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"Xue, Min"
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A highly heterogeneous mutational pattern in POEMS syndrome
POEMS syndrome is a rare plasma cell dyscrasia. Little is known about its pathogenesis and genetic features. We analyzed the mutational features of purified bone marrow plasma cells from 42 patients newly diagnosed with POEMS syndrome using a two-step strategy. Whole exome sequencing of ten patients showed a total of 170 somatic mutations in exonic regions and splicing sites, with paired peripheral blood mononuclear cells as a control. Three significantly mutated genes—LILRB1 (10%), HEATR9 (20%), and FMNL2 (10%)—and eight mutated known driver genes (MYD88, NFKB2, CHD4, SH2B3, POLE, STAT3, CHD3, and CUX1) were identified. Target region sequencing of 77 genes were then analyzed to validate the mutations in an additional 32 patients. A total of 32 mutated genes were identified, and genes recurrently mutated in more than three patients included CUX1 (19%), DNAH5 (16%), USH2A (16%), KMT2D (16%), and RYR1 (12%). Driver genes of multiple myeloma (BIRC3, LRP1B, KDM6A, and ATM) and eleven genes reported in light-chain amyloidosis were also identified in target region sequencing. Notably, VEGFA mutations were detected in one patient. Our study revealed heterogeneous genomic profiles of bone marrow plasma cells in POEMS syndrome, which might share some similarity to that of other plasma cell diseases.
Journal Article
GCG inhibits SARS-CoV-2 replication by disrupting the liquid phase condensation of its nucleocapsid protein
Lack of detailed knowledge of SARS-CoV-2 infection has been hampering the development of treatments for coronavirus disease 2019 (COVID-19). Here, we report that RNA triggers the liquid–liquid phase separation (LLPS) of the SARS-CoV-2 nucleocapsid protein, N. By analyzing all 29 proteins of SARS-CoV-2, we find that only N is predicted as an LLPS protein. We further confirm the LLPS of N during SARS-CoV-2 infection. Among the 100,849 genome variants of SARS-CoV-2 in the
GISAID
database, we identify that ~37% (36,941) of the genomes contain a specific trio-nucleotide polymorphism (GGG-to-AAC) in the coding sequence of N, which leads to the amino acid substitutions, R203K/G204R. Interestingly, N
R203K/G204R
exhibits a higher propensity to undergo LLPS and a greater effect on
IFN
inhibition. By screening the chemicals known to interfere with N-RNA binding in other viruses, we find that (-)-gallocatechin gallate (GCG), a polyphenol from green tea, disrupts the LLPS of N and inhibits SARS-CoV-2 replication. Thus, our study reveals that targeting N-RNA condensation with GCG could be a potential treatment for COVID-19.
Coronavirus nucleocapsid (N) protein is important for viral genome packaging and virion assembly. Here the authors show that natural chemical (-)-gallocatechin gallate (GCG) disrupts the liquid–liquid phase separation of N and inhibits SARS-CoV-2 replication.
Journal Article
تدويل العملات والتحكم الكلي بالمخاطر المالية
شهد الاقتصاد الصيني مؤخرا طبيعة جديدة مع الانتعاش الاقتصادي العالمي وديناميكية السوق المالي. ورغم الضغوطات الاقتصادية المحلية والعالمية وتغير قيمة العملة، لا يزال تدويل العملة في الصين يكتسب زخما كبيرا مع إطلاق المرحلة الأولى من نظام الحدود بين البنوك (CIPS) وتنفيذ مبادرة الحزام والطريق. من هنا، يعالج هذا الكتاب موضوع تدويل العملة في الصين والتحكم الكلي بالمخاطر المالية المحدقة، بهدف إلقاء الضوء على أسباب تقدم الاقتصاد الصيني، وإعطاء القارئ لمحة موجزة عن السياسة الحكيمة التي اعتمدتها حكومة جمهورية الصين الشعبية للنهوض باقتصادها والوصول به إلى مصاف الدول المتقدمة.
Quantum transport in topological nodal-line semimetals
Topological nodal-line semimetals offer an attractive research platform for exploring a variety of novel phenomena, which have attracted great research interest in the past decade. There are three unique features of the nodal-line semimetals: (i) band crossing along the closed loop that carries
Berry phase, (ii) torus-shaped Fermi surface as the Fermi energy deviates from the nodal loop, and (iii) drumhead-like surface states induced by the band topology, which comprise the main scenarios for most of its electronic properties. Here, we review recent progress on the quantum transport theory of nodal-line semimetals. We show that the properties (i) and (ii) result in a fascinating interplay between the effective dimensionality of electron diffusion and the band topology, which may give rise to 3D weak localization or 2D weak anti-localization effect that can be probed by the magnetoconductivity induced by a weak magnetic field. Moreover, (i) and (ii) can also be revealed by the pattern of the Shubnikov-de Hass oscillation in a strong magnetic field. For the massive nodal-line semimetals with spin-orbit coupling, we show that the magnetic field can induce a topological Lifshitz transition of the Fermi torus from genus 1 to 0. Interestingly, the Lifshitz transition is in good coincidence with the sign reversal of the magnetoresistivity. Compared to the conventional Fermi sphere, the Fermi torus possesses multiple reflection channels, which may give rise to novel scattering processes such as anomalous Andreev reflection at the interface between the semimetal and a superconductor. Besides the bulk states, the drumhead surface states also possess interesting properties. It is shown that the spin polarization of the surface states can induce resonant spin-flipped reflection, which can be detected through both spin and charge transport measurements. We also briefly review the recent experimental progress on the transport properties of nodal-line semimetals and compare the results with the theoretical predictions.
