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N6-methyladenosine (m6A) is widely recognized as the predominant form of RNA modification in higher organisms, with the capability to finely regulate RNA metabolism, thereby influencing a series of crucial physiological and pathological processes. These processes include regulation of gene expression, cell proliferation, invasion and metastasis, cell cycle control, programmed cell death, interactions within the tumour microenvironment, energy metabolism, and immune regulation. With advancing research into the mechanisms of RNA methylation, the pivotal role of m6A modification in the pathophysiology of reproductive system tumours, particularly cervical cancer, has been progressively unveiled. This discovery has opened new research avenues and presented significant potential for the diagnosis, prognostic evaluation, and treatment of diseases. This review delves deeply into the biological functions of m6A modification and its mechanisms of action in the onset and progression of cervical cancer. Furthermore, it explores the prospects of m6A modification in the precision diagnosis and treatment of cervical cancer, aiming to provide new perspectives and a theoretical basis for innovative and advanced treatment strategies for cervical cancer.

BackgroundThis study examines the relationship between Hb, RDW and their association and both short-term and long-term mortality in patients with acute aortic dissection (AAD), aiming to establish combined effect between Hb and RDW as a potential prognostic biomarker for AAD outcomes.MethodsWe extracted clinical data from the Medical Information Mart for Intensive Care (MIMIC) databases for this analysis. Using adjusted Cox regression and Kaplan-Meier survival curve analyses, we assessed the relationship between Hb, RDW and their association at admission and mortality at multiple post-discharge intervals (30 days, 90 days, 1 year, and 5 years) among patients with AAD. Additionally, subgroup analyses and receiver operating characteristic (ROC) curve analyses were conducted to evaluate the predictive accuracy of Hb, RDW and their association for mortality in this patient population.ResultsHigh RDW combined with low Hb (RDW ≥ 13.60 and Hb

Background Prior prediction models used for screening preeclampsia (PE) in twin pregnancies were found to be inadequate. In singleton pregnancies, various maternal biomarkers have been shown to be correlated with negative pregnancy outcomes. However, the impact of these biomarkers in twin pregnancies remained uncertain. Methods A retrospective cohort study was carried out on 736 twin pregnancies at a tertiary hospital in Hangzhou, China. Multivariable logistic models were employed to examine the association between levels of serological markers and the likelihood of adverse pregnancy outcomes. The final logistic model was formulated as a user-friendly nomogram. The primary outcome assessed was the occurrence of PE. Results were presented as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Results The prevalence of PE in the study was 10.3%. When comparing women diagnosed with PE to those without, it was evident that the former group experienced a significantly higher risk of unfavorable maternal and neonatal outcomes. A multivariable logistic regression analysis revealed notable associations between various factors including maternal age, parity, gestational weight gain, a family history of hypertension, as well as levels of cholesterol, albumin, and creatinine and the risk of developing PE, with a significance level of P < 0.05. The concordance index for the constructed nomogram was determined to be 0.792 (95% CI: [0.739–0.844]). Furthermore, an increment of 1 * 1012/L in red blood cell (RBC) count was associated with more than a two-fold increase in the odds of experiencing adverse maternal outcomes (OR 2.247, 95% CI: [1.229–4.107]). However, no significant correlations were identified between any of the examined variables and neonatal outcomes. Conclusions In this study, we developed a user-friendly predictive model that achieves notable detection rates by incorporating maternal serum biomarker levels alongside maternal characteristics and medical history. Our findings indicate that the probability of adverse maternal outcomes increases with elevated levels of RBCs. Obstetricians should consider intensifying surveillance for these women in clinical practice.

Background: Traditional working procedures requires a lot of clinical processes and processing time. Methods: The orthodontic metal appliances were made by applying oral scanners, digital images, computer-aided design and computer-aided manufacturing (CAD-CAM) printers. Results: The computer digital technology simplified the manufacturing process for dental appliances and shorten the duration for clinical operation and technical processing. Conclusions: The technique described in this paper can guarantee the accuracy of orthodontic appliances and bring revolution the field. Clinical significance: The CAD-CAM technology provides a fully digital workflow for manufacturing metal orthodontic appliances, which saves a considerable amount of labor and material costs, and significantly reduces heavy metal pollution in the working environment of dental technicians.

Abstract As a new concrete crack patching technology, microbial self-healing slurries offer favourable characteristics including non-pollution, ecological sustainability and good compatibility with concrete. In this paper, a nano-sio2-modified microbial bacteria liquid, combined with sodium alginate and polyvinyl alcohol, was used to prepare a nano-modified microbial self-healing slurry. This slurry was used to coat concrete under negative pressure in order to verify its restoration effect, and the micromorphology of the resulting microbial mineralization products was observed. The results revealed that patching the concrete using the nano-modified microbial slurry significantly improved its permeability, and increased its carbonization resistance by three times in comparison with the control group. Through a combination of Scanning electron microscopy (SEM) and X-ray diffraction (XRD) observation, it was determined that the microbial mineralization reaction products were mainly calcite crystals, which, integrated with the nano-sio2, sodium alginate and polyvinyl alcohol at the microscopic level, filled the internal pores of concrete, thus improving its durability.

The airborne intelligent hydraulic system is an effective way to solve the ineffective power consumption and temperature rise of an aircraft hydraulic system. An intelligent pump that can work in a variety of modes according to the change of flight conditions is an inevitable requirement for the realization of airborne intelligent hydraulic system, and it is also the development trend of aviation pumps in the future. In this paper, key technologies for aviation intelligent pumps are reviewed. This paper briefly describes its development process and summarizes the research on aviation intelligent pumps from the aspects of the system scheme, working mode, structure form, and control strategy. Finally, the conclusions and trends of the research status of intelligent pumps are given, which can provide a reference for subsequent research on further improving the performance of aviation intelligent pumps.

Abstract Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies.

Heat-resistant materials, applied to manufacturing high-temperature components, are pivotal for raising the steam temperature parameters of advanced ultra-supercritical power plants. Alumina-forming austenitic (AFA) stainless steel, a promising candidate material applied to manufacture high-temperature components in fossil-fired ultra-supercritical steam plants, has been concerned by researchers. In this review, the recent progress of AFA steels with considerations of precipitations, high-temperature creep properties, and oxidation resistance was summarized. The stability of precipitates at high temperatures was discussed along with their competitive precipitation behavior. Furthermore, the factors which affect high-temperature creep properties of AFA steels were discussed. Simultaneously, the oxidation behaviors of AFA steels in diverse settings were evaluated.

