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Liver is the major metabolic organ. We analyzed single cell RNA-sequencing (scRNA-seq) data collected from mouse liver to study its postnatal development and tumorigenesis. The postnatal development and maturation of liver are inadequately understood. We analyzed 52,834 single cell transcriptomes collected at postnatal day 1, 3, 7, 21 and 56. We observed unexpectedly high levels of hepatocyte heterogeneity in the developing liver and progressive construction of the zonated metabolic functions from pericentral to periportal hepatocytes, which was orchestrated with development of sinusoid endothelial, stellate and Kupffer cells. Trajectory and gene regulatory analyses captured 36 transcription factors, including a circadian regulator Bhlhe40, in programming liver development. Remarkably, we identified a special group of macrophages enriched at day 7 with a hybrid phenotype of macrophages and endothelial cells, which may regulate sinusoidal construction and regulatory T (Treg) cell function. For tumorigenesis, we show that Myc-driven hepatocellular carcinoma (HCC) was dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion. However, Myc-induced tumors developed selectively from the rare Shp2-positive hepatocytes in Shp2-deficent liver, and Myc-driven oncogenesis depended on an intact Ras-Erk signaling ensued by Shp2 to sustain Myc stability. Despite a stringent requirement of Shp2 cell-autonomously, Shp2 deletion induced an immune-suppressive environment, resulting in defective clearance of tumor-initiating cells and aggressive tumor progression. The basal Wnt/beta-catenin signaling was upregulated in Shp2-deficient liver, which was further augmented by Myc transfection. Ablating Ctnnb1 suppressed Myc-induced HCC in Shp2-deficient livers, revealing an essential role of beta-catenin. Consistently, Myc overexpression and CTNNB1 mutations were frequently co-detected in HCC patients with poor prognosis. These data elucidate complex mechanisms of liver tumorigenesis driven by cell-intrinsic oncogenic signaling in cooperation with environmental tumor-promoting factors generated by disrupting the specific oncogenic pathway.

A total of 244 Candida albicans isolates recovered from vulvovaginal candidiasis (VVC) patients in Suzhou, Eastern China, were investigated. According to CLSI documents M27-A4 and M59-3ed/M60-2ed, the MIC geometric means of nine antifungals in increasing order were micafungin (0.048 mg/L), anidulafungin (0.132 mg/L), caspofungin (0.19 mg/L), itraconazole (0.23 mg/L), posaconazole (0.25 mg/L), voriconazole (0.28 mg/L), 5-flucytosine (0.44 mg/L), amphotericin B (0.49 mg/L) and fluconazole (2.01 mg/L) respectively. Of note, 6.5% (16/244) C. albicans isolates showed resistance mainly to anidulafungin (mono-echinocandin resistance), while voriconazole had the lowest susceptibility rate of 34.8% (85/244), followed by fluconazole 59.4% (145/244), respectively. All isolates were genotyped by allelic combination of 3 microsatellite markers (CEF3, CAIII and LOC4). A total of 129 different allelic genotypes were identified, in which seven different clades were recognized with a discriminatory power of 0.96. Genotypes A-D were present in 35% of the isolates. In conclusion, decrease in antifungal drug susceptibility to C. albicans isolates from VVC is alarming. Our findings revealed the genetic diversity of C. albicans isolates among VVC patients and provided insights into the molecular epidemiology of Candida infections in China.

Magnusiomyces capitatus is an emerging opportunistic yeast, thus far mainly reported from the Western world where fungemia is the most frequent presentation in immunocompromised patients with high mortality. We described a rare case of Magnusiomyces capitatus infection from our hospital in China and reviewed six further cases published to date in Chinese literature. It is noted that half more of the cases (4/7) presented with fungemia in younger, immunosuppressed patients, whereas the remaining cases were with pneumonia in elderly, immunocompetent patients. All seven Chinese cases had favourable outcome with antifungal therapy. Based on the limited in vitro and clinical data, a combination of amphotericin B either with 5-fluorocytosine or voriconazole for fungemia in immunocompromised patients, and although fluconazole is not recommended as first-line therapy in the guideline, in our study, fluconazole alone or with 5-fluorocytosine for local pulmonary infection in immunocompetent patients is effective with good outcome.

Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

Pantoea ananatis is a phytopathogen infecting many economically important crops, including rice worldwide. Here, we report the complete genome of P. ananatis strain TZ39 identified as causative agent of a new bacterial blight of rice that emerged in China in 2020. The assembled genome consists of one circular chromosome of 4,483,976 bp and two plasmids of 135,135 and 276,579 bp. This complete genome of the first Chinese pathogenic P. ananatis strain will provide new insights into the traits of pathogenicity on genomic level from China and worldwide.

The maintenance of homeostasis of cytochromes P450 enzymes (P450s) under both physiologic and xenobiotic exposure conditions is ensured by the action of positive and negative regulators. In the current study, the hepatocyte nuclear factor 4α (HNF4A) antisense RNA 1 (HNF4A-AS1), an antisense long noncoding RNA of HNF4A, was found to be a negative regulator of the basal and rifampicin (RIF)-induced expression of nuclear receptors and downstream P450s. In Huh7 cells, knockdown of HNF4A-AS1 resulted in elevated expression of HNF4A, pregnane X receptor (PXR), and P450s (including CYP3A4) under both basal and RIF-induced conditions. Conversely, overexpression of HNF4A-AS1 led to decreased basal expression of constitutive androstane receptor, aryl hydrocarbon receptor, PXR, and all studied P450s. Of note, significantly diminished induction levels of PXR and CYP1A2, 2C8, 2C19, and 3A4 by RIF were also observed in HNF4A-AS1 plasmid-transfected Huh7 cells. Moreover, the negative feedback of HNF4A on HNF4A-AS1-mediated gene expression was validated using a loss-of-function experiment in this study. Strikingly, our data showed that increased enrichment levels of histone 3 lysine 4 trimethylation and HNF4A in the CYP3A4 promoter contribute to the elevated CYP3A4 expression after HNF4A-AS1 knockdown. Overall, the current study reveals that histone modifications contribute to the negative regulation of nuclear receptors and P450s by HNF4A-AS1 in basal and drug-induced levels. SIGNIFICANCE STATEMENT: Utilizing loss-of-function and gain-of-function experiments, the current study systematically investigated the negative regulation of HNF4A-AS1 on the expression of nuclear receptors (including HNF4A, constitutive androstane receptor, aryl hydrocarbon receptor, and pregnane X receptor) and P450s (including CYP1A2, 2E1, 2B6, 2D6, 2C8, 2C9, 2C19, and 3A4) in both basal and rifampicin-induced levels in Huh7 cells. Notably, this study is the first to reveal the contribution of histone modification to the HNF4A-AS1-mediated expression of CYP3A4 in Huh7 cells.

Background Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for regenerative medicine and in drugs screening. Despite displaying key cardiomyocyte phenotypic characteristics, they more closely resemble fetal/neonatal cardiomyocytes and are still immature; these cells mainly rely on glucose as a substrate for metabolic energy, while mature cardiomyocytes mainly employ oxidative phosphorylation of fatty acids. Studies showed that the alteration of metabolism pattern from glycolysis to oxidative phosphorylation improve the maturity of hiPSC-CMs. As a transcription factor, accumulating evidences showed the important role of NRF2 in the regulation of energy metabolism, which directly regulates the expression of mitochondrial respiratory complexes. Therefore, we hypothesized that NRF2 is involved in the maturation of hiPSC-CMs. Methods The morphological and functional changes related to mitochondria and cell maturation were analyzed by knock-down and activation of NRF2. Results The results showed that the inhibition of NRF2 led to the retardation of cell maturation. The activation of NRF2 leads to a more mature hiPSC-CMs phenotype, as indicated by the increase of cardiac maturation markers, sarcomere length, calcium transient dynamics, the number and fusion events of mitochondria, and mitochondrial respiration. Bioinformatics analysis showed that in addition to metabolism-related genes, NRF2 also activates the expression of myocardial ion channels. Conclusions These findings indicated that NRF2 plays an important role in the maturation of hiPSC-CMs. The present work provides greater insights into the molecular regulation of hiPSC-CMs metabolism and theoretical basis in drug screening, disease modeling, and alternative treatment.

