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With growing complexity and uncertainty from distributed generations and active customers, distribution networks are facing more unexpected events and topology changes; while very limited measurements may degrade the observability of distribution system states and endanger the security of the system. Meanwhile, massive data from various types of users (if they can be used), can be valuable for power utilities. This makes privacy and data security a more critical issue, while being endowed with operation and market flexibilities. Thus, we propose a blockchain-based privacy-protecting approach for Dynamic Topology Awareness (DTA) to distinguish topology changes from cyber anomalies, including physical, cyber and business layers. At the bottom layer (physical layer), the distribution network is partitioned into subareas and tie-line areas, coping with local data from measurement devices or users. Estimated border values from parallel local estimations would be examined through data consistency checking. And DTA consensus algorithm might be triggered, querying historical status stored as blockchain contracts for anomalies detections and new block formations. Voting mechanism is then adopted to verify new blocks from data tampering. The performance of the proposed DTA approach is validated through simulations to identify topology changes and cyber anomalies, with additional discussions on the trade-off between DTA sensitivity and estimation accuracy.

The frequent switching operations and triggering events of automation devices are poorly documented in distribution management systems, leading to challenging work regarding the timely detection of system state changes. Additionally, the limited measurements in distribution networks and the randomness of plug-and-play devices make obtaining real-time observations of system states difficult. Furthermore, distributed generation (DG) output uncertainties exacerbate the situation. Thus, we propose a dynamic topology awareness (DTA) approach to make judgments regarding operational states and identify all possible topology changes (including normal operations, islanding and outages) in the absence of real-time DG measurements. The method consists of two steps. The first step applies parallel Gaussian mixture model-based probabilistic state estimators (GMM-PSEs) of subareas and extended subareas to calculate the probability distributions of border bus voltages with full consideration of DG uncertainties. The second step utilizes the Kullback-Leibler (KL) divergence measure to evaluate the difference between the two probability distributions estimated by subareas and extended subareas, thereby obtaining an indicator (average KL divergence) for identifying possible topologies. The effectiveness of the proposed method is examined on the IEEE 33-bus and IEEE 123-bus test cases. It is computationally efficient and accurate when identifying all possible topologies under limited measurements and DG uncertainties.

We report a case of inflammatory myofibroblastic tumor of the bladder (IMTB) that arises from left posterior bladder wall. The IMTB usually demonstrates slight hypointensity on T1WI, heterogeneous bright hyperintensity on T2WI, hyperintensity on DWI, and no restricted diffusion on ADC map. IMTB exhibits irregular ring enhancement and scatters stripe-like enhancement in central area with progressive and persistent enhancement pattern on CE-MRI. High-contrast multisequence MRI may be a potential technique to distinguish IMTB from other bladder tumors.

Despite the well-established role of CMTM6 in the stabilization of cell surface PD-L1 in cancer cells, the mechanisms underlying CMTM6 expression and regulation are still largely unknown. Here we unexpectedly find a strikingly positive correlation between CMTM6 and Hu-Antigen R (HuR) expression in most types of cancer. Mechanistically, we elucidate HuR stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3′UTR and predominantly up-regulates CMTM6, which is readily abolished by HuR-specific inhibitor, MS-444. Phenotypically, we notice abundant cell surface PD-L1 in HuR-high cancer cells, which significantly inhibits immune activation of co-cultured T cells as indicated by IL-2 production. Treatment with MS-444 completely relieves immune suppression imposed by HuR-overexpression and further stimulates immune responses. Ectopic HuR accelerates allograft tumor progression in vivo, which is greatly compromised by simultaneous administration with MS-444. Our study uncovers a novel mechanism in control of CMTM6 and therefore PD-L1 expression, and suggests the potential of combining HuR inhibitor with PD-1/PD-L1 antibodies for cancer immunotherapy.

