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The ErbB3 receptor–binding protein EBP1 encodes two alternatively spliced isoforms P48 and P42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. Here, we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 P48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 P48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 P42 bound to both the F-box domain of FBXW7 as well as FBXW7 substrates. This adapter function of EBP1 P42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumor-suppressing function. Overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoform-specific functions of EBP1 in cancer. Cancer Res; 77(8); 1983–96. ©2017 AACR.

This part contains supplementary figure legends and supplementary Table 1.

This part describes further supportive information for the distinctive interactions of EBP1 isoforms with FBXW7 including the data to describe that FBXW7-mediated ubiquitination and degradation of EBP1 P48 in a GSK3β-dependent manner and to illustrate that FBXW7 binds to P48 through its WD domain and P48 S44 is crucial for its interaction with FBXW7.

Dendritic cell (DC)-derived small extracellular vesicles (DEVs) are recognized as a highly promising alternative to DC vaccines; however, the clinical testing of DEV-based immunotherapy has shown limited therapeutic efficacy. Herein, we develop a straightforward strategy in which DCs serve as a cell reactor to exocytose high-efficient DEV-mimicking aggregation-induced emission (AIE) nanoparticles (DEV-AIE NPs) at a scaled-up yield for synergistic photodynamic immunotherapy. Exocytosed DEV-AIE NPs inherit not only the immune-modulation proteins from parental DCs, enabling T cell activation, but also the loaded AIE-photosensitizer MBPN-TCyP, inducing superior immunogenic cell death (ICD) by selectively accumulating in the mitochondria of tumor cells. Eventually, DEV-AIE synergistic photodynamic immunotherapy elicits dramatic immune responses and efficient eradication of primary tumors, distant tumors, and tumor metastases. In addition, cancer stem cells (CSCs) in 4T1 and CT26 solid tumors were significantly inhibited by the immune functional DEV-AIE NPs. Our work presents a facile method for the cellular generation of EV-biomimetic NPs and demonstrates that the integration of DEVs and AIE photosensitizers is a powerful direction for the production of clinical anticancer nanovaccines.

BackgroundFocusing on antiangiogenesis may provide promising choices for treatment of gastric cancer (GC). This study aimed to investigate the mechanistic role of BCAT1 in the pathogenesis of GC, particularly in angiogenesis.MethodsBioinformatics and clinical samples analysis were used to investigate the expression and potential mechanism of BCAT1 in GC. BGC823 cells with BCAT1 overexpression or silencing were induced by lentiviral transduction. Cell phenotypes and angiogenesis were evaluated. The relevant proteins were quantized by Western blotting, immunohistochemistry, or immunofluorescence. Xenograft models were constructed to confirm the role of BCAT1 in vivo.ResultsBCAT1 was overexpressed in GC patients and associated with lower survival. BCAT1 expression was correlated with proliferation-, invasion-, or angiogenesis-related markers expression and pathways. Silencing BCAT1 expression suppressed cell viability, colony formation, cycle progression, invasion, and angiogenesis of BGC823 cells, as well as the tumor growth of xenograft models, whereas overexpressing BCAT1 had the opposite results both in vitro and in vivo. Bioinformatics analysis and Western blotting demonstrated that BCAT1 activated the PI3K/AKT/mTOR pathway. The addition of LY294002 reversed the tumor growth induced by BCAT1 overexpression, further verifying this mechanism.ConclusionBCAT1 might act as an oncogene by facilitating proliferation, invasion, and angiogenesis through activation of the PI3K/AKT/mTOR pathway. This finding could aid the optimization of antiangiogenesis strategies.

Donor-specific antibodies (DSAs) play a key role in chronic kidney allograft injury. Follicular T helper (Tfh) cells trigger the humoral alloimmune response and promote DSA generation, while T-follicular regulatory (Tfr) cells inhibit antibody production by suppressing Tfh and B cells. Interleukin (IL)-21 exerts a distinct effect on Tfh and Tfr. Here, we studied whether blocking IL-21R with anti-IL-21R monoclonal antibody (αIL-21R) changes the Tfh/Tfr balance and inhibits DSA generation. First, we investigated the impact of αIL-21R on CD4+ T cell proliferation and apoptosis. The results showed that αIL-21R did not have cytotoxic effects on CD4+ T cells. Next, we examined Tfh and regulatory T cells (Tregs) in an in vitro conditioned culture model. Naïve CD4+ T cells were isolated from 3-month-old C57BL/6 mice and cultured in Tfh differentiation inducing conditions in presence of αIL-21R or isotype IgG and differentiation was evaluated by CXCR5 expression, a key Tfh marker. αIL-21R significantly inhibited Tfh differentiation. In contrast, under Treg differentiation conditions, FOXP3 expression was inhibited by IL-21. Notably, αIL-21R rescued IL-21-inhibited Treg differentiation. For in vivo investigation, a fully mismatched skin transplantation model was utilized to trigger the humoral alloimmune response. Consistently, flow cytometry revealed a reduced Tfh/Tfr ratio in recipients treated with αIL-21R. Germinal center response was evaluated by flow cytometry and lectin histochemistry. We observed that αIL-21R significantly inhibited germinal center reaction. Most importantly, DSA levels after transplantation were significantly inhibited by αIL-21R at different time points. In summary, our results demonstrate that αIL-21R shifts the Tfh/Tfr balance toward DSA inhibition. Therefore, αIL-21R may be a useful therapeutic agent to prevent chronic antibody mediated rejection after organ transplantation.

