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Poker is the typical game of incomplete information, and remains a longstanding challenge problem in artificial intelligence (AI). The poker game of Dou Dizhu has been viewed as a thorny topic in AI because of its own characteristics. This article introduces a developed Monte Carlo tree search (MCTS) method for Dou Dizhu to solve the decision making effectively. We built the winning rate prediction model (WRPM) to predict the winning rate of moves as the initial situation estimation and improve the model to be more applicable to different player roles. Then, the WRPM is embedded as the core algorithm into MCTS for extension and simulation and named it WRPM-MCTS. In addition, we also train a card distribution prediction model to predict the holding cards of opponents for further improving the performance of WRPM-MCTS on the agent of Dou Dizhu . Experiments show that the WRPM-MCTS has a statistically significant performance better than the pure MCTS and the pure WRPM. In the game with human players from an online game platform, the WRPM-MCTS-based agent had the winning rate of 52.86% in 4 000 000 games and ranked in top 1.22% among 500 000 human players, indicating that this agent had reached the expert level of humans.

This study proposes a novel best-first search algorithm, called Valuation Increment Search Algorithm (VIS), which applies the increment of exploratory value change to predict the valuation and guide the selection of the game tree. The proposed method can effectively use node valuation and game tree size information to solve the game tree by fewer exploration steps. The relevant assumptions and search principles of the proposed algorithm are detailed. Moreover, comparative experiments with Alpha–Beta Search (α–β search), Proof-Number Search (PNS) and Monte-Carlo Tree Search (MCTS) in the domain of Dou Dizhu has been performed to verify the performance. Result demonstrate that VIS is superior to α–β search, PNS and MCTS algorithm in solving the game tree and finding the best move for some game scenarios by consuming less time and few memory resources. The improvement effect of the average Increment, magnitude of Increment, and the number of visits to node on the original VIS was validated. Also, a new selection strategy is defined for the improved VIS algorithm combined with these factors. The experimental comparison results show that improved VIS has a better performance in solving game tree with less nodes generated and expanded than original VIS.

The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and overactive immune response in the late stage of infection; However, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3, STAT1, and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress the ubiquitination and activation of retinoic acid-inducible gene I (RIG-I). Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

It is not clear how hepatitis B virus (HBV) modulates host immunity during chronic infection. In addition to the key mediators of inflammatory response in viral infection, monocytes also express a high-level IFN-stimulated gene, CH25H, upon response to IFN-α exerting an antiviral effect. In this study, the mechanism by which HBV manipulates IFN signaling in human monocytes was investigated. We observed that monocytes from chronic hepatitis B patients express lower levels of IFN signaling/stimulated genes and higher levels of inflammatory cytokines compared with healthy donors. HBV induces monocyte production of inflammatory cytokines via TLR2/MyD88/NF-κB signaling and STAT1-Ser727 phosphorylation and inhibits IFN-α–induced stat1, stat2, and ch25h expression through the inhibition of STAT1-Tyr701 phosphorylation and in an IL-10–dependent, partially autocrine manner. Further, we found that enhancement of STAT1 activity with a small molecule (2-NP) rescued HBV-mediated inhibition of IFN signaling and counteracted the induction of inflammatory cytokines. In conclusion, HBV contributes to the monocyte inflammatory response but inhibits their IFN-α/β responsiveness to impair antiviral innate immunity. These effects are mediated via differential phosphorylation of Tyr701 and Ser727 of STAT1.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of current COVID-19 pandemic, and insufficient production of type I interferon (IFN-I) is associated with the severe forms of the disease. Membrane (M) protein of SARS-CoV-2 has been reported to suppress host IFN-I production, but the underlying mechanism is not completely understood. In this study, SARS-CoV-2 M protein was confirmed to suppress the expression of IFNβ and interferon-stimulated genes induced by RIG-I, MDA5, IKKϵ, and TBK1, and to inhibit IRF3 phosphorylation and dimerization caused by TBK1. SARS-CoV-2 M could interact with MDA5, TRAF3, IKKϵ, and TBK1, and induce TBK1 degradation via K48-linked ubiquitination. The reduced TBK1 further impaired the formation of TRAF3–TANK–TBK1-IKKε complex that leads to inhibition of IFN-I production. Our study revealed a novel mechanism of SARS-CoV-2 M for negative regulation of IFN-I production, which would provide deeper insight into the innate immunosuppression and pathogenicity of SARS-CoV-2.

