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Xanthomonas oryzae pv. oryzae is the causal agent of bacterial blight, one of the most devastating diseases of rice. Here, a hypervirulent strain, C9-3, defeating Xa1, Xa10, xa13, and Xa23 resistance genes, was used to extract genomic DNA for single molecule real-time (SMRT) sequencing. After assembly, the genome consists of a single-circular chromosome with the size of 4,924,298 bp with G+C content of 63.7% and contains 4,715 genes. Annotation and analysis of the TALE genes using a suite of applications named AnnoTALE suggested that 17 transcription activator-like effectors, including 15 typical TALEs and 2 iTALEs/truncTALEs, were encoded in the genome. The approach and genome resource will contribute to the discovery of new virulence effectors and understanding on rice-X. oryzae pv. oryzae interactions.

Bone loss remains a major health concern for astronauts during space flight. Increased osteoclast activity is one of the main causes of bone loss in astronauts subjected to microgravity conditions. However, the underlying molecular mechanisms remain unclear. Microtubule actin crosslinking factor 1 (MACF1) has been implicated in the regulation of cytoskeletal distribution, cell migration, and cell differentiation. Our previous studies have shown that MACF1 promotes the differentiation of pre-osteoclasts. However, whether MACF1 regulates the migration and cytoskeletal arrangement of pre-osteoclasts under microgravity conditions has not yet been elucidated. In this study, we used a hind-limb unloading (HLU) mouse model and a random positioning machine (RPM) to simulate the effects of microgravity on pre-osteoclasts. In the HLU mouse model, the expression of MACF1 was upregulated in primary pre-osteoclasts of mice, accompanied by enhanced migration in vivo. Moreover, simulated microgravity using the RPM also promoted MACF1 expression and migration of pre-osteoclasts in vitro. Additionally, knockdown of MACF1 disrupted cytoskeletal arrangement (F-actin and microtubules) and further inhibited the migration of pre-osteoclasts via the RhoA/ROCK1 signaling pathway. We further demonstrated that knockdown of MACF1 disrupted the enhanced migration and cytoskeleton arrangement of pre-osteoclasts induced by simulated microgravity. These data demonstrate that MACF1 positively regulates the migration and cytoskeletal organization of pre-osteoclasts under simulated microgravity, suggesting that MACF1 may be a therapeutic target for the treatment of bone loss induced by microgravity.

Chemodynamic therapy (CDT) is widely explored for tumor-specific therapy by converting endogenous H2O2 to lethal ·OH to destroy cancer cells. However, ·OH scavenging by glutathione (GSH) and insufficient intratumoral H2O2 levels seriously hinder the application of CDT. Herein, we reported the fabrication of copper ion-doped ZIF-8 loaded with gold nanozymes and doxorubicin hydrochloride (DOX) for the chemotherapy and CDT synergistic treatment of tumors with the assistance of tumor microenvironment (TME)-activated fluorescence imaging. The Cu2+-doped ZIF-8 shell was gradually degraded to release DOX and gold nanoclusters responding to the acidic TME. The fluorescence signal of the tumor region was acquired after the quenched fluorescence of the gold nanoclusters by Cu2+ and DOX by aggregation-induced quenching was turned on because of the interaction of GSH with Cu2+ and the release of free DOX. The Cu2+ ions could deplete the GSH via redox reactions and the generated Cu+ could convert internal H2O2 to ·OH for tumor CDT. The chemotherapeutic effect of DOX was strengthened through drug efflux inhibition and drug sensitivity increase due to the consumption of GSH and ·OH burst. Moreover, DOX could raise the level of H2O2 and augment the effect of CDT. In addition, the fluorescent gold nanoclusters not only served as a peroxidase to convert H2O2 to ·OH but also employed as an oxidase to consume GSH, resulting in the amplification of chemotherapy and CDT. This work presents an approach to construct tumor microenvironment-activated theranostic probes without external stimuli and to achieve the tumor elimination through cascade reactions and synergistic treatment.

Based on 15N tracer technique, absorption of different concentrations of ammonium nitrogen (N-NH4+), nitrate nitrogen (N-NO3-) and glycine (N-Gly) by root of six species of alpine forage (Puccinellia tenuiflora, Poa crymophila, Festuca sinensis, Elymus nutans, Elymus sibiricus and Bromus inermis) was studied in a hydroponic culture. The uptake kinetic parameter was analyzed according to Michaelis-Menten equation. The Michaelis-Menten equation represents the velocity equation for the relationship between the initial rate of an enzymatic reaction and the substrate concentration. The result showed that the absorption range of ammonium nitrogen, nitrate nitrogen and glycine by root of six species of alpine plant were 1.1–20.9 μmol·g–1·h–1, 0.4–3.4 μmol·g–1·h–1 and 0.1–3.7 μmol·g–1·h–1, which accounts for 68.8%-74.7%, 12.0%-27.0% and 4.3%-13.4% of total absorptivity, respectively. The six kinds of P. tenuiflora, P. crymophila, F. sinensis, E. nutans, E. sibiricus and B. inermis showed significant difference in nitrogen absorption. At the same concentration, the absorption of nitrogen in different forms of the same herbage is different. The absorptive amount of ammonium nitrogen was the highest among them, then the glycine, the nitrate nitrogen was least absorbed. The results could provide a theoretical basis for nitrogen utilization in alpine forages. For example, P. tenuiflora showed a much higher ability of absorbing nitrogen nutrition in a high salt environment and could be a more suitable herbage to be planted in saline-alkali soil in the Qinghai-Tibet Plateau as compared with E. nutans.

Noncanonical nucleic acid structures, such as G-quadruplex (G4) and i-Motif (iM), have attracted increasing research interests because of their unique structural and binding properties, as well as their important biological activities. To date, thousands of small molecules that bind to varying G4/iM structures have been designed, synthesized and tested for diverse chemical and biological uses. Because of the huge potential and increasing research interests on G4-targeting ligands, we launched the first G4 ligand database G4LDB in 2013. Here, we report a new version, termed G4LDB 2.2 (http://www.g4ldb.com), with upgrades in both content and function. Currently, G4LDB2.2 contains >3200 G4/iM ligands, ∼28 500 activity entries and 79 G4–ligand docking models. In addition to G4 ligand library, we have also added a brand new iM ligand library to G4LDB 2.2, providing a comprehensive view of quadruplex nucleic acids. To further enhance user experience, we have also redesigned the user interface and optimized the database structure and retrieval mechanism. With these improvements, we anticipate that G4LDB 2.2 will serve as a comprehensive resource and useful research toolkit for researchers across wide scientific communities and accelerate discovering and validating better binders and drug candidates.

Genome-wide association studies (GWAS) have identified a large number of schizophrenia risk variants, and most of them are mapped to noncoding regions. By leveraging multiple joint-tissue gene expression data and GWAS data, we herein performed a transcriptome-wide association study (TWAS) and Mendelian randomization (MR) analysis and identified 144 genes whose mRNA levels were related to genetic risk of schizophrenia. Most of these genes exhibited diametrically opposite trends of expression in prenatal and postnatal brain tissues, despite that their expression levels in dorsolateral prefrontal cortex (DLPFC) tissues did not significantly differ between schizophrenics and healthy controls. We then found significant enrichment of these genes in dopamine-related pathways that were repeatedly implicated in schizophrenia pathogenesis and in the action of antipsychotic drugs. Gene expression analysis using single cell RNA-sequencing (scRNA-seq) data of mid-gestation fetal brains further revealed enrichment of these genes in glutamatergic excitatory neurons and cycling progenitors. These lines of evidence, in consistency with previous findings, confirmed the polygenic nature of schizophrenia and highlighted involvement of early neurodevelopment aberrations in this disorder. Further investigations using advanced algorithms in both bulk brain tissues and in single cells and at different developmental stages are necessary to characterize transcriptomic features of schizophrenia pathogenesis along brain development.

