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In recent years, spatial-keyword queries have attracted much attention with the fast development of location-based services. However, current spatial-keyword techniques are disk-based, which cannot fulfill the requirements of high throughput and low response time. With the surging data size, people tend to process data in distributed in-memory environments to achieve low latency. In this paper, we present the distributed solution, i.e., Skia (Spatial-Keyword In-memory Analytics), to provide a scalable backend for spatial-textual analytics. Skia introduces a two-level index framework for big spatial-textual data including: (1) efficient and scalable global index, which prunes the candidate partitions a lot while achieving small space budget; and (2) four novel local indexes, that further support low latency services for exact and approximate spatial-keyword queries. Skia can support common spatial-keyword queries via traditional SQL programming interfaces. The experiments conducted on large-scale real datasets have demonstrated the promising performance of the proposed indexes and our distributed solution.

Glioma stem-like cells (GSCs) are a subset of tumor cells that initiate malignant growth and promote the therapeutic resistance of glioblastoma, the most lethal primary brain tumor. Ribosome biogenesis is an essential cellular process to maintain cell growth, but its regulatory mechanism in GSCs remains largely unknown. Here, we show that WD repeat domain 12 (WDR12), a component of the Pes1-Bop1 complex (PeBoW), is required for ribosome biogenesis in GSCs. WDR12 is preferentially expressed in GSCs compared to non-stem tumor cells and normal brain cells. High levels of WDR12 are associated with glioblastoma progression and poor prognosis. Silencing WDR12 results in the degradation of PeBoW complex components and prevents the maturation of 28S rRNA, thereby inhibiting ribosome biogenesis in GSCs. Subsequently, WDR12 depletion compromises GSC proliferation, inhibits GSC-derived orthotopic tumor growth, and extends animal survival. Together, our results suggest that WDR12 is crucial for ribosome biogenesis in GSCs, and is thus a potential target for GSC-directed therapy of glioblastoma.

The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understood. In this study, we interrogated metabolites that are preferentially secreted from GSCs and found that GSCs produce and secrete histamine to shape a pro-angiogenic tumor microenvironment. This histamine-producing ability is attributed to H3K4me3 modification-activated histidine decarboxylase (HDC) transcription via MYC. Notably, HDC is highly expressed in GBM, which is associated with poor survival of these patients. GSC-secreted histamine activates endothelial cells by triggering a histamine H1 receptor (Hsub1/subR)-Casup2+/sup-NF-κB axis, thereby promoting angiogenesis and GBM progression. Importantly, pharmacological blockage of Hsub1/subR using antihistamines impedes the growth of GBM xenografts in mice. Our findings establish that GSC-specific metabolite secretion remodels the tumor microenvironment and highlight histamine targeting as a potential strategy for GBM therapy.

Tumor mutation burden (TMB) is an independent indicator used to select patients sensitive to immunotherapy. The present study aimed to investigate the clinicopathological and molecular characteristics of patients with hypermutant lung cancer to identify an economical, simple and complementary method for predicting TMB and immunotherapy responses. In total, 1,000 patients with lung cancer were randomly selected, and their samples were submitted to next-generation sequencing, with their TMB status reviewed. The threshold of hypermutation was set to 17.24 mutations (muts)/Mb. The proportion of smokers was higher in the hypermutant cohort (n=67) compared with in the non-hypermutant cohort (n=933; 85.1 vs. 46.6%; P

The nano-ZIF-8@GO hybrids were synthesized and blended with poly(lactic acid) (PLA) by solution method. The effect of nano-ZIF-8@GO hybrids on the crystallization was investigated by DSC and POM. The results showed that low addition amount of nano-ZIF-8@GO had a significant influence on the crystallization behavior of PLA. The tensile strength and elongation at break of the PLA/ZIF-8@GO nanocomposites with 0.5 wt% of ZIF-8@GO were increased to 49.63 MPa and 24.10% compared with 35.83 MPa and 17.66% of the pure PLA, respectively. The addition of nano-ZIF-8@GO hybrids also enhanced the flame retardancy of PLA, and the mechanism was proposed.