Colon cancer is a common malignancy of the digestive tract, mostly occurring at the junction of the rectum and colon. It easily invades multiple internal organs and tissues, causing systemic injury and mortality to patients. The occurrence and development of colon cancer involve multiple genes and multiple factors. It is greatly significant to identify oncogenes and tumor suppressor genes that influence the development of colon cancer and to study their mechanism of action for colon cancer diagnosis and treatment. Furthermore, circRNA are involved in the development of several types of tumors by affecting miRNA regulation on target gene expression. In the present study, circ_0005075 siRNA and circ_0005075 siRNA + mir-335 inhibitor were transfected into colon cancer SW620 cells, and circ_0005075 gene expression was significantly decreased after transfecting circ_0005075 siRNA into SW620 cells. Silencing circ_0005075 expression significantly inhibited SW620 cell proliferation, invasion, and migration, and promoted apoptosis, downregulated PCNA and vimentin expression, and upregulated E-cadherin and cleaved caspase3 expression. After circ_0005075 siRNA + mir-335 was transfected, it inhibited circ_0005075 and mir-335 expression, which significantly affected the vigor, invasion and migration ability, apoptosis rate of SW620 cells, as well as PCNA, E-cadherin, vimentin, and cleaved caspase3 expression. Therefore, the present study demonstrated that circ_0005075 silencing inhibited the proliferation, invasion, and migration of SW620 cells and promoted apoptosis by upregulating mir-335 expression.

Sheath blight is a serious rice disease that causes great yield losses worldwide. Sheath blight resistance is controlled by genes with minor effect. It is an urgent need to identify the resistance genes in rice germplasm and utilize them in breeding. The purpose of this study is to identify the sheath blight-resistant alleles in different rice germplasm by association mapping and explore the potential of the resistance alleles in utilization. A total of 273 rice genotypes were inoculated and evaluated for sheath blight resistance in the field for 5 years, and 158 genotypes with relatively stable disease resistance phenotype were chosen for association mapping. A wide range of phenotypic variation for sheath blight resistance was observed in the 158-genotype population. Structure analyses divided the 158 genotypes into 4 subgroups, which was consistent with principal component analysis and cluster analysis. Association mapping performed using mixed linear model with 213 markers identified 14 resistance loci, locating on all chromosomes except chromosome 6, 10 and 12. Three novel resistance loci (D704, D855, and D905) which were different from the previously reported were detected. Thirty-eight alleles were detected at the 14 loci, among which favorable alleles at 11 loci showed consistent resistance across 5 years. It was found that the favorable resistance alleles can be pyramided to improve sheath blight resistance. These results enhance the understanding of how different resistance alleles at multiple loci in regulating sheath blight resistance, and provide markers for sheath blight resistance breeding in rice.

Noninvasive tumor therapy requires a new generation of bionanomaterials towards sensitive response to the unique tumor microenvironment to achieve accurate and effective treatment. Herein, we have developed a tumor therapy nanoplatform by immobilizing natural glucose oxidase (GOD) onto Cu-based layered double hydroxide (CuFe-LDH) nanosheets, which for the first time integrates acid-enhanced photothermal therapy (PTT), and pH-responsive and heat-facilitated chemodynamic therapy (CDT) simultaneously. As demonstrated by EXAFS and HRTEM, CuFe-LDH nanosheets possess a considerable number of defects caused by different acid conditions, resulting in a significantly acid-enhanced photothermal conversion efficiency (83.2% at pH 5.4 vs. 46.0% at pH 7.4). Moreover, GOD/CuFe-LDH nanosheets can convert a cascade of glucose into hydroxyl radicals (˙OH) under tumor acid conditions, which is validated by a high maximum velocity (Vmax = 2.00 × 10−7 M) and low Michaelis–Menten constant (KM = 12.01 mM). With the combination of PTT and CDT, the tumor tissue in vivo is almost eliminated with low-dose drug injection (1 mg kg−1). Therefore, this novel pH-responsive Cu-based nanoplatform holds great promise in tumor-specific CDT/PTT synergistic therapy., A pH-responsive multifunctional nanosystem was synthesized by loading glucose oxidase (GOD) onto CuFe-layered double hydroxide (LDH) nanosheets, which exhibited synchronous acid-enhanced/responsive photothermal and chemodynamic synergistic therapy.