Oxide dispersion strengthened tungsten (ODS-W) alloy was prepared by chemical method, conventional sintering and hot-rolling method, which breaks through the research bottleneck of preparing tungsten alloys with excellent comprehensive mechanical properties. More specifically, it can exhibit ultrahigh strength and superior toughness when tested at 200°C. In addition, the nil ductility temperature (NDT) can also dramatically decrease to 100–150°C. The bimodal structure formed by the uneven distribution of yttria and the lamellar structure formed by hot rolling in this ODS-W alloy provide a feasible way to develop other engineering materials with ultra-high strength and ductility.

Objective: Sialic acid is a terminal monosaccharide of glycans in glycoproteins and glycolipids, and its derivation from glucose is regulated by the rate-limiting enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). Although the glycans on key endogenous hepatic proteins governing glucose metabolism are sialylated, how sialic acid synthesis and sialylation in the liver influence glucose homeostasis is unknown. Studies were designed to fill this knowledge gap. Methods: To decrease the production of sialic acid and sialylation in hepatocytes, a hepatocyte-specific GNE knockdown mouse model was generated, and systemic glucose metabolism, hepatic insulin signaling and glucagon signaling were evaluated in vivo or in primary hepatocytes. Peripheral insulin sensitivity was also assessed. Furthermore, the mechanisms by which sialylation in the liver influences hepatic insulin signaling and glucagon signaling and peripheral insulin sensitivity were identified. Results: Liver GNE deletion in mice caused an impairment of insulin suppression of hepatic glucose production. This was due to a decrease in the sialylation of hepatic insulin receptors (IR) and a decline in IR abundance due to exaggerated degradation through the Eph receptor B4. Hepatic GNE deficiency also caused a blunting of hepatic glucagon receptor (GCGR) function which was related to a decline in its sialylation and affinity for glucagon. An accompanying upregulation of hepatic FGF21 production caused an enhancement of skeletal muscle glucose disposal that led to an overall increase in glucose tolerance and insulin sensitivity. Conclusion: These collective observations reveal that hepatic sialic acid synthesis and sialylation modulate glucose homeostasis in both the liver and skeletal muscle. By interrogating how hepatic sialic acid synthesis influences glucose control mechanisms in the liver, a new metabolic cycle has been identified in which a key constituent of glycans generated from glucose modulates the systemic control of its precursor.

The strengthening of micro-sized phases and nano-precipitates to the Al–Mg2Si–Cu(–Ni) alloys was studied at 25 °C and 350 °C. In the Al–15%Mg2Si–5%Cu alloy, lots of nano-precipitates (θ″, θ′, σ and Q′ precursor) are formed with the dissolution of Cu-rich phases after heat treatment. The high number density of nano-precipitates contributes to the high strength of alloy (357 MPa) at 25 °C. For the Al–15%Mg2Si–5%Cu–1%Ni alloy, more micro-sized Cu/Ni-rich phases are retained and fewer nano-precipitates (θ″, θ′, σ and S phase) are formed after heat treatment. The existence of high-temperature stable micro-sized Cu/Ni-rich phases produce an enhanced strengthening effect (109 MPa) to the alloy at 350 °C, compared to that of Al–15%Mg2Si–5%Cu alloy (82 MPa).

Abstract Objectives This study aimed to determine the prevalence and independent risk factors of SDB, and explore its association with malocclusion among 6–11-year-old children in Shanghai, China. Methods A cluster sampling procedure was adopted in this cross-sectional study. Pediatric Sleep Questionnaire (PSQ) was applied to evaluate the presence of SDB. Questionnaires including PSQ, medical history, family history, and daily habits/environment were completed by parents under instruction, and oral examinations were implemented by well-trained orthodontists. Multivariable logistic regression was applied to identify independent risk factors for SDB. Chi-square tests and Spearman's Rank Correlation were used to estimate the relationship between SDB and malocclusion. Results A total of 3433 subjects (1788 males and 1645 females) were included in the study. The SDB prevalence was about 17.7%. Allergic rhinitis (OR 1.39, 95% CI 1.09–1.79), adenotonsillar hypertrophy (OR 2.39, 95% CI 1.82–3.19), paternal snoring (OR 1.97, 95% CI 1.53–2.53), and maternal snoring (OR 1.35, 95% CI 1.05–1.73) were independent risk factors for SDB. The SDB prevalence was higher in children with retrusive mandibles than in proper or excessive ones. No significant difference was observed in the correlation between SDB and lateral facial profile, mandible plane angle, constricted dental arch form, the severity of anterior overjet and overbite, degree of crowding and spacing, and the presence of crossbite and open bite. Conclusions The prevalence of SDB in primary students in the Chinese urban population was high and highly associated with mandible retrusion. The independent risk factors included Allergic rhinitis, adenotonsillar hypertrophy, paternal snoring, and maternal snoring. More efforts should be made to enhance public education about SDB and related dental-maxillofacial abnormalities.

The aviation intelligent pump system is an effective solution to aircraft hydraulic systems’ inefficient power consumption and temperature increase. A self-supplied aviation intelligent pump (SAIP) has a high power-to-weight ratio and compact structure, making it the optimal choice for an intelligent pump. To analyze the output characteristics of a novel aviation intelligent pump, it is crucial to establish an accurate mathematical model that describes its dynamic characteristics. This can be achieved by analyzing the working principle and exploring the influence of critical parameters. The paper introduces the composition and working principle of a self-supplied electro-hydraulic servo variable displacement pump. It then establishes a mathematical model of the whole pump, with a detailed analysis and modeling of the critical variable mechanism and the swash plate assembly’s load moment. A simulation model was created to examine the impact of crucial structural parameters, such as the offset spring’s stiffness and control piston’s diameter, on the output characteristics of the intelligent pump. An experimental platform was also constructed, and the experimental results confirm the accuracy of the SAIP model presented in this paper. The investigation of the output characteristics fully reveals the dynamic performance of the SAIP. This provides the basis for the subsequent design of high-performance flow and pressure control strategies and aids in researching intelligent aircraft hydraulic systems.

