When confronted with an infection, immune cells are rapidly activated to fight the threat. However, like all cells, they require energy to act. While most cells reduce their activity when nutrients are scarce, the immune system cannot afford to do so, as halting its response could put the entire body at risk from infection.

It is not clear how immune cells manage this complex nutritional budgeting. Previous studies of fruit fly larvae infected with a parasitoid wasp revealed that immune cells secure extra energy by releasing a molecule called adenosine. This slows the metabolism of non-immune tissues, leaving more nutrients available for immune cells. However, the exact mechanism that immune cells use to produce adenosine remained uncertain.

To further examine this process, Nedbalova et al. – who are part of the research group that carried out the previous work – extracted activated immune cells from a parasitoid-infected larva and fed them a labelled amino acid. Tracing this label revealed an increase in the number of chemical units known as methyl groups that had been added to molecules within the cell. This process, known as methylation, can regulate metabolic activity within cells and produces adenosine as a byproduct.

Further genetic studies showed that if nutrient supplies were sufficient, the immune cells recycled this adenosine back into ATP, the body’s main energy currency. This suggests that if there were not enough nutrients to do this, the excess adenosine would slow the metabolism of non-immune cells, therefore securing more nutrients for the immune cells. Therefore, Nedbalova et al. hypothesise that these two processes could form the basis of a feedback mechanism that allows the immune cells to regulate their energy demands.

Taken together, the findings suggest that adenosine may act as a sensor to reflect immune activity, with it being released when the cells are stimulated and recycled if they have enough energy. This hypothesis still requires further testing but, as adenosine pathways are present across all organisms, it could have implications for many physiological and disease-related processes.

Upon activation, immune cells fundamentally change their metabolism, requiring an increased supply of nutrients, which is essential for their effective function. Additional nutrients are delivered to immune cells by redirecting metabolites away from other tissues, making the immune system metabolically privileged, or selfish within an organism. The concept of selfish immunity proposes insulin resistance as a mechanism by which activated immune cells ensure adequate nutrient supply (Straub, 2014; Dolezal, 2015; Krejčová et al., 2023). For example, we have recently shown that immune cells produce cytokines Upd2 and Upd3, which induce the production of the insulin signaling inhibitor Impl2 in muscle tissue via the Jak/Stat signaling pathway. Impl2 reduces the consumption of carbohydrates by muscle, making nutrients more available to immune cells (McMullen et al., 2024). Another mechanism by which immune cells gain privileged access to nutrients is through the release of adenosine. Extracellular adenosine signaling, through the adenosine receptor, reduces nutrient consumption by non-immune tissues and slows the development of the organism, again leaving more nutrients available for the immune system (Bajgar et al., 2015; Dolezal, 2015; Bajgar and Dolezal, 2018).

Adenosine signaling plays a variety of roles, especially in more complex organisms such as mammals. However, the release of adenosine as a signaling molecule from cells plays a universal role from the most primitive organisms, such as social bacteria, to humans (Newby, 1984; Boison and Jarvis, 2021). The release of adenosine is an indication of metabolic stress and signals to neighbouring cells to adjust their behaviour accordingly. For example, the bacterium Myxococcus xanthus responds to nutrient depletion by releasing adenosine, which initiates the aggregation of bacteria into fruiting bodies (Shimkets and Dworkin, 1981). In mammals, the heart muscles secrete adenosine during ischemia, which causes blood vessels to dilate to increase blood flow and delivery of oxygen and nutrients (Lloyd et al., 1988; Deussen et al., 1989; Kroll et al., 1992; Reiss et al., 2019). Adenosine also plays an important role in the induction of sleep, torpor and hibernation, physiological states associated with energy conservation (Fredholm et al., 2011; Boison and Jarvis, 2021). Therefore, the use of extracellular adenosine by immune cells to suppress nutrient consumption in non-immune tissues, thereby conserving energy for the immune response, fits well with this evolutionarily conserved role of adenosine signaling.

