1. From isles of Königsberg to islets of Langerhans: examining the function of the endocrine pancreas through network scienceAndraž Stožer, Marko Šterk, Eva Paradiž, Rene Markovič, Maša Skelin, Cara E. Ellis, Lidija Križančić Bombek, Jurij Dolenšek, Patrick E. MacDonald, Marko Gosak, 2022, pregledni znanstveni članek Opis: 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. Ključne besede: pancreatic islets, beta cells, calcium imaging, intercellular communication, functional networks, multilayer networks Objavljeno v DKUM: 20.12.2024; Ogledov: 0; Prenosov: 3
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2. Both electrical and metabolic coupling shape the collective multimodal activity and functional connectivity patterns in beta cell collectives : a computational model perspectiveMarko Šterk, Uroš Barać, Andraž Stožer, Marko Gosak, 2023, izvirni znanstveni članek Opis: Pancreatic beta cells are coupled excitable oscillators that synchronize their activity via different communication pathways. Their oscillatory activity manifests itself on multiple timescales and consists of bursting electrical activity, subsequent oscillations in the intracellular Ca 2 + , as well as oscillations in metabolism and exocytosis. The coordination of the intricate activity on the multicellular level plays a key role in the regulation of physiological pulsatile insulin secretion and is incompletely understood. In this paper, we investigate theoretically the principles that give rise to the synchronized activity of beta cell populations by building up a phenomenological multicellular model that incorporates the basic features of beta cell dynamics. Specifically, the model is composed of coupled slow and fast oscillatory units that reflect metabolic processes and electrical activity, respectively. Using a realistic description of the intercellular interactions, we study how the combination of electrical and metabolic coupling generates collective rhythmicity and shapes functional beta cell networks. It turns out that while electrical coupling solely can synchronize the responses, the addition of metabolic interactions further enhances coordination, the spatial range of interactions increases the number of connections in the functional beta cell networks, and ensures a better consistency with experimental findings. Moreover, our computational results provide additional insights into the relationship between beta cell heterogeneity, their activity profiles, and functional connectivity, supplementing thereby recent experimental results on endocrine networks. Ključne besede: pancreatic, beta cells, oscilators, calcium signaling, cells signaling Objavljeno v DKUM: 10.12.2024; Ogledov: 0; Prenosov: 2
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3. Network representation of multicellular activity in pancreatic islets : Technical considerations for functional connectivity analysisMarko Šterk, Yaowen Zhang, Viljem Pohorec, Eva Paradiž, Jurij Dolenšek, Richard K. P. Benninger, Andraž Stožer, Vira Kravets, Marko Gosak, 2024, izvirni znanstveni članek Opis: 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. Ključne besede: islets of Langerhans, beta cells, calcium signaling, intercellular communication, functional networks, myosin model Objavljeno v DKUM: 09.12.2024; Ogledov: 0; Prenosov: 3
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4. NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity : insights through multilayer network analysisMarko Šterk, Lidija Križančić Bombek, Maša Skelin, Marjan Rupnik, Marko Marhl, Andraž Stožer, Marko Gosak, 2021, izvirni znanstveni članek Opis: NMDA receptors promote repolarization in pancreatic beta cells and thereby reduce glucose-stimulated insulin secretion. Therefore, NMDA receptors are a potential therapeutic target for diabetes. While the mechanism of NMDA receptor inhibition in beta cells is rather well understood at the molecular level, its possible effects on the collective cellular activity have not been addressed to date, even though proper insulin secretion patterns result from well-synchronized beta cell behavior. The latter is enabled by strong intercellular connectivity, which governs propagating calcium waves across the islets and makes the heterogeneous beta cell population work in synchrony. Since a disrupted collective activity is an important and possibly early contributor to impaired insulin secretion and glucose intolerance, it is of utmost importance to understand possible effects of NMDA receptor inhibition on beta cell functional connectivity. To address this issue, we combined confocal functional