Objectives Osseointegration of oral implants has a low success rate in patients with type 2 diabetes. This is because of the inhibition of osteogenic differentiation in the jawbone marrow mesenchymal stem cells, in which the expression of microRNA(miR)-491-5p is significantly downregulated, as ascertained through gene chip screening. However, the underlying mechanisms are unclear. Here, we aimed to clarify the mechanisms involved in the influence of miR-491-5p on osteogenic differentiation. Subjects and methods Jawbone marrow mesenchymal stem cells were isolated from jawbones of patients with type 2 diabetes and subjected to bioinformatics and functional analyses. Osteogenesis experiments were conducted using the isolated cells and an in vivo model. Results Knockdown and overexpression experiments revealed the positive effects of miR-491-5p expression on osteogenic differentiation in vivo and in vitro. Additionally, a dual-luciferase assay revealed that miR-491-5p targeted the SMAD/RUNX2 pathway by inhibiting the expression of epidermal growth factor receptor. Conclusions miR-491-5p is vital in osteogenic differentiation of jawbone mesenchymal stem cells; its downregulation in type 2 diabetes could be a major cause of decreased osteogenic differentiation. Regulation of miR-491-5p expression could improve osteogenic differentiation of jawbone mesenchymal stem cells in patients with type 2 diabetes.

Summary Upon fungal and bacterial pathogen attack, plants launch pattern‐triggered immunity (PTI) by recognizing pathogen‐associated molecular patterns (PAMPs) to defend against pathogens. Although PTI‐mediated response has been widely studied, a systematic understanding of the reprogrammed cellular processes during PTI by multi‐omics analysis is lacking. In this study, we generated metabolome, transcriptome, proteome, ubiquitome and acetylome data to investigate rice (Oryza sativa) PTI responses to two PAMPs, the fungi‐derived chitin and the bacteria‐derived flg22. Integrative multi‐omics analysis uncovered convergence and divergence of rice responses to these PAMPs at multiple regulatory layers. Rice responded to chitin and flg22 in a similar manner at the transcriptome and proteome levels, but distinct at the metabolome level. We found that this was probably due to post‐translational regulation including ubiquitination and acetylation, which reshaped gene expression by modulating enzymatic activities, and possibly led to distinct metabolite profiles. We constructed regulatory atlas of metabolic pathways, including the defence‐related phenylpropanoid and flavonoid biosynthesis and linoleic acid derivative metabolism. The multi‐level regulatory network generated in this study sets the foundation for in‐depth mechanistic dissection of PTI in rice and potentially in other related poaceous crop species.

Ectomycorrhiza-associated bacteria, especially endofungal bacterial microbiota (EBM) in the fruiting body, play important roles in driving the establishment and function of ectomycorrhizae. However, the influence of ectomycorrhizal fungus bolete identity on their EBM is still unclear. We analysed the EBM of three different bolete fruiting body species on Thousand Island Lake, including Tylopilus felleus, Tylopilus areolatus and Boletus queletii, and compared them with their corresponding mycosphere soil bacterial microbiota by high-throughput sequencing. The EBM was classified into Bacillus, Pseudomonas, Burkholderia and Stenotrophomonas genera. Proteobacteria, Bacteroidetes and Acidobacteria were predominant in the EBM of bolete fruiting bodies as well as their mycosphere soil, while Firmicutes was significantly higher in the EBM. Moreover, the core microbiome (342 operational taxonomic units) of the EBM was shared among the three bolete fungal species. The relative abundances of gene families related to cell cycle control and nucleotide, coenzyme and lipid metabolism were significantly higher in the EBM than in the corresponding mycosphere soil bacterial microbiota, but there was no difference among the three different boletes. The results suggested that the host identity of ectomycorrhizal fungus boletes could affect the EBM, which might be mainly due to the selection of host fungi for the different functional EBM needed.

Esophageal squamous cell carcinoma (ESCC) is a highly malignant gastrointestinal cancer with a high recurrence rate and poor prognosis. Although N6-methyladenosine (m6A), the most abundant epitranscriptomic modification of mRNAs, has been implicated in several cancers, little is known about its participation in ESCC progression. We found reduced expression of ALKBH5, an m6A demethylase, in ESCC tissue specimens with a more pronounced effect in T3-T4, N1-N3, clinical stages III-IV, and histological grade III tumors, suggesting its involvement in advanced stages of ESCC. Exogenous expression of ALKBH5 inhibited the in vitro proliferation of ESCC cells, whereas depletion of endogenous ALKBH5 markedly enhanced ESCC cell proliferation in vitro. This suggests ALKBH5 exerts anti-proliferative effects on ESCC growth. Furthermore, ALKBH5 overexpression suppressed tumor growth of Eca-109 cells in nude mice; conversely, depletion of endogenous ALKBH5 accelerated tumor growth of TE-13 cells in vivo. The growth-inhibitory effects of ALKBH5 overexpression are partly attributed to a G1-phase arrest. In addition, ALKBH5 overexpression reduced the in vitro migration and invasion of ESCC cells. Altogether, our findings demonstrate that the loss of ALKBH5 expression contributes to ESCC malignancy.

Soil sterilization integrated with agronomic measures is an effective method to reduce soilborne replant diseases. However, the effect of vermicompost or biochar application after soil sterilization on soilborne diseases is poorly understood. A pot experiment was conducted in American ginseng to investigate the effects of vermicompost (VF), biochar (BF), and a combination of vermicompost and biochar (VBF) applied after soil sterilization on the incidence of Fusarium root rot using natural recovery (F) as control. After one growing season, the disease index of root rot, the phenolic acids, and the microbial communities of American ginseng rhizosphere soil were analyzed. The disease index of VF, BF, and VBF decreased by 33.32%, 19.03%, and 80.96%, respectively, compared with F. The highest bacterial richness and diversity were observed in the rhizosphere soil of VBF. Besides, VF and VBF significantly increased the relative abundance of beneficial bacteria (Pseudomonas, Lysobacter, and Chryseolinea) in the rhizosphere soil. Higher concentrations of vanillin, one of the phenolic acids in the roots exudates, were recorded in the rhizosphere soils of BF and VBF. The vanillin concentration showed a significant negative correlation with the disease index. To conclude, vermicompost improved the beneficial bacteria of the rhizosphere soil, while biochar regulated the allelopathic effect of the phenolic acids. The study proposes a combined application of biochar and vermicompost to the rhizosphere soil to control Fusarium root rot of replanted American ginseng effectively. KEY POINTS: Vermicompost improves the relative abundance of rhizosphere beneficial bacteria. Biochar inhibits the degradation of phenolic acids by adsorption. The combination of vermicompost and biochar enhances the disease control effect.

