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• Combined genetic-pharmacologic ADAMTS1 and ADAMTS5 inactivation in mice. • Degradomics identification of putative ADAMTS1 and ADAMTS5 substrates. • A requirement for versican proteolysis and glypican-6 in heart development. • Novel roles for ADAMTS1, ADAMTS5 and glypican-6 in hedgehog signaling in the heart. Extracellular matrix remodeling mechanisms are understudied in cardiac development and congenital heart defects. We show that matrix-degrading metalloproteases ADAMTS1 and ADAMTS5, are extensively co-expressed during mouse cardiac development. The mouse mutants of each gene have mild cardiac anomalies, however, their combined genetic inactivation to elicit cooperative roles is precluded by tight gene linkage. Therefore, we coupled Adamts1 inactivation with pharmacologic ADAMTS5 blockade to uncover stage-specific cooperative roles and investigated their potential substrates in mouse cardiac development. ADAMTS5 blockade was achieved in Adamts1 null mouse embryos using an activity-blocking monoclonal antibody during distinct developmental windows spanning myocardial compaction or cardiac septation and outflow tract rotation. Synchrotron imaging, RNA in situ hybridization, immunofluorescence microscopy and electron microscopy were used to determine the impact on cardiac development and compared to Gpc6 and ADAMTS-cleavage resistant versican mutants. Mass spectrometry-based N-terminomics was used to seek relevant substrates. Combined inactivation of ADAMTS1 and ADAMTS5 prior to 12.5 days of gestation led to dramatic accumulation of versican-rich cardiac jelly and inhibited formation of compact and trabecular myocardium, which was also observed in mice with ADAMTS cleavage-resistant versican. Combined inactivation after 12.5 days impaired outflow tract development and ventricular septal closure, generating a tetralogy of Fallot-like defect. N-terminomics of combined ADAMTS knockout and control hearts identified a cleaved glypican-6 peptide only in the controls. ADAMTS1 and ADAMTS5 expression in cells was associated with specific glypican-6 cleavages. Paradoxically, combined ADAMTS1 and ADAMTS5 inactivation reduced cardiac glypican-6 and outflow tract Gpc6 transcription. Notably, Gpc6 −/− hearts demonstrated similar rotational defects as combined ADAMTS inactivated hearts and both had reduced hedgehog signaling. Thus, versican proteolysis in cardiac jelly at the canonical Glu441-Ala442 site is cooperatively mediated by ADAMTS1 and ADAMTS5 and required for proper ventricular cardiomyogenesis, whereas, reduced glypican-6 after combined ADAMTS inactivation impairs hedgehog signaling, leading to outflow tract malrotation. [ABSTRACT FROM AUTHOR]

• HFPO-TA exposure causes linearized heart, affects gene expression related to heart looping. • HFPO-TA induces sprouting angiogenesis, and disturbs gene expression of VEGF signaling pathway in vascular development. • HFPO-TA reduces erythropoiesis, resulting in heme metabolism disruption. • HFPO-TA induces oxidative stress, inhibits cell proliferation, and causes apoptosis. As an increasingly used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been widely detected in global water environments. However, little is known regarding its toxic effects on cardiovascular development. Here, zebrafish embryos were treated with egg water containing 0, 60, 120, or 240 mg/L HFPO-TA. Results showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart rate. Furthermore, HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance (SV-BA) in Tg (myl7: GFP) transgenic larvae, disrupting the expression of genes involved in heart development and thus causing abnormal heart looping. Obvious sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg (fli: GFP) transgenic larvae. HFPO-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor (VEGF) pathway and embryonic vascular development. HFPO-TA exposure significantly decreased erythrocyte number in Tg (gata1: DsRed) transgenic embryos and influenced gene expression associated with the heme metabolism pathway. HFPO-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis, inhibiting cell proliferation while promoting apoptosis. Therefore, HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos, suggesting it may not be a suitable or safe alternative for PFOA. [Display omitted] [ABSTRACT FROM AUTHOR]

• TGF beta2 heterozygosity synergizes with fibrillin1 hypomorphism to cause early death in mice. • Death is not from dissection and rupture. • Mortality is associated with abnormal aortic valves. To assess the contribution of individual TGF-β isoforms to aortopathy in Marfan syndrome (MFS), we quantified the survival and phenotypes of mice with a combined fibrillin1 (the gene defective in MFS) hypomorphic mutation and a TGF-β1, 2, or 3 heterozygous null mutation. The loss of TGF-β2, and only TGF-β2, resulted in 80% of the double mutant animals dying earlier, by postnatal day 20, than MFS only mice. Death was not from thoracic aortic rupture, as observed in MFS mice, but was associated with hyperplastic aortic valve leaflets, aortic regurgitation, enlarged aortic root, increased heart weight, and impaired lung alveolar septation. Thus, there appears to be a relationship between loss of fibrillin1 and TGF-β2 in the postnatal development of the heart, aorta and lungs. [ABSTRACT FROM AUTHOR]

Normal ECG standards in newborns, infants, children and adolescents have been collected and published by many authors. Only those by Davignon et al., Rijinbeek et al. and our two studies covered all ages from birth to adolescence. The standards reflecting the growth and development of the heart in infants, children and adolescents remained to be studied and explored. We selected from our ECG database, after discussions and consultation, 15 key ECG parameters and analyzed for their age- and sex-specific mean, standard deviation and 2nd to 98th percentiles and their percentile charts were constructed. The ranges and distributions of the normal ECG standards, means and 2nd to 98th percentiles of 15 key parameters were established. A complete set of normal ECG standards of 15 key parameters from birth to adolescents is available for clinicians and researchers. [ABSTRACT FROM AUTHOR]

Organogenesis requires the orchestrated development of multiple cell lineages that converge, interact, and specialize to generate coherent functional structures, exemplified by transformation of the cardiac crescent into a four-chambered heart. Cardiomyocytes originate from the first and second heart fields, which make different regional contributions to the definitive heart. In this review, a series of recent single-cell transcriptomic analyses, together with genetic tracing experiments, are discussed, providing a detailed panorama of the cardiac progenitor cell landscape. These studies reveal that first heart field cells originate in a juxtacardiac field adjacent to extraembryonic mesoderm and contribute to the ventrolateral side of the cardiac primordium. In contrast, second heart field cells are deployed dorsomedially from a multilineage-primed progenitor population via arterial and venous pole pathways. Refining our knowledge of the origin and developmental trajectories of cells that build the heart is essential to address outstanding challenges in cardiac biology and disease. This review discusses a series of recent single cell transcriptomic studies that provide new insights into the developmental trajectories of cardiac progenitor cells during early heart morphogenesis. [ABSTRACT FROM AUTHOR]

The light provide during incubation can influence hatching characteristics (hatching time, hatchability, etc.) and embryo development in chickens, geese, and turkeys. However, relevant studies on this factor in pigeons are lacking. This study investigated the effects of in ovo photostimulation during embryogenesis on hatching performance, squab quality, and embryo development in pigeons. 400 eggs from paired- bred pigeons were randomly distributed into 4 incubation lighting treatments, with 2 replicates per treatment. The treatments included dark as a control (NL), 12-h light, and 12-h dark photoperiods of white light (WL), red light (RL), and green light (GL) (100 lx at egg level) during the first 15 d of incubation. A total of 1,600 eggs in 4 batches from White King pigeons were used. The results showed that hatching time of the WL group was significantly shorter than that of the dark light group (P < 0.05). The hatchability of fertile eggs in the WL group was significantly higher (P < 0.05), whereas the hatchability of fertile eggs in the RL group was significantly lower (P < 0.05) than that of in the control group. Light stimulation had no effect on time to 90% hatching or average hatching time (P > 0.05). In addition, the hatch window was not extended by light stimulation (P > 0.05). The group incubated under GL showed an increase in embryo weight and relative leg muscle on embryonic d 14 and the hatching day compared to the dark incubation (P < 0.05). Green light stimulated the heart and liver development during the early and middle stages of embryogenesis. It was concluded that white light stimulation during embryogenesis accelerated the hatching process, whereas monochromatic green light had a positive effect on embryo development. Our findings provide important guidance for developing light protocols for pigeon egg incubation. [ABSTRACT FROM AUTHOR]