Adenosine is produced intracellularly in two ways (Figure 1), by conversion from AMP by nucleotidases or in the S-adenosylmethionine (SAM) transmethylation pathway from S-adenosylhomocysteine (SAH) by S-adenosylhomocysteinase (Ahcy). The increase in AMP mainly reflects the lack of energy and metabolic stress. Cells use adenylate kinase to produce one ATP and one AMP from two ADP molecules. Increased AMP activates AMPK, which suppresses energy-consuming processes in the cell and activates energy-producing processes (Kloor and Osswald, 2004; Dzeja and Terzic, 2009). AMP is also converted by nucleotidases to adenosine, which is released from the cell via the equilibrative nucleoside transporter (ENT), where it signals the metabolic stress of the cell to surrounding cells and tissues via adenosine receptors (Dolezelova et al., 2007; Fenckova et al., 2011). This is typical of cells during ischemia when they are deprived of nutrients (Deussen et al., 1989; Schädlich et al., 2023). Since activated AMPK suppresses the function of immune cells (Salminen et al., 2011), we would expect that in the absence of nutrients and decreasing ATP levels, the accumulated AMP would be converted to adenosine and released from the cells, thus demanding a greater supply of nutrients.

Figure 1

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In the SAM transmethylation pathway, ATP and methionine combine to produce SAM, which is the major methyl group donor for most methylations in the cell. The SAM transmethylation pathway is one of the largest consumers of ATP when the adenosyl moiety of ATP is incorporated into SAM (i.e. it is not a conversion of ATP to ADP as in energy transfer). After the methyl group is transferred to the target molecule by methyltransferase, SAM becomes SAH, which must be rapidly converted to homocysteine and adenosine, or it will block further methylation. As methylation increases in the cell, more SAM is formed and at the same time SAH is cleared more rapidly, leading to an increase in the SAM:SAH ratio, known as the methylation index. SAH is converted to homocysteine and adenosine by Ahcy, which works in both directions; for the ‘SAM to homocysteine +adenosine’ direction to prevail, homocysteine and adenosine must also be metabolized or excreted from the cell very rapidly (Lu, 2000; Kloor and Osswald, 2004; Yu et al., 2019; Roy et al., 2020; Vizán et al., 2021).

Homocysteine can either be recycled back to methionine, or further metabolized in the transsulfuration pathway (source of cysteine, H₂S, and antioxidants) (Sbodio et al., 2019). Adenosine can be catabolized to inosine by adenosine deaminase (Novakova and Dolezal, 2011), or recycled to AMP by adenosine kinase and further to ATP by adenylate kinase, glycolysis or oxidative phosphorylation (Zeleznikar et al., 1990; Zeleznikar et al., 1995; Dzeja et al., 2007; Dzeja and Terzic, 2009). The importance of adenosine recycling to AMP by adenosine kinase is indicated by the dependence of the methylation cycle on the concomitant function of this enzyme (Lecoq et al., 2001; Bjursell et al., 2011; Moffatt et al., 2002). Since every single methylation in the cell is associated with the formation of one adenosine molecule, the amount of adenosine accurately reflects the intensity of the SAM transmethylation pathway. In a sense, it reflects the activity of the cell, because the more processes the cell has to activate, the more new molecules it has to methylate.

We have previously shown that activated immune cells preferentially acquire nutrients during immune response by releasing adenosine, subsequently reducing nutrient uptake in non-immune tissues, thereby leading to a delay in development (Bajgar et al., 2015; Bajgar and Dolezal, 2018). To elucidate the origin of adenosine in activated immune cells, we investigated the role of the SAM transmethylation pathway. Given its upregulation and critical function in mammalian immune cells (Lawson et al., 2012; Yu et al., 2019; Roy et al., 2020), we hypothesized that this pathway is also a major source of adenosine in Drosophila immune cells. Our results confirm that the SAM transmethylation pathway is indeed upregulated in Drosophila hemocytes upon parasitoid wasp infection. In addition, we show that this pathway is not only essential for the immune response, but also a source of extracellular adenosine that slows larval development. Moreover, not all adenosine is released from hemocytes, but it can be recycled back into ATP and thus re-enter the SAM transmethylation pathway.