Xin Wang,1,* Ya Cheng,1,* Liang-liang Yan,2 Ran An,1 Xing-yu Wang,1 Heng-yi Wang1 1Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China; 2Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heng-yi Wang Tel +86-156-0551-1180Email why00606@sina.comBackground: Hepatocellular carcinoma (HCC) includes cryptogenic hepatocellular carcinomas (CR-HCC) that lack a defined cause. Specific DNA methylation patterns and comparisons of the aberrant alterations in DNA methylation between CR-HCC and adjacent peritumor tissues (APTs) have not yet been reported.Methods: The SureSelectXT Methyl-Seq Target Enrichment System was used to sequence targeted DNA methylation in three paired CR-HCC tissues and APTs. Gene Ontology (GO) enrichment and KEGG pathway analysis were performed to investigate the DNA methylation mechanism of CR-HCC. The mRNA expression levels of HOXB-AS3, HOXB6, HOXB3, USP18, MAP3K6, TIRAP, TNNI2, SHC3, CTTN, and TFAP2A, selected from the identified signaling pathways, were evaluated by quantitative real-time PCR (qPCR).Results: A total of 1728 differentially methylated regions (DMRs) were identified in tumor tissues compared with non-tumor tissues, of which 868 DMRs were hypermethylated and 860 were hypomethylated. The DMRs were mapped within 2091 DMR-associated genes (DMGs). The mRNA expression of HOXB-AS3, HOXB3, and MAP3K6 was downregulated in CR-HCC tissues compared to the APTs. However, the mRNA expression of TIRAP, SHC3, and CTTN was upregulated in the CR-HCC tissues. Differences between the mRNA expression of HOXB6, USP18, TNNI2, and TFAP2A in the CR-HCC and APTS tissues were not statistically significant. GO analysis showed that the molecular functions of “binding”, “protein binding”, and “cytoskeletal protein binding” were the main categories for the hypermethylated DMGs. The hypomethylated DMGs were mostly enriched in the molecular functions “binding”, “protein binding”, “calcium ion binding”, among others. KEGG pathway analysis showed that the hypermethylated DMGs were enriched in several pathways such as “estrogen signaling pathway”, while hypomethylated DMGs were enriched in several pathways such as “proteoglycans in cancer”, suggesting that epigenetic modifications play important roles in the cryptogenic hepatocarcinogenesis.Conclusion: These results provide useful information for future work to characterize the functions of epigenetic mechanisms on CR-HCC.Keywords: cryptogenic hepatocellular carcinomas, DNA methylation, DMR

DNA damage can occur naturally or through environmental factors, leading to mutations in DNA replication and genomic instability in cells. Normally, natural d-nucleotides were selected by DNA polymerases. The template l-thymidine (l-T) has been shown to be bypassed by several types of DNA polymerases. However, DNA replication fidelity of nucleotide incorporation opposite l-thymidine in vivo remains unknown. Here, we constructed plasmids containing a restriction enzyme (PstI) recognition site in which the l-T lesion was site-specifically located within the PstI recognition sequence (CTGCAG). Further, we assessed the efficiencies of nucleotide incorporation opposite the l-T site and l-T lesion bypass replication in vitro and in vivo. We found that recombinants containing the l-T lesion site inhibited DNA replication. In addition, A was incorporated opposite the l-T lesion by routine PCR assay, whereas preference for nucleotide incorporation opposite the l-T site was A (13%), T (22%), C (46%), and G (19%), and no nucleotide insertion and deletions were detected in E. coli cells. In particular, a novel restriction enzyme-mediated method for detection of the mutagenic properties of DNA lesion was established, which allows us to readily detect restriction-digestion of the l-T-bearing plasmids. The study provided significant insight into how mirror-image nucleosides perturb the fidelity of DNA replication in vivo and whether they elicit mutagenic effects, which may help to understand both how DNA damage interferes with the flow of genetic information during DNA replication and development of diseases caused by gene mutation.

Potato common scab is an important soilborne disease worldwide that can significantly reduce the quality and economic values of potato. The disease is caused by multiple species of Streptomyces, which are not well controlled due to lack of effective strategies. Streptomyces galilaeus has been recently identified as a dominant species causing potato common scab in Inner Mongolia, China. This study was focused on screening and characterizing antagonists for biological control against pathogenic S. galilaeus. Bacterial strain PBSH9 was isolated from a potato tuber. PBSH9 was identified as a Streptomyces sp. on the basis of morphological, physiological, and biochemical characteristics, as well as DNA sequence analysis. PBSH9 inhibited S. galilaeus with a diameter of inhibitory zone of 19.8 mm on agar plates. The extracellular filtrate of PBSH9 also inhibited S. galilaeus growth with a diameter of inhibition zone of 10.0 mm. Furthermore, PBSH9 promoted potato sprouting and emergence. Disease control was up to 81.88% in greenhouse trials, and from 47.64 to 73.97% in 3-year field trials. Among the tested inoculation methods, seed treatment was more effective than soil drenching for PBSH9 application. PBSH9 not only effectively controlled potato common scab but also increased potato growth. Thus, it can be a potential candidate for biocontrol agent.

