bluuebunny/crossref_metadata_2025 huggingface dataset:
Energy enhancement in grid-connected photovoltaic generation systems using adaptive control technique
Authors: V Pushpabala , C Christober Asir Rajan
Published: May 2024

This research paper presents an innovative adaptive control technique for enhancing energy efficiency in grid-connected photovoltaic (PV) generation systems. By integrating an advanced high-gain DC-DC converter with adaptive and non-linear control methods, the proposed system ensures optimal power absorption from various renewable resources and maintains robust power transfer efficiency and reliability. Key results from the implementation at the Union Territory of Puducherry substation demonstrate significant improvements: the adaptive control system dynamically adjusts to changes in source voltage and load conditions, maintaining a constant output voltage with minimized steady-state error and low overshoot. The feedback controller effectively responds to fluctuations in duty cycle and output load, ensuring stable operation under varying environmental conditions. These enhancements contribute to a reliable and efficient integration of renewable energy sources into the power grid, addressing critical challenges in renewable energy technology.
Machine learning inspired models for Hall effects in non-collinear magnets
Authors: Kipp Jonathan , Lux Fabian R , Pürling Thorben , Morrison Abigail , Blügel Stefan , Pinna Daniele , Mokrousov Yuriy
Published: May 2024

The anomalous Hall effect has been front and center in solid state research and material science for over a century now, and the complex transport phenomena in nontrivial magnetic textures have gained an increasing amount of attention, both in theoretical and experimental studies. However, a clear path forward to capturing the influence of magnetization dynamics on anomalous Hall effect even in smallest frustrated magnets or spatially extended magnetic textures is still intensively sought after. In this work, we present an expansion of the anomalous Hall tensor into symmetrically invariant objects, encoding the magnetic configuration up to arbitrary power of spin. We show that these symmetric invariants can be utilized in conjunction with advanced regularization techniques in order to build models for the electric transport in magnetic textures which are, on one hand, complete with respect to the point group symmetry of the underlying lattice, and on the other hand, depend on a minimal number of order parameters only. Here, using a four-band tight-binding model on a honeycomb lattice, we demonstrate that the developed method can be used to address the importance and properties of higher-order contributions to transverse transport. The efficiency and breadth enabled by this method provides an ideal systematic approach to tackle the inherent complexity of response properties of noncollinear magnets, paving the way to the exploration of electric transport in intrinsically frustrated magnets as well as large-scale magnetic textures.
Mariner: explore the Hi-Cs
Authors: Davis Eric S , Parker Sarah M , Kramer Nicole E , Flores J P , Kiran Manjari , Phanstiel Douglas H
Published: May 2024

Motivation

3D chromatin structure plays an important role in regulating gene expression and alterations to this structure can result in developmental abnormalities and disease. While genomic approaches like Hi-C and Micro-C can provide valuable insights in 3D chromatin architecture, the resulting datasets are extremely large and difficult to manipulate.

Results

Here, we present mariner, a rapid and memory efficient tool to extract, aggregate, and plot data from Hi-C matrices within the R/Bioconductor environment. Mariner simplifies the process of querying and extracting contacts from multiple Hi-C files using a parallel and block-processing approach. Modular functions allow complete workflow customization for advanced users, yet all-in-one functions are available for running the most common types of analyses. Finally, tight integration with existing Bioconductor infrastructure enables complete analysis and visualization of Hi-C data in R.

Availability and implementation

Available on GitHub at https://github.com/EricSDavis/mariner and on Bioconductor at https://www.bioconductor.org/packages/release/bioc/html/mariner.html.
Northern blotting of endogenous full-length human-specific LINE-1 RNA
Authors: Alkailani Maisa I
Published: May 2024

LINE-1 belongs to a family of DNA elements that move to new locations in the genome in a process called “retrotransposition.” This is achieved by a copy-and-paste mechanism with the aid of an RNA intermediate. The full-length LINE-1 is responsible for most retrotransposition activity in the human genome. Detecting the active LINE-1 RNA at the endogenous level is challenging due to its small percentage among inactive copies and its different forms of transcripts. Here, we describe a method of designing RNA probes to detect active LINE-1 by northern blotting and use optimized conditions and tools to make the detection practical. This method uses a classical long RNA probe and provides an alternative way to detect LINE-1 RNA using multiple short RNA probes.
Implications of lung shunt fraction calculation discrepancy in Yttrium-90 radioembolization treatment from 2D planar vs 3D single photon emission CT imaging
Authors: Gamero Kubota Paula , Molvar Christopher , Wagner Robert , Allam Emad , Halama James , James Judy R
Published: May 2024

The safety and efficacy of Yttrium-90 (Y-90) radio-embolization therapy is partly dependent on the lung shunt fraction (LSF). There may be a notable disparity between LSF when calculated using 2D planar imaging vs 3D single photon emission CT (SPECT); this can affect the total allowable Y-90 dose delivered and therefore change the effectiveness of the procedure. The case presented demonstrates an 81% decrease in LSF when calculated by SPECT as compared to 2D planar imaging. This case highlights the importance of considering the imaging technique and the potential discrepancies that can arise between planar and SPECT imaging in LSF assessment.
Chelate extraction of metal ions in aqueous/chloroform system based on molecular crowding environment
Authors: Miyagawa Akihisa , Komatsu Hiroyuki , Nagatomo Shigenori , Nakatani Kiyoharu
Published: May 2024

