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Background Sepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication. Methods Preliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results. Results Four hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally. Conclusions We identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

Rationale: Malignant ascites caused by cancer cells results in poor prognosis and short average survival time. No effective treatment is currently available for malignant ascites. In this study, the effects of lentinan (LNT)-functionalized selenium nanoparticles (Selene) on malignant ascites were evaluated. Furthermore, the mechanism of Selene targeting mitochondria of tumor cells were also investigated. Methods: Selene were synthesized and characterized by TEM, AFM and particle size analysis. The OVCAR-3 and EAC cells induced ascites models were used to evaluate the effects of Selene on malignant ascites. Proteomic analysis, immunofluorescence, TEM and ICP-MS were used to determine the location of Selene in tumor cells. Mitochondrial membrane potential, ROS, ATP content, and caspase-1/3 activity were detected to evaluate the effect of Selene on mitochondrial function and cell apoptosis. Immunofluorescence, Co-IP, pull-down, duolink, Western blot, and FPLC were used to investigate the pathway of Selene targeting mitochondria. Results: Selene could effectively inhibit ascites induced by OVCAR-3 and EAC cells. Selene was mainly located in the mitochondria of tumor cells and induced apoptosis of tumor cells. The LNT in Selene was involved in caveolae-mediated endocytosis through the interaction between toll-like receptor-4 (TLR4) and caveolin 1 (CAV1). Furthermore, the Selene in the endocytic vesicles could enter the mitochondria via the mitochondrial membrane fusion pathway, which was mediated by TLR4/TNF receptor associated factor 3 (TRAF3)/mitofusin-1 (MFN1) protein complex. Conclusion: Selene is a candidate anticancer drug for the treatment of malignant ascites. And TLR4/TRAF3/MFN1 may be a specific nano-drug delivery pathway that could target the mitochondria.

Three new pimarane diterpenes, eutypellenoids A–C (1–3), together with a known compound, eutypenoid C (4), were isolated from the culture extract of Eutypella sp. D-1 derived from the Arctic region. Compounds 1–3 possessed an uncommon tetrahydrofuran-fused pimarane diterpene skeleton. The structures of all compounds were determined by detailed spectroscopic analysis, electronic circular dichroism (ECD) analysis, as well as a comparison with the literature data. Antibacterial, antifungal, and cytotoxic activities of these compounds were evaluated. Compound 2 displayed antibacterial activity against Staphylococcus aureus and Escherichia coli with MIC values of 8 and 8 μg/mL, respectively. Additionally, compound 2 showed antifungal activity against Candida parapsilosis, Candida albicans, Candida glabrata, and Candida tropicalis with MIC values of 8, 8, 16, and 32 μg/mL, respectively. Furthermore, compound 2 exhibited moderate cytotoxic activity against HCT-116 cell line with IC50 value of 3.7 μM.

Matrine is an alkaloid extracted from a Chinese herb Sophora flavescens Ait, which has shown chemopreventive potential against various cancers. In this study, we evaluated the anticancer efficacy of a novel derivative of matrine, （6aS, 10S, 11aR, 11bR, 11cS）- lO-methylamino-dodecahydro-3a,7a-diazabenzo （de） anthracene-8-thione （MASM）, against human hepatocellular carcinoma （HCC） ceils and their corresponding sphere cells in vitro and in vivo. Human HCC cell lines （Hep3B and Huh7） were treated with MASM. Cell proliferation was assessed using CCK8 and colony assays; cell apoptosis and cel{ cycle distributions were examined with flow cytometry. The expression of cell markers and signaling molecules was detected using Western blot and qRT-PCR analyses. A sphere culture technique was used to enrich cancer stem cells （CSC） in Hep3B and Huh7 cells. The in vivo antitumor efficacy of MASM was evaluated in Huh7 cell xenograft model in BALB/c nude mice, which were administered MASM （10 mg.kg-~-d~, ig） for 3 weeks. After the treatment was completed, tumor were excised and weighed. A portion of tumor tissue was enzymatically dissociated to obtain a single cell suspension for the spheroid formation assays. MASM （2, 10, 20 pmol/L） dose-dependently iahibited the proliferation of HCC cells, and induced apoptosis, which correlated with a reduction in Bcl-2 expression and an increase in PARP cleavage. MASM also induced cell cycle arrest in Go/G~ phase, which was accompanied by increased p27 and decreased Cyclin D1 expression, interestingly, MASM （2, 10, and 20 pmoVL） drastically reduced the EpCAM＋/CD133＊ cell numbers, suppressed the sphere formation, inhibited the expression of stem cell marker genes and promoted the expression of mature hepatocyte markers in the Hep3B and Huh7 spheroids. Additionally, MASM dose-dependently suppressed the PI3K/AKT/mTOR and AKT/GSK313/13-catenin signaling pathways in Hep3B and Huh7 cells. In Huh7 xenograft bearing nude mice, MASM administration significantly inhibited Huh7 xenograft tumor growth and markedly reduced the number of surviving cancer stem-like cells in the tumors. MASM administration also reduced the expression of stem cell markers while increasing the expression of mature hepatocyte markers in the tumor tissues. The novel derivative of matrine, MASM, markedly suppresses HCC tumor growth through multiple mechanisms, and it may be a promising candidate drug for the treatment of hepatocellular carcinoma.