In utero cigarette smoking/nicotine exposure during pregnancy significantly affects fetal development and increases the risk of cardiovascular disease late in life. However, the underlying molecular mechanisms remain largely unknown. We tested the hypothesis that fetal nicotine aerosol exposure reprograms ischemia-sensitive gene expressions, resulting in increased heart susceptibility to ischemic injury and cardiac dysfunction in adulthood. Pregnant rats were exposed to chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21. Experiments were performed on 6-month–old adult offspring. CINA exposure increased ischemia-induced cardiac injury and cardiac dysfunction compared to the control group, which was associated with over- expression of angiotensin II receptor (ATR) protein in the left ventricle (LV) of adult offspring. Meanwhile, CINA exposure up-regulated cardiac TGF-β/SMADs family proteins in the LV. In addition, CINA exposure enhanced cardiac reactive oxygen species (ROS) production and increased the DNA methylation level. The levels of phosphorylated-Akt were upregulated but LC3B-II/I protein abundances were downregulated in the hearts isolated from the CINA-treated group. Fetal nicotine aerosol exposure leads to cardiac dysfunction in response to ischemic stimulation in adulthood. Two molecular pathways are implicated. First, fetal CINA exposure elevates cardiac ATR levels, affecting the TGFβ-SMADs pathway. Second, heightened Angiotensin II/ATR signaling triggers ROS production, leading to DNA hypermethylation, p-Akt activation, and autophagy deficiency. These molecular shifts in cardiomyocytes result in the development of a heart ischemia-sensitive phenotype and subsequent dysfunction in adult offspring. [Display omitted] • Prenatal nicotine aerosol exposure leads to fetal programming of cardiac dysfunction. • Cardiac dysfunction is associated with the heightened Angiotensin II/ATR signaling. • The heightened Angiotensin II/ATR upregulates the TGF-β/SMADs pathway. • Heightened Angiotensin II/ATR leads to ROS production and DNA hypermethylation. • Prenatal nicotine exposure activates p-Akt/Akt but attenuates autophagic influx. [ABSTRACT FROM AUTHOR]

In mammal, the myocardium loss cannot be recovered spontaneously due to the negligible proliferation ability of mature mammalian cardiomyocyte. However, accumulated evidence has shown that terminally differentiated mammalian cardiomyocyte also has proliferation potency, which can be mediated by several mechanisms. Here, we reported that circNCX1, the most abundant circular RNA in mammalian hearts, can affect the proliferation of murine cardiomyocytes. The level of circNCX1 is significantly elevated during heart development. Forced expression of circNCX1 inhibits cardiomyocyte proliferation, while silencing of endogenous circNCX1 in cardiomyocyte shows reversed effect in vitro. Mechanistically, circNCX1 functions via negatively regulating transcription activator BRG1. It bridges BRG1 and FBXW7 to enhance the ubiquitination and degradation of BRG1, decreasing the expression of BMP10 to lead cell cycle arrest. In summary, our study first revealed that circNCX1 is a modulator of cardiomyocyte proliferation. • The heart-enriched circular RNA-circNCX1 inhibits cardiomyocyte proliferation. • CircNCX1 bridges BRG1 and FBW7 to increase the ubiquitination and degradation of BRG1. • CircNCX1 regulates expression of BMP10 and CDKN1C by targeting BRG1. • The regulation of cardiomyocyte proliferation by circNCX1 is BRG1-dependent. [ABSTRACT FROM AUTHOR]

Ventricular septal defects (VSD) with outflow tract (OFT) malalignment are a common group of congenital heart diseases with varying severity. The developmental process of these defects is challenging to understand due to the complex nature of cardiac morphogenesis and the difficulties in visualizing the temporal and spatial changes that occur during pathogenesis. However, recent advancements in imaging techniques, such as high-resolution episcopic microscopy, have provided valuable insights into the normal septation of ventricular chambers and OFT alignment. Building upon this knowledge, we have utilized lightsheet microscopy, another innovative imaging method, to further investigate the developmental processes that lead to abnormal formation of the ventricular septum and the malalignment of arterial roots with the ventricular chambers. Our study highlights endocardial cushion hypoplasia and insufficient rotation of the outflow tract as two interrelated central factors contributing to the pathogenesis of these defects. This finding has the potential to enhance our understanding of the etiology of congenital heart diseases and may contribute to the development of improved diagnostic and therapeutic strategies in the future. [Display omitted] • E9.5 administration of dofetilide or deletion of Notch1 in cardiac lineages can induce OA/VSD or DORV/VSD in mouse embryos. • The reduction of endocardial cushion size at both outflow tract and atrioventricular canal is a key factor in causing the defects. • The outflow tract malalignment defects of OA and DORV reflect a spectrum of OFT rotation insufficiency. • Insufficient rightward expansion of the AVC tubercule also contributes to the final closure of the interventricular septum. [ABSTRACT FROM AUTHOR]

• Changes in tissue mechanics coevolve with changes in ECM composition. • Fibrillar collagen abundance scales with tissue stiffness across healthy tissues, during development, and in fibrosis. • Proteomics studies reveal extensive changes in core fibrotic matrisome and matrisomeassociated proteins. • Increased collagen stiffens fibrotic tissues; other matrisome components organize ECM and facilitate interactions with cells. • Reductionist models of stiff, fibrotic ECM suggest a feedback loop maintains profibrotic cell states. Fibrillar proteins are principal components of extracellular matrix (ECM) that confer mechanical properties to tissues. Fibrosis can result from wound repair in nearly every tissue in adults, and it associates with increased ECM density and crosslinking as well as increased tissue stiffness. Such fibrotic tissues are a major biomedical challenge, and an emerging view posits that the altered mechanical environment supports both synthetic and contractile myofibroblasts in a state of persistent activation. Here, we review the matrisome in several fibrotic diseases, as well as normal tissues, with a focus on physicochemical properties. Stiffness generally increases with the abundance of fibrillar collagens, the major constituent of ECM, with similar mathematical trends for fibrosis as well as adult tissues from soft brain to stiff bone and heart development. Changes in expression of other core matrisome and matrisome-associated proteins or proteoglycans contribute to tissue stiffening in fibrosis by organizing collagen, crosslinking ECM, and facilitating adhesion of myofibroblasts. Understanding how ECM composition and mechanics coevolve during fibrosis can lead to better models and help with antifibrotic therapies. [ABSTRACT FROM AUTHOR]

