Exercise training decreases lactylation and prevents myocardial ischemia-reperfusion injury by inhibiting YTHDF2.

Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.

Analysis of the chain mediation effect between intergenerational support and mental health of older adults in urban China: a structural equation model.

BACKGROUND: This study aimed investigate the impact of intergenerational support on the mental health of older adults in urban China. It also sought to evaluate the chain mediation effect of attitudes toward younger people and willingness to interact with younger people within a non-familial context between intergenerational support and mental health. METHODS: Data were derived from a community survey that adopted quota sampling in mainland China in 2022 (N = 780). Structural equation modeling was used to analyze the data, and the bootstrap technique was used to test the mediation effect. RESULTS: A significant positive association was found between intergenerational support and the mental health of older adults in urban China (B = 0.852, 95% confidence interval CI [0.157,1.617]). Intergenerational support had a specific indirect effect on mental health through older adults' attitudes toward younger people within a non-familial context (B = 0.665, 95% CI [0.443,1.046]). There was a chain mediation effect (B = 0.126, 95% CI [0.069,0.224]) in relation to attitudes toward younger people and the willingness to interact with younger people between intergenerational support and mental health. Mediation accounted for 44.44% of the total effects in the model. CONCLUSION: These findings help identify modifiable factors that can improve the mental health of older adults. In line with the proposed serial multiple mediation model, this study provides theoretical and practical insights concerning the synergistic effect of intergenerational support at the family level and intergenerational interaction at the community level. Policy and social service implications are also discussed.

Frequency-Domain Robust PCA for Real-Time Monitoring of HIFU Treatment.

High intensity focused ultrasound (HIFU) is a thriving non-invasive technique for thermal ablation of tumors, but significant challenges remain in its real-time monitoring with medical imaging. Ultrasound imaging is one of the main imaging modalities for monitoring HIFU surgery in organs other than the brain, mainly due to its good temporal resolution. However, strong acoustic interference from HIFU irradiation severely obscures the B-mode images and compromises the monitoring. To address this problem, we proposed a frequency-domain robust principal component analysis (FRPCA) method to separate the HIFU interference from the contaminated B-mode images. Ex-vivo and in-vivo experiments were conducted to validate the proposed method based on a clinical HIFU therapy system combined with an ultrasound imaging platform. The performance of the FRPCA method was compared with the conventional notch filtering method. Results demonstrated that the FRPCA method can effectively remove HIFU interference from the B-mode images, which allowed HIFU-induced grayscale changes at the focal region to be recovered. Compared to notch-filtered images, the FRPCA-processed images showed an 8.9% improvement in terms of the structural similarity (SSIM) index to the uncontaminated B-mode images. These findings demonstrate that the FRPCA method presents an effective signal processing framework to remove the strong HIFU acoustic interference, obtains better dynamic visualization in monitoring the HIFU irradiation process, and offers great potential to improve the efficacy and safety of HIFU treatment and other focused ultrasound related applications.

AbDPP: Target-oriented antibody design with pretraining and prior biological structure knowledge.

Antibodies represent a crucial class of complex protein therapeutics and are essential in the treatment of a wide range of human diseases. Traditional antibody discovery methods, such as hybridoma and phage display technologies, suffer from limitations including inefficiency and a restricted exploration of the immense space of potential antibodies. To overcome these limitations, we propose a novel method for generating antibody sequences using deep learning algorithms called AbDPP (target-oriented antibody design with pretraining and prior biological knowledge). AbDPP integrates a pretrained model for antibodies with biological region information, enabling the effective use of vast antibody sequence data and intricate biological system understanding to generate sequences. To target specific antigens, AbDPP incorporates an antibody property evaluation model, which is further optimized based on evaluation results to generate more focused sequences. The efficacy of AbDPP was assessed through multiple experiments, evaluating its ability to generate amino acids, improve neutralization and binding, maintain sequence consistency, and improve sequence diversity. Results demonstrated that AbDPP outperformed other methods in terms of the performance and quality of generated sequences, showcasing its potential to enhance antibody design and screening efficiency. In summary, this study contributes to the field by offering an innovative deep learning-based method for antibody generation, addressing some limitations of traditional approaches, and underscoring the importance of integrating a specific antibody pretrained model and the biological properties of antibodies in generating novel sequences. The code and documentation underlying this article are freely available at https://github.com/zlfyj/AbDPP.

