CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes.

Microproteins synthesized through non-canonical translation pathways are frequently found within mitochondria. However, the functional significance of these mitochondria-localized microproteins in energy-intensive organs such as the heart remains largely unexplored. In this study, we demonstrate that the long non-coding RNA CD63-AS1 encodes a mitochondrial microprotein. Notably, in ribosome profiling data of human hearts, there is a positive correlation between the expression of CD63-AS1 and genes associated with cardiomyopathy. We have termed this microprotein CEAM (CD63-AS1 encoded amyloid-like motif containing microprotein), reflecting its sequence characteristics. Our biochemical assays show that CEAM forms protease-resistant aggregates within mitochondria, whereas deletion of the amyloid-like motif transforms CEAM into a soluble cytosolic protein. Overexpression of CEAM triggers mitochondrial stress responses and adversely affect mitochondrial bioenergetics in cultured cardiomyocytes. In turn, the expression of CEAM is reciprocally inhibited by the activation of mitochondrial stresses induced by oligomycin. When expressed in mouse hearts via adeno-associated virus, CEAM impairs cardiac function. However, under conditions of pressure overload-induced cardiac hypertrophy, CEAM expression appears to offer a protective benefit and mitigates the expression of genes associated with cardiac remodeling, presumably through a mechanism that suppresses stress-induced translation reprogramming. Collectively, our study uncovers a hitherto unexplored amyloid-like microprotein expressed in the human cardiomyocytes, offering novel insights into myocardial hypertrophy pathophysiology.

The triglyceride-glucose index, ventricular arrhythmias and major cardiovascular events in patients at high risk of sudden cardiac death.

BACKGROUND: The association between the triglyceride-glucose (TyG) index and ventricular arrhythmias (VAs) is unclear. This study aimed to investigate the relationship between the TyG index, VAs, and major cardiovascular events in patients at high risk of sudden cardiac death (SCD). METHODS: We enrolled 1046 patients at high risk of SCD with an indication for implantable cardioverter-defibrillator (ICD) implantation at the Chinese National Center for Cardiovascular Diseases. The primary outcome was VAs, defined as sustained ventricular tachycardia and ventricular fibrillation documented by the ICD. The secondary outcomes were cardiac mortality, heart transplantation, and rehospitalization for heart failure. RESULTS: The mean (± SD) age was 59.6 ± 14.0 years old, and 25.7% were female. During the mean follow-up of 36.1 months, 342 (32.7%) patients had VAs, and 185 (17.7%) patients had major cardiovascular events. The mean fasting glucose and triglyceride levels were 111.9 ± 42.7 mg/dL and 140.0 ± 95.4 mg/L, respectively, with a TyG index range of 6.96-11.8. In the Fine-Gray subdistribution hazard model analysis, an increase in the TyG index was associated with a significant increase in the VAs (per 1 TyG index, hazard ratio [HR] 2.95; 95% confidence interval [CI], 2.29-3.80) and secondary outcome (HR 2.84; 95% CI 1.86-4.34). When stratified into tertiles, the risk of VAs was significantly higher in the highest tertile (HR 4.08; 95% CI, 2.81-5.92) than in the lowest tertile. Analysis of the secondary outcome revealed similar findings (HR 3.18; 95% CI, 1.73-5.85). CONCLUSIONS: In our cohort, the pre-operational TyG index is significantly associated with VAs and major cardiovascular events for patients with high risk of SCD.

Modifiable risk factors mediating the impact of educational inequality on heart failure: A Mendelian randomization study.

BACKGROUND: Heart failure (HF) is a rapidly growing global disease burden with high mortality rates. We aimed to utilize mendelian randomization (MR) analyses to investigate the association between educational attainment (EA) and HF, and to evaluate the contribution of modifiable risk factors as mediators. METHODS: We applied a two-sample MR approach based on the largest genome-wide association studies (GWAS) to investigate the causal relationship between EA and HF. Data collection was conducted in July 2023. We then conducted mediation analyses to explore whether body mass index (BMI), blood pressure, and type 2 diabetes mellitus (T2DM) mediate the effect of EA on HF, and utilized multivariable MR to estimate the proportion of mediation attributed to these factors. RESULTS: Genetically predicted 3.4 years of additional education was associated with a decrease in the risk of HF (OR 0.76 for each 3.4 years of schooling; 95% CI 0.72, 0.81). BMI, T2DM, systolic blood pressure, and diastolic blood pressure mediated 40.82% (95% CI: 28.86%, 52.77%), 18.00% (95% CI: 12.10%, 23.90%), 11.60% (95% CI: 7.63%, 15.56%), and 7.80% (95% CI: 4.63%, 10.96%) of the EA-HF association, respectively. All risk factors combined were estimated to mediate 63.81% (95% CI: 45.91%, 81.71%) of the effect of EA on HF. CONCLUSION: Higher EA has a protective effect against the risk of HF, and potential mechanisms may include regulation of BMI, blood pressure, and blood glucose. Further research is needed to understand whether interventions targeting these factors could influence the association between EA and HF risk.