Monolithic fault detection methods have low accuracy for comprehensive faults detection, because they can only detect specific type of faults. Therefore, it is necessary to study the combination of fault detection methods to improve the detection accuracy. In this paper, based on the fault propagation on component-based aerospace embedded software architecture, we analyze occur reasons, manifestations and effects of instruction-, component- and system-level faults whose root cause is single event upset (SEU) which is the main reason of aerospace embedded software, and propose a hierarchical fault model to specify characteristics of the three levels faults. And based on the hierarchical fault model, a hierarchical detection method is proposed to combine the three levels monolithic fault detection methods. The experimental results show that the hierarchical fault detection method has higher fault detection accuracy than the monolithic fault detection methods for comprehensive faults detection.

The purpose of cross-project defect prediction is to predict whether there are defects in this project module by using a prediction model trained by the data of other projects. For the divergence of the data distribution between different projects, the performance of cross-project defect prediction is not as good as within-project defect prediction. To reduce the difference as much as possible, researchers have proposed a variety of methods to filter training data from the perspective of transfer learning. In this paper, we introduce a “project-instance-metric" hierarchical filtering strategy to select training data for the defect prediction model. Using the three-level filtering method, the candidate projects that are most similar to the target project, the instances that are most similar to the target instance, and the metrics with the highest correlation to the prediction result are filtered out respectively. We compared three-level filtering with project-level filtering, instance-level filtering, and the combination of project-level and instance-level filtering methods in four classification algorithms using NASA open source data sets. Our experiments show that the three-level filtering method achieves more significant f-measure and AUC values than the single level training data filtering method.

Aiming at the low efficiency of the traditional design method of spacecraft information flow based on text mode, combing with the method of Model Based System Engineering, this paper presents the design idea of spacecraft information flow modeling. Modeling of spacecraft information flow will speed up the process of the design phase of the spacecraft information system and ensure the reliability and traceability of information flow through model. Model Based System Engineering provides a new idea for the design of spacecraft information flow.

At present, the research on lunar communication mainly focuses on the analysis and research of communication node level and link level. There are few studies on multi-device broadband wireless networking and protocol. The existing point-to-point communication mechanism poses challenges to multi-device missions on lunar. Facing the increasingly complex mission requirements of lunar exploration and scientific research station, it is urgent to build an efficient multi-node broadband wireless communication system to ensure the smooth implementation of the follow-up missions of lunar exploration. It analyses and compares the current wireless communication protocol technologies, studies the foreign lunar protocol schemes, and presents the design of the lunar’s multi-device broadband wireless network architecture. It focuses on the design of networking protocol system, which is compatible with the existing earth-moon communication protocol system, and supports the broadband wireless communication between multiple devices. Through the research in this paper, we can realize the efficient interconnection of multiple devices and provide the technical basis for the construction of the broadband wireless networking infrastructure on lunar.

To analyze the various non-functional properties of the AADL (Architecture Analysis and Design Language) model, many model transformation processes transform different AADL elements to different Petri nets. Unifying these transformation processes into a single process can greatly facilitate architects analyzing multiple properties simultaneously. The difficulty is that the specific elements in specific Petri nets lead to different transformation rules of different transformation processes. Some studies transformed AADL model to Petri Net Markup Language (PNML), the interexchange format of different kinds of Petri nets, to realize the unification, but only supported the transformation of part of the AADL architecture model elements. This paper proposes a framework for analysis of non-functional properties of AADL model, improving the unification work by supporting more AADL elements transforming to PNML. We establish the transformation rules mapping elements in AADL error model and behavior model to PNML. In addition, we transform AADL properties to tool specific information in PNML to generate specific Petri nets.

