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The unfoldase CDC48 (Cell Division Cycle 48) is highly conserved in eukaryotes, serving as an AAA + ATPase to extract ubiquitinated proteins from large protein complexes and membranes. Although its biochemical properties have been studied extensively in yeast and animal systems, the biological roles and regulations of the plant CDC48s have been explored only recently. Here we describe the identification of a novel E3 ligase from the SNIPER (snc1-influencing plant E3 ligase reverse genetic) screen, which contributes to plant defense regulation by targeting CDC48A for degradation. SNIPER7 encodes an F-box protein and its overexpression leads to autoimmunity. We identified CDC48s as interactors of SNIPER7 through immunoprecipitation followed by mass spectrometry proteomic analysis. SNIPER7 overexpression lines phenocopy the autoimmune mutant Atcdc48a-4. Furthermore, CDC48A protein levels are reduced or stabilized when SNIPER7 is overexpressed or inhibited, respectively, suggesting that CDC48A is the ubiquitination substrate of SCFSNIPER7 . Taken together, this study reveals a new mechanism where a SCFSNIPER7 complex regulates CDC48 unfoldase levels and modulates immune output.

Background & Aims Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying causes of this aberrant activation remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor that acts via the mTORC1 axis. Methods We performed quantitative reverse-transcription PCR (92 pairs), western blot (30 pairs), and immunostaining (225 cases) assays in HCC tissue samples to evaluate VEPH1 expression. We explored the functional effects of VEPH1 on tumor growth and metastasis. Molecular and biochemical strategies were used to gain insight into mechanisms underlying the tumor-suppressive function of VEPH1. Results VEPH1 is frequently silenced in HCC tissues, primarily resulting from let-7d upregulation. Decreased VEPH1 expression is associated with poor prognosis and aggressive tumor phenotypes in patients with HCC. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion in vitro and in vivo. The VEPH1 fragments 580–625aa and 447–579 aa bind directly to TSC1 (719–1,164aa) and TSC2 (1–420 aa), respectively, enhancing TSC1/TCS2 binding and promoting translocation of TSC2 to the membrane, which leads to increased TSC2 Ser1387 phosphorylation. Subsequently, Rheb is inactivated by the GTPase activity of TSC2, inhibiting mTORC1 signaling and contributing to changes in HCC carcinogenesis and metastasis. Rapamycin, the mTOR inhibitor, can inhibit the pro-tumorigenic effect of VEPH1 knockdown. Loss of VEPH1 correlates with decreased TSC2 Ser1387 phosphorylation and increased mTOR activity in HCC specimens. Conclusions The loss of VEPH1 leads to aberrantly activated mTORC1 signaling in HCC; rapamycin (or rapalogs) may serve as an effective treatment option for patients with HCC and dampened VEPH1 expression. Lay summary Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression.

Background: Src family kinases (SFKs) belong to the non-receptor protein tyrosine kinases family which are generally dysregulated in a variety of tumors. This study aims to thoroughly investigate the mutation status, expression level, prognostic value and relationship with immune infiltration of SFKs in hepatocellular carcinoma (HCC). Methods: TIMER2.0, UALCAN, cBioPortal, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, STRING, GeneMANIA and XIANTAO platform were utilized to analyze differential expression, genetic alteration, prognostic value and immune cell infiltration of SFKs in HCC patients. Furthermore, we used quantitative real-time PCR (qPCR) and western blot analysis to measure SFKs mRNA and protein expression in matching specimens of normal tissue versus HCC. We analyzed the biological effects of overexpressing FYN in Huh7 cells and subcutaneous xenograft tumor model. Results: The mRNA expression levels of LYN, SRC and SRM were elevated in HCC tissues, whereas FYN was reduced. Around 10% genetic alterations rate of SFKs was observed in HCC. The mRNA levels of BLK, BRK, FRK, FYN, LCK, LYN, SRC, SRM and YES were correlated with clinical cancer stage. Elevated FYN mRNA level in HCC was positively correlated with overall survival (OS), while SRC was negatively correlated with OS. The interaction network and functional enrichment analysis implied that SFKs were closely associated with the regulation of immune cells, cell adhesion molecules and signaling pathways involved in tumorigenesis and development. And all SFKs members in HCC were significantly relevant to at least half of the six imune-infiltrating cells, including B cells, macrophages, dendritic cells, neutrophils, CD4+ T cells and CD8+ T cells. Furthermore, we confirmed that the protein expression level of FYN was decreased in HCC patients and human hepatoma cell line. Overexpression of FYN suppressed Huh7 cell proliferation, migration, invasion, and tumorigenesis in xenografts nude mice.Conclusion: Dysregulated FYN and SRC expression in HCC is associated with poor prognosis and might be used as novel potential prognostic biomarkers in HCC patients.