Dengue virus (DENV) utilizes host factors throughout its life cycle. In this study, we identified RNA helicase A (RHA), a member of the DEAD/H helicase family, as an important host factor of DENV. In response to DENV2 infection, nuclear RHA protein was partially redistributed into the cytoplasm. The short interfering RNA-mediated knockdown of RHA significantly reduced the amounts of infectious viral particles in various cells. The RHA knockdown reduced the multistep viral growth of DENV2 and Japanese encephalitis virus but not Zika virus. Further study showed that the absence of RHA resulted in a reduction of both viral RNA and protein levels, and the data obtained from the reporter replicon assay indicated that RHA does not directly promote viral protein synthesis. RHA bound to the DENV RNA and associated with three nonstructural proteins, including NS1, NS2B3, and NS4B. Further study showed that different domains of RHA mediated its interaction with these viral proteins. The expression of RHA or RHA-K417R mutant protein lacking ATPase/helicase activity in RHA-knockdown cells successfully restored DENV2 replication levels, suggesting that the helicase activity of RHA is dispensable for its proviral effect. Overall, our work reveals that RHA is an important factor of DENV and might serve as a target for antiviral agents. IMPORTANCE Dengue, caused by dengue virus, is a rapidly spreading disease, and currently there are no treatments available. Host factors involved in the viral replication of dengue virus are potential antiviral therapeutic targets. Although RHA has been shown to promote the multiplication of several viruses, such as HIV and adenovirus, its role in the flavivirus family, including dengue virus, Japanese encephalitis virus, and emerging Zika virus, remains elusive. The current study revealed that RHA relocalized into the cytoplasm upon DENV infection and associated with viral RNA and nonstructural proteins, implying that RHA was actively engaged in the viral life cycle. We further provide evidence that RHA promoted the viral yields of DENV2 independent of its helicase activity. These findings demonstrated that RHA is a new host factor required for DENV replication and might serve as a target for antiviral drugs.

e15255 Background: Tumor mutation burden (TMB) has been confirmed to predict the sensitivity to immunotherapy across multiple tumor types. Multiple genetic factors have been confirmed to increase the level of TMB, such as mutations in DNA damage repair (DDR) genes, POLE/POLD1, and high microsatellite instability (MSI). However, the extent that these factors contribute to hypermutation in lung cancer has not been fully investigated. Methods: We retrospectively reviewed the genetic profiles of 1000 lung cancer patients (pts) who underwent 1021-panel matched tumor-normal next-generation sequencing using tumor tissue samples and peripheral blood. Their TMB status were analyzed to determine the threshold of hypermutation. The clinicopathological characteristics, genetic profiles and genetic factors related to hypermutation were investigated for the pts in hypermutant cohort. Results: The threshold of hypermutation was determined as 19 muts/MB (top 5% in 1000 pts). As a result, 53 pts were included in the hypermutant cohort. A total of 1725 nonsynonymous somatic variants in 506 genes were identified. The most frequently mutated genes included TP53 (88.7%), LRP1B (71.7%), MLL2 (35.8%), EPHA5 (34.0%), and FAT1 (34.0%). KRAS was mutated in 17% pts, whereas mutations in EGFR, BRAF, ERBB2, MET were identified less commonly. MSI-high was observed in 5 cases. A germline mutation in BRCA1 gene was identified in an adenocarcinoma patient. Compared to genetic profiles of non-small cell lung cancer from TCGA database, mutations in multiple DDR genes were enriched in the hypermutant cohort (Table). No known driver mutation in POLE/POLD1 was identified. Conclusions: MSI-high and mutations in DDR genes may be associated with high level of TMB, whereas POLE/POLD1 driver mutations may not be related to hypermutant lung cancer. Hypermutant lung cancer displays distinctive molecular features that may be used as complementary indicators to screening pts sensitive to immunotherapy. [Table: see text]

