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10‐Gingerol (10‐Gin), an active ingredient extracted from ginger, has been reported to have beneficial effects on the cardiovascular system. However, 10‐Gin has not been proved to offer protection against cardiomyocyte injury induced by hypoxia/reoxygenation (H/R). This study aimed to investigate the protective effects of 10‐Gin against H/R‐induced injury and its potential mechanisms in cardiomyocytes. A H/R injury model of H9c2 cardiomyocytes was established using 600 μmol/L CoCl2 to induce hypoxia in the cells for 24 hr and then reoxygenated for 3 hr. 10‐Gin was pretreated with H9c2 cardiomyocytes for 24 hr to assess its cardiomyocyte protection. Our results showed that 10‐Gin improved the viability of H9c2 cardiomyocytes in the H/R model and decreased the activities of creatine kinase, lactate dehydrogenase, and the generation of reactive oxygen species. By intracellular Ca2+ ([Ca2+]i) fluorescence, we found that 10‐Gin could significantly reduce the [Ca2+]i concentration. 10‐Gin administration increased the activities of antioxidase and reduced malondialdehyde content and inflammatory cytokine levels. 10‐Gin also reduced the apoptosis levels. Importantly, 10‐Gin administration decreased the gene and protein expressions of Wnt5a and Frizzled‐2. In conclusion, 10‐Gin alleviates H/R‐induced cardiomyocyte injury, which is associated with the antioxidation, anti‐inflammation, antiapoptosis action, and reduction of [Ca2+]i overload by suppressing the Wnt5a/Frizzled‐2 pathway., 10‐Gingerol can attenuate the injury caused by hypoxia /reoxygenation reduce oxidative stress, Ca2+ overload, inflammation, and apoptosis, which is related to the inhibition of the Wnt5a/Frizzled‐2 pathway. Our research provides an experimental basis and new treatment strategies for MIRI. However, further research will be needed before these treatments can be used in clinics.

Bin Zheng,1,* Yakun Yang,1,* Jinghan Li,1 Jing Li,1 Saijie Zuo,1 Xi Chu,2 Shan Xu,3 Donglai Ma,1 Li Chu1,4 1School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China; 2Department of Pharmacy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 3Hebei Province Hospital of Chinese Medicine, Affiliated Hospital of Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China; 4Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China*These authors contributed equally to this workCorrespondence: Donglai Ma; Li ChuSchool of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of ChinaTel/Fax +86 311 89926719Email mdl_hebei@aliyun.com; chuli0614@126.comPurpose: Magnesium isoglycyrrhizinate (MgIG), a single stereoisomer magnesium salt of glycyrrhizic acid, has beneficial effects on the cardiovascular system through anti-inflammatory, anti-oxidation, and anti-apoptotic actions. However, MgIG has not been shown to provide protection against cardiotoxicity induced by arsenic trioxide (ATO). This study aims to demonstrate the protection of MgIG against ATO-induced cardiac toxicity in mice and to investigate the underlying mechanism.Methods: A mouse cardiotoxicity model was established by administering 5 mg/kg ATO for 7 days. MgIG used in conjunction with the ATO to assess its cardioprotection.Results: MgIG administration could significantly reduce reactive oxygen species generation and the changes in tissue morphology. Also, MgIG administration increased the activity of antioxidase, such as superoxide dismutase, catalase, and glutathione peroxidase, and reduced malondialdehyde content and pro-inflammatory cytokine levels. Western blotting showed decreased expression of Bcl-2 associated X protein and Caspase-3, with increased expression of B-cell lymphoma 2. Importantly, MgIG administration increased nuclear factor-erythroid-2-related factor 2 (Nrf2) expression, while the expressions of nuclear factor kappa-B (NF-κB) and toll-like receptor-4 (TLR4) were significantly decreased.Conclusion: Our data showed that MgIG alleviates ATO-induced cardiotoxicity, which is associated to the anti-inflammation, anti-oxidation, and anti-apoptosis action, potentially through activation of the Nrf2 pathway and suppression of the TLR4/NF-κB pathway.Keywords: magnesium isoglycyrrhizinate, arsenic trioxide, cardiotoxicity, Nrf2, TLR4/NF-κB

We investigated the mechanisms affecting tumor progression and survival outcomes in Polybromo-1-mutated (PBRM1MUT) clear cell renal cell carcinoma (ccRCC) patients. PBRM1MUT ccRCC tissues contained higher numbers of mast cells and lower numbers of CD8+ and CD4+ T cells than tissues from PBRM1WT ccRCC patients. Hierarchical clustering, pathway enrichment and GSEA analyses demonstrated that PBRM1 mutations promote tumor progression by activating hypoxia inducible factor (HIF)-related signaling pathways and increasing expression of vascular endothelial growth factor family genes. PBRM1MUT ccRCC tissues also show increased expression of C-C motif chemokine ligand 5 (CCL5). PBRM1-silenced ccRCC cells exhibited greater Matrigel tube formation and cell proliferation than controls. In addition, HMC-1 human mast cells exhibited CCL5-dependent in vitro migration on Transwell plates. High CCL5 expression in PBRM1MUT ccRCC patients correlated with increased expression of genes encoding IFN-γ, IFN-α, IL-6, JAK-STAT3, TNF-α, and NF-ΚB. Moreover, high CCL5 expression was associated with poorer survival outcomes in ccRCC patients. These findings demonstrate that CCL5-dependent mast cell infiltration promotes immunosuppression within the tumor microenvironment, resulting in tumor progression and adverse survival outcomes in PBRM1MUT ccRCC patients.

Two new species, Tetradinodula gaoligongensis Li et Mao, sp. nov. and T. reticulata Mao et Li, sp. nov., are described and photographed from China. The differential diagnosis of all known species o...

Prostate cancer (PCa) is the second leading cause of cancer-associated mortality in men. Speckle-type pox virus and zinc finger protein (SPOP), the most frequently mutated gene in PCa, functions as a tumor suppressor via degradation of cancer-promoting substrates. However, its upstream regulation in PCa metastasis remains poorly determined. Here, in a Snail-induced metastatic PCa model, we observed an accelerated degradation of SPOP protein in cells, which is crucial for the PCa migration and activation of the AKT signaling pathway. Mechanistically, we demonstrated that binding to Snail promoted SPOP ubiquitination and degradation. Moreover, the bric-a-brac/tramtrack/broad complex (BTB) domain of SPOP is turned out to be essential for Snail-mediated SPOP degradation. Thus, our findings reveal a post-translational level regulation of SPOP expression that facilitates the metastasis of PCa cells.