The lack of filler materials is the crucial issue that restricts the wide application of the advanced heat-resistance steel G115 in ultra-super critical (USC) power plants. In the present work, a new welding filler material with alloying system of 8.8Cr-2.7W-2.8Co was successfully developed to fabricate the G115 steel welded joint by the gas tungsten arc welding (GTAW), and post weld heat treatments (PWHT) involving different temperatures were proposed to tailor the mechanical properties. The filler material exhibited perfect compatibility with the base material (BM), and the manufactured welded joint displayed satisfactory appearance and defect-free weld section. After PWHT, full martensitic lath structure decorated with high density of dislocations and dispersed strengthening precipitates M23C6 and MX formed in the weld metal (WM), which was similar with that of the BM. Meanwhile, the welded joint was sensitive to the PWHT temperature, and an optimal combination of hardness (∼240 HV), tensile strength (∼679.9 MPa at 25 °C, and ∼344.6 MPa at 650 °C), elongation (∼13.1% at 25 °C, and ∼15.6% at 650 °C) and impact toughness (∼73.8 J/cm2) could be achieved after PWHT at 760 °C for 240 min. Comprehensively considering the obtained results, the designed filler material was feasible and reliable for matching the novel G115 steel, and satisfied the service demands of the G115 steel pipes in USC power plants.

Over the past several years, high-βN experiments have been carried out on HL-2A. The high-βN is realized using double transport barriers (DTBs) with hybrid scenarios. A stationary high-βN (>2) scenario was obtained by pure neutral-beam injection (NBI) heating. Transient high performance was also achieved, corresponding to βN≥3, ne/neG∼0.6, H98∼1.5, fbs∼30%, q95∼4.0, and G∼0.4. The high-βN scenario was successfully modeled using integrated simulation codes, that is, the one modeling framework for integrated tasks (OMFIT). In high-βN plasmas, magnetohydrodynamic (MHD) instabilities are abundant, including low-frequency global MHD oscillation with n = 1, high-frequency coherent mode (HCM) at the edge, and neoclassical tearing mode (NTM) and Alfvénic modes in the core. In some high-βN discharges, it is observed that the NTMs with m/n=3/2 limit the growth of the plasma energy and decrease βN. The low-n global MHD oscillation is consistent with the coupling of destabilized internal (m/n = 1/1) and external (m/n = 3/1 or 4/1) modes, and plays a crucial role in triggering the onset of ELMs. Achieving high-βN on HL-2A suggests that core-edge interplay is key to the plasma confinement enhancement mechanism. Experiments to enhance βN will contribute to future plasma operation, such as international thermonuclear experimental reactor .

Abstract Introduction The basis of orthodontic tooth movement (OTM) is the reconstruction of periodontal tissue under stress. Increasing the speed of OTM has always been the focus of attention. Objectives Periodontal ligament stem cells (PDLSCs) are direct effector cells of mechanical force, but the mechanism by which PDLSCs sense mechanical stimuli is unclear. Methods Human PDLSCs (hPDLSCs) were analyzed in the presence or absence of force loading with the Flexcell loading system in vitro. Then, periodontal tissues were analyzed after mechanical stimulation in vivo. In addition, cells in a confined microenvironment were analyzed to observe changes in the cytoskeleton and migration. Finally, TRPC6−/− mice were used to further verify the effect of TRPC6. After force application, the OTM distance, bone marrow density (BMD), TRPC6 and COL1 expression, and TRAP staining were evaluated in periodontal tissues. Results RNA sequencing (RNA-seq) and western blot analyses revealed that TRPC6 was important during mechanical force application to hPDLSCs. Appropriate mechanical force application also induced TRPC6 activation in the OTM model and the confined microenvironment. Under a slightly confined microenvironment, treatment with the TRPC6 inhibitor SKF96365 and TRPC6 knockout decreased the migration speed of hPDLSCs and mouse bone marrow mesenchymal stem cells (mBMSCs). In addition, TRPC6−/− mice showed lower OTM distances and reduced osteogenic and osteoclastic differentiation. Conclusion In summary, TRPC6 activation in PDLSCs mediated by appropriate mechanical force application contributes to periodontal tissue reconstruction. Graphical abstract PDLSCs modulate periodontal tissue remodeling under appropriate mechanical stimulation through TRPC6; however, under excessive stress, alveolar bone and tooth roots are readily absorbed. Under this condition, environmental factors play a leading role, and the regulatory effect of TRPC6 is not obvious.

In this paper, a Fe, Cr-rich multiphase Ni3Al-based alloy is joined through transient liquid phase bonding (TLP) technique. Different from typical γ+γ′ dual phase Ni3Al-based alloys, the joint can be divided into three distinct zones: isothermal solidification zone (ISZ), gamma prime zone (GPZ) and diffusion affected zone (DAZ). Interestingly, the massive fine grains with γ+γ′ dual phase are observed inside the ISZ, and the GPZ consists of blocky γ′ phase. The precipitation of Cr-rich borides in DAZ provides an advantageous compositional condition for the local coarsening of γ′ phase. In addition, hardness value of the bonded samples fluctuates from the centerline to the BM and reaches the peak at the DAZ. The bonded specimens share equivalent room-temperature tensile strength and elongation to failure with the parent metal after the weld thermal cycle. Moreover, the fracture path propagates along the base metal (BM), which indicates excellent tensile properties of the joint.

Abstract Background Orthodontic treatment is commonly more time-consuming in adults than in teenagers, especially when it comes to the maxillary en-masse retraction, which may take 9 months or even longer. As to solve this concern, orthodontists have been striving to seek new methods for shortening orthodontic treatment time. Piezocision, as a popular alternative treatment, has been widely used in different types of tooth movement. However, its effect on en-masse retraction of maxillary anterior teeth remains unclear. This randomized controlled trial intends to figure out the role piezocision plays in accelerating en-masse retraction. Methods This protocol is designed for a prospective, single-center, assessor-blinded and parallel-group randomized controlled trial. Twenty adult patients aged from 18 to 40 whose orthodontic treatment required bilateral maxillary first premolars extraction will be randomly assigned to the piezocision group and the control group at a ratio of 1:1. The piezocision group will undergo en-masse retraction immediately after the piezo surgery, while the control group will start en-masse retraction directly. Both groups will be followed up every 2 weeks to maintain the retraction force until the end of space closure. The space closing time is set as the primary endpoint. Meanwhile, the secondary endpoints include the change of root length, labial and palatal alveolar bone thickness, vertical bone height, probing depth of maxillary anterior teeth, cephalometric measurements, visual analogue scale, and postoperative satisfaction questionnaire. Discussion This study will attempt to provide more convincing evidence to verify whether piezocision will shorten the time of en-masse retraction or not. Distinguished with previous studies, our study has made some innovations in orthodontic procedure and primary outcome measurement, aiming to clarify the efficacy and safety of piezocision-assisted en-masse retraction in Chinese population. Trial registration Chinese Clinical Trial Registry ChiCTR 1900024297 . Registered on 5 July 2019