In spite of extensive research, protein aggregation still remains one of the most difficult phenomena to be understood in the field of biologics research and development. Protein aggregation is a complex process which results in the formation of a variety of supramolecular protein structures. Nucleation is the core step that initiates the cascade of molecular events leading to the formation of protein aggregates. Understanding and characterizing nucleation is therefore crucial to avoid undesired protein aggregation. Here we review the state of the art on protein aggregation in biotherapeutics, primarily focusing on the nucleation events, stimulating discussions about key open questions, and clarifying the peculiarities of aggregation process relative to other protein phase separation processes, such as crystallization. We summarize recent progress in the identification of the sources of protein aggregation and in the development of analytical tools to characterize this process. Moreover, we discuss significant gaps in the analysis and understanding of nucleation in non-native aggregation of biologics. [ABSTRACT FROM AUTHOR]

Transcriptional regulation of gene expression plays a crucial role in orchestrating complex morphogenetic and molecular events during heart development and function. Mediator complex is an essential multi-subunit protein complex that governs gene expression in eukaryotic cells. Although Mediator subunits (MEDs) work integrally in the complex, individual MED component displays specialized functions. MED27, categorized as an Upper Tail subunit, possesses an as-yet-uncharacterized function. In this study, we aimed to investigate the physiological role of MED27 in cardiomyocytes. we generated a Med27 floxed mouse line, which was further used to generate constitutive (cKO) and inducible (icKO) cardiomyocyte-specific Med27 knockout mouse models. Morphological, histological analysis and cardiac physiological studies were performed in Med27 cKO and icKO mutants. Transcriptional profiles were determined by RNA sequencing (RNAseq) analysis. Ablation of MED27 in developing mouse cardiomyocytes results in embryonic lethality, while its deletion in adult cardiomyocytes leads to heart failure and mortality. Similar to the ablation of another Upper Tail subunit, MED30 in cardiomyocytes, deletion of MED27 leads to decreased protein levels of most MEDs in cardiomyocytes. Interestingly, overexpression of MED30 fails to restore the protein levels of Mediator subunits in MED27-deficient cardiomyocytes, demonstrating that the role of MED27 in maintaining the integrity and stability of the Mediator complex is independent of MED30. Our results revealed an essential role of MED27 in cardiac development and function by maintaining the stability of the Mediator core. [ABSTRACT FROM AUTHOR]

The presence of the organotin compound tributyltin (TBT) in aquatic ecosystems has been a serious environmental problem for decades. Although a number of studies described the negative impact of TBT on mollusks at different levels, investigations connected to its potential effects during embryogenesis have been neglected. For a better understanding of the impact of TBT on mollusks, in the present study, embryos of previously TBT-treated or not treated specimens of the great pond snail (Lymnaea stagnalis) were exposed to 100 ng L−1 TBT from egg-laying (single-cell stage) until hatching. According to our results, TBT significantly delayed hatching and caused shell malformation. TBT transiently decreased the locomotion (gliding) and also reduced the feeding activity, demonstrating for the first time that this compound can alter the behavioral patterns of molluscan embryos. The heart rate was also significantly reduced, providing further support that cardiac activity is an excellent indicator of metal pollution in molluscan species. At the histochemical level, tin was demonstrated for the first time in TBT-treated hatchlings with intensive reaction in the central nervous system, kidney, and hepatopancreas. Overall, the most notable effects were observed in treated embryos derived from TBT treated snails. Our findings indicate that TBT has detrimental effects on the development and physiological functions of Lymnaea embryos even at a sub-lethal concentration, potentially influencing their survival and fitness. Highlighting our observations, we have demonstrated previously unknown physiological changes (altered heart rate, locomotion, and feeding activity) caused by TBT, as well as visualized tin at the histochemical level in a molluscan species for the first time following TBT exposure. Further studies are in progress to reveal the cellular and molecular mechanisms underlying the physiological and behavioral changes described in the present study. [Display omitted] • The effect of 100 ng L−1 TBT on Lymnaea embryos was investigated. • TBT significantly delayed hatching and caused shell malformation. • Decrease in heart rate, gliding, and feeding were observed. • Tin accumulated in the nervous system, kidney, and hepatopancreas of hatchlings. [ABSTRACT FROM AUTHOR]

The "International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates—2024" updates and replaces the "Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates—2006" and the "2016 International Society for Heart Lung Transplantation Listing Criteria for Heart Transplantation: A 10-year Update." The document aims to provide tools to help integrate the numerous variables involved in evaluating patients for transplantation, emphasizing updating the collaborative treatment while waiting for a transplant. There have been significant practice-changing developments in the care of heart transplant recipients since the publication of the International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 and the 10-year update in 2016. The changes pertain to 3 aspects of heart transplantation: (1) patient selection criteria, (2) care of selected patient populations, and (3) durable mechanical support. To address these issues, 3 task forces were assembled. Each task force was cochaired by a pediatric heart transplant physician with the specific mandate to highlight issues unique to the pediatric heart transplant population and ensure their adequate representation. This guideline was harmonized with other ISHLT guidelines published through November 2023. The 2024 ISHLT guidelines for the evaluation and care of cardiac transplant candidates provide recommendations based on contemporary scientific evidence and patient management flow diagrams. The American College of Cardiology and American Heart Association modular knowledge chunk format has been implemented, allowing guideline information to be grouped into discrete packages (or modules) of information on a disease-specific topic or management issue. Aiming to improve the quality of care for heart transplant candidates, the recommendations present an evidence-based approach. [ABSTRACT FROM AUTHOR]

Pyraclostrobin, a typical representative of strobilurin fungicides, is extensively used in agriculture to control fungi and is often detected in water bodies and food. However, the comprehensive toxicological molecular mechanism of pyraclostrobin requires further study. To assess the toxic effects and underlying mechanisms of pyraclostrobin on aquatic organisms, zebrafish embryos were exposed to pyraclostrobin (20, 40, and 60 μg/L) until 96 h post fertilization (hpf). These results indicated that exposure to pyraclostrobin induces morphological alterations, including spinal curvature, shortened body length, and smaller eyes. Furthermore, heart developmental malformations, such as pericardial edema and bradycardia, were observed. This indicated severe cardiotoxicity induced by pyraclostrobin in zebrafish embryos, which was confirmed by the dysregulation of genes related to heart development. Besides, our findings also demonstrated that pyraclostrobin enhanced the contents of reactive oxygen species (ROS) and malondialdehyde (MDA), up-regulated catalase (CAT) activity, but inhibited superoxide dismutase (SOD) activity. Subsequently, the NF-κb signaling pathway was further studied, and the results indicated that the up-regulation of tnf-α , tlr-4 , and myd88 activated the NF-κb signaling pathway and up-regulated the relative expression level of pro-inflammatory cytokines, such as cc - chemokine, ifn-γ, and cxcl - clc. Collectively, this study revealed that pyraclostrobin exposure induces developmental toxicity and cardiotoxicity, which may result from a combination of oxidative stress and inflammatory responses. These findings provide a basis for continued evaluation of the effects and ecological risks of pyraclostrobin on the early development of aquatic organisms. [Display omitted] • Pyraclostrobin significantly decreased survival rate and increased aberration rate. • Pyraclostrobin led to developmental toxicity and cardiotoxicity in zebrafish embryos. • Pyraclostrobin caused alterations in the antioxidant system, indicating oxidative stress. • Pyraclostrobin induced cell apoptosis and inflammation dysfunction. [ABSTRACT FROM AUTHOR]

