scholarly journals RhoGEF12 controls cardiac remodeling by integrating G protein– and integrin-dependent signaling cascades

2013 ◽  
Vol 210 (4) ◽  
pp. 665-673 ◽  
Author(s):  
Mikito Takefuji ◽  
Marcus Krüger ◽  
Kishor K. Sivaraj ◽  
Kozo Kaibuchi ◽  
Stefan Offermanns ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Small Gtpase ◽  
Signaling Cascades ◽  
Term Survival ◽  
Rhoa Activation

Structural cardiac remodeling, including hypertrophy and fibrosis, plays a crucial role in the pathogenesis of heart failure. In vitro studies suggested a role of the small GTPase RhoA in hypertrophic cardiomyocyte growth, but neither the molecular mechanisms leading to RhoA activation nor their relevance in vivo are known. We use here a mass spectrometric approach to identify Rho guanine nucleotide exchange factors (RhoGEFs) activated during cardiac pressure overload in vivo and show that RhoGEF12 is a central player during cardiac remodeling. We show that RhoGEF12 is required for stretch-induced RhoA activation and hypertrophic gene transcription in vitro and that its activation depends on integrin β1 and heterotrimeric G proteins of the G12/13 family. In vivo, cardiomyocyte-specific deletion of RhoGEF12 protects mice from overload-induced hypertrophy, fibrosis, and development of heart failure. Importantly, in mice with preexisting hypertrophy, induction of RhoGEF12 deficiency protects from cardiac decompensation, resulting in significantly increased long-term survival. Collectively, RhoGEF12 acts as an integrator of stretch-induced signaling cascades in cardiomyocytes and is an interesting new target for therapeutic intervention in patients with pressure overload–induced heart failure.

Abstract P478: Farnesyl Transferase Inhibitor Tipifarnib Reduces Circulating Exosomes And Protects Against Pressure Overload-mediated Cardiac Hypertrophy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Vandana Mallaredy
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitor

Clinically, Hypertrophic cardiomyopathy (HCM) in response to pathophysiological stress is one of the major initiating factors for the onset of cardiac remodeling leading to heart failure. Studies have revealed that HCM characterized by left ventricular hypertrophy, hypercontractility, and impaired relaxation is mainly driven by an intricate crosstalk among the multiple cellular and molecular mechanisms, which leads to heart failure. In agreement with this observation, we investigated if the Tipifarnib-mediated reduction/alteration of circulating exosomes mediates cardiac cell communication during HCM. Several studies have shown Tipifarnib as a potential Farnesyl transferase inhibitor. However, in recent past Tipifarnib has been shown to target exosomes biogenesis by several mechanisms such as inhibiting Ras pathway, ESCRT complex etc. Tipifarnib treatment in mice significantly reduced the number of circulating plasma exosomes. We examined the response of Tipifarnib treatment (10 mg/kg body weight) in C57BL6J male mice subjected to transverse aortic constriction (TAC) surgery. Untreated TAC mice had worsening of systolic Left Ventricular function at 4 weeks that further deteriorated at 8 weeks, while the treatment with Tipifarnib substantially improved cardiac functions by reducing cardiac hypertrophy and fibrosis. Exosomes isolated from the serum of sham and TAC mice with or without tipifarnib were used for in vitro cell based analyses. We observed that the exosomes isolated from Tipifarnib treated TAC mice reduced isoproterenol (ISO)-induced cardiomyoblast hypertrophy and fibrosis-associated genes in adult cardiac fibroblasts. Taken together, our studies suggest Tipifarnib protects against pressure overload induced cardiac remodeling and dysfunction by altering hypertrophic and fibrotic gene expression, by potentially reducing circulating exosomes or by altering exosome contents. Ongoing studies will clarify the molecular mechanisms of these observations.