Effects of long-term exposure to ambient fine particulate matter and its specific components on blood pressure and hypertension incidence.

BACKGROUND: Epidemiological evidence on the association of PM2.5 (particulate matter with aerodynamic diameter ≤ 2.5 µm) and its specific components with hypertension and blood pressure is limited. METHODS: We applied information of participants from the World Health Organization's (WHO) Study on Global Ageing and Adult Health (SAGE) to estimate the associations of long-term PM2.5 mass and its chemical components exposure with blood pressure (BP) and hypertension incidence in Chinese adults ≥ 50 years during 2007-2018. Generalized linear mixed model and Cox proportional hazard model were applied to investigate the effects of PM2.5 mass and its chemical components on the incidence of hypertension and BP, respectively. RESULTS: Each interquartile range (IQR = 16.80 µg/m3) increase in the one-year average of PM2.5 mass concentration was associated with a 17 % increase in the risk of hypertension (HR = 1.17, 95 % CI: 1.10, 1.24), and the population attributable fraction (PAF) was 23.44 % (95 % CI: 14.69 %, 31.55 %). Each IQR µg/m3 increase in PM2.5 exposure was also related to increases of systolic blood pressure (SBP) by 2.54 mmHg (95 % CI:1.99, 3.10), and of diastolic blood pressure (DBP) by 1.36 mmHg (95 % CI: 1.04, 1.68). Additionally, the chemical components of SO42-, NO3-, NH4+, OM, and BC were also positively associated with an increased risk of hypertension incidence and elevated blood pressure. CONCLUSIONS: These results indicate that long-term exposure to PM2.5 mass and its specific components may be major drivers of escalation in hypertension diseases.

Suppressing HIFU interference in ultrasound images using 1D U-Net-based neural networks.

Objective.One big challenge with high-intensity focused ultrasound (HIFU) is that the intense acoustic interference generated by HIFU irradiation overwhelms the B-mode monitoring images, compromising monitoring effectiveness. This study aims to overcome this problem using a one-dimensional (1D) deep convolutional neural network.Approach. U-Net-based networks have been proven to be effective in image reconstruction and denoising, and the two-dimensional (2D) U-Net has already been investigated for suppressing HIFU interference in ultrasound monitoring images. In this study, we propose that the one-dimensional (1D) convolution in U-Net-based networks is more suitable for removing HIFU artifacts and can better recover the contaminated B-mode images compared to 2D convolution.Ex vivoandinvivoHIFU experiments were performed on a clinically equivalent ultrasound-guided HIFU platform to collect image data, and the 1D convolution in U-Net, Attention U-Net, U-Net++, and FUS-Net was applied to verify our proposal.Main results.All 1D U-Net-based networks were more effective in suppressing HIFU interference than their 2D counterparts, with over 30% improvement in terms of structural similarity (SSIM) to the uncontaminated B-mode images. Additionally, 1D U-Nets trained usingex vivodatasets demonstrated better generalization performance ininvivoexperiments.Significance.These findings indicate that the utilization of 1D convolution in U-Net-based networks offers great potential in addressing the challenges of monitoring in ultrasound-guided HIFU systems.

Corrigendum to "Engineering exosomes and their application in cardiovascular field: Bibliometric analysis from 2002 to 2022" [Heliyon 9(8) (August 2023) e18809].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e18809.].

Extracellular Vesicles and Vascular Inflammation.