[Display omitted] Cardiac ATP production is tightly regulated in order to satisfy the evolving energetic requirements imposed by different cues during health and pathological conditions. In order to sustain high ATP production rates, cardiac cells are endowed with a vast mitochondrial network that is essentially acquired during the perinatal period. Nevertheless, adult cardiac cells also adapt their mitochondrial mass and oxidative function to changes in energy demand and substrate availability by fine-tuning the pathways and mitochondrial machinery involved in energy production. The reliance of cardiac cells on mitochondrial metabolism makes them particularly sensitive to alterations in proper mitochondrial function, so that deficiency in energy production underlies or precipitates the development of heart diseases. Mitochondrial biogenesis is a complex process fundamentally controlled at the transcriptional level by a network of transcription factors and co-regulators, sometimes with partially redundant functions, that ensure adequate energy supply to the working heart. Novel uncovered regulators, such as RIP140, PERM1, MED1 or BRD4 have been recently shown to modulate or facilitate the transcriptional activity of the PGC-1s/ERRs/PPARs regulatory axis, allowing cardiomyocytes to adapt to a variety of physiological or pathological situations requiring different energy provision. In this review, we summarize the current knowledge on the mechanisms that regulate cardiac mitochondrial biogenesis, highlighting the recent discoveries of new transcriptional regulators and describing the experimental models that have provided solid evidence of the relevant contribution of these factors to cardiac function in health and disease. [ABSTRACT FROM AUTHOR]

Congenital heart disease is the most common birth defect worldwide. Defective cardiac myogenesis is either a major presentation or associated with many types of congenital heart disease. Non-myocardial tissues, including endocardium and epicardium, function as a supporting hub for myocardial growth and maturation during heart development. Recent research findings suggest an emerging role of epigenetics in nonmyocytes supporting myocardial development. Understanding how growth signaling pathways in non-myocardial tissues are regulated by epigenetic factors will likely identify new disease mechanisms for congenital heart diseases and shed lights for novel therapeutic strategies for heart regeneration. [ABSTRACT FROM AUTHOR]

The G-quadruplex (G4) resolvase RNA helicase associated with AU-rich element (RHAU) possesses the ability to unwind G4 structures in both DNA and RNA molecules. Previously, we revealed that RHAU plays a critical role in embryonic heart development and postnatal heart function through modulating mRNA translation and stability. However, whether RHAU functions to resolve DNA G4 in the regulation of cardiac physiology is still elusive. Here, we identified a phenotype of noncompaction cardiomyopathy in cardiomyocyte-specific Rhau deletion mice, including such symptoms as spongiform cardiomyopathy, heart dilation, and death at young ages. We also observed reduced cardiomyocyte proliferation and advanced sarcomere maturation in Rhau mutant mice. Further studies demonstrated that RHAU regulates the expression levels of several genes associated with ventricular trabeculation and compaction, including the Nkx2-5 and Hey2 that encode cardiac transcription factors of NKX2-5 and Hey2, and the myosin heavy chain 7 (Myh7) whose protein product is MYH7. While RHAU modulates Nkx2-5 mRNA and Hey2 mRNA at the post-transcriptional level, we uncovered that RHAU facilitates the transcription of Myh7 through unwinding of the G4 structures in its promoter. These findings demonstrated that RHAU regulates ventricular chamber development through both transcriptional and post-transcriptional mechanisms. These results contribute to a knowledge base that will help to understand the pathogenesis of diseases such as noncompaction cardiomyopathy. [ABSTRACT FROM AUTHOR]

• Neonatal 5-Aza exposure inhibits cardiac DNA methylation persisting into adulthood. • Neonatal DNA demethylation produces a growth restriction and heart hypertrophy. • DNA demethylation enhances cardiac ATR and miR-181a expression. • DNA demethylation alters cardiac ischemia-sensitive biomarkers (PKCε, Atg5 & GSK3β). • Neonatal DNA demethylation programs of a heart ischemic-sensitive phenotype. Adverse environmental stress exposure at critical perinatal stages can alter cardiovascular development, which could persist into adulthood and develop a cardiovascular dysfunctional phenotype late in life. However, the underlying molecular mechanisms remain largely unknown. The present study provided a direct evidence that DNA methylation is a key epigenetic mechanism contributing to the developmental origins of adult cardiovascular disease. We hypothesized that DNA hypomethylation at neonatal stage alters gene expression patterns in the heart, leading to development of a cardiac ischemia-sensitive phenotype late in life. To test this hypothesis, a DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza) was administered in newborn rats from postnatal day 1–3. Cardiac function and related key genes were measured in 2-week- and 2-month-old animals, respectively. 5-Aza treatment induced an age- and sex-dependent inhibition of global and gene-specific DNA methylation levels in left ventricles, resulting in a long-lasting growth restriction but an asymmetry increase in the heart-to-body weight ratio. In addition, treatment with 5-Aza enhanced ischemia and reperfusion-induced cardiac dysfunction and injury in adults as compared with the saline controls, which was associated with up-regulations of miRNA-181a and angiotensin II receptor type 1 & 2 gene expressions, but down-regulations of PKCε, Atg5, and GSK3β gene expressions in left ventricles. In conclusion, our results provide compelling evidence that neonatal DNA methylation deficiency is a key mechanism contributing to differentially reprogram cardiac gene expression patterns, leading to development of a heart ischemia-sensitive phenotype late in life. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart. [ABSTRACT FROM AUTHOR]

Chest radiation therapy (CRT) for malignant thoracic neoplasms is associated with development of valvular heart disease years later. As previous radiation exposure can complicate surgical treatment, transcatheter aortic valve replacement (TAVR) has emerged as an alternative. However, outcomes data are lacking for TAVR patients with a history of CRT. We conducted a retrospective study of all patients who underwent a TAVR procedure at a single institution between September 2012 and November 2018. Among 1341 total patients, 50 had previous CRT. These were propensity-matched in a 1:2 ratio to 100 patients without history of CRT. Thirty-day adverse events were analyzed with generalized estimating equation models. Overall mortality was analyzed with stratified Cox regression modelling. Median clinical follow-up was 24 months (interquartile range [IQR], 12–44 months). There was no difference between CRT and non-CRT patients in overall mortality (hazard ratio [HR] 0.84 [0.37–1.90], P = 0.67), 30-day mortality (HR 3.1 [0.49–20.03], P = 0.23), or 30-day readmission rate (HR 1.0 [0.43–2.31], P = 1). There were no differences in the rates of most adverse events, but patients with CRT history had higher rates of postprocedural respiratory failure (HR 3.63 [1.32–10.02], P = 0.01) and permanent pacemaker implantation (HR 2.84 [1.15–7.01], P = 0.02). For patients with aortic valve stenosis and previous CRT, TAVR is safe and effective, with outcomes similar to those in the general aortic stenosis population. Patients with history of CRT are more likely to have postprocedural respiratory failure and to require permanent pacemaker implantation. Unlabelled Image • Patients with history of chest radiation for thoracic malignancy who subsequently had TAVR were matched in 1:2 ratio to patients with or without CRT. • Overall, the two matched cohorts had similar survival rates at a median clinical follow-up of 24 months (interquartile range 12–44 months). • Those with a history of chest radiation therapy had higher rates of post-procedure permanent pacemaker implantation and respiratory failure. [ABSTRACT FROM AUTHOR]

The circadian clock synchronizes the body into 24-h cycles, thereby anticipating variations in tissue-specific diurnal tasks, such as response to increased cardiac metabolic demand during the active period of the day. As a result, blood pressure, heart rate, cardiac output, and occurrence of fatal cardiovascular events fluctuate in a diurnal manner. The heart contains different cell types that make up and reside in an environment of biochemical, mechanical, and topographical signaling. Cardiac architecture is essential for proper heart development as well as for maintenance of cell homeostasis and tissue repair. In this review, we describe the possibilities of studying circadian rhythmicity in the heart by using advanced in vitro systems that mimic the native cardiac 3D microenvironment which can be tuned in time and space. Harnessing the knowledge that originates from those in vitro models could significantly improve innovative cardiac modeling and regenerative strategies. [ABSTRACT FROM AUTHOR]