The differences of onboard faults characteristics and severity result in different models, methods and interfaces of fault diagnosis. Thus, FDIR (Fault Discovery, Identification and Recovery) systems usually use a hierarchical architecture in centralized or distributed styles. It is difficult for the centralized FDIR to guarantee the timeliness and coverage of fault diagnosis simultaneously, and the distributed one would bring safety problems. Both of them only focus on the health states of spacecrafts, while not considering its own reliability and reusability. Taking advantage of the above two, the architecture proposed by this paper keeps synthetic views of the spacecraft health states at higher levels and distributes local FDIR at lower levels to improve the timeliness and coverage of fault diagnosis simultaneously, which is based on the hierarchical architecture of spacecrafts and fault severity levels. To ensure the safety and reliability of the FDIR system, a highly decoupled runtime model is proposed. To improve the reusability of the architecture, a unified FDIR model is proposed, which includes hierarchical programming interfaces, etc.

Aiming at the problem that the time of current on-board computer processing complex computing tasks is tight and the data transmission rate between on-board computers is low, a high-performance on-board computer based on S698PM processor and time-triggered Ethernet is designed. The on-board computer uses a CPCI internal bus with a data transmission rate of 1 Gbps, which matches the 1 Gbps data transmission rate of time-triggered Ethernet, so that the computer has a high data throughput performance. In this paper, the principles of the computer design and the block diagrams of key modules are introduced in details, and the actual test results are given. The results show that the computing performance and the bus communication speed of the on-board computer are improved by 1–2 orders of magnitude compared with the current existing computers, and the design goal is successfully achieved.

Aims Gastric cancer stem cells (GCSCs) have been used as a therapeutic target. This study aims to estimate the role of miR-98-5p (termed miR-98) in the development of GCSCs. Main methods The expression of miR-98 in CD44+ GCSCs was verified by RT-PCR. The miR-98 was overexpressed in CD44+ GCSCs by Lentivirus. The ability of self-renewal, invasion, chemoresistance and tumorigenicity was detected in vitro or in vivo after overexpression of miR-98. The target genes of miR-98 were predicted and verified by luciferase reporter assays. The effects miR-98/BCAT1 signaling on the chemoresistance and tumorigenicity of CD44+ GCSCs were investigated in a xenograft model by rescue experiments. Key findings We have shown that miR-98 was decreased in CD44+ GCSCs. The overexpression of miR-98 could inhibit the expression of stem-related genes and the ability of self-renewal, invasion, and tumorigenicity of GCSCs. Also, we found that miR-98 overexpression enhances the sensitivity to cisplatin treatment in vitro. Using a xenograft model, we showed that miR-98 overexpression reversed paclitaxel resistance to CD44+ GCSCs. Finally, we found that branched-chain aminotransferases 1 (BCAT1) is a target gene of miR-98. Overexpressed BCAT1 reversed xenograft tumor formation ability and attenuated the paclitaxel chemosensitivity induced by miR-98 downregulation. Furthermore, BCAT1 restoration affected the expression of invasion and drug resistance-related genes. Significance This study revealed miR-98 inhibits gastric cancer cell stemness and chemoresistance by targeting BCAT1, suggesting that this miR-98/BCAT1 axis represents a potential therapeutic target in gastric cancer.

The α-enolase (ENO1) plays pivotal roles in several types of cancer, but its clinical significance, functional role, and possible mechanism in colorectal cancer (CRC) have remained unclear. Expression level of ENO1 in CRC tissues was examined by qRT-PCR, Western blot, and immunohistochemistry. The effects of ENO1 on cell growth were investigated by MTT, colony formation, flow cytometry assays, and in vivo tumorigenic capacity analysis. The impacts of ENO1 on cell migration and invasion were also explored by scratch-healing, Transwell or Matrigel chamber assays, and in vivo metastatic capacity analysis. Our results showed that the expression level of ENO1 was significantly elevated in CRC tissues. High expression level of ENO1 was associated with disease progression in CRC patients. Overexpression of ENO1 in HCT116 cell line promoted cell proliferation, migration, and invasion in vitro as well as tumorigenesis and metastasis in vivo. In other hand, ablation of ENO1 in HCT116 cells led to totally reverse effects. Mechanistically, we revealed ENO1 could regulate AMPK/mTOR signaling pathway. AMPK pathway activation or mTOR pathway suppression blocked these ENO1 induced alterations. Together, our results demonstrated that ENO1 is a potent promoter of CRC genesis and metastasis at least in part though regulating AMPK/mTOR pathway. These findings also suggested that ENO1 may be a promising therapeutic target in CRC patients.