Introduction Laryngeal squamous cell carcinoma (LSCC) is the most common histological subtype of laryngeal cancer. The involved molecular mechanisms and suitable therapeutic targets for LSCC still need to be further investigated. Checkpoint kinase 2 (CHK2) participates in several cellular physiology pathways and plays a role in tumor progression. However, the roles of CHK2 in LSCC remain unclear. Methods mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) database, and bioinformatic analysis was performed. Western blot and immunohistochemical analyses were conducted to detect protein expression. MTS assays were performed to examine cell growth of LSCC-derived cell lines. Results In the present study, we found that both active form of CHK2 and total CHK2 protein expressions were up-regulated in LSCC tissues. Positive expression of CHK2 was closely associated with advanced clinical features and poor prognosis. Moreover, potential CHK2-involving bioprocesses and signaling pathways were analyzed. In addition, repressed proliferation of LSCC cells was induced by CHK2 inhibitor. Discussion Taken together, our findings elucidated that CHK2 may act as an oncogenic factor in LSCC, suggesting a potential target for clinical treatment.

Two series of novel triazolo-pyridazine/-pyrimidine derivatives were designed, synthesized, and evaluated for their inhibitory activity against c-Met kinase, as well as three c-Met overexpressed cancer cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes cell line LO2 in vitro. The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound 12e exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC50 values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 μM, respectively. Moreover, the inhibitory activity of compound 12e against c-Met kinase (IC50 = 0.090 μM) was equal to that of Foretinib (IC50 = 0.019 μM). The result of the acridine orange (AO) single staining test demonstrated that compound 12e could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound 12e could induce late apoptosis of A549 cells and stimulate A549 cells arresting in the G0/G1 phase. Structure-activity relationships (SARs), pharmacological results, and docking studies indicated that the introduction of 5-methylthiazole fragment to the five-atom moiety was beneficial for the activity. So far, the existing data indicated that compound 12e may become a potential class II c-Met inhibitor.

The activity of soil microbes is strongly constrained by water availability. However, it is unclear how microbial activity responds to spatial and temporal changes in precipitation, particularly to long-term precipitation changes. To identify the spatiotemporal patterns of microbial responses to precipitation changes of differing durations, we conducted a meta-analysis of data from 95 field studies with drought treatments and 109 field studies with elevated precipitation treatments. Our results indicated that microbial biomass carbon (MBC) decreased by 17% under drought and increased by 18% under elevated precipitation. Across all studies, the phospholipid fatty acid (PLFA) biomarkers for fungi and bacteria decreased significantly under drought but increased under elevated precipitation. In addition, the negative effect of drought on MBC tended to be greater at sites with a high aridity index, but the effect of elevated precipitation on MBC did not differ among sites. More importantly, the responses of MBC, fungal and bacterial PLFA abundance did not vary with treatment duration under drought, but under elevated precipitation, they increased in the first five years of treatment and declined thereafter. These results are important for our prediction of microbial responses to long-term precipitation change, because they imply that microbes acclimate to long-term elevated precipitation.

Significance Carotenoids are essential molecules in oxygenic photoautotrophs, and they fulfill essential requirements for human and animal nutrition. How carotenoid accumulation is regulated in the chloroplast, a cyanobacterium-derived organelle, remains poorly understood, despite significant advancements in identifying enzymes of the carotenoid biosynthetic pathway. This study identifies a role of chloroplast Sec14-like 1 (CPSFL1), a CRAL-TRIO protein of eukaryotic origin, in modulation of carotenoid biosynthesis and accumulation in the chloroplast. The CPSFL1 protein represents an isoprenoid- and carotenoid-binding protein that associates with membranes through interactions with the phospholipid phosphatidic acid. These findings have implications for understanding carotenoid biosynthesis and optimizing algal carotenoid nutritional quality., Plastid isoprenoid-derived carotenoids serve essential roles in chloroplast development and photosynthesis. Although nearly all enzymes that participate in the biosynthesis of carotenoids in plants have been identified, the complement of auxiliary proteins that regulate synthesis, transport, sequestration, and degradation of these molecules and their isoprenoid precursors have not been fully described. To identify such proteins that are necessary for the optimal functioning of oxygenic photosynthesis, we screened a large collection of nonphotosynthetic (acetate-requiring) DNA insertional mutants of Chlamydomonas reinhardtii and isolated cpsfl1. The cpsfl1 mutant is extremely light-sensitive and susceptible to photoinhibition and photobleaching. The CPSFL1 gene encodes a CRAL-TRIO hydrophobic ligand-binding (Sec14) domain protein. Proteins containing this domain are limited to eukaryotes, but some may have been retargeted to function in organelles of endosymbiotic origin. The cpsfl1 mutant showed decreased accumulation of plastidial isoprenoid-derived pigments, especially carotenoids, and whole-cell focused ion-beam scanning-electron microscopy revealed a deficiency of carotenoid-rich chloroplast structures (e.g., eyespot and plastoglobules). The low carotenoid content resulted from impaired biosynthesis at a step prior to phytoene, the committed precursor to carotenoids. The CPSFL1 protein bound phytoene and β-carotene when expressed in Escherichia coli and phosphatidic acid in vitro. We suggest that CPSFL1 is involved in the regulation of phytoene synthesis and carotenoid transport and thereby modulates carotenoid accumulation in the chloroplast.

Two series of [1,2,4]triazolo[4,3-a]pyrazine derivatives bearing 4-oxo-pyridazinone moieties (compounds 21a–l and 22a–l) were designed and their IC50 values were evaluated against three cancer cell lines (A549, MCF-7 and HeLa) and c-Met kinase. Among them, the compound with most potential, 22i, exhibited excellent anti-tumor activity against A549, MCF-7 and HeLa cancer cell lines with IC50 values of 0.83 ± 0.07 μM, 0.15 ± 0.08 μM and 2.85 ± 0.74 μM, respectively, and it also possessed superior c-Met kinase inhibition ability at the nanomolar level (IC50 = 48 nM). Moreover, dose-dependent experiments, AO fluorescence staining, cell cycle assay, Annexin V-FITC/PI staining and docking studies were carried out in this study. The results demonstrated that compound 22i could be a potential c-Met kinase inhibitor.

Aim Here, we aim to evaluate the chemopreventive efficacy of kava root extracts (KRE) in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and investigate potential molecular targets of kavalactones, the main components of kava. Methods TRAMP mice were administrated with KRE formulated food for different periods of time, and then the incidences of high-grade prostatic intraepithelial neoplasia (HG-PIN) and adenocarcinomas and tumor burdens were compared between vehicle control and KRE food fed groups. In addition, the inhibitory effect of the KRE and kavalactones on monoamine oxidase A (MAO-A) and lysine-specific demethylase 1 (LSD1) enzyme activities were examined by commercially available inhibitor screening kits. Histone H3 lysine 9 dimethylation was also evaluated in prostate cancer cells and tumor tissues using Western blotting analysis. Results Dietary feeding of 0.3% and 0.6% KRE to TRAMP mice from ages of 6 weeks to 12 weeks inhibited HG-PIN by 43.5% and 59.7%, respectively, and prostate adenocarcinoma by 53.5% and 66.4%, respectively. In addition, 0.6% KRE fed TRAMP mice from ages of 6 weeks to 24 weeks exhibited a significant reduction of genitourinary weight (a surrogate of tumor burden) by 54.5% and reduced body weight gain. Furthermore, the KRE and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities. Conclusion Our results suggest that consumption of kava products through diet can delay prostate cancer development and progression and that kavalactones may be a new structure model for developing a potent dual inhibitor of LSD1 and MAO-A.