Vascular inflammation is the most common pathological feature in the pathogenesis of human disease. It is a complex immune process involved with many different types of cells including platelet, monocytes, macrophages, endothelial cells, and others. It is widely accepted that both innate and adaptive immune responses are important for the initiation and progression of vascular inflammation. The cell-cell interaction constitutes an important aspect of those immune responses in the vascular inflammation. Extracellular vesicles (EVs) are nanometer-sized double-layer lipid membrane vesicles released from most types of cells. They have been proved to play critical roles in intercellular communication in the occurrence and development of multisystem diseases. With the advancement of basal medical science, the biological roles of EVs in vascular inflammation have been clearer today. In this chapter, we will summarize the advance progress of extracellular vesicles in regulating vascular inflammation and its potential application in the clinical.

Joint Effects of Long-Term Exposure to Ambient Fine Particulate Matter and Ozone on Asthmatic Symptoms: Prospective Cohort Study.

BACKGROUND: The associations of long-term exposure to air pollutants in the presence of asthmatic symptoms remain inconclusive and the joint effects of air pollutants as a mixture are unclear. OBJECTIVE: We aimed to investigate the individual and joint associations of long-term exposure to ambient fine particulate matter (PM2.5) and daily 8-hour maximum ozone concentrations (MDA8 O3) in the presence of asthmatic symptoms in Chinese adults. METHODS: Data were derived from the World Health Organization Study on Global Ageing and Adult Health (WHO SAGE) cohort study among adults aged 50 years or older, which was implemented in 1 municipality and 7 provinces across China during 2007-2018. Annual average MDA8 O3 and PM2.5 at individual residential addresses were estimated by an iterative random forest model and a satellite-based spatiotemporal model, respectively. Participants who were diagnosed with asthma by a doctor or taking asthma-related therapies or experiencing related conditions within the past 12 months were recorded as having asthmatic symptoms. The individual associations of PM2.5 and MDA8 O3 with asthmatic symptoms were estimated by a Cox proportional hazards regression model, and the joint association was estimated by a quantile g-computation model. A series of subgroup analyses was applied to examine the potential modifications of some characteristics. We also calculated the population-attributable fraction (PAF) of asthmatic symptoms attributed to PM2.5 and MDA8 O3. RESULTS: A total of 8490 adults older than 50 years were included, and the average follow-up duration was 6.9 years. During the follow-up periods, 586 (6.9%) participants reported asthmatic symptoms. Individual effect analyses showed that the risk of asthmatic symptoms was positively associated with MDA8 O3 (hazard ratio [HR] 1.12, 95% CI 1.01-1.24, for per quantile) and PM2.5 (HR 1.18, 95% CI 1.05-1.31, for per quantile). Joint effect analyses showed that per equal quantile increment of MDA8 O3 and PM2.5 was associated with an 18% (HR 1.18, 95% CI 1.05-1.33) increase in the risk of asthmatic symptoms, and PM2.5 contributed more (68%) in the joint effects. The individual PAFs of asthmatic symptoms attributable to PM2.5 and MDA8 O3 were 2.86% (95% CI 0.17%-5.50%) and 4.83% (95% CI 1.42%-7.25%), respectively, while the joint PAF of asthmatic symptoms attributable to exposure mixture was 4.32% (95% CI 1.10%-7.46%). The joint associations were greater in participants with obesity, in urban areas, with lower family income, and who used unclean household cooking fuel. CONCLUSIONS: Long-term exposure to PM2.5 and MDA8 O3 may individually and jointly increase the risk of asthmatic symptoms, and the joint effects were smaller than the sum of individual effects. These findings informed the importance of joint associations of long-term exposure to air pollutants with asthma.

Engineering exosomes and their application in cardiovascular field: Bibliometric analysis from 2002 to 2022.