Retroperitoneal liposarcoma (RLPS) is one of the most common types of retroperitoneal sarcomas, and has a high recurrence rate. There is an urgent need to further explore its pathogenesis and develop more effective treatment strategies. The aim of the present study was to identify potential driver genes of RLPS through bioinformatics analysis and molecular biology to elucidate potential targets that are suitable for further analysis for the treatment of RLPS. Differentially expressed genes (DEGs) between liposarcoma and normal fatty (NF) tissues were identified based on microarray data through bioinformatics analysis, and thymidylate synthase (TYMS) was selected from the DEGs, based on high content screening (HCS). TYMS expression was evaluated in RLPS tumor tissues and cell lines. A total of 21 RLPS tissues and 10 NF frozen tissues were used for reverse transcription-quantitative PCR, and 47 RLPS formalin-fixed specimens were used for immunohistochemical analysis. The effect of TYMS downregulation on cell proliferation, apoptosis, cell cycle progression, and cell migration and invasion were evaluated using lentivirus-mediated short hairpin RNA. The underlying mechanisms of TYMS in RLPS were examined by protein microarray and verified by western blotting. A total of 855 DEGs were identified. TYMS knockdown had the most notable effect on the proliferative capacity of RLPS cells according to the HCS results. TYMS mRNA expression levels were higher in RLPS tissues compared with NF tissues (P

We developed and identified a new set of polymorphic EST-SSR markers in Sophora japonica Linn. and analyzed their genetic diversity. Sophora japonica is a native species in China with ornamental and medicinal value. To explore the genetic diversity and the genetic differentiation of this species, expressed sequence tag-simple sequence repeat (EST-SSR) markers were developed based on de novo transcriptome sequencing. In total 35,844 unigenes were obtained with an average length of 923 bp. 7,520 potential EST-SSRs were identified from 6,084 unigenes, of which there was one SSR per 4.40 kb. The dinucleotide repeats were the most common SSRs. Based on the SSR-containing sequence, 30 superior EST-SSRs were developed from 100 primer pairs and further used to characterize the genetic diversity and genetic differentiation of S. japonica in five populations. The results showed that the genetic diversity of the five groups was high, but the frequency of gene exchange between the groups was not. The analysis of molecular variance (AMOVA) showed that the genetic variation within individuals was 86.10%, which means the individual variation was the more significant in selective breeding of S. japonica. Nei’s genetic identity and genetic distance analyses yielded a high genetic identity value of 0.896 and mean genetic distance of 0.1095 suggesting high similarities among the five tested S. japonica populations. Based on genetic distance, S. japonica populations were classified into two groups. The findings of this study provide insights into the genetic information of S. japonica and will guide the development of conservation and management strategies for existing S. japonica germplasm.

Objective: We investigated the temporal expression profiles of long noncoding RNA (lncRNA) and mRNA in the peripheral blood of pigs during development and identified the lncRNAs that are related to the blood-based immune system.Methods: Peripheral blood samples were obtained from the pigs at 0, 7, 28, and 180 days and 2 years of age. RNA sequencing was performed to survey the lncRNA and mRNA transcriptomes in the samples. Short time-series expression miner (STEM) was used to show temporal expression patterns in the mRNAs and lncRNAs. Gene ontology and Kyoto encyclopedia of genes and genomes analyses were performed to assess the genes’ biological relevance. To predict the functions of the identified lncRNAs, we extracted mRNAs that were nearby loci and highly correlated with the lncRNAs.Results: In total of 5,946 lncRNA and 12,354 mRNA transcripts were identified among the samples. STEM showed that most lncRNAs and mRNAs had similar temporal expression patterns during development, indicating the expressional correlation and functional relatedness between them. The five stages were divided into two classes: the suckling period and the late developmental stage. Most genes were expressed at low level during the suckling period, but at higher level during the late stages. Expression of several T-cell-related genes increased continuously during the suckling period, indicating that these genes are crucial for establishing the adaptive immune system in piglets at this stage. Notably, lncRNA TCONS-00086451may promote blood-based immune system development by upregulating nuclear factor of activated T-cells cytoplasmic 2 expression.Conclusion: This study provides a catalog of porcine peripheral blood-related lncRNAs and mRNAs and reveals the characteristics and temporal expression profiles of these lncRNAs and mRNAs during peripheral blood development from the newborn to adult stages in pigs.

