Metal-bonded perovskite lead hydride with phonon-mediated superconductivity exceeding 46 K under ambient pressure.

In the search for high-temperature superconductivity in hydrides, a plethora of multi-hydrogen superconductors have been theoretically predicted, and some have been synthesized experimentally under ultrahigh pressures of several hundred GPa. However, the impracticality of these high-pressure methods has been a persistent issue. In response, we propose a new approach to achieve high-temperature superconductivity under ambient pressure by implanting hydrogen into lead to create a stable few-hydrogen binary perovskite, Pb4H. This approach diverges from the popular design methodology of multi-hydrogen covalent high critical temperature (Tc) superconductors under ultrahigh pressure. By solving the anisotropic Migdal-Eliashberg equations, we demonstrate that perovskite Pb4H presents a phonon-mediated superconductivity exceeding 46 K with inclusion of spin-orbit coupling, which is six times higher than that of bulk Pb (7.22 K) and comparable to that of MgB2, the highestTcachieved experimentally at ambient pressure under the Bardeen, Cooper, and Schrieffer framework. The highTccan be attributed to the strong electron-phonon coupling strength of 2.45, which arises from hydrogen implantation in lead that induces several high-frequency optical phonon modes with a relatively large phonon linewidth resulting from H atom vibration. The metallic-bonding in perovskite Pb4H not only improves the structural stability but also guarantees better ductility than the widely investigated multi-hydrogen, iron-based and cuprate superconductors. These results suggest that there is potential for the exploration of new high-temperature superconductors under ambient pressure and may reignite interest in their experimental synthesis in the near future.

Genetic and cultural adaptations underlie the establishment of dairy pastoralism in the Tibetan Plateau.

BACKGROUND: Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products. RESULTS: We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that - 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele - 13838G > A with low frequency (~ 6-7%) and absence of selection corresponds - 13910C > T in pastoralists across eastern Eurasia steppe. CONCLUSIONS: Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.

Apoe-knockout induces strong vascular oxidative stress and significant changes in the gene expression profile related to the pathways implicated in redox, inflammation, and endothelial function.

Apolipoprotein E (APOE) was recognized as a key regulator of lipid metabolism, which prompted the Apoe-knockout (Apoe-/-) mouse to be the most widely used atherosclerotic model. However, with more and more important physiological roles of APOE being revealed, it is necessary to reacquaint its comprehensive function in the aorta. In this study, we aimed to reveal how Apoe-knockout impacts the gene pathways and phenotypes in the aorta of mice. We performed transcriptome sequencing to acquire the gene expression profile (GEP) for C57BL/6J and Apoe-/- mouse aorta, and used enrichment analysis to reveal the signal pathways enriched for differentially expressed genes (DEGs). In addition, we used immunofluorescence and ELISA to detect the phenotypic differences of vascular tissues and plasma in the two-group mice. Apoe-knockout resulted in significant changes in the expression of 538 genes, among which about 75% were up-regulated and 134 genes were altered more than twice. In addition to the lipid metabolism pathways, DEGs were also mainly enriched in the pathways implicated in endothelial cell proliferation, migration of epithelial cells, immune regulatory, and redox. GSEA shows that the up-regulated genes are mainly enriched in 'immune regulation pathways' and 'signal regulation' pathways, while the down-regulated genes are enriched in lipid metabolism pathways, 'regulation_of_nitric_oxide_synthase_activity' and the pathways involved in redox homeostasis, including 'monooxygenase regulation', 'peroxisomes' and 'oxygen binding'. A significant increase of reactive oxygen species and a remarkable reduction of GSH/GSSG ratio were respectively observed in the vascular tissues and plasma of Apoe-/- mice. In addition, endothelin-1 significantly increased in the vascular tissue and the plasma of Apoe-/- mice. Taken together, our results suggest that besides functioning in lipid metabolism, APOE may be an important signal regulator that mediates the expression of the genes related to the pathways involved in redox, inflammation, and endothelial function. Apoe-knockout-induced strong vascular oxidative stress is also the key factor contributing to atherosclerosis.

Enhancement for phonon-mediated superconductivity up to 37 K in few-hydrogen metal-bonded layered magnesium hydride under atmospheric pressure.