AbstractExcessive inflammatory response is a critical pathogenic factor for the tissue damage and organ failure caused by systemic inflammatory response syndrome (SIRS) and sepsis. In recent years, drugs targeting RIPK1 have proved to be an effective anti-inflammatory strategy. In this study, we identified a novel anti-inflammatory lead compound 4–155 that selectively targets RIPK1. Compound 4–155 significantly inhibited necroptosis of cells, and its activity is about 10 times higher than the widely studied Nec-1 s. The anti-necroptosis effect of 4–155 was mainly dependent on the inhibition of phosphorylation of RIPK1, RIPK3, and MLKL. In addition, we demonstrated that 4–155 specifically binds RIPK1 by drug affinity responsive target stability (DARTS), immunoprecipitation, kinase assay, and immunofluorescence microscopy. More importantly, compound 4–155 could inhibit excessive inflammation in vivo by blocking RIPK1-mediated necroptosis and not influence the activation of MAPK and NF-κB, which is more potential for the subsequent drug development. Compound 4–155 effectively protected mice from TNF-induced SIRS and sepsis. Using different doses, we found that 6 mg/kg oral administration of compound 4–155 could increase the survival rate of SIRS mice from 0 to 90%, and the anti-inflammatory effect of 4–155 in vivo was significantly stronger than Nec-1 s at the same dose. Consistently, 4–155 significantly reduced serum levels of pro-inflammatory cytokines (TNF-α and IL-6) and protected the liver and kidney from excessive inflammatory damages. Taken together, our results suggested that compound 4–155 could inhibit excessive inflammation in vivo by blocking RIPK1-mediated necroptosis, providing a new lead compound for the treatment of SIRS and sepsis.

The study proposes and demonstrates an enhancement of a touch display panel (TDP) through a polymer-based protection structure to achieve higher bendability and reliability. The bending performance of the TDP without or with the protection structure designs is addressed using three-dimensional geometry-nonlinear finite element analysis and mechanical testing. The elastic properties of the components in the TDP structure are derived from nanoindentation and uniaxial tensile/compressive testing. The calculated results are compared with each other and also against the experimental bending fatigue test data. At last, a design guideline and optimal factor setting for enhanced bending performance are sought through parametric FE analysis and Taguchi experimental design, respectively. The optimal design is compared with the original in terms of bending stress. The simulation results show that bending would create significant tensile and compressive bending stresses on the indium tin oxide/dielectric layers, which are the main cause of several commonly observed failures, such as thin film cracking and delamination, in a thin rigid film coating on a thick compliant substrate. It also turns out that a substrate with a lower stiffness has a better mechanical stability against bending stress.

Background. MASM, a novel derivative of matrine, has inhibitory effects on activation of macrophages, dendritic cells, and hepatic stellate cells and binds to ribosomal protein S5 (RPS5). This study was designed to evaluate the effect of MASM on murine-established lethal sepsis and its mechanisms. Methods. Mouse peritoneal macrophages and RAW264.7 cells that were infected with recombinant lentiviruses encoding shRPS5 were incubated with lipopolysaccharide (LPS) in the absence or presence of MASM in vitro. Endotoxemia induced by LPS injection and sepsis induced by cecal ligation and puncture was followed by MASM treatment. Results. MASM markedly attenuated LPS-induced release and messenger RNA expression of tumor necrosis factor α, interleukin 6, and NO/inducible NO synthase in murine peritoneal macrophages and RAW264.7 cells. Meanwhile, MASM inhibited LPS-induced activation of nuclear factor kB and MAPK pathways. Consistently, RPS5 suppressed LPS-induced inflammatory responses and at least in part mediated the antiinflammatory effect of MASM in vitro. Remarkably, delayed administration of MASM could significantly reduce mortality in mouse sepsis models, which was associated with the reduction in the inflammatory response, the attenuation in multiple organ injury, and the enhanced bacterial clearance. Conclusions. MASM could be further explored for the treatments of sepsis, especially for administration later after the onset of sepsis.

Vehicular edge computing (VEC) is emerging as a novel computing paradigm to meet low latency demands for computation-intensive vehicular applications. However, most existing offloading schemes do not take the dynamic edge-cloud computing environment into account, resulting in high delay performance. In this paper, we propose an efficient offloading scheme based on deep reinforcement learning for VEC with edge-cloud computing cooperation, where computation-intensive tasks can be executed locally or can be offloaded to an edge server, or a cloud server. By jointly considering: i) the dynamic edge-cloud computing environment; ii) fast offloading decisions, we leverage deep reinforcement learning to minimize the average processing delay of tasks by effectively integrating the computation resources of vehicles, edge servers, and the cloud server. Specifically, a deep Q-network (DQN) is used to adaptively learn optimal offloading schemes in the dynamic environment by balancing the exploration process and the exploitation process. Furthermore, the offloading scheme can be quickly learned by speeding up the convergence of the training process of DQN, which is good for fast offloading decisions. We conduct extensive simulation experiments and the experimental results show that the proposed offloading scheme can achieve a good performance.

[This corrects the article DOI: 10.7150/thno.46467.].[This corrects the article DOI: 10.7150/thno.46467.].