Metastasis of breast cancer represents the major reason for its poor prognosis, leading to high mortality. In breast cancer, a tumor suppressor gene TP53 is commonly mutated. TP53 mutation leads to an altered expression of various genes, an event that is associated with aggressive tumor and is a strong independent marker for survival. In this study, we identified a novel p53 target gene, immunoglobulin superfamily 9 (IGSF9). IGSF9 is generally down-regulated in breast cancer tissues. Loss of IGSF9 is associated with frequent metastasis and poor prognosis of breast cancer patients. Wild-type p53, but not R175H mutant, trans-activates the transcription of IGSF9 via binding to its promoter (−137 to −131 bp), inhibits epithelial-mesenchymal transition (EMT), consequently the inhibition of breast cancer cells migration and invasion. IGSF9 interacts with focal adhesion kinase (FAK) and inhibits FAK/AKT signaling activity. PND1186, FAK inhibitor, inhibits breast cancer metastasis induced by IGSF9 knockdown in vitro and in vivo. Taken together, IGSF9 is trans-activated by p53 and inhibits breast cancer metastasis by modulating FAK/AKT signaling pathway. IGSF9 could serve as a prognostic marker and potential therapeutic target for breast cancer.

Although SWI/SNF chromatin remodelling complexes are known to regulate diverse biological functions in plants, the classification, compositions and functional mechanisms of the complexes remain to be determined. Here we comprehensively characterized SWI/SNF complexes by affinity purification and mass spectrometry in Arabidopsis thaliana, and found three classes of SWI/SNF complexes, which we termed BAS, SAS and MAS (BRM-, SYD- and MINU1/2-associated SWI/SNF complexes). By investigating multiple developmental phenotypes of SWI/SNF mutants, we found that three classes of SWI/SNF complexes have both overlapping and specific functions in regulating development. To investigate how the three classes of SWI/SNF complexes differentially regulate development, we mapped different SWI/SNF components on chromatin at the whole-genome level and determined their effects on chromatin accessibility. While all three classes of SWI/SNF complexes regulate chromatin accessibility at proximal promoter regions, SAS is a major SWI/SNF complex that is responsible for mediating chromatin accessibility at distal promoter regions and intergenic regions. Histone modifications are related to both the association of SWI/SNF complexes with chromatin and the SWI/SNF-dependent chromatin accessibility. Three classes of SWI/SNF-dependent accessibility may enable different sets of transcription factors to access chromatin. These findings lay a foundation for further investigation of the function of three classes of SWI/SNF complexes in plants.