The discovery of superconductivity in layered MgB2 has renewed interest in the search for high-temperature conventional superconductors, leading to the synthesis of numerous hydrogen-dominated materials with high critical temperatures (Tc) under high pressures. However, achieving a high-Tc superconductor under ambient pressure remains a challenging goal. In this study, we propose a novel approach to realize a high-temperature superconductor under ambient pressure by introducing a hexagonal H monolayer into the hexagonal close-packed magnesium lattice, resulting in a new and stable few-hydrogen metal-bonded layered magnesium hydride (Mg4)2H1. This compound exhibits superior ductility compared to multi-hydrogen, cuprate, and iron-based superconductors due to its metallic bonding. Our unconventional strategy diverges from the conventional design principles used in hydrogen-dominated covalent high-temperature superconductors. Using anisotropic Migdal-Eliashberg equations, we demonstrate that the stable (Mg4)2H1 compound is a typical phonon-mediated superconductor, characterized by strong electron-phonon coupling and an excellent Tc of 37 K under ambient conditions, comparable to that of MgB2. Our findings not only present a new pathway for exploring high-temperature superconductors but also provide valuable insights for future experimental synthesis endeavors.

Erratum: Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition: Erratum.

[This corrects the article DOI: 10.7150/thno.22788.].

A Machine Learning Model Based on Genetic and Traditional Cardiovascular Risk Factors to Predict Premature Coronary Artery Disease.

BACKGROUND: Premature coronary artery disease (PCAD) has a poor prognosis and a high mortality and disability rate. Accurate prediction of the risk of PCAD is very important for the prevention and early diagnosis of this disease. Machine learning (ML) has been proven a reliable method used for disease diagnosis and for building risk prediction models based on complex factors. The aim of the present study was to develop an accurate prediction model of PCAD risk that allows early intervention. METHODS: We performed retrospective analysis of single nucleotide polymorphisms (SNPs) and traditional cardiovascular risk factors (TCRFs) for 131 PCAD patients and 187 controls. The data was used to construct classifiers for the prediction of PCAD risk with the machine learning (ML) algorithms LogisticRegression (LRC), RandomForestClassifier (RFC) and GradientBoostingClassifier (GBC) in scikit-learn. Three quarters of the participants were randomly grouped into a training dataset and the rest into a test dataset. The performance of classifiers was evaluated using area under the receiver operating characteristic curve (AUC), sensitivity and concordance index. R packages were used to construct nomograms. RESULTS: Three optimized feature combinations (FCs) were identified: RS-DT-FC1 (rs2259816, rs1378577, rs10757274, rs4961, smoking, hyperlipidemia, glucose, triglycerides), RS-DT-FC2 (rs1378577, rs10757274, smoking, diabetes, hyperlipidemia, glucose, triglycerides) and RS-DT-FC3 (rs1169313, rs5082, rs9340799, rs10757274, rs1152002, smoking, hyperlipidemia, high-density lipoprotein cholesterol). These were able to build the classifiers with an AUC >0.90 and sensitivity >0.90. The nomograms built with RS-DT-FC1, RS-DT-FC2 and RS-DT-FC3 had a concordance index of 0.94, 0.94 and 0.90, respectively, when validated with the test dataset, and 0.79, 0.82 and 0.79 when validated with the training dataset. Manual prediction of the test data with the three nomograms resulted in an AUC of 0.89, 0.92 and 0.83, respectively, and a sensitivity of 0.92, 0.96 and 0.86, respectively. CONCLUSIONS: The selection of suitable features determines the performance of ML models. RS-DT-FC2 may be a suitable FC for building a high-performance prediction model of PCAD with good sensitivity and accuracy. The nomograms allow practical scoring and interpretation of each predictor and may be useful for clinicians in determining the risk of PCAD.

2D Graphene-Like Pb-Free Perovskite Semiconductor CsSb(Br1-xIx)4 with Quasi-linear Electronic Dispersion and Direct Bandgap Close to Germanium.