Journal Article
Circular RNA circ-CPA4/ let-7 miRNA/PD-L1 axis regulates cell growth, stemness, drug resistance and immune evasion in non-small cell lung cancer (NSCLC)
Non-small cell lung cancer (NSCLC) cells derived intracellular and extracellular programmed cell death ligand 1 (PD-L1) promoted cancer progression and drug resistance, and facilitated tumor immune evasion. However, the detailed molecular mechanisms are still largely unknown. In the present study, we aimed to explore the role of circular RNA circ-CPA4/let-7 miRNA/PD-L1 axis in the regulation of NSCLC progression, drug resistance and tumor immune microenvironment.
Real-Time qPCR and Western Blot analysis were conducted to examine gene expressions at transcriptional and translated levels, respectively. The regulatory mechanisms of circ-CPA4, let-7 miRNA and PD-L1 were validated by dual-luciferase reporter gene system and RNA pull-down assay. Cell growth and apoptosis were determined by CCK-8 assay, colony formation assay and Annexin V-FITC/PI double staining assay. Cell mobility was evaluated by transwell assay.
Circ-CPA4 and PD-L1 were high-expressed, while let-7 miRNA was low-expressed in NSCLC cells and cancer tissues compared to the human bronchial epithelial (HBE) cells and their paired clinical normal adjacent tissues, respectively. Besides, knock-down of circ-CPA4 inhibited cell growth, mobility and epithelial-mesenchymal transition (EMT), and promoted cell death in NSCLC cells by downregulating PD-L1 through serving as a RNA sponge for let-7 miRNA. In addition, the NSCLC cells derived PD-L1-containing exosomes promoted cell stemness and increased resistance of NSCLC cells to cisplatin. Notably, by co-culturing the NSCLC cells with CD8
T cells isolated from human peripheral blood mononuclear cells (hPBMCs) in a transwell co-culturing system, we found that NSCLC cells inactivated CD8
T cells in a secreted PD-L1-dependent manner. Further results suggested that circ-CPA4 also positively regulated exosomal PD-L1, and the NSCLC cells with circ-CPA4 ablation re-activated CD8
T cells in the co-culturing system.
Taken together, circ-CPA4 regulated cell growth, mobility, stemness and drug resistance in NSCLC cells and inactivated CD8
T cells in the tumor immune microenvironment through let-7 miRNA/PD-L1 axis.
Journal Article
Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy
Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.
Journal Article
RPV‐modified epirubicin and dioscin co‐delivery liposomes suppress non‐small cell lung cancer growth by limiting nutrition supply
Chemotherapy for non‐small cell lung cancer (NSCLC) is far from satisfactory, mainly due to poor targeting of antitumor drugs and self‐adaptations of the tumors. Angiogenesis, vasculogenic mimicry (VM) channels, migration, and invasion are the main ways for tumors to obtain nutrition. Herein, RPV‐modified epirubicin and dioscin co‐delivery liposomes were successfully prepared. These liposomes showed ideal physicochemical properties, enhanced tumor targeting and accumulation in tumor sites, and inhibited VM channel formation, tumor angiogenesis, migration and invasion. The liposomes also downregulated VM‐related and angiogenesis‐related proteins in vitro. Furthermore, when tested in vivo, the targeted co‐delivery liposomes increased selective accumulation of drugs in tumor sites and showed extended stability in blood circulation. In conclusion, RPV‐modified epirubicin and dioscin co‐delivery liposomes showed strong antitumor efficacy in vivo and could thus be considered a promising strategy for NSCLC treatment. Targeted epirubicin and dioscin co‐delivery liposomes modified with RPV increased cellular uptake and accumulation in the A549 cells. The RPV‐modified epirubicin and dioscin co‐delivery liposomes enhanced anti‐tumor efficacy in vitro and in vivo. The RPV‐modified epirubicin and dioscin co‐delivery liposomes inhibited NSCLC migration and invasion by limiting tumor angiogenesis and vasculogenic mimicry formation.
Journal Article
Exosomes from Drug-Resistant Breast Cancer Cells Transmit Chemoresistance by a Horizontal Transfer of MicroRNAs
Adriamycin and docetaxel are two agents commonly used in treatment of breast cancer, but their efficacy is often limited by the emergence of chemoresistance. Recent studies indicate that exosomes act as vehicles for exchange of genetic cargo between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development and progression. However, the specific contribution of breast cancer-derived exosomes is poorly understood. Here we reinforced other's report that human breast cancer cell line MCF-7/S could acquire increased survival potential from its resistant variants MCF-7/Adr and MCF-7/Doc. Additionally, exosomes of the latter, A/exo and D/exo, significantly modulated the cell cycle distribution and drug-induced apoptosis with respect to S/exo. Exosomes pre-treated with RNase were unable to regulate cell cycle and apoptosis resistance, suggesting an RNA-dependent manner. Microarray and polymerase chain reaction for the miRNA expression profiles of A/exo, D/exo, and S/exo demonstrated that they loaded selective miRNA patterns. Following A/exo and D/exo transfer to recipient MCF-7/S, the same miRNAs were significantly increased in acquired cells. Target gene prediction and pathway analysis showed the involvement of miR-100, miR-222, and miR-30a in pathways implicated in cancer pathogenesis, membrane vesiculation and therapy failure. Furthermore, D/exo co-culture assays and miRNA mimics transfection experiments indicated that miR-222-rich D/exo could alter target gene expression in MCF-7/S. Our results suggest that drug-resistant breast cancer cells may spread resistance capacity to sensitive ones by releasing exosomes and that such effects could be partly attributed to the intercellular transfer of specific miRNAs.
Journal Article