Host-mediated RNA editing in viruses.

Viruses rely on hosts for life and reproduction, cause a variety of symptoms from common cold to AIDS to COVID-19 and provoke public health threats claiming millions of lives around the globe. RNA editing, as a crucial co-/post-transcriptional modification inducing nucleotide alterations on both endogenous and exogenous RNA sequences, exerts significant influences on virus replication, protein synthesis, infectivity and toxicity. Hitherto, a number of host-mediated RNA editing sites have been identified in diverse viruses, yet lacking a full picture of RNA editing-associated mechanisms and effects in different classes of viruses. Here we synthesize the current knowledge of host-mediated RNA editing in a variety of viruses by considering two enzyme families, viz., ADARs and APOBECs, thereby presenting a landscape of diverse editing mechanisms and effects between viruses and hosts. In the ongoing pandemic, our study promises to provide potentially valuable insights for better understanding host-mediated RNA editing on ever-reported and newly-emerging viruses.

Gene Expression Nebulas (GEN): a comprehensive data portal integrating transcriptomic profiles across multiple species at both bulk and single-cell levels.

Transcriptomic profiling is critical to uncovering functional elements from transcriptional and post-transcriptional aspects. Here, we present Gene Expression Nebulas (GEN, https://ngdc.cncb.ac.cn/gen/), an open-access data portal integrating transcriptomic profiles under various biological contexts. GEN features a curated collection of high-quality bulk and single-cell RNA sequencing datasets by using standardized data processing pipelines and a structured curation model. Currently, GEN houses a large number of gene expression profiles from 323 datasets (157 bulk and 166 single-cell), covering 50 500 samples and 15 540 169 cells across 30 species, which are further categorized into six biological contexts. Moreover, GEN integrates a full range of transcriptomic profiles on expression, RNA editing and alternative splicing for 10 bulk datasets, providing opportunities for users to conduct integrative analysis at both transcriptional and post-transcriptional levels. In addition, GEN provides abundant gene annotations based on value-added curation of transcriptomic profiles and delivers online services for data analysis and visualization. Collectively, GEN presents a comprehensive collection of transcriptomic profiles across multiple species, thus serving as a fundamental resource for better understanding genetic regulatory architecture and functional mechanisms from tissues to cells.

BrainBase: a curated knowledgebase for brain diseases.

Brain is the central organ of the nervous system and any brain disease can seriously affect human health. Here we present BrainBase (https://ngdc.cncb.ac.cn/brainbase), a curated knowledgebase for brain diseases that aims to provide a whole picture of brain diseases and associated genes. Specifically, based on manual curation of 2768 published articles along with information retrieval from several public databases, BrainBase features comprehensive collection of 7175 disease-gene associations spanning a total of 123 brain diseases and linking with 5662 genes, 16 591 drug-target interactions covering 2118 drugs/chemicals and 623 genes, and five types of specific genes in light of expression specificity in brain tissue/regions/cerebrospinal fluid/cells. In addition, considering the severity of glioma among brain tumors, the current version of BrainBase incorporates 21 multi-omics datasets, presents molecular profiles across various samples/conditions and identifies four groups of glioma featured genes with potential clinical significance. Collectively, BrainBase integrates not only valuable curated disease-gene associations and drug-target interactions but also molecular profiles through multi-omics data analysis, accordingly bearing great promise to serve as a valuable knowledgebase for brain diseases.

Selective STAT3 Inhibitor Alantolactone Ameliorates Osteoarthritis via Regulating Chondrocyte Autophagy and Cartilage Homeostasis.

Osteoarthritis (OA), which is identified by chronic pain, impacts the quality of life. Cartilage degradation and inflammation are the most relevant aspects involved in its development. Signal transducer and activator of transcription 3(STAT3), a member of the STATs protein family, is associated with inflammation. Alantolactone (ALT), a sesquiterpene lactone compound, can selectively suppress the phosphorylation of STAT3. However, the pharmacological effect of ALT on OA is still imprecise. In this study, IL-1ß (10 ng/ml) was applied to cartilage chondrocytes, which were treated with different concentrations of Alantolactone for 24 h. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2(COX2), matrix metalloproteinases (MMPs) and thrombospondin motifs-5 (ADAMTS5) were detected by western blot. Protein expression of Collagen Ⅱ was observed by western blot, safranin O staining and immunofluorescence. Manifestation of autophagy related proteins such as autophagy-related gene-5 (ATG5), P62, LC3Ⅱ/Ⅰ and PI3K/AKT/mTOR-related signaling molecules were measured by western blot and autophagic flux monitored by confocal microscopy. Expression of STAT3 and NF-κB-related signaling molecules were evaluated by western blot and immunofluorescence. In vivo, 2 mg/kg ALT or equal bulk of vehicle was engaged in the destabilization of medial meniscus (DMM) mouse models by intra-articular injection, the degree of cartilage destruction was classified by Safranin O/Fast green staining. Our findings reported that the enhance of inflammatory factors containing iNOS, COX2, MMPs and ADAMTS5 induced by IL-1ß could be ameliorated by ALT. Additionally, the diminish of Collagen Ⅱ and autophagy which was stimulated by IL-1ß could be alleviated by ALT. Mechanistically, STAT3, NF-κB and PI3K/AKT/mTOR signal pathways might be involved in the effect of ALT on IL-1ß-induced mouse chondrocytes. In vivo, ALT protected cartilage in the DMM mouse model. Overall, this study illustrated that ALT attenuated IL-1ß-induced inflammatory responses, relieved cartilage degeneration and promoted impaired autophagy via restraining of STAT3 and NF-κB signal pathways, implying its auspicious therapeutical effect for OA.