Prognostic implications of premature ventricular contractions and non-sustained ventricular tachycardia in light-chain cardiac amyloidosis.

AIMS: Premature ventricular contractions (PVC) and non-sustained ventricular tachycardia (NSVT) are commonly observed in light chain cardiac amyloidosis (AL-CA), but their association with prognosis is still unclear. We aimed to evaluate the prognostic value of PVCs and NSVT in patients with moderate-to-advanced AL-CA. METHODS AND RESULTS: We retrospectively included patients with AL-CA at modified 2004 Mayo stages II-IIIb between February 2014 and December 2020. Twenty-four-hour Holter recordings were assessed on admission. The outcomes included (i) new onset of adverse ventricular arrhythmia (VA) or sudden cardiac death (SCD) and (ii) cardiac death during follow-up. Of the 143 patients studied (60.41 ± 11.06 years, male 64.34%), 132 (92.31%) had presence of PVC, and 50 (34.97%) had NSVT on Holter. Twelve (8.4%) patients died in hospital and 131 patients were followed up (median 24.4 months), among whom 71 patients had cardiac death, and 15 underwent adverse VA/SCD. NSVT [hazard ratio (HR): 13.57, 95% confidence interval (CI): 3.06-60.18, P < 0.001], log-transformed PVC counts (HR: 1.46, 95%CI: 1.15-1.86, P = 0.002) and PVC burden (HR: 1.43 95%CI:1.14-1.80, P = 0.002) were predictive of new onset of adverse VA/SCD. The highest tertile of PVC counts (HR: 2.33, 95%CI: 1.27-4.28, P = 0.006) and PVC burden (HR: 2.58, 95%CI: 1.42-4.69, P = 0.002), rather than NSVT (HR: 1.16, 95%CI: 0.67-1.98, P = 0.603), was associated with cardiac death. Higher PVC counts/burden provided incremental value on modified 2004 Mayo stage in predicting cardiac death, with C index increasing from 0.681 to 0.712 and 0.717, respectively (P values <0.05). CONCLUSION: PVC count, burden, and NSVT significantly correlated with adverse VA/SCD during follow-up in patients with AL-CA. Higher PVC counts/burdens added incremental value for predicting cardiac death.

Sodium catalytic phenylpentazole cracking: a theoretical study.

This work presents an in-depth investigation into the cracking reaction mechanism of phenylpentazole (C6H5N5) under the catalytic influence of sodium metal, utilizing density functional theory. The geometries of the reactants, transition states, intermediates, and products are meticulously optimized employing the GGA/PW91/DNP level of theory. Also, a rigorous analysis is undertaken, encompassing various key factors including configuration parameters, Mulliken charges, densities of states, and reaction energies. Three distinct reaction pathways are comprehensively examined, shedding light on the intricate details and intricacies of each pathway. The results show that a remarkable outcome in which the activation energy of the C6H5N5 cracking reaction releases N2, facilitated by catalytic metal Na, reveals a strikingly reduced value of a mere 5.2 kcal mol-1 compared to the previously reported activation energies ranging from 20 to 30 kcal mol-1. Evidently, this significantly lowered barrier can be readily surpassed at typical room temperatures, exhibiting practical applicability. Notably, the alkali metal Na effectively serves as a catalyst, successfully diminishing the activation energy required for N2 production through the pyrolysis of pentazole compounds. This breakthrough discovery provides a theoretical basis for experimental research on the low-temperature cracking of pentazole compounds. It also offers valuable insights for the development and application of new high energy density materials, contributing to the creation of a green and low-carbon circular economic system.

A novel approach to terminate roof-dependent atrial flutter with epicardial conduction through septopulmonary bundle.