We have previously shown that adenosine, released from Drosophila hemocytes, is required for systemic metabolic switch and to slow development so that there are enough nutrients for an effective immune response (Bajgar et al., 2015). Here, we show that this signal is generated in hemocytes by the SAM transmethylation pathway, which is enhanced upon infection and is required for the immune response. This novel observation links SAM transmethylation in immune cells to the production of adenosine as a systemic metabolic regulator. In addition, we show that adenosine is not only released from hemocytes but is also recycled to ATP and SAM, mediated by Adk3 and the Ak1, which are necessary for the increase in SAM transmethylation during infection, and therefore effective immune response.

The SAM transmethylation pathway is part of the one-carbon metabolism interconnecting the metabolism of serine, glycine, folates, and methionine, supporting de novo synthesis of purines and thymidine, and maintaining redox balance. The SAM transmethylation pathway itself controls antioxidant synthesis, sulfur metabolism, polyamine synthesis, and epigenetic programming via methylation (Ducker and Rabinowitz, 2017; Vizán et al., 2021). Therefore, Ahcy activity, removing SAH and producing adenosine and homocysteine, is essential, not only for keeping proper function of diverse methyltransferases, but also for a wide range of other essential metabolic processes inside the cell.

There is increasing evidence showing the crucial role of the SAM transmethylation pathway in immune cells (Lawson et al., 2012; Klein Geltink and Pearce, 2019). It was shown as early as the 80 s that peripheral blood mononuclear cells in a ‘resting’ state consume approximately three to five times more SAM for methylation than other, nonhepatic, tissues. Once activated, their SAM consumption is further increased. High SAM utilization was also observed in cultured growing lymphoblasts (German et al., 1983). The proper function of the SAM transmethylation pathway and efficient removal of SAH by Ahcy is necessary for chemotaxis in human monocytes, and neutrophils and for lymphocyte effector function (Pike and DeMeester, 1988; Zimmerman et al., 1978; Pike et al., 1978). More recently, stable isotope labeling techniques have allowed deeper insight into metabolic set up of activated immune cells. It has been shown that LPS-activated macrophages synergistically increase glycolysis, one carbon metabolism, serine synthesis pathway, pentose phosphate pathway, de novo purine synthesis, and SAM transmethylation pathway activity, to induce, and maintain a proinflammatory phenotype. Interestingly, the homocysteine produced by these macrophages is not recycled back into methionine, but SAM synthesis is likely fed exclusively with exogenous methionine transported into the cells (Yu et al., 2019). Roy et al., 2020 demonstrated the metabolic changes that occur in activated CD4 +and CD8+T lymphocytes. They identified methionine as a crucial metabolite in driving T cells proinflammatory phenotype via epigenetic reprogramming and demonstrated dietary methionine restriction as an effective intervention for autoimmune disease. Activated T lymphocytes, like macrophages, upregulate glycolysis, serine, glycine, and one-carbon metabolism including the SAM transmethylation pathway. These studies indicated that the folate cycle and the SAM transmethylation pathway are uncoupled and homocysteine is not remethylated. Importantly, SAM is synthesized from exogenous methionine and ATP, predominantly produced by de novo purine synthesis. Here, we show that in Drosophila immune cells, SAM is also synthesized mostly from exogenous methionine, and homocysteine is not remethylated back to methionine, but rather used in transsulfuration pathway. Interestingly, our results also suggest an alternative means of CTH production from methionine, independent of Ahcy, although this is not further explored here. Activated hemocytes also increase de novo purine synthesis, supported by increased pentose phosphate pathway activity (Kazek et al., 2024).

