Abnormal cardiac fibrosis indicates cardiac dysfunction and poor prognosis in myocardial infarction (MI) patients. Many studies have demonstrated that the ubiquitin proteasome system (UPS) plays a ...significant role in the pathogenesis of fibrosis. Ubiquitin C-terminal hydrolase L1 (UCHL1), a member of the UPS, is related to fibrosis in several heart diseases. However, whether UCHL1 regulates cardiac fibrosis following MI has yet to be determined. In the present study, we found that UCHL1 was dramatically increased in infarct hearts and TGF-β1-stimulated cardiac fibroblasts (CFs). Inhibition of UCHL1 with LDN57444 (LDN) reversed the myocardial fibrosis in post-MI heart and improved cardiac function. Treatment of LDN or UCHL1 siRNA abolished the TGF-β1-induced fibrotic response of CFs. We further identified GRP78 as an interactor of UCHL1 through screening using immunoprecipitation-mass spectrometer. We determined that UCHL1 interacted with glucose-regulated protein of 78 kDa (GRP78) and prompted GRP78 degradation via ubiquitination. Furthermore, we found that GRP78 was upregulated after UCHL1 knockdown and that the GRP78 inhibitor HA15 diminished the antifibrotic function exerted by UCHL1 knockdown in CFs stimulated with TGF-β1. This suggests that UCHL1 regulates cardiac fibrosis post MI through interactions with GRP78. This work identifies that the UCHL1-GRP78 axis is involved in cardiac fibrosis after MI.
The importance of cell pyroptosis in immunity regulation is becoming increasingly obvious, especially in diseases of the cardiovascular system. Nevertheless, it is unknown whether the pyroptosis ...signalling pathway is involved in the immune microenvironment regulation of dilated cardiomyopathy (DCM). Therefore, the purpose of the study was to investigate the influence of pyroptosis on the immune environment in dilated cardiomyopathy. We found that expression of 19 pyrolysis-related genes (PRGs) in DCM samples was altered compared to healthy samples. Subsequently, based on these 12 hub pyrolysis-related genes, we developed a classifier that can distinguish between healthy samples and DCM samples. Among the hub pyrolysis-related genes, RT–PCR analyses demonstrated that five of them exhibited significant differential expression in DCM. Interestingly, we observed that immune characteristics are correlated with pyroptosis: higher expression of GSDMD is positively correlated with infiltrating activated pDCs; GSDMD is negatively correlated with Tregs; CASP1 is positively related to parainflammation; and CASP9 is negatively related to the type II IFN response. In addition, distinct pyroptosis-mediated patterns were identified, and immune characteristics under distinct patterns were revealed: pattern B mediates an active immune response, and pattern A leads to a relatively mild immune response to DCM. We also compared the biological functions between these patterns. Compared with pattern A, pattern B had more abundant pathways, such as the NOTCH signalling pathway and pentose phosphate pathway. In summary, this study proves the important influence of pyrolysis on the immune microenvironment of dilated cardiomyopathy and provides new clues for understanding the pathogenesis of dilated cardiomyopathy.
Summary
With the development of the vehicular ad hoc network, the security and privacy are now becoming vital concerns, especially when the attacker owns more and more resources. In order to address ...these concerns, a dynamic anonymous identity authentication scheme is proposed using Elliptic Curve Discrete Logarithm Problem and blockchain method, which guarantees the security and fast off‐line authentication for vehicle‐to‐infrastructure. Specifically, a dynamic pseudonym key is generated using tamper proof device (TPD) for off‐line authentication and anonymity when a vehicle roams among different roadside units' (RSUs) communication ranges. Even if all RSUs are compromised, vehicle's identity is still privacy. Moreover, two additional design goals are more suitable for the practical environment: (1) the reduced assumption of TPD; (2) certification authority can trace vehicle under the authorization by law.
A dynamic anonymous identity authentication scheme is proposed for vehicular ad hoc network, which is more suitable for the practical situation. The analysis and the simulation show that the proposed scheme not only guarantees the offline update, traceable pseudonyms, and anonymous identity authentication, but also improves the efficiency for key pairs dynamically changement.