Atrial flutter, a prevalent cardiac arrhythmia, is primarily characterized by reentrant circuits in the right atrium. However, atypical forms of atrial flutter present distinct challenges in terms of diagnosis and treatment. In this study, we examine three noteworthy clinical cases of atypical atrial flutter, which offer compelling evidence indicating the implication of the lesser-known Septopulmonary Bundle (SPB). This inference is based on the identification of distinct electrocardiographic patterns observed in these patients and their favorable response to catheter ablation, which is a standard treatment for atrial flutter. Remarkably, in each case, targeted ablation at the anterior portion of the left atrial roof effectively terminated the arrhythmia, thus providing further support for the hypothesis of SPB involvement. These insightful observations shed light on the potential significance of the SPB in the etiology of atypical atrial flutter and introduce a promising therapeutic target. We anticipate that this paper will stimulate further exploration into the role of the SPB in atrial flutter and pave the way for the development of targeted ablation strategies.

Fate mapping RNA-sequencing reveal Malat1 regulates Sca1+ progenitor cells to vascular smooth muscle cells transition in vascular remodeling.

Regeneration of smooth muscle cells (SMCs) is vital in vascular remodeling. Sca1+ stem/progenitor cells (SPCs) can generate de novo smooth muscle cells after severe vascular injury during vessel repair and regeneration. However, the underlying mechanisms have not been conclusively determined. Here, we reported that lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was down-regulated in various vascular diseases including arteriovenous fistula, artery injury and atherosclerosis. Using genetic lineage tracing mice and veingraft mice surgery model, we found that suppression of lncRNA Malat1 promoted Sca1+ cells to differentiate into SMCs in vivo, resulting in excess SMC accumulation in neointima and vessel stenosis. Genetic ablation of Sca1+ cells attenuated venous arterialization and impaired vascular structure normalization, and thus, resulting in less Malat1 down-regulation. Single cell sequencing further revealed a fibroblast-like phenotype of Sca1+ SPCs-derived SMCs. Protein array sequencing and in vitro assays revealed that SMC regeneration from Sca1+ SPCs was regulated by Malat1 through miR125a-5p/Stat3 signaling pathway. These findings delineate the critical role of Sca1+ SPCs in vascular remodeling and reveal that lncRNA Malat1 is a key regulator and might serve as a novel biomarker or potential therapeutic target for vascular diseases.

Comprehensive Investigation into the Impact of Degradation of Recycled Polyethylene and Recycled Polypropylene on the Thermo-Mechanical Characteristics and Thermal Stability of Blends.

The impact of degradation on plastics is a critical factor influencing their properties and behavior, particularly evident in polyethylene (PE) and polypropylene (PP) and their blends. However, the effect of photoaging and thermal degradation, specifically within recycled polyethylene (rPE) and recycled polypropylene (rPP), on the thermo-mechanical and thermostability aspects of these blends remains unexplored. To address this gap, a range of materials, including virgin polyethylene (vPE), recycled polyethylene (rPE), virgin polypropylene (vPP), recycled polypropylene (rPP), and their blends with different ratios, were comprehensively investigated. Through a systematic assessment encompassing variables such as melting flow index (MFI), functional groups, mechanical traits, crystallization behavior, microscopic morphology, and thermostability, it was found that thermo-oxidative degradation generated hydroxyl and carboxyl functional groups in rPE and rPP. Optimal mechanical properties were achieved with a 6:4 mass ratio of rPE to rPP, as validated by FTIR spectroscopy and microscopic morphology. By establishing the chemical model, the changes in the system with an rPE-rPP ratio of 6:4 and 8:2 were monitored by the molecular simulation method. When the rPE-rPP ratio was 6:4, the system's energy was lower, and the number of hydrogen bonds was higher, which also confirmed the above experimental results. Differential scanning calorimetry revealed an increased crystallization temperature in rPE, a reduced crystallization peak area in rPP, and a diminished crystallization capacity in rPE/rPP blends, with rPP exerting a pronounced influence. This study plays a pivotal role in enhancing recycling efficiency and reducing production costs for waste plastics, especially rPE and rPP-the primary components of plastic waste. By uncovering insights into the degradation effects and material behaviors, our research offers practical pathways for more sustainable waste management. This approach facilitates the optimal utilization of the respective performance characteristics of rPE and rPP, enabling the development of highly cost-effective rPE/rPP blend materials and promoting the efficient reuse of waste materials.