Anlotinib is a novel multi-targeted tyrosine kinase inhibitor with activity against soft tissue sarcoma, small cell lung cancer, and non-small cell lung cancer (NSCLC). Potentiating the anticancer effect of anlotinib in combination strategies remains a clinical challenge. Metformin is an oral agent that is used as a first-line therapy for type 2 diabetes. Interesting, metformin also exerts broad anticancer effects through the activation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR). Here, we evaluated the possible synergistic effect of anlotinib and metformin in NSCLC cells. The results showed that metformin enhanced the antiproliferative effect of anlotinib. Moreover, anlotinib combined with metformin induced apoptosis and oxidative stress, which was associated with the activation of AMPK and inhibition of mTOR. Reactive oxygen species (ROS)- mediated p38/JNK MAPK and ERK signaling may be involved in the anticancer effects of this combination treatment. Our results show that metformin potentiates the efficacy of anlotinib in vivo by increasing the sensitivity of NSCLC cells to the drug. These data provide a potential rationale for the combination of anlotinib and metformin for the treatment of patients with NSCLC or other cancers.

Objective: To explore the molecular mechanism of Scutellaria baicalensis Georgi in treating gastric cancer by network pharmacological analysis and molecular docking.Methods: Taking Scutellaria baicalensis Georgi as the object, the active components and corresponding potential drug targets in Scutellaria baicalensis Georgi were obtained from the database of TCM Pharmacological System Analysis Platform (TCMSP). GeneCards/OMIM/DrugBank and other databases were used to collect gastric cancer-related genes, and the obtained genes were intersected with drug targets to obtain the target genes of Scutellaria baicalensis Georgi on gastric cancer. Furthermore, the interaction network of Scutellaria baicalensis Georgi-active ingredients-target-gastric cancer-related genes was constructed. Protein–protein interaction analysis and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on target genes. The PubChem website was used to screen the compounds corresponding to the target genes, and the target protein and 3D structure pdb format files were obtained from the PDB database. Finally, the molecular docking calculation was performed by the AutoDock Vina program. The in vivo cell experiments on the effect of Scutellaria baicalensis on proliferation and migration of gastric cancer cells were used to determine the therapeutic effect of Scutellaria baicalensis on gastric cancer, and the two genes ESR1 and FOS are the key targets of Scutellaria baicalensis on gastric cancer.Results: A total of 10 gastric cancer-related target genes were screened out, and Scutellaria baicalensis Georgi contained 10 active compounds targeting 10 gene sites. There are 30 effective compounds in Scutellaria baicalensis Georgi targeted to treat gastric cancer, and there are 91 corresponding targeting gene sites, involving a total of 10 pathways. The results of molecular docking show that ESR1, FOS, and Scutellaria baicalensis Georgi have good binding free energy and docking fraction. The docking fraction of FOS is −4.200 and the binding free energy is −27.893 kcal/mol. The docking fraction of ESR1 is −5.833 and the binding free energy is −30.001 kcal/mol. The effect of Scutellaria baicalensis Georgi on gastric cancer was verified by in vitro cell experiments and Western blotting.Conclusion:Scutellaria baicalensis Georgi can target and regulate multiple signal pathways by acting on ESR1 and FOS gene loci, thus having a potential therapeutic effect on gastric cancer.

Microsporidia comprise a phylum of single cell, intracellular parasites and represent the earliest diverging branch in the fungal kingdom. The microsporidian parasite Nosema ceranae primarily infects honey bee gut epithelial cells, leading to impaired memory, suppressed host immune responses and colony collapse under certain circumstances. As the genome of N. ceranae is challenging to assembly due to very high genetic diversity and repetitive region, the genome was re-sequenced using long reads. We present a robust 8.8 Mbp genome assembly of 2,280 protein coding genes, including a high number of genes involved in transporting nutrients and energy, as well as drug resistance when compared with sister species Nosema apis. We also describe the loss of the critical protein Dicer in approximately half of the microsporidian species, giving new insights into the availability of RNA interference pathway in this group. Our results provided new insights into the pathogenesis of N. ceranae and a blueprint for treatment strategies that target this parasite without harming honey bees. The unique infectious apparatus polar filament and transportation pathway members can help to identify treatments to control this parasite.

Zika virus is a positive single-strand RNA virus whose replication involved RNA unwinding and synthesis. ZIKV NS3 contains a helicase domain, but its enzymatic activity is not fully characterized. Here, we established a dsRNA unwinding assay based on the FRET effect to study the helicase activity of ZIKV NS3, which provided kinetic information in real time. We found that ZIKV NS3 specifically unwound dsRNA/dsDNA with a 3′ overhang in the 3′ to 5′ direction. The RNA unwinding ability of NS3 significantly decreased when the duplex was longer than 18 base pairs. The helicase activity of NS3 depends on ATP hydrolysis and binding to RNA. Mutations in the ATP binding region or the RNA binding region of NS3 impair its helicase activity, thus blocking viral replication in the cell. Furthermore, we showed that ZIKV NS5 interacted with NS3 and stimulated its helicase activity. Disrupting NS3-NS5 interaction resulted in a defect in viral replication, revealing the tight coupling of RNA unwinding and synthesis. We suggest that NS3 helicase activity is stimulated by NS5; thus, viral replication can be carried out efficiently. Our work provides a molecular mechanism of ZIKV NS3 unwinding and novel insights into ZIKV replication.