Coronavirus disease 2019 (COVID-19) is a recently emerged disease with formidable infectivity and high mortality. Emerging data suggest that diabetes is one of the most prevalent comorbidities in ...patients with COVID-19. Although their causal relationship has not yet been investigated, preexisting diabetes can be considered as a risk factor for the adverse outcomes of COVID-19. Proinflammatory state, attenuation of the innate immune response, possibly increased level of ACE2, along with vascular dysfunction, and prothrombotic state in people with diabetes probably contribute to higher susceptibility for SARS-CoV-2 infection and worsened prognosis. On the other hand, activated inflammation, islet damage induced by virus infection, and treatment with glucocorticoids could, in turn, result in impaired glucose regulation in people with diabetes, thus working as an amplification loop to aggravate the disease. Therefore, glycemic management in people with COVID-19, especially in those with severe illness, is of considerable importance. The insights may help to reduce the fatality in the effort against COVID-19.
Abstract Lateral momentum conservation is typically kept in a non-absorptive rotationally symmetric system through mirror symmetry via Noether’s theorem when illuminated by a homogeneous light wave. ...Therefore, it is still very challenging to break the mirror symmetry and generate a lateral optical force (LOF) in the rotationally symmetric system. Here, we report a general dynamic action in the SO (2) rotationally symmetric system, originating from the polarization-tuned mirror symmetry breaking (MSB) of the light scattering. We demonstrate theoretically and experimentally that MSB can be generally applied to the SO (2) rotationally symmetric system and tuned sinusoidally by polarization orientation, leading to a highly tunable and highly efficient LOF (9.22 pN/mW/μm −2 ) perpendicular to the propagation direction. The proposed MSB mechanism and LOF not only complete the sets of MSB of light-matter interaction and non-conservative force only using a plane wave but also provide extra polarization manipulation freedom.
Abstract
Background
The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic ...targets for DCM.
Methods
We downloaded four datasets from the Gene Expression Omnibus (GEO) database: GSE141910, GSE3585, GSE42955 and GSE79962. Weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed to identify gene panels related to DCM. Meanwhile, the CIBERSORT algorithm was used to estimate the immune cells in DCM tissues. Multiple machine learning approaches were used to screen the hub genes and immune cells. Finally, the diagnostic value of the hub genes was assessed by receiver operating characteristic (ROC) analysis. An experimental mouse model of dilated cardiomyopathy was used to validate the bioinformatics results.
Results
FRZB and EXT1 were identified as hub biomarkers, and the ROC curves suggested an excellent diagnostic ability of the above genes for DCM. In addition, naive B cells were upregulated in DCM tissues, while eosinophils, M2 macrophages, and memory CD4 T cells were downregulated in DCM tissues. The increase in two hub genes and naive B cells was validated in animal experiments.
Conclusion
These results indicated that FRZB and EXT1 could be used as promising biomarkers, and eosinophils, M2 macrophages, resting memory CD4 T cells and naive B cells may also affect the occurrence of DCM.
Abstract It has been reported that some single-nucleotide polymorphisms (SNPs) are associated with the risk of Parkinson's disease (PD), but whether a combination of these SNPs would have a stronger ...association with PD than any individual SNP is unknown. Sixteen SNPs located in the 8 genes and/or loci ( SNCA , LRRK2 , MAPT , GBA , HLA-DR , BST1 , PARK16 , and PARK17 ) were analyzed in a Chinese cohort consisting of 1061 well-characterized PD patients and 1066 control subjects from Central South of Mainland China. We found that Rep1, rs356165, and rs11931074 in SNCA gene; G2385R in LRRK2 gene; rs4698412 in BST1 gene; rs1564282 in PARK17 ; and L444P in GBA gene were associated with PD with adjustment of sex and age ( p < 0.05) in the analysis of 16 variants. PD risk increased when Rep1 and rs11931074, G2385R, rs1564282, rs4698412; rs11931074 and G2385R, rs1564282, rs4698412; G2385R and rs1564282, rs4698412; and rs1564282 and rs4698412 were combined for the association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (odds ratio for carrying 3 variants, 3.494). In summary, we confirmed that Rep1, rs356165, and rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17 , and L444P in GBA gene have an independent and combined significant association with PD. SNPs in these 4 genes have a cumulative effect with PD.