In order to find out the deformation behavior and mechanical properties of 42CrMo steel under warm upsetting conditions, the Gleeble-3500 thermal simulation testing machine was used to carry out a warm upsetting physical simulation experiment on 42CrMo steel. By controlling deformation temperature, strain rate, and constant temperature deformation pass, the microstructure evolution rule under different warm upsetting conditions was analyzed, and its hardness value was measured. Then, the simulation experiment is carried out based on the Deform-3D finite element platform. The results show that, with the increase in deformation temperature, 42CrMo steel has a temperature rise softening effect, which significantly reduces the peak value of rheological stress. At 650 °C, the maximum peak value of rheological stress is only 45.3% of that of cold upsetting deformation at room temperature, and the stress-strain curve tends to be gentle at the plastic deformation stage, which is the most suitable temperature for warm upsetting deformation. The maximum peak flow stress of 42CrMo steel increases with the increase in strain rate, but the number of deformation channels has little influence on the stress-strain curve. The warm, upsetting deformation can refine the internal grain structure significantly, and the grain refinement mechanism is mechanical crushing. When the temperature is slightly higher, the broken grain will recover, and the grain size will grow. During the process of warm upsetting, the strain rate has a great influence on the microhardness of the sample. The deformation pass has little influence on the hardness, and the hardness increases slightly with the increase in the deformation pass. Through the Deform-3D simulation, the correlation coefficient R and the average absolute relative error (AARE) between the simulation value and the experimental value were calculated, and the correlation coefficient R-value was 0.9948, and the average absolute relative error (AARE) was 2.05%, indicating that the simulation can accurately reflect the relationship between displacement and applied load.

The Langmuir probe observed an increase in density and floating potential fluctuations after the sawtooth crash at the edge of HL-2A neutral beam injection heated plasma. This process initiates fluctuating-induced radial inward particle transport once the plasma enters a period with strong sawtooth crash. The inward transport comprises broad-band fluctuations with varying scales, which occur uniquely in the immediate aftermath of the sawtooth crash-driven outflow, signifying a transient phenomenon confined to that specific interval. These results demonstrate that the sawtooth crash can significantly impact edge turbulence by modifying electrostatic fluctuations. This modification changes the direction of electric fluctuation-induced particle transport, thereby reducing the influence of the intense sawtooth crash-driven outflow. Furthermore, the observations support the existence of a damping mechanism for the outflow during the formation of inward flux after the sawtooth crash, which may be associated with the recovery process of sawtooth cycle.

The effect of solution temperature on the aging hardening behavior of Al-15%Mg2Si(-1%Cu) alloys was studied by characterizing the precipitation behaviors of nano-precipitates. After the solution temperature rises from 520 °C to 550 °C, more solute atoms are available for precipitation, and the formation activation energies of precipitates (β'' and S) decrease. So the formation of β''/β′ in Al-15%Mg2Si alloy and S in Al-15%Mg2Si-1%Cu alloy is accelerated at a solution temperature of 550 °C, which enhances the hardness and ultimate tensile strength (UTS) of the two alloys.

Abstract. Objective:. Long-term diabetes can result in ventricular hypertrophic remodeling, tissue fibrosis, myocardial metabolic defection, and eventually, heart failure. Silent information regulator 6 (SIRT6) exerts beneficial effects against cardiovascular diseases. This study is aimed to investigate whether the direct regulation of myocardial SIRT6 signaling affects cardiac performance in the case of diabetes. Meanwhile, we sought to explore the underlying mechanisms. Methods:. Sprague Dawley (SD) rats were used in this experiment. Briefly, type 2 diabetic animal model was generated by streptozotocin administration along with feeding a high-fat diet. The SD rats were randomly assigned to non-diabetic group, diabetic group, diabetic injected with empty adenoviral vectors group and diabetic injected with adenoviral vectors expressing SIRT6 group (n = 10, respectively). The animals were kept for another 4 weeks before sacrifice. Cardiac performance was evaluated by echocardiography. Myocardial fibrosis was determined by Masson's trichrome staining. Myocardial SIRT6 signaling and fibrosis related molecules were measured by western blotting. Results:. The diabetic myocardium exhibited markedly enhanced TGFβ1-Smad2/3-induced myocardial fibrosis and reduced SIRT6 and AMP-activated protein kinase (AMPK) signaling. After 4 weeks of SIRT6 adenoviral vector infection, myocardial tissues exhibited markedly enhanced SIRT6 and AMPK signaling. Additionally, myocardial fibrosis and TGFβ1-Smad2/3 signaling were both attenuated in the diabetic injected with adenoviral vectors expressing SIRT6 group. Conclusions:. SIRT6-AMPK signaling suppressed the progression of tissue fibrosis in diabetes mellitus rats by inhibiting TGFβ1 and its downstream effector Smad2/3. SIRT6 might serve as an alternative therapeutic target for diabetes-related cardiovascular diseases.

The potential coexistence of Alzheimer's disease (AD) and atrial fibrillation (AF) is increasingly common as aging-related diseases. However, little is known about mechanisms responsible for atrial remodeling in AD pathogenesis. α7 nicotinic acetylcholine receptors (α7nAChR) has been shown to have profound effects on mitochondrial oxidative stress in both organ diseases. Here, we investigate the role of α7nAChR in mediating the effects of amyloid-β (Aβ) in cultured mouse atrial cardiomyocytes (HL-1 cells) and AD model mice (APP/PS1). In vitro, apoptosis, oxidative stress and mitochondrial dysfunction induced by Aβ long-term (72h) in HL-1 cells were prevented by α-Bungarotoxin(α-BTX), an antagonist of α7nAChR. This cardioprotective effect was due to reinstating Ca2+ mishandling by decreasing the activation of CaMKII and MAPK signaling pathway, especially the oxidation of CaMKII (oxi-CaMKII). In vivo studies demonstrated that targeting knockdown of α7nAChR in cardiomyocytes could ameliorate AF progression in late-stage (12 months) APP/PS1 mice. Moreover, α7nAChR deficiency in cardiomyocytes attenuated APP/PS1-mutant induced atrial remodeling characterized by reducing fibrosis, atrial dilation, conduction dysfunction, and inflammatory mediator activities via suppressing oxi-CaMKII/MAPK/AP-1. Taken together, our findings suggest that diminished α7nAChR could rescue Aβ-induced atrial remodeling through oxi-CaMKII/MAPK/AP-1-mediated mitochondrial oxidative stress in atrial cells and AD mice.