Internet protocol (IP) and time-triggered Ethernet (TTE) are two important emerging technologies for spacecraft information systems and networks. How the TCP/IP protocol stack, including the IPv6 protocol and the TTE be integrated into the integrated electronic system of spacecraft is introduced. In particular, it is studied that the implementation method of using IPv6 protocol on the time-triggered Ethernet. The problem that the embedded TTE network card does not have the built-in IPv6 protocol and cannot directly support IPv6 is solved. The integration and application of TTE and IPv6 are realized in the spacecraft integrated electronic software architecture. The experiments and tests can indicate its correctness and the effectiveness.

The integrated space-ground network and its architecture are the focus and difficulty in research. Aiming at the problems of the incompatibility between satellite networks, satellite networks and ground networks, and the insufficiency of space network address resources, we propose an integrated space-ground network architecture based on the next generation Internet protocol IPv6. It combines the space communication protocols defined by CCSDS. The network layer protocol based on IPv6 is the foundation of the architecture. It ensures the interconnection and interoperability among inter-satellite networks and intra-satellite networks. The protocol of each layer in the architecture is designed. The IPv6 protocol, inter-satellite and intra-satellite transmission format, inter-satellite routing and intra-satellite communications are analyzed and designed. The experimental results show that the designed satellite router realizes the network communication and routing of IPv6 packets in intra-satellite and inter-satellite networks. It shields the differences between the satellite and ground network systems at the protocol level. It makes the satellite networks have good scalability and adaptability as with as the ground networks.

For the purpose of Spacecraft Networking, considering the factor of the deployment of SPP within SOIS protocol system and the deployment of IPv6 in ground network with its development in the future, we present a set of scheme about design and realization, with software, of onboard router based on IPv6 and SPP. The design and realization of onboard router provides a new idea on constructing the Integrated Space-Ground Network, establishing the foundation of Spacecraft Networking in the future.

The global commercialization of satellites has intensified, and the types and numbers of new spacecrafts have increased year by year. However, the repeated functional construction and “islandization” characteristics of spacecraft severely restrict the use efficiency of space resources. How to realize the open interconnection and self-adaptation optimization cooperation of satellite resources and encourage more and more on-orbit spacecrafts to share spatial data services and routing resources is a severe challenge for the new generation space network communication protocol. This paper builds the Incentive Protocol of Routing based on the TCP/IP protocol family under the CCSDS spatial communication protocol standard framework. Using blockchain distributed database technology and consensus mechanism, combined with routing flow identification technology, design, and implement a network route incentive protocol and game model based on spacecraft route contribution proof consensus mechanism, intended to provide a feasible technical framework and feasible solution for the construction of the integrated digital intelligent economic ecology of the world.

The AIS communication system is a global positioning aided navigation system, which can improve the safety of ship operation and the reliability of navigation. A spaceborne AIS system can dynamically monitoring ships in the global area. But It has many challenges such as message collision and signal transmission loss. This paper first designed a LEO AIS constellation, analyzed the coverage of this constellation, and then carried out the design of the on board AIS receiving system, including an array antenna and a receiver. Finally, the method of multi-user signal separation and detection was expounded.

Background Tumor recurrence, the chief reason for poor prognosis of glioma, is largely attributed to glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT). However, the mechanisms among them remain unknown. Here, we determined whether leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), known as a stem cell marker for colon cancer and gastric cancer, can serve as a novel GSC marker involved in EMT and a therapeutic target in glioma. Methods Stemness properties were examined in FACS-isolated LGR5+/LGR5− cells. Reported stem cell markers, EMT and the Wnt/β-catenin pathway were examined in stable LGR5 knockdown or overexpressed GSCs by Western Blot. The treatment experiment was performed in an intracranial orthotopic xenograft model by knockdown of LGR5 or by using the Wnt/β-catenin pathway inhibitor Wnt-C59. LGR5 expression was determined in 268 glioma specimens by immunohistochemistry. Results LGR5+ cells possessed stronger stemness properties compared to LGR5− cells. The expression of SOX2, Nanog, CD133, CD44, CD24 and EpCAM was modulated by LGR5. Both LGR5 knockdown and Wnt-C59 reduced tumor invasion and migration and blocked EMT by inhibiting the Wnt/β-catenin pathway in vitro and suppressed the intracranial orthotopic xenograft growth and prolonged the survival of xenograft mice in vivo. Moreover, LGR5 was positively correlated with Ki67, N-cadherin and WHO grade and negatively correlated with IDH1. Glioma patients with high expression of LGR5 showed significantly poorer prognosis. Conclusions LGR5 is a new functional GSC marker and prognostic indicator that can promote EMT by activating the Wnt/β-catenin pathway and would thus be a novel therapeutic target for glioma. Electronic supplementary material The online version of this article (10.1186/s13046-018-0864-6) contains supplementary material, which is available to authorized users.