In this study, we propose a novel concept for the solvent extraction of metal ions (Co, Zn, and Pb) by mimicking a molecular crowding environment using dextran (Dex). The metal ions were extracted from the aqueous phase into the organic phase (chloroform) in the presence of 8-hydroxyquinoline (HQ). The extraction constant of the metal complex (Kex) increased with increasing Dex concentration (CDex) for all metal ions. When examining the dependence of CDex on the four equilibrium constants (distribution coefficient of HQ, acid dissociation of HQ, complexation constant of metal complex (β), and distribution coefficient of the metal complex) that contribute to Kex, only β increased with CDex. This suggests that an increase in, β, a parameter reflecting the molecular crowding effect, results in an increase in Kex. The increase in β was analyzed based on volume exclusion and osmotic pressure effects. The analytical model effectively explained the enhanced the complexation due to the increase in β and volume exclusion, whereas the osmotic pressure suppressed β. Consequently, we unveiled the effect of molecular crowding on the solvent extraction of metal ions for the first time.
Soberanas de nuestros cuerpos: networked framing of abortion legalization in Argentina
Authors: Cabas-Mijares Ayleen , Wichowsky Amber
Published: May 2024

This study presents a critical discourse analysis (CDA) of the networked frames built in Twitter trending hashtags by proponents and opponents of abortion legalization in Argentina. The online discourses exemplified the dynamics of networked framing, where activists reshaped their framing of issues through crowdsourcing practices. While both sides focused their attention on defining violence and deservingness, the impact of abortion on democracy, and the appropriate geopolitical scope of the debate, they developed stark oppositional views. Supporters of legalization defined illegal abortion as state-sponsored violence against gestating people and highlighted transnational solidarities. On the other hand, pro-life users identified legal abortion as state-sponsored violence against the unborn and accused pro-abortion politicians of subverting the democratic rights of the pro-life majority. Both movements portrayed themselves as embodying reason and righteousness while projecting negative connotations onto their counterparts. Our findings provide a nuanced examination of the discursive work of Global South feminists whose advocacy shifted policy against formidable opposition.
Heat exposure limits pentose phosphate pathway activity in bumblebees
Authors: Rossi Giulia S , Elbassiouny Alaa , Jamison Jerrica , Welch Jr. Kenneth C
Published: May 2024

Bumblebee populations across the globe are experiencing substantial declines due to climate change, with major consequences for pollination services in both natural and agricultural settings. Using an economically important species, Bombus impatiens, we explored the physiological mechanisms that may cause susceptibility to extreme heat events. We tested the hypothesis that heat exposure limits the activity of the pentose phosphate pathway (PPP)—a parallel pathway to glycolysis that can use nectar sugar to generate antioxidant potential and combat oxidative stress. Using isotopically labelled glucose, we tracked PPP activity in B. impatiens at rest, during exercise and during a post-exercise recovery period under two different temperature regimes (22°C and 32°C). We found that the PPP is routinely used by B. impatiens at moderate temperatures, but that its activity is markedly reduced when ATP demands are high, such as during periods of exercise and heat exposure. We also exposed B. impatiens to either 22°C or 32°C for 5 hours and assessed levels of oxidative damage (lipid peroxidation, protein carbonyls) and antioxidant potential [reduced (GSH) and oxidized (GSSG) glutathione concentrations]. Interestingly, bees exhibited little oxidative damage after the thermal exposure, but we found a lower GSH:GSSG ratio in 32°C-exposed bees, reflecting lower antioxidant potential. Overall, our study demonstrates that acute heat stress severely limits PPP activity and may constrain antioxidant potential in B. impatiens. The repeated attenuation of this pathway in a warming climate may have more severe physiological consequences for this species, with potential implications for pollination services across North America.
miR-1 modulates HDAC4, calmodulin and MAPK1/Erk2 during early atrial differentiation
Authors: Franco D , Garcia-Padilla C , Lozano-Velasco E , Garcia-Lopez V , Aranega A , Garcia-Martinez V , Lopez-Sanchez C
Published: May 2024

Funding Acknowledgements

None.

Introduction

A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development.

Purpose

The aim of this work is to analyze the miR-1 modulation role in cardiac chamber differentiation through specific signaling pathways.

Methods

By means of microinjections in both primitive endocardial tubes of chick embryo culture, gain- and loss-of-function experiments were performed with premiR-1 and anti-miR-1, respectively. Subsequently, embryos were subjected to whole mount in situ hybridization with Tbx5, Gata4 and AMHC1 probes, as well as immunohistochemistry with Mef2c, HDAC4, Calmodulin/Calm1 and MAPK1/Erk2 antibodies. Also, we carried out RT-qPCR analysis of control and experimental embryos, including CRABPI, CRABPII and retinoic acid receptors (RAR and RXR).

Results

Our results reveal that miR-1 increases specific atrial gene expression such as Tbx5, Gata4 and AMHC1, while this microRNA diminishes Mef2c expression. Furthermore, we observed that miR-1 upregulates CRABPII and RARß, and downregulates CRABPI, which are three crucial factors in retinoic acid signaling pathway. Interestingly, we also observed that miR-1 actively interacts with HDAC4, Calmodulin and Erk2/MAPK1, key factors involved in Mef2c regulation.