We aimed to explore the effects of Fallopia multiflora–Andrographis paniculata intercropping model on yield, quality, soil nutrition and rhizosphere microorganisms of F. multiflora, an important raw material of a traditional Chinese medicine. The data will provide empirical evidence for the application and promotion of the system in agricultural production. F. multiflora’s yield, potential medicinal quality, and rhizosphere soil nutrient contents, pH, enzyme activities, and microbial characteristics (such as diversity and structure of the bacterial community) were compared between the intercropped system and a monoculture of F. multiflora. Compared with the monoculture of F. multiflora, F. multiflora–A. paniculata intercropping significantly increased the stem diameter, root fresh weight, yield and stilbene glycoside content of F. multiflora. The activities of urease and sucrase and the amounts of bacteria and actinomycetes in rhizosphere soil of intercropped F. multiflora were significantly higher than those in rhizosphere soil of the monoculture. Intercropping increased the diversity of rhizosphere bacteria and the relative abundances of potentially beneficial microorganisms. Correlation analysis shows that the yield and quality of F. multiflora were closely related to urease and invertase activities, alkaline hydrolysis nitrogen content, soil organic matter content, bacterial biomass, and pH. The results of principal component analysis show that the score of intercropping soil was higher than that of monoculture soil. A. paniculata intercropping has a significant impact on the rhizosphere soil of F. multiflora, and can improve the yield and quality of F. multiflora by improving the rhizosphere soil ecological environment and soil quality.

Ustilaginoidea virens, causing rice false smut (RFS) is an economically important ascomycetous fungal pathogen distributed in rice-growing regions worldwide. Here, we identified a novel transcription factor UvCGBP1 (Cutinase G-box binding protein) from this fungus, which is unique to ascomycetes. Deletion of UvCGBP1 affected development and virulence of U. virens. A total of 865 downstream target genes of UvCGBP1 was identified using ChIP-seq and the most significant KEGG enriched functional pathway was the MAPK signaling pathway. Approximately 36% of target genes contain the AGGGG (G-box) motif in their promoter. Among the targets, deletion of UvCGBP1 affected transcriptional and translational levels of UvPmk1 and UvSlt2, both of which were important in virulence. ChIP-qPCR, yeast one-hybrid and EMSA confirmed that UvCGBP1 can bind the promoter of UvPmk1 or UvSlt2. Overexpression of UvPmk1 in the ∆UvCGBP1-33 mutant restored partially its virulence and hyphae growth, indicating that UvCGBP1 could function via the MAPK pathway to regulate fungal virulence. Taken together, this study uncovered a novel regulatory mechanism of fungal virulence linking the MAPK pathway mediated by a G-box binding transcription factor, UvCGBP1.

The post-translational modification lysine 2-hydroxyisobutyrylation (Khib ) plays an important role in gene transcription, metabolism, and enzymatic activity. Khib sites have been identified in rice (Oryza sativa). However, the Khib status of proteins in rice flowers during pathogen infection remains unclear. Here, we report a comprehensive identification of Khib -modified proteins in rice flowers, and the changes in these proteins during infection with the fungal pathogen Ustilaginoidea virens. By using a tandem mass tag-based quantitative proteomics approach, we identified 2,891 Khib sites on 964 proteins in rice flowers. Our data demonstrated that 2-hydroxyisobutyrylated proteins are involved in diverse biological processes. Khib levels were substantially reduced upon infection with U. virens. Chromatin immunoprecipitation polymerase chain reaction (PCR) and reverse transcription quantitative PCR analyses revealed that histone Khib is involved in the expression of disease-resistance genes. More importantly, most quantified sites on core histones H3 were downregulated upon U. virens infection. In addition, the histone deacetylases HDA705, HDA716, SRT1, and SRT2 are involved in the removal of Khib marks in rice. HDA705 was further confirmed to negatively regulate rice disease resistance to pathogens U. virens, Magnaporthe oryzae, and Xanthomonas oryzae pv. oryzae (Xoo). Our data suggest that U. virens could modulate Khib in rice flowers during infection.

The use of lytic bacteriophages for treating harmful bacteria (phage therapy) is faced with the challenge of bacterial resistance evolution. Phage strains with certain traits, for example, rapid growth and relatively broad infectivity ranges, may enjoy an advantage in slowing bacterial resistance evolution. Here, we show the possibility for laboratory selection programs (“evolutionary training”) to yield phage genotypes with both high growth rate and broad infectivity, traits between which a trade‐off has been assumed. We worked with a lytic phage that infects the bacterium Pseudomonas fluorescens and adopted three types of training strategies: evolution on susceptible bacteria, coevolution with bacteria, and rotation between evolution and coevolution phases. Overall, there was a trade‐off between growth rate and infectivity range in the evolved phage isolates, including those from the rotation training programs. A small number of phages had both high growth rate and broad infectivity, and those trade‐off‐overcoming phages could slow or even completely prevent resistance evolution in initially susceptible bacterial populations. Our findings show the promise of well‐designed evolutionary training programs, in particular an evolution/coevolution rotation selection regime, for obtaining therapeutically useful phage materials.

Tunicosaponins are natural products extracted from Psammosilene tunicoides, which is an important ingredient of Yunnan Baiyao Powder, an ancient and famous Asian herbal medicine. The representative aglycones of tunicosaponins are the oleanane-type triterpenoids of gypsogenin and quillaic acid, which were found to manipulate a broad range of virus-host fusion via wrapping the heptad repeat-2 (HR2) domain prevalent in viral envelopes. However, the unknown biosynthetic pathway and difficulty in chemical synthesis hinder the therapeutic use of tunicosaponins. Here, two novel cytochrome P450-dependent monooxygenases that take part in the biosynthesis of tunicosaponins, CYP716A262 (CYP091) and CYP72A567 (CYP099), were identified from P. tunicoides. In addition, the whole biosynthesis pathway of the tunicosaponin aglycones was reconstituted in yeast by transforming the platform strain BY-bAS with the CYP716A262 and CYP716A567 genes, the resulting strain could produce 146.84 and 314.01 mg/L of gypsogenin and quillaic acid, respectively. This synthetic biology platform for complicated metabolic pathways elucidation and microbial cell factories construction can provide alternative sources of important natural products, helping conserve natural plant resources.

Identification of transcription factor binding sites is one of the most important steps in understanding the function of transcription factors and regulatory networks in organisms. The assay for transposase accessible chromatin sequencing (ATAC-seq) is a simple protocol for detection of open chromatin that could be a powerful tool to advance studies of protein-DNA interactions. Although ATAC-seq has been used in systematic identification of cis-regulatory regions in animal and plant genomes, this method has been rarely applied in fungi. Here, we describe a valuable ATAC-seq resource in the genome of an economically important phytopathogen, the rice false smut fungus Ustilaginoidea virens. The ATAC-seq data of U. virens mycelia collected from potato sucrose broth (PSB) and PSB supplied with rice spikelet extract were both generated. This is the first genome-wide profiling of open chromatin and transcription factor binding sites in U. virens. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

A series of 1,3-diphenylurea quinoxaline derivatives were synthesized and characterized by 1H, 13C NMR, and HR-ESI-MS analyses. In vitro cytotoxicity of the synthesized compounds was evaluated by MTT assay against MGC-803, H460, T-24, HeLa, HepG2, and SMMC-7721 human cancer cell lines. The results showed that most of the compounds exhibited effective cytotoxicity to the tested cancer cell lines. The mechanism of action of the two best active quinoxaline derivatives, compounds 2d and 2g was also investigated. They may be potent anticancer agents.