Somatosensory Electro-Thermal Actuator through the Laser-Induced Graphene Technology.

The biological system realizes the unity of action and perception through the muscle tissue and nervous system. Correspondingly, artificial soft actuators realize the unity of sensing and actuating functions in a single functional material, which will have tremendous potential for developing intelligent and bionic soft robotics. This paper reports the design of a laser-induced graphene (LIG) electrothermal actuator with self-sensing capability. LIG, a functional material formed by a one-step direct-write lasing procedure under ambient air, is used as electrothermal conversion materials and piezoresistive sensing materials. By transferring LIG to a flexible silicone substrate, the design ability of the LIG-based actuator unit is enriched, along with an effectively improved sensing sensitivity. Through the integration of different types of well-designed LIG-based actuator units, the transformations from multidimensional precursors to 2D and 3D structures are realized. According to the piezoresistive effect of the LIG units during the deformation process, the visual synchronous deformation state feedback of the LIG-based actuator is proposed. The multimodal crawling soft robotics and the switchable electromagnetic shielding cloak serve as the demonstrations of the self-sensing LIG-based actuator, showing the advantage of the design in remote control of the soft robot without relying on the assistance of visual devices.

Comparison of strategies for catheter ablation of left posterior fascicular ventricular tachycardia.

AIMS: Traditional ablation strategies including targeting the earliest Purkinje potential (PP) during left posterior fascicular (LPF) ventricular tachycardia (VT) or linear ablation at the middle segment of LPF during sinus rhythm are commonly used for the treatment of LPF-VT. Catheter ablation for LPF-VT targeting fragmented antegrade Purkinje (FAP) potential during sinus rhythm is a novel approach. We aimed to compare safety and efficacy of different ablation strategies (FAP ablation vs. traditional ablation) for the treatment of LPF-VT. METHODS AND RESULTS: Consecutive patients with electrocardiographically documented LPF-VT referred for catheter ablation received either FAP ablation approach or traditional ablation approach. Electrophysiological characteristics, procedural complications, and long-term clinical outcome were assessed. A total of 189 consecutive patients who underwent catheter ablation for LPF-VT were included. Fragmented antegrade Purkinje ablation was attempted in 95 patients, and traditional ablation was attempted in 94 patients. Acute ablation success with elimination of LPF-VT was achieved in all patients. Left posterior fascicular block occurred in 11 of 95 (11.6%) patients in the FAP group compared with 75 of 94 (79.8%) patients in the traditional group (P < 0.001). Fragmented antegrade Purkinje ablation was associated with significant shorter procedure time (94 ± 26 vs. 117 ± 23 min, P = 0.03) and fewer radiofrequency energy applications (4.1 ± 2.4 vs. 6.3 ± 3.5, P = 0.003) compared with the traditional group. One complete atrioventricular block and one left bundle branch block were seen in the traditional group. Over mean follow-up of 65 months, 89 (93.7%) patients in the FAP group and 81 (86.2%) patients in the traditional group remained free of recurrent VT off antiarrhythmic drugs (P = 0.157). CONCLUSION: Left posterior fascicular-ventricular tachycardia ablation utilizing FAP and traditional ablation approaches resulted in similar acute and long-term procedural outcomes. Serious His-Purkinje injury did occur infrequently during traditional ablation. The use of FAP ablation approach was associated with shorter procedure time and fewer radiofrequency energy applications, especially for non-inducible patients.

Hardness and electronic properties of Si-C-N structures.

Three novel hexagonal Si-C-N structures, namely SiC3N3, SiC7N6, and SiC13N14, were constructed on the basis of the α-Si3N4 crystal structure. The stability of the three structures is demonstrated by analyzing their elastic constants and phonon dispersion spectra and by calculating their formation energies. The calculated band structures and partial densities of states suggest that the SiC3N3 and SiC7N6 structures possess hole conductivity. The electron orbital analyses indicate that the SiC3N3 and SiC7N6 crystals possess three-dimensional and one-dimensional conductivity, respectively. SiC13N14 is a semiconductor with a wide bandgap of 4.39 eV. Based on two different hardness models and indentation shear stress calculations, the Vickers hardness values of SiC3N3, SiC7N6, and SiC13N14 are estimated to be 28.04/28.45/16.18 GPa, 31.17/34.19/20.24 GPa, and 40.60/41.59/36.40 GPa. This result indicates that SiC3N3 and SiC7N6 are conductive hard materials while SiC13N14 is a quasi superhard material.