Aberrant activation of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome drives the development of many complex inflammatory diseases, such as obesity, Alzheimer's disease, and atherosclerosis. However, no medications specifically targeting the NLRP3 inflammasome have become clinically available. Therefore, we aim to identify new inhibitors of the NLRP3 inflammasome in this study. Methods: Vesicle-like nanoparticles (VLNs) were extracted from garlic chives and other Allium vegetables and their effects on the NLRP3 inflammasome were evaluated in primary macrophages. After garlic chive-derived VLNs (GC-VLNs) were found to exhibit potent anti-NLRP3 inflammasome activity in cell culture, such function was further assessed in a murine acute liver injury disease model, as well as in diet-induced obesity. Finally, GC-VLNs were subjected to omics analysis to identify the active components with anti-NLRP3 inflammasome function. Results: GC-VLNs are membrane-enclosed nanoparticles containing lipids, proteins, and RNAs. They dose-dependently inhibit pathways downstream of NLRP3 inflammasome activation, including caspase-1 autocleavage, cytokine release, and pyroptotic cell death in primary macrophages. The inhibitory effects of GC-VLNs on the NLRP3 inflammasome are specific, considering their marginal impact on activation of other inflammasomes. Local administration of GC-VLNs in mice alleviates NLRP3 inflammasome-mediated inflammation in chemical-induced acute liver injury. When administered orally or intravenously, GC-VLNs accumulate in specific tissues and suppress activation of the NLRP3 inflammasome and chronic inflammation in diet-induced obese mice. The phospholipid 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) in GC-VLNs has been identified to inhibit NLRP3 inflammasome activation. Conclusions: Identification of GC-VLNs and their active component DLPC as potent inflammasome inhibitors provides new therapeutic candidates in the treatment of NLRP3 inflammasome-driven diseases.

The pioneering work from Lieping Chen’s laboratory identified Siglec‐15 as a novel tumor immune suppressor, while the regulatory mechanisms underlying the broad upregulation of Siglec‐15 in human cancers remain obscure. Here we found that long non–coding RNA (lncRNA) LINC00973 was higher in Siglec‐15‐positive clear‐cell renal cell carcinoma (ccRCC), and LINC00973 positively regulated Siglec‐15 expression at transcriptional level. This effect was evidently dependent on miR‐7109‐3p (designated as miR‐7109 hereafter), and we provided evidence that Siglec‐15 is a direct target of miR‐7109. Through sponging miR‐7109, LINC00973 functioned as competing endogenous RNA (ceRNA) to control cell surface abundance of Siglec‐15, and, consequently, was involved in cancer immune suppression. We further demonstrated that LINC00973 and miR‐7109 expression in ccRCC antagonistically influenced immune activation of co–cultured Jurkat cells. Our study highlighted the importance of LINC00973‐miR‐7109‐Siglec‐15 in immune evasion in ccRCC, which offers significant opportunity for both therapeutic intervention and diagnostic/prognostic exploitations., Through sponging miR‐7109, LINC00973 functioned as competing endogenous RNA (ceRNA) to control cell surface abundance of Siglec‐15, and, consequently, was involved in cancer immune suppression. LINC00973 and miR‐7109 expression in ccRCC antagonistically influenced immune activation of co–cultured Jurkat cells.

The clinical success of immune checkpoint blockade against diverse human cancers highlights the critical importance of insightful understanding into mechanisms underlying PD-L1 regulation. IFN-γ released by intratumoral lymphocytes regulates PD-L1 expression in tumor cells through JAK-STAT-IRF1 pathway, while the molecular events prime IRF1 to translocate into nucleus are still obscure. Here we identified STXBP6, previously recognized involving in SNARE complex assembly, negatively regulates PD-L1 transcription via retention of IRF1 in cytoplasm. IFN-γ exposure stimulates accumulation of cytosolic IRF1, which eventually saturates STXBP6 and triggers nuclear translocation of IRF1. Nuclear IRF1 in turn inhibits STXBP6 expression and thereby liberates more IRF1 to migrate to nucleus. Therefore, we identified a novel positive feedback loop between STXBP6 and IRF1 in regulation of PD-L1 expression in cancer. Furthermore, we demonstrate STXBP6 overexpression significantly inhibits T cell activation both in vitro and in vivo. These findings offer new insight into the complexity of PD-L1 expression in cancer and suggest a valuable measure to predict the response to PD-1/PD-L1-based immunotherapy.