AimsIncreasing evidence suggests that metformin can affect bone metabolism beyond its hypoglycemic effects in diabetic patients. However, the effects of metformin on fracture risk in type 2 diabetes mellitus (T2DM) patients remain unclear. A systematic review and meta-analysis were performed in this study to evaluate the association between metformin application and fracture risk in T2DM patients based on previous studies published until June 2021.MethodsA systematic search was performed to collect publications on metformin application in T2DM patients based on PubMed, Embase, Cochran, and Web of Science databases. Meta-analysis was performed by using a random-effects model to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). Subgroup analyses based on cohort/case-control and ethnicity and sensitivity analyses were also performed.ResultsEleven studies were included in the meta-analysis. Results demonstrated metformin use was not significantly associated with a decreased risk of fracture (RR, 0.91; 95% CI, 0.81–1.02; I2 = 96.8%). Moreover, metformin use also demonstrated similar results in subgroup analyses of seven cohort studies and four case-control studies, respectively (RR, 0.90; 95% CI, 0.76–1.07; I2 = 98.0%; RR, 0.96; 96% CI, 0.89–1.03; I2 = 53.7%). Sensitivity analysis revealed that there was no publication bias.ConclusionThere was no significant correlation between fracture risk and metformin application in T2DM patients. Due to a limited number of existing studies, further research is needed to make a definite conclusion for clinical consensus.

BackgroundAtrial fibrillation (AF) is the most frequent arrythmia managed in clinical practice. Several mechanisms have been proposed to contribute to the occurrence and persistence of AF, in which oxidative stress plays a non-negligible role. The endocannabinoid system (ECS) is involved in a variety physiological and pathological processes. Cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) are expressed in the heart, and studies have shown that activating CB2R has a protective effect on the myocardium. However, the role of CB2R in AF is unknown.Materials and methodsAngiotensin II (Ang II)-infused mice were treated with the CB2R agonist AM1241 intraperitoneally for 21 days. Atrial structural remodeling, AF inducibility, electrical transmission, oxidative stress and fibrosis were measured in mice.ResultsThe susceptibility to AF and the level of oxidative stress were increased significantly in Ang II-infused mice. In addition, nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), NOX4, and oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) were highly expressed. More importantly, treatment with AM1241 activated CB2R, resulting in a protective effect.ConclusionThe present study demonstrates that pharmacological activation of CB2R exerts a protective effect against AF via a potential NOX/CaMKII mechanism. CB2R is a potential therapeutic target for AF.

Sialylation is a dynamically regulated modification, which commonly occurs at the terminal of glycan chains in glycoproteins and glycolipids in eukaryotic cells. Sialylation plays a key role in a wide array of biological processes through the regulation of protein–protein interactions, intracellular localization, vesicular trafficking, and signal transduction. A majority of the proteins involved in lipoprotein metabolism and atherogenesis, such as apolipoproteins and lipoprotein receptors, are sialylated in their glycan structures. Earlier studies in humans and in preclinical models found a positive correlation between low sialylation of lipoproteins and atherosclerosis. More recent works using loss- and gain-of-function approaches in mice have revealed molecular and cellular mechanisms by which protein sialylation modulates causally the process of atherosclerosis. The purpose of this concise review is to summarize these findings in mouse models and to provide mechanistic insights into lipoprotein sialylation and atherosclerosis.

Aggregation and coarsening of the second-phase oxide particles at grain boundaries have been a bottleneck for improving mechanical properties of oxide-dispersion-strengthened (ODS) alloys. Here the authors employ core-shell nanopowder precursors to achieve uniform dispersion of oxides in ODS alloys.

Two oxide dispersion strengthened (ODS) steels with compositions of 9Cr-ODS (9Cr-ODS) and 9Cr-3Al-ODS (9Cr-ODS-Al) were fabricated by hot isostatic pressing (HIP). The microstructures and precipitates of the ODS samples were characterized by scanning electron microscopy (SEM), electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM). The results showed that the addition of Al could reduce the precipitation of coarse M23C6 and optimized the size of carbides in ODS steels. Furthermore, it was found that the mean size of nanoparticles in 9Cr-ODS-Al is larger than that in 9Cr-ODS due to the formation of large-size Y–Al–O nanoparticles with Al addition. The tensile test results indicated that the addition of Al slightly decreased the strength of ODS steels, but substantially increased the ductility.

The modeling of austenite grain growth of 25Cr2Ni4MoV steel for super-large nuclear-power rotors was investigated during the common heating process including the continuous heating and isothermal heating process. Based on the isothermal grain growth model considering the steady-state grain size and the rule of additivity, a new grain growth model during the continuous heating process was established. The comparison between experimental and predicted results indicates the model has good predictability. To describe the anisotropic and isotropic grain growth during the different isothermal heating stages of the super-large nuclear-power rotor, a cellular automaton model considering anisotropic grain boundary energy for grain growth of 25Cr2Ni4MoV steel was developed. It is found that the anisotropic grain boundary energy mainly exists in the early isothermal heating stage at lower temperatures, and the normal grain growth occurs under anisotropic grain boundary energy conditions. When the temperature is not less than 1273 K and the cellular automaton step is not less than 15, the normal grain growth containing only isotropic grain boundary energy occurs. The analysis of the morphology, energy variance, topology and growth kinetics further indicates that normal grain growth of 25Cr2Ni4MoV steel can be simulated fairly well by the present CA model.

In this paper, the creep deformation behavior, microstructure evolution, and damage mechanism of Super304H oxide dispersion strengthened (ODS) steel have been systematically investigated at 650 °C. The creep behavior of the ODS steel could be understood by virtue of a dislocation creep deformation mechanism. Interrupted creep experiments under 100 MPa were conducted to further study the microstructure evolution during long-term creep deformation. The grains began to refine at the initial stage, and some M23C6 phases were observed at grain boundaries, which enhanced the microhardness during the first creep stage. Along with creep, both Y2O3 and Cu-rich precipitates exhibited good coherence with the matrix. The Y2O3 precipitates showed better thermal stability than the Cu-rich phase. During the second creep stage, some cavities emerged around the M23C6 phase and at grain boundaries. The cavities gradually developed into significant cracks, causing the steel to fracture. The creep damage due to cavity growth could be determined according to the creep damage tolerance factor value.