e21646 Background: Identifying targetable genetic variants may help maximize clinical benefit of non-small cell lung cancer (NSCLC). Here, we retrospectively analyzed the benefit of next-generation sequencing (NGS) for NSCLC in routine clinical practice. Methods: A total of 59 NSCLC patients were enrolled in the study from Jun. 2018 to Dec. 2019. Formalin-fixed paraffin-embedded tissues samples were collected and sequenced by NGS, which detects single-nucleotide variants, small insertions/deletions, rearrangements, and copy-number alterations of either 59 or 1021 tumor related genes. The tumor response was evaluated using RECIST v1.1. Results: The detection rate of targetable variants was 59.32% (35/59), including EGFR mutation 49.15% (29/59), ALK rearrangement 5.08% (3/59), ROS1 rearrangement 1.69% (1/59), BRAF V600E mutation 1.69% (1/59), and ERBB2 mutation 1.69% (1/59). Of 29 patients with EGFR mutations, 5 patients (17.24%) had multiple EGFR mutations, including 2 patients (6.89%) with uncommon mutations. 25patients (86.21%) harbored concurrent mutations that may limit the efficacy of EGFR-TKIs, including EGFR amplification, activation of bypass signaling pathways, TP53 exon8 mutation, BCL2L11 deletion polymorphism, and PI3K-AKT-mTOR and cell cycle gene alterations. Among 25 patients received EGFR-TKIs, TKI effectiveness was evaluated in 18 patients. The disease control rate was 100% and overall response rate was 27.78%. The proportion of patients with TMB-H and/or PD-L1≥1, and targetable variants negative was 33.89% (20/59). Only one patient of this group received immunotherapy with pembrolizumab and achieved SD at the 2nd month. The proportion of patients with targetable variants negative, TMB-L, and PD-L1 < 1 or unknow patients was 6.78% (4/59), two patients of them left hospital without additional treatment, two patients received chemotherapy and the KRAS mutation present in one of them suggested that he might be resistant to EGFR-TKIs. Conclusions: More than half of NSCLC patients have targetable genetic variants and more than 30% patients have a molecular signature that can be treated with immunotherapy. Compared with immunotherapy, targeted therapy has higher acceptability in real-world. NGS-based genetic testing may have clinical value to predict the effectiveness of targeted therapy and immunotherapy. It can be widely implemented and standardized into clinical use.

Spatio-temporal semantics based on “object views” or “event views” has few abilities to represent and model the continuity and gradual oceanic phenomena or objects, which seriously limits the specific marine applications and knowledge discovery and data mining, so this paper proposes a hierarchical abstraction semantics with “marine spatio-temporal process→life span phases→evolution sequences→state units” and process objects included by level with “marine process objects→phase objects→sequence object→state objects” with the oceanic process characteristics into the marine process semantics. In addition, this paper designs the storage and representation of marine process objects using the backus normal forms (BNF) and abstract data type (ADT). Base on El Nino Southern Oscilation (ENSO) index and Chinese rain gauging station data, this paper also gives a case of study. The spatio-temporal analysis between ENSO process and Chinese rainfall anomalies shows that the marine spatio-temporal semantics not only can illustrate the spatial distribution of Chinese rainfall anomalies in different time scales at ENSO process, life span phases and state units, but also analyze the dynamic changes of Chinese rainfall anomalies in different life span phases or state units within ENSO evolution.

In this paper, it mainly research on the application of geography information technology in the popular science educational fields. It applies the space-time attribute and the graph visualization technology into the popular science knowledge creation, establishes the space-time information model of the popular science knowledge, and combines with the digital earth technology to make information of popular science to be expressed and exhibited in the method of graphical visually. It improves the accessibility of the popular science knowledge, and realizes an new method to popular science knowledge.