Purpose Little is known about the relationship between the level of platelet NOD-like receptor protein 3 (NLRP3) and the severity of acute coronary syndrome (ACS) or the prognostic value of platelet NLRP3 for percutaneous coronary intervention (PCI). Methods Platelets collected from 25 healthy subjects, 23 patients with stable angina pectoris (SAP), and 72 patients with ACS were analyzed by Western blotting and real-time fluorescence quantitative PCR (qPCR). A total of 152 patients with ACS who had undergone PCI were included in this study to evaluate the prognostic value of platelet NLRP3. Results The levels of platelet NLRP3 in both the healthy and SAP groups were clearly lower than in the ACS group (P

Necroptosis, a form of programmed cell death, is characterized by the loss of membrane integrity and release of intracellular contents, the execution of which depends on the membrane-disrupting activity of the Mixed Lineage Kinase Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers committed MLKL-dependent necroptosis after muscle injury. Either pharmacological inhibition of the necroptosis upstream kinase Receptor Interacting Protein Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to significant muscle regeneration defects. By releasing factors into the muscle stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to be critical for MuSC proliferation. The temporary expression of TNC in myofibers is tightly controlled by necroptosis; the extracellular release of TNC depends on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR) signaling pathway in MuSCs through its N-terminus assembly domain together with the EGF-like domain. These findings indicate that necroptosis plays a key role in promoting MuSC proliferation to facilitate muscle regeneration.

In this study, the ultra-high-frequency (UHF) antenna for partial discharge (PD) detection is optimised to simultaneously satisfy the requirements of low return loss and high fidelity factor (FF) in the frequency band of interest by using the modified non-dominated sorting genetic algorithm II (MNSGA-II). Based on the labour division strategy, the MNSGA-II adopts an adaptive crossover and mutation possibilities instead of the fixed ones, resulting in the significant improvement of convergence rate and exploration ability. One of the Pareto-optimal solutions is presented as the authors’ proposed UHF antenna, whose performance is compared with those of both the antenna optimised by genetic algorithm and the existing wideband antennas. The experimental results show that the proposed antenna with a compact size of 0.201 λ L × 0.198 λ L realises the reflection coefficient less than −10 dB from 490 MHz to 1.52 GHz, and its FFs in the face-to-face and side-by-side scenarios are 0.897 and 0.845, respectively. Furthermore, the simulation results reveal that the high FF of antenna greatly increases the accuracy of PD source localisation. It indicates that the MNSGA-II provides an excellent solution to the multiobjective optimisation problems in antenna design.

Imitation Switch (ISWI) chromatin remodelers are known to function in diverse multi-subunit complexes in yeast and animals. However, the constitution and function of ISWI complexes in Arabidopsis thaliana remain unclear. In this study, we identified forkhead-associated domain 2 (FHA2) as a plant-specific subunit of an ISWI chromatin-remodeling complex in Arabidopsis. By in vivo and in vitro analyses, we demonstrated that FHA2 directly binds to RLT1 and RLT2, two redundant subunits of the ISWI complex in Arabidopsis. The stamen filament is shorter in the fha2 and rlt1/2 mutants than in the wild type, whereas their pistil lengths are comparable. The shorter filament, which is due to reduced cell size, results in insufficient pollination and reduced fertility. The rlt1/2 mutant shows an early-flowering phenotype, whereas the phenotype is not shared by the fha2 mutant. Consistent with the functional specificity of FHA2, our RNA-seq analysis indicated that the fha2 mutant affects a subset of RLT1/2-regulated genes that does not include genes involved in the regulation of flowering time. This study demonstrates that FHA2 functions as a previously uncharacterized subunit of the Arabidopsis ISWI complex and is exclusively involved in regulating stamen development and plant fertility.