Conclusion

All these data suggest that miR-1 functions as an epigenetic factor modulating complementary actions performed by retinoic acid and Mef2c, which are required to properly assign cells as sinoatrial precursors.
MicroRNA-127-3p regulates inflammatory response in injury-induced vascular remodeling and cellular senescence in vascular smooth muscle cells through mTor
Authors: Daniel F , Kalies K , Hehl L , Guerlach S , Koester J M , Boettcher S , Knoepp K , Dutzmann J , Sedding D
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Martin-Luther-Universität Halle-Wittenberg

Background and Purpose

The accumulation of senescent cells in the vasculature contributes to impaired vascular function over the lifetime. Micro RNAs (miRs) are promising therapeutic targets due to their cell-specific functions. Targeting miR-127-3p emerges as an attractive approach to enhance vascular healing and limit angioplasty-related complications.

Here, we focus on elucidating the role of miR-127-3p in vascular smooth muscle cells (VSMC) to characterize their role in cellular function and vascular senescence.

Methods

Utilizing reverse transcription and qRT-PCR we checked expression levels of miR-127-3p in human and murine aortic VSMCs. After overexpression and downregulation via transfection of pre-miR and antagomiR, we evaluated the influence of miR-127-3p on cellular functions such as proliferation and migration of human (non-) replicative senescent VSMCs. Potential targets were selected via target prediction analysis and verified on mRNA and protein levels. Morphological changes were visualized via high-resolution fluorescence microscopy. Senescence marker expression was checked after transfection by qRT-PCR.

Results

MiR-127-3p is highly upregulated in femoral artery tissue on day 10 after wire-induced injury in C57Bl6 mice, serving as restenosis model (p<0.001) and aged C57BL/6 mice (3 months vs. 22 months, p<0.0001). Replicative senescent human VSMC exhibit increased miR-127-3p expression (p<0.05). In vitro, miR-127-3p overexpression reduces proliferation in senescent (p<0.001) and non-senescent (p<0.01) cells. It hinders migration in non-senescent cells (p<0.0001) but has a reverse effect in senescent cells (p<0.01). Potential targets affecting cellular functions, inflammatory pathways, and cellular aging were identified as mTOR, AXL, and TEAD3 (p<0.05). Transfection of pre-miR leads to increase in cell size and the acquisition of a flattened morphology of human VSMC. P14arf and laminB1, as senescence-associated genes, showed downregulation after overexpression of miR-127-3p on mRNA level (p<0.05). When VSMCs were stimulated with anti-miR-127-3p, increased mRNA levels of p14arf and laminB1 were detected (p<0.05).

Conclusion

This study identifies miR-127-3p as a contributor to cellular functions including cellular proliferation and migration and seems to have opposing effects in non- and replicative senescent VSMC. Further research is needed to validate miR-127-3p as a therapeutic target for vascular aging and remodeling in vitro and in vivo.
Acquired control over proliferation and differentiation of ventricular cardiomyocytes to break down the mechanisms of cardiac repair
Authors: Ramkisoensing A , Zhang J , Pijnappels D A , De Vries A A F
Published: May 2024

Funding Acknowledgements 

None.

Loss of myocardial tissue remains a leading cause of morbidity and mortality by causing heart rhythm disturbances and heart failure. The (pre-)clinical effects of inducing cardiac regeneration by cardiac cell therapy have been disappointing. In order to find new curative options for these disabling cardiac diseases a shift of focus towards steering the heart to regenerate itself is needed. The aim of this study was to generate a robust ventricular cardiomyocyte model in which proliferation and differentiation could be tightly controlled to investigate cardiac regeneration. To accomplish this we have generated a line of immortalized neonatal rat ventricular cardiomyocytes (nrVMs) through expression of the cell cycle regulators cyclin-dependent kinase 4 and cyclin D1 (CDK4-D1). The CDK4-D1 expressing nrVMs were positive for the proliferation marker Ki67 in contrast to control nrVMs. Cardiomyogenic differentiation could still be induced after multiple passages (> passage 10) as evidenced by immunocytochemistry and optical voltage mapping. These contractile and excitable cells were indeed positive for the cardiac-specific sarcomeric proteins alpha actinin and troponin T in a sarcomeric pattern similar to native nrVMs. Passaging of the control nrVM cultures, however, ultimately led to a senescent cell population lacking sarcomeric markers after passage 3. Electrophysiological analysis of immortalized monolayers, after inducing cardiomyogenic differentiation, showed not only uniform propagation of electrical signal throughout the cultures, but also re-entrant activity although at low frequency. In conclusion, these data show that were able to immortalize ventricular cardiomyocytes by preserving their contractile and excitable phenotype upon significant expansion. Further optimisation of this model will lead to a research model of ventricular cardiomyocytes which will give us the opportunity to unravel the process of cardiomyogenesis and uncover mechanisms which could allow us to enhance the ability of the heart to regenerate itself.
MiR-92b-3p modulates apoptosis in smooth muscle cells through BCL2L11 regulation, unravelling novel therapeutic strategies for unstable plaques
Authors: Koester J , Kalies K , Boettcher S , Guerlach S , Daniel F , Hehl L , Sedding D G
Published: May 2024

Funding Acknowledgements 

None.