Background and objective Tangeretin demonstrates broad anti-inflammatory effects. The present study aimed to assess whether tangeretin functions in regulating T-regulatory cells (Tregs) and alleviating allergic rhinitis (AR). Methods An ovalbumin (OVA)-induced AR animal model was constructed to monitor the changes in the allergic symptom score, OVA-specific IgE titers, histopathological characteristics and T-helper cell (Th1, Th2, and Th17)-related cytokine levels under tangeretin or dexamethasone (DXM) administration. The expression levels of Notch1/Jagged1 and FOXP3, and the proportion of Tregs in the spleens of these animals, were also detected. Furthermore, purified naive CD4 + T cells were utilized to assess the effects of tangeretin on Notch1 expression and their differentiation in vitro. Results Both tangeretin and DXM administration alleviated airway inflammation, decreased the production of serum OVA-induced IgE, but only tangeretin administration restored the balance of cytokine profiles compared with those in the AR group. The abundance of splenic CD4 + CD25 + FOXP3 + Treg cells and the transcription factor FOXP3 were significantly increased under tangeretin treatment, either in AR mice or in naive CD4 + T-cell differentiation, followed by a concomitant reduction in Notch1/Jagged1 expression. However, as a positive control, the treatment of allergic rhinitis with dexamethasone was not related to the expression of Notch1/Jagged1 or the differentiation of Treg cells. Conclusion Tangeretin could promote regulatory T cell responses by inhibiting Notch1/Jagged1 expression, followed by promoting FOXP3/Treg cell differentiation and thus could serve as a novel curative therapeutic for AR.

Verticillium wilt caused by Verticillium alfalfae results in severe production losses in alfalfa crops and is a Class A quarantined disease in China. During 2015 to 2017, 365 alfalfa fields from 21 locations in six provinces were surveyed, and 45 fields from three closely located sites in Gansu, China were found to have alfalfa plants with symptoms typical of Verticillium wilt, with disease incidence of 12.6 to 53.6%. Isolates were identified to species using morphological characteristics and a maximum likelihood phylogeny of the concatenated partial sequences of actin, elongation factor, glyceraldehyde-3-phosphate dehydrogenase, and tryptophan synthase gene regions of Verticillium isolates. Isolation incidence was 93.9% from roots, 71.7% from stems, 66.1% from petioles, and 32.2% from leaves of field-infected plants, indicative of systemic disease and sporadic distribution of this pathogen. In greenhouse tests, the pathogen infected seedlings and colonized vascular tissues when inoculated on seeds, on root tips, in soil, or in injured, but not uninjured, aerial tissues, causing systemic symptoms like those in the field and significant losses. Pathogenicity testing also revealed that five locally grown perennial legumes (stylo, milkvetch, sainfoin, white clover, and red clover) could host V. alfalfae, with a high virulence to milkvetch, sainfoin, and stylo. This study confirmed that V. alfalfae has become established in some regions of Gansu, China and that is a risk to the alfalfa industry in China.

Background High vascularization is a major characteristic of renal cell carcinoma (RCC). Thus, exploration of molecules promoting the tumor vascularization in RCC is urgent. Yes-associated Protein (YAP) is an oncogene in many cancer types, and high YAP expression was correlated with worse overall survival of RCC patients according to The Cancer Genome Atlas (TCGA) database. However, whether YAP promotes tumor angiogenesis of RCC is still unknown. Methods Western blotting assay, real-time Quantitive PCR analysis, and ELISA assay were used to detect the related gene expression. The function of YAP on tumor angiogenesis was investigated by HUVEC recruitment, tube formation, and rabbit cornea assay. The clinical relevance of several genes was analyzed in a public database. Results knockdown of YAP decreased RCC cell-inducing HUVEC recruitment and tube formation. Moreover, tumor angiogenesis ability of 786-O cells was crippled by YAP knockdown in vivo. In addition, the expression of Vascular endothelial growth factors A (VEGFA) was positively correlated with YAP expression in RCC tumor tissues, and YAP promoted expression and secretion of VEGFA in RCC cells. Mechanistically, GLI family zinc finger 2 (Gli2) knockdown in RCC cells reduced both basic and YAP-induced VEGFA expression, HUVECs recruitment, and tube formation, indicating that Gli2 is necessary for YAP to promote expression of VEGFA. Conclusion Taken together, our results demonstrate that YAP/Gli2 promotes VEGFA expression and tumor angiogenesis in RCC cells, which could provide novel therapeutic targets in RCC treatment.

Clear cell renal cell carcinoma (ccRCC) is a common urinary neoplasm, looking for useful candidates to establish scientific foundation for the therapy of ccRCC is urgent. We downloaded genomic profiles of GSE781, GSE6244, GSE53757, and GSE66271 from the Gene Expression Omnibus (GEO) database. GEO2R was used to analyze the derivative genes, while hub genes were screened by protein‐protein interactions and cytoscape. Further, overall survival, gene methylation, gene mutation, and gene expression were all analyzed using bioinformatics tools. Colony formation and cell‐cycle assay were used to detect the biological function of GNG7 in vitro. We found that GNG7 was downregulated in ccRCC tissues and negatively associated with overall survival in ccRCC patients. We also found that promoter methylation and frequent gene mutation were responsible for GNG7 gene suppression. GNG7 low expression was related to upregulation of enhancer of zeste homolog 2 and downregulation of disabled homolog 2‐interacting protein. Further, Gene Set Enrichment Analysis results showed that mTOR1, E2F, G2M, and MYC pathways were all significantly altered in response to GNG7 low expression. In vitro, A498 and 786‐O cells in which GNG7 expression was silenced, exhibited a lower G1 phase when compared to the negative control cells. Taken together, our findings suggest that GNG7 is a tumor suppressor gene in ccRCC progression and represents a novel candidate for ccRCC treatment.

Plant stoichiometry is critical for the structure and functions of ecosystems. Previous studies on large-scale patterns of plant stoichiometry have focused on single tissues; and the controlling factors have focused on climatic factors or plant functional groups. Here we present results based on an intensive field investigation across China’s forest ecosystems, to comprehensively assess the effect of climatic factors, plant functional groups, soil N and P stoichiometry on N and P stoichiometry of different tree tissues. The P concentrations in all tissues were significantly lower when mean annual temperature (MAT) and mean annual precipitation (MAP) were higher, and the N:P ratios in all tissues were significantly higher when MAT and MAP were higher. The N concentrations of branches and trunks were negatively related to MAT and MAP, however, the leaf N concentrations did not change with MAT and MAP. The root N also did not change with MAT, but decreased significantly with MAP. Soil total N had little influence on tree N, however, tree tissue P concentrations significantly increased when soil P increased. The N contents of all tissues were mainly affected by plant functional groups, however, climate factors and soil P content were the main predictors of P and N:P ratios of all tissues. Our results suggest that tree tissue N:P ratios were largely related to climatic factors, and were shaped by soil P rather than soil N in China’s forest ecosystems.

Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.