IC4R-2.0: Rice Genome Reannotation Using Massive RNA-seq Data.

Genome reannotation aims for complete and accurate characterization of gene models and thus is of critical significance for in-depth exploration of gene function. Although the availability of massive RNA-seq data provides great opportunities for gene model refinement, few efforts have been made to adopt these precious data in rice genome reannotation. Here we reannotate the rice (Oryza sativa L. ssp. japonica) genome based on integration of large-scale RNA-seq data and release a new annotation system IC4R-2.0. In general, IC4R-2.0 significantly improves the completeness of gene structure, identifies a number of novel genes, and integrates a variety of functional annotations. Furthermore, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are systematically characterized in the rice genome. Performance evaluation shows that compared to previous annotation systems, IC4R-2.0 achieves higher integrity and quality, primarily attributable to massive RNA-seq data applied in genome annotation. Consequently, we incorporate the improved annotations into the Information Commons for Rice (IC4R), a database integrating multiple omics data of rice, and accordingly update IC4R by providing more user-friendly web interfaces and implementing a series of practical online tools. Together, the updated IC4R, which is equipped with the improved annotations, bears great promise for comparative and functional genomic studies in rice and other monocotyledonous species. The IC4R-2.0 annotation system and related resources are freely accessible at http://ic4r.org/.

Microstructure evolution and mechanical properties of tempered 5140 alloy steel after proton irradiation at different temperatures.

: This article introduces the effect of tempered 5140 alloy steel commonly used in engineering on its structure and mechanical properties under the action of proton irradiation. In the present study, the irradiation energy of 160 keV is applied to experimentally investigate the proton irradiation with different cumulative fluences on the tempered 5140 alloy steel. The effect of the cumulative fluence of the proton irradiation on the microstructure evolution of tempered 5140 alloy steel is studied through transmission electron microscopy. Moreover, the morphology of the tensile fracture is analyzed by scanning electron microscope. The effect of the cumulative fluence of the proton irradiation on the nanomechanical properties of tempered 5140 alloy steel is investigated with a nanomechanical tester. It is found that the surface hardening effect formed by the proton irradiation damage causes the dislocation density in the structure near the tempered 5140 alloy steel surface layer and such effect increases as the proton irradiation cumulative fluence increases. The results obtained show that the yield and tensile strength of the tempered 5140 alloy steel increase slightly as the cumulative fluence of the proton irradiation increases. However, the corresponding elongation decreases. For a stable pressure load of the nanoindentation, the hardness of the nanoindentation of the tempered 5140 alloy steel increases as the proton irradiation fluence increases. However, the corresponding indentation depth decreases. Based on the obtained results, it is concluded that proton irradiation has no significant effect on the macro- and nanomechanical properties of the tempered 5140 alloy steel. This may be attributed to the low energy of the proton irradiation, and the resulting radiation damage only acts on the thin layer of the tempered 5140 alloy steel surface.

Compositional Variability and Mutation Spectra of Monophyletic SARS-CoV-2 Clades.

COVID-19 and its causative pathogen SARS-CoV-2 have rushed the world into a staggering pandemic in a few months, and a global fight against both has been intensifying. Here, we describe an analysis procedure where genome composition and its variables are related, through the genetic code to molecular mechanisms, based on understanding of RNA replication and its feedback loop from mutation to viral proteome sequence fraternity including effective sites on the replicase-transcriptase complex. Our analysis starts with primary sequence information, identity-based phylogeny based on 22,051 SARS-CoV-2 sequences, and evaluation of sequence variation patterns as mutation spectra and its 12 permutations among organized clades. All are tailored to two key mechanisms: strand-biased and function-associated mutations. Our findings are listed as follows: 1) The most dominant mutation is C-to-U permutation, whose abundant second-codon-position counts alter amino acid composition toward higher molecular weight and lower hydrophobicity, albeit assumed most slightly deleterious. 2) The second abundance group includes three negative-strand mutations (U-to-C, A-to-G, and G-to-A) and a positive-strand mutation (G-to-U) due to DNA repair mechanisms after cellular abasic events. 3) A clade-associated biased mutation trend is found attributable to elevated level of negative-sense strand synthesis. 4) Within-clade permutation variation is very informative for associating non-synonymous mutations and viral proteome changes. These findings demand a platform where emerging mutations are mapped onto mostly subtle but fast-adjusting viral proteomes and transcriptomes, to provide biological and clinical information after logical convergence for effective pharmaceutical and diagnostic applications. Such actions are in desperate need, especially in the middle of the War against COVID-19.