In the ageing skeleton, the balance of bone reconstruction could commonly be broken by the increasing of bone resorption and decreasing of bone formation. Consequently, the bone resorption gradually occupies a dominant status. During this imbalance process, osteoclast is unique cell linage act the bone resorptive biological activity, which is a highly differentiated ultimate cell derived from monocyte/macrophage. The erosive function of osteoclasts is that they have to adhere the bone matrix and migrate along it, in which adhesive cytoskeleton recombination of osteoclast is essential. In that, the podosome is a membrane binding microdomain organelle, based on dynamic actin, which forms a cytoskeleton superstructure connected with the plasma membrane. Otherwise, as the main adhesive protein, integrin regulates the formation of podosome and cytoskeleton, which collaborates with the various molecules including: c‐Cbl, p130Cas, c‐Src and Pyk2, through several signalling cascades cross talking, including: M‐CSF and RANKL. In our current study, we discuss the role of integrin and associated molecules in osteoclastogenesis cytoskeletal, especially podosomes, regulation and relevant signalling cascades cross talking.

2-Phenylethyl acetate (2-PEA) is a desired aroma compound in wine due to its honey- and flowery-like characteristics. The effects of adding l -phenylalanine (Phe) during 2-PEA production were investigated in the co-fermentation of Hanseniaspora vineae (HV6) and Saccharomyces cerevisiae BDX. BDX and HV6 strains overproduced 2-phenylethyl alcohol (2-PE) and 2-PEA, respectively. The co-fermentation of BDX and HV6 achieved a 14.9 fold increase in 2-PEA odour activity value (OAV) but a 42.0 % reduction of 2-PE OAV compared to BDX fermentation; the 2-PEA concentration was significantly higher than the sum of BDX and HV6 pure fermentations. This suggests that BDX and HV6 have synergistic effects on 2-PEA formation in mixed culture. Adding 151.6 mg/L Phe enhanced the OAV of 2-PEA by 52.8 % compared to the control. The combination of Phe addition with the co-fermentation of S. cerevisiae and H. vineae is a potential way to increase 2-PEA production and improve wine aromatic quality.

Tumor hypoxia is known to be one of the vital factors that aggravate tumor resistance to radiation therapy (RT) in which oxygen plays a critical role in tumor destruction. Herein, we synthesize a simple nanoradiosensitizer based on ultrathin BiO2-x nanosheets (NSs) modified with Tween 20 (T-BiO2-x NSs) to overcome the hypoxia-induced radioresistance as well as increase the efficacy of RT. On the one hand, bismuth as a high-Z element can effectively enhance the sensitivity of RT by depositing a higher radiation dose in tumors. The semiconductor property also endows its photocatalytic ability to produce extra reactive oxygen species (ROS) by reaction with the surrounding water. On the other hand, the defect-abundant BiO2-x NSs are also found to decompose the highly expressed hydrogen peroxide (H2O2) at the tumor site into oxygen (O2) for combating hypoxia. Both in vitro and in vivo experiments indicate that the as-prepared T-BiO2-x NSs could effectively inhibit tumor growth with X-ray irradiation. Our work thus provides a simple nanoradiosensitizer with multifunctionalities for increasing the RT efficacy while alleviating tumor hypoxia at the same time.

Accumulating evidence has indicated that microRNAs can regulate downstream signaling pathways and play an important role in various tumors. In this study, we found that miR-223-3p was differentially expressed in 40 paired gastric cancer tissues and adjacent tissues and that miR-223-3p was positively correlated with tumor invasion depth and lymph node metastasis. Luciferase reporter assay confirmed that Arid1a was the target gene of miR-223-3p. Functional assays showed that miR-223-3p promoted the proliferation and invasion of gastric cancer cells by regulating the expression of Arid1a. We also confirmed that miR-223-3p regulated the growth of gastric cancer cells in vivo, while an antagomir against miR-223-3p significantly inhibited tumor growth. In conclusion, our results demonstrated that miR-223-3p inhibits gastric cancer cell progression by decreasing the expression of Arid1a. Therefore, miR-223-3p may act as a potential therapeutic target for patients with gastric cancer.