The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and a cytokine storm in the late stage of infection, however, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein interacted with the tripartite motif protein 25 (TRIM25), thereby dually regulating the phosphorylation and nuclear translocation of IRF3, STAT1 and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress retinoic acid-inducible gene I (RIG-I) ubiquitination and activation. Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

Owing to its broad-spectrum antivirus activities, interferon (IFN) is an important alternative agent for use in the treatment of hepatitis B virus (HBV)-infected patients; however, the mechanism involved in the inhibition of HBV infection and replication by IFN remains unclear. We previously reported that the induction of TRIM5γ is important in the IFN treatment of HBV patients as it promotes the degradation of the HBx protein, while the manner in which TRIM5γ is induced by IFN and how TRIM5γ interacts with HBx remain unestablished until date. Our present findings confirmed the TRIM5γ-HBx-DDB1 interactions in the HBV-infected Primary human hepatocytes (PHH), and we further found that STAT3, and not STAT1, was responsible for the induction of TRIM5γ upon IFN stimulation and that the zinc binding site His123 on the BBOX domain was a decisive site in the interaction between TRIM5γ BBOX and HBx. In addition, based on the BBOX domain, we detected a 7-amino acid peptide with the potential of promoting HBx degradation and inhibiting HBV replication. On the other hand, we noted that the TRIM5γ expression was inhibited by HBV in chronically HBV infected patients. Thus, our study identified the crucial role of STAT3 in the induction of TRIM5γ, as well as proposed a 7-amino acid, small peptide as a potential candidate for the development of therapeutic agents targeting HBx.

TRIM5γ, together with TRIM31, has been shown to promote HBx ubiquitination and degradation. This study aimed to explore whether a patient with HCC (hepatic cell carcinoma) having a small nucleotide inserted into the TRIM31 gene, which made a shorter transcript stop at 768 bp, would result in blocking the activity of TRIM31 in promoting HBx degradation. Besides, this study aimed to determine the binding region of the TRIM31-TRIM5γ-HBx complex. HBV (Hepatitis B virus) infection was reported to induce type-III IFN but not type-I or type-II IFNs, here TRIM31 was found to be a type III rather than a type I stimulated gene, which was indispensable in inhibiting the hepatitis B virus replication by the interferon families. Thus, this study further identified the critical role of TRIM31 in the host-hepatitis B virus interaction.

Hepatitis B virus (HBV) and its associated chronic infection remain serious health threats worldwide. However, there is still no impactful approach for clinical treatment of hepatitis B patients. Therefore, developing a better understanding of the interactions between HBV and its host is particularly important. HBV infection has been reported to induce type-III but not type-I or type-II interferon (IFN). In this study, we identified CBFβ, an HIV enhancer, as an HBV restriction factor that is specifically induced by type-III IFN in the early stages of HBV infection. Type-III IFN-induced IL-10 played an important role in the production of CBFβ. Interestingly, the interaction between CBFβ- and HBV-encoded regulatory protein X (HBx) enhanced the stability of CBFβ, but notably blocked HBx-mediated promotion of HBV replication. CBFβ expression was lower in HBV patients than in healthy persons, and the addition of serum from HBV patients inhibited CBFβ expression in HepG2 cells. On the contrary, HBV via HBsAg inhibited type-III IFN-induced CBFβ expression and decreased the anti-HBV activity of type-III IFN, suggesting that HBV inhibits antiviral interferon-stimulated gene (ISG) expression and induces IFN resistance. Collectively, our results demonstrate that type-III IFN-triggered and IL-10-induced CBFβ are crucial factors for inhibiting HBV replication, and the HBx-CBFβ-HBsAg axis reveals a new molecular mechanism of interaction between HBV and its hosts.

// Na Li 1 , Lufei Wang 2 , Guangyun Tan 3 , Zhiheng Guo 1 , Lei Liu 1 , Ming Yang 4, * and Jin He 1, * 1 Department of Gynecology and Obstetrics, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China 2 Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130022, PR China 3 Department of Immunology, Institute of Translational Medicine of The First Hospital of Jilin University, Changchun, Jilin 130021, PR China 4 Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China * These authors have contributed equally to this work Correspondence to: Ming Yang, email: yangming196701@163.com Jin He, email: jinhe1204@126.com Keywords: MiR-218, ovarian cancer, RUNX2, proliferation, invasion Received: April 07, 2017 Accepted: July 19, 2017 Published: September 16, 2017 ABSTRACT MicroRNA-218 (miR-218) has been implicated in the development and progression of multiple cancers. We investigated the role of miR-218 in ovarian cancer progression. We found that miR-218 expression levels were lower in ovarian cancer tissues and cell lines than in adjacent normal tissues or a normal ovarian cell line.miR-218 levels associated with International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. Exogenous expression of miR-218 inhibited cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth in a tumor-bearing nude mouse model. Runt-related transcription factor 2 (RUNX2) was identified as a direct functional target of miR-218, and its expression was inversely correlated with miR-218 expression in ovarian cancer tissues. RUNX2 overexpression rescued the suppressive effect of miR-218 on ovarian cancer cell proliferation, colony formation, migration, and invasion. These findings highlight an important role played bymiR-218 in the regulation of cancer growth and metastasis, in part by repressing RUNX2 , and revealed the potential of miR-218 as a new therapeutic target inovarian cancer.