Highly Reactive Thermite Energetic Materials: Preparation, Characterization, and Applications: A Review.

As a promising kind of functional material, highly reactive thermite energetic materials (tEMs) with outstanding reactive activation can release heat quickly at a high reaction rate after low-energy stimulation, which is widely used in sensors, triggers, mining, propellants, demolition, ordnance or weapons, and space technology. Thus, this review aims to provide a holistic view of the recent progress in the development of multifunctional highly reactive tEMs with controllable micro/nano-structures for various engineering applications via different fabricated techniques, including the mechanical mixing method, vapor deposition method, assembly method, sol-gel method, electrospinning method, and so on. The systematic classification of novel structured tEMs in terms of nano-structural superiority and exothermic performance are clarified, based on which, suggestions regarding possible future research directions are proposed. Their potential applications within these rapidly expanding areas are further highlighted. Notably, the prospects or challenges of current works, as well as possible innovative research ideas, are discussed in detail, providing further valuable guidelines for future study.

Interfacial Adhesion Property of Asphalt Binder with Calcium Alginate Carrier of Asphalt Rejuvenator.

Recently calcium alginate has been successfully applied to encapsulate asphalt rejuvenator, which can protect asphalt rejuvenator from early leakage and release asphalt rejuvenator when triggered by specific factors such as cracks. The interfacial adhesion property of asphalt binder with calcium alginate carrier is of great importance to its actual performance. In this paper, the molecular model of the interface region between asphalt binder and calcium alginate was established, and molecular dynamics simulations were performed on it to investigate the molecular interaction at the interface region. By extracting and processing the data during the simulation process, the interfacial adhesion behavior was expounded using the spreading coefficient (S), permeation depth and permeation degree. Furthermore, the interfacial adhesion strength was evaluated by adopting the interfacial adhesion work. Results showed that the value of S was greater than 0, implying that asphalt binder could wet the surface of calcium alginate. Saturate had the highest value of permeation degree, followed by resin, aromatic and asphaltene. However, asphalt binder could not infiltrate into the interior of TiO2, only accumulating and spreading on the surface of TiO2. The interfacial adhesion work of unaged and aged asphalt binder to calcium alginate was -114.18 mJ/m2 and -186.37 mJ/m2, respectively, similar to that of asphalt-aggregate interface. The van der Waals interactions contributed the most to the formation of the interfacial adhesion strength. In addition, a certain degree aging of asphalt binder and addition of titanium dioxide in the calcium alginate carrier were helpful to enhance the interfacial adhesion strength.

Endothelial repair by stem and progenitor cells.

The integrity of the endothelial barrier is required to maintain vascular homeostasis and fluid balance between the circulatory system and surrounding tissues and to prevent the development of vascular disease. However, the origin of the newly developed endothelial cells is still controversial. Stem and progenitor cells have the potential to differentiate into endothelial cell lines and stimulate vascular regeneration in a paracrine/autocrine fashion. The one source of new endothelial cells was believed to come from the bone marrow, which was challenged by the recent findings. By administration of new techniques, including genetic cell lineage tracing and single cell RNA sequencing, more solid data were obtained that support the concept of stem/progenitor cells for regenerating damaged endothelium. Specifically, it was found that tissue resident endothelial progenitors located in the vessel wall were crucial for endothelial repair. In this review, we summarized the latest advances in stem and progenitor cell research in endothelial regeneration through findings from animal models and discussed clinical data to indicate the future direction of stem cell therapy.

The AIM2 inflammasome: A novel biomarker and target in cardiovascular disease.

Absent in melanoma 2 (AIM2) is a cytoplasmic sensor that recognises the double-strand DNA. AIM2 inflammasome is a protein platform in the cell that initiates innate immune responses by cleaving pro-caspase-1 and converting IL-1ß and IL-18 to their mature forms. Additionally, AIM2 inflammasome promotes pyroptosis by converting Gasdermin-D (GSDMD) to GSDMD-N fragments. An increasing number of studies have indicated the important and decisive roles of the AIM2 inflammasome, IL-1ß, and pyroptosis in cardiovascular diseases, such as coronary atherosclerosis, myocardial infarction, ischaemia/reperfusion injury, heart failure, aortic aneurysm and ischaemic stroke. Here, we review the molecular mechanism of the activation and effect of the AIM2 inflammasome in cardiovascular disease, revealing new insights into pathogenic factors that may be targeted to treat cardiovascular disease and related dysfunctions.