Ahcy was shown to play an important role in adenosine production in heart muscle cells, under normoxic conditions (Lloyd et al., 1988; Deussen et al., 1989). Adenosine produced by Ahcy contributes to viability of hepatocellular carcinoma cells (HepG2), since Ahcy knockdown followed by adenosine depletion leads to activation of the DNA damage response, cell cycle arrest, a decreased proliferation rate and DNA damage (Belužić et al., 2018). However, the adenosine formed in the SAM transmethylation pathway is usually referred to in studies as a by-product that needs to be removed quickly to avoid Ahcy reverse function, which would block further methylation. Here, we show that adenosine formed in the SAM transmethylation pathway is not a mere by-product but can have a significant impact on the immune response and the physiology of the whole organism. With the increase of SAM transmethylation pathway activity in activated hemocytes, more adenosine is produced. As intracellularly adenosine decreases, it is released to the extracellular space; this leads to suppression of metabolism in non-immune tissues, and consequently a development delay. This metabolic suppression is crucial for redirecting nutrients towards the immune system and mounting an effective immune response (Bajgar et al., 2015). Knockdown of Ahcy by RNAi suppresses the infection-induced increase in extracellular adenosine, as well as the delay in development, demonstrating that this important systemic signal is most likely generated by the SAM transmethylation pathway. It is important to emphasize that we measured adenosine release only ex vivo (short incubation of hemocytes obtained by larval bleeding), because it is extremely challenging to analyze extracellular adenosine levels in vivo due to the rapid removal of this molecule. Of course, the in vivo situation may be different. We have only been able to detect changes in adenosine levels in vivo in a null mutant for the secreted adenosine deaminase ADGF-A (Dolezal et al., 2005) and therefore we rely on genetic manipulations in in vivo studies. Using such manipulations, we have shown in previous work that it is activated hemocytes that secrete adenosine as a signal leading to developmental delay (Bajgar et al., 2015). Simply measuring the increase in SAM transmethylation pathway activity in hemocytes, which inevitably leads to increased adenosine production, shows that this pathway at least contributes to the production of this extracellular signal. This is then strongly supported by the phenotypes obtained here using Ahcy-RNAi, which correspond to phenotypes observed after adenosine manipulations (Bajgar et al., 2015).

At the same time, we do not want to suggest that SAM transmethylation in hemocytes is the only source of adenosine during infection. Ectoenzymes are an important source of extracellular adenosine that convert extracellular ATP to ADP, AMP, and adenosine. This cascade is an important immunomodulator in mammals (Antonioli et al., 2022). Drosophila also has this cascade of ectoenzymes (Fenckova et al., 2011), which appears not to have an immunomodulatory role, likely due to more rudimentary adenosine signaling (Dolezelova et al., 2007), but could still serve as a source of extracellular adenosine.

It is also important to add that while adenosine-mediated metabolic suppression and developmental delay are important for an effective immune response, it is likely that the ineffective immune response in Ahcy RNAi animals is at least in part due to suppression of the SAM transmethylation pathway itself in hemocytes, which is required for their function. Ahcy RNAi not only suppresses the production of adenosine, but also homocysteine, an important precursor for the transsulfuration pathway and thus the production of antioxidants and H₂S; interestingly, our work suggests an alternative production of homocysteine upon Ahcy RNAi. Ahcy RNAi also leads to extensive accumulation of SAH, so we cannot exclude that some phenotypes are due to this accumulation. Even if accumulated SAH would not cause any harm, it suppresses transmethylation reactions and polyamine synthesis, which certainly affects the function of immune cells (Latour et al., 2020; Xuan et al., 2023). Therefore, we expect that the effect of Ahcy RNAi on the function of hemocytes is not primarily due to the lack of adenosine as a signal, but rather to the suppression of the SAM transmethylation pathway and its branches. Nevertheless, the increase in the SAM transmethylation pathway in activated hemocytes, leading to increased adenosine production in wild-type hemocytes, and the absence of an increase in extracellular adenosine (at least ex vivo) together with the reduced developmental delay (phenotype obtained by manipulating extracellular adenosine by other means) upon hemocyte-specific knockdown of Ahcy strongly suggest the essential role of the SAM transmethylation pathway in generating adenosine as a systemic signal.

