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"Shen, Xi"
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أفكار حول تعميق الإصلاح
يناقش الكتاب سلسلة من الإيضاحات الهامة قدمها الرئيس الصيني والأمين العام للجنة المركزية للحزب الشيوعي الصيني، شي جين بينغ، وتدور حول أفكار الإصلاح وتوسيع الانفتاح على نحو شامل في الصين. يضم الكتاب أكثر من 70 وثيقة هامة على صورة كلمات شي جين بينغ وخطاباته وتعليقاته وتوجيهاته وينقسم الكتاب إلى 12 موضوعا خاصا تتضمن 274 قطعة من مقتطفات الأقوال، نشر بعضها لأول مرة.
Book
Impaired mitophagy triggers NLRP3 inflammasome activation during the progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis
Activation of inflammation is an important mechanism in the development of nonalcoholic steatohepatitis (NASH). This study aims to delineate how mitophagy affects NLRP3 inflammasome activation in hepatic lipotoxicity. Mice were fed a high fat/calorie diet (HFCD) for 24 weeks. Primary rat hepatocytes were treated with palmitic acid (PA) for various periods of time. Mitophagy was measured by protein levels of LC3II and P62. NLRP3, caspase-1, interleukin (IL)-18, and IL-1β at mRNA and protein levels were used as indicators of inflammasome activation. Along with steatotic progression in HFCD-fed mice, ratio of LC3II/β-actin was decreased concurrently with increased levels of liver P62, NLRP3, caspase-1, IL-1β, IL-18, and serum IL-1β levels in late-stage NASH. PA treatment resulted in mitochondrial oxidative stress and initiated mitophagy in primary hepatocytes. The addition of cyclosporine A did not change LC3II/Τοmm20 ratios; but P62 levels were increased after an extended duration of PA exposure, indicating a defect in autophagic activity. Along with impaired mitophagy, mRNA and protein levels of NLRP3, caspase-1, IL-18 and IL-1β were upregulated by PA treatment. Pretreatment with MCC950, N-acetyl cysteine or acetyl-l-carnitine reversed inflammasome activation and a pyroptotic cascade. Additionally, mitophagic flux was partially recovered as indicated by increases in LC3II/Tomm20 ratio, parkin, and PINK1 expression, and decreased P62 expression. The findings suggest that impaired mitophagy triggers hepatic NLRP3 inflammasome activation in a murine NASH model and primary hepatocytes. The new insights into inflammasome activation through mitophagy advance our understanding of how fatty acids elicit lipotoxicity through oxidant stress and autophagy in mitochondria.
Journal Article
Unveiling the relationship between social anxiety, loneliness, motivations, and problematic smartphone use: A network approach
Previous studies suggested social anxiety as an essential risk factor for problematic smartphone use, but the complex interactions and the most influential components affecting this relationship remain unclear. This study capitalizes on network analysis to identify the central factors and possible mediating paths among social anxiety, loneliness, five types of motivation, and problematic smartphone use.
Employing 549 emerging adults, we obtained a stable network of the above variables. The central components and the stability of this network were also identified.
Within this network, the edge linking withdrawal behavior and use of application (APP) exhibits the most robust edge intensity. The central components include social comfort, use of APP, withdrawal behavior, and companionship while the bridge central nodes include social anxiety and escapism motivation. The direct link between social anxiety and PSU revealed only fragile edges with both withdrawal behavior and use of APP. Considering the possible mediating pathways, three pathways were observed in our network. Loneliness and escapism mediated the relationship between social anxiety and social comfort. Moreover, another mediating way was from social anxiety, loneliness, social interaction motivation, and escapism motivation to social comfort.
Based on the above identification of related components and pathways, future researchers could intervene against problematic smartphone usage in this socially anxious population.
•We capitalized on network analysis to examine social anxiety, loneliness, motivations, and problematic smartphone use•Formulated the importance of loneliness and diverse motivations in affecting PSU for these socially anxious individuals•Provided the skills or intervene in coping strategies that guide these emerging adults to cope with life problems
Journal Article
High expression of neuro-oncological ventral antigen 1 correlates with poor prognosis in hepatocellular carcinoma
Neuro-oncological ventral antigen 1 (Nova1) is a neuron-specific RNA-binding protein in human paraneoplastic opsoclonus-myoclonus ataxia accompanying with malignant tumors, but its role in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that overexpressed intratumoral Nova1 was associated with poor survival rate and increased recurrence rate of HCC, especially early recurrence, and was an independent prognostic factor for overall survival rate and tumor recurrence. HCC cell lines over-expressing Nova1 exhibited greater potentials in cell proliferation, invasion and migration, while knockdown of Nova1 had the opposite effects. All these findings indicate that Nova1 may act as a prognostic marker for poor outcome and high recurrence in HCC.
Journal Article
Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation
Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.
One-sentence summary
GSDME inflames ICI-associated myocarditis.
ICI-induced myocarditis is fatal, but its mechanism is unclear. Here, the authors identify GSDME as a key driver by promoting cGAS-STING signaling, enhancing our understanding of its pathogenesis.
Journal Article
Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence
Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD
+
loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD
+
loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.
Ferroptosis is a novel form of regulated cell death associated with lipid oxidation. Here, the authors demonstrate that the proferroptosis signal is activated and drives vascular aging by inducing senescence in vascular smooth muscle cells.