Figure S1. Flow cytometry (FCM) analyses of LGR5 in glioma cells. (a) FCM analyses of LGR5 positive proportion in parent and enriched cells. (b) Fluorescence-activated cell sorting (FACS) of LGR5+ cells in U251 glioma cells and 8591 primary glioma cells. (PPTX 2348 kb)

Short tandem repeat (STR) profiling of 8591. (PDF 2185 kb)

Figure S4. The transfection efficiency of transfected GSCs. (a) The transfection efficiency of transfected U251 GSCs by FCM analyses. (b) The transfection efficiency of transfected U251 GSCs by FCM analyses. (PPTX 2671 kb)

Figure S2. Stemness properties of LGR5+ 8591 cells in vitro. (a) Cell proliferation assays of LGR5+ and LGR5− 8591 cells (P

Short tandem repeat (STR) profiling of U251. (PDF 2190 kb)

Figure S3. Stemness properties of LGR5+ 8591 cells in vivo. (a) Xenografts produced by LGR5+ and LGR5− 8591 cells. (b) The subcutaneous xenografts growth rate generated by LGR5+ and LGR5− 8591 cells in BALB/c-nu mice (two-way ANOVA, P = 0.001). Data are shown as the mean ± SD (LGR5+ 8591: n = 5, LGR5− 8591: n = 5). (c) IHC staining of LGR5, Ki67, N-cadherin, SOX2and CD44 expression in LGR5+ xenografts and LGR5− xenografts (magnification × 200). (d) The percentage of positive expression of LGR5, Ki67, N-cadherin, SOX2and CD44 in LGR5+ xenografts and LGR5− xenografts (n = 5, Student t test). Error bars represent the mean ± SD. (e) The correlation between the levels of LGR5 and Ki67 by Spearman correlation analysis (P

Satellite network has the advantage of global coverage and simple access, so it is considered to be an important part of next generation Internet. In this paper, we propose a network status adaptive QoS dynamic routing algorithm for satellite networks, which is called SADR. It uses heuristic techniques to do the task of dynamic routes searching, routing tables updating and maintaining. In the condition of topology and network status changing, SADR can ensure the path in the routing tables to be alive and effective. SADR improves the heuristic algorithm to fit satellite network. In the end, the performances of end-to-end QoS status and delay are evaluated by simulations.

The ErbB3 receptor–binding protein EBP1 encodes two alternatively spliced isoforms P48 and P42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. Here, we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 P48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 P48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 P42 bound to both the F-box domain of FBXW7 as well as FBXW7 substrates. This adapter function of EBP1 P42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumor-suppressing function. Overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoform-specific functions of EBP1 in cancer. Cancer Res; 77(8); 1983–96. ©2017 AACR.

Objective To investigate the role of miR-221/222 in cell proliferation and apoptosis in human prostate cancer cells, and examine the effects of miR-221/222 on caspase-10 expression. Methods Prostate cancer cells were transfected with miR-221/222 mimics or inhibitors. Cell proliferation was assessed by MTT assay. The expression levels of miR-221/222 were detected with quantitative real-time PCR. Apoptosis was induced with TNF-α/CHX treatment, and evaluated by Hoechst 33342 staining, propidium iodide (PI) flow cytometric analysis, caspase-3 activity measurement, and Western blot analysis. Luciferase activity assay, quantitative real-time PCR, and Western blot were performed to evaluate the effects of miR-221/222 on caspase-10 expression. Results Our results showed that miR-221/222 could promote the proliferation of prostate cancer cells, including LNCaP and PC3 cells. After transfection and apoptosis induction, Hoechst 33342 staining and PI flow cytometric assay showed that apoptosis was dramatically decreased in prostate cancer cells treated with miR-221/222 mimics. Moreover, caspase-3 activity was dramatically decreased, and the cleaved forms of caspase-3 were reduced, in the miR-221/222 mimic-treated group. On the contrary, miR-221/222 knockdown sensitized the prostate cancer cells to TNF-α/CHX-induced apoptosis. In addition, a negative correlation was observed between the expressions of miR-221/222 and caspase-10 in prostate cancer cells. miR-221/222 could repress the expression of caspase-10, which was confirmed by the luciferase reporter assay. Conclusion miR-221/222 promote cell proliferation and repress apoptosis, through suppressing caspase-10, in prostate cancer cells. Our results provide promising evidence for the miRNA-based therapeutic strategy of prostate cancers.