Smooth muscle cell (SMC) apoptosis is a contributory factor to plaque rupture in atherosclerosis, thereby promoting plaque destabilization through various mechanisms such as thrombogenic activation and plaque microcalcification. Immunohistochemical analysis has revealed elevated expression of proteins associated with intrinsic apoptosis, such as BCL2L11 (Bim), in unstable atherosclerotic plaques. Our hypothesis posits that Bim is a direct target of miR-92b-3p, an understudied microRNA, prompting an investigation into its role in regulating apoptosis in SMCs. Our objective is to discern a novel therapeutic axis for preventing plaque rupture by employing miRNA-based targeted interventions.

Within a model of primary human vascular cells, we employed various in vitro techniques, including PCR, Western Blot, Live cell imaging, and ELISA. Lipotransfection facilitated transient modulation of miR-92b-3p, using both knockdown and elevation, while an siRNA transfection model was also utilized.

MiR-92b-3p exhibits robust expression in late atherosclerotic lesions in vivo (p<0.001) and demonstrates heightened levels in smooth muscle cells (SMCs) compared to endothelial cells (ECs) in vitro (p<0.01) and in vivo in respective tissues (p<0.01). Bim, a direct target of miR-92b-3p, experiences upregulation post-miR-92b-3p knockdown and downregulation following pre-miR-92b-3p introduction into SMCs, both at mRNA and protein levels (p<0.01, p<0.01). Apoptosis increases in growth-medium cultured SMCs after miR-92b-3p knockdown (p<0.05), but not in senescent SMCs, ECs, or basal-medium treated SMCs. Live-cell imaging reveals a reduction in SMC count after anti-miR-92b-3p transfection (p<0.01), accompanied by cell shrinkage indicative of apoptosis 72 hours post-transfection (p<0.05). Growth factor stimulation results in miR-92b-3p upregulation (p>0.05) and Bim downregulation in SMCs. SiRNA knockdown of BIM in SMCs abolishes apoptosis induction through miR-92b-3p knockdown (p<0.05). Conversely, in apoptotic SMCs, miR-92b-3p upregulation protects cells from apoptosis (p<0.05).

MiR-92b-3p effectively modulates mitochondrial apoptosis in SMCs by targeting BIM. This regulatory impact is exclusive to proliferative SMCs, known for their deleterious involvement in atherosclerotic plaques. Cumulatively, the elevation of miR-92b-3p via targeted miRNA therapeutics or miRNA-drug interactions in the advanced stages of atherosclerosis presents a potential therapeutic avenue for averting plaque rupture.
Mechanical load regulates the proliferation of multiple cell types in the heart
Authors: Ciucci G , Colliva A , Vodret S , Texler B , Cardini B , Oberhuber R , Vuerich R , Zago E , Maglione M , Sinagra G , Giacca M , Eschenhagen T , Golino P , Loffredo F , Zacchigna S
Published: May 2024

Funding Acknowledgements

None.

Introduction

The adult mammalian heart has a poor regenerative and angiogenic potential. At the same time, both primary cardiac tumors and cardiac metastases are extremely rare. This suggests that shared mechanisms may halt the proliferation of cardiac (both cardiomyocyte and endothelial) and cancer cells. Among the mechanisms that have been claimed to be responsible for the loss of proliferative potential of cardiomyocytes early after birth is a sudden increase in mechanical load.

Purpose

Here, we investigate whether alterations in mechanical load affect the proliferation of multiple cell types in the heart.

Methods

Adult heart unloading in vivo was achieved using a mouse model of heterotopic heart transplantation, followed by EdU injection to label proliferating cells. Engineered heart tissues (EHTs) were generated using neonatal cardiomyocytes and fibroblasts, with a modified protocol allowing to finely tune mechanical load. Primary cardiac endothelial cells and multiple types of cancer cells (lung, melanoma and colon cancer) along with adult cardiac endothelial cells were included in EHTs.

Results

In line with our hypothesis, unloaded, heterotransplanted hearts showed a significant number of proliferating cardiomyocytes and endothelial cells, which were almost absent in native hearts. While cancer cells did not grow in native hearts, they massively proliferated in unloaded hearts. Consistent with in vivo results, mechanical unloading in EHTs significantly increased the percentage of EdU-positive cardiomyocytes, endothelial and cancer cells. In contrast, increasing afterload reduced cell proliferation in all cell types. Mechanistically, we identified Nesprin2 as an essential factor in sensing mechanical load and translating it into a cell proliferation arrest.

Conclusions

Overall, these data indicate that variations in mechanical load have a dramatic effect on the proliferation of multiple cell types within the heart tissue, including cardiomyocytes, endothelial and cancer cells and that Nesprin2 is required to mediate this effect.Unloading in the heartUnloading in EHT
SGK1 inhibition normalizes action potential duration in transgenic LQT2 rabbits but not in LQT1, suggesting a novel gene-specific therapeutic approach in long QT syndrome
Authors: Barbieri M , Lourdaour J , Alerni N , Giammarino L , Nimani S , Matas L , Horvath A , Odening K E
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): SNSF (Swiss National Science Fundation)

Background

Increasing evidence suggests that secondary remodeling in Na+ and Ca2+ homeostasis may further enhance the propensity to develop arrhythmias in K-channelopathies LQT1 and LQT2 syndrome. In this context, the Serum and Glucocorticoid regulated Kinase-1 (SGK-1) was recently identified as a major regulator of sodium channels in cardiomyocytes. It is mainly activated in pathological conditions, leading to increased INaLate, prolongation of action potential duration (APD) and increased susceptibility to ventricular arrhythmias, recapitulating LQTS phenotype. SGK1 inhibition might hence be a novel therapeutic target also in genetic LQTS subtypes.