Highlights • PEDV ORF3 is a transmembrane protein that localizes at endoplasmic reticulum to induce ER stress response. • PEDV ORF3 protein has no effect on apoptosis, but induces autophagy dependent on ER stress response. • This work provides some new findings for the biological function of the PEDV ORF3 protein., Porcine epidemic diarrhea virus (PEDV), the causative agent of PED, is an enveloped, positive-stranded RNA virus in the genus Alphacoronavirus, family Coronaviridae, order Nidovirales. PEDV non-structural accessory protein ORF3 is an ion channel related to viral infectivity and pathogenicity. Our previous study showed that PEDV ORF3 has expression characteristic of aggregation in cytoplasm, but its biological function remains elusive. Thus in this study, we initiated the construction of various vectors to express ORF3, and found ORF3 localized in the cytoplasm in the aggregation manner. Subsequently, confocal microscopy analysis showed that the aggregated ORF3 localized in endoplasmic reticulum (ER) to trigger ER stress response via up-regulation of GRP78 protein expression and activation of PERK-eIF2α signaling pathway. In addition, our results showed that PEDV ORF3 could induce the autophagy through inducing conversion of LC3-I to LC3-II, but couldn’t influence the apoptosis. In contrast, conversion of LC3-I/LC3-II could be significantly inhibited by 4-PBA, an ER stress inhibitor, indicating that ORF3-induced autophagy is dependent on ER stress response. This work not only provides some new findings for the biological function of the PEDV ORF3 protein, but also help us for the further understanding the molecular interaction between PEDV ORF3 protein and cells.

In addition to the power network, the integrated energy system also includes other energy networks, such as heating and cooling networks, combined cooling, heating and power (CCHP) units, electric boilers, heating pumps and other coupling equipment with different properties. The traditional estimation method of power networks ignores the information from heating/cooling networks. To take into account the interconnections between the networks, this paper focuses on integrated energy system modeling and state estimation (SE) algorithm, and studies the relevant SE theories. To improve the estimation accuracy and reduce the computational complexity, based on the Weighted Least Squares (WLS) algorithm, the heating network - cooling network – power network SE is decoupled into several estimation processes with CCHP coupling alternating iterative constraint conditions. Thus, a decoupling SE method for microgrid park of integrated energy is proposed. Finally, the feasibility of the decoupling SE method and its advantages over the traditional SE method of the power network are verified by the simulations in a 59-node microgrid park with CCHP.

Porcine epidemic diarrhea virus (PEDV) encodes many multifunctional proteins that inhibit host innate immune response during virus infection. As one of important structural proteins, PEDV E protein has been found to block the production of type I interferon (IFN) in virus life cycle, but little is known about this process that E protein subverts host innate immune. Thus, in this present study, we initiated the construction of eukaryotic expression vectors to express PEDV E protein. Subsequently, cellular localization analysis was performed and the results showed that the majority of PEDV E protein distributed at cytoplasm and localized in endoplasmic reticulum (ER). Over-expression of PEDV E protein significantly inhibited poly(I:C)-induced IFN-β and IFN-stimulated genes (ISGs) productions. We also found that PEDV E protein remarkably suppressed the protein expression of RIG-I signaling-associated molecules, but all their corresponding mRNA levels remained unaffected and unchanged. Furthermore, PEDV E protein obviously interfered with the translocation of IRF3 from cytoplasm to nucleus through direct interaction with IRF3, which is crucial for the IFN-β production induced by poly(I:C). Taken together, our results suggested that PEDV E protein acts as an IFN-β antagonist through suppression of the RIG-I-mediated signaling. This study will pave the way for the further investigation into the molecular mechanisms by which PEDV E protein evades host innate immune response.

Hybrid AC/DC power grids with various distributed power generations are considered to be the emerging architecture of future power system, where highly penetrated power electronic devices (Voltage Source Converters) as well as DGs can increase operation flexibilities, and would also cause new difficulties for system state estimation. Therefore, it is necessary to develop pseudo measurement modelling method for converters and DGs, especially when the control parameters of converters are unknown. In this paper, the model of VSCs considering their losses are used for pseudo measurement modelling of converters: control information-based modelling method for the observable VSCs and Gaussian Mixture Model (GMM)-based modelling method for unobservable VSCs. Developed from Weighted Least Squares (WLS), an improved AC/DC hybrid grid state estimation algorithm is proposed. Simulations for algorithm validations are carried out with modified IEEE-14 bus system. Results show that the effectiveness of proposed state estimation algorithm does not depend on measurement configurations or communications between operation center and VSC stations, and shows robustness with data errors existing in the adopted historic DG power outputs.

