Extended time Petri nets

In many complex systems that can be modeled using Petri nets time can be a very important factor which should be taken into account during creation and analysis of the model. Time data can describe starting moments of some actions or their duration before their immediate effects start to influence some other areas of the modeled system. Places in a Petri net often describe static components of the system, but they can also describe states. Such a state can have time restrictions, for example, telling how long it can influence other elements in the model. Time values describing some system may be inconsistent or incomplete, which can cause problems during the creation of the model. In this paper, a new extension of time Petri nets is proposed, which allows the creation of models with different types of time data, which previously were possible to be properly used in separate types of well-known time Petri nets. The proposed new time Petri net solves this problem by integrating different aspects of already existing time Petri nets into one unified net

Restriction of access to the central cavity is a major contributor to substrate selectivity in plant ABCG transporters

ABCG46 of the legume Medicago truncatula is an ABC-type transporter responsible for highly selective translocation of the phenylpropanoids, 4-coumarate, and liquiritigenin, over the plasma membrane. To investigate molecular determinants of the observed substrate selectivity, we applied a combination of phylogenetic and biochemical analyses, AlphaFold2 structure prediction, molecular dynamics simulations, and mutagenesis. We discovered an unusually narrow transient access path to the central cavity of MtABCG46 that constitutes an initial filter responsible for the selective translocation of phenylpropanoids through a lipid bilayer. Furthermore, we identified remote residue F562 as pivotal for maintaining the stability of this filter. The determination of individual amino acids that impact the selective transport of specialized metabolites may provide new opportunities associated with ABCGs being of interest, in many biological scenarios

Modelling of the iron participation in the development of atherosclerosis - a systemic approach

Hipotezę zakładającą, że wyższe stężenie żelaza w surowicy odgrywa ważną rolę w rozwoju chorób układu sercowo-naczyniowego zaproponował w 1981 r. J.L. Sullivan. Dziś, wyniki coraz liczniejszych badań potwierdzają istotne znaczenie żelaza w rozwoju miażdżycy. Zasadniczą rolę przypisuje się katalizowanej przez jony tego pierwiastka reakcji Fentona, w następstwie której powstaje silnie toksyczny rodnik hydroksylowy, biorący udział w peroksydacji lipidów. W następstwie wspomnianego procesu powstają zmienione cząsteczki lipidowe, które w sposób nieograniczony wyłapywane są przez komórki jednojądrzaste i stają się komórkami piankowatymi, a potem ciałkami apoptotycznymi tworzącymi blaszkę miażdżycową. W pracy tej przedstawiono systemowe podejście do badania prezentowanego zagadnienia. W tym celu został zbudowany model dotyczący udziału żelaza w powstawaniu miażdżycy oparty na sieciach Petriego. Analiza tego modelu pozwoliła na wyciągnięcie wniosków, iż bez reakcji Fentona, którą katalizuje żelazo, blaszka miażdżycowa nie może powstać.The hypothesis that higher serum iron concentration plays an important role in the development of diseases of the cardiovascular system has been proposed in 1981 by J.L. Sullivan. Nowadays, more and more research results confirm importance of iron in the development of atherosclerosis. The essential role plays Fenton reaction catalyzed by ions of this chemical element, which produces highly toxic hydroxyl radical involved in lipids peroxidation. As a result of this process, modified lipid molecules are produced and phagocytosed in unlimited way by mononuclear cells to become foam cells and then apoptotic bodies that form atherosclerotic plaque. In this paper, a systemic approach to the study of these issue is presented. For this purpose, a model based on Petri nets of the iron participation in the development of atherosclerosis has been built. The analysis of this model allowed us to draw the conclusion that without the Fenton reaction, which is catalyzed by iron, atherosclerotic plaque cannot actually arise

A Role of Inflammation and Immunity in Essential Hypertension—Modeled and Analyzed Using Petri Nets

Recent studies have shown that the innate and adaptive immune system, together with low-grade inflammation, may play an important role in essential hypertension. In this work, to verify the importance of selected factors for the development of essential hypertension, we created a Petri net-based model and analyzed it. The analysis was based mainly on t-invariants, knockouts of selected fragments of the net and its simulations. The blockade of the renin-angiotensin (RAA) system revealed that the most significant effect on the emergence of essential hypertension has RAA activation. This blockade affects: (1) the formation of angiotensin II, (2) inflammatory process (by influencing C-reactive protein (CRP)), (3) the initiation of blood coagulation, (4) bradykinin generation via the kallikrein-kinin system, (5) activation of lymphocytes in hypertension, (6) the participation of TNF alpha in the activation of the acute phase response, and (7) activation of NADPH oxidase—a key enzyme of oxidative stress. On the other hand, we found that the blockade of the activation of the RAA system may not eliminate hypertension that can occur due to disturbances associated with the osmotically independent binding of Na in the interstitium. Moreover, we revealed that inflammation alone is not enough to trigger primary hypertension, but it can coexist with it. We believe that our research may contribute to a better understanding of the pathology of hypertension. It can help identify potential subprocesses, which blocking will allow better control of essential hypertension