Methods

In cardiomyocytes (CM) isolated from wild type (WT), LQT1 and LQT2 adult rabbits patch-clamp experiments were performed to record AP with SGK1-inhibitor(SGK1-inh, 3 µM) or DMSO vehicle control.

Results

In the perforated patch configuration at 37°C, 3 μM of SGK1-inh shortened APD90 in LQT2 CMs at 1 Hz (DMSO-control [ms]: 477.3 vs treated cells[ms]: 362.8 p < 0.0001) and at 2 Hz (DMSO-cells: 325.7 vs treated cells:295.4,p <0.05). In contrast, in WT and LQT1 CMs, no effect on APD90 was observed neither at 1 Hz (WT, DMSO-cells: 329.2 vs treated cells: 301.6 p=ns; LQT1, DMSO-cells: 429.8 vs treated cells: 431.6, p=ns) nor at 2 Hz (WT, DMSO-cells:256.8 vs treated cells:242 p=ns; LQT1,DMSO cells:310.4 vs treated cells: 315.8,p=ns). Importantly, the SGK1-inhibitor effect in LQT2 rabbit CMs was so pronounced that it normalized APD to the wildtype level (LQT2+SGK1-Inh: 362.8 vs WT:329.2, ps=ns). Furthermore, short-term-variability in APD was markedly reduced by SGK1-Inh in LQT2, indicating an antiarrhythmic effect.

Conclusions

SGK1-inhibition exerts a beneficial APD-shortening effect only in LQT2, indicating a gene-specific efficacy. The underlying mechanism is still unclear. We hypothesize that the SGK1 pathway/INaLate activation in LQT1 might not be as active as in LQT2. We are currently conducting more experiments on potential genotype differences in SGK1 activity and SGK1-mediated INaLate inhibition to further elucidate the differences.Effects of SGK1-inh on AP characteristic
The smooth-walled human RVOT contains trabeculations that cause conduction delay
Authors: Jensen B , Bosada F M , Blok M , Scholman K T , Efimov I R , Boukens B J
Published: May 2024

Funding Acknowledgements

None.

Background

The right ventricular outflow tract (RVOT) is the outlet from the right ventricle and is the initiating substrate of life-threatening arrhythmias. While the luminal wall of the RVOT is often assumed to be without the complex trabecular meshwork that characterizes the right ventricular free wall, the anatomy of the RVOT is an understudied subject.

Aim

to investigate whether trabeculations occur in the RVOT and to assess whether this impacts electrical propagation.

Methods

Human hearts were investigated using high-resolution MRI, histology, RNA-sequencing, and optical and electrical mapping.

Results

We used high-resolution MRI and serial sectioning to reconstruct the macroscopic details of the human RVOT and identified cases exhibiting much trabeculation. The smooth lumen of the RVOT varied between 9% and 23% of the total RV anterior surface (N=11). Histological analysis on additional six hearts indicated that the RVOT compact layer is thinner when trabeculations are present. RNA sequencing of four human donor hearts revealed enrichment in the subendocardial region of 88 genes associated with cardiac conduction and trabeculations (P adjusted<0.05). Finally, we selected two human donor hearts showing trabeculations in the RVOT from which we generated wedge preparation and performed optical and electrical mapping. The trabecular regions demonstrated high degree of fractionation when compared to non-trabeculated regions, which coincided with delayed activation.

Conclusion

Trabeculations are found in the RVOT, and their extent varies among individuals. This impacts on the thickness of the compact wall in the RVOT, restricting the depth of tissue at which clinical interventions can be performed, as well as influencing electrical propagation and possible arrhythmogenicity.
Postnatal overfeeding in mice induces early lipidic changes in heart tissue and impacts cardiomyocyte proliferation
Authors: Josse M , Rigal E , Rosenblatt N , Rochais F , Pais De Barros J P , Rochette L , Vergely C
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): French Federation of Cardiology

Foundation of France

Background

Shortly after birth, cardiomyocytes lose their ability to proliferate to switch towards a hypertrophic growth and this ability is known to be influenced by nutritional factors. Postnatal overfeeding (PNOF) induced by litter size reduction in rodents reproduces the impact of childhood overnutrition. While PNOF was shown to induce major cardiac and metabolic alterations in adulthood, little is known about its impact during the first days of life.

Purpose

The objective of this project was to investigate the early changes induced by PNOF induced in heart tissue in terms of lipid profile and cardiomyocyte proliferation.

Methods

Two days after birth, C57BL/6 male pups were randomly distributed in litters adjusted to either 9 or 3 pups to form normally fed (NF) or postnatally overfed (PNOF) group, respectively. At 7, 10 and 24 postnatal days (D7, D10 and D24, respectively), hearts were harvested for immunostaining of the proliferation marker Ki67. Cardiac and plasma lipid composition of NF and PNOF was evaluated using liquid chromatography coupled to mass spectrometry technique. Finally, cardiomyocytes from D24 hearts were isolated and counted on Malassez counting chamber.