Thanks to its ultrahigh carrier mobility (∼104-105 cm2 V-1 s-1), graphene shows tremendous application potential in nanoelectronics, but it cannot be applied in effective field-effect transistors (FETs) because of its intrinsic gapless band structure. Thus, introducing a bandgap for graphene is a prerequisite to realize an FET for logic applications. Herein, through first-principles GW calculations, we have predicted a series of novel Dion-Jacobson (DJ) phase halide perovskite semiconductors CsSb(Br1-xIx)4 (x = 0, 0.5, 1) with the quasi-linear (graphene-like) band edge dispersion; as the best one of which, CsSbBr2I2 exhibits a direct bandgap (0.52 eV) as well as a quasi-linear electronic dispersion, yielding an ultrasmall carrier effective mass (0.03 m0) and a high estimated carrier mobility (5 × 103 cm2 V-1 s-1). This gives a significant reference to the exploration of semiconductors with excellent transport properties. Moreover, our calculations also implicate that the DJ perovskites CsSb(Br1-xIx)4 (x = 0, 0.25, 0.5, 0.75, 1) show soft and anisotropic mechanical characteristics as well as excellent electronic, transport, and optical properties, which demonstrate their multifunctional application in infrared optoelectronic, high-speed electronics, and photovoltaics.

High hydrogen production in the InSe/MoSi2N4 van der Waals heterostructure for overall water splitting.

Very recently, the septuple-atomic-layer MoSi2N4 has been successfully synthesized by a chemical vapor deposition method. However, pristine MoSi2N4 exhibits some shortcomings, including poor visible-light harvesting capability and a low separation rate of photo-excited electron-hole pairs, when it is applied in water splitting to produce hydrogen. Fortunately, we find that MoSi2N4 can be considered as a good co-catalyst to be stacked with InSe forming an efficient heterostructure photocatalyst. Here, the electronic and photocatalytic properties of the two-dimensional (2D) InSe/MoSi2N4 heterostructure have been systematically investigated by density functional theory for the first time. The results demonstrate that 2D InSe/MoSi2N4 has a type-II band alignment with a favourable direct bandgap of 1.61 eV and exhibits suitable band edge positions for overall water splitting. Particularly, 2D InSe/MoSi2N4 has high electron mobility (104 cm2 V-1 s-1) and shows a noticeable optical absorption coefficient (105 cm-1) in the visible-light region of the solar spectrum. These brilliant properties declare that 2D InSe/MoSi2N4 is a potential photocatalyst for overall water splitting.

Layered Dion-Jacobson-Type Chalcogenide Perovskite CsLaM2X7 (M = Ta/Nb; X = S/Se) with a Narrow Band Gap of ∼1 eV as a Promising Rear Cell for All-Perovskite Tandem Solar Cells.

Perovskite-perovskite tandem solar cells have bright prospects to improve the power conversion efficiency (PCE) beyond the Shockley-Queisser (SQ) limit of single-junction solar cells. The star lead-based halide perovskites are well-recognized as suitable candidates for the front cell, thanks to their suitable band gap (∼1.8 eV), strong optical absorption, and high certified PCE. However, the toxicity of lead for the front cell and the lack of a narrow band gap (∼1.1 eV) for the rear cell seriously restrict the development of the two-junction tandem cell. To break through this bottleneck, a novel Dion-Jacobson (DJ)-type (n = 2) chalcogenide perovskite CsLaM2X7 (M = Ta, Nb; X = S, Se) has been found based on the powerful first-principles and advanced many-body perturbation GW calculations. Their excellent electronic, transport, and optical properties can be summarized as follows. (1) They are stable and environmentally friendly lead-free materials. (2) The direct band gap of CsLaTa2Se7 (0.96-1.10 eV) is much smaller than those of lead-based halide perovskites and very suitable for the rear cell in the two-junction tandem cell. (3) The carrier mobility in CsLaTa2Se7 reaches 1.6 × 103 cm2 V-1 s-1 at room temperature. (4) The absorption coefficients (3-5 × 105 cm-1) are 1 order higher than that of Si (104 cm-1). (5) The estimated PCEs of the Cs2Sb2Br8-CsLaTa2Se7 tandem cell (33.3%) and the concentrator solar cell (35.8% in 100 suns) are higher than those of the best recorded GaAs-Si tandem cell (32.8%) and the perovskite-perovskite tandem solar cell (24.8%). These energetic results strongly demonstrate that the novel lead-free chalcogenide perovskites CsLaM2X7 are good candidates for the rear cell of tandem cells.