Honey has been used as a nutrient, an ointment, and a medicine worldwide for many centuries. Modern research has demonstrated that honey has many medicinal properties, reflected in its anti‐microbial, anti‐oxidant, and anti‐inflammatory bioactivities. Honey is composed of sugars, water and a myriad of minor components, including minerals, vitamins, proteins and polyphenols. Here, we report a new bioactive component‒vesicle‐like nanoparticles‒in honey (H‐VLNs). These H‐VLNs are membrane‐bound nano‐scale particles that contain lipids, proteins and small‐sized RNAs. The presence of plant‐originated plasma transmembrane proteins and plasma membrane‐associated proteins suggests the potential vesicle‐like nature of these particles. H‐VLNs impede the formation and activation of the nucleotide‐binding domain and leucine‐rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, which is a crucial inflammatory signalling platform in the innate immune system. Intraperitoneal administration of H‐VLNs in mice alleviates inflammation and liver damage in the experimentally induced acute liver injury. miR‐4057 in H‐VLNs was identified in inhibiting NLRP3 inflammasome activation. Together, our studies have identified anti‐inflammatory VLNs as a new bioactive agent in honey.

Our previous study identified a novel VHLα isoform which negatively modulated hnRNPA2B1 expression and therefore influenced pyruvate kinase transcript splicing in renal cancer, while the regulation and initiation of alternative translation are largely unknown. Here we unraveled the CUG-mediated translation start of VHLα, which was subjected to the regulation by both eukaryotic initiator factor eIF2A and RNA helicase eIF4A. Unexpectedly, we found hnRNPA2B1 promoted VHLα alternative translation as well via direct interaction with its octadic pentamer region of VHL transcript. The N-terminal of VHLα was indispensable in mediating ubiquitination of hnRNPA2B1 at lysine residues 274 and 305. We further identified aberrant overexpression of c-myc as upstream oncogenic signaling to positively regulate hnRNPA2B1 transcription in renal cancer. Therefore, our data suggested an anti-tumoral feedback loop between VHLα and hnRNPA2B1.

Enterovirus 71 (EV71) is a human pathogen that induces hand, foot, and mouth disease (HFMD) and fatal neurological diseases in young children and infants. Pathogenicity of EV71 is likely related to its ability to evade host innate immunity through inhibiting cellular type I interferon signaling. However, it is less well understood the molecular events governing this process. In this study, we found that EV71 infection suppressed the induction of antiviral immunity by inhibiting the expression levels of IFN-β and IFN-stimulated genes (ISGs), such as ISG54 and ISG56, at the late stage of viral infection. At the same time, our results showed that EV71 infection significantly inhibited ubiquitination of RIG-I. In contrast, up-regulation of RIG-I ubiquitination promoted expression of IFN-β and ISGs, suggesting that inhibition of cellular type I interferon signaling was caused by down-regulation of RIG-I ubiquitination during EV71 infection. These results suggest that inhibition of RIG-I-mediated type I IFN responses by EV71 may contribute to the pathogenesis of viral infection.

Coxsackievirus A16 (CA16) is one of predominant Enterovirus that possesses high pathogenicity. Lipid rafts, as cholesterol - and sphingolipid - enriched membrane nanodomains, are involved into many aspects of the virus life cycle. Our previous study found that lipid rafts integrity was essential for CA16 replication, but how lipid rafts regulate CA16 replication through activating downstream signaling remains largely unknown. Thus, in this study, we revealed that lipid rafts were required for activation of PI3K/Akt signaling at early stage of CA16 infection. Treatment with wortmannin significantly reduced the expression of virus protein, indicating PI3K/Akt signaling was beneficial for early stage of virus infection. In addition, lipid rafts integrity was also indispensable for PI3K/Akt activation during the late stage of CA16 infection, which played critical functions in mediating sterol regulatory element-binding proteins 1 (SREBP1) maturation. Whereas, over-expression of SREBP1 exhibited inhibition on virus replication, suggesting that PI3K/Akt signaling and SREBP1 might positively and negatively influence virus replication in two different stages of infection, respectively. Taken together, our study demonstrates an important role of the lipid raft-associated PI3K/Akt/SREBP1 signaling in modulating CA16 replication, which will deepen our understanding mechanism of CA16 infection.

Porcine epidemic diarrhea virus (PEDV) is an enveloped, single-stranded positive-sense RNA virus that belongs to a porcine entero-pathogenic alphacoronavirus, causing lethal watery diarrhea in piglets. Despite existing study reports the sole accessory protein ORF3 identified as NF-κB antagonist, the contribution of PEDV ORF3 to production of the pro-inflammatory cytokines mediated by NF-κB signaling remains largely unknown. Thus in this present study, we showed that PEDV ORF3 protein significantly inhibited the productions of pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8. The phosphorylation of IκBα was inhibited by ORF3 protein, but no degradation of IκBα was induced in ORF3-expressing cells. Furthermore, PEDV ORF3 inhibited NF-κB activation through preventing nuclear factor p65 phosphorylation and down-regulating p65 expression level, as well as interfering nuclear translocation of p65, eventually resulting into the inhibition of IL-6 and IL-8 production. Our study definitely links PEDV ORF3 to inhibition of pro-inflammatory cytokines production, which will provide new insight into the molecular mechanisms of NF-κB activity inhibited by PEDV proteins to facilitate virus evasion of host innate immune.

