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"Shen, Ming"
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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
Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19
Coronaviruses (CoVs) are a group of enveloped, single-stranded positive genomic RNA viruses and some of them are known to cause severe respiratory diseases in human, including Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the ongoing coronavirus disease-19 (COVID-19). One key element in viral infection is the process of viral entry into the host cells. In the last two decades, there is increasing understanding on the importance of the endocytic pathway and the autophagy process in viral entry and replication. As a result, the endocytic pathway including endosome and lysosome has become important targets for development of therapeutic strategies in combating diseases caused by CoVs. In this mini-review, we will focus on the importance of the endocytic pathway as well as the autophagy process in viral infection of several pathogenic CoVs inclusive of SARS-CoV, MERS-CoV and the new CoV named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and discuss the development of therapeutic agents by targeting these processes. Such knowledge will provide important clues for control of the ongoing epidemic of SARS-CoV-2 infection and treatment of COVID-19.
Journal Article
Distinct JNK/VEGFR signaling on angiogenesis of breast cancer‐associated pleural fluid based on hormone receptor status
Malignant pleural effusion is a common complication in metastatic breast cancer (MBC); however, changes in the pleural microenvironment are poorly characterized, especially with respect to estrogen receptor status. Histologically, MBC presents with increased microvessels beneath the parietal and visceral pleura, indicating generalized angiogenic activity. Breast cancer‐associated pleural fluid (BAPF) was collected and cultured with HUVECs to recapitulate the molecular changes in subpleural endothelial cells. The clinical progression of triple‐negative breast cancer (TNBC) is much more aggressive than that of hormone receptor‐positive breast cancer (HPBC). However, BAPF from HPBC (BAPF‐HP) and TNBC (BAPF‐TN) homogeneously induced endothelial proliferation, migration, and angiogenesis. In addition, BAPF elicited negligible changes in the protein marker of endothelial‐mesenchymal transition. Both BAPF‐HP and BAPF‐TN exclusively upregulated JNK signaling among all MAPKs in HUVECs. By contrast, the response to the JNK inhibitor was insignificant in Transwell and tube formation assays of the HUVECs cultured with BAPF‐TN. The distinct contribution of p‐JNK to endothelial angiogenesis was consequently thought to be induced by BAPF‐HP and BAPF‐TN. Due to increased angiogenic factors in HUVECs cultured with BAPF, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor was applied accordingly. Responses to VEGFR2 blockade were observed in both BAPF‐HP and BAPF‐TN concerning endothelial migration and angiogenesis. In conclusion, the above results revealed microvessel formation in the pleura of MBC and the underlying activation of p‐JNK/VEGFR2 signaling. Distinct responses to blocking p‐JNK and VEGFR2 in HUVECs cultured with BAPF‐HP or BAPF‐TN could lay the groundwork for future investigations in treating MBC based on hormone receptor status. Current study evaluated the angiogenic response of HUVECs cultured with breast cancer‐associated pleural fluid (BAPF) obtained from hormone positive (HP) and triple negative (TN) breast cancer, respectively. Both BAPF‐HP and BAPF‐TN stimulated endothelial angiogenesis with upregulation of vascular endothelial growth factor receptor 2 (VEGFR2) and p‐JNK expressions. In contrast, application of p‐JNK inhibitor only showed efficacy in HUVECs cultured with BAPF‐HP, but not BAPF‐TN. Blockade of VEGFR2 signaling revealed potent inhibition on endothelial motility and angiogenesis induced by BAPF‐HP and BAPF‐TN.
Journal Article
Sonochemical Synthesis of Sulfur Doped Reduced Graphene Oxide Supported CuS Nanoparticles for the Non-Enzymatic Glucose Sensor Applications
Over the present material synthesis routes, the sonochemical route is highly efficient and comfortable way to produce nanostructured materials. In this way, the copper sulfide (CuS-covellite) and sulfur doped reduced graphene oxide (S-rGO) nanocomposite was prepared by sonochemical method. Interestingly, the structure of the as-prepared S-rGO/CuS was changed from the covellite to digenite phase. Herein, the S-rGO was act as a mild oxidizer and liable for the structural transformations. These structural changes are sequentially studied by various physicochemical characterizations such as Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and Transmission electron microscopy (TEM). After scrupulous structural evaluations, the transformation of CuS phase was identified and documented. This oxidized CuS has an excellent electrocatalytic activity when compare to the bulk CuS. This S-rGO/CuS was further used for the determination of glucose and acquired good electrocatalytic performances. This S-rGO/CuS was exhibited a wide linear concentration range, 0.0001–3.88 mM and 3.88–20.17 mM, and a low-level detection limit of 32 nM. Moreover, we have validated the practicability of our developed glucose sensor in real biological samples.
Journal Article
The emerging mechanisms and functions of microautophagy
‘Autophagy’ refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes for degradation. Different forms of autophagy have been described on the basis of the nature of the cargoes and the means used to deliver them to lysosomes. At present, the prevailing categories of autophagy in mammalian cells are macroautophagy, microautophagy and chaperone-mediated autophagy. The molecular mechanisms and biological functions of macroautophagy and chaperone-mediated autophagy have been extensively studied, but microautophagy has received much less attention. In recent years, there has been a growth in research on microautophagy, first in yeast and then in mammalian cells. Here we review this form of autophagy, focusing on selective forms of microautophagy. We also discuss the upstream regulatory mechanisms, the crosstalk between macroautophagy and microautophagy, and the functional implications of microautophagy in diseases such as cancer and neurodegenerative disorders in humans. Future research into microautophagy will provide opportunities to develop novel interventional strategies for autophagy- and lysosome-related diseases.Microautophagy involves direct engulfment of cytoplasmic components, including proteins and organelles, by lysosomes and late endosomes for degradation. Although it is one of three main types of autophagy — along with macroautophagy and chaperone-mediated autophagy — its mechanisms and physiological roles have only recently begun to emerge.