In the paper, we investigate double differential detection (DD) for a two-way relaying network using multiple antennas with unknown carrier frequency offsets. The vast majority of existing research on two-way relaying hypotheses that all devices have perfect channel knowledge and no carrier frequency offsets (CFO). However, for fast changing channels, it is hard to receive certain channel state information (CSI), and the system capability is significantly reduced by reason of increasing the computational complexity of channel estimation and commonly existing CFOs. Accordingly, a signal detection method based on double differential is proposed to remove the interference caused by CFOs for a MIMO bi-directional relaying system. For superior system performance, all transmitters adopt orthogonal space-time block codes (OSTBC). Obviously, the simulation results turn out that the suggested DD scheme can not only remove the carrier offsets effectively without CSI knowledge, but also carry out full diversity order with acceptable linear computational complexity.

SUMMARY To understand the molecular mechanisms that mediate the anti-hepatitis B virus (HBV) effect of interferon (IFN) therapy, we conduct high-throughput bimolecular fluorescence complementation screening to identify potential physical interactions between the HBx protein and 145 IFN-stimulated genes (ISGs). Seven HBx-interacting ISGs have consistent and significant inhibitory effects on HBV replication, among which TRIM5γ suppresses HBV replication by promoting K48-linked ubiquitination and degradation of the HBx protein on the K95 ubiquitin site. The B-Box domain of TRIM5γ under overexpression conditions is sufficient to trigger HBx degradation and is responsible both for interacting with HBx and recruiting TRIM31, which is an ubiquitin ligase that triggers HBx ubiquitination. High expression levels of TRIM5γ in IFN-α-treated HBV patients might indicate a better therapeutic effect. Thus, our studies identify a crucial role for TRIM5γ and TRIM31 in promoting HBx degradation, which may facilitate the development of therapeutic agents for the treatment of patients with IFN-resistant HBV infection., Graphical Abstract, In Brief In brief, Tan et al. find that IFN-induced TRIM5γ recruits TRIM31 to degrade HBx, resulting in suppression of hepatitis B virus replication.

Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4+ T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications., Dendritic cells instruct different types of T cell responses depending on the types of microbial ligands sensed. Here the authors show that dendritic cells stimulated via Dectin-1 receptor upregulate TNFSF15 and OX40L and induce T helper 9 response and efficient antitumour immunity in mouse models.

Interferon (IFN) is a regularly utilized therapeutic for the treatment of chronic hepatitis B and appears to induce superior HBeAg seroconversion comparing nucleos/tide analogs. However, the mechanisms underlying IFN inhibition of HBV replication, as well as poor responses to IFN are unclear. Apobec3G has been reported to be involved in regulating HBV replication. In this study, we investigated Apobec3G expression and regulatory pathways during HBV infection. We show that over-expression of A3G leads to inhibition of HBV replication. We also show that IFN induces a significant increase in A3G protein expression, which is associated with STAT3 activation. We further show that A3G expression in HBV patients is lower compared to non-infected controls, possibly by HBsAg which inhibits IFN induced A3G up-regulation in a dose dependent manner. This process is likely mediated through inhibition of STAT3-Ser727 phosphorylation. The results presented in this study indicate that STAT3 plays an important role in IFN-induced A3G production, and HBsAg may correlated with poor response to IFN treatment.

The developmental ability among embryos produced by three different techniques were examined: there were no significant differences in the developmental rate in porcine embryos produced by in vitro fertilization (IVF) and first generation of somatic cell nucleus transfer (SCNT), but the developmental rate dropped sharply at the 2- to four-cell stage in recloned (second generation of SCNT) embryos. In most recloned embryos, Oct4 and Klf4 were under-expressed at all stages, whereas Sox2 and Nanog were over-expressed at the two-cell stage. In contrast, Nanog was absent in IVF and SCNT embryos at the two-cell stage. The recloned embryos were treated with valproic acid to enhance developmental capacity and this led to an increase in the rate of blastocyst formation and total cell number compared with the findings for untreated recloned embryos (29.8 vs. 12.4 %, 39 vs. 25, respectively, p