Puerarin ameliorated pressure overload-induced cardiac hypertrophy in ovariectomized rats through activation of the PPARα/PGC-1 pathway.

Estrogen deficiency induces cardiac dysfunction and increases the risk of cardiovascular disease in postmenopausal women and in those who underwent bilateral oophorectomy. Previous evidence suggests that puerarin, a phytoestrogen, exerts beneficial effects on cardiac function in patients with cardiac hypertrophy. In this study, we investigated whether puerarin could prevent cardiac hypertrophy and remodeling in ovariectomized, aortic-banded rats. Female SD rats subjected to bilateral ovariectomy (OVX) plus abdominal aortic constriction (AAC). The rats were treated with puerarin (50 mg·kg-1 ·d-1, ip) for 8 weeks. Then echocardiography was assessed, and the rats were sacrificed, their heart tissues were extracted and allocated for further experiments. We showed that puerarin administration significantly attenuated cardiac hypertrophy and remodeling in AAC-treated OVX rats, which could be attributed to activation of PPARα/PPARγ coactivator-1 (PGC-1) pathway. Puerarin administration significantly increased the expression of estrogen-related receptor α, nuclear respiratory factor 1, and mitochondrial transcription factor A in hearts. Moreover, puerarin administration regulated the expression of metabolic genes in AAC-treated OVX rats. Hypertrophic changes could be induced in neonatal rat cardiomyocytes (NRCM) in vitro by treatment with angiotensin II (Ang II, 1 µM), which was attenuated by co-treatemnt with puerarin (100 µM). We further showed that puerarin decreased Ang II-induced accumulation of non-esterified fatty acids (NEFAs) and deletion of ATP, attenuated the Ang II-induced dissipation of the mitochondrial membrane potential, and improved the mitochondrial dysfunction in NRCM. Furthermore, addition of PPARα antagonist GW6471 (10 µM) partially abolished the anti-hypertrophic effects and metabolic effects of puerarin in NRCM. In conclusion, puerarin prevents cardiac hypertrophy in AAC-treated OVX rats through activation of PPARα/PGC-1 pathway and regulation of energy metabolism remodeling. This may provide a new approach to prevent the development of heart failure in postmenopausal women.

Aspirin-omitted dual antithrombotic therapy in non-valvular atrial fibrillation patients presenting with acute coronary syndrome or undergoing percutaneous coronary intervention: results of a meta-analysis.

AIMS: To investigate the effects of aspirin-omitted dual antithrombotic therapy (DAT) on myocardial infarction and stent thrombosis in non-valvular atrial fibrillation (NVAF) patients presenting with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: A systematic review and meta-analysis were performed using PubMed to search for randomized clinical trials comparing DAT with triple antithrombotic therapy (TAT) in this setting. Three trials involving 8845 patients were included (4802 and 4043 patients treated with DAT and TAT, respectively). There were no significant differences in all-cause death and stroke between the aspirin-omitted DAT group and TAT group. Otherwise, the incidence of myocardial infarction was significantly higher with aspirin-omitted DAT vs. TAT [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.02-1.63; P = 0.04; I2 = 0%]. Similarly, the incidence of stent thrombosis increased in patients treated with aspirin-omitted DAT vs. TAT (OR: 1.61, 95% CI: 1.02-2.53; P = 0.04; I2 = 0%). The occurrence of major bleeding and clinically relevant non-major bleeding events, as defined by the International Society on Thrombosis and Haemostasis, was significantly lower with aspirin-omitted DAT vs. TAT (OR: 0.61, 95% CI: 0.48-0.78; P = 0.02; I2 = 76%). Similar results were found according to the International Society on Thrombosis and Haemostasis major bleeding, Thrombolysis in Myocardial Infarction major or minor bleeding, and Thrombolysis in Myocardial Infarction major bleeding scales. CONCLUSION: Aspirin-omitted DAT reduces the occurrence of bleeding episodes, with a higher rate of myocardial infarction and stent thrombosis in NVAF patients presenting with ACS or undergoing PCI.