Cardiovascular disease (CVD) is the leading cause of death around the world, warranting an increasing number of studies for its treatment. Among all of its therapeutical strategies, engineered exosomes are attracting growing attention due to their excellent biocompatibility, non-immunogenicity, and favorable plasticity. Despite its increasing popularity, there is yet to be a bibliometric analysis regarding the application of exosomes in CVD treatment. Therefore, the present study assessed the current trends in engineered exosomes in treating CVD by conducting a bibliometric analysis. All associated literatures published between years 2002-2022 were collected, through the Web of Science Core Collection. Our results showed that related studies robustly increased in 2020, followed by a gradual increase from 2020 to 2022, indicating that this field attracted growing attention. Additionally, we described critical network of countries, institutions, authors, top-cited references, and keywords. The present bibliometric study provides systematic observations on engineering exosomes in treating CVD, reveals potential challenges and future direction for additional studies, and may inspire more researchers to commit to investigating treatments for CVD.

Long-Term Exposure to Ambient PM2.5 and Age-Related Cataracts among Chinese Middle-Aged and Older Adults: Evidence from Two National Cohort Studies.

Cataract is one key cause of visual disability and blindness. Ambient particulate matter is more likely to increase cataract risk due to eye continuous exposure to the environment. However, less is known about whether long-term exposure to particulate matter 2.5 (PM2.5) is related to age-related cataracts. We conducted a population-based study among 22,298 adults from two multicenter cohort studies [China Family Panel Studies (CFPS) and Chinese Longitudinal Healthy Longevity Survey (CLHLS)]. The associations between PM2.5 and age-related cataracts were analyzed by Cox proportional hazard regression models, which were also stratified according to demographic characteristics. The restricted cubic spline (RCS) model was used to explore the dose-response relationships between PM2.5 and age-related cataracts. The population attributable fraction (PAF) was calculated to assess the burden of age-related cataracts that can be attributed to PM2.5. In the final analysis, 1897 participants reported age-related cataracts during follow-up. Long-term exposure to PM2.5 was associated with age-related cataracts, with HRs of 1.165 (1.130, 1.201), 1.138 (1.103, 1.173), and 1.091 (1.057, 1.126) for per 10 µg/m3 increase at one-, two-, and three-year before the end of follow-up, respectively. Furthermore, associations between PM2.5 and age-related cataracts were also demonstrated in RCS models. The PAF of age-related cataracts to PM2.5 in the total participants was 24.63%. Our research found that long-term exposure to PM2.5 may increase the risk of age-related cataracts, and age-related cataracts should be considered as an important public health issue due to air pollution.

RNA m6A-Regulated circ-ZNF609 Suppression Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating FTO.

Cardiac death is a major burden for cancer survivors, yet there is currently no effective treatment for doxorubicin (DOX)-induced cardiotoxicity. Here, we report that circ-ZNF609 knockdown knockdown had cardioprotective effects against DOX-induced cardiomyocyte toxicity. Mechanistically, circ-ZNF609 knockdown alleviated DOX-induced cardiotoxicity through attenuating cardiomyocyte apoptosis, reducing reactive oxygen species production, ameliorating mitochondrial nonheme iron overload. circ-ZNF609 inhibition blocked the elevation of RNA N6-methyladenosine (RNA m6A) methylation level in DOX-treated mice hearts, whereas m6A demethylase fat mass and obesity associated (FTO) acted as the downstream factor of circ-ZNF609. Moreover, the stability of circ-ZNF609 was regulated by RNA m6A methylation alteration, and suppression of RNA m6A methylation by methyltransferase like 14 (METTL14) modulated the function of circ-ZNF609. These data suggest that circ-ZNF609 inhibition represents a potential therapy for DOX-induced cardiotoxicity.

Dynamic Event-Driven Finite-Horizon Optimal Consensus Control for Constrained Multiagent Systems.