After ATP, SAM is the most used substrate in the cell, with up to half of the daily methionine intake in humans used for SAM synthesis, the vast majority of which is used for methylation (Lu, 2000). If all the adenosine produced by Ahcy was released to hemolymph, hemocytes would likely lose a huge amount of ATP due to SAM synthetase utilizing the adenosyl group of ATP and methionine to create SAM. Increased ATP consumption by the accelerating the SAM transmethylation pathway must be supported by de novo purine synthesis. Previous work (Kazek et al., 2024) as well as results presented here, show increased de novo purine synthesis in activated immune cells. However, this consumes a considerable amount of energy (six ATP for one IMP molecule) and takes 11 steps to produce IMP from the initial ribose-5-phosphate. Thus, it is more efficient to recycle at least some ATP from the adenosine generated in the SAM transmethylation pathway via coordinated action of adenosine kinase, cytosolic adenylate kinase, and glycolysis. This is in line with ATP synthesis from adenosine via AMP and ADP shown to be significantly increased in activated rat peritoneal macrophages (Barankiewicz and Cohen, 1985).

Adenosine kinase has been shown to be coupled with Ahcy to effectively remove adenosine and keep the SAM transmethylation pathway running (Moffatt et al., 2002; Xu et al., 2017; Murugan et al., 2021). Subsequently, the AMP produced can be utilized by the adenylate kinase catalyzing phosphoryl exchange reaction AMP +ATP ↔ 2 ADP. Adenylate kinase is crucial for cellular energy homeostasis, by regulating nucleotides ratio, AMP production and direction to diverse metabolic sensors (e.g. AMPK). In addition, it is responsible for the transfer of ATP-energy-rich phosphoryl between energy producing and energy utilizing sites by a sequence of repeated reactions, creating an effective energy transfer shuttle across the cell (Zeleznikar et al., 1990; Zeleznikar et al., 1995; Dzeja et al., 2007; Dzeja and Terzic, 2009). Our hemocyte RNAseq and qPCR data show that Drosophila Adk3 and Ak1 are expressed at low levels in quiescent hemocytes, but their expression increases dramatically during infection. Experiments using 13C-labeled adenosine show its incorporation into AMP, ADP, ATP, and especially into SAM, in which the incorporation is significantly increased upon hemocyte activation. These results connect adenosine recycling with the SAM transmethylation pathway. Without infection, the methylation index of Adk3 and Ak1 RNAi in hemocytes is the same as in control cells. However, upon infection, there is no increase in the methylation index in Adk3 and Ak1 RNAi cells. When the SAM transmethylation pathway is not accelerated, Ahcy does not produce more adenosine, and consequently the adenosine-induced developmental delay during infection is reduced in Adk3 and Ak1 RNAi, whereas without infection, RNAi larvae develop at the same rate as controls. Our results therefore demonstrate a novel functional connection of adenosine recycling to ATP with SAM transmethylation pathway. At least under energy demanding conditions, as during the activation of immune cells, Adk and cytosolic Ak activities appear to support SAM transmethylation pathway activity.

Similar to Ahcy RNAi, Adk3 and Ak1 RNAi in hemocytes also negatively affects immune response efficiency. We see a significant decrease in lamellocytes number in our infected knockdown larvae, resulting in decreased survival. It is important to note, that while Ak1 RNAi most likely also affects de novo purine synthesis, the Adk3 RNAi effects we observed are due to impairments in adenosine recycling. Connecting the SAM transmethylation pathway-driven production of adenosine with its recycling via Adk3 and Ak1 leads us to following hypothesis (Figure 6):

Figure 6

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Most cellular processes involve methylation, therefore the SAM transmethylation pathway reflects the activity of the cell. While a wide variety of molecules are methylated, adenosine is the universal product of each individual methylation. Thus, adenosine production reflects the sum of all methylations (where SAM has been used) and therefore the overall activity of the cell. Adenosine must be removed quickly as to not block the SAM transmethylation pathway. The preferred fate is to recycle adenosine to AMP and eventually ATP so that the cell does not lose its adenosyl pool. However, this requires nutrients, adenosine kinase requires ATP, adenylate kinase produces ADP from AMP and ATP and the resulting ADP is recycled to ATP in glycolysis, consuming glucose. If the cell’s nutrient supply is inadequate, AMP begins to accumulate, due to the opposite action of adenylate kinase, preventing adenosine from being recycled to AMP by adenosine kinase. In this case, the accumulating adenosine is pushed out of the cell via ENT, where it becomes a signaling molecule, informing surrounding tissues of the need for more nutrients. We therefore look at adenosine as a sensitive sensor of the balance between cell activity (reflected in methylation) and nutrient supply – the better the balance, the less adenosine is released and the more is recycled.