This study assessed the diversity and distribution of fungal communities in thirteen marine seawater samples from four sites (L1, L3, L4 and L7) of the Mariana Trench, with a depth range of 1000–4000 meters, using Illumine Hiseq sequencing with fungal-specific primers targeting the internal transcribed spacer (ITS) region of the ribosomal rRNA gene. Sedimentary fungal communities showed high diversity with 209 880 reads belonging to 91 operational taxonomic units (OTUs). Of these OTUs, 45 belonged to the Ascomycota, 37 to Basidiomycota, 3 to Chytridiomycota, 1 to Glomeromycota, 1 to Cryptomycota, and 4 to unknown fungi. The major fungal orders included Saccharomycetales and Sporidiobolales. The commonly found fungal genera were Candida, Malassezia and Cryptococcus. These results suggest the existence of diverse fungal communities in the Mariana Trench marine seawater, which can be considered as a useful community model for further ecological and evolutionary study of fungi in the trench.

Plant invasion is a major threat to natural ecosystems, and mangrove forests are among the most threatened ecosystems in the world. However, since mangrove species primarily occur in the saline and intertidal environment that is inhospitable for most terrestrial and freshwater plants, it is commonly assumed that mangrove forests are resilient to plant invasion. Still, many salt tolerant aquatic and terrestrial plants as well as epiphytes are found to invade the mangrove forests, and we know little about those invasive plants, their functional traits, invasion patterns and pathways and their ecological consequences. In a survey of global literature, we found a total of 57 plants reportedly invasive in the world’s mangrove forests. These plants possessed the traits of salinity tolerance, tolerance to anaerobic condition, high fecundity and rapid growth. About 19% of invasive plants were anthropogenically introduced for coastal land stabilization, and the rests were accidental introduction. Invaders were found to colonize along the forest edges or forest interior, but mostly in the raised lands. That is, the presence of diversified microhabitats such as raised land and intertidal mudflat might help both halophytic and non-halophytic plants to invade the mangrove forests. Some invaders (30%) were transient, but many (70%) could persist for a longer time; and these species could modify habitat conditions, impede natural regeneration of mangroves and disrupt their faunal assemblage. Together, plant invasion in mangrove forests is much more widespread and problematic than commonly perceived, underscoring the need for the integration of invasive plant management strategy into mangrove forest management.

Memory-guided social recognition identifies someone from previous encounters or experiences, but the mechanisms of social memory remain unclear. Here, we find that a short-term memory from experiencing a stranger mouse lasting under 30 min interval is essential for subsequent social recognition in mice, but that interval prolonged to hours by replacing the stranger mouse with a familiar littermate. Optogenetic silencing of dorsal CA1 neuronal activity during trials or inter-trial intervals disrupted short-term memory-guided social recognition, without affecting the ability of being sociable or long-term memory-guided social recognition. Postnatal knockdown or knockout of autism spectrum disorder (ASD)-associated phosphatase and tensin homolog (PTEN) gene in dorsal hippocampal CA1 similarly impaired neuronal firing rate in vitro and altered firing pattern during social recognition. These PTEN mice showed deficits in social recognition with stranger mouse rather than littermate and exhibited impairment in T-maze spontaneous alternation task for testing short-term spatial memory. Thus, we suggest that a temporal activity of dorsal CA1 neurons may underlie formation of short-term memory to be critical for organizing subsequent social recognition but that is possibly disrupted in ASD.

Microtubules play a major role in intracellular trafficking of vesicles in endocrine cells. Detailed knowledge of microtubule organization and their relation to other cell constituents is crucial for understanding cell function. However, their role in insulin transport and secretion is under debate. Here, we use FIB-SEM to image islet β cells in their entirety with unprecedented resolution. We reconstruct mitochondria, Golgi apparati, centrioles, insulin secretory granules, and microtubules of seven β cells, and generate a comprehensive spatial map of microtubule–organelle interactions. We find that microtubules form nonradial networks that are predominantly not connected to either centrioles or endomembranes. Microtubule number and length, but not microtubule polymer density, vary with glucose stimulation. Furthermore, insulin secretory granules are enriched near the plasma membrane, where they associate with microtubules. In summary, we provide the first 3D reconstructions of complete microtubule networks in primary mammalian cells together with evidence regarding their importance for insulin secretory granule positioning and thus their supportive role in insulin secretion.

Background Bladder carcinoma is one of the most common urological cancers. ITPR3, as a ubiquitous endoplasmic reticulum calcium channel protein, was reported to be involved in the development and progression of various types of cancer. However, the potential roles and molecular mechanism of ITPR3 in bladder cancer are still unclear. Herein, we elucidated a novel role of ITPR3 in regulating the proliferation, metastasis, and stemness of bladder cancer cells. Methods The expression of ITPR3 in bladder cancer was analyzed using public databases and bladder cancer tissue microarrays. To demonstrate the role of ITPR3 in regulating the NF-ĸB/CD44 pathway and the progression of bladder cancer, a series of molecular biology and biochemistry methods was performed on clinical tissues, along with in vivo and in vitro experiments. The methods used included western blot assay, quantitative RT-PCR assay, immunofluorescence assay, immunohistochemistry (IHC) assays, wound healing assay, Transwell assay, colony formation assay, tumorsphere formation assay, cell flow cytometry analysis, EdU assay, MTT assay, cell transfection, bisulfite sequencing PCR (BSP), a xenograft tumor model and a tail vein cancer metastasis model. Results Higher ITPR3 expression was found in bladder cancer tissues and bladder cancer cells compared with the corresponding normal peritumor tissues and SV-HUC-1 cells, which was attributed to demethylation in the ITPR3 promoter region. ITPR3 promoted the proliferation of bladder cancer by accelerating cell cycle transformation and promoted local invasion and distant metastasis by inducing epithelial-to-mesenchymal transition (EMT). Meanwhile, ITPR3 maintained the cancer stemness phenotype by regulating CD44 expression. NF-κB, which is upstream of CD44, also played a critical role in this process. Conclusions Our study clarifies that ITPR3 serves as an oncogene in bladder cancer cells and represents a novel candidate for bladder cancer diagnosis and treatment.

Gefitinib (GEB) is one of the drugs used for patients with epidermal growth factor receptor (EGFR)-positive mutations in non-small cell lung cancer (NSCLC). However, application of GEB is limited by its low water solubility, stability, and utilization rate, especially the side effects while GEB is given by oral. In this study, nanoliposome was used as a carrier to prepare nanoliposome compound drug (GL) by embedding GEB in the nanoliposome perfectly combined with green nontoxic solvent and thin-film dispersion method. The nanoliposome structure was expected to improve the water solubility and biocompatibility of GEB, thus improving the effect of cancer treatment. The surface electronegative nanoliposomes can effectively avoid protein adsorption and prolong the circulation time in vivo. Meanwhile, the ratio of lecithin to cholesterol (LE/CH) was explored to maximize the encapsulation efficiency of nanoliposome. Subsequent test results showed that GL exhibited better stability, smaller particle size and higher encapsulation efficiency. In addition, in vitro drug release curve also further confirmed that GL had a promising drug sustained-release effect. In particular, a series of in vitro tests such as cell activity, apoptosis, colony formation, scratch, invasion, and cell cycle assays were performed. The results indicated that GL significantly enhanced the pro-apoptotic effect on A549 cells. Most cell cycles of A549 cells were blocked in the G0/G1 phase influenced by GL, thus inhibiting the proliferation of cancer cells. In vivo anti-tumor studies showed that compared with pure GEB, GL had a significant inhibiting effect on NSCLC. In conclusion, the GL which was synthesized by a simple method in this study significantly improved the treatment effect of cancer cells, which proved that the nanoliposome carrier had an excellent application prospect in the treatment of lung cancer.