The seed setting rate (spikelet fertility) is an important determinant of rice yield. In the past few decades, genes that control rice seed set have been cloned, and many quantitative trait loci (QTL) have been identified. However, the epistasis influencing rice seed set remains largely unclear. In this study, a recombinant inbred line population, which consisted of 219 lines developed by crossing the Lemont and Yangdao4 rice cultivars, was grown in five environments to identify the QTL and epistatic loci related to seed set. A total of 26 minor-effect QTL were detected by multiple interval mapping, which explained less than 12.7% of the phenotypic variation individually. A pair of new epistatic loci were detected and confirmed by two-way analysis of variance; the homozygous Yangdao4 allele at the qSS6.1 locus interacted with the homozygous Lemont allele at the qSS8.1 locus and resulted in a low seed setting rate. A linear regression analysis and a multiple comparison test suggested that eight alleles at four QTL (qSS1.3, qSS6.3, qSS7.1, and qSS8.1) control seed set simultaneously. Marker-assisted selection using these four loci guaranteed a greater than 70% average seed setting rate in all five environments.

Exosomes mediate the interaction between cancer cells and their microenvironment, and play a key role in tumor development. Although exosomes can package lncRNAs to mediate extracellular communication, the role of exosomal lncRNA AY927529 in prostate cancer (PCa) remains unclear. Exosomes were extracted from normal human prostatic epithelial cell lines (BPH-1 and RWPE-1) and PCa cell lines (VCaP and LNCaP, DU145, PC3) by ultrahigh speed centrifugation. Results of Western blot indicated that Alix, HSC70 and TSGl01 protein levels were upregulated in exosomes derived from PCa cells. LncAY927529 level was upregulated in PCa cells and exosomes derived from PCa patient serum and human PCa cells. CCK-8, Transwell and Flow cytometry assays demonstrated that bone marrow stromal cell line (ST2) conditioned medium (ST2-CM), treated with exosomes derived from PCa cells with high lncAY927529 level, promoted proliferation and invasion of PC3 and DU145 cells, and inhibited cell apoptosis. RT-qPCR assay indicated that lncAY927529 level was downregulated in PC3 and DU145 cells, exosomes derived from PCa cells (PCa-Exo) and ST2-CM treated with PCa-Exo with low expression of lncAY927529, and overexpression of lncAY927529 had the opposite results. In addition, Western blot assay showed that the autophagy related protein LC3II level was increased in ST2 cells treated with exosomes derived from DU145 cells with high expression of lncAY927529, and LC3I protein level was decreased. CXCL14 acted as a RNA-binding protein of lncAY927529, and exosome-mediated lncAY927529 positively regulated CXCL14 levels in ST2 cells. In general, exosome-mediated lncAY927529 could promote PCa cell proliferation and invasion by regulating bone microenvironment, suggesting that exosomal lncAY927529 may be a potential molecular diagnostic marker of PCa.

Increasing attention has been given to the impact of extreme drought stress on ecosystem ecological processes. Ecosystem respiration (Re) and soil respiration (Rs) play a significant role in the regulation of the carbon (C) balance because they are two of the largest terrestrial C fluxes in the atmosphere. However, the responses of Re and Rs to extreme drought in alpine regions are still unclear, particularly with respect to the driver mechanism in plant and soil extracellular enzyme activities. In this study, we imposed three periods of extreme drought events based on field experiments on an alpine peatland: (1) early drought, in which the early stage of plant growth occurred from June 18 to July 20; (2) midterm drought, in which the peak growth period occurred from July 20 to August 23; and (3) late drought, in which the wilting period of plants occurred from August 23 to September 25. After 5 years of continuous extreme drought events, Re exhibited a consistent decreasing trend under the three periods of extreme drought, while Rs exhibited a non-significant decreasing trend in the early and midterm drought but increased significantly by 58.48% (p < 0.05) during the late drought compared with the ambient control. Plant coverage significantly increased by 79.3% (p < 0.05) in the early drought, and standing biomass significantly decreased by 18.33% (p < 0.05) in the midterm drought. Alkaline phosphatase, polyphenol oxidase, and peroxidase increased significantly by 76.46, 77.66, and 109.60% (p < 0.05), respectively, under late drought. Structural equation models demonstrated that soil water content (SWC), pH, plant coverage, plant standing biomass, soil β-D-cellobiosidase, and β-1,4-N-acetyl-glucosaminidase were crucial impact factors that eventually led to a decreasing trend in Re, and SWC, pH, β-1,4-glucosidase (BG), β-1,4-xylosidase (BX), polyphenol oxidase, soil organic carbon, microbial biomass carbon, and dissolved organic carbon were crucial impact factors that resulted in changes in Rs. Our results emphasize the key roles of plant and soil extracellular enzyme activities in regulating the different responses of Re and Rs under extreme drought events occurring at different plant growth stages.