In the past two decades, significant progress has been made in the past two decades towards the understanding of the basic mechanisms underlying cancer growth and angiogenesis. In this context, receptor tyrosine kinases (RTKs) play a pivotal role in cell proliferation, differentiation, growth, motility, invasion, and angiogenesis, all of which contribute to tumor growth and progression. Mutations in RTKs lead to abnormal signal transductions in several pathways such as Ras-Raf, MEK-MAPK, PI3K-AKT and mTOR pathways, affecting a wide range of biological functions including cell proliferation, survival, migration and vascular permeability. Increasing evidence demonstrates that multiple kinases are involved in angiogenesis including RTKs such as vascular endothelial growth factor, platelet derived growth factor, epidermal growth factor, insulin-like growth factor-1, macrophage colony-stimulating factor, nerve growth factor, fibroblast growth factor, Hepatocyte Growth factor, Tie 1 & 2, Tek, Flt-3, Flt-4 and Eph receptors. Overactivation of RTKs and its downstream regulation is implicated in tumor initiation and angiogenesis, representing one of the hallmarks of cancer. This review discusses the role of RTKs, PI3K, and mTOR, their involvement, and their implication in pro-oncogenic cellular processes and angiogenesis with effective approaches and newly approved drugs to inhibit their unrestrained action.

BackgroundMutation accumulation (MA) has profound ecological and evolutionary consequences. One example is that accumulation of conditionally neutral mutations leads to fitness trade-offs among heterogenous habitats which cause population divergence. Here we suggest that temperature, which controls the rates of all biochemical and biophysical processes, should play a crucial role for determining mutational effects. Particularly, warmer temperatures may mitigate the effects of some, not all, deleterious mutations and cause stronger environmental dependence in MA effects.ResultsWe experimentally tested the above hypothesis by measuring the growth performance of tenEscherichia coligenotypes on six carbon resources across ten temperatures, where the ten genotypes were derived from a single ancestral strain and accumulated spontaneous mutations. We analyzed resource dependence of MA consequences for growth yields. The MA genotypes typically showed reduced growth yields relative to the ancestral type; and the magnitude of reduction was smaller at intermediate temperatures. Stronger resource dependence in MA consequences for growth performance was observed at higher temperatures. Specifically, the MA genotypes were more likely to show impaired growth performance on all the six carbon resources when grown at lower temperatures; but suffered growth performance loss only on some, not all the six, carbon substrates at higher temperatures.ConclusionsHigher temperatures increase the chance that MA causes conditionally neutral fitness effects while MA is more likely to cause fitness loss regardless of available resources at lower temperatures. This finding has implications for understanding how geographic patterns in population divergence may emerge, and how conservation practices, particularly protection of diverse microhabitats, may mitigate the impacts of global warming.

Background: Despite the better prognosis given by surgical resection and chemotherapy in low-grade glioma (LGG), progressive transformation is still a huge concern. In this case, the S100A gene family, being capable of regulating inflammatory responses, can promote tumor development. Methods: The analysis was carried out via ONCOMINE, GEPIA, cBioPortal, String, GeneMANIA, WebGestalt, LinkedOmics, TIMER, CGGA, R 4.0.2 and immunohistochemistry. Results: S100A2, S100A6, S100A10, S100A11, and S100A16 were up-regulated and S100A1 and S100A13 were down-regulated in LGG compared to normal tissues. S100A3, S100A4, S100A8, and S100A9 expression was up-regulated during the progression of glioma grade. In addition, genetic variation of the S100A family was high in LGG, and the S100A family genes mostly function through IL-17 signaling pathway, S100 binding protein, and inflammatory responses. The TIMER database also revealed a relationship between gene expression and immune cell infiltration. High expression of S100A2, S100A3, S100A4, S100A6, S100A8, S100A9, S100A10, S100A11, S100A13, and S100A16 was significantly associated with poor prognosis in LGG patients. S100A family genes S100A2, S100A3, S100A6, S100A10, and S100A11 may be prognosis-related genes in LGG, and were significantly associated with IDH mutation and 1p19q codeletion. The immunohistochemical staining results also confirmed that S100A2, S100A3, S100A6, S100A10, and S100A11 expression was upregulated in LGG. Conclusion: The S100A family plays a vital role in LGG pathogenesis, presumably facilitating LGG progression via modulating inflammatory state and immune cell infiltration.

Camellia nut shell was collected, dried at room temperature and ground to get fine powder. The powder was extracted three times with 95% EtOH, combined, evaporated, and then freeze dried. The crude powder was dissolved in H2O and then sequentially fractionated with n-hexane, CH2Cl2, EtOAc and n-BuOH. A part of EtOAc fraction was chromatographed on a silica gel and on a Sephadex LH-20 columns using MeOH, aqueous MeOH, EtOAc-n-hexane and EtOH-n-hexane to isolate gallotannins. Three gallotannins, 1,2-di-O-galloyl-β-D-glucopyranoside (2), 1,2,6-tri-Ogalloyl- β-D-glucopyranoside (3) and 1,2,3,6-tetra-O-galloyl-β-D-glucopyranoside (4), including gallic acid (1), were isolated and elucidated by NMR and Mass spectroscopies. Although nothing new, these gallotannins were first reported from the nut shell extractives of camellia tree (Camellia oleifera C. Abel). This study was to investigate the chemical constituents, especially hydrolysable tannins, of nut shell extractives of Camellia oleifera and to provide basic information for the future chemical utilization of this species.

Understanding the essential processes of heredity, mechanisms of metabolism, and evolutionary traits of this ginkgo (Ginkgo biloba L.) in terms of molecular biology is necessary. The extraction of high-quality and high-integrity RNA from ginkgo is one of the basic techniques of molecular biology. Therefore, this study aimed to compare the efficacy of the six commonly used RNA extraction methods for detection. TRIzol, modified TRIzol, cetyltrimethylammonium bromide (CTAB), modified CTAB, sodium dodecyl sulfate (SDS), and RNeasy Plant Mini Kit (Qiagen) methods, were evaluated for their capacity to extract high-quality and high-quantity RNA from the embryo and endosperm of ginkgo. The advantages and disadvantages of each method were analyzed to evaluate the isolation process. The optimized modified CTAB method for embryo prevented the precipitation of RNA for a long period and reduced complex separation and precipitation processes. In addition, the modified TRIzol method is more effective in endosperm. Obvious differences in RNA quality and quantity were observed between the embryo and endosperm when the same method is used. Modified TRIzol, modified CTAB, SDS and RNeasy Plant Mini Kit (Qiagen) methods were applied to RNA extraction from other different ginkgo tissues. The modified CTAB is efficient and recommended for the isolation of good-quality total RNA from all tissues with reduced chemical use, costs, and RNA loss. The results of quantitative real-time PCR confirmed that modified CTAB methods could obtain showing low Ct values and high amplification efficiency and enabled the successful isolation of RNA from all tissues.