• We introduce a novel fetal rat model of ventricular noncompaction (NVM) caused by intrauterine hyperglycemia, induced by a combination of a high-fat diet and STZ injections. • Intrauterine hyperglycemia or elevated RA can result in NVM features in embryos, accompanied by endoplasmic reticulum stress in cardiomyocytes. • An adverse intrauterine developmental environment plays a significant role in the onset of NVM. This study aims to develop a fetal rat model of ventricular noncompaction (NVM) using streptozotocin (STZ)-induced gestational hyperglycemia and compare it with a retinoic acid (RA) model. Female SD rats were categorized into STZ, RA, and normal control (NC) groups. The STZ group was given a high-fat diet pre-pregnancy and 35 mg/kg of 2% STZ postpregnancy. The RA group received a 90 mg/kg dose of RA on day 13 postpregnancy. Embryonic myocardial morphology was analyzed through HE staining, and embryonic cardiomyocyte ultrastructures were studied using electron microscopy. Diagnoses of NVM were based on a ratio of noncompact myocardium (N) to compact myocardium (C) >1.4, accompanied by thick myocardial trabeculae and a thin myocardial compaction layer. Kruskal-Wallis test determined N/C ratio differences among groups. Both STZ and RA groups displayed significant NVM characteristics. The left ventricular (LV) N/C in the STZ, RA, and NC groups were 1.983 (1.423-3.527), 1.640 (1.197-2.895), and 0.927 (0.806-1.087), respectively, with a statistically significant difference (P<0.001). The right ventricular (RV) N/C in the STZ, RA, and NC groups were 2.097 (1.364-3.081), 1.897 (1.337-2.662), and 0.869 (0.732-1.022), respectively, with a significant difference (P <0.001). Electron microscopy highlighted marked endoplasmic reticulum swelling in embryonic cardiomyocytes from both STZ and RA groups. Our model underscores the pivotal role of an adverse intrauterine developmental environment in the onset of NVM. This insight holds significant implications for future studies exploring the pathogenesis of NVM. [ABSTRACT FROM AUTHOR]

Recent evidence indicates that PM 2.5 poses a risk for congenital heart diseases , but the mechanisms remain unclear. We hypothesized that AHR activated by PM 2.5 might cause mitochondrial damage via PGC-1α dysregulation, leading to heart defects. We initially discovered that the PGC-1α activator ZLN005 counteracted cardiac defects in zebrafish larvae exposed to EOM (extractable organic matter) from PM 2.5. Moreover, ZLN005 attenuated EOM-induced PGC-1α downregulation, mitochondrial dysfunction/biogenesis, and apoptosis. EOM exposure not only decreased PGC-1α expression levels, but suppressed its activity via deacetylation, and SIRT1 activity is required during both processes. We then found that SIRT1 expression levels and NAD+/NADH ratio were reduced in an AHR-dependent way. We also demonstrated that AHR directly suppressed the transcription of SIRT1 while promoted the transcription of TiPARP which consumed NAD+. In conclusion, our study suggests that PM 2.5 induces mitochondrial damage and heart defects via AHR/SIRT1/PGC-1α signal pathway. [Display omitted] • PGC-1α mediates EOM-induced mitochondrial dysfunction, leading to heart defects. • EOM suppresses PGC-1α expression and activity via SIRT1 inhibition. • AHR directly inhibits SIRT1 transcription. • EOM reduces NAD+ levels via AHR-mediated suppression of TiPARP transcription. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) are RNA molecules that regulate gene expression at several levels, including transcriptional, post-transcriptional, and translational. They have a length of more than 200 nucleotides and cannot code. Many human diseases have been linked to aberrant lncRNA expression, highlighting the need for a better knowledge of disease etiology to drive improvements in diagnostic, prognostic, and therapeutic methods. Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. LncRNAs play an essential role in the complex process of heart formation, and their abnormalities have been associated with several CVDs. This Review article looks at the roles and relationships of long non-coding RNAs (lncRNAs) in a wide range of CVDs, such as heart failure, myocardial infarction, atherosclerosis, and cardiac hypertrophy. In addition, the review delves into the possible uses of lncRNAs in diagnostics, prognosis, and clinical treatments of cardiovascular diseases. Additionally, it considers the field's future prospects while examining how lncRNAs might be altered and its clinical applications. [ABSTRACT FROM AUTHOR]

Unlike the adult mammalian heart, which has limited regenerative capacity, the zebrafish heart fully regenerates following injury. Reactivation of cardiac developmental programs is considered key to successfully regenerating the heart, yet the regulation underlying the response to injury remains elusive. Here, we compared the transcriptome and epigenome of the developing and regenerating zebrafish epicardia. We identified epicardial enhancer elements with specific activity during development or during adult heart regeneration. By generating gene regulatory networks associated with epicardial development and regeneration, we inferred genetic programs driving each of these processes, which were largely distinct. Loss of Hif1ab, Nrf1, Tbx2b, and Zbtb7a, central regulators of the regenerating epicardial network, in injured hearts resulted in elevated epicardial cell numbers infiltrating the wound and excess fibrosis after cryoinjury. Our work identifies differences between the regulatory blueprint deployed during epicardial development and regeneration, underlining that heart regeneration goes beyond the reactivation of developmental programs. [Display omitted] • Epicardial gene expression in regenerating and developing zebrafish heart is distinct • Epicardial chromatin accessibility differs between heart regeneration and development • Hif1ab, Nrf1, Tbx2b, and Zbtb7a are key regulators of the regenerating epicardium • Loss of Hif1ab, Nrf1, Tbx2b, and Zbtb7a increases tcf21 + cell numbers following injury Weinberger and Simões et al. detail transcriptomic and epigenomic differences between regenerating adult and developing larval zebrafish epicardium. Constructing gene regulatory networks, they identify transcription factors regulating each setting, with loss of adult epicardial regulators Hif1ab, Nrf1, Tbx2b, and Zbtb7a increasing epicardial cell numbers following injury and affecting heart regeneration. [ABSTRACT FROM AUTHOR]

Farmed Atlantic salmon suffer from deviating cardiac morphology, likely compromising fish health and robustness. To mitigate the potentially devastating consequences of morphological deviations of the heart, the cause and consequences of these abnormalities need to be elucidated. This endeavour is, however, complicated by several obstacles. First, a detailed nomenclature of gross anatomical structures of the pyramidal fish heart is needed to develop standardized descriptions of morphological deviations. Second, standardized methods and scoring systems for quantitative and qualitative descriptions of cardiac anatomy are lacking. Lastly, the normal morphological development of the heart through the life cycle of wild specimens has not been described, making it challenging to identify deviating morphology at different life stages of farmed salmon. Here, we develop a nomenclature for the exterior of a pyramidal teleost heart, using the Atlantic salmon heart as a model. Further, we have unified and described the most common quantitative methods used for measuring heart morphology and developed a qualitative methodology to detect morphological abnormalities not identified by the quantitative methods. We describe the methodologies' applicability and assess the qualitative method's robustness. Using quantitative measures, heart morphology in the wild and farmed salmon is compared throughout their life cycles. Further, we show that the qualitative method is superior to the quantitative method in detecting traits more prevalent in deceased fish after exposure to stressful routine field treatments, illustrating the complementary nature of these two methods. • Novel nomenclature for the pyramidal teleost heart. • Quantitative & qualitative methods for standardized assessment of heart morphology. • Comprehensive description of wild salmon's heart development throughout life cycle. • Identify cardiac deformities associated with mortality, aiding in risk assessment. • Integrates novel methodology to enhance aquaculture management insights. [ABSTRACT FROM AUTHOR]

