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1.
Aging transitions of multimodal oscillators in multilayer networks
Uroš Barać, Matjaž Perc, Marko Gosak, 2024, izvirni znanstveni članek

Opis: When individual oscillators age and become inactive, the collective dynamics of coupled oscillators is often affected as well. Depending on the fraction of inactive oscillators or cascading failures that percolate from crucial information exchange points, the critical shift toward macroscopic inactivity in coupled oscillator networks is known as the aging transition. Here, we study this phenomenon in two overlayed square lattices that together constitute a multilayer network, whereby one layer is populated with slow Poincaré oscillators and the other with fast Rulkov neurons. Moreover, in this multimodal setup, the excitability of fast oscillators is influenced by the phase of slow oscillators that are gradually inactivated toward the aging transition in the fast layer. Through extensive numerical simulations, we find that the progressive inactivation of oscillators in the slow layer nontrivially affects the collective oscillatory activity and the aging transitions in the fast layer. Most counterintuitively, we show that it is possible for the intensity of oscillatory activity in the fast layer to progressively increase to up to 100%, even when up to 60% of units in the slow oscillatory layer are inactivated. We explain our results with a numerical analysis of collective behavior in individual layers, and we discuss their implications for biological systems.
Ključne besede: collective dynamics, coupled oscillators, dynamics of networks, network resilience, robustness, synchronization transition
Objavljeno v DKUM: 28.02.2025; Ogledov: 0; Prenosov: 425
.pdf Celotno besedilo (5,87 MB)
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Ultrafast multicellular calcium imaging of calcium spikes in mouse beta cells in tissue slices
Jurij Dolenšek, Viljem Pohorec, Maša Skelin, Marko Gosak, Andraž Stožer, 2025, izvirni znanstveni članek

Opis: Background: The crucial steps in beta cell stimulus-secretion coupling upon stimulation with glucose are oscillatory changes in metabolism, membrane potential, intracellular calcium concentration, and exocytosis. The changes in membrane potential consist of bursts of spikes, with silent phases between them being dominated by membrane repolarization and absence of spikes. Assessing intra- and intercellular coupling at the multicellular level is possible with ever-increasing detail, but our current ability to simultaneously resolve spikes from many beta cells remains limited to double-impalement electrophysiological recordings. Methods: Since multicellular calcium imaging of spikes would enable a better understanding of coupling between changes in membrane potential and calcium concentration in beta cell collectives, we set out to design an appropriate methodological approach. Results: Combining the acute tissue slice method with ultrafast calcium imaging, we were able to resolve and quantify individual spikes within bursts at a temporal resolution of >150 Hz over prolonged periods, as well as describe their glucose-dependent properties. In addition, by simultaneous patch-clamp recordings we were able to show that calcium spikes closely follow membrane potential changes. Both bursts and spikes coordinate across islets in the form of intercellular waves, with bursts typically displaying global and spikes more local patterns. Conclusions: This method and the associated findings provide additional insight into the complex signaling within beta cell networks. Once extended to tissue from diabetic animals and human donors, this approach could help us better understand the mechanistic basis of diabetes and find new molecular targets.
Ključne besede: beta cell, calcium imaging, calcium oscillations, calcium spikes, physiology
Objavljeno v DKUM: 24.01.2025; Ogledov: 0; Prenosov: 7
.pdf Celotno besedilo (9,70 MB)
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4.
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, 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: 79
.pdf Celotno besedilo (14,78 MB)
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5.
Interlayer connectivity affects the coherence resonance and population activity patterns in two-layered networks of excitatory and inhibitory neurons
David Ristič, Marko Gosak, 2022, izvirni znanstveni članek

Opis: The firing patterns of neuronal populations often exhibit emergent collective oscillations, which can display substantial regularity even though the dynamics of individual elements is very stochastic. One of the many phenomena that is often studied in this context is coherence resonance, where additional noise leads to improved regularity of spiking activity in neurons. In this work, we investigate how the coherence resonance phenomenon manifests itself in populations of excitatory and inhibitory neurons. In our simulations, we use the coupled FitzHugh-Nagumo oscillators in the excitable regime and in the presence of neuronal noise. Formally, our model is based on the concept of a two-layered network, where one layer contains inhibitory neurons, the other excitatory neurons, and the interlayer connections represent heterotypic interactions. The neuronal activity is simulated in realistic coupling schemes in which neurons within each layer are connected with undirected connections, whereas neurons of different types are connected with directed interlayer connections. In this setting, we investigate how different neurophysiological determinants affect the coherence resonance. Specifically, we focus on the proportion of inhibitory neurons, the proportion of excitatory interlayer axons, and the architecture of interlayer connections between inhibitory and excitatory neurons. Our results reveal that the regularity of simulated neural activity can be increased by a stronger damping of the excitatory layer. This can be accomplished with a higher proportion of inhibitory neurons, a higher fraction of inhibitory interlayer axons, a stronger coupling between inhibitory axons, or by a heterogeneous configuration of interlayer connections. Our approach of modeling multilayered neuronal networks in combination with stochastic dynamics offers a novel perspective on how the neural architecture can affect neural information processing and provide possible applications in designing networks of artificial neural circuits to optimize their function via noise-induced phenomena.
Ključne besede: neuronal dynamics, coherence resonance, excitatory neurons, inhibitory neurons, neural network, multilayer network, interlayer connectivity
Objavljeno v DKUM: 20.12.2024; Ogledov: 0; Prenosov: 4
.pdf Celotno besedilo (6,72 MB)
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6.
Both electrical and metabolic coupling shape the collective multimodal activity and functional connectivity patterns in beta cell collectives : a computational model perspective
Marko 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: 5
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7.
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, 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: 4
.pdf Celotno besedilo (4,48 MB)
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8.
NMDA receptor inhibition increases, synchronizes, and stabilizes the collective pancreatic beta cell activity : insights through multilayer network analysis
Marko 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: 2
.pdf Celotno besedilo (4,64 MB)
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9.
Socio-demographic and health factors drive the epidemic progression and should guide vaccination strategies for best COVID-19 containment
Rene 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: 12
.pdf Celotno besedilo (7,09 MB)
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10.
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, pregledni znanstveni članek

Opis: 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.
Ključne besede: cAMP, beta cells, stimulus-secretion coupling, intercellular coupling, PKA, Epac2A
Objavljeno v DKUM: 16.10.2024; Ogledov: 0; Prenosov: 6
.pdf Celotno besedilo (19,95 MB)
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