Abstract 285: Cardiac Inflammation and Fibrosis Induced by Heart Failure Are Reversed by Short-Duration Estrogen Therapy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Andrea Iorga ◽  
Rangarajan Nadadur ◽  
Salil Sharma ◽  
Jingyuan Li ◽  
Mansoureh Eghbali
Keyword(s):  
Heart Failure ◽  
Estrogen Therapy ◽  
Pressure Overload ◽  
Decompensated Heart Failure ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
In Vivo Model ◽  
Anti Inflammatory

Heart failure is generally characterized by increased fibrosis and inflammation, which leads to functional and contractile defects. We have previously shown that short-term estrogen (E2) treatment can rescue pressure overload-induced decompensated heart failure (HF) in mice. Here, we investigate the anti-inflammatory and anti-fibrotic effects of E2 on reversing the adverse remodeling of the left ventricle which occurs during the progression to heart failure. Trans-aortic constriction procedure was used to induce HF. Once the ejection fraction reached ∼30%, one group of mice was sacrificed and the other group was treated with E2 (30 αg/kg/day) for 10 days. In vitro, co-cultured neonatal rat ventricular myocytes and fibroblasts were treated with Angiotensin II (AngII) to simulate cardiac stress, both in the presence or absence of E2. In vivo RT-PCR showed that the transcript levels of the pro-fibrotic markers Collagen I, TGFβ, Fibrosin 1 (FBRS) and Lysil Oxidase (LOX) were significantly upregulated in HF (from 1.00±0.16 to 1.83±0.11 for Collagen 1, 1±0.86 to 4.33±0.59 for TGFβ, 1±0.52 to 3.61±0.22 for FBRS and 1.00±0.33 to 2.88±0.32 for LOX) and were reduced with E2 treatment to levels similar to CTRL. E2 also restored in vitro AngII-induced upregulation of LOX, TGFβ and Collagen 1 (LOX:1±0.23 in CTRL, 6.87±0.26 in AngII and 2.80±1.5 in AngII+E2; TGFβ: 1±0.08 in CTRL, 3.30±0.25 in AngII and 1.59±0.21 in AngII+E2; Collagen 1: 1±0.05 in CTRL.2±0.01 in AngII and 0.65±0.02 (p<0.05, values normalized to CTRL)). Furthermore, the pro-inflammatory interleukins IL-1β and IL-6 were upregulated from 1±0.19 to 1.90±0.09 and 1±0.30 to 5.29±0.77 in the in vivo model of HF, respectively, and reversed to CTRL levels with E2 therapy. In vitro, IL-1β was also significantly increased ∼ 4 fold from 1±0.63 in CTRL to 3.86±0.14 with AngII treatment and restored to 1.29±0.77 with Ang+E2 treatment. Lastly, the anti-inflammatory interleukin IL-10 was downregulated from 1.00±0.17 to 0.49±0.03 in HF and reversed to 0.67±0.09 in vivo with E2 therapy (all values normalized to CTRL). This data strongly suggests that one of the mechanisms for the beneficial action of estrogen on left ventricular heart failure is through reversal of inflammation and fibrosis.

scholarly journals Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine

2018 ◽  
Vol 125 (1) ◽  
pp. 86-96 ◽  
Author(s):  
T. Dylan Olver ◽  
Jenna C. Edwards ◽  
Brian S. Ferguson ◽  
Jessica A. Hiemstra ◽  
Pamela K. Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Interval Exercise

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca2+-activated K+ (BKCa) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BKCa channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BKCa channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BKCa channel-mediated coronary vascular dysfunction, it did not change BKCa channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BKCa channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BKCa channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

scholarly journals Molecular Mechanisms for the Mechanical Modulation of Airway Responsiveness

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Wenwu Zhang ◽  
Susan J. Gunst
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Actin Polymerization ◽  
Molecular Mechanisms ◽  
Airway Responsiveness ◽  
Small Gtpase ◽  
Cortical Actin

The smooth muscle of the airways is exposed to continuously changing mechanical forces during normal breathing. The mechanical oscillations that occur during breathing have profound effects on airway tone and airway responsiveness both in experimental animals and humans in vivo and in isolated airway tissues in vitro. Experimental evidence suggests that alterations in the contractile and mechanical properties of airway smooth muscle tissues caused by mechanical perturbations result from adaptive changes in the organization of the cytoskeletal architecture of the smooth muscle cell. The cytoskeleton is a dynamic structure that undergoes rapid reorganization in response to external mechanical and pharmacologic stimuli. Contractile stimulation initiates the assembly of cytoskeletal/extracellular matrix adhesion complex proteins into large macromolecular signaling complexes (adhesomes) that undergo activation to mediate the polymerization and reorganization of a submembranous network of actin filaments at the cortex of the cell. Cortical actin polymerization is catalyzed by Neuronal-Wiskott–Aldrich syndrome protein (N-WASP) and the Arp2/3 complex, which are activated by pathways regulated by paxillin and the small GTPase, cdc42. These processes create a strong and rigid cytoskeletal framework that may serve to strengthen the membrane for the transmission of force generated by the contractile apparatus to the extracellular matrix, and to enable the adaptation of smooth muscle cells to mechanical stresses. This model for the regulation of airway smooth muscle function can provide novel perspectives to explain the normal physiologic behavior of the airways and pathophysiologic properties of the airways in asthma.