Journal Article
Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study
Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.
This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755.
Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported.
BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.
Novartis Pharmaceuticals.
Journal Article
Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.
Journal Article
STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism
Mitophagy is the selective autophagic targeting and removal of dysfunctional mitochondria. While PINK1/Parkin-dependent mitophagy is well-characterized, PINK1/Parkin-independent route is poorly understood. Using structure illumination microscopy (SR-SIM), we demonstrate that the SNARE protein Syntaxin 17 (STX17) initiates mitophagy upon depletion of outer mitochondrial membrane protein Fis1. With proteomics analysis, we identify the STX17-Fis1 interaction, which controls the dynamic shuffling of STX17 between ER and mitochondria. Fis1 loss results in aberrant STX17 accumulation on mitochondria, which exposes the N terminus and promotes self-oligomerization to trigger mitophagy. Mitochondrial STX17 interacts with ATG14 and recruits core autophagy proteins to form mitophagosome, followed by Rab7-dependent mitophagosome-lysosome fusion. Furthermore, Fis1 loss impairs mitochondrial respiration and potentially sensitizes cells to mitochondrial clearance, which is mediated through canonical autophagy machinery, closely linking non-selective macroautophagy to mitochondrial turnover. Our findings uncover a PINK1/Parkin-independent mitophagic mechanism in which outer mitochondrial membrane protein Fis1 regulates mitochondrial quality control.
Mitophagy plays a critical role in cellular homeostasis, and PINK1/Parkin-mediated mitophagy is the most thoroughly characterized. Here, Xian et al. show that STX17 induces mitophagy via a macroautophagy pathway regulated by Fis1, by a PINK1/Parkin-independent route.
Journal Article
Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p
Background
The function of a new long non-coding RNA linc00673 remains unclear. While identified as an oncogenic player in non-small cell lung cancer (NSCLC), linc00673 was found to be anti-oncogenic in pancreatic ductal adenocarcinoma (PDAC). However whether linc00673 regulated malignancy and epithelial mesenchymal transition (EMT) has not been characterized.
Methods
Cell proliferation was assessed using CCK-8 and EdU assays, and cell migration and invasion were assessed using scratch assays and transwell invasion assays. Epithelial mesenchymal transition was examined using western blot, qRT-PCR and immunofluorescence staining. Interaction between miRNA and linc00673 was determined using luciferase reporter assays. In vivo experiments were performed to assess tumor formation. In addition, the expression data of NSCLC specimens of TCGA and patient survival data were utilized to explore the prognostic significance of linc00673.
Results
In the present study, we found high linc00673 expression was associated with poor prognosis of NSCLC patients. In vitro experiments showed linc00673 knockdown reversed TGF-β induced EMT, and miR-150-5p was predicted to target linc00673 through bioinformatics tools. Overexpression of miR-150-5p suppressed lin00673’s expression while inhibition of miR-150-5p led to significant upregulation of lin00673, suggesting that linc00673 could be negatively regulated by miR-150-5p, which was further confirmed by the inverse correlation between linc00673 and miR-150-5p in NSCLC patients’ specimen. Furthermore, we proved that miR-150-5p could directly target linc00673 through luciferase assay, so linc00673 could sponge miR-150-5p and modulate the expression of a key EMT regulator ZEB1 indirectly. In addition, miR-150-5p inhibition abrogated linc00673 silence mediated proliferation, migration, invasion and EMT suppressing effect. Moreover, the inhibition of linc00673 significantly attenuated the tumorigenesis ability of A549 cells in vivo.
Conclusions
We validated linc00673 as a novel oncogenic lncRNA and demonstrated the molecular mechanism by which it promotes NSCLC, which will advance our understanding of its clinical significance.
Journal Article
A core-shell molybdenum nanoparticles entrapped f-MWCNTs hybrid nanostructured material based non-enzymatic biosensor for electrochemical detection of dopamine neurotransmitter in biological samples
Dopamine (DA) is a critical neurotransmitter and has been known to be liable for several neurological diseases. Hence, its sensitive and selective detection is essential for the early diagnosis of diseases related to abnormal levels of DA. In this study, we reported novel molybdenum nanoparticles self-supported functionalized multiwalled carbon nanotubes (Mo NPs@
f
-MWCNTs) based core-shell hybrid nanomaterial with an average diameter of 40–45 nm was found to be the best for electrochemical DA detection. The Mo NPs@
f
-MWCNTs hybrid material possesses tremendous superiority in the DA sensing is mainly due to the large surface area and numerous electroactive sites. The morphological and structural characteristics of the as-synthesized hybrid nanomaterial were examined by XRD, Raman, FE-SEM, HR-TEM, EDX. The electrochemical characteristics and catalytic behavior of the as-prepared Mo NPs@
f
-MWCNTs modified screen-printed carbon electrode for the determination of DA were systematically investigated via electrochemical impedance spectroscopy, cyclic voltammetry, and amperometry. The results demonstrate that the developed DA biosensor exhibit a low detection limit of 1.26 nM, excellent linear response of 0.01 µM to 1609 µM with good sensitivity of 4.925 µA µM
−1
cm
−2
. We proposed outstanding appreciable stability sensor was expressed to the real-time detection of DA in the real sample analysis of rat brain, human blood serum, and DA hydrochloride injection.
Journal Article