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn−/−) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn−/− mice. Adult Nptn−/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn−/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn−/− mice. Conditional ablation of neuroplastin in Nptnlox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult NptnΔlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

The thick shell mussel Mytilus coruscus has developed into a model species for studying the interaction between molluscs and environmental stimuli. Herein, integrated analysis of miRNAome and transcriptome was performed to reveal miRNA-mRNA network regulation in Vibrio alginolyticus infected M. coruscus. There have detected some histological abnormalities in digestive gland and gills of V. alginolyticus challenged mussels, ascertaining the effective irritation by the present bacterial strain. A total of 265 novel miRNAs were finally predicted, of which 26 were differentially expressed miRNAs (DEMs). Additionally, 667 differentially expressed genes (DEGs) were detected, which may be potentially associated with innate immune response to V. alginolyticus infection. A regulatory network linked to 22 important pathways and 16 DEMs and 34 OGs was constructed. Some traditional immune-related signaling pathways such as toll-like receptor signaling pathway (TLR) signaling pathway, transforming growth factor-beta (TGF-beta) signaling pathway, peroxisome, phagosome, lysosome, mammalian target of rapamyoin (mTOR) signaling pathway were linked to specific miRNAs and genes in this network. Further, interactional relationship between certain miRNAs and TLR pathway was dissected, which the results predicted that a number of TLRs and TLR-associated signaling genes including TLR1, TLR2, TLR4, TLR6, IRAK1, TRAF6, MAPK, and IL-17 were negatively regulated by novel_miR_11, novel_miR_145, novel_miR_196, novel_miR_5, novel_miR_163 and novel_miR_217 in the TLR pathway. Additionally, interactional relationship between novel_miR_145 and TLR2 was validated by laboratory experiment. The integrated analysis of mRNA and microRNA deep sequencing data exhibited a sophisticated miRNA-mRNA regulation network in M. coruscus in response to V. alginolyticus challenge, which shed a new light on the underlying mechanism of molluscan confronting bacterial infection.

Rice false smut (RFS) caused by Ustilaginoidea virens is one of the most important diseases in the majority of rice-growing areas worldwide. Rice false smut causes not only yield loss, but also threatens human or animal health by producing cyclopeptide mycotoxins. Cultivar resistance is the most economical, effective and environmentally friendly approach to control RFS. However, development of RFS-resistant rice cultivar still faces big challenges. In the field, disease severity of RFS is largely affected by rice growth period and variable weather conditions. To date, quite a few cultivars with stable resistance to RFS have been identified and could be used as resistant resource for disease-resistance breeding (Sun et al., 2020).

The fuzzy planar cell polarity protein (Fuz) is an effector component of the planar cell polarity (PCP) signaling. Together with other core and effector proteins, the PCP pathway controls polarized cell movements. Fuz was also reported as a negative regulator of cell survival. In this study, we performed a pan-cancer survey to demonstrate the role of Fuz in multiple types of cancer. In head-neck squamous cell carcinoma and lung adenocarcinoma tumor samples, a reduction of Fuz transcript expression was detected. This coincides with the poor overall survival probabilities of these patients. We further showed that Fuz promoter hypermethylation contributes to its transcriptional downregulation. Meanwhile, we also identified a relatively higher mutation frequency at the 404th arginine amino acid residue in the coding sequence of Fuz locus, and further demonstrated that mutant Fuz proteins perturb the pro-apoptotic function of Fuz. In summary, our study unveiled an intriguing relationship between Fuz dysregulation and cancer prognosis, and further provides mechanistic insights of Fuz's involvement in carcinogenesis.

Glycosylation is a conserved set of post‐translational modifications that exists in all eukaryotic cells. During the last decade, the role of glycosylation in plant pathogenic fungi has received significant attention and considerable progress has been made, especially in Ustilago maydis and Magnaporthe oryzae. Here, we review recent advances in our understanding of the role of N‐glycosylation, O‐glycosylation and glycosylphosphatidylinositol (GPI) anchors during plant infection by pathogenic fungi. We highlight the roles of these processes in regulatory mechanisms associated with appressorium formation, host penetration, biotrophic growth and immune evasion. We argue that improved knowledge of glycosylation pathways and the impact of these modifications on fungal pathogenesis is overdue and could provide novel strategies for disease control.

Lysine 2-hydroxyisobutyrylation (Khib ) is a newly identified post-translational modification (PTM) that plays important roles in transcription and cell proliferation in eukaryotes. However, its function remains unknown in phytopathogenic fungi. Here, we performed a comprehensive assessment of Khib in the rice false smut fungus Ustilaginoidea virens, using Tandem Mass Tag (TMT)-based quantitative proteomics approach. A total of 3 426 Khib sites were identified in 977 proteins, suggesting that Khib is a common and complex PTM in U. virens. Our data demonstrated that the 2-hydroxyisobutyrylated proteins are involved in diverse biological processes. Network analysis of the modified proteins revealed a highly interconnected protein network that included many well-studied virulence factors. We confirmed that the Zn-binding reduced potassium dependency3-type histone deacetylase (UvRpd3) is a major enzyme that removes 2-hydroxyisobutyrylation and acetylation in U. virens. Notably, mutations of Khib sites in the mitogen-activated protein kinase (MAPK) UvSlt2 significantly reduced fungal virulence and decreased the enzymatic activity of UvSlt2. Molecular dynamics simulations demonstrated that 2-hydroxyisobutyrylation in UvSlt2 increased the hydrophobic solvent-accessible surface area and thereby affected binding between the UvSlt2 enzyme and its substrates. Our findings thus establish Khib as a major post-translational modification in U. virens and point to an important role for Khib in the virulence of this phytopathogenic fungus.

East Asian region is home to wild soybean and has high topographic complexity. Measuring genetic diversity and geographical distribution patterns are essential steps to expand the germplasm base. We used SoySNP6K to determine the genetic diversity and population genetic structure of the wild soybean populations from four East-Asian geographies i.e. China, Japan, Korea, and Russian Far East. The wild soybean populations from China, Japan, and Korea are distinct from one another based on genetic structure, whereas the one from Russian Far East was not distinguishable from the Chinese wild soybeans. These populations share three ancestral populations and have a large number of common SNPs. Despite the low genetic diversity scores between the populations, the Chinese accessions had the highest genetic diversity values while the accession from Russian Far East had the lowest. Our analysis also showed that the population is showing a departure from the Hardy–Weinberg equilibrium and there is a possibility of inbreeding for most of the loci. The results showed that the genetic variation follows the geographic distribution within each geographically distinct wild soybeans population. Therefore, a diverse collection of wild soybeans representing all-natural habitats should include representatives from each of these sub-centers. This population would provide important breeding materials to expand the allelic pool of cultivated soybeans through introgression. Based on these criteria, the Chung’s wild legume germplasm collection from Korea provides a good representation of the genetic diversity in wild soybeans for use in soybean breeding programs.