Background Ischemic stroke (IS) is a serious global health burden. In order to improve our understanding of the risk factors associated with IS, we investigated the combined effect of the methylation of five genes related to the metabolism of homocysteine on developing IS. Methods Quantitative methylation‐specific PCR was used to measure the levels of promoter methylation in hypertensive and stroke patients. The cutoff value calculated by the maximum Youden index was used to classify the levels of gene methylation as hypomethylation and hypermethylation. Logistic regression was used to explore the relationship between gene methylation and IS. Results The methylation levels of the genes encoding methylenetetrahydrofolate dehydrogenase 1 [MTHFD1], cystathionine β‐synthase [CBS], and dihydrofolate reductase [DHFR] in hypertensive patients were higher than those in stroke patients (all p, A significant linear relationship between the number of elevated biomarkers and the risk of stroke.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain., eLife digest Animal brains of all sizes, from the smallest to the largest, work in broadly similar ways. Studying the brain of any one animal in depth can thus reveal the general principles behind the workings of all brains. The fruit fly Drosophila is a popular choice for such research. With about 100,000 neurons – compared to some 86 billion in humans – the fly brain is small enough to study at the level of individual cells. But it nevertheless supports a range of complex behaviors, including navigation, courtship and learning. Thanks to decades of research, scientists now have a good understanding of which parts of the fruit fly brain support particular behaviors. But exactly how they do this is often unclear. This is because previous studies showing the connections between cells only covered small areas of the brain. This is like trying to understand a novel when all you can see is a few isolated paragraphs. To solve this problem, Scheffer, Xu, Januszewski, Lu, Takemura, Hayworth, Huang, Shinomiya et al. prepared the first complete map of the entire central region of the fruit fly brain. The central brain consists of approximately 25,000 neurons and around 20 million connections. To prepare the map – or connectome – the brain was cut into very thin 8nm slices and photographed with an electron microscope. A three-dimensional map of the neurons and connections in the brain was then reconstructed from these images using machine learning algorithms. Finally, Scheffer et al. used the new connectome to obtain further insights into the circuits that support specific fruit fly behaviors. The central brain connectome is freely available online for anyone to access. When used in combination with existing methods, the map will make it easier to understand how the fly brain works, and how and why it can fail to work correctly. Many of these findings will likely apply to larger brains, including our own. In the long run, studying the fly connectome may therefore lead to a better understanding of the human brain and its disorders. Performing a similar analysis on the brain of a small mammal, by scaling up the methods here, will be a likely next step along this path.

Epidermal growth factor receptor (EGFR) is a receptor for epithelial growth factor (EGF) cell proliferation and signaling, which is related to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and apoptosis. Thus, it has become an important target for the treatment of non-small cell lung cancer (NSCLC). The first to the third-generation EGFR inhibitors have demonstrated powerful efficacy and brought a prospect to patients. Unfortunately, after 9-15 months of treatment, they all developed resistance without exception. As for the resistance of third-generation inhibitors, no major breakthrough has been made in this field. In this review, we discussed the recent advances in medicinal chemistry of fourth-generation EGFR-TKIs, as well as further discussed the clinical challenges and future prospects of treating patients with EGFR mutations resistant to third-generation EGFR-TKIs.

Alginate oligosaccharides produced by enzymatic degradation show versatile physiological functions and biological activities. In this study, a new alginate lyase encoding gene alyS02 from Flavobacterium sp. S02 was recombinantly expressed at a high level in Yarrowia lipolytica, with the highest extracellular activity in the supernatant reaching 36.8 &plusmn, 2.1 U/mL. AlyS02 was classified in the polysaccharide lyase (PL) family 7. The optimal reaction temperature and pH of this enzyme were 30 &deg, C and 7.6, respectively, indicating that AlyS02 is a cold-adapted enzyme. Interestingly, AlyS02 contained more than 90% enzyme activity at 25 &deg, C, higher than other cold-adapted enzymes. Moreover, AlyS02 is a bifunctional alginate lyase that degrades both polyG and polyM, producing di- and trisaccharides from alginate. These findings suggest that AlyS02 would be a potent tool for the industrial applications.

Ripe fruits of Amomum villosum Lour. are important traditional Chinese medicines and food spices. Due to similar morphological and anatomical characteristics, fruits from some Alpinia species are used clinically as substitutes or adulterants of Fructus Amomi. In this study, we determined the nrDNA ITS1 (internal transcribed space 1) sequences from Amomum villosum and ten Alpinia species, which are adulterants of Fructus Amomi. The ITS1 sequences of these species were 175~179 bp in length, and the G+C contents were 53.37~56.74%. Sequence alignment revealed that there were 55 polymorphic nucleotide sites among the tested species. The base substitution were 0.57~9.60% within the ten Aplinia species, but 17.61~21.59% between Amomum villosum and the Alpinia species. These molecular data indicated that ITS1 sequences can be used to differentiate Fructus Amomi and its substitutes or adulterants from various Alpinia species.

Background The identification of endometrial stem/progenitor cells in a high turnover rate tissue suggests that a well-orchestrated underlying network controls the behaviour of these stem cells. The thickness of the endometrium can grow from 0.5–1 mm to 5–7 mm within a week indicating the need of stem cells for self-renewal and differentiation during this period. The cyclical regeneration of the endometrium suggests specific signals can activate the stem cells during or shortly after menstruation. Methods Endometrial mesenchymal stem-like cells (eMSCs) were cocultured with endometrial epithelial or stromal cells from different phases of the menstrual cycle; the clonogenicity and the phenotypic expression of eMSC markers (CD140b and CD146) were assessed. The functional role of WNT/β-catenin signalling on eMSC was determined by western blot analysis, immunofluorescent staining, flow cytometry, quantitative real-time PCR and small interfering RNA. The cytokine levels in the conditioned medium of epithelial or stromal cells cocultured with eMSCs were evaluated by enzyme-linked immunosorbent assays. Results Coculture of endometrial cells (epithelial or stromal) from the menstrual phase enhanced the clonogenicity and self-renewal activities of eMSCs. Such phenomenon was not observed in niche cells from the proliferative phase. Coculture with endometrial cells from the menstrual phase confirmed an increase in expression of active β-catenin in the eMSCs. Treatment with IWP-2, a WNT inhibitor, suppressed the observed effects. Anti-R-spondin-1 antibody reduced the stimulatory action of endometrial niche cells on WNT/β-catenin activation in the T cell factor/lymphoid enhancer-binding factor luciferase reporter assay. Moreover, the mRNA level and protein immunoreactivities of leucine-rich repeat-containing G-protein coupled receptor 5 were higher in eMSCs than unfractionated stromal cells. Conditioned media of endometrial niche cells cocultured with eMSCs contained increased levels of C-X-C motif ligand 1 (CXCL1), CXCL5 and interleukin 6. Treatment with these cytokines increased the clonogenic activity and phenotypic expression of eMSCs. Conclusions Our findings indicate a role of WNT/β-catenin signalling in regulating activities of endometrial stem/progenitor cells during menstruation. Certain cytokines at menstruation can stimulate the proliferation and self-renewal activities of eMSCs. Understanding the mechanism in the regulation of eMSCs may contribute to treatments of endometrial proliferative disorders such as Asherman’s syndrome.