Abstract 379: Inhibition of Bcl-x Phosphorylation Prevents Cardiomyocyte Death, Cardiac Remodeling and Heart Failure After Myocardial Infarction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Dominic D Re ◽  
Junichi Sadoshima
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Ischemia Reperfusion ◽  
Resistant Mutant ◽  
Cardiac Contraction ◽  
Dependent Manner ◽  
Infarct Area

Cardiac remodeling promotes heart failure (HF). Cardiomyocyte (CM) death is one of the mechanisms to develop cardiac remodeling. We recently reported that Mst1 phosphorylates Bcl-xL at Ser14, which promotes apoptosis by inducing dissociation of Bcl-xL from Bax and consequent activation of Bax in CMs. Its phosphorylation is increased in response to ischemia-reperfusion (IR) in an Mst1-dependent manner. However, the functional significance of endogenous Bcl-xL phosphorylation remains unclear in vivo. To address this question, knock-in (KI) mice with alanine mutation at Ser14 in Bcl-x were generated. At baseline, cardiac function was similar between wild-type (WT) and heterozygous KI (HKI) mice (EF 76% and 79%, respectively). HKI mice exhibited smaller % infarct area (30%) than WT (43%) (p=0.016) upon IR, suggesting that phosphorylation of endogenous Bcl-xL at Ser14 plays an essential role in mediating IR injury. In order to test the role of Bcl-xL phosphorylation in the development of HF, HKI and WT mice were subjected to permanent ligation of LAD for 4 weeks. During progression of cardiac remodeling, Mst1 was activated in both WT and HKI mice. Phosphorylation of Bcl-xL and Bcl-xS, an alternative transcriptional variant of Bcl-x, both at Ser14, were increased in WT mice, which were abrogated in HKI mice. The infarct area evaluated with TTC staining at Day 1 was similar in WT and HKI mice (59.1% and 61.2%, p=0.65). Four weeks after myocardial infarction (MI), WT mice exhibited lower cardiac contraction (EF 46.5%) and higher LVEDP (10.8mmHg) than those in HKI mice (EF 68.9% and LVEDP 7.0mmHg) (both p<0.05). Scar area and TUNEL-positive CMs were greater in WT (49.0% and 1.6%, respectively) than in HKI mice (29.2% and 0.4%, respectively) (both p<0.05). Cleaved caspase 3 and 9 were significantly increased (3.2- and 5.7-fold, respectively) in WT but not in HKI mice. In vitro experiments with overexpression of phospho-mimicking mutant (Bcl-xS-S14D) showed 13% reduction in cell viability compared with that of phospho-resistant mutant (Bcl-xS-S14A) (p=0.01%). Our results suggest that phosphorylation of Bcl-xL and Bcl-xS at Ser14 contributes to CM death in response to IR and chronic MI in vivo, thereby promoting cardiac remodeling and HF.

scholarly journals Cardiomyocyte-Specific RIP2 Overexpression Exacerbated Pathologic Remodeling and Contributed to Spontaneous Cardiac Hypertrophy

2021 ◽  
Vol 9 ◽  
Author(s):  
Jing-jing Yang ◽  
Nan Zhang ◽  
Zi-ying Zhou ◽  
Jian Ni ◽  
Hong Feng ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cardiac Remodeling ◽  
Specific Inhibitor ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Hek293 Cells ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes

