREDNOSTNE ANALIZE V MANAGEMENTU VREDNOSTI
Ines Paradiž, 2016, undergraduate thesis

Abstract: V diplomskem delu je predstavljena in opisana uporaba vrednostne analize pri obravnavanju managementa vrednosti novega izdelka. Uporaba tehnik vrednostne analize temelji na optimizaciji izdelka. Osnovno vodilo pri delu z vrednostno analizo je obdržati čim večjo kakovost s čim nižjimi stroški. V nalogi so predstavljeni koraki poteka pri delu ter uporaba primernih metod na vsakem izmed teh. Metode, uporabljene pri delu so: brainstorming, metoda 635, izbirna lista za vrednotenje idej, vzročno - posledični diagram, Pareto diagram, benchmarking, FMEA metoda, SWOT analiza, SWOT matrika, FAST diagram, funkcijsko – stroškovna matrika, QFD in Combinex metoda. V nalogi je vsaka izmed metod predstavljena s praktičnim primerom, v zaključku pa podane smernice koristnosti uporabe.
Keywords: management vrednosti, vrednostna analiza, ustvarjalne metode, vrednotenje idej
Published in DKUM: 29.09.2016; Views: 2220; Downloads: 170
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10.
RESNA IGRA 3D PUZZLE-PLATFORMER ZA ZDRAVO ŽIVLJENJE
Dejan Paradiž, 2016, undergraduate thesis

Abstract: V diplomskem delu smo najprej pregledali osnove brezplačne (»personal«) različice razvojnega okolja Unity. S pridobljenim znanjem smo nato v programu Unity izdelali preprosto računalniško igro »3D Puzzle-Platformer«. Delo je zajemalo iskanje brezplačnih zvočnih datotek za zvočne učinke in brezplačnih tekstur. Hkrati smo sprogramirali skripte za vse potrebne objekte v igri (dvigalo, premikajočo ploščad, past, sistem za izbor in izpis vprašanj, barikade itd.), pripravili smo tudi uporabniški vmesnik ter vse skupaj tudi sproti testirali. Na koncu smo pregledali še nekaj literature o zdravem življenju in s pomočjo svojega znanja sestavili nekaj vprašanj, na katera se mora odgovoriti pravilno za napredovanje v igri. Rezultat je računalniška igra, ki jo je mogoče igrati na operacijskem sistemu Windows in nas med igranjem poučuje o zdravem življenju.
Keywords: Unity, resne igre, razvoj iger, zdravo življenje
Published in DKUM: 06.09.2016; Views: 1613; Downloads: 112  (1 vote)
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