Genomic regulation of cardiomyocyte differentiation is central to heart development and function. This study uses genetic loss-of-function human-induced pluripotent stem cell-derived cardiomyocytes to evaluate the genomic regulatory basis of the non-DNA-binding homeodomain protein HOPX. We show that HOPX interacts with and controls cardiac genes and enhancer networks associated with diverse aspects of heart development. Using perturbation studies in vitro , we define how upstream cell growth and proliferation control HOPX transcription to regulate cardiac gene programs. We then use cell, organoid, and zebrafish regeneration models to demonstrate that HOPX-regulated gene programs control cardiomyocyte function in development and disease. Collectively, this study mechanistically links cell signaling pathways as upstream regulators of HOPX transcription to control gene programs underpinning cardiomyocyte identity and function. [Display omitted] • HOPX directly regulates cardiomyocyte developmental and maturation gene programs • Cell growth and proliferation stimuli compete for transcriptional control of HOPX • HOPX regulates cardiomyocyte physiology in vitro and in vivo • hopx regulates cardiomyocyte proliferation during zebrafish heart regeneration Friedman et al. define how the DNA-associated factor HOPX controls the maturation state of cardiomyocytes. HOPX controls the genomic and transcriptional state of cardiomyocytes to influence cell physiology during heart development and disease. [ABSTRACT FROM AUTHOR]

Mevinphos, an organophosphate insecticide, is widely used to control pests and enhance crop yield. Because of its high solubility, it can easily flow into water and threaten the aquatic environment, and it is known to be hazardous to non-target organisms. However, little is known about its developmental toxicity and the underlying toxic mechanisms. In this study, we utilized zebrafish, which is frequently used for toxicological research to estimate the toxicity in other aquatic organisms or vertebrates including humans, to elucidate the developmental defects induced by mevinphos. Here, we observed that mevinphos induced various phenotypical abnormalities, such as diminished eyes and head sizes, shortened body length, loss of swim bladder, and increased pericardiac edema. Also, exposure to mevinphos triggered inflammation, apoptosis, and DNA fragmentation in zebrafish larvae. In addition, MAPK and Akt signaling pathways, which control apoptosis, inflammation, and proper development of various organs, were also altered by the treatment of mevinphos. Furthermore, these factors induced various organ defects which were confirmed by various transgenic models. We identified neuronal toxicity through transgenic olig2:dsRed zebrafish, cardiovascular toxicity through transgenic fli1:eGFP zebrafish, and hepatotoxicity and pancreatic toxicity through transgenic lfabp:dsRed;elastase:GFP zebrafish. Overall, our results elucidated the developmental toxicities of mevinphos in zebrafish and provided the parameters for the assessment of toxicities in aquatic environments. [Display omitted] • Mevinphos induces morphological abnormalities during zebrafish development. • Mevinphos triggers apoptosis and inflammation in zebrafish. • Mevinphos disrupts heart and vascular development in zebrafish larvae. • Mevinphos impairs the development of the notochord and liver in zebrafish. • Mevinphos may cause detrimental effects in the aquatic ecosystems. [ABSTRACT FROM AUTHOR]

Volatile organic compounds (VOCs) are common air pollutants and water contaminants. We previously found maternal exposure to VOCs was associated with offspring congenital heart disease (CHD). However, little information is available about the effects of VOCs on cardiovascular development at embryonic stage and the underlying mechanism remains unclear. In this study , we aimed to investigate the effects of a mixture of six VOCs on cardiovascular development in zebrafish embryos. Embryos were exposed to different concentrations of VOCs mixture (32 mg/L, 64 mg/L and 128 mg/L) for 96 h, cardiovascular abnormalities including elongated heart shape, increased distance between sinus venosus and bulbus arteriosus, slowed circulation and altered heart rate were observed in a dose- and time-dependent manner. Meanwhile, VOCs exposure increased global DNA methylation levels in embryos. Analysis identified hundreds of differentially methylated sites and the enrichment of differentially methylated sites on cardiovascular development. Two differentially methylated-associated genes involved in MAPK pathway, hgfa and ntrk1 , were identified to be the potential genes mediating the effects of VOCs. By enzyme-linked immunosorbent assay, altered human serum hgf and ntrk1 levels were detected in abnormal pregnancies exposed to higher VOCs levels with fetal CHD. For the first time, our study revealed exposure to VOCs induced severe cardiovascular abnormalities in zebrafish embryos. The toxicity might result from alterations in DNA methylation and corresponding expression levels of genes involved in MAPK pathway. Our study provides important information for the risk of VOCs exposure on embryonic cardiovascular development. [Display omitted] • VOCs exposure induced severe cardiovascular abnormalities in zebrafish embryos. • VOCs exposure induced genomic-wide DNA methylation changes in zebrafish embryos. • VOCs exposure altered expression levels of hgfa and ntrk1 in zebrafish embryos. • Higher VOCs exposure altered hgf and ntrk1 levels in serum of pregnant women. [ABSTRACT FROM AUTHOR]

The endless problem of energy supplies are always floating on the surface. As a result, there are a daily improvement to optimize power generators, networks and system configuration. Renewable distributed generators (RDG) are in the heart of these developments. The size of RDG is increasing daily so, it must be optimized to maximize benefits and eliminate drawbacks. Optimization algorithms are one of the fast growing techniques. In this study the Manta Ray Foraging optimization algorithm (MRFO) is applied to minimize power losses through sizing and allocation of DG type I integrated into radial distribution network (RDN). The proposed technique was tested on three different networks, IEEE 33, 69 and 85 test systems. Also, three cases were assumed to evaluate the effectiveness of MRFO algorithm. The results were compared to recent applied techniques. [ABSTRACT FROM AUTHOR]

• Beyond their role in development, Semaphorins are involved in adult neural plasticity, in neural regeneration after injury, and in neurodegenerative diseases. • Semaphorins control cardiovascular development, both physiological and pathological angiogenesis, and bone homeostasis. • Semaphorins regulate innate and adaptive immune responses and are implicated in immunopathologies. • Semaphorins control cancer cell behavior and hijack the function of normal cells in the tumor microenvironment. Cell-cell communication is pivotal to guide embryo development, as well as to maintain adult tissues homeostasis and control immune response. Among extracellular factors responsible for this function, are the Semaphorins, a broad family of around 20 different molecular cues conserved in evolution and widely expressed in all tissues. The signaling cascades initiated by semaphorins depend on a family of conserved receptors, called Plexins, and on several additional molecules found in the receptor complexes. Moreover, multiple intracellular pathways have been described to act downstream of semaphorins, highlighting significant diversity in the signaling cascades controlled by this family. Notably, semaphorin expression is altered in many human diseases, such as immunopathologies, neurodegenerative diseases and cancer. This underscores the importance of semaphorins as regulatory factors in the tissue microenvironment and has prompted growing interest for assessing their potential relevance in medicine. This review article surveys the main contexts in which semaphorins have been found to regulate developing and healthy adult tissues, and the signaling cascades implicated in these functions. Vis a vis, we will highlight the main pathological processes in which semaphorins are thought to have a role thereof. [ABSTRACT FROM AUTHOR]