The formation of cytoplasmic stress granules and the innate immune response are two distinct cellular stress responses. Our study investigated the involvement of four innate immune proteins - retinoic-acid-inducible gene I (RIG-I, also known as DDX58), melanoma differentiation-associated gene 5 (MDA5, also known as IFIH1), IFN-β promoter stimulator (IPS-1, also known as MAVS) and protein kinase regulated by dsRNA (PKR, also known as EIF2AK2) in the formation of stress granules. Knockdown of IPS-1 or PKR significantly decreased the formation of stress granules induced by double-stranded (ds)RNA. IPS-1 depletion markedly attenuated the phosphorylation of PKR and eIF2α that was triggered by dsRNA, and IPS-1 facilitated the in vitro autophosphorylation of PKR. In IPS-1-depleted cells, the dsRNA-mediated dimerization of PKR through its dsRNA-binding domains was significantly abrogated, suggesting that IPS-1 might be involved in PKR dimerization. By co-immunoprecipitation and pulldown assays, our data demonstrate that IPS-1 directly binds to PKR through the IPS-1 caspase activation and recruitment domain (CARD), suggesting that the effect of IPS-1 on the formation of stress granules might be exerted through interacting with PKR and mediating its activation. PKR was recruited into stress granules upon activation, whereas the majority of IPS-1 protein formed clusters on mitochondrial membranes. Our work provides the first evidence that the innate signaling molecule IPS-1 plays an essential role in stress granule formation.

The formation of cytoplasmic stress granules and the innate immune response are two distinct cellular stress responses. Our study investigated the involvement of four innate immune proteins - retinoic-acid-inducible gene I (RIG-I, also known as DDX58), melanoma differentiation-associated gene 5 (MDA5, also known as IFIH1), IFN-β promoter stimulator (IPS-1, also known as MAVS) and protein kinase regulated by dsRNA (PKR, also known as EIF2AK2) in the formation of stress granules. Knockdown of IPS-1 or PKR significantly decreased the formation of stress granules induced by double-stranded (ds)RNA. IPS-1 depletion markedly attenuated the phosphorylation of PKR and eIF2α that was triggered by dsRNA, and IPS-1 facilitated the in vitro autophosphorylation of PKR. In IPS-1-depleted cells, the dsRNA-mediated dimerization of PKR through its dsRNA-binding domains was significantly abrogated, suggesting that IPS-1 might be involved in PKR dimerization. By co-immunoprecipitation and pulldown assays, our data demonstrate that IPS-1 directly binds to PKR through the IPS-1 caspase activation and recruitment domain (CARD), suggesting that the effect of IPS-1 on the formation of stress granules might be exerted through interacting with PKR and mediating its activation. PKR was recruited into stress granules upon activation, whereas the majority of IPS-1 protein formed clusters on mitochondrial membranes. Our work provides the first evidence that the innate signaling molecule IPS-1 plays an essential role in stress granule formation.

Existing reliability models evaluate the lifetime of storage systems well. However, few models aim to analysis parallel storage systems, especially systems equipped with energy-efficient solutions. MREED model provides an inspiring reliability analysis idea for energy-efficient parallel storage systems, especially RAIDs. Unfortunately, the MREED has its disadvantage that it can evaluate RAID-0 only, in which a basic method of data-stripping is applied. In this paper, we extend the MREED model to cover the most energy-efficient RAID setups including RAID-1, which introduces disk-mirroring techniques, and RAID-5, which applies a data-parity techniques based on data-stripping schemes for a data recovery purpose. The MREED is then applied to evaluate an existing well-known power-aware RAID system-PARAID. Experimental results indicate the data locality affection and data parity impaction on the reliability of PARAID. Furthermore, we investigate a fundamental trade-off between reliability and energy-efficiency in terms of energy-saving RAID systems. A tradeoff curve is provided to justify whether it worth to sacrifice reliability for better energy efficiency.