Yi Li,1,* Yizhao Xie,1,* Chengcheng Gong,1 Yannan Zhao,1 Jian Zhang,1 Sheng Zhang,1 Leiping Wang,1 She Chen,2 Xichun Hu,1 Biyun Wang1 1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 2Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Biyun Wang; Xichun HuDepartment of Medical Oncology, Fudan University Shanghai Cancer Center, #270 Dongan Road, Xuhui District, Shanghai 200032, People’s Republic of ChinaEmail wangbiyun0107@hotmail.com; huxichun2017@163.comBackground: Fulvestrant (FUL) and the combination of everolimus and exemestane (EVE-EXE) were the options to treat hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) patients who were refractory to aromatase inhibitors (AIs). The practical knowledge of treatment patterns and outcomes between the two regimens is essential for improving treatment decisions.Methods: HR+/HER2− MBC patients, who were refractory to AI, were treated with FUL or EVE-EXE from June 2013 to June 2016 were included. Treatment patterns, progression-free survival (PFS), overall survival (OS), and toxicity were reported. Propensity score matching (PSM) was used to minimize potential confounders.Results: A total of 168 patients were enrolled. Of 168 patients, 124 patients were treated with FUL and 44 patients received EVE-EXE. Patients who were treated with EVE-EXE were younger, more likely to have visceral, liver, multiple sites of metastases, and had received more prior chemotherapy. After adjusting for propensity score matching (PSM), no significant difference in PFS was found between two groups (P=0.419). However, in the subgroup of multiple metastatic sites, the median PFS was significantly improved in the EVE-EXE arm compared with FUL arm (6.1 vs 3.2 months, respectively, P=0.012). More patients in EVE-EXE arm discontinued treatment due to adverse events than in the FUL arm.Conclusion: A substantial difference in treatment patterns was observed between the two arms. Clinical outcomes were comparable after PSM.Clinicaltrials.gov Identifier: NCT03695341 (May 14, 2018).Keywords: fulvestrant, everolimus, exemestane, metastatic breast cancer, endocrine therapy

The Diels-Alder reaction is one of the most powerful and widely used methods in synthetic chemistry for the stereospecific construction of carbon-carbon bonds. Despite the importance of Diels-Alder reactions in the biosynthesis of numerous secondary metabolites, no naturally occurring stand-alone Diels-Alderase has been demonstrated to catalyse intermolecular Diels-Alder transformations. Here we report a flavin adenine dinucleotide-dependent enzyme, Morus alba Diels-Alderase (MaDA), from Morus cell cultures, that catalyses an intermolecular [4+2] cycloaddition to produce the natural isoprenylated flavonoid chalcomoracin with a high efficiency and enantioselectivity. Density functional theory calculations and preliminary measurements of the kinetic isotope effects establish a concerted but asynchronous pericyclic pathway. Structure-guided mutagenesis and docking studies demonstrate the interactions of MaDA with the diene and dienophile to catalyse the [4+2] cycloaddition. MaDA exhibits a substrate promiscuity towards both dienes and dienophiles, which enables the expedient syntheses of structurally diverse natural products. We also report a biosynthetic intermediate probe (BIP)-based target identification strategy used to discover MaDA.

Necroptosis is a regulated necrotic cell death pathway involved in development and disease. Its signaling cascade results in the formation of disulfide bond-dependent amyloid-like polymers of mixed lineage kinase domain-like protein (MLKL), which mediate proinflammatory cell membrane disruption. We screened compound libraries provided by the National Cancer Institute and identified a small-molecule inhibitor of necroptosis named necroptosis-blocking compound 1 (NBC1). Biotin-labeled NBC1 specifically conjugates to heat shock protein Hsp70. NBC1 and PES-Cl, a known Hsp70 substrate-binding inhibitor, block the formation of MLKL polymers, but not MLKL tetramers in necroptosis-induced cells. In vitro, recombinant Hsp70 interacts with the N-terminal domain (NTD) of MLKL and promotes NTD polymerization, which has been shown to mediate the cell killing activity. Furthermore, the substrate-binding domain (SBD) of Hsp70 is sufficient to promote MLKL polymerization. NBC1 covalently conjugates cysteine 574 and cysteine 603 of the SBD to block its function. In addition, an SBD mutant with both cysteines mutated to serines loses its ability to promote MLKL polymerization. Interestingly, knockdown of Hsp70 in cells leads to MLKL destabilization, suggesting that MLKL might also be a client protein of Hsp70. In summary, using NBC1, an inhibitor of necroptosis, we identified Hsp70 as a molecular chaperone performing dual functions in necroptosis. It stabilizes MLKL protein under normal condition and promotes MLKL polymerization through its substrate-binding domain during necroptosis.