Household distributed energy resources (DER) have gained in popularity with the growing interest in environmental protection and with the technological development of internal combustion (IC) engines, gas turbines, microturbines, photovoltaics, fuel cells and wind power. It is understood that DER are able to reduce emissions by replacing fossil fuels with renewable energy sources. Meanwhile, there is no consensus regarding whether the installation of household DER increase or inhibit the use of electricity for original consumers. It is widely accepted that the installation of household DER should stimulate electricity consumption through more self-allocation. However, such conclusions are normally drawn based on linear regression models while ignoring certain important variables. After analyzing data from 409 households from 2016 to 2017 using an interactive regression model with human behavior indicators, contrary to the wildly accepted view that new technologies can have a rebound effect (RE), it is found that house DER not only facilitate environment protection in terms of limiting emissions but also inhibit electricity usage through a negative rebound effect.

Erythromelalgia (EM) is a debilitating neurovascular disease that is refractory to numerous treatment modalities. The present study reported the case of a 72-year-old woman diagnosed with EM secondary to polycythemia vera (PV), who was effectively treated with the use of patient-controlled epidural analgesia (PCEA) and interferon α-2b therapy. The study aimed to provide clinical information on this condition based on the findings of the present case and previously-reported cases. PCEA containing local anesthetics and dexamethasone or fentanyl resulted in nearly complete relief of symptoms. Furthermore, continuous use of interferon α-2b for the treatment of the PV completely relieved the EM symptoms. In conclusion, PCEA and interferon α-2b may be promising treatments for EM secondary to PV.

Stress granules (SGs) are host translationally silent ribonucleo-proteins formed in cells in response to multiple types of environmental stress, including viral infection. We previously showed that the nuclear protein, 68-kDa Src-associated in mitosis protein (Sam68), is recruited to cytoplasm and form the Sam68-positive SGs at 6 hpi, but the Sam68-positive SGs disassembled beyond 12 hpi, suggesting that the SGs might be inhibited during the late stage of Enterovirus 71 (EV71) infection. However, the mechanism and function of this process remains poorly understood. Thus in this study, we demonstrated that EV71 initially induced SGs formation at the early stage of EV71 infection, and confirmed that 2Apro of EV71 was the key viral component that triggered SG formation. In contrast, SGs were diminished as EV71 infection proceeding. At the same time, arsenite-induced SGs were also blocked at the late stage of EV71 infection. This disruption of SGs was caused by viral protease 3Cpro-mediated G3BP1 cleavage. Furthermore, we demonstrated that over-expression of G3BP1-SGs negatively impacted viral replication at the cytopathic effect (CPE), protein, RNA, and viral titer levels. Our novel finding may not only help us to better understand the mechanism how EV71 interacts with the SG response, but also provide mechanistic linkage between cellular stress responses and innate immune activation during EV71 infection.

Fulminant hepatic failure (FHF) is a rare, life-threatening liver disease with a poor prognosis. Administration of D-galactosamine (GalN) and lipopolysaccharide (LPS) triggers acute liver injury in mice, simulating many clinical features of FHF in humans, therefore, this disease model is often used to investigate potential therapeutic interventions to treat FHF. Recently, suppression of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, was shown to alleviate the severity of GalN/LPS-induced liver damage in mice. Therefore, the goal of this study was to find dietary exosome-like nanoparticles (ELNs) with therapeutic potential in curbing FHF by suppressing the NLRP3 inflammasome. Seven commonly consumed mushrooms were used to extract ELNs. These mushrooms were found to contain ELNs composed of RNAs, proteins, and lipids. Among these mushroom-derived ELNs, only shiitake mushroom-derived ELNs (S-ELNs) substantially inhibited NLRP3 inflammasome activation by preventing inflammasome formation in primary macrophages. S-ELNs also suppressed the secretion of interleukin (IL)-6, as well as both protein and mRNA levels of the Il1b gene. Remarkably, pre-treatment with S-ELNs protected mice from GalN/LPS-induced acute liver injury. Therefore, S-ELNs, identified as potent new inhibitors of the NLRP3 inflammasome, represent a promising class of agents with the potential to combat FHF.