This article investigates the event-driven finite-horizon optimal consensus control problem for multiagent systems with symmetric or asymmetric input constraints. Initially, in order to overcome the difficulty that the Hamilton-Jacobi-Bellman equation is time-varying in finite-horizon optimal control, a single critic neural network (NN) with time-varying activation function is applied to obtain the approximate optimal control. Meanwhile, for minimizing the terminal error to satisfy the terminal constraint of the value function, an augmented error vector containing the Bellman residual and the terminal error is constructed to update the weight of the NN. Furthermore, an improved learning law is proposed, which relaxes the tricky persistence excitation condition and eliminates the requirement of initial stability control. Moreover, a specific algorithm is designed to update the historical dataset, which can effectively accelerate the convergence rate of network weight. In addition, to improve the utilization rate of the communication resource, an effective dynamic event-triggering mechanism (DETM) composed of dynamic threshold parameters (DTPs) and auxiliary dynamic variables (ADVs) is designed, which is more flexible compared with the ADV-based DETM or DTP-based DETM. Finally, to support the effectiveness of the proposed method and the superiority of the designed DETM, a simulation example is provided.

Diagnosis of acute myocardial infarction using a combination of circulating circular RNA cZNF292 and clinical information based on machine learning.

Circulating circular RNAs (circRNAs) are emerging as novel biomarkers for cardiovascular diseases (CVDs). Machine learning can provide optimal predictions on the diagnosis of diseases. Here we performed a proof-of-concept study to determine if combining circRNAs with an artificial intelligence approach works in diagnosing CVD. We used acute myocardial infarction (AMI) as a model setup to prove the claim. We determined the expression level of five hypoxia-induced circRNAs, including cZNF292, cAFF1, cDENND4C, cTHSD1, and cSRSF4, in the whole blood of coronary angiography positive AMI and negative non-AMI patients. Based on feature selection by using lasso with 10-fold cross validation, prediction model by logistic regression, and ROC curve analysis, we found that cZNF292 combined with clinical information (CM), including age, gender, body mass index, heart rate, and diastolic blood pressure, can predict AMI effectively. In a validation cohort, CM + cZNF292 can separate AMI and non-AMI patients, unstable angina and AMI patients, acute coronary syndromes (ACS), and non-ACS patients. RNA stability study demonstrated that cZNF292 was stable. Knockdown of cZNF292 in endothelial cells or cardiomyocytes showed anti-apoptosis effects in oxygen glucose deprivation/reoxygenation. Thus, we identify circulating cZNF292 as a potential biomarker for AMI and construct a prediction model "CM + cZNF292."

Nanoemulsification of soybean oil using ultrasonic microreactor: Process optimization, scale-up and numbering-up in series.

Ultrasonically-induced nanoemulsions have been widely investigated for the development of functional food, cosmetics, and pharmaceuticals due to ideal droplet sizes (DS), low polydispersity index (PDI), and superior physical stability. However, a series of frequently-used ultrasonic set-ups mainly suffered from a low ultrasonic energy efficiency caused by the large acoustic impedance and energy consumption, subordinately confronted with a low throughput, complicated fabrication with complex structure and weak ultrasonic cavitation. Herein, we employed a typical ultrasonic microreactor (USMR) that ensured the high-efficient energy input and generated intense cavitation behavior for efficient breakage of droplets and continuous production of unified oil-in-water (O/W) nanoemulsions in a single cycle and without any pre-emulsification treatment. The emulsification was optimized by tuning the formula indexes, technological parameters, and numerical analysis using Response Surface Methodology (RSM), followed by a comparison with the emulsification by a traditional ultrasonic probe. The USMR exhibited superior emulsification efficiency and easy scale-up with remarkable uniformity by series mode. In addition, concurrent and uniform nanoemulsions with high throughput could also be achieved by a larger USMR with high ultrasonic power. Based on RSM analysis, uniform DS and PDI of 96.4 nm and 0.195 were observed under the optimal conditions, respectively, well consistent with the predicted values. Impressively, the optimal nanoemulsions have a uniform spherical morphology and exhibited superior stability, which held well in 45 days at 4℃ and 25℃. The results in the present work may provide a typical paradigm for the preparation of functional nanomaterials based on the novel and efficient emulsification tools.