Magnolia sieboldii K. Koch is endemic to China and has high medicinal and ornamental values. However, its seed exhibits morphophysiological dormancy, and the molecular mechanisms of which are not clearly understood. To reveal the regulation mechanism of the ABA signal in seed dormancy, the M. sieboldii ABA receptor Pyrabactin Resistance 1 (PYR1) gene was cloned and analyzed. Analysis of the MsPYR1 sequence analysis showed that the full-length cDNA contained a complete open reading frame of 987 bp and encoded a predicted protein of 204 amino acid residues. The protein had a relative molecular weight of 22.661 kDa and theoretical isoelectric point of 5.01. The transcript levels of MsPYR1 were immediately upregulated at 16 DAI and then decreased at 40 DAI. The highest transcript level of MsPYR1 was found in the dry seeds, indicating that the MsPYR1 gene may play an important role in the regulation of dormancy. The MsPYR1 gene cDNA was successfully expressed in E. coli Rosetta (DE3), and the protein bands were consistent with the prediction. The Anti-MsPYR1antibody could detect the expression of MsPYR1 in M. sieboldii. The results provided a foundation for further study of the function of the MsPYR1 gene. ABBREVIATIONS ABA: Abscisic acid; MPD: morphophysiological; PYR1: Pyrabactin Resistance1; PYL: Pyr1-Like; RCAR: Regulatory Components of Aba Receptors; PP2C: protein phosphatases 2C; SnRK2: sucrose non-fermenting1-related protein kinase2; DAI: day after imbibition; NCBI: National Center for Biotechnology Information; BCA: Bicinchoninic acid; CDD: Conserved Domains.

Heterotopic ossification (HO) is frequently seen in patients with spinal injuries. Therefore, this study aimed to characterize the association of HO with ankylosing spondylitis (AS) through gene expression profiling. The human transcriptomic datasets (GSE73754 and GSE94683) were obtained from the Gene Expression Omnibus database for analysis. Overlapping differentially expressed genes (DEGs) were identified between AS and HO disease states. Subsequently, weighted gene co-expression network analysis (WGCNA) was performed for constructing and identifying hub genes for each condition. Finally, a consensus of the overlapping DEGs and the hub genes in AS and HO was taken for determining the key genes involved in AS-induced HO. Quantitative real-time polymerase chain reaction and western blotting were used to detect the mRNA and protein expression levels in mesenchymal stem cells of AS patients and controls. Additionally, immunohistochemistry was performed on interspinous ligament samples for experimental validation of genes. DEG analysis identified 355 overlapping genes between HO and AS. WGCNA indicated that the salmon module of the 22 modules constructed, was most significantly correlated with AS-induced HO. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the salmon module indicated the presence of genes enriched in proteasome regulatory particle and proteasome pathways. mRNA expression analysis identified TCP1 and PSMC1 as the key genes in AS-induced HO. Further validation of these genes could help elucidate their role in the complex association of AS and HO.

Rationale: Stroke is a leading cause of adult disability worldwide, but no drug provides functional recovery during the repair phase. Accumulating evidence demonstrates that environmental enrichment (EE) promotes stroke recovery by enhancing network excitability. However, the complexities of utilizing EE in a clinical setting limit its translation. Methods: We used multifaceted approaches combining electrophysiology, chemogenetics, optogenetics, and floxed mice in a mouse photothrombotic stroke model to reveal the key target of EE-mediated stroke recovery. Results: EE reduced tonic gamma-aminobutyric acid (GABA) inhibition and facilitated phasic GABA inhibition in the peri-infarct cortex, thereby promoting network excitability and stroke recovery. These beneficial effects depended on GAT-1, a GABA transporter regulating both tonic and phasic GABA signaling, as EE positively regulated GAT-1 expression, trafficking, and function. Furthermore, GAT-1 was necessary for EE-induced network plasticity, including structural neuroplasticity, input synaptic strengthening in the peri-infarct cortex, output synaptic strengthening in the corticospinal tract, and sprouting of uninjured corticospinal axons across the midline into the territory of denervated spinal cord, and functional recovery from stroke. Moreover, restoration of GAT-1 function in the peri-infarct cortex by its overexpression showed similar beneficial effects on stroke recovery as EE exposure. Conclusion: GAT-1 is a key molecular substrate of the effects of EE on network excitability and consequent stroke recovery and can serve as a novel therapeutic target for stroke treatment during the repair phase.

The effective strategies to neutralize the New Delhi metallo-β-lactamase (NDM-1) activity offer unique opportunities to combination therapy because NDM-1 inactivates all classes of carbapenem antibiotics, which are widely regarded as the last resort of drugs for treating serious bacterial infections. Here we describe the efficient construction of a series of trans-1,3,4-trisubstituted pyrrolidines via boric acid-catalyzed 1,3-dipolar cycloaddition of N-benzylazomethine ylide with methyl ferulate for the biological evaluation of their cytotoxicity and synergistic activity in combination with meropenem towards NDM-1 positive carbapenem-resistant Enterobacteriaceae (CRE). The cell-based screens generated one promising hit, namely compound 10e, which exhibited low cytotoxicity (IC50 > 128 μM), moderate NDM-1 enzyme inhibition (IC50 = 51 μM), and potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE with fractional inhibitory concentration indexes ranging from 0.01 to 0.25. Structure–activity relationship studies revealed that the zinc-chelating moiety of 2-(bis(pyridin-2-ylmethyl)-amino)acetyl group of compound 10e plays a pivotal role for potent activity. Regarding the inhibition mechanism, a series of biochemical assays revealed that compound 10e may inactivate NDM-1 activity by displacing both zinc ions from the active site of the enzyme. Altogether, our studies indicate that compound 10e represents an important pyrrolidine-type scaffold targeting NDM-1, providing a promising starting point to be further developed as carbapenem antibiotic adjuvants.

Without an effective vaccine against SARS-CoV-2, the build-up of herd immunity through natural infection has been suggested as a means to control COVID-19. Although population immunity is typically estimated by the serological investigation of recovered patients, humoral immunity in asymptomatic subjects has not been well studied, although they represent a large proportion of all SARS-CoV-2 infection cases. In this study, we conducted a serosurvey of asymptomatic infections among food workers and performed serological and cellular response analyses of asymptomatic subjects in Wuhan, the original epicenter of the COVID-19 outbreak. Our data showed that up to 5.91% of the food workers carried SARS-CoV-2 IgG antibodies asymptomatically; however, in 90.4% of them, the antibody level declined over a 2-week period. IgM and IgG antibodies, including neutralizing antibodies, were significantly lower in asymptomatic subjects than in recovered symptomatic patients with similar disease courses. Furthermore, the asymptomatic subjects showed lymphopenia and a prominent decrease in the B-cell population, as well as a low frequency of antibody-secreting cells and a low cytokine response. These factors probably contributed to the low and unsustained antibody levels in asymptomatic subjects. Our results show that asymptomatic subjects are likely to be vulnerable to SARS-CoV-2 reinfection, and neither the proportion of population immunity nor the breadth of immune responses is sufficient for herd immunity.

Background: Acute kidney injury (AKI) is a severe clinical syndrome, causing a profound medical and socioeconomic burden worldwide. This study aimed to explore underlying molecular targets related to the progression of AKI. Methods: A public database originated from the NCBI GEO database (serial number: GSE121190) and a well-established and unbiased method of weighted gene co-expression network analysis (WGCNA) to identify hub genes and potential pathways were used. Furthermore, the unbiased hub genes were validated in 2 classic models of AKI in a rodent model: chemically established AKI by cisplatin- and ischemia reperfusion-induced AKI. Results: A total of 17 modules were finally obtained by the unbiased method of WGCNA, where the genes in turquoise module displayed strong correlation with the development of AKI. In addition, the results of gene ontology revealed that the genes in turquoise module were involved in renal injury and renal fibrosis. Thus, the hub genes were further validated by experimental methods and primarily obtained Rplp1 and Lgals1 as key candidate genes related to the progression of AKI by the advantage of quantitative PCR, Western blotting, and in situ tissue fluorescence. Importantly, the expression of Rplp1 and Lgals1 at the protein level showed positive correlation with renal function, including serum Cr and BUN. Conclusions: By the advantage of unbiased bioinformatic method and consequent experimental verification, this study lays the foundation basis for the pathogenesis and therapeutic agent development of AKI.