multicellular calcium imaging in mouse tissue slices with network science approaches. Our results revealed that NMDA receptor inhibition increases, synchronizes, and stabilizes beta cell activity without affecting the velocity or size of calcium waves. To explore intercellular interactions more precisely, we made use of the multilayer network formalism by regarding each calcium wave as an individual network layer, with weighted directed connections portraying the intercellular propagation. NMDA receptor inhibition stabilized both the role of wave initiators and the course of waves. The findings obtained with the experimental antagonist of NMDA receptors, MK-801, were additionally validated with dextrorphan, the active metabolite of the approved drug dextromethorphan, as well as with experiments on NMDA receptor KO mice. In sum, our results provide additional and new evidence for a possible
role of NMDA receptor inhibition in treatment of type 2 diabetes and introduce the multilayer network paradigm as a general strategy to examine effects of drugs on connectivity in multicellular systems. Ključne besede: pancreas, beta cells, insulin, Islets of Langerhans Objavljeno v DKUM: 29.11.2024; Ogledov: 0; Prenosov: 0
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5. Socio-demographic and health factors drive the epidemic progression and should guide vaccination strategies for best COVID-19 containmentRene Markovič, Marko Šterk, Marko Marhl, Matjaž Perc, Marko Gosak, 2021, izvirni znanstveni članek Opis: We propose and study an epidemiological model on a social network that takes into account heterogeneity of the population and different vaccination strategies. In particular, we study how the COVID-19 epidemics evolves and how it is contained by different vaccination scenarios by taking into account data showing that older people, as well as individuals with comorbidities and poor metabolic health, and people coming from economically depressed areas with lower quality of life in general, are more likely to develop severe COVID-19 symptoms, and quicker loss of immunity and are therefore more prone to reinfection. Our results reveal that the structure and the spatial arrangement of subpopulations are important epidemiological determinants. In a healthier society the disease spreads more rapidly but the consequences are less disastrous as in a society with more prevalent chronic comorbidities. If individuals with poor health are segregated within one community, the epidemic outcome is less favorable. Moreover, we show that, contrary to currently widely adopted vaccination policies, prioritizing elderly and other higher-risk groups is beneficial only if the supply of vaccine is high. If, however, the vaccination availability is limited, and if the demographic distribution across the social network is homogeneous, better epidemic outcomes are achieved if healthy people are vaccinated first. Only when higher-risk groups are segregated, like in elderly homes, their prioritization will lead to lower COVID-19 related deaths. Accordingly, young and healthy individuals should view vaccine uptake as not only protecting them, but perhaps even more so protecting the more vulnerable socio-demographic groups. Ključne besede: epidemic model, COVID-19, vaccination strategy, vaccination strategy, population heterogeneity, socio-demographic structure, metabolic disease, social network Objavljeno v DKUM: 14.11.2024; Ogledov: 0; Prenosov: 9
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6. Uporaba večceličnih modelov in mrežnih analiz za preučevanje kolektivne celične dinamike v Langerhansovih otočkih : doktorska disertacija po skandinavskem modeluMarko Šterk, 2024, doktorska disertacija Opis: V doktorski disertaciji smo se osredotočili na pereča vprašanja s področja fiziologije Langerhansovih otočkov, ki igrajo ključno vlogo pri uravnavanju glukozne homeostaze v telesu. Z uporabo inovativnih računalniških tehnik smo analizirali vpliv 3D citoarhitekture otočkov na večcelično dinamiko v opazovani 2D optični rezini, vpliv inhibicije NMDA receptorjev na kolektivno dinamiko celic beta, različne subpopulacije celic beta in njihov vpliv na kolektivno dinamiko ter vpliv metabolne sklopitve celic na kompleksnost funkcionalnih omrežij.