Effect of long-term exposure to PM2.5 on the risk of type 2 diabetes and arthritis in type 2 diabetes patients: Evidence from a national cohort in China.

BACKGROUND: It remains unclear whether type 2 diabetes and the complication of arthritis are causally related to the PM2.5 pollutant. Therefore, we aimed to investigate the associations of long-term PM2.5 exposure with type 2 diabetes and with arthritis in type 2 diabetes patients. MATERIALS AND METHODS: This study used data from the China Health and Retirement Longitudinal Survey (CHARLS) implemented during 2011-2018. The associations were analyzed by Cox proportional hazards regression models, and the population-attributable fraction (PAF) was calculated to assess the burden of type 2 diabetes and arthritis-attributable to PM2.5. RESULTS: A total of 21,075 participants were finally included, with 19,121 analyzed for PM2.5 and type 2 diabetes risk and 12,427 analyzed for PM2.5 and arthritis risk, of which 1,382 with newly-diagnosed type 2 diabetes and 1,328 with arthritis during the follow-up. Overall, each 10 µg/m3 increment in PM2.5 concentration was significantly associated with an increase in the risk of type 2 diabetes (HR = 1.26, 95 %CI1.22 to 1.31), and the PAF of type 2 diabetes attributable to PM2.5 was 13.54 %. In type 2 diabetes patients, each 10 µg/m3 increment in PM2.5 exposure was associated with an increase in arthritis (HR = 1.42, 95 %CI: 1.28 to 1.57), and the association was significantly greater than that (H = 1.23, 95 %CI: 1.19 to 1.28) in adults without type 2 diabetes. The PAFs of arthritis-attributable to PM2.5 in participants with and without type 2 diabetes were 18.54 % and 10.69 %, respectively. CONCLUSION: Long-term exposure to PM2.5 may increase the risk of type 2 diabetes and make type 2 diabetes patients susceptible to arthritis.

LncRNA TUG1 Exacerbates Myocardial Fibrosis in Diabetic Cardiomyopathy by Modulating the microRNA-145a-5p/Cfl2 Axis.

ABSTRACT: Nowadays, there is limited prevention and treatment for myocardial fibrosis in diabetic cardiomyopathy (DCM). Our study aimed to depict the mechanism of the lncRNA TUG1/miR-145a-5p/Cfl2 axis in DCM and to provide a molecular basis for the study of this disease. Male C57BL/6J mice were intraperitoneally injected with streptozotocin to establish DCM mouse models. The expression levels of lncRNA TUG1, miR-145a-5p, and Cfl2 in myocardial tissues of mice were tested by RT-qPCR or Western blot. Cardiac function was assessed by echocardiography. The contents of Ang-II, TNF-α, and IL-1ß were measured using ELISA. The histopathological observation was performed by HE staining and Masson staining. The expression levels of myocardial fibrosis-related genes COL1A1, MMP2, and FN1 were determined by RT-qPCR. In addition, bioinformatics website, RIP assay, pull-down assay, and luciferase activity assay were conducted to verify the relationships of lncRNA TUG1, miR-145a-5p, and Cfl2. In the DCM mouse model, lncRNA TUG1 and Cfl2 expression levels were upregulated and miR-145a-5p expression was downregulated. Downregulation of lncRNA TUG1 improved cardiac function and myocardial fibrosis; decreased COL1A1, MMP2, and FN1 expression levels; as well as TNF-α, IL-1ß, and Ang-II contents in myocardial tissues of DCM mice. Upregulation of miR-145a-5p showed the same trend as downregulation of lncRNA TUG1. In addition, upregulating miR-145a-5p reversed the promotion roles of lncRNA TUG1 on myocardial fibrosis in DCM mice, and upregulating Cfl2 compromised the improvement effect of downregulated lncRNA TUG1 on myocardial fibrosis in DCM mice. Mechanistically, there was a binding site between lncRNA TUG1 and miR-145a-5p, and miR-145a-5p had a targeting relationship with Cfl2. This study highlights that lncRNA TUG1 sponges miR-145a-5p to aggravate myocardial fibrosis in DCM mice by promoting Cfl2.