Posttraumatic stress disorder subjects usually show impaired recall of extinction memory, leading to extinguished fear relapses. However, little is known about the neural mechanisms underlying the impaired recall of extinction memory. We show here that the activity of dorsal hippocampus (dHPC) to infralimbic (IL) cortex circuit is essential for the recall of fear extinction memory in male mice. There were functional neural projections from the dHPC to IL. Using optogenetic manipulations, we observed that silencing the activity of dHPC-IL circuit inhibited recall of extinction memory while stimulating the activity of dHPC-IL circuit facilitated recall of extinction memory. “Impairment of extinction consolidation caused by” conditional deletion of extracellular signal-regulated kinase 2 (ERK2) in the IL prevented the dHPC-IL circuit-mediated recall of extinction memory. Moreover, silencing the dHPC-IL circuit abolished the effect of intra-IL microinjection of ERK enhancer on the recall of extinction memory. Together, we identify a dHPC to IL circuit that mediates the recall of extinction memory, and our data suggest that the dysfunction of dHPC-IL circuit and/or impaired extinction consolidation may contribute to extinguished fear relapses.

The paraventricular nucleus of the thalamus (PVT), which serves as a hub, receives dense projections from the medial prefrontal cortex (mPFC) and projects to the lateral division of central amygdala (CeL). The infralimbic (IL) cortex plays a crucial role in encoding and recalling fear extinction memory. Here, we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval. Silencing PVT neurons inhibited extinction retrieval at recent time point (24 h after extinction), while activating them promoted extinction retrieval at remote time point (7 d after extinction), suggesting a critical role of the PVT in extinction retrieval. In the mPFC-PVT circuit, projections from IL rather than prelimbic cortex to the PVT were dominant, and disrupting the IL-PVT projection suppressed extinction retrieval. Moreover, the axons of PVT neurons preferentially projected to the CeL. Silencing the PVT-CeL circuit also suppressed extinction retrieval. Together, our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00603-6) contains supplementary material, which is available to authorized users.

Background: Dysfunction of the corticostriatal network has been implicated in the pathophysiology of schizophrenia, but findings are inconsistent within and across imaging modalities. We used multimodal neuroimaging to analyze functional and structural connectivity in the corticostriatal network in people with schizophrenia and unaffected first-degree relatives. Methods: We collected resting-state functional magnetic resonance imaging and diffusion tensor imaging scans from people with schizophrenia (n = 47), relatives (n = 30) and controls (n = 49). We compared seed-based functional and structural connectivity across groups within striatal subdivisions defined a priori. Results: Compared with controls, people with schizophrenia had altered connectivity between the subdivisions and brain regions in the frontal and temporal cortices and thalamus; relatives showed different connectivity between the subdivisions and the right anterior cingulate cortex (ACC) and the left precuneus. Post-hoc t tests revealed that people with schizophrenia had decreased functional connectivity in the ventral loop (ventral striatum–right ACC) and dorsal loop (executive striatum–right ACC and sensorimotor striatum–right ACC), accompanied by decreased structural connectivity; relatives had reduced functional connectivity in the ventral loop and the dorsal loop (right executive striatum–right ACC) and no significant difference in structural connectivity compared with the other groups. Functional connectivity among people with schizophrenia in the bilateral ventral striatum–right ACC was correlated with positive symptom severity. Limitations: The number of relatives included was moderate. Striatal subdivisions were defined based on a relatively low threshold, and structural connectivity was measured based on fractional anisotropy alone. Conclusion: Our findings provide insight into the role of hypoconnectivity of the ventral corticostriatal system in people with schizophrenia.

Duane retraction syndrome (DRS) is a neuromuscular dysfunction of the eyes. Although many causative genes of DRS have been identified in Europe and the United States, few reports have been published in regard to Chinese DRS. The aim of the present study was to explore the genetic defect of DRS in a Chinese family. Exome sequencing was used to identify the disease-causing gene for the two affected family members. Ophthalmic and physical examinations, as well as genetic screenings for variants in chimerin 1 (CHN1), were performed for all family members. Functional analyses of a CHN1 variant in 293T cells included a Rac-GTP activation assay, α2-chimaerin translocation assay, and co-immunoprecipitation assay. Genetic analysis revealed a NM_001822.7: c.637T > G variant in the CHN1 gene, which resulted in the substitution of a highly conserved C1 domain with valine at codon 213 (NP_001813.1: p.(Phe213Val)) (ClinVar Accession Number: SCV001335305). In-silico analysis revealed that the p.(Phe213Val) substitution affected the protein stability and connections among the amino acids of CHN1 in terms of its tertiary protein structure. Functional studies indicated that the p.(Phe213Val) substitution reduced Rac-GTP activity and enhanced membrane translocation in response to phorbol-myristoyl acetate (PMA). Together with previous studies, our present findings demonstrate that CHN1 may be an important causative gene for different ethnicities with DRS.

Both bone mineral density (BMD) and lean body mass (LBM) are important physiological measures with strong genetic determination. Besides, BMD and LBM might have common genetic factors. Aiming to identify pleiotropic genomic loci underlying BMD and LBM, we performed bivariate genome-wide association study meta-analyses of femoral neck bone mineral density and LBM at arms and legs, and replicated in the large-scale UK Biobank cohort sample. Combining the results from discovery meta-analysis and replication sample, we identified three genomic loci at the genome-wide significance level (p < 5.0 × 10(−8)): 2p23.2 (lead SNP rs4477866, discovery p = 3.47 × 10(−8), replication p = 1.03 × 10(−4)), 16q12.2 (rs1421085, discovery p = 2.04 × 10(−9), replication p = 6.47 × 10(−14)) and 18q21.32 (rs11152213, discovery p = 3.47 × 10(−8), replication p = 6.69 × 10(−6)). Our findings not only provide useful insights into lean mass and bone mass development, but also enhance our understanding of the potential genetic correlation between BMD and LBM.