Effects of Y2W3O12 particle inclusions and content on damping capacity of Al–12Si composites have been investigated. The Y2W3O12, which is a kind of negative thermal expansion material, can generate high local strain in the composites. Thermal expansion testing shows that the coefficient of thermal expansion (CTE) of Y2W3O12 has obvious changes between 100 and 200 °C The Y2W3O12/Al–12Si composites show damping peaks and display higher damping capacities than the pure Al–12Si alloy. The damping capacities of composites strongly depends on the content of Y2W3O12 inclusions. A thermal strain damping model is also established. Based on the model analysis results, there is a significant contribution of thermal strain to the damping capacity in the composites; the change in CTE of Y2W3O12 could cause the generation of damping peaks. Moreover, dislocation damping and interfacial damping are also main damping mechanisms in the investigated composites.

Abstract Background Pediatric obstructive sleep apnea/hypopnea syndrome (OSAHS) is a multifactorial syndrome caused by many risk factors, such as craniofacial anomalies, adenotonsillar hypertrophy, obesity, and airway inflammation. Although new treatment patterns have recently been proposed, treatment methods for children remain particularly challenging and controversial. This randomized controlled trial was designed to investigate the efficacy of adenotonsillectomy and/or orthodontic treatment for children who have mild OSAHS with mandibular retrognathia. Methods A sample of 352 children with mild OSAHS and mandibular retrognathia, who are aged between 7 and 10 years, will be enrolled in the study. They will be randomized into four groups: the drug treatment group, the surgical treatment group, the orthodontic treatment group, or the surgery and postoperative orthodontic group. After randomization the children will receive treatments within 4 weeks. Outcome assessment will take place at the following points: (1) baseline, (2) 7 months after the treatment starting point, (3) 12 months after the treatment starting point, and (4) 24 months after the treatment starting point. The primary endpoint of the trial is the mean change in obstructive apnea/hypopnea index. Other endpoints will consist of the lowest oxygen saturation, apnea index, and hypopnea index assessed by polysomnography, subjective symptoms (assessed by the OSA-20 questionnaire), cephalometric measurements, and morphologic analysis of the upper airway. Discussion The results of this study will provide valuable evidence for the merits and long-term efficacy of different treatment approaches and contribute to facilitating the multidisciplinary treatment of pediatric OSAHS. Trial registration ClinicalTrials.gov : NCT03451318. Registered on 2 March 2018 (last update posted 19 April 2018).

Introduction Orthodontic treatment and adenotonsillectomy (AT) are both conventional treatments for paediatric obstructive sleep apnoea (OSA). Each approach has distinct treatment advantages; however, there is currently a lack of solid evidence to support their efficacy comparison. We hypothesise that the objective effect of orthodontic treatment is not inferior to AT in children with moderate OSA and mandibular retrognathia, but orthodontic treatment has the advantage of promoting dentofacial growth.Methods and analysis This is a randomised, open-label, parallel-group, active controlled trial that will study the efficacy of orthodontic treatment versus AT in children with moderate OSA accompanied by tonsillar adenoid hypertrophy and mandibular retrognathia. A total of 98 patients will be enrolled and randomised in a 2:1 ratio to either orthodontic treatment or AT group. Participants will be recruited at Shanghai Stomatological Hospital, Shanghai Children’s Hospital of Shanghai Jiaotong University and Children’s Hospital of Fudan University, which are all located in Shanghai, China. The primary endpoint is the per cent change in the obstructive apnoea–hypopnoea index from baseline (month 0) to the primary endpoint (month 7), and the mean reduction in A point, nasion and B point angle on cephalometric measurements by lateral X-ray films. Important secondary efficacy endpoints include sleep duration with oxygen saturation below 90% according to polysomnography and subjective symptoms (assessed by the OSA-20 questionnaire), etc. Safety endpoints will also be evaluated.Ethics and dissemination The study was approved by the ethics committees of Shanghai Stomatological Hospital (approval no. (2021)002), Shanghai Children’s Hospital of Shanghai Jiaotong University (approval no. 2021R046-F01) and Children’s Hospital of Fudan University (approval no. (2021)136). Before enrolment, a qualified clinical research assistant will obtain written informed consent from both the participants and their guardians after full explanation of this study. The results will be presented at national or international conferences and published in peer-reviewed journals.Trial registration number ChiCTR2000037288.

Myocardial infarction (MI) is regarded as a serious ischemic heart disease on a global level. The current study set out to explore the mechanism of the Notch signaling pathway in the regulation of fibrosis remodeling after the occurrence of MI. First, experimental mice were infected with recombination signal binding protein J (RBP-J) shRNA and empty adenovirus vector, followed by the establishment of MI mouse models and detection of cardiac function. After 4 weeks of MI, mice in the sh-RBP-J group were found to exhibit significantly improved cardiac function relative to the sh-NC group. Moreover, knockdown of RBP-J brought about decreased infarct area, promoted cardiac macrophages M2 polarization, reduced cardiac fibrosis, and further decreased transcription and protein expressions of inflammatory factors and fibrosis-related factors. Furthermore, downregulation of cylindromatosis (CYLD) using si-CYLD reversed the results that knockdown of RBP-J inhibited fibrogenesis and the release of inflammatory factors. Altogether, our findings indicated that the blockade of Notch signaling promotes M2 polarization of cardiac macrophages and improves cardiac function by inhibiting the imbalance of fibrotic remodeling after MI.

Aim. Printing parameters have been studied extensively to improve printing performance, while resins have been studied to a lesser extent. Therefore, we explore the impact of value in the Munsell color system on the mechanical properties and accuracy of printed products. Materials and Methods. Resins having different values were prepared by mixing transparent resin and color pastes. We used plate models for mechanical measurement, crown-and bridge models for accuracy measurement, and disc models for color measurement. Results. The Group E resin, which had the lowest value, had the minimum ultimate flexural strength (61.199 MPa) and a relatively low elastic modulus (19.015 MPa). Excluding the d index, no significant difference in accuracy was observed. In terms of the d index of trueness, the result of the Group E resin was significantly low. The relative errors of trueness were less than 0.0727 μm. The relative errors of precision were less than 0.0093 μm. Conclusion. The value of a resin affects the mechanical properties and accuracy of printed products. It is better to secure flexural strength by using a lower-value resin. High-value resins have relatively low accuracies.