NF-κB activation induced by genotoxic treatment in cancer cells has been associated with therapeutic resistance in multiple human malignancies. Therapeutic resistance also correlates with high metastatic potential in human cancers, including breast cancer. Whether genotoxic treatment-activated NF-κB also contributes to cancer metastasis following radiation and chemotherapy is unclear. Here, we show that chemotherapeutic drug-induced NF-κB activation promotes breast cancer cell migration and invasion. The increased metastatic potential is dependent on IL-6 induction mediated by genotoxic NF-κB activation. Moreover, genotoxic treatment also up-regulates oncogenic microRNA-21 (miR-21) expression through eliciting NF-κB recruitment to the miR-21 promoter region, where it cooperates with signal transducer and activator of transcription 3 (STAT3) to activate miR-21 transcription. DNA damage-induced histone H3 phosphorylation via activated MSK1 creates an open chromatin structure for NF-κB/STAT3-driven transactivation of miR-21. NF-κB-dependent IL-6 up-regulation is responsible for STAT3 activation and recruitment to the miR-21 promoter upon genotoxic stress. Induction of miR-21 may enable cancer cells to elude DNA damage-induced apoptosis and enhance the metastatic potential of breast cancer cells through repressing expression of PTEN and PDCD4. Our data support a critical role of DNA damage-induced NF-κB activation in promoting cancer metastasis following genotoxic treatment, and NF-κB-dependent miR-21 induction may contribute to both therapeutic resistance and metastasis in breast cancer.

DNA damage response upon UV radiation involves a complex network of cellular events required for maintaining the homeostasis and restoring genomic stability of the cells. As a new class of players involved in DNA damage response, the regulation and function of microRNAs in response to UV remain poorly understood. Here we show that UV radiation induces a significant increase of miR-22 expression, which appears to be dependent on the activation of DNA damage responding kinase ATM (ataxia telangiectasia mutated). Increased miR-22 expression may result from enhanced miR-22 maturation in cells exposed to UV. We further found that tumor suppressor gene phosphatase and tensin homolog (PTEN) expression was inversely correlated with miR-22 induction and UV-induced PTEN repression was attenuated by overexpression of a miR-22 inhibitor. Moreover, increased miR-22 expression significantly inhibited the activation of caspase signaling cascade, leading to enhanced cell survival upon UV radiation. Collectively, these results indicate that miR-22 is an important player in the cellular stress response upon UV radiation, which may promote cell survival via the repression of PTEN expression.

UV-induced stress response involves expression change of a myriad of genes, which play critical roles in modulating cell cycle arrest, DNA repair, and cell survival. Alteration of microRNAs has been found in cells exposed to UV, yet their function in UV stress response remains elusive. Here, we show that UV radiation induces up-regulation of miR-125b, which negatively regulates p38α expression through targeting its 3′-UTR. Increase of miR-125b depends on UV-induced NF-κB activation, which enhances miR-125b gene transcription upon UV radiation. The DNA damage-responsive kinase ATM (ataxia telangiectasia mutated) is indispensable for UV-induced NF-κB activation, which may regulate p38α activation and IKKβ-dependent IκBα degradation in response to UV. Consequently, repression of p38α by miR-125b prohibits prolonged hyperactivation of p38α by UV radiation, which is required for protecting cells from UV-induced apoptosis. Altogether, our data support a critical role of NF-κB-dependent up-regulation of miR-125b, which forms a negative feedback loop to repress p38α activation and promote cell survival upon UV radiation.

SummaryThis study was conducted to establish pig embryonic stem (ES)-like cell lines from nuclear transfer blastocysts. A green fluorescent protein (GFP)-expressing cell line was used as the source of donor cells injected into the enucleated oocytes. Blastocysts were collected at D5 (the fifth day), D7 (the seventh day) and D9 (the ninth day). Differential staining was used to assay the viability and development of blastocysts from the 3 days. The number of inner cell mass (ICM) cells increased from 1.83 ± 0.8 (D5) to 5.37 ± 1.2 (D7) to 7.56 ± 1.5 (D9). The expression profiles of embryonic stem (ES) cell factors (OCT4, SOX2, KLF4 and c-MYC) correlated best with the undifferentiated ES state and were identified by qPCR. The expression of the four factors was increased from D5 to D7, whereas the expression decreased from D7 to D9. We tried to isolate ES-like cells from these embryos. However, ES-like cells from the D7 blastocysts grew slowly and expressed alkaline phosphatase. The cells from the D9 blastocysts grew rapidly but did not express alkaline phosphatase. ES-like cells were not isolated from the D5 blastocysts. These results show that the cells from the D7 embryos are pluripotent but grow slowly. The cells from the D9 embryos grow rapidly but start to lose pluripotency.