MEF2A Is the Trigger of Resveratrol Exerting Protection on Vascular Endothelial Cell.

Both resveratrol and myocyte enhancer factor 2A (MEF2A) may protect vascular endothelial cell (VEC) through activating the expression of SIRT1. However, the relationship between resveratrol and MEF2A is unclear. We aimed to investigate the deeper mechanism of resveratrol in protecting vascular endothelial cells and whether MEF2A plays a key role in the protective function of resveratrol. Human umbilical vein endothelial cell (HUVEC) was used for in vitro study, and small interfere RNA was used for silencing MEF2A. Silencing MEF2A in the vascular endothelium (VE) of ApoE-/- mice was performed by tail injection with adeno associated virus expressing si-mef2a-shRNA. The results showed that treatment of HUVEC with resveratrol significantly up-regulated MEF2A, and prevented H2O2-induced but not siRNA-induced down-regulation of MEF2A. Under various experimental conditions, the expression of SIRT1 changed with the level of MEF2A. Resveratrol could rescue from cell apoptosis, reduction of cell proliferation and viability induced by H2O2, but could not prevent against that caused by silencing MEF2A with siRNA. Silencing MEF2A in VE of apoE-/- mice decreased the expression of SIRT1, increased the plasma LDL-c, and abrogated the function of resveratrol on reducing triglyceride. Impaired integrity of VE and aggravated atherosclerotic lesion were observed in MEF2A silenced mice through immunofluorescence and oil red O staining, respectively. In conclusion, resveratrol enhances MEF2A expression, and the upregulation of MEF2A is required for the endothelial protective benefits of resveratrol in vitro via activating SIRT1. Our work has also explored the in vivo relevance of this signaling pathway in experimental models of atherosclerosis and lipid dysregulation, setting the stage for more comprehensive phenotyping in vivo and further defining the molecular mechanisms.

Homotopic Commissural Projections of Area Prostriata in Rat and Mouse: Comparison With Presubiculum and Parasubiculum.

Area prostriata in primates has recently been found to play important roles in rapid detection and processing of peripheral visual, especially fast-moving visual information. The prostriata in rodents was not discovered until recently and its connectivity is largely unknown. As a part of our efforts to reveal brain-wide connections of the prostriata in rat and mouse, this study focuses on its commissural projections in order to understand the mechanisms underlying interhemispheric integration of information, especially from peripheral visual field. Using anterograde, retrograde and Cre-dependent tracing techniques, we find a unique commissural connection pattern of the prostriata: its layers 2-3 in both hemispheres form strong homotopic commissural connections with few heterotopic projections to bilateral medial entorhinal cortex. This projection pattern is in sharp contrast to that of the presubiculum and parasubiculum, two neighbor regions of the prostriata. The latter two structures project very strongly to bilateral medial entorhinal cortex and to their contralateral counterparts. Our results also suggest the prostriata is a distinct anatomical structure from the presubiculum and parasubiculum and probably plays differential roles in interhemispheric integration and the balancing of spatial information between two hemispheres.

Deubiquitinase Inhibitor b-AP15 Attenuated LPS-Induced Inflammation via Inhibiting ERK1/2, JNK, and NF-Kappa B.

b-AP15 is a deubiquitinase (DUB) inhibitor of 19S proteasomes, which in turn targets ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14). Nuclear factor kappa B (NF-κB) is closely linked to cellular response in macrophages when the organism is in the state of microbial infection, and it acts as a vital part in the mechanism of inflammatory reaction. However, the molecular mechanism by which DUB inhibitors, especially b-AP15, regulates inflammation remains poorly understood. This study aimed to investigate the relationship between b-AP15 and inflammation. The results showed that b-AP15 treatment significantly reduced the amounts of inflammatory indicators, such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in lipopolysaccharide (LPS)-stimulated THP-1 and macrophages. Meanwhile, similar results were obtained from in vivo experiments. In addition, b-AP15 also significantly improved the survival rate of sepsis mouse via high-density LPS mediation. Furthermore, b-AP15 also inhibited the ERK1/2 and JNK phosphorylation, increased IκBα levels, and inhibited NF-κB p65 by removing them from the cytoplasm into the nucleus. All these findings suggested that b-AP15 has anti-inflammatory action and acts as a potential neoteric target drug for treating microbial infection.