Several sets of energetic particle diagnostics, including a set of neutron flux monitoring systems, a solid-state neutral particle analyzer and a fast ion loss probe (FILP), have been used to investigate the energetic ion losses induced by the long-lived saturated internal mode (LLM) in the HL-2A tokamak. Clear experimental evidence for different levels of energetic ion losses induced by LLM, sawtooth and minor disruption has been observed. A numerical calculation for the evolution of neutron emissions was carried out with the FBURN code, and it shows that the neutron emission drop rate linearly increases with the LLM amplitude and no threshold perturbation amplitude exists, illustrating that the loss mechanism for LLM induced energetic ion loss is dominantly convective. In addition, measurement results of the FILP demonstrate that LLM tends to expel energetic ions with relatively low energy ( $E \lt 27\,$ keV) and high pitch angle ( $\theta\gt60^{\circ}$ ), and can suppress the prompt loss of energetic ions with high energy and low pitch angle to a certain degree. Furthermore, the physical process for LLM induced energetic ion loss can be explained by orbit calculations, which show that LLM induced lost energetic ions will transport from center to peripheral region first, and then get lost out of plasma. The experimental observations are successfully reproduced by calculations using the ORBIT code combined with both the NUBEAM code and the MARS-K code. The paper clearly describes the whole physical process of LLM induced energetic ion loss for the first time in the HL-2A tokamak.

Obstructive sleep apnea (OSA) is a common syndrome that features a complex etiology and set of mechanisms. Here we summarized the molecular pathogenesis of OSA, especially the prospective mechanism of upper? airway dilator fatigue and the current breakthroughs. Additionally, we also introduced the molecular mechanism of OSA in terms of related studies on the main signaling pathways and epigenetics alterations, such as microRNA, long non-coding RNA, and DNA methylation. We also reviewed small molecular compounds, which are potential targets for gene regulations in the future, that are involved in the regulation of OSA. This review will be beneficial to point the way for OSA research within the next decade.

A new cellular automaton (CA) model of abnormal grain growth (AGG) that considers anisotropic grain boundary energies was developed in this paper. The anisotropic grain boundary energy was expressed based on two types of grains, which correspond to two components of different crystallographic orientation in textured materials. The CA model was established by assigning different grain boundary energies and grain-growth-driven mechanisms to four types of grain boundaries formed by two types of grains. The grain boundaries formed by different kinds of grains adopted the lowest energy principle, while the grain boundaries formed by the same kind of grains adopted the curvature-driven mechanism. The morphology calculated by the CA model shows the characteristics of AGG. Then, the Johnson–Mehl–Avrami (JMA) model was fitted to predict the growth kinetics. By analyzing the fitting results, the JMA model is capable of predicting the growth kinetics of AGG. The Avrami exponent p decreases from about 1.5 to 1 with the initial number of Type II grains increasing. The investigation of the Hillert model and grain size distribution further indicates that the microstructure evolution is consistent with AGG. Therefore, the analysis of morphology and kinetics indicates that AGG can be fairly well-simulated by the present CA model.

In order to explore water distribution in sprinkler irrigation systems under dynamic water pressure, an irrigation test was conducted in a sprinkler irrigation system equipped with the Hunter MP2000 full circular rotator ray sprinkler under “trapezoidal” waveform pressure to explore the influencing factors such as basic water pressure, dynamic pressure period, and the sprinkler combination spacing. The result shows that the basic pressure, sprinkler combination spacing, and their interaction significantly affected the coefficient of variation, average intensity, and coefficient of uniformity. The normalized comprehensive evaluation indexes were selected as the measurement standards. The optimal factor combination was found to be the basic pressure of 250 kPa, the dynamic pressure period of 200 s, and the sprinkler combination spacing of 6 m, and the corresponding evaluation index values were 0.08, 10.54 mm/h, and 93.20%, respectively. The uniformity coefficient was increased by 6.54% compared with the constant pressure of the same flow rate. Compared with the constant pressure of the same flow rate, the sprinkler area and the average intensity increased by 39.67% and decreased by 8.62% when the basic pressure was 250 kPa and the dynamic pressure period was 200 s. The average uniformity coefficient increased by 11.76% at the combined spacing of 6.0, 6.5, 7.0, 7.5, and 8.0 m. The results provide a theoretical basis for sprinkler irrigation decisions under dynamic pressure.

Cardiac hypertrophy is a key pathophysiological process in the heart in response to stress cues. Although taking place in cardiomyocytes, the hypertrophic response is influenced by other cell types, both within the heart and derived from circulation. In the present study we investigated the myeloid-specific role of megakaryocytic leukemia 1 (MKL1) in cardiac hypertrophy. Following transverse aortic constriction (TAC), myeloid MKL1 conditional knockout (MFCKO) mice exhibit an attenuated phenotype of cardiac hypertrophy compared to the WT mice. In accordance, the MFCKO mice were protected from excessive cardiac inflammation and fibrosis as opposed to the WT mice. Conditioned media collected from macrophages enhanced the pro-hypertrophic response in cardiomyocytes exposed to endothelin in an MKL1-dependent manner. Of interest, expression levels of macrophage derived miR-155, known to promote cardiac hypertrophy, were down-regulated in the MFCKO mice compared to the WT mice. MKL1 depletion or inhibition repressed miR-155 expression in macrophages. Mechanistically, MKL1 interacted with NF-κB to activate miR-155 transcription in macrophages. In conclusion, our data suggest that MKL1 may contribute to pathological hypertrophy via regulating macrophage-derived miR-155 transcription.

FeCrAl oxide dispersion strengthened (ODS) steels are an important kind of cladding material for accident-tolerant fuels. Their radiation resistance and mechanical properties are closely related to the grain size and dispersed second phases. In order to tailor the microstructure and provide an experimental basis for the composition design of FeCrAl ODS steels, in this paper FeCrAl ODS steels with different Zr contents were prepared by mechanical alloying and the subsequent hot isostatic pressing (MA-HIP) process. The effects of Zr content on the grain size distribution and the precipitation of dispersed second phases in FeCrAl ODS steels were investigated by electron back-scattered diffraction (EBSD) and transmission electron microscopy (TEM). The results showed that the grain size decreased first and then increased as the Zr content increased, and that the average grain size achieved the minimum value of 2.092 μm when the Zr content was 0.6 wt.%. The Zr content had a negligible effect on the grain orientation of FeCrAl ODS steels, but the dispersed second phase changed from the Al2Y4O9 phase with monoclinic structure to the Y4Zr3O12 phase with hexagonal structure as the Zr content increased.