Results

At D7, D10 and D24, body weight and cardiac mass of PNOF pups were significantly higher than these of NF controls. Interestingly, at D7, lipid composition of PNOF hearts was decreased in cardiolipins, fatty acids and cholesterol derivatives. Moreover, plasma triglyceride levels were lower in D10 PNOF pups. These modifications were associated with a significant reduction of cardiomyocytes’ proliferation rate and an increased hypertrophy in PNOF hearts at D7, resulting in the reduction of cardiomyocyte number at D24 in PNOF mice.

Conclusion

Only five days after litter size reduction, PNOF induced major lipidic changes both in the cardiac tissue and in the plasma. In parallel, PNOF shortened the cardiomyocyte proliferative window and induced earlier cardiomyocyte maturation. Given the importance of fatty acid metabolism in cardiac development and function, these early changes could be linked to the long-term cardiometabolic alterations observed later in life.
The role of serotonin receptor 7 signalling in macrophages for the inflammatory response after myocardial infarction
Authors: Bahr F S , Mueller F E , Weber N , Aguapong W , Neumueller S , Benen N , Ricke-Hoch M , Ponimaskin E
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Background

The hormone and neurotransmitter serotonin regulates multiple processes, including immune responses and inflammatory signalling. After a cardiac injury, such as myocardial infarction (MI), a precise regulation of the local inflammation is determining the healing process and therefore functional outcome. Immune cells invading the infarcted tissue can be critical modulators, and various immune cells, including macrophages, express different serotonin receptors.

Purpose

We characterized the importance of serotonin receptor 7 (5-HT7R) signalling in the regulation of macrophage function, which infiltrate the heart after MI and thus can determine the course of cardiac remodelling processes.

Methods

For investigation of 5-HT7R signalling on a cellular level, we used two in vitro models: primary murine bone marrow-derived macrophages (BMDM) and secondary human THP-1-derived macrophages. To validate the impact of macrophages on intact cardiac tissue, we pre-treated pro-inflammatory M1-like BMDMs with a selective 5-HT7R agonist and then co-cultured them with living cardiac rat slices for up to 48 h (ex vivo) followed by functional analysis.

Results

We detected 5-HT7R expression in both models during all stages of macrophage polarization at mRNA as well as protein levels. Pro-inflammatory THP-1-derived macrophages displayed significantly enhanced mRNA expression levels of IL-1β and CD80, while pro-inflammatory differentiated M1-like BMDMs showed increased levels of CD38 and TNFα. Pharmacological activation of 5-HT7R with LP-211 reduced phagocytic activity up to 4-fold in THP-1-derived pro-inflammatory macrophages, altered their cytokine secretion profile and inhibited their migration ability (recovered area in scratch assay 1.3 % after LP-211 treatment compared to 6.1 % in control). A reduction in phagocytic activity was also verified in pro-inflammatory BMDMs. Our results also indicate reduced ability of LP-211 treated M1-like BMDMs to infiltrate living cardiac slices 3, 12, 24 and 48 h after seeding.

Conclusion

5-HT7R signalling affects the functional properties of pro-inflammatory macrophages, including phagocytic activity, motility and secretion profile. Targeted manipulation of 5-HT7R activity in macrophages represents thus a possibility to modulate their inflammatory profile, which might be a reasonable approach to guide recovery post MI.
Increased perivascular fibrosis and pro-fibrotic cellular transition in intramyocardial blood vessels in patients with myocardial infarction
Authors: Jiang Z , Sorrentino G , Simsek S , Niessen H W M , Krijnen P A J
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): China Scholarship Council

Background

Myocardial infarction (MI) is pathologically characterized by irreversible myocardial necrosis caused by ischemia. Intramyocardial vascular dysfunction is believed to increase the risk of MI. In this study, we investigated intramyocardial blood vessels in deceased patients during the early and chronic phases of MI to explore the involvement of perivascular fibrosis and pro-fibrotic cellular transitions in the pathological process of MI.

Methods

Left ventricular tissue (LV) was obtained from the infarction area of autopsied patients with early-phase MI (3-6 hours old; n=23), chronic-phase MI (5-14 days old; n=12), and from non-infarcted controls (n=14). We quantified perivascular fibrosis using EVG staining and fibroblast activation protein (FAP) expression using immunohistochemistry. Co-localization of smooth muscle actin (SMA) or CD31 with fibroblast marker S100A4 indicative of transition of smooth muscle cells (SMC) and endothelial cells (EC) toward fibroblast-like cells in intramyocardial vessels was quantified using immunofluorescent microscopy.

Results

Compared to controls (61.03%), perivascular fibrosis was significantly elevated in MI patients (early-phase 77.20%; chronic-phase 82.58%)(p<0.0001), with the highest level observed in the infarct cores of chronic-phase patients (95.18%). Compared to controls, FAP expression was 3.5-fold higher in early-phase- and 15.3-fold higher in chronic-phase MI patients (p<0.05), wherein FAP expression again was highest in the infarct cores. Furthermore, in both early- and chronic-phase MI, SMC- and EC fibroblast-like cellular transition was increased. The fraction of SMA+S100A4+ vessels was significantly higher in early-phase MI (31.96%) and chronic-phase MI (21.9%: border zone; 37.25%: infarct core) compared to controls (8.95%)(p<0.05). Similarly, the fraction of CD31+S100A4+ area was significantly increased in early-phase MI (10.14%) and chronic-phase MI (8.31%: border zone 10.15%: infarct core) compared to controls (2.67%)(p<0.05).