Ugotovili smo, da je pri analizi medceličnih kalcijevih valov treba upoštevati 3D citoarhitekturo Langerhansovih otočkov, saj velik delež medceličnih kalcijevih valov izvira izven opazovane optične rezine, kar vpliva na opazovano hitrost širjenja valovne fronte. Nadalje je naša analiza pokazala, da inhibicija NMDA receptorjev blagodejno vpliva na delovanje posameznih celic beta kakor tudi na njihovo kolektivno dinamiko, kar se odraža v povečani stabilnosti poteka medceličnih kalcijevih valov. Podrobna analiza subpopulacij celic beta je razkrila, da centralne celice in celice, ki sprožajo valove, igrajo ključno vlogo pri širjenju medceličnih valov in sinhronosti celic, kar je izjemnega pomena za zagotavljanje normalne fiziološke funkcije. Naši izsledki kažejo, da ti dve vrsti celic predstavljata različni subpopulaciji, ki se med seboj ne prekrivata. Poleg tega s teoretičnim raziskovanjem mehanizmov sinhronizacije celic beta podrobneje prikazujemo, da je za koordinirano aktivnost celic beta dovolj samo električna sklopitev, vendar dodatna metabolna sklopitev še dodatno okrepi sinhrono delovanje in s tem vpliva na lastnosti pridobljenih funkcionalnih omrežij, zaradi česar so ta bolj podobna tistim, ki jih opazimo v eksperimentih.
Z izvedenimi raziskavami smo prispevali k razumevanju, kako je vzpostavljeno koordinirano delovanje v kolektivih celic beta, kar odpira nove možnosti za razvoj zdravil za sladkorno bolezen tipa 2. Ključne besede: celice beta, kompleksna omrežja, diabetes tipa 2, večcelični modeli, celična dinamika Objavljeno v DKUM: 25.04.2024; Ogledov: 317; Prenosov: 38
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7. Functional characteristics of hub and wave-initiator cells in ▫$\beta$▫ cell networksMarko Šterk, Jurij Dolenšek, Maša Skelin, Lidija Križančić Bombek, Eva Paradiž, Jasmina Kerčmar, Matjaž Perc, Marjan Rupnik, Andraž Stožer, Marko Gosak, 2023, izvirni znanstveni članek Ključne besede: islets of Langerhans, beta cells, insulin Objavljeno v DKUM: 12.12.2023; Ogledov: 578; Prenosov: 17
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8. Maksimalna produkcija entropije in maksimalna shannonova informacijska entropija v encimski kinetikiMarko Šterk, 2018, magistrsko delo Opis: Princip maksimalne produkcije entropije je osrednji optimizacijski princip neravnovesne termodinamike. Princip je dobro raziskan in uveljavljen v sistemih, kjer je zveza med silami in tokovi linearna. Za sisteme, kjer je ta zveza nelinearna pa princip še ni povsem uveljavljen. Primer sistema, kjer je zveza med silami in tokovi nelinearna, so encimske reakcije. V tem magistrskem delu z uporabo principa maksimalne produkcije entropije analiziramo encimsko reakcijo, ki jo poganja encim trioza-fosfat izomeraza, ki je pomemben člen v procesu glikolize in s tem pri proizvodnji energije v večini organizmov. Encim poganja reverzibilno reakcijo v kateri pretvarja substrat dihidroksi acetonfosfat v gliceraldehid-3-fosfat preko vmesnega člena iz skupine enediolov. Z upoštevanjem zakona o ohranitvi mase sistema, ohranitvi encima in fiksne ravnovesne konstante reakcije pokažemo, da v neravnovesnem stacionarnem stanju sistema obstaja maksimum produkcije entropije v odvisnosti od poljubno izbrane kinetične konstante encima. Pokazano je tudi, da v stanju z maksimalno produkcijo entropije soobstajata maksimuma Shannonove informacijske entropije in kinetične fleksibilnosti, kar pomeni, da je stanje z maksimalno produkcijo entropije hkrati tudi najverjetnejše stacionarno stanje, v katerem je encim najfleksibilnejši. Tako napovedane optimalne kinetične konstante encima trioza-fosfat izomeraza primerjamo z eksperimentalno določenimi vrednostmi iz literature in s teoretičnimi napovedmi, ki so jih podali drugi raziskovalci z uporabo svojih optimizacijskih metod. Ključne besede: trioza-fosfat izomeraza, encimska kinetika, produkcija entropije, informacijska entropija, kinetična fleksibilnost Objavljeno v DKUM: 04.02.2021; Ogledov: 1281; Prenosov: 67
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