Coxsackievirus B3 (CVB3)-induced myocardial damage always leads to serious heart failure by inducing cardiac injury. NLRP3 inflammasome activation has been identified as a central player in the ...pathogenesis of CVB3-induced viral myocarditis. Therefore, restraining NLRP3 inflammasome activation has been supposed to significantly alleviate the severity of myocardial damage and improve cardiac function. Morroniside (MR), one of the main iridoid glycosides, has the ability to depress the production of reactive oxygen species (ROS) and restrain the expression of caspase-3 and -9. Of importance, ROS and caspase are essential for NLRP3 inflammasome activation in response to CVB3 infection. Therefore, in the present study, MR was selected as a model drug to alleviate CVB3-induced myocardial damage. The results of cardiac function index determination showed that abnormal indexes including mean arterial pressure, heart rate, and left ventricular systolic pressure of myocardial damage rats could be recovered by treating with MR. Such results can be further verified by histopathological evaluation, with the heart tissues of CVB3-infected rats displaying the most amount of H&E and TUNEL positive cells. The underlying mechanism by which MR improves the cardiac function was subsequently investigated. The detection of various gene levels indicated that NLRP3 inflammasome activation was inhibited by MR through down-regulating the expression of pro-inflammatory cytokines: interleukin (IL)-β and IL-18, the pivotal factors that lead to inflammatory responses. More importantly, the related genes, cardiac function indexes, and various myocardial damage markers of normal rats treated with MR did not exhibit any obvious changes compared with the control group, indicating a satisfactory biocompatibility of MR. In summary, MR holds a great potential in the alleviation of CVB3-induced myocardial damage with a negligible cytotoxicity to normal heart tissues.
Coxsackievirus B3 (CVB3)-induced myocardial damage always leads to serious heart failure by inducing cardiac injury.
Hypoxic-ischemic brain injury (HIBI) results in death or long-term neurologic impairment in both adults and children. In this study, we investigated the effects of microRNA-132 (miR-132) ...dysregulation on oxygen-glucose deprivation (OGD)-induced apoptosis in fetal rat hippocampal neurons, in order to reveal the therapeutic potential of miR-132 on HIBI. MiR-132 dysregulation was induced prior to OGD exposure by transfection of primary fetal rat hippocampal neurons with miR-132 mimic or miR-132 inhibitor. The effects of miR-132 overexpression and suppression on OGD-stimulated hippocampal neurons were evaluated by detection of cell viability, apoptotic cells rate, and the expression of apoptosis-related proteins. Besides, TargetScan database and dual luciferase activity assay were used to seek a target gene of miR-132. As a result, miR-132 was highly expressed in hippocampal neurons following 2 h of OGD exposure. MiR-132 overexpression significantly increased OGD-diminished cell viability and reduced OGD-induced apoptosis at 12, 24, and 48 h post-OGD. MiR-132 overexpression significantly down-regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2. Caspase-3 activity was also significantly decreased by miR-132 overexpression. Furthermore, FOXO3 was a direct target of miR-132, and it was negatively regulated by miR-132. To conclude, our results provide evidence that miR-132 protects hippocampal neurons against OGD injury by inhibiting apoptosis.
As smart grid advance, Power Load Forecasting (PLF) has become a research hotspot. As the foundation of the forecasting model, the Power Load Monitoring (PLM) data takes on great importance due to ...its completeness, reliability and accuracy. However, monitoring equipment failures, transmission channel congestion and anomalies result in missing PLM data, which directly affects the performance of the PLF model. To address this issue, this paper proposes an L 1 -and-L 2 -Regularized Nonnegative Tensor Factorization (LNTF) model to impute PLM missing data. Its main idea is threefold: (1) combining L 1 and L 2 norms to achieve effective feature extraction and improve the model’s robustness; (2) incorporating two temporal-dependent linear biases to describe the fluctuations of PLM data; (3) adding nonnegative constraints to precisely define the nonnegativity of PLM data. Extensive empirical studies on two publicly real-world PLM datasets with 1,569,491 and 413,357 known entries and missing rates of 93.35% and 96.75% demonstrate that the proposed LNTF improves 14.04%, 59.31%, and 71.43% on average over the state-of-the-art imputation models in terms of imputation error, convergence rounds, and time cos, respectively. Its high computational efficiency and low imputation error make practical sense for PLM data imputation.
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