Conclusion

We observed increased perivascular fibrosis, fibroblast activation and fibroblast-like cellular transition toward a pro-fibrotic phenotype of vascular cells in intramyocardial blood vessels in MI patients, that may contribute to the development of MI. The further increase of FAP expression and perivascular fibrosis, particularly in the infarct core, in the chronic-phase suggest that MI itself can exacerbate fibroblast activation and perivascular fibrosis, theoretically increasing the risk of reinfarction.FAP expression and perivascular fibrosispro-fibrotic vascular cellular transitio
Sex differences in cardiac ferroptosis after acute myocardial infarction in wild type and aryl hydrocarbon receptor knockout mice
Authors: Delgado C , Fedichkina R , Martin-Nunes L , Piedras M J , Ramiro-Ponce V , Alvarez-Lucena C , Gil-Fernandez M , Fernandez-Velasco M , Bosca L
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): MICIN/Agencia Estatal de Investigación (DOI: 10.13039/50110001103) (NextGeneration, EU/PRTR)

Background and Purpose

Ferroptosis is a new regulated programmed cell death pathway, driven by iron-dependent phospholipid peroxidation, that plays an important role in the development of cardiovascular diseases. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor of the basic Helix-Loop-Helix-PER-ARNT-SIM superfamily. Upon ligand binding, AhR translocates into the nucleus and dimerizes with the AhR nuclear translocator; the heterodimer then binds to dioxin-response elements located in the promoter region of receptor-regulated genes, most of which are involved in xenobiotic metabolism. Beyond its role in metabolizing exogenous toxins as part of an adaptive chemical response, it is well known that AhR is activated by endogenous ligands and it has been postulated that AhR has important functions in physiological and/or pathological conditions. Here we studied sex differences in cardiac ferroptosis after acute myocardial infarction (AMI) in mice and the implication of defective AhR signalling on this process.

Methods and Results

AMI was induced in 8–10-weeks-old males and females AhR+/+ and AhR-/- mice by ligation of the left anterior descending coronary artery. Animal care and experimental procedures followed the principles of animal care (NIH publication Nº85-23 revised 1985) and the guidelines for ethical care of experimental animals of the European Union (2010/63/EU). Survival analysis showed that 16% of AhR+/+male mice and 14% of AhR+/+ female mice died 72 h after AMI surgery whereas the mortality was 100% in AhR-/-male mice and only 17% in AhR-/- female mice group. The treatment of AhR-/- AMI male mice with ferrostatin (1 mg/kg i.p) increased survival to 40%. Immunofluorescence analysis of cardiac staining levels of 8-hydroxy-2’-deoxyguanosine revealed higher oxidative stress in AhR+/+AMI male mice compared with AhR+/+AMI females, 24 h after surgery. The absence of AhR in AMI males showed an increased oxidative stress that was similar to that obtained in AMI AhR+/+ males but significantly greater than that observed in AhR-/- AMI females. Finally, analysis of differential expressions of classical genes related to ferroptosis in AhR-/- AMI male and AMI female mice, 24 h after surgery, showed, only in males, a reduced expression of ferritin heavy chain 1 and ferroportin, and an increased expression of phospholipase A2.

Conclusion

Our results show that loss of AhR in males but not in females favours the ferroptosis process associated with myocardial ischemia, highlighting a possible role for this nuclear receptor in cardiac remodelling and survival after AMI.
Epicardial cell participation in cardiac repair requires epithelial-to-mesenchymal transition
Authors: Smits A M , Streef T J , Van Herwaarden T , Balbi C , Vegh A , Groeneveld E , Goumans M J
Published: May 2024

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation

During development, the epicardium forms as a single cell layer on the outside of the heart. Part of these cells undergo epithelial-to-mesenchymal transition (EMT) and migrate into the myocardium where epicardial-derived cells (EPDCs) participate in the formation of the heart by contributing cells and by producing paracrine factors. In the adult heart the epicardium exists as a dormant layer until there is ischemic injury which leads to a partial reactivation and participation in the repair process. Therefore, the epicardium is considered an interesting cell source for endogenous cardiac repair.

Aim

to establish if differences between developmental and adult epicardium exist, and in which state (pre- or post-EMT) epicardial cells contribute efficiently to cardiac repair.

Methods

Primary epicardial cells were isolated from human fetal and adult cardiac tissue samples and cultured as epicardial cells (EPIs) or as EPDCs after inducing EMT with TGFβ3. Cells were subjected to RNA-sequencing or 24hrs of conditioning medium. Myocardial infarction (MI) and intramyocardially injection of EPIs and EPDCs was performed in NOD-SCID mice.

Results

Fetal and adult EPDCs displayed similar transcriptomic and paracrine profiles. In vitro, the conditioned medium of both cell types equally conveyed cardioprotection to staurosporin-treated cardiomyocytes. Next, we studied the effect of EMT: comparison of adult EPIs with EPDCs revealed that EPDCs have a angiogenic profile. Six weeks post-MI transplantation of adult EPIs or EPDCs resulted in a higher EF (25.4±3.8 vs. 11.1±4.6%, P<0.005), lower ESV (139.6±13.5 vs, 91.37±14.2ul, P<0.05), and a smaller infarct size in EPDC-recipients. EPDC-recipient hearts contained more proliferating cells at 3 days, and a higher vessel density at 6wks post-MI. Interestingly, while cell engraftment was equal in both groups at 3days, no cells were retrieved at 6wks supporting a paracrine effect.