Lath martensite transformation in low carbon steel relates to the discontinuity of the transformation rate, which exhibits a series of martensite transformation rate maxima (peaks), especially in low cooling rates. In the present work, we put an emphasis on the influence of annealing twins in parent austenite grains (PAGs) and cooling rates on the discontinuity of lath martensite transformation rate in a low carbon reduced activation ferritic/martensitic (RAFM) steel. Lath martensite microstructure is hierarchical and the lath martensite transformation rate peaks are hierarchical during the cooling process. If the cooling rate was not high enough, the lath martensite transformation rate peaks will be divided into two groups by annealing twins in parent austenite. These transformation rate peaks in the first group were mainly caused by lath martensite transformation in the non–twin zones in the PAGs. Then, the second group mainly consisted of a single transformation rate peak, which was primarily caused by the martensite transformation in the twin zones in the PAGs. In the present work, a new “localized stress field” theory is proposed and successfully used for interpreting the classification mechanism of lath martensite transformation rate peaks and the evolution of these peaks with changing cooling rate.

Sex-determining region Y-related high mobility group-box 10 (SOX10), a member of the SOX family, has recently been highlighted as an essential transcriptional factor involved in developmental biology. Recently, the functionality of SOX 10 has been increasingly revealed by researchers worldwide. It has been reported that SOX10 significantly regulates the proliferation, migration, and apoptosis of tumors and is closely associated with the progression of cancer. In this review, we first introduce the basic background of the SOX family and SOX10 and then discuss the pathophysiological roles of SOX10 in cancer. Besides, we enumerate the application of SOX10 in the pathological diagnosis and therapeutic potential of cancer. Eventually, we summarize the potential directions and perspectives of SOX10 in neoplastic theranostics. The information compiled herein may assist in additional studies and increase the potential of SOX10 as a therapeutic target for cancer.

The matricellular protein SPON2 plays diverse roles in the development of cardiovascular diseases. SPON2 is expressed in endothelial cells, but its transcription regulation in the context of atherogenesis remains incompletely appreciated. Here we report that SPON2 expression was up-regulated by pro-atherogenic stimuli (oxLDL and TNF-α) in vascular endothelia cells. In addition, endothelial SPON2 was elevated in Apoe–/– mice fed on a Western diet compared to the control mice. Induction of SPON2 in endothelial cells by pro-atherogenic stimuli was mediated by BRG1, a chromatin remodeling protein, both in vitro and in vivo. Further analysis revealed that BRG1 interacted with the sequence-specific transcription factor Egr-1 to activate SPON2 transcription. BRG1 contributed to SPON2 trans-activation by modulating chromatin structure surrounding the SPON2 promoter. Functionally, activation of SPON2 transcription by the Egr-1/BRG1 complex provided chemoattractive cues for macrophage trafficking. SPON2 depletion abrogated the ability of BRG1 or Egr-1 to stimulate endothelial derived chemoattractive cue for macrophage migration. On the contrary, recombinant SPON2 rescued endothelial chemo-attractability in the absence of BRG1 or Egr-1. In conclusion, our data have identified a novel transcriptional cascade in endothelial cells that may potentially promote macrophage recruitment and vascular inflammation leading to atherogenesis.

Vascular endothelial cells contribute to the pathogenesis of cardiovascular diseases by producing and disseminating angiocrine factors. Nitric oxide (NO), catalyzed by endothelial NO synthase (eNOS), is one of the prototypical angiocrine factors. eNOS activity is modulated by site-specific phosphorylation. We have previously shown that endothelial-specific knockdown of BRG1 in Apoe–/– mice attenuates the development of atherosclerosis, in which eNOS-dependent NO catalysis plays an antagonizing role. Here we report that attenuation of atherogenesis in mice by BRG1 knockdown was accompanied by partial restoration of NO biosynthesis by 44% in the arteries and a simultaneous up-regulation of eNOS serine 1177 phosphorylation by 59%. Indeed, BRG1 depletion or inhibition ameliorated oxLDL-induced loss of NO bioavailability and eNOS phosphorylation in cultured endothelial cells. Further analysis revealed that BRG1 regulated eNOS phosphorylation and NO synthesis by activating the transcription of protein phosphatase 2A (PP2A) structural subunit a (encoded by PR65A). BRG1 interacted with ETS1, was recruited by ETS1 to the PR65A promoter, and cooperated with ETS1 to activate PR65A transcription. Finally, depletion of ETS1, similar to BRG1, repressed PR65A induction, normalized eNOS phosphorylation, and rescued NO biosynthesis in endothelial cells treated with oxLDL. In conclusion, our data characterize a novel transcriptional cascade that regulates NO bioavailability in vascular endothelial cells.

Endothelial cell derived angiocrine factors contribute to the disruption of homeostasis and the pathogenesis of cardiovascular diseases in response to stress stimuli. In the present study we investigated the role of BRG1, a key component of the chromatin remodeling complex, in the regulation of angiocrine signaling. We report that angiotensin II (Ang II) induced pathological cardiac hypertrophy was attenuated in mice with endothelial-specific ablation of BRG1 (ecKO) compared to the control mice (WT). Mitigation of cardiac hypertrophy as a result of BRG1 deficiency was accompanied by decreased macrophage homing to the hearts. This could be explained by the observation that the ecKO mice exhibited down-regulation of myeloid-related protein 8 (MRP8), a well-established chemokine for macrophages, in vascular endothelial cells compared to the WT mice. Further analysis revealed that BRG1 mediated the activation of MRP8 expression by Ang II treatment in endothelial cells to promote macrophage migration. BRG1 was recruited to the MRP8 promoter by interacting with hypoxia-inducible factor 1 (HIF-1α). Reciprocally, BRG1 facilitated the binding of HIF-1α to the MRP8 promoter by sequentially recruiting histone acetyltransferase p300 and histone demethylase KDM3A. Depletion of either p300 or KDM3A repressed the induction of MRP8 expression by Ang II and ameliorated macrophage migration. In conclusion, our data delineate a novel epigenetic pathway whereby Ang II stimulates MRP8 production and macrophage homing to promote cardiac hypertrophy.