The pre-ablation triglyceride-glucose index predicts late recurrence of atrial fibrillation after radiofrequency ablation in non-diabetic adults.

BACKGROUND: Current prognostic risk scoring systems and biomarkers are routinely used as non-invasive methods for assessing late recurrence of atrial fibrillation (AF) in patients who have undergone radiofrequency catheter ablation (RFCA). This study aimed to investigate the predictive value of the triglyceride-glucose (TyG) index for late AF recurrence after RFCA in non-diabetic patients. METHODS: In total, 275 patients with AF who underwent RFCA at the Fuwai hospital (Beijing, China) between January 2016 and December 2018 were enrolled in this study. During follow up, patients were divided into late and non-late AF recurrence groups, based on whether they had experienced late AF recurrence determined by electrocardiography (ECG) examine or 48 h Holter monitoring. The TyG index was calculated using the following equation: ln [fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2]. RESULTS: During a median follow-up of 26.1 months, late AF recurrence event rates significantly increased in the highest TyG index tertile group (tertile 3) compared to the lowest group (tertile 1) (54% versus 12%, respectively; p < 0.001). The mean TyG index was higher in the late AF recurrence group compared to the non- late AF recurrence group (9.42 ± 0.6 versus 8.68 ± 0.70, respectively; p < 0.001). On multivariate Cox regression analysis, the pre-ablation TyG index was an independent risk factor for late recurrence of AF after RFCA (hazard ratio [HR] 2.015 [95% confidence interval (CI): 1.408-4.117]; p = 0.009). Receiver operating characteristic (ROC) curve analysis revealed that TyG index was a significant predictor of late AF recurrence after RFCA, with an area under the ROC curve (AUC) of 0.737 (95% CI: 0.657-0.816; p < 0.001). In addition, the AUC of left atrial diameter (LAD) was 0.780 (95%CI: 0.703-0.857, p < 0.001). Finally, the TyG index positively correlated with LAD (r = 0.133, p = 0.027), high sensitivity C-reactive protein (r = 0.132, p = 0.028) and N-terminal pro B-type natriuretic peptide (r = 0.291, p < 0.001) levels. CONCLUSIONS: An elevated pre-ablation TyG index was associated with an increased risk of late AF recurrence after RFCA in non-diabetic patients. The TyG index may be potentially useful as a novel biomarker for the risk stratification of late AF recurrence in non-diabetic patients.

Harnessing the interface mechanics of hard films and soft substrates for 3D assembly by controlled buckling.

Techniques for forming sophisticated, 3D mesostructures in advanced, functional materials are of rapidly growing interest, owing to their potential uses across a broad range of fundamental and applied areas of application. Recently developed approaches to 3D assembly that rely on controlled buckling mechanics serve as versatile routes to 3D mesostructures in a diverse range of high-quality materials and length scales of relevance for 3D microsystems with unusual function and/or enhanced performance. Nonlinear buckling and delamination behaviors in materials that combine both weak and strong interfaces are foundational to the assembly process, but they can be difficult to control, especially for complex geometries. This paper presents theoretical and experimental studies of the fundamental aspects of adhesion and delamination in this context. By quantifying the effects of various essential parameters on these processes, we establish general design diagrams for different material systems, taking into account 4 dominant delamination states (wrinkling, partial delamination of the weak interface, full delamination of the weak interface, and partial delamination of the strong interface). These diagrams provide guidelines for the selection of engineering parameters that avoid interface-related failure, as demonstrated by a series of examples in 3D helical mesostructures and mesostructures that are reconfigurable based on the control of loading-path trajectories. Three-dimensional micromechanical resonators with frequencies that can be selected between 2 distinct values serve as demonstrative examples.

Progesterone Receptor Modulates Extraembryonic Mesoderm and Cardiac Progenitor Specification during Mouse Gastrulation.