This study aimed to investigate the role and mechanisms of Receptor interacting protein kinase 2 (RIP2) in pressure overload-induced cardiac remodeling. Human failing or healthy donor hearts were collected for detecting RIP2 expression. RIP2 cardiomyocyte-specific overexpression, RIP2 global knockout, or wild-type mice were subjected to sham or aortic banding (AB) surgery to establish pressure overload-induced cardiac remodeling in vivo. Phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) were used for further investigation in vitro. The expression of RIP2 was significantly upregulated in failing human heart, mouse remodeling heart, and Ang II-treated NRCMs. RIP2 overexpression obviously aggravated pressure overload-induced cardiac remodeling. Mechanistically, RIP2 overexpression significantly increased the phosphorylation of TAK1, P38, and JNK1/2 and enhanced IκBα/p65 signaling pathway. Inhibiting TAK1 activity by specific inhibitor completely prevented cardiac remodeling induced by RIP2 overexpression. This study further confirmed that RIP2 overexpression in NRCM could exacerbate PE-induced NRCM hypertrophy and TAK1 silence by specific siRNA could completely rescue RIP2 overexpression-mediated cardiomyocyte hypertrophy. Moreover, this study showed that RIP2 could bind to TAK1 in HEK293 cells, and PE could promote their interaction in NRCM. Surprisingly, we found that RIP2 overexpression caused spontaneous cardiac remodeling at the age of 12 and 18 months, which confirmed the powerful deterioration of RIP2 overexpression. Finally, we indicated that RIP2 global knockout attenuated pressure overload-induced cardiac remodeling via reducing TAK1/JNK1/2/P38 and IκBα/p65 signaling pathways. Taken together, RIP2-mediated activation of TAK1/P38/JNK1/2 and IκBα/p65 signaling pathways played a pivotal role in pressure overload-induced cardiac remodeling and spontaneous cardiac remodeling induced by RIP2 overexpression, and RIP2 inhibition might be a potential strategy for preventing cardiac remodeling.

scholarly journals Citri Reticulatae Pericarpium Alleviates Postmyocardial Infarction Heart Failure by Upregulating Pparγ Expression

2021 ◽  
Author(s):  
Mengli Chen ◽  
Hongyan Zhu ◽  
Qingqing Zhu ◽  
Xiaodong Wu ◽  
Yufei Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Systolic Function ◽  
Tunel Staining ◽  
Mouse Heart ◽  
Coronary Artery Ligation ◽  
Traditional Chinese Herbal Medicine

Abstract PurposeHeart failure after myocardial infarction (MI) is the leading cause of death worldwide. Citri Reticulatae Pericarpium (CRP) is a traditional Chinese herbal medicine that has been used in the clinic for centuries. In this study, we aimed to investigate the roles of CRP in cardiac remodeling and heart failure after MI, as well as the molecular mechanisms involved.MethodsMale C57BL/6 mice aged 8 weeks were subjected to coronary artery ligation to mimic the clinical situation in vivo. Echocardiography was used to assess the systolic function of the mouse heart. Masson trichrome staining and Wheat germ agglutinin (WGA) staining were utilized to determine the fibrotic area and cross-sectional area of the mouse heart, respectively. Cardiomyocytes and fibroblasts were isolated from neonatal rats aged 0–3 days in vitro using enzyme digestion. TUNEL staining and EdU staining were performed to evaluate apoptosis and proliferation, respectively. Gene expression changes were analyzed by qRT–PCR, and protein expression changes were assessed by Western blotting.ResultsOur findings revealed that CRP attenuated cardiac hypertrophy, fibrosis and apoptosis and alleviated heart failure after MI in vivo. Furthermore, CRP mitigated cardiomyocyte apoptosis and fibroblast proliferation and differentiation into myofibroblasts. In addition, the PPARγ inhibitor T0070907 completely abolished the abovementioned beneficial effects of CRP, and the PPARγ activator rosiglitazone failed to further ameliorate cardiac apoptosis and fibrosis in vitro.ConclusionCRP alleviates cardiac hypertrophy, fibrosis, and apoptosis and can ameliorate heart failure after MI via activation of PPARγ.