The MTHFR gene encodes methylenetetrahydrofolate reductase required for the metabolism of homocysteine (Hcy) – a previously reported independent risk factor for ischemic stroke (IS). In this study, we first aimed to clarify the association between DNA methylation levels in the MTHFR promoter and the risk of IS, followed by the analysis of potential interactions between environmental factors and DNA methylation levels that affect IS risk. We recruited 164 patients with hypertension and IS (case group) and 345 age- and sex-matched patients with hypertension only (control group). Demographic and clinical information was obtained using questionnaires, and blood samples were collected for biochemical analyses. Fluorescence quantitative methylation-specific PCR (qMSP) was used to detect MTHFR promoter methylation levels. A logistic regression analysis was performed to determine the relationship between environmental factors, MTHFR promoter methylation levels, and IS risk. We finally generated a receiver operating characteristic (ROC) curve to determine whether MTHFR promoter methylation levels can predict IS. The mean MTHFR methylation levels in case group (8.10 ± 6.14) were significantly lower than those in control group (17.44 ± 3.16; p < 0.05). MTHFR promoter methylation levels were also lower in patients with plasma Hcy levels ≥15 μmol/L (10.65 ± 4.05) than in those with Hcy levels

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain.

Objective This study aimed to describe the mechanism of exosome-derived miR-486-5p underlying the cell cycle and progression in lung adenocarcinoma (LUAD). Methods Bioinformatics methods were applied for identifying the differentially expressed genes (DEGs) in the GEO-LUAD dataset, predicting where the potential target miRNA was expressed and exploring the corresponding downstream target mRNA. qRT-PCR was conducted to detect the levels of the target genes in cancer cells. Thereafter, a series of in vitro experiments were performed for cell activities evaluation, including CCK-8, EdU, colony formation assay and transwell. Besides, Western blot was applied to determine the protein levels of the migration and invasion-related factors (NEK2, E-cadherin, N-cadherin, Vimentin, MMP-2, and MMP-9). Dual-luciferase reporter gene assay was employed for validating the targeted relationship between the target genes. Furthermore, nude mouse transplantation tumor experiment was conducted to further validate the role of the target miRNA in tumor development, and immunohistochemistry was used for Ki67 detection and TUNEL was applied for cell apoptosis assay. Results miR-486-5p was observed to be enriched in serum exosomes, and seen to be significantly down-regulated in cancer tissues as well as in cancer serum exosomes. It was proven that exosomes could release miR-486-5p, thus regulating LUAD progression and affecting cell cycle. Moreover, NEK2 was identified as a target of miR-486-5p both in vivo and in vitro. Enrichment analysis revealed that NEK2 was mainly activated in cell cycle and mitosis-related pathways. Meanwhile, NEK2 was found to present significant difference in different TNM stages. Furthermore, rescue experiments indicated that the inhibitory effect of miR-486-5p overexpression on LUAD progression could be abrogated when miR-486-5p and NEK2 were simultaneously up-regulated. Conclusion Exosome-derived miR-486-5p is responsible for cell cycle arrest as well as the inhibition of cell proliferation and metastasis in LUAD via targeting NEK2.

Objective. To investigate the mechanism of miR-30a-5p inhibiting proliferation and migration of lung squamous cell carcinoma (LSCC) cells by targeting FOXD1. Methods. Bioinformatics was used to analyze differentially expressed genes in the TCGA_LUSC database. qRT-PCR was used to detect the expression levels of miR-30a-5p and FOXD1 in human normal lung epithelial cell line and human LSCC cell lines. The protein expression of FOXD1 was detected by western blot. The cell viability and colony formation abilities were examined by CCK-8 and colony formation assays, respectively. Wound healing and Transwell assays were performed to examine the migration and invasion abilities of cells. The targeted binding sites of miR-30a-5p and FOXD1 were predicted by bioinformatics, and dual luciferase assay was used to verify the targeted binding relationship between miR-30a-5p and FOXD1. Result. miR-30a-5p was downregulated in LSCC tissues and cells, while FOXD1 was highly expressed. Overexpression of miR-30a-5p or silencing FOXD1 inhibited cell viability, colony formation ability, migration, and invasion of LSCC cells. miR-30a-5p inhibited the proliferation and migration of LSCC cells by downregulating the expression of FOXD1. Conclusion. miR-30a-5p can downregulate the expression of FOXD1 and inhibit the proliferation and migration of LSCC.

BACKGROUND The study aimed to investigate the associations of baseline serum albumin level and its dynamic change with type 2 diabetes mellitus (T2DM) risk in a large Chinese cohort study. METHODS This cohort study included 30 442 adults without T2DM at first entry, who completed at least one follow-up of annual examinations between 2009 and 2016. Serum albumin level was measured at baseline and at every annual check-up. The dynamic change in serum albumin level (∆ALB) was calculated by subtracting serum albumin level at baseline from that at the last follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox regression models. RESULTS During 7 years of follow-up, we identified 1634 T2DM events. From the lowest to the highest quartile of serum albumin level, adjusted HRs (95% CI) were 1.00 (reference), 0.96 (0.94, 1.01), 0.98 (0.95, 1.02) and 0.88 (0.85, 0.98), respectively. As compared with stable change in serum albumin (-0.2 ≤ ∆ALB

Interferon-γ (IFN-γ)-mediated adaptive resistance is one major barrier to improving immunotherapy in solid tumors. However, the mechanisms are not completely understood. Here, we report that IFN-γ promotes nuclear translocation and phase separation of YAP after anti-PD-1 therapy in tumor cells. Hydrophobic interactions of the YAP coiled-coil domain mediate droplet initiation, and weak interactions of the intrinsically disordered region in the C terminus promote droplet formation. YAP partitions with the transcription factor TEAD4, the histone acetyltransferase EP300, and Mediator1 and forms transcriptional hubs for maximizing target gene transcriptions, independent of the canonical STAT1-IRF1 transcription program. Disruption of YAP phase separation reduced tumor growth, enhanced immune response, and sensitized tumor cells to anti-PD-1 therapy. YAP activity is negatively correlated with patient outcome. Our study indicates that YAP mediates the IFN-γ pro-tumor effect through its nuclear phase separation and suggests that YAP can be used as a predictive biomarker and target of anti-PD-1 combination therapy.