Necroptosis is a regulated necrotic cell death pathway, mediated by a supermolecular complex called the necrosome, which contains receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Phosphorylation of human RIPK3 at serine 227 (S227) has been shown to be required for downstream MLKL binding and necroptosis progression. Tandem immunoprecipitation of RIPK3 reveals that casein kinase 1 (CK1) family proteins associate with the necrosome upon necroptosis induction, and this interaction depends on the kinase activity of RIPK3. In addition, CK1 proteins colocalize with RIPK3 puncta during necroptosis. Importantly, CK1 proteins directly phosphorylate RIPK3 at S227 in vitro and in vivo. Loss of CK1 proteins abolishes S227 phosphorylation and blocks necroptosis. Furthermore, a RIPK3 mutant with mutations in the CK1 recognition motif fails to be phosphorylated at S227, does not bind or phosphorylate MLKL, and is unable to activate necroptosis. These results strongly suggest that CK1 proteins are necrosome components which are responsible for RIPK3-S227 phosphorylation.

An experimental platform was established to study the influence of gas pressure on SF 6 decomposition characteristics under AC corona discharge. Content variation of typical products including SOF 2 , SO 2 F 2 , SO 2 , CO 2 under different pressures and the influence mechanism was observed and analyzed in detail. The results indicate that the contents of all four typical products decrease with the increase of pressure. The values of ϕ(SOF 2 +SO 2 +SO 2 F 2 )/ϕ(CO 2 ) and ϕ(SO 2 F 2 )/ϕ(SOF 2 +SO 2 ) present an overall decreasing trend with pressure. Besides, relational model between content of products and pressure was proposed. The value of CO 2 could be imitated by a quasi-linear fitting equation: f(P)=(a/(P+b))+c. The variation trend of the contents of three sulfur-containing products with the pressure could be fitted by a function of f(P)=(ae−bP)/(P2+cP+d).

To observe the clinical therapeutic effect on functional erectile dysfunction (FED) of kidney deficiency and liver stagnation treated byA total of 120 patients with FED were randomized into an observation group (60 cases, 2 cases dropped off) and a control group (60 cases, 4 cases dropped off). In the control group, the patients were treated with oralAfter treatment, the scores of IIEF5, EHS and EDITS were all increased as compared with the values before treatment (The combined therapy of

Plants employ cell-surface-localized pattern recognition receptors (PRRs) to recognize immunogenic patterns and activate defenses. How these receptors regulate immune signaling in the nucleus is not well understood. Our previous studies showed that BIK1, a central kinase associated with PRRs, phosphorylates a plant-specific Gα protein called extra-large G protein 2 (XLG2) to positively regulate immunity. Here, we show that this phosphorylation promotes XLG2 nuclear translocation, which is essential for antibacterial immunity. XLG2 interacts with nuclear-localized MUT9-like kinases (MLKs) to regulate transcriptome programming. MLKs negatively regulate plant immunity in a kinase activity-dependent manner, whereas XLG2 promotes defense gene expression and antibacterial immunity likely by inhibiting MLK kinase activity. A C-terminal motif in MLKs is essential for the interaction with XLG2, and this motif is required for the XLG2-mediated defense activation. Together, our findings reveal a previously unknown pathway and mechanisms by which cell surface receptors regulate transcriptome during pathogen invasion.