αß-Dehydrocurvularin isolated from the fungus Aspergillus welwitschiae effectively inhibited the behaviour and development of the root-knot nematode Meloidogyne graminicola in rice roots.

BACKGROUND: The root-knot nematode Meloidogyne graminicola has become a serious threat to rice production as a result of the cultivation changes from transplanting to direct seeding. The nematicidal activity of Aspergillus welwitschiae have been investigated in vitro, and the disease control efficacy of the active compound has been evaluated under greenhouse and field conditions. RESULTS: The active compound αß-dehydrocurvularin (αß-DC), isolated by nematicidal assay-directed fractionation, showed significant nematicidal activity against M. graminicola, with a median lethal concentration (LC50) value of 122.2 µg mL- 1. αß-DC effectively decreased the attraction of rice roots to nematodes and the infection of nematodes and also suppressed the development of nematodes under greenhouse conditions. Moreover, αß-DC efficiently reduced the root gall index under field conditions. CONCLUSIONS: To our knowledge, this is the first report to describe the nematicidal activity of αß-DC against M. graminicola. The results obtained under greenhouse and field conditions provide a basis for developing commercial formulations from αß-DC to control M. graminicola in the future.

Improved Properties of Metallocene Polyethylene/Poly(ethylene terephthalate) Blends Processed by an Innovative Eccentric Rotor Extruder.

* Correspondence: pmhzhe@scut [...].

A self-doping conductive polymer hydrogel that can restore electrical impulse propagation at myocardial infarct to prevent cardiac arrhythmia and preserve ventricular function.

Following myocardial infarction (MI), necrotic cardiomyocytes (CMs) are replaced by fibroblasts and collagen tissue, causing abnormal electrical signal propagation, desynchronizing cardiac contraction, resulting in cardiac arrhythmia. In this work, a conductive polymer, poly-3-amino-4-methoxybenzoic acid (PAMB), is synthesized and grafted onto non-conductive gelatin. The as-synthesized PAMB-G copolymer is self-doped in physiological pH environments, making it an electrically active material in biological tissues. This copolymer is cross-linked by carbodiimide to form an injectable conductive hydrogel (PAMB-G hydrogel). The un-grafted gelatin hydrogel is prepared in a similar manner as a control. Both test hydrogels not only provide an optimal matrix for CM adhesion and growth but also maintain CM morphology and functional proteins. The conductivity of PAMB-G hydrogel is ca. 12 times higher than that of gelatin hydrogel. Microelectrode array analyses reveal that a heart placed on the PAMB-G hydrogel has a higher field potential amplitude than that placed on the gelatin hydrogel and can pass current from one heart to excite another heart at a distance. The injection of PAMB-G hydrogel into the scar zone following an MI in a rat heart improves electrical impulse propagation over that in a heart that has been treated with gelatin hydrogel, and synchronizes heart contraction, leading to preservation of the ventricular function and reduction of cardiac arrhythmia, demonstrating its potential for use in treating MI.

Long-term repopulation of aged bone marrow stem cells using young Sca-1 cells promotes aged heart rejuvenation.

Reduced quantity and quality of stem cells in aged individuals hinders cardiac repair and regeneration after injury. We used young bone marrow (BM) stem cell antigen 1 (Sca-1) cells to reconstitute aged BM and rejuvenate the aged heart, and examined the underlying molecular mechanisms. BM Sca-1+ or Sca-1- cells from young (2-3 months) or aged (18-19 months) GFP transgenic mice were transplanted into lethally irradiated aged mice to generate 4 groups of chimeras: young Sca-1+ , young Sca-1- , old Sca-1+ , and old Sca-1- . Four months later, expression of rejuvenation-related genes (Bmi1, Cbx8, PNUTS, Sirt1, Sirt2, Sirt6) and proteins (CDK2, CDK4) was increased along with telomerase activity and telomerase-related protein (DNA-PKcs, TRF-2) expression, whereas expression of senescence-related genes (p16INK4a , P19ARF , p27Kip1 ) and proteins (p16INK4a , p27Kip1 ) was decreased in Sca-1+ chimeric hearts, especially in the young group. Host cardiac endothelial cells (GFP- CD31+ ) but not cardiomyocytes were the primary cell type rejuvenated by young Sca-1+ cells as shown by improved proliferation, migration, and tubular formation abilities. C-X-C chemokine CXCL12 was the factor most highly expressed in homed donor BM (GFP+ ) cells isolated from young Sca-1+ chimeric hearts. Protein expression of Cxcr4, phospho-Akt, and phospho-FoxO3a in endothelial cells derived from the aged chimeric heart was increased, especially in the young Sca-1+ group. Reconstitution of aged BM with young Sca-1+ cells resulted in effective homing of functional stem cells in the aged heart. These young, regenerative stem cells promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells.

