1. The changing world dynamics of research performanceMarko Marhl, Rene Markovič, Vladimir Grubelnik, Matjaž Perc, 2025, izvirni znanstveni članek Opis: In recent years, a notable diversification in the geographical representation of the World's top universities could be observed. Chinese universities play an increasingly prominent role in these rankings, thus indicating that we might be in the midst of a regional shift in academic performance. To explore this dynamics, we analyze seven years' worth of data used for university rankings by academic subjects from the Academic Ranking of World Universities (ARWU). We focus on China, Europe, the USA, and other global regions of the world. We find that China has indeed seen an unprecedented growth in Engineering and Life Sciences research, positioning itself rather firmly as a leader in these fields. Conversely, the USA leads in the Social Sciences, while Europe excels in Geography, Ecology, Public and Business Administration, and Pharmacy. Other regions worldwide stand out in Transportation Science, Nursing, and Hospitality & Tourism Management. These results reveal the evolving landscape of global academic research, highlighting regional strengths and emerging world trends in subject-specifc excellence.
Ključne besede: research dynamics, academic excellence, geographical diversifcation, University rankings
Objavljeno v DKUM: 11.02.2025; Ogledov: 0; Prenosov: 8
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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: 2
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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: 12
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6. Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic ▫$\alpha$▫-cellsVladimir Grubelnik, Rene Markovič, Saška Lipovšek Delakorda, Gerd Leitinger, Marko Gosak, Jurij Dolenšek, Ismael Valladolid-Acebes, Per-Olof Berggren, Andraž Stožer, Matjaž Perc, Marko Marhl, 2020, izvirni znanstveni članek Opis: Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of
cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can
account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.
Ključne besede: diabetes, pancreatic alpha cells, glucagon, mitochondrial dysfunction, free fatty acid
Objavljeno v DKUM: 03.09.2024; Ogledov: 49; Prenosov: 6
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7. Mitochondrial dysfunction in pancreatic alpha and beta cells associated with type 2 diabetes mellitusVladimir Grubelnik, Jan Zmazek, Rene Markovič, Marko Gosak, Marko Marhl, 2020, izvirni znanstveni članek Opis: Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30-40% reduction in alpha cells' mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases.
Ključne besede: pancreatic endocrine cells, mathematical model, mitochondrial dysfunction, cellular bioenergetics, diabetes, glucagon, insulin
Objavljeno v DKUM: 03.09.2024; Ogledov: 47; Prenosov: 16
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8. Cardiovascular comorbidities in COVID-19 : comprehensive analysis of key topicsRene Markovič, Luka Ternar, Tim Trstenjak, Marko Marhl, Vladimir Grubelnik, 2024, izvirni znanstveni članek Ključne besede: hypertension, hyperglycemia, embolism, thrombosis, heart failure, vascular disease
Objavljeno v DKUM: 22.08.2024; Ogledov: 53; Prenosov: 10
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9. What do stimulated beta cells have in common with cancer cells?Marko Marhl, 2024, izvirni znanstveni članek Opis: This study investigates the metabolic parallels between stimulated pancreatic beta cells and cancer cells, focusing
on glucose and glutamine metabolism. Addressing the significant public health challenges of Type 2 Diabetes
(T2D) and cancer, we aim to deepen our understanding of the mechanisms driving insulin secretion and cellular
proliferation. Our analysis of anaplerotic cycles and the role of NADPH in biosynthesis elucidates their vital
functions in both processes. Additionally, we point out that both cell types share an antioxidative response
mediated by the Nrf2 signaling pathway, glutathione synthesis, and UCP2 upregulation. Notably, UCP2 facilitates the transfer of C4 metabolites, enhancing reductive TCA cycle metabolism. Furthermore, we observe that
hypoxic responses are transient in beta cells post-stimulation but persistent in cancer cells. By synthesizing these insights, the research may suggest novel therapeutic targets for T2D, highlighting the shared metabolic strategies of stimulated beta cells and cancer cells. This comparative analysis not only illuminates the metabolic complexity of these conditions but also emphasizes the crucial role of metabolic pathways in cell function and survival, offering fresh perspectives for tackling T2D and cancer challenges.
Ključne besede: reductive metabolism, succinate
Objavljeno v DKUM: 06.08.2024; Ogledov: 89; Prenosov: 19
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10. The role of anaplerotic metabolism of glucose and glutamine in insulin secretion : a model approachVladimir Grubelnik, Jan Zmazek, Marko Gosak, Marko Marhl, 2024, izvirni znanstveni članek Opis: We propose a detailed computational beta cell model that emphasizes the role of anaplerotic metabolism under glucose and glucose-glutamine stimulation. This model goes beyond the traditional focus on mitochondrial oxidative phosphorylation and ATP-sensitive K+ channels, highlighting the predominant generation of ATP from phosphoenolpyruvate in the vicinity of KATP channels. It also underlines the modulatory role of H2O2 as a signaling molecule in the first phase of glucose-stimulated insulin secretion. In the second phase, the model emphasizes the critical role of anaplerotic pathways, activated by glucose stimulation via pyruvate carboxylase and by glutamine via glutamate dehydrogenase. It particularly focuses on the production of NADPH and glutamate as key enhancers of insulin secretion. The predictions of the model are consistent with empirical data, highlighting the complex interplay of metabolic pathways and emphasizing the primary role of glucose and the facilitating role of glutamine in insulin secretion. By delineating these crucial metabolic pathways, the model provides valuable insights into potential therapeutic targets for diabetes.
Ključne besede: mathematical models, pancreatic beta cell, pyruvate-malate cycle
Objavljeno v DKUM: 06.06.2024; Ogledov: 162; Prenosov: 16
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