Echocardiographic studies in human neonatology has demonstrated that prematurity can lead to cardiovascular dysfunction and especially compromises the left ventricular (LV) systolic and diastolic functions. As echocardiographic studies have not been performed on cardiovascular dysfunction in premature calves, we echocardiographically evaluated and compared the LV systolic and diastolic function in full-term and premature calves. We followed the hemodynamical changes of LV during first 3 days of life. Twenty premature calves and 10 healthy term calves were enrolled in the study. 2D, M-mode and Doppler echocardiographic examinations were performed at days 1, 2 and 3 after birth to evaluate LV systolic and diastolic functions. Our findings demonstrated that not only was there LV diastolic dysfunction (55% premature calves, 10% term calf at day 1; 65% premature calves, 10% term calf at day 2 and, 75% premature calves, 20% term calf at day 3), but also LV systolic dysfunction (55% premature calves, 60% term calf at day 1; 55% premature calves, 50% term calf at day 2, and 45% premature calves, 40% term calf at day 3) deteriorated in both term and premature calves. In conclusion, the present study, which was the first comparative echocardiographic assessment of LV systolic and diastolic functions in term and premature newborn calves, showed that both systolic and diastolic dysfunctions might occur in term and premature calves. • Numerous echocardiographic studies have been shown cardiovascular problems in premature human infants. • The literature information about the cardiovascular function in premature and term neonatal calves is not sufficient. • Both LV systolic and diastolic dysfunctions may occur in term and premature calves during the neonatal period. • Echocardiography is a useful tool for evaluating cardiac functions and following heart development in neonatal animals. [ABSTRACT FROM AUTHOR]

• Seaweed represents an important future biorefinery feedstock. • The world market has reached more than 30 million tonnes per year. • Cascaded valorization provides food, feed, functional materials, chemicals and energy. • Metabolic engineered cell factories can convert seaweed sugars into novel products. Sustainable production from seaweed has grown into an area of intense research and development. Meanwhile, more than 30 million tonnes of seaweed are produced, of which 70% are used as food and 30% have other applications such as feed, fertilizer, chemicals, and energy. Towards biorefining seaweed in an environmentally friendly and economically viable manner, we need efficient approaches that convert its biomass and residuals into added value products. Smart cell factories and fermentation strategies which can be integrated into future seaweed biorefineries are at the heart of the development and therefore receive increasing attention. Here, we review advances in the field including novel fermentation routes from seaweed to chemicals, materials, pharmaceuticals, fuels and energy, and discuss challenges and opportunities. [ABSTRACT FROM AUTHOR]

Congenital heart disease is one of the most common cardiac malformation-related diseases worldwide. Some causative genes have been identified but can explain only a small proportion of all cases; therefore, the discovery of novel susceptibility genes and/or modifier genes for abnormal cardiac development remains a major challenge. We used a single nucleotide polymorphism (SNP) array, and next-generation sequencing (NGS) was conducted to screen and quickly identify candidate genes. KIAA0196 knockout zebrafish and mice were generated by CRISPR/Cas9 to detect whether or how KIAA0196 deficiency would influence cardiac development. Homozygous, but not heterozygous, zebrafish and mice showed early embryonic lethality. At the embryonic stage, microscopic examination and dissection revealed pericardial edema and ventricle enlargement in homozygous zebrafish and obviously delayed cardiac development in heterozygous mice, while echocardiography and tissue staining showed that significantly decreased cardiac function, ventricle enlargement, myofibril loss, and significantly reduced trabecular muscle density were observed in adult heterozygous zebrafish and mice. Most importantly, immunostaining and electron microscopy showed that there was a significant increase in sarcomere structural disorganization and myofibril structural integrity loss in KIAA0196 mutants. Furthermore, substantial downregulation in other sarcomeric genes and proteins was detected and verified in a mouse model via transcriptome and proteomics analyses; these changes especially affected the myosin heavy or light chain (MYH or MYL) family genes. We identified KIAA0196 for the first time as a susceptibility gene for abnormal cardiac development. KIAA0196 deficiency may cause abnormal heart development by influencing the structural integrity of myofibrils. • We identified KIAA0196 may as a susceptibility gene of cardiac development. • Loss-of-function of KIAA0196 in zebrafish and mouse model leads to cardiac dysfunction. • KIAA0196 insufficiency induced sarcomere disorganization and myofibril disruption. • Transcriptomic and proteomic show KIAA0196 deficiency affects sarcomere proteins/RNAs. [ABSTRACT FROM AUTHOR]

Recent advances in stem cell biology and tissue engineering have laid the groundwork for building complex tissues in a dish. We propose that these technologies are ready for a new challenge: recapitulating cardiac morphogenesis in vitro. In development, the heart transforms from a simple linear tube to a four-chambered organ through a complex process called looping. Here, we re-examine heart tube looping through the lens of an engineer and argue that the linear heart tube is an advantageous starting point for tissue engineering. We summarize the structures, signaling pathways, and stresses in the looping heart, and evaluate approaches that could be used to build a linear heart tube and guide it through the process of looping. There is high potential for current technologies to be used to recapitulate heart development in vitro by focusing on its earliest stage of morphogenesis: the embryonic heart tube. Recent advances in stem cell biology have enabled the production of cardiac progenitor lineages for bioengineering approaches. Biofabrication techniques can create structures and features of the heart tube at the appropriate scale. Biochemical cues that govern cardiac morphogenesis can be controlled and studied through techniques such as engineered diffusion gradients, functionalized hydrogels, and optogenetics. Mechanical cues that influence cardiac growth and remodeling can be applied to engineered heart tubes using hemodynamic flow and direct or field-based micromanipulation techniques. [ABSTRACT FROM AUTHOR]

Cancer and inflammation are strongly interconnected processes. Chronic inflammatory pathologies can be at the heart of tumor development; similarly, tumor-elicited inflammation is a consequence of many cancers. The mechanistic interdependence between cancer and inflammatory pathologies points toward common protein effectors which represent potential shared targets for pharmacological intervention. Epigenetic mechanisms often drive resistance to cancer therapy and immunomodulatory strategies. The bromodomain and extraterminal domain (BET) proteins are epigenetic adapters which play a major role in controlling cell proliferation and the production of inflammatory mediators. A plethora of small molecules aimed at inhibiting BET protein function to treat cancer and inflammatory diseases have populated academic and industry efforts in the last 10 years. In this review, we will discuss recent pharmacological approaches aimed at targeting a single or a subset of the eight bromodomains within the BET family which have the potential to tease apart clinical efficacy and safety signals of BET inhibitors. [ABSTRACT FROM AUTHOR]

At birth, weight of the neonate is used as a marker of the 9-month journey as a fetus. Those neonates born less than the 10th centile for their gestational age are at risk of being intrauterine growth restricted. However, this depends on their genetic potential for growth and the intrauterine environment in which they grew. Alterations in the supply of oxygen and nutrients to the fetus will decrease fetal growth, but these alterations occur due to a range of causes that are maternal, placental or fetal in nature. Consequently, IUGR neonates are a heterogeneous population. For this reason, it is likely that these neonates will respond differently to interventions compared not only to normally grown fetuses, but also to other neonates that are IUGR but have travelled a different path to get there. Thus, a range of models of IUGR should be studied to determine the effects of IUGR on the development and function of the heart and lung and subsequently the impact of interventions to improve development of these organs. Here we focus on a range of models of IUGR caused by manipulation of the maternal, placental or fetal environment on cardiorespiratory outcomes. • As fetal supply of oxygen can be influenced by maternal, placental or fetal problems; intrauterine growth restriction is heterogenous in nature. • Comparisons between different models of IUGR may help to understand how the IUGR fetus may respond differently to potential interventions. • This review discusses the consequences of the timing, severity and duration of different models of IUGR on cardiorespiratory outcomes. [ABSTRACT FROM AUTHOR]