Lung cancer is a common malignant cancer. Kirsten rat sarcoma oncogene (KRAS) mutations have been considered as a key driver for lung cancers. KRAS p.G12C mutations were most predominant in NSCLC which was comprised about 11–16% of lung adenocarcinomas (p.G12C accounts for 45–50% of mutant KRAS). But it is still not clear how the KRAS mutation triggers lung cancers. To study the molecular mechanisms of KRAS mutation in lung cancer. We analyzed the gene expression profiles of 156 KRAS mutation samples and other negative samples with two stage feature selection approach: (1) minimal Redundancy Maximal Relevance (mRMR) and (2) Incremental Feature Selection (IFS). At last, 41 predictive genes for KRAS mutation were identified and a KRAS mutation predictor was constructed. Its leave one out cross validation MCC was 0.879. Our results were helpful for understanding the roles of KRAS mutation in lung cancer.

Production of anti-sperm antibody (ASA) often suffers from autoimmune reaction against sperms in human infertility. The antibodies are measured in both blood and seminal plasma of males. Here, we reported a simple protein biochip methodology that takes advantage of a functionalized self-assembled monolayer modified by N-hydroxysuccinimide (NHS) and enables identification of anti-sperm antibody in Chinese male infertility. To validate this biochip platform, we immobilized purified sperm protein on the biochip surface and tested a variety of parameters in quality controls for the protein assay, respectively. Then, we analyzed serum samples from 368 patients with infertility and 116 healthy donors by means of this biochip simultaneously. We found that positive rate of serum ASA was 20.92% (77/368) in the cases and 1.72% (2/116) in the controls, respectively. Furthermore, we further corroborated the biochip assay in comparison with ELISA method. We found that both methods were compatible for the detection of serum ASA in the patients. In addition, a follow-up study for natural conception in ASA-positive and ASA-negative patients was conducted. The result showed a significant correlation between serum ASA expression and natural pregnancy rate 6.5% in ASA-positive patients while 18.9% in ASA-negative patients, indicating the potential roles of ASA in naturally reproductive processes.

CD82 acts as a tumor suppressor in a series of steps in malignant progression. Here, we identified a novel function of CD82 on posttranslational regulating E-cadherin in prostate cancer. In our study, the declined expression of CD82 was verified in prostate cancer tissues and cell lines compared with normal tissue and cell lines. Functionally, CD82 inhibited cell migration and E-cadherin cleavage from the cell membrane in prostate cancer cell. Further study proved that a disintegrin and metalloproteinase ADAM17 as an executor of E-cadherin cleavage mediated the inhibitory regulation of CD82 in E-cadherin shedding in prostate cancer. Specifically, CD82 interacted with ADAM17 and inhibited its metalloprotease activity, which led to the descent of E-cadherin shedding. These results show a nuanced but important role of CD82 in nontranscriptional regulation of E-cadherin, which may help to understand the intricate regulation of dysfunctional adhesion molecule in cancer progression.

Feasibility of subcriticality monitoring with a digital reactivity meter based on inverse kinetics method has been investigated at the lead-based zero power reactor VENUS-II. A series of control rod drop experiments have been carried out in this work. The subcriticality before and after the rod drop were estimated considering the effect of external neutron source. The control rod worth was also extracted from the rod drop experiments. The measurement results exhibited obvious spatial dependence induced by the control rod insertion, and they could be corrected by correction factors calculated with MCNP code. The corrected values of control rod worth were found to be consistent with the reference ones predetermined at critical condition. Moreover, this method could also provide real time subcriticality without any correction when the detectors were placed at appropriate positions at slightly subcritical state. Based on these measurements, it has been proved that the digital reactivity meter could be a useful tool for continuous reactivity monitoring in the operation of ADS in future.

In this article, we report a benchmark experiment of the tungsten reactivity worth under a super-critical state which has been conducted at the VENUS-II facility of CIAE in Beijing. The cylindrical tungsten target reactivity worth was measured and extracted as −1.234 ± 0.114 × 10−3 Δk/k using a period method. The resultant tungsten reactivity worth was compared with those from the MCNP Monte Carlo simulations with five evaluated libraries, i.e., ENDF/B-VII.0, ENDF/B-VII.1, CENDL-3.1, JENDL-4.0 and JEFF-3.2. It is found that the results from the MCNP simulations with ENDF/B-VII.0, ENDF/B-VII.1, JENDL-4.0 and JEFF-3.2 are overestimated, whereas that of CENDL-3.1 is underestimated, and those from the MCNP simulations with the ENDF/B-VII.1 and ENDF/B-VII.0 libraries show slight better agreement with the experiment data within errors. A correlation analysis was used to address these issues. We conclude that it is the discrepancy of the (n, γ) channel at the epithermal neutron region that mainly results in the difference between the measured and MCNP simulated tungsten reactivity worth values.

Endoscopic endonasal approach for craniopharyngioma (CP) resection provides a wide view and direct observation of hypothalamus and origin of tumor. Under endoscopy, 92 CPs were classified into 2 types: Peripheral and Central, according to its relation to pituitary stalk. Peripheral type was further divided into 3 subtypes: Hypothalamic stalk, Suprasellar stalk and Intrasellar stalk CP, according to the different origin site along hypothalamus-pituitary axis. Peripheral type arisen from the stalk but expanded and grown laterally in an exophytic pattern, accounting for 71.7% of all CPs, preservation rate of stalk was higher (76.0%). Central type grew within and along pituitary stalk and located strictly in the midline. The pituitary stalk was hardly preserved (only15.4%). Hypothalamic stalk CPs (n = 36, 54.6%) developed from the junction of hypothalamus and stalk, hypothalamus damage was found in all of this subtype after surgery. Suprasellar stalk CPs (n = 14, 21.2%) originated from the lower portion of stalk and displaced hypothalamus upward rather than infiltrated it. Intrasellar stalk CPs (n = 16, 24.2%) arose from the subdiaphragma portion of the stalk, with less hypothalamus damage. Recoginzing the origin of CP is helpful to understand its growth pattern and relation to hypothalamus, which is critical in planning the most appropriate surgical approach and degree of excision.