Plant editosome database: a curated database of RNA editosome in plants.

RNA editing plays an important role in plant development and growth, enlisting a number of editing factors in the editing process and accordingly revealing the diversity of plant editosomes for RNA editing. However, there is no resource available thus far that integrates editosome data for a variety of plants. Here, we present Plant Editosome Database (PED; http://bigd.big.ac.cn/ped), a curated database of RNA editosome in plants that is dedicated to the curation, integration and standardization of plant editosome data. Unlike extant relevant databases, PED incorporates high-quality editosome data manually curated from related publications and organelle genome annotations. In the current version, PED integrates a complete collection of 98 RNA editing factors and 20 836 RNA editing events, covering 203 organelle genes and 1621 associated species. In addition, it contains functional effects of editing factors in regulating plant phenotypes and includes detailed experimental evidence. Together, PED serves as an important resource to help researchers investigate the RNA editing process across a wide range of plants and thus would be of broad utility for the global plant research community.

EWAS Atlas: a curated knowledgebase of epigenome-wide association studies.

Epigenome-Wide Association Study (EWAS) has become increasingly significant in identifying the associations between epigenetic variations and different biological traits. In this study, we develop EWAS Atlas (http://bigd.big.ac.cn/ewas), a curated knowledgebase of EWAS that provides a comprehensive collection of EWAS knowledge. Unlike extant data-oriented epigenetic resources, EWAS Atlas features manual curation of EWAS knowledge from extensive publications. In the current implementation, EWAS Atlas focuses on DNA methylation-one of the key epigenetic marks; it integrates a large number of 329 172 high-quality EWAS associations, involving 112 tissues/cell lines and covering 305 traits, 1830 cohorts and 390 ontology entities, which are completely based on manual curation from 649 studies reported in 401 publications. In addition, it is equipped with a powerful trait enrichment analysis tool, which is capable of profiling trait-trait and trait-epigenome relationships. Future developments include regular curation of recent EWAS publications, incorporation of more epigenetic marks and possible integration of EWAS with GWAS. Collectively, EWAS Atlas is dedicated to the curation, integration and standardization of EWAS knowledge and has the great potential to help researchers dissect molecular mechanisms of epigenetic modifications associated with biological traits.

Editome Disease Knowledgebase (EDK): a curated knowledgebase of editome-disease associations in human.

RNA editing, as an essential co-/post-transcriptional RNA modification type, plays critical roles in many biological processes and involves with a variety of human diseases. Although several databases have been developed to collect RNA editing data in both model and non-model animals, there still lacks a resource integrating associations between editome and human disease. In this study, we present Editome-Disease Knowledgebase (EDK; http://bigd.big.ac.cn/edk), an integrated knowledgebase of RNA editome-disease associations manually curated from published literatures. In the current version, EDK incorporates 61 diseases associated with 248 experimentally validated abnormal editing events located in 32 mRNAs, 16 miRNAs, 1 lncRNA and 11 viruses, and 44 aberrant activities involved with 6 editing enzymes, which together are curated from more than 200 publications. In addition, to facilitate standardization of editome-disease knowledge integration, we propose a data curation model in EDK, factoring an abundance of relevant information to fully capture the context of editome-disease associations. Taken together, EDK is a comprehensive collection of editome-disease associations and bears the great utility in aid of better understanding the RNA editing machinery and complex molecular mechanisms associated with human diseases.

ICG: a wiki-driven knowledgebase of internal control genes for RT-qPCR normalization.

Real-time quantitative PCR (RT-qPCR) has become a widely used method for accurate expression profiling of targeted mRNA and ncRNA. Selection of appropriate internal control genes for RT-qPCR normalization is an elementary prerequisite for reliable expression measurement. Here, we present ICG (http://icg.big.ac.cn), a wiki-driven knowledgebase for community curation of experimentally validated internal control genes as well as their associated experimental conditions. Unlike extant related databases that focus on qPCR primers in model organisms (mainly human and mouse), ICG features harnessing collective intelligence in community integration of internal control genes for a variety of species. Specifically, it integrates a comprehensive collection of more than 750 internal control genes for 73 animals, 115 plants, 12 fungi and 9 bacteria, and incorporates detailed information on recommended application scenarios corresponding to specific experimental conditions, which, collectively, are of great help for researchers to adopt appropriate internal control genes for their own experiments. Taken together, ICG serves as a publicly editable and open-content encyclopaedia of internal control genes and accordingly bears broad utility for reliable RT-qPCR normalization and gene expression characterization in both model and non-model organisms.