Congenital heart defects are a leading cause of neonatal morbidity and mortality. Accurate prenatal diagnosis of congenital heart defects can reduce morbidity and mortality by improving prenatal care, facilitating predelivery pediatric cardiology consultation, and directing delivery to facilities with resources to manage the complex medical and surgical needs of newborns with congenital heart defects. Unfortunately, less than one half of congenital heart defect cases are detected prenatally, resulting in lost opportunities for counseling, shared decision-making, and delivery at an appropriate facility. Quality improvement initiatives to improve prenatal congenital heart defects detection depend on the ability to measure the rate of detection at the level of providers, facilities, or populations, but no standard metric exists for measuring the detection of congenital heart defects at any level. The need for such a metric was recognized at a Cooperative Workshop held at the 2016 Annual Meeting of the Society for Maternal-Fetal Medicine, which recommended the development of a quality metric to assess the rate of prenatal detection of clinically significant congenital heart defects. In this paper, we propose potential quality metrics to measure prenatal detection of critical congenital heart defects, defined as defects with a high rate of morbidity or mortality or that require surgery or tertiary follow-up. One metric is based on a retrospective approach, assessing whether postnatally diagnosed congenital heart defects had been identified prenatally. Other metrics are based on a prospective approach, assessing the sensitivity and specificity of prenatal diagnosis of congenital heart defects by comparing prenatal ultrasound findings with newborn findings. Potential applications, limitations, challenges, barriers, and value for both approaches are discussed. We conclude that future development of these metrics will depend on an expansion of the International Classification of Diseases system to include specific codes that distinguish fetal congenital heart defects from newborn congenital heart defects and on the development of record systems that facilitate the linkage of fetal records (in the maternal chart) with newborn records. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with metastatic neuroendocrine neoplasms (NEN) continues to improve with modern oncological therapy. In the subgroup of patients with carcinoid syndrome, the development of carcinoid heart disease (CaHD) severely impacts long term survival. Valve surgery has been demonstrated to improve survival and symptoms in patients with CaHD. We sought to assess the outcomes of surgery for CaHD from a single Neuroendocrine Service.Methods: We retrospectively reviewed outcomes of patients with CaHD and metastatic NEN who underwent valvular surgery over a 4-year period (2012-2016).Results: Twenty (20) patients (mean age 64 years, range 29-77 years), all with metastatic small intestinal NEN treated with somatostatin analogues, underwent surgery. Tumour grade was: G1 (n=8), G2 (n=9), and unknown (n=3). Preoperative New York Heart Association (NYHA) class was III/IV in 15 patients (75%). The valves affected were: tricuspid (n=20; 19 replace, 1 repair), pulmonary (n=14; 14 replace), mitral (n=2; two replace) and aortic valve (n=2; two replace). Concomitant procedures included patent foramen ovale closure (n=9), right ventricular outflow tract (RVOT) (n=4) augmentation and coronary artery bypass grafting (n=3). There were two operative deaths (10%) due to right heart and liver failure. At 6 weeks, all surviving patients had symptom improvement (NYHA I/II). Median follow-up was 2±1.5 years (<1 month to 5 years). One asymptomatic patient developed RVOT obstruction after pulmonary replacement. Two patients had valvular recurrence. One and 2-year survival were 74% and 48% respectively. Of 13 late deaths, 12 were cancer-related (two with uncorrected progressive pulmonary regurgitation).Conclusions: Surgery for CaHD can be performed with satisfactory early results, leading to an improvement of cardiac symptoms, survival and enabling subsequent oncologic treatment. Further studies are required to improve longer term outcomes in these complex patients with CaHD. [ABSTRACT FROM AUTHOR]

Infection is still a leading cause of death during the first year after heart transplantation. We evaluated the pre-transplant levels of HLA (Human Leukocyte antigen) – G molecules as a means of identifying heart recipients at risk of serious infections. We prospectively analyzed 122 adult heart transplant (HT) recipients. Serum samples were collected before transplantation and analyzed for sHLA-G levels by ELISA assay. The clinical follow-up period lasted 5 years. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 39 patients (32%) developed at least 1 serious bacterial infection. Higher pre-transplant sHLA-G levels were a risk factor for serious infection (above median value 5.4 ng/ml; relative risk 3.70; 95% confidence interval 1.03–12.64; p = 0.043). Patients with high levels of pre-transplant sHLA-G are also characterized by a lower overall survival at 5 years (p = 0.017), with microbial infections as major causes of death. No association was observed with the development rejection episode. Early monitoring of sHLA-G molecules proved useful for the identification of heart recipients who are at risk of serious infections. [ABSTRACT FROM AUTHOR]

SUMOylation, covalent conjugation of small ubiquitin-related modifier (SUMO), has been emerging as a critical posttranslational modification of developmental transcription factors, as well as key regulators in the adult heart. Identifying the SUMOylated targets within cardiac transcription factors will facilitate to unravel the roles of SUMOylation in heart development and disease. Here, we show that Gata6, an essential cardiac transcription factor, can be modified by SUMO in vivo. Mutation of potential SUMOylation sites reveals that a lysine residue at amino acid position 12 of Gata6 serves as the major attachment site for SUMO. Pias1, as an E3 SUMO ligase, preferentially enhances the conjugation of SUMO1 to Gata6 through its RING finger domain. Functional analyses with SUMOylation-deficient mutant indicate that SUMOylation does not affect the subcellular localization but instead represses Gata6 transcriptional activity. Our data suggest that posttranslational modification of Gata6 by SUMO conjugation provides a novel mechanism to regulate Gata6 activity. • 1.Cardiac transcriptial factor Gata6 is a novel SUMO target. • Lysine 12 is the major SUMOylation site within zebrafish Gata6. • SUMOylation represses the transcriptional activity of Gata6. [ABSTRACT FROM AUTHOR]

The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in WT postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in WT hearts. [ABSTRACT FROM AUTHOR]

• The development of a novel heart rate analysis algorithm is discussed. • HeartPy is validated on PPG and ECG datasets, and the results show good performance. • The performance is compared to two other open source available algorithms. • An integrated method of breathing rate estimation is discussed. • Limitations and future research directions are discussed. Heart rate data are often collected in human factors studies, including those into vehicle automation. Advances in open hardware platforms and off-the-shelf photoplethysmogram (PPG) sensors allow the non-intrusive collection of heart rate data at very low cost. However, the signal is not trivial to analyse, since the morphology of PPG waveforms differs from electrocardiogram (ECG) waveforms and shows different noise patterns. Few validated open source available algorithms exist that handle PPG data well, as most of these algorithms are specifically designed for ECG data. In this paper we present the validation of a novel algorithm named HeartPy, useful for the analysis of heart rate data collected in noisy settings, such as when driving a car or when in a simulator. We benchmark the performance on two types of datasets and show that the developed algorithm performs well. Further research steps are discussed. [ABSTRACT FROM AUTHOR]