Influence of Trichosanthes pericarpium extract on improving microcirculation and outcomes of patients with acute myocardial infarction after percutaneous coronary intervention.

Background: Microcirculatory dysfunction is an independent risk factor for a poor prognosis after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI). Trichosanthes pericarpium is a well-known Chinese traditional herb described with the effect of activating blood circulation to dissipate blood stasis and improve blood circulation. However, its effects on microcirculation in patients with AMI after primary PCI remain unknown. This study aimed to investigate the effect of Trichosanthes pericarpium extract (TPE) on improving microcirculation and outcomes in patients with AMI after PCI. Methods: This study included 155 patients with a history of emergency PCI treatment. In this cohort, 31 patients received a course of TPE, defined as intravenous TPE infusion (12 ml TPE dissolved in 250 ml 5% Glucose Injection) once daily for 7 days on the background of standard treatment after PCI; 124 who did not receive TPE were regarded as the control group and received standard treatment after PCI. The corrected thrombolysis in myocardial infarction frame count (CTFC) and index of microcirculatory resistance (IMR) were used to evaluate myocardial microcirculation. Cardiac function was measured by echocardiography during hospitalization and follow-up. Major adverse cardiac events (MACEs) were recorded for prognostic analysis. Results: At the 6-month follow-up, AMI patients who received TPE after primary PCI had significantly lower levels of CTCF (24.27 ± 2.40 vs. 21.88 ± 1.92, P < 0.001) and IMR (20.02 ± 2.20 vs. 17.80 ± 2.11, P < 0.001) than patients in the control group. Left ventricular ejection fraction and left ventricular internal dimension at systolic at 6-month follow-up in the TPE group significantly improved than in the control group (56.6 ± 4.5 vs. 62.1 ± 3.5, P < 0.001; 32.5 ± 1.5 vs. 30.2 ± 1.8, P < 0.001). Kaplan-Meier curve analysis indicated that patients with AMI who received TPE had significantly lower rates of MACEs than the control group at 6-month follow-up (P = 0.042). Conclusion: In the context of standard treatment, Trichosanthes pericarpium further improved coronary microcirculation, increased cardiac function, and reduced short-term MACEs rate. Our data suggest that TPE could be used in combination therapy for patients with AMI after primary PCI.

The dephosphorylation of FADD at S191 induces an excessive expansion of TCRαß+ IELs in the intestinal mucosa.

Intestinal intraepithelial lymphocytes (IELs) play a crucial role in host defence against pathogens in the intestinal mucosa. The development of intestinal IELs is distinct from peripheral T lymphocytes and remains elusive. Fas-associated protein with death domain (FADD) is important for T cell development in the thymus. Here we describe a novel function of FADD in the IEL development. FADD (S191A), a mouse FADD mutant at Ser191 to Ala mimicking constitutively unphosphorylated FADD, promoted a rapid expansion of TCRαß+ IELs, not TCRγδ+ IELs. Mechanism investigation indicated that the dephosphorylation of FADD was required for cell activation mainly in TCRαß+ CD8+ T cells. Consistently, FADD (S191A) as dephosphorylated FADD led to a high NF-κB activation in the TCR-dependent cell expansion. In addition, The FADD (S191A)-induced abnormal IEL populations resulted in the increased incidence and severity of colitis in mice. In summary, FADD signalling is involved in the intestinal IEL development and might be a regulator for intestinal mucosal homeostasis.

Targeting miR-30d reverses pathological cardiac hypertrophy.

BACKGROUND: Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed. METHODS: The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d. FINDINGS: miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes. INTERPRETATION: Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy. FUNDING: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).