Background Long noncoding RNAs (lncRNAs), a type of pervasive genes that regulates various biological processes, are differentially expressed in different types of malignant tumors. The role of lncRNAs in the carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we investigated the role of the lncRNA DKFZp434J0226 in PDAC. Methods Aberrantly expressed mRNAs and lncRNAs among six PDAC and paired non-tumorous tissues were profiled using microarray analysis. Quantitative real-time polymerase chain reaction was used to evaluate DKFZp434J0226 expression in PDAC tissues. CCK-8 assay, wound-healing assay, soft agar colony formation assay, and transwell assay were performed to assess the invasiveness and proliferation of PDAC cells. Furthermore, RNA pull-down, immunofluorescence, RNA immunoprecipitation, and western blotting assays were performed to investigate the association between DKFZp434J0226 and SF3B6. Tumor xenografts in mice were used to test for tumor formation in vivo. Results In our study, 222 mRNAs and 128 lncRNAs were aberrantly expressed (≥ twofold change). Of these, 66 mRNAs and 53 lncRNAs were upregulated, while 75 lncRNAs and 156 mRNAs were downregulated. KEGG pathway analysis and the Gene ontology category indicated that these genes were associated with the regulation of mRNA alternative splicing and metabolic balance. Clinical analyses revealed that overexpression of DKFZp434J0226 was associated with worse tumor grading, frequent perineural invasion, advanced tumor-node-metastasis stage, and decreased overall survival and time to progression. Functional assays demonstrated that DKFZp434J0226 promoted PDAC cell migration, invasion, and growth in vitro and accelerated tumor proliferation in vivo. Mechanistically, DKFZp434J0226 interacted with the splicing factor SF3B6 and promoted its phosphorylation, which further regulated the alternative splicing of pre-mRNA. Conclusions This study indicates that DKFZp434J0226 regulates alternative splicing through phosphorylation of SF3B6 in PDAC and leads to an oncogenic phenotype in PDAC.

Purpose Paclitaxel, belongs to tubulin-binding agents (TBAs), showed a great efficacy against breast cancer via stabilizing microtubules. Drug resistance limits its clinical application. Here we aimed to explore a role of Polarity protein Par3 in improving paclitaxel effectiveness.Methods Breast cancer specimens from 45 patients were collected to study the relationship between Par3 expression and paclitaxel efficacy. The Kaplan–Meier method was used for survival analysis. Cell viability was measured in breast cancer cells (SK-BR-3 and T-47D) with Par3 over-expression or knockdown. The flow cytometry assays were performed to measure cell apoptosis and cell cycle. BrdU incorporation assay and Hoechst 33258 staining were performed to measure cell proliferation and cell apoptosis, respectively. Immunofluorescence was used to detect microtubule structures. Results Par3 expression is associated with good response of paclitaxel in breast cancer patients. Consistently, Par3 overexpression significantly sensitizes breast cancer cells to paclitaxel by promoting cell apoptosis and reducing cell proliferation. In Par3 overexpressing cells upon paclitaxel treatment, we observed intensified cell cycle arrests at metaphase. Further exploration showed that Par3 overexpression stabilizes microtubules of breast cancer cells in response to paclitaxel, and resists to microtubules instability induced by nocodazole, a microtubule-depolymerizing agent. Conclusion Par3 facilitates polymeric forms of tubulin and stabilizes microtubule structure, which aggravates paclitaxel-induced delay at the metaphase-anaphase transition, leading to proliferation inhibition and apoptosis of breast cancer cells. Par3 has a potential role in sensitizing breast cancer cells to paclitaxel, which may provide a more precise assessment of individual treatment and novel therapeutic targets.

The canonical function of phosphodiesterase 3A (PDE3A) is to hydrolyze the phosphodiester bonds in second messenger molecules, such as cyclic AMP (cAMP) and cyclic guanosine monophosphate (cGMP). Recently, a phosphodiesterase-activity-independent role for PDE3A was reported. In this noncanonical function, PDE3A physically interacts with Schlafen 12 (SLFN12) upon treatment of cells with cytotoxic PDE3A modulators. Here, we confirmed that the cytotoxic PDE3A modulators act as molecular glues to initiate the association of PDE3A and SLFN12. The PDE3A-SLFN12 interaction increases the protein stability of SLFN12 located in the cytoplasm, while at the same time also inducing SLFN12 dephosphorylation (including serines 368 and 573). Mutational analysis demonstrates that dephosphorylation is required for cell death induced by cytotoxic PDE3A modulators. Finally, we found that dephosphorylation promoted the rRNA RNase activity of SLFN12 and show that this nucleolytic activity is essential for SLFN12's cell-death-inducing function. Thus, our study deepens the understanding of the biochemical mechanisms underlying SLFN12-mediated cell death.