Progesterone treatment is commonly employed to promote and support pregnancy. While maternal tissues are the main progesterone targets in humans and mice, its receptor (PGR) is expressed in the murine embryo, questioning its function during embryonic development. Progesterone has been previously associated with murine blastocyst development. Whether it contributes to lineage specification is largely unknown. Gastrulation initiates lineage specification and generation of the progenitors contributing to all organs. Cells passing through the primitive streak (PS) will give rise to the mesoderm and endoderm. Cells emerging posteriorly will form the extraembryonic mesodermal tissues supporting embryonic growth. Cells arising anteriorly will contribute to the embryonic heart in two sets of distinct progenitors, first (FHF) and second heart field (SHF). We found that PGR is expressed in a posterior-anterior gradient in the PS of gastrulating embryos. We established in vitro differentiation systems inducing posterior (extraembryonic) and anterior (cardiac) mesoderm to unravel PGR function. We discovered that PGR specifically modulates extraembryonic and cardiac mesoderm. Overexpression experiments revealed that PGR safeguards cardiac differentiation, blocking premature SHF progenitor specification and sustaining the FHF progenitor pool. This role of PGR in heart development indicates that progesterone administration should be closely monitored in potential early-pregnancy patients undergoing infertility treatment.

Endothelial Scaffolding Protein ENH (Enigma Homolog Protein) Promotes PHLPP2 (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase 2)-Mediated Dephosphorylation of AKT1 and eNOS (Endothelial NO Synthase) Promoting Vascular Remodeling.

OBJECTIVE: A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multiple protein kinases, but whether it regulates eNOS activation and vascular remodeling remains unknown. Approach and Results: ENH was upregulated in injured mouse arteries and human atherosclerotic plaques and was associated with coronary artery disease. Neointima formation in carotid arteries, induced by ligation or wire injury, was greatly decreased in endothelium-specific ENH-knockout mice. Vascular ligation reduced AKT and eNOS phosphorylation and nitric oxide production in the endothelium of control but not ENH-knockout mice. ENH was found to interact with AKT1 and its phosphatase PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2). AKT and eNOS activation were prolonged in VEGF (vascular endothelial growth factor)-induced ENH- or PHLPP2-deficient endothelial cells. Inhibitors of either AKT or eNOS effectively restored ligation-induced neointima formation in ENH-knockout mice. Moreover, endothelium-specific PHLPP2-knockout mice displayed reduced ligation-induced neointima formation. Finally, PHLPP2 was increased in the endothelia of human atherosclerotic plaques and blood cells from patients with coronary artery disease. CONCLUSIONS: ENH forms a complex with AKT1 and its phosphatase PHLPP2 to negatively regulate AKT1 activation in the artery endothelium. AKT1 deactivation, a decrease in nitric oxide generation, and subsequent neointima formation induced by vascular injury are mediated by ENH and PHLPP2. ENH and PHLPP2 are thus new proatherosclerotic factors that could be therapeutically targeted.

Overexpression of FNTB and the activation of Ras induce hypertrophy and promote apoptosis and autophagic cell death in cardiomyocytes.

Farnesyltransferase (FTase) is an important enzyme that catalyses the modification of protein isoprene downstream of the mevalonate pathway. Previous studies have shown that the tissue of the heart in the suprarenal abdominal aortic coarctation (AAC) group showed overexpression of FTaseß (FNTB) and the activation of the downstream protein Ras was enhanced. FTase inhibitor (FTI) can alleviate myocardial fibrosis and partly improve cardiac remodelling in spontaneously hypertensive rats. However, the exact role and mechanism of FTase in myocardial hypertrophy and remodelling are not fully understood. Here, we used recombinant adenovirus to transfect neonatal rat ventricular cardiomyocytes to study the effect of FNTB overexpression on myocardial remodelling and explore potential mechanisms. The results showed that overexpression of FNTB induces neonatal rat ventricular myocyte hypertrophy and reduces the survival rate of cardiomyocytes. FNTB overexpression induced a decrease in mitochondrial membrane potential and increased apoptosis in cardiomyocytes. FNTB overexpression also promotes autophagosome formation and the accumulation of autophagy substrate protein, LC3II. Transmission electron microscopy (TEM) and mCherry-GFP tandem fluorescent-tagged LC3 (tfLC3) showed that FNTB overexpression can activate autophagy flux by enhancing autophagosome conversion to autophagolysosome. Overactivated autophagy flux can be blocked by bafilomycin A1. In addition, salirasib (a Ras farnesylcysteine mimetic) can alleviate the hypertrophic phenotype of cardiomyocytes and inhibit the up-regulation of apoptosis and autophagy flux induced by FNTB overexpression. These results suggest that FTase may have a potential role in future treatment strategies to limit the adverse consequences of cardiac hypertrophy, cardiac dysfunction and heart failure.