Cholesterol Metabolism Pathways Disturbances in Atherosclerosis—Analyses Using Stochastic Petri Net-Based Model

Atherosclerosis is a multifactorial disease that affects large arteries and causes much morbidity and mortality worldwide. Despite ongoing research for several decades, it is still a global health problem that cannot be stopped and cured completely. Furthermore, the development of this disease is contributed to by various processes, primarily disturbances in cholesterol metabolism, local low-grade inflammation, and oxidative stress, resulting in the formation of atherosclerotic plaques. In this work, a stochastic Petri net model was constructed and subsequently analyzed to examine the impact of these factors on the development and progression of atherosclerosis. The use of knockout- and simulation-based analysis allowed for a comprehensive investigation of the studied phenomena. Our research has demonstrated that while cholesterol is a contributing factor in atherosclerosis, blocking its impact alone is insufficient in halting the progression of this disorder. Inhibition of oxidative stress is also important when blocking the impact of phosphoprotein phosphatase inhibitor-1 (PPI-1), microsomal triglyceride transfer protein (MTTP), and 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), as our model shows that this action reduces the number of foam cells underlying atherosclerosis. The results obtained further support the previous observations that the combined treatment is significantly effective in enhancing therapeutic efficacy against atherosclerosis

A Role of Inflammation and Immunity in Essential Hypertension—Modeled and Analyzed Using Petri Nets

Recent studies have shown that the innate and adaptive immune system, together with low-grade inflammation, may play an important role in essential hypertension. In this work, to verify the importance of selected factors for the development of essential hypertension, we created a Petri net-based model and analyzed it. The analysis was based mainly on t-invariants, knockouts of selected fragments of the net and its simulations. The blockade of the renin-angiotensin (RAA) system revealed that the most significant effect on the emergence of essential hypertension has RAA activation. This blockade affects: (1) the formation of angiotensin II, (2) inflammatory process (by influencing C-reactive protein (CRP)), (3) the initiation of blood coagulation, (4) bradykinin generation via the kallikrein-kinin system, (5) activation of lymphocytes in hypertension, (6) the participation of TNF alpha in the activation of the acute phase response, and (7) activation of NADPH oxidase—a key enzyme of oxidative stress. On the other hand, we found that the blockade of the activation of the RAA system may not eliminate hypertension that can occur due to disturbances associated with the osmotically independent binding of Na in the interstitium. Moreover, we revealed that inflammation alone is not enough to trigger primary hypertension, but it can coexist with it. We believe that our research may contribute to a better understanding of the pathology of hypertension. It can help identify potential subprocesses, which blocking will allow better control of essential hypertension.</jats:p

A Stochastic Petri Net-Based Model of the Involvement of Interleukin 18 in Atherosclerosis

Interleukin 18 (IL-18) is a proinflammatory and proatherogenic cytokine with pleiotropic properties, which is involved in T and NK cell maturation and the synthesis of other inflammatory cytokines and cell adhesion molecules. It plays a significant role in orchestrating the cytokine cascade, accelerates atherosclerosis and influences plaque vulnerability. To investigate the influence of IL-18 cytokine on atherosclerosis development, a stochastic Petri net model was built and then analyzed. First, MCT-sets and t-clusters were generated, then knockout and simulation-based analysis was conducted. The application of systems approach that was used in this research enabled an in-depth analysis of the studied phenomenon. Our results gave us better insight into the studied phenomenon and allow revealing that activation of macrophages by the classical pathway and IL-18-MyD88 signaling axis is crucial for the modeled process.</jats:p

Control of Cholesterol Metabolism Using a Systems Approach

Cholesterol is an essential component of mammalian cells and is involved in many fundamental physiological processes; hence, its homeostasis in the body is tightly controlled, and any disturbance has serious consequences. Disruption of the cellular metabolism of cholesterol, accompanied by inflammation and oxidative stress, promotes the formation of atherosclerotic plaques and, consequently, is one of the leading causes of death in the Western world. Therefore, new drugs to regulate disturbed cholesterol metabolism are used and developed, which help to control cholesterol homeostasis but still do not entirely cure atherosclerosis. In this study, a Petri net-based model of human cholesterol metabolism affected by a local inflammation and oxidative stress, has been created and analyzed. The use of knockout of selected pathways allowed us to observe and study the effect of various combinations of commonly used drugs on atherosclerosis. The analysis results led to the conclusion that combination therapy, targeting multiple pathways, may be a fundamental concept in the development of more effective strategies for the treatment and prevention of atherosclerosis