Background Dengue virus (DENV) is found in the tropical and subtropical regions and affects millions of people annually. Currently, no specific vaccine or antiviral treatment against dengue virus is available. Innate immunity has been shown to be important for host resistance to DENV infection. Although protein kinase regulated by double-stranded RNA (PKR) has been found to promote the innate signaling in response to infection by several viruses, its role in the innate response to DENV infection is still unclear. Our study aimed to investigate the role of PKR in DENV-induced innate immune responses. Methodology/Principal Findings By RNAi, silencing of PKR significantly enhanced the expression of interferon (IFN)-β in DENV infected human lung epithelial A549 cells. Western blot and immunofluorescence microscopy data showed that PKR knockdown upregulated the activation of innate signaling cascades including p38 and JNK mitogen-activated protein kinases (MAPKs), interferon regulatory factor-3 and NF-κB, following DENV2 infection. Likewise, a negative regulatory effect of PKR on the IFN production was also observed in poly(IC) challenged cells. Moreover, the PKR knockdown-mediated IFN induction was attenuated by RIG-I or IPS-1 silencing. Finally, overexpression of a catalytically inactive PKR mutant (K296R), but not of a mutant lacking dsRNA binding activity (K64E) or the double mutant (K64EK296R), reversed the IFN induction mediated by PKR knockdown, suggesting that the dsRNA binding activity is required for PKR to downregulate IFN production. Conclusions/Significance PKR acts as a negative regulator of IFN induction triggered by DENVs and poly(IC), and this regulation relies on its dsRNA binding activity. These findings reveal a novel regulatory role for PKR in innate immunity, suggesting that PKR might be a promising target for anti-DENV treatments.

To clone and express protein kinase regulated by double-stranded RNA (PKR) gene, and to purify and isolate PKR interacting proteins.By using specific primers, PKR gene fragments tagged with HA and FLAG (FLAG-PKR-HA, and HA-PKR-FLAG) were amplified by PCR, and cloned into pSG5 vector. The recombinant plasmids were transfected into PKR knockdown (PKR(kd);) HeLa cells by Lipfectamine(TM); 2000. The expression of tagged PKR was confirmed by Western blotting. Finally, the PKR interacting proteins were isolated by tandem affinity purification (TAP) system using HA and FLAG antibodies, and visualized by Western blotting and SDS-PAGE silver staining.PKR expression plasmids were constructed and TAP system was successfully established. Silver staining showed that PKR, and two potential PKR interacting protein fragments were isolated by SDS-PAGE.We have successfully purified and isolated PKR interacting proteins, thus providing a basis for future research.

In this study we develop a secure allocating processing(SAP) algorithm for the S-FAS scheme [13] to improve the security level and consider its performance using the heterogeneous feature of a large distributed system. The SAP allocation algorithm considers load balancing, delayed effects caused by the workload variance of many consecutive requests, and the heterogeneous feature of the storage nodes in the system. We develop a prototype using the multi-threading technique for the S-FAS scheme with the SAP algorithm to guide the file allocation. We did some experiments and the results show that the proposed solution can not only improve the security level, but also improve the throughput of the distributed storage system with heterogeneous vulnerabilities by using the multi-thread technique.

There is a growing demand for large-scale distributed storage systems to support resource sharing and fault tolerance. Although heterogeneity issues of distributed systems have been widely investigated, little attention has yet been paid to security solutions designed for distributed storage systems with heterogeneous vulnerabilities. This fact motivates us to investigate a fragment allocation scheme called S-FAS to improve security of a distributed system where storage sites have a wide variety of vulnerabilities. In the S-FAS approach, we integrate file fragmentation with the secret sharing technique in a distributed storage system with heterogeneous vulnerabilities. Storage sites in a distributed systems are classified into a variety of different server types based on vulnerability characteristics. Given a file and a distributed system, S-FAS allocates fragments of the file to as many different types of nodes as possible in the system. Data confidentiality is preserved because fragments of a file are allocated to multiple storage nodes. We develop storage assurance and dynamic assurance models to evaluate the quality of security offered by S-FAS. Analysis results show that fragment allocations made by S-FAS lead to enhanced security because of the consideration of heterogeneous vulnerabilities in distributed storage systems.