The XLPE cables are a vital part of power transportation. Defects in the insulation of the cable body and its accessories may lead to economic losses or safety hazards, and the current installation quality of cable terminal joints lacks effective detection methods. Since the permittivity of the cable insulation will change accordingly when there is a defect in the cable insulation, Electrical capacitance tomography (ECT) is a technique that can display the spatial distribution of permittivity of different media. In this work ECT is applied to the detection of insulation defects in XLPE cables. An eight-electrode array sensor is manufactured, and the cable capacitance is detected with an impedance meter. The cable sample sheath layer was cut into a defect area with a length of 20 mm, a width of 10 mm, and a thickness of 1 mm to simulate an air gap defect. The capacitance value of the intact cable and the defective cable is measured by the sensor and impedance analyzer, and the image of the internal structure of the cable is established using the linear back-projection algorithm. Experimental results show that ECT algorithm can detect the air gap defect in the XLPE cable insulation, but the imaging accuracy still needs to be improved.

Streamers are a rapidly moving ionization front in gas, liquid, or solid. In this work, photoionization model of dry and humid air is integrated into a macroscopic 3D streamer discharge mechanism. By calculating the electric field and charge field in 3D streamer, the charge transport in streamer channel is described by the law of charge conservation. Streamer discharge results of positive streamer in dry and humid air within 50ns are obtained by simulation. The results show that the macroscopic values of streamer discharge will change. Compared with dry air, the channel electric field of streamer discharge increases in humid air, but its propagation velocity and diameter decrease. For a single streamer, water molecules weaken the photoionization rate of streamer head, so streamer branches more frequently in humid air.

Patients with Crohn’s disease (CD) are inclined to have platelet hyperactivity and an increased risk of intestinal micro-thrombosis. However, the mechanisms underlying platelet hyperactivity in CD are not well understood. We investigated the assembly of platelet NLRP3 inflammasome in patients with active CD and its correlation with platelet hyperactivity. In this study, Real-time PCR and western blotting analyses uncovered that ASC, NLRP3, and active caspase-1 were significantly upregulated in platelets from patients with active CD compared with healthy subjects. As revealed by flow cytometry (FCM) and ELISA analyses, the levels of interleukin-1β in both serum and isolated platelets were elevated in patients with active CD. Co-immunoprecipitation and immunofluorescence experiments revealed an increased assembly of NLRP3 inflammasome in platelets from patients with active CD. In addition, higher levels of intracellular reactive oxygen species (ROS) were observed in these platelets by FCM. Furthermore, elevated levels of platelet P-selectin exposure and fibrinogen binding were demonstrated in patients with active CD by FCM. They were positively correlated with the protein levels of NLRP3 inflammasome components. Collectively, our results indicate that the ROS-NLRP3 inflammasome-interleukin-1β axis may contribute to platelet hyperactivity in active CD.

Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF2α induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF2α but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knock-in mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.