Journal Article
Experimental demonstration of anomalous Floquet topological insulator for sound
Time-reversal invariant topological insulator is widely recognized as one of the fundamental discoveries in condensed matter physics, for which the most fascinating hallmark is perhaps a spin-based topological protection, the absence of scattering of conduction electrons with certain spins on matter surface. Recently, it has created a paradigm shift for topological insulators, from electronics to photonics, phononics and mechanics as well, bringing about not only involved new physics but also potential applications in robust wave transport. Despite the growing interests in topologically protected acoustic wave transport,
T
-invariant acoustic topological insulator has not yet been achieved. Here we report experimental demonstration of anomalous Floquet topological insulator for sound: a strongly coupled metamaterial ring lattice that supports one-way propagation of pseudo-spin-dependent edge states under
T
-symmetry. We also demonstrate the formation of pseudo-spin-dependent interface states due to lattice dislocations and investigate the properties of pass band and band gap states.
Topological protected acoustic wave propagation has been predicted, but yet awaits for experimental demonstration. Here, Peng
et al
. report one-way propagation of pseudo-spin-dependent edge states for sound, analogous to Floquet topological insulator in solid state.
Journal Article
Classification of breast cancer histopathological images using interleaved DenseNet with SENet (IDSNet)
In this study, we proposed a novel convolutional neural network (CNN) architecture for classification of benign and malignant breast cancer (BC) in histological images. To improve the delivery and use of feature information, we chose the DenseNet as the basic building block and interleaved it with the squeeze-and-excitation (SENet) module. We conducted extensive experiments with the proposed framework by using the public domain BreakHis dataset and demonstrated that the proposed framework can produce significantly improved accuracy in BC classification, compared with the state-of-the-art CNN methods reported in the literature.
Journal Article
Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis
Ferroptosis is a new form of regulated cell death characterized by excessive iron accumulation and uncontrollable lipid peroxidation. The role of ferroptosis in metabolic dysfunction-associated fatty liver disease (MAFLD) is not fully elucidated. In this study we compared the therapeutic effects of ferroptosis inhibitor liproxstatin-1 (LPT1) and iron chelator deferiprone (DFP) in MAFLD mouse models. This model was established in mice by feeding a high-fat diet with 30% fructose in water (HFHF) for 16 weeks. The mice then received LPT1 (10 mg·kg
−1
·d
−1
, ip) or DFP (100 mg·kg
−1
·d
−1
, ig) for another 2 weeks. We showed that both LPT1 and DFP treatment blocked the ferroptosis markers ACSL4 and ALOX15 in MAFLD mice. Furthermore, LPT1 treatment significantly reduced the liver levels of triglycerides and cholesterol, lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), and ameliorated the expression of lipid synthesis/oxidation genes (
Ppar
α
, Scd1, Fasn, Hmgcr
and
Cpt1a
), insulin resistance, mitochondrial ROS content and liver fibrosis. Importantly, LPT1 treatment potently inhibited hepatic apoptosis (Bax/Bcl-xL ratio and TUNEL
+
cell number), pyroptosis (cleavages of Caspase-1 and GSDMD) and necroptosis (phosphorylation of MLKL). Moreover, LPT1 treatment markedly inhibited cleavages of PANoptosis-related caspase-8 and caspase-6 in MAFLD mouse liver. In an in vitro MAFLD model, treatment with LPT1 (100 nM) prevented cultured hepatocyte against cell death induced by pro-PANoptosis molecules (TNF-α, LPS and nigericin) upon lipid stress. On the contrary, DFP treatment only mildly attenuated hepatic inflammation but failed to alleviate lipid deposition, insulin resistance, apoptosis, pyroptosis and necroptosis in MAFLD mice. We conclude that ferroptosis inhibitor LPT1 protects against steatosis and steatohepatitis in MAFLD mice, which may involve regulation of PANoptosis, a coordinated cell death pathway that involves apoptosis, pyroptosis and necroptosis. These results suggest a potential link between ferroptosis and PANoptosis.
Journal Article
Serum microRNA signatures and metabolomics have high diagnostic value in colorectal cancer using two novel methods
Recently, many new diagnostic biomarkers have been developed for colorectal cancer. We chose 2 methods with high diagnostic efficiency, the detection of serum microRNA and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and aimed to establish appropriate models. We reviewed the diagnostic value of all microRNA identified by previous diagnostic tests. We selected appropriate microRNA to validate their diagnostic efficiency, and determined the optimal combination. We included 85 patients with colorectal cancer (CRC) and 78 healthy controls (HC) and detected the expression of the microRNA. GC/MS analysis was conducted, and we used 3 multivariate statistical methods to establish diagnostic models. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA19‐9) were detected for comparison with the novel models. Ultimately, 62 published studies and 63 microRNA were included in this review. MiR‐21, miR‐29a, miR‐92a, miR‐125b and miR‐223 were selected to further validate their diagnostic value. The serum levels of the 5 microRNA in CRC patients were significantly higher than those in the HC. The combination of miR‐21, miR‐29a, miR‐92a and miR‐125b had the highest area under the curve (AUC) at 0.952, with a sensitivity of 84.7% and a specificity of 98.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. With regard to traditional biomarkers, the AUC of CEA and CA19‐9 were 0.808 and 0.705, respectively. The application prospects are good for microRNA and metabolomics as new diagnostic methods because of their high diagnostic value compared with traditional biomarkers. The combination of miR‐21, miR‐29a, miR‐92a and miR‐125b had the highest area under the curve (AUC) at 0.952 with a sensitivity of 84.7% and a specificity of 98.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. There is a good application prospect for microRNAs and metabolomics as new diagnostic methods because of their high diagnostic value compared with traditional biomarkers.
Journal Article