Myocyte enhancer factor 2A delays vascular endothelial cell senescence by activating the PI3K/p-Akt/SIRT1 pathway.

Myocyte enhancer factor 2A (MEF2A) dysfunction is closely related to the occurrence of senile diseases such as cardiocerebrovascular diseases, but the underlying molecular mechanism is unclear. Here, we studied the effects of MEF2A on the senescent phenotype of vascular endothelial cells (VEC) and downstream signaling pathway, and the association between plasma MEF2A levels and coronary artery disease (CAD). Results showed that MEF2A silencing promoted cell senescence and down-regulated PI3K/p-AKT/Sirtuin 1 (SIRT1) expression. MEF2A overexpression delayed cell senescence and up-regulated PI3K/p-AKT/SIRT1. Hydrogen peroxide (H2O2) treatment induced cellular senescence and down-regulated the expression of MEF2A and PI3K/p-AKT/SIRT1. MEF2A overexpression inhibited cellular senescence and the down-regulation of PI3K/p-AKT/SIRT1 induced by H2O2. Further study revealed that MEF2A directly up-regulated the expression of PIK3CA and PIK3CG through MEF2 binding sites in the promoter region. Pearson correlation and logistic regression analysis showed that the plasma level of MEF2A was negatively correlated with CAD, and with age in the controls. These results suggested that MEF2A can directly up-regulate PI3K gene expression, and one of the molecular mechanisms of delaying effect of MEF2A on VEC cell senescence was SIRT1-expression activation through the PI3K/p-Akt pathway. Moreover, the plasma MEF2A levels may be a potential biomarker for CAD risk prediction.

MEF2A alters the proliferation, inflammation-related gene expression profiles and its silencing induces cellular senescence in human coronary endothelial cells.

BACKGROUND: Myocyte enhancer factor 2A (MEF2A) plays an important role in cell proliferation, differentiation and survival. Functional deletion or mutation in MEF2A predisposes individuals to cardiovascular disease mainly caused by vascular endothelial dysfunction. However, the effect of the inhibition of MEF2A expression on human coronary artery endothelial cells (HCAECs) is unclear. In this study, expression of MEF2A was inhibited by specific small interference RNA (siRNA), and changes in mRNA profiles in response to MEF2A knockdown were analyzed using an Agilent human mRNA array. RESULTS: Silencing of MEF2A in HCAECs accelerated cell senescence and suppressed cell proliferation. Microarray analysis identified 962 differentially expressed genes (DEGs) between the MEF2A knockdown group and the negative control group. Annotation clustering analysis showed that the DEGs were preferentially enriched in gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to proliferation, development, survival, and inflammation. Furthermore, 61 of the 578 downregulated DEGs have at least one potential MEF2A binding site in the proximal promoter and were mostly enriched in the GO terms "reproduction" and "cardiovascular." The protein-protein interaction network analyzed for the downregulated DEGs and the DEGs in the GO terms "cardiovascular" and "aging" revealed that PIK3CG, IL1B, IL8, and PRKCB were included in hot nodes, and the regulation of the longevity-associated gene PIK3CG by MEF2A has been verified at the protein level, suggesting that PIK3CG might play a key role in MEF2A knockdown induced HCAEC senescence. CONCLUSIONS: MEF2A knockdown accelerates HCAEC senescence, and the underlying molecular mechanism may be involved in down-regulation of the genes related with cell proliferation, development, inflammation and survival, in which PIK3CG may play a key role.