KLF15 Is an Essential Negative Regulatory Factor for the Cardiac Remodeling Response to Pressure Overload

Cardiology ◽  
2015 ◽  
Vol 130 (3) ◽  
pp. 143-152 ◽  
Author(s):  
Yang Yu ◽  
Jie Ma ◽  
Yingbin Xiao ◽  
Qingjun Yang ◽  
Huali Kang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Heart Function ◽  
Pressure Overload ◽  
Tissue Growth ◽  
Mrna Levels ◽  
Expression Levels

Objective: To investigate the mechanism of Krüppel-like factor 15 (KLF15) in cardiac remodeling and interstitial fibrosis. Methods: A rat model was established by in vivo aortic coarctation followed by a period of pressure unloading and used to measure heart function, myocardial pathological changes, and KLF15, transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), and myocardin-related transcription factor A (MRTF-A) expression levels. In addition, cardiac fibroblasts were cultured in vitro and treated with KLF15-shRNA or KLF15 recombinant adenovirus to establish a TGF-β-mediated cardiac fibroblast hypertrophy model and analyze cell morphology, collagen secretion, and changes in the expression levels of 4 cytokines. Results: In vivo pressure overload impaired cardiac function and resulted in myocardial hypertrophy and fibrosis. These changes were accompanied by the downregulation of KLF15 mRNA levels and increased expression of the other factors. The response to unloading was the opposite. In in vitro cell experiments, by specifically targeting the KLF15 gene, changes in the expression levels of the 4 cytokines and the amounts of collagen I and III were observed. Conclusions: In myocardial remodeling processes induced by mechanical or metabolic factors, KLF15 regulates TGF-β, CTGF, and MRTF-A expression and can ameliorate or even reverse myocardial fibrosis and improve cardiac function.

scholarly journals Cardiac fibroblasts acquire properties of matrifibrocytes in vitro and in mice with pressure overload-induced congestive heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.M Herum ◽  
G Gilles ◽  
A Romaine ◽  
A.O Melleby ◽  
G Christensen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Funding Source ◽  
High Stiffness

Abstract Introduction Activation of cardiac fibroblasts (CFB) is a key step in development of fibrosis in the heart. It was recently shown that, in addition to the well-studied myofibroblast (myoFB) phenotype, activated cardiac fibroblasts can adopt a newly defined matrifibrocyte phenotype, characterized by expression of extracellular matrix (ECM) genes associated with bone, cartilage and tendon development. However, it is unknown whether matrifibrocytes exists in the pressure-overloaded fibrotic and failing heart, and whether substrate stiffness drives differentiation. Hypothesis Matrifibrocyte differentiation occurs in vitro during culturing of primary cardiac fibroblasts, and in vivo in response to left ventricular pressure overload. Methods Left ventricular pressure overload induced by o-ring aortic banding (ORAB) induced cardiac phenotypes of concentric hypertrophic remodelling and congestive heart failure. Primary CFB from adult mice were cultured on plastic or soft polyacrylamide hydrogels (4.5 kPa) for various times. mRNA expression of phenotypic markers were measured by RT-PCR. Presence of smooth muscle α-actin (SMA) fibers was determined by immunocytochemistry. Results ECM genes normally expressed in bone and cartilage (COMP, CILP-2, OPG and SCX) were upregulated in hypertrophic left ventricles of mice with congestive heart failure. The myoFB marker acta2 was increased 2 weeks after ORAB, returned to baseline at 4 weeks and increased again at 20 weeks when the left ventricle was dilating and failing, indicating that the myoFB phenotype is not permanent. In vitro, primary CFB upregulated bone/cartilage-associated ECM genes after 12 days of culturing on plastic. Acta2 mRNA and SMA protein levels peaked after 9 days in culture whereafter they declined, indicating a shift in phenotype. Culturing primary CFB on soft (4.5 kPa) hydrogels delayed, but did not prevent, myoFB differentiation while expression of bone/cartilage ECM genes was absent or low, indicating that high stiffness is a driver of the matrifibrocyte phenotype. Blockers of mechanotransduction, SB431542 (TGFβRI inhibitor), Y27623 (ROCK inhibitor) and cyclosporine A (calcineurin inhibitor), completely inhibited myoFB differentiation but upregulated several matrifibrocyte markers, indicating that distinct signaling pathways regulate myoFB and matrifibrocyte differentiation. Removing inhibitors re-induced myofibroblast markers in cells on plastic but not on soft gels consistent with high stiffness promoting myofibroblast differentiation. Conclusion Primary cardiac fibroblasts acquire characteristics of matrifibrocytes in vitro when cultured for long time on plastic and in vivo in left ventricles of mice with pressure overload-induced congestive heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Marie Sklodowska-Curie Individual Fellowship

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