Conclusion

epicardial EMT is essential to unleash the predominantly paracrine contribution of epicardial cells in cardiac repair.
Targeting serotonin receptor 7 to improve survival after myocardial infarction
Authors: Mueller F , Erschow S , Bahr F S , Benen N , Ponimaskin E , Ricke-Hoch M
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Background

Myocardial infarction (MI) is among the leading causes of death worldwide. Survival and long-term recovery are highly dependent on regeneration of the cardiac tissue, mediated by precisely regulated inflammatory processes and invading immune cells. The serotonergic system is known to regulate the functions of various cells of the immune system, and is also affected in several cardiovascular diseases.

Purpose

We investigated the role of the serotonin receptor 7 (5-HT7R) in regulation of the inflammatory response after MI and its contribution to cardiac outcome.

Methods

Permanent left ascending coronary artery ligation (LAD) in mice was used as a model for MI. We compared the impact of MI on heart function and tissue integrity in WT and 5-HT7R-KO mice. In addition, we performed a systemic treatment with the selective 5-HT7R agonist LP-211.

Results

Murine C57BL/6N hearts reveal an upregulation of 5-HT7R mRNA expression in the infarct region compared to remote myocardium and sham operated mice at 3, 7 and 14 days after MI. Immunohistochemistry demonstrates 5-HT7R expression mainly on CD68+, CD206+ and CD80+ macrophages but not on cardiomyocytes and fibroblasts. Systemic 5-HT7R-KO mice display normal cardiac function and dimensions at 3-4 months of age comparable to their wildtype (WT) littermates. In response to MI, 5-HT7R-KO mice show a higher decrease in left ventricular (LV) function (assessed by transthoracic echocardiography as fractional area change, FAC%) and increased signs of tissue inflammation 14 days post-MI, while the infarct size remains unchanged. Interestingly, systemic treatment with the selective 5-HT7R agonist LP-211 enhances survival rates 14d post MI, without improving cardiac functional output.

Conclusion

5-HT7R expression is upregulated post-MI in heart-invading inflammatory cells, such as macrophages. Loss of systemic 5-HT7R may contribute to pronounced functional cardiac impairment 14 days after MI, while systemic activation of 5-HT7R shows positive effects on survival, possibly through mediated inflammatory signalling of immune cells. Therefore, 5-HT7R activity could represent a novel therapeutic target to dampen inflammation and improve cardiac repair.
The diabetic myocardial transcriptome reveals Erbb3 as a novel biomarker of incident heart failure
Authors: Conning-Rowland M , Giannoudi M , Drozd M , Brown O , Yuldasheva N , Cheng C , Meakin P , Straw S , Gierula J , Ajjan R , Kearney M , Levelt E , Roberts L , Griffin K , Cubbon R
Published: May 2024

Funding Acknowledgements

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart Foundation

Background/Introduction

People with diabetes mellitus (DM) are at high risk of developing heart failure, but the molecular basis of this is not well understood. Elucidating the mechanistic pathways may help to improve patient stratification and develop targeted therapies.

Purpose

We set out to define differentially expressed genes (DEGs) in diabetic myocardium and validate arising hits in their circulating protein form, with a view to informing biomarker development and improving understanding of diabetic heart disease.

Methods

Transcriptomic (RNA-seq) data from the Genotype-Tissue Expression (GTEx) project was used to compare gene expression in participants with (n=>100) versus without (n>300) DM (pooled type 1 and 2 diabetes mellitus), in both the right atrial (RA) and left ventricular (LV) myocardium; analyses were adjusted for technical, demographic and disease covariates. Where available, plasma proteomic data from the UK Biobank (UKB) cohort was used to validate DEGs from GTEx in their circulating protein form. Hits with directionally concordant differential expression in GTEx and UKB were further characterised as plasma proteins in UKB, including over 50,000 participants irrespective of DM status; this included analysis of incident heart failure, cardiovascular mortality and left ventricular function on cardiac magnetic resonance imaging.

Results

Pooled across the RA and LV, there were 64 DEGs associated with DM, with no overlap between the RA and LV hits. UKB plasma protein data was available for 6 of these. Only ERBB3 showed directional concordance with transcriptomic data, being lower in the myocardium and blood of people with DM. People in the lowest quartile of ERBB3 plasma protein had increased adjusted risk of incident heart failure and cardiovascular death than participants in all other quartiles. Lower concentrations of plasma ERBB3 protein were also associated with increased LV mass and impaired LV contractility.

Conclusion

Lower plasma ERBB3 concentration is more common in people with DM and is associated with LV dysfunction, incident heart failure and cardiovascular mortality. This highlights the potential of ERBB3 as a novel biomarker for individuals at risk of heart failure. Importantly, cancer therapies targeting ERBB3 and related family members can induce heart failure, and recombinant forms of the ERBB3 ligand neuregulin-1 appear to improve LV contractility, further suggesting a role of ERBB3 in the development of diabetic heart disease.