To experimentally test this hypothesis will require extremely well-controlled conditions, as offered for example by uniform cell culture in precisely controlled media, and delicate manipulation of the important players. The proposed role of adenosine as a sensitive sensor between cell activity and nutrient supply might have far-reaching implications. The production of adenosine by nucleotidase as the ADP/ATP ratio rises is known, for example, to generate a signal in ischemic tissue to inform surrounding tissues of metabolic stress (e.g. vasodilation to increase blood flow). However, the generation of such a signal as a result of an imbalance between cell activity and nutrient supply is a novel and exciting hypothesis.

The fate of adenosine is determined by biochemical properties and the expression of enzymes and transporters. The Km values of Drosophila Adk2 and Adk3 are not known (Fleischmannova et al., 2012; Stenesen et al., 2013), but it is possible that they differ, and that increased expression of Adk3 specifically during infection is important in readjusting the balances between AMP and adenosine, which are determined by the properties of nucleotidases and adenosine kinases (Boison, 2013). The expression levels and properties of nucleoside transporters and adenosine deaminase also play important roles. The specific setup of this whole system in certain cell types under certain conditions determines what happens with adenosine (Dulla and Masino, 2013; Dale, 2021). Studying this setup is essential to understanding the role of this system in specific situations, such as those in which adenosine may be generated by imbalances in activity and energy supply. For example, does it play a role in the early activation of immune cells, regulating nutrient supply to their site of activation? In addition, in the tumor microenvironment, adenosine inhibits infiltrating immune cells (Boison and Yegutkin, 2019). Until now adenosine ectoenzymes have been mainly studied in this respect. However, the SAM transmethylation pathway is very active in tumor cells (Vizán et al., 2021) – can tumors regulate their environment by releasing adenosine, which is produced according to our hypothetical mechanism? Basically, any cell/tissue in which the SAM transmethylation pathway is active can potentially use adenosine as a sensor of the balance between its activity and nutrient supply. Some tissues will probably be more privileged and demand nutrients by releasing adenosine because they have more nucleoside transporters expressed. For example, in the brain, the transmethylation pathway is important for many different processes (Jin et al., 2018), and extracellular adenosine is an important neuromodulator and regulator of blood flow (Peng et al., 2020). Less privileged tissues with lower expression of nucleoside transporters may be more likely to convert adenosine to AMP and activate AMPK during nutrient deprivation to dampen their overactivity. These speculations, of course, need to be tested in the future.

Raw data of metabolomics and stable 13C isotope tracing in circulating hemocytes during parasitoid wasp infection have been deposited to figshare and are available at https://doi.org/10.6084/m9.figshare.27291300.v1. RNAseq raw data are available at The European Nucleotide Archive under study accession number: PRJEB74490 (secondary acc: ERP159178) (https://www.ebi.ac.uk/ena/browser/view/PRJEB74490). All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for Figures 2–5.

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Author details

1. Pavla Nedbalová

   Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

2. Nikola Kaislerova

   Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic

   Contribution

   Investigation, Visualization

   Competing interests

   No competing interests declared

3. Lenka Chodakova

   Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic

   Contribution

   Investigation, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

4. Martin Moos

   1. Laboratory of Analytical Biochemistry and Metabolomics, Institute of Entomology, Biology Centre, Czech Academy of Sciences, České Budějovice, Czech Republic
   2. Department of Applied Chemistry, Faculty of Agriculture and Technology, University of South Bohemia, České Budějovice, Czech Republic

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing – review and editing

   For correspondence

   moos@bclab.eu

   Competing interests

   No competing interests declared

5. Tomáš Doležal

   Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   tomas.dolezal@prf.jcu.cz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5217-4465

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