Potential substitutes for SF 6 such as fluoroketone (C 6 F 12 O and C 5 F 10 O) and fluoronitrile (C 4 F 7 N and C 3 F 5 N) gases have been widely studied. The electron impact ionization cross section (Q ion ) is the key parameter in the simulation of gas discharges. Moreover, the Q ion can be used in the preliminary screening of large scale alternatives of SF 6 . In this paper, the Q ion of C 6 F 12 O, C 5 F 10 O, C 4 F 7 N and C 3 F 5 N are calculated via the BEB method. The orbital parameters are obtained by M⊘ller-Plesset perturbation function with second order approximation (MP2), which is validated by comparing the theoretical and experimental Q ion for CH 3 CN, CF 3 CN, C 2 H 4 O, C 3 H 6 O and C 4 H 8 O. The linear relationship between the maximum Q ion and polarisability supports the validity of the BEB method with MP2 function, which suggests that the results of the calculated maximum Q ion for C 5 F 10 O and C 4 F 7 N are reasonable by BEB method. Lastly, the correlation between the maximum Q ion and E r is discussed. The analysis shows that there is a correlation between the maximum Q ion and E r , and the correlation coefficient reaches 0.598. It is thought that Q ion can be as a new predictor to estimate the dielectric strengths for SF 6 replacements.

Corona discharges on high-voltage transmission lines cause the problems of energy waste and electromagnetic interferences. Previous studies on negative DC corona discharges are mainly on the effects of various environmental factors on the corona inception voltage, Trichel pulse frequency etc. However, few researches are focused on Trichel pulses-pulseless glow mode transition, and their transition mechanisms are still lacking. In this paper, a vacuum vessel is built up in which the humidity and pressure can be accurately controlled to simulate corona discharges under different climatic conditions. The pressure range is 50–101 kPa and the relative humidity (RH) is 10–90%. A needle-plane electrode with different radius of curvature is used to produce negative corona discharges. It is found that the transition voltage increases with the RH and air pressure. A higher humidity results in the formation of hydrated ions with lower ion mobility and the increase in the gas temperature around the needle electrode. The experimental results demonstrate that the effect of reduced ion mobility is greater than the gas temperature rise. Furthermore, an interim process, in which the Trichel pulses and the pulseless glow exist simultaneously, appears during the discharge modes transition for the needle electrode with a larger radius of curvature.

Corona discharge is a self-sustained discharge of gaseous medium in inhomogeneous electric fields, which often occurs on transmission lines and has some adverse effect on the power transmission system. In this paper, a kinetic model of corona discharges is presented to simulate the evolution process of charged particles and neutral species in humid air. To investigate the effect of humidity, our model consists of 69 species and 393 chemical reactions which consider important reactions containing H2O molecules and hydrates. In addition, CO2 molecules are also included to improve the integrity of reaction database. A temporal evolution of reduced electric field strengths E/N, which are typical experimental values of corona discharges, is used as input. The simulation results show that H3O+ is one of the dominant positive ions which is in qualitative agreement with previous experimental results. The effect of humidity and pulse width on the plasma chemistry is also discussed. It is found that the humidity affects the maximum density and life time of the specific species. Meanwhile, the plasma chemistry could be affected by different pulse widths of the input electric field.

The grading capacitor (GC) of circuit breaker (CB) is one of the most cost-effective methods to suppress secondary arc. Taking the double-break CB as an example, its topology is briefly introduced. The electric circuit for power system with GC is then established. From the perspective of minimizing secondary arc current, the formula for the capacitance of GC is deduced according to the Kirchhoff's voltage law. Based on the equal-area criterion, the transient process of power angle and speed of generator in the event of fault is investigated, and the role of GC in the transient stability is quantitatively investigated. Meanwhile, the expressions for the accelerating and decelerating areas are computed through the numerical calculus, and the impact of GC capacitance on the critical clearing time (CCT) is discussed. Furthermore, to verify the aforementioned analysis, a model is established in the environment of MATLAB/Simulink, and two cases are considered, i.e., a single machine infinite bus (SMIB) power system and a multi-machine power system. Both the theoretical analysis and the simulation results demonstrate that the use of GC can strength the electrical connection between two remote power sources, undermines the oscillating amplitude of power angle, and shorten the attenuation duration. As a result, the CCT and transient margin would be increased. In other words, we can prong the dead time and guarantee the successfulness for autoreclosure scheme. The GC of CB is much superior to the existing four-legged shunt reactor and high speed grounding switch in addressing the secondary arc issue.