Although bacterial small noncoding RNAs (sRNAs) are known to play a critical role in various cellular processes, including pathogenesis, the identity and action of such sRNAs are still poorly understood in many organisms. Here we have performed a genome‐wide screen and functional analysis of the sRNAs in Xanthomonas campestris pv. campestris (Xcc), an important phytopathogen. The 50–500‐nt RNA fragments isolated from the wild‐type strain grown in a virulence gene‐inducing condition were sequenced and a total of 612 sRNA candidates (SRCs) were identified. The majority (82%) of the SRCs were derived from mRNA, rather than specific sRNA genes. A representative panel of 121 SRCs were analysed by northern blotting; 117 SRCs were detected, supporting the contention that the overwhelming majority of the 612 SRCs identified are indeed sRNAs. Phenotypic analysis of strains overexpressing different candidates showed that a particular sRNA, RsmU, acts as a negative regulator of virulence, the hypersensitive response, and cell motility in Xcc. In vitro electrophoretic mobility shift assay and in vivo coimmunoprecipitation analyses indicated that RsmU interacted with the global posttranscriptional regulator RsmA, although sequence analysis displayed that RsmU is not a member of the sRNAs families known to antagonize RsmA. Northern blotting analyses demonstrated that RsmU has two isoforms that are processed from the 3′‐untranslated region of the mRNA of XC1332 predicted to encode ComEA, a periplasmic protein required for DNA uptake in bacteria. This work uncovers an unexpected major sRNA biogenesis strategy in bacteria and a hidden layer of sRNA‐mediated virulence regulation in Xcc., The RsmA‐sequestering noncoding RNA RsmU derived from the 3′‐UTR of XC1332 mRNA negatively regulates virulence, the hypersensitive response, and cell motility in Xanthomonas campestris.

Cervical cancer is induced by persistent infections with high‐risk human papillomaviruses (HPVs), which produce the early protein 6 of HPVs (E6)/E7 protein that is involved in cell transformation by interacting with several oncoproteins or tumor suppressors. However, the role of noncoding RNA in mediating the pathogenesis of cervical cancer remains unclear. Here, we report that the novel signal transducer and activator of transcription 3 (STAT3)‐microRNA‐223‐3p (miR‐223)‐TGFBR3/HMGCS1 axis regulated by the E6 protein controls cervical carcinogenesis. miR‐223 was highly expressed in cervical tumor tissues, whereas TGFBR3 or HMGCS1 was significantly downregulated. miR‐223 targeted the 3′‐UTRs of TGFBR3 and HMGCS1 and suppressed their expression, leading to increased anchorage‐independent growth and cervical squamous cell carcinoma (CSCC) tumor growth in vitro and in vivo. The increased expression of miR‐223 was mediated by the transcription factor STAT3, whose activity was enhanced by E6 in the context of interleukin (IL)‐6 stimulation. In addition, exosomal miR‐223 derived from CSCC cells induced IL‐6 secretion by monocyte/macrophage in a coculture system in vitro, and IL‐6 secretion, in turn, led to enhanced STAT3 activity in CSSC cells, forming a positive feedback loop. Furthermore, modified miR‐223 inhibitor effectively suppressed tumor growth in cell line‐derived xenograft model, suggesting that miR‐223 is a potential promising therapeutic target in CSCC. In conclusion, our results demonstrate that the STAT3‐miR‐223‐HMGCS1/TGFBR3 axis functions as a key signaling pathway in cervical cancer progression and provides a new therapeutic target., Human papillomaviruses (HPVs) produce early protein 6 of HPVs protein in infected female cervical tissue cells to enhance signal transducer and activator of transcription 3 (STAT3) activation, which promotes microRNA‐223‐3p (miR‐223) transcription, leading to normal tissue to cervical squamous cancer transformation. Mechanistically, miR‐223 represses TGFBR3 or HMGCS1 at post‐transcriptional level. In tumor loci, exosomal miR‐223 derived from cervical cancer cells induces interleukin‐6 secretion of monocyte/macrophage, which, in turn, stimulates STAT3 signals.

The western flower thrips, Frankliniella occidentalis, is a major invasive pest of commercially important crops worldwide. We compared the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) and the expressions of two putative SOD and two putative POD sequences in second instar larvae and adults after three generations of adaptation to kidney bean and broad bean plants. The results showed that the SOD, POD, and CAT activities in adults were significantly higher than those in the second instar larvae. The SOD activities were significantly higher in both the second instar larvae and the adults fed on kidney bean (Phaseolus vulgaris) plants versus broad bean (Vicia faba) plants, whereas the POD and CAT activities showed the opposite trend. The gene expression data showed that the FoPOD-2 expression levels were lower in the second instar larvae after three generations of feeding on broad bean plants versus kidney bean plants. The expression levels of FoSOD-1 and FoSOD-2, and FoPOD-1 under broad bean plant treatment were higher than those under kidney bean plant treatment. Additionally, gene expression fluctuated among the different generations. Our results indicated that western flower thrips demonstrated plasticity in gene expression and activity of protective enzymes, which is related to their adaptability to the host plants. Western flower thrips can change the expression of protective enzyme genes and enzyme activity in vivo to better adapt to kidney bean and broad bean plants.

In this study, an avian leukosis virus (ALV) strain (GX-2020-01) was isolated from a three-yellow chicken, and its complete genome was 7570 bp long with the typical organization “5’LTR-gag-pol-env-3’LTR.” Phylogenetic analysis and sequence comparison revealed that it belongs to the ALV-J subgroup. However, the LTR region of GX-2020-01 is highly similar to that of reference strains of ALV-K/E (96.61%-97.10%), demonstrating that this novel isolate is a natural recombinant. The replication efficiency of GX-2020-01 was significantly lower than the previously isolated ALV-J strain (NX0101), indicating that the recombination event might have resulted in slower virus replication, making it harder for it to be detected through routine testing.

BACKGROUND: Fat mass and lean mass are two biggest components of body mass. Both fat mass and lean mass are under strong genetic determinants and are correlated. METHODS: We performed a bivariate genome-wide association meta-analysis of (lean adjusted) leg fat mass and (fat adjusted) leg lean mass in 12,517 subjects from 6 samples, and followed by in silico replication in large-scale UK biobank cohort sample (N = 370 097). RESULTS: We identified four loci that were significant at the genome-wide significance (GWS, α = 5.0 × 10(−8)) level at the discovery meta-analysis, and successfully replicated in the replication sample: 2q36.3 (rs1024137, p(discovery) = 3.32 × 10(−8), p(replication) = 4.07 × 10(−13)), 5q13.1 (rs4976033, p(discovery) = 1.93 × 10(−9), p(replication) = 6.35 × 10(−7)), 12q24.31 (rs4765528, p(discovery) = 7.19 × 10(−12), p(replication) = 1.88 × 10(−11)) and 18q21.32 (rs371326986, p(discovery) = 9.04 × 10(−9), p(replication) = 2.35 × 10(−95)). The above four pleiotropic loci may play a pleiotropic role for fat mass and lean mass development. CONCLUSIONS: Our findings further enhance the understanding of the genetic association between fat mass and lean mass and provide a new theoretical basis for their understanding.

Mesenchymal stem/stromal cells (MSCs) reside in the perivascular niche and modulate tissue/organ homeostasis; however, little is known about whether and how their localization and function are linked. Particularly, whether specific MSC subsets couple with and regulate specialized vessel subtypes is unclear. Here, we show that Gli1+ cells, which are a subpopulation of MSCs couple with and regulate a specialized form of vasculature. The specific capillaries, i.e., CD31hiEMCNhi type H vessels, are the preferable vascular subtype which Gli1+ cells are adjacent to in bone. Gli1+ cells are further identified to be phenotypically coupled with type H endothelium during bone growth and defect healing. Importantly, Gli1+ cell ablation inhibits type H vessel formation associated with suppressed bone generation and regeneration. Mechanistically, Gli1+ cells initiate angiogenesis through Gli and HIF-1α signaling. These findings suggest a morphological and functional framework of Gli1+ cells modulating coupled type H vasculature for tissue homeostasis and regenerative repair.