Autophagy is an intracellular catabolic process that degrades cytoplasmic components for recycling in response to stressed conditions, such as nutrient deprivation. Dysregulation of autophagy is associated with various diseases, including cancer. Although autophagy plays dichotomous and context-dependent roles in cancer, evidence has emerged that cancer cells exploit autophagy for metabolic adaptation. Autophagy is upregulated in many cancer types through tumor cell-intrinsic proliferation demands and the hypoxic and nutrient-limited tumor microenvironment (TME). Autophagy-induced breakdown products then fuel into various metabolic pathways to supply tumor cells with energy and building blocks for biosynthesis and survival. This bidirectional regulation between autophagy and tumor constitutes a vicious cycle to potentiate tumor growth and therapy resistance. In addition, the pro-tumor functions of autophagy are expanded to host, including cells in TME and distant organs. Thus, inhibition of autophagy or autophagy-mediated metabolic reprogramming may be a promising strategy for anticancer therapy. Better understanding the metabolic rewiring mechanisms of autophagy for its pro-tumor effects will provide insights into patient treatment.

A Gram-reaction-negative, yellow-pigmented, non-spore-forming rod, aerobic, motile bacterium, designated SJY3T, was isolated from soil samples collected from a Pu-erh tea cellar in Bolian Pu-erh tea estate Co. Ltd. in Pu'er city, Yunnan, south-west China. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate belonged to the genus Massilia . The closest phylogenetic relative was Massilia arenae CICC 24458T (99.5 %), followed by M. timonae CCUG45783T (97.9 %), M. oculi CCUG43427AT (97.8 %), and M. aurea DSM 18055T (97.8 %). The major fatty acids were C16 : 0 and C16 : 1 ω7c and/or C16 : 1 ω6c. The major respiratory quinone was ubiquinone Q-8 and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. Genome sequencing revealed a genome size of 5.97 M bp and a G+C content of 65.4 mol%. Pairwise determined whole genome average nucleotide identity (gANI) values and digital DNA–DNA hybridization (dDDH) values were all below the threshold. Although the 16S rRNA gene similarity of stain SJY3T and Massilia arenae CICC 24458T was more than 99 %, the gANI, dDDH values and genomic tree clearly indicated that they were not of the same species. In summary, strain SJY3T represents a new species, for which we propose the name Massilia puerhi sp. nov. with the type strain SJY3T (=CGMCC 1.17158T=KCTC 82193T).

Immune escape is one of the hallmarks of cancer. While metabolic reprogramming provides survival advantage to tumor cancer cells, accumulating data also suggest such metabolic rewiring directly affects the activation, differentiation and function of immune cells, particularly in the tumor microenvironment. Understanding how metabolic reprogramming affects both tumor and immune cells, as well as their interplay, is therefore critical to better modulate tumor immune microenvironment in the era of cancer immunotherapy. In this review, we discuss alterations in several essential metabolic pathways in both tumor and key immune cells, provide evidence on their dynamic interaction, and propose innovative strategies to improve cancer immunotherapy via the modulation of metabolic pathways.

In this work, we discovered a new fermentation broth that can prevent and regulate alcoholic liver disease (ALD) and intestinal flora, which fermented the mixture of Pueraria lobata, Lonicera japonica, and Crataegus pinnatifida by Lactobacillus rhamnosus 217-1. The contents of polyphenols, puerarin, total isoflavones, and amino acids were significantly increased. Animal experiments showed that the fermentation broth could improve the liver indexes of ALD mice model, increase the activity of superoxide dismutase and glutathione in liver tissue, and reduce the level of malondialdehyde (MDA). Furthermore, the fermentation broth can reduce the levels of serum lipopolysaccharide (LPS), inflammatory factors interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Importantly, intestinal flora analysis showed that the fermentation broth could increase the abundance of Lactobacillales and reduce the production of Gram-negative bacteria, thereby reducing the abnormal increase in bacterial diversity caused by alcohol. In conclusion, we may have discovered a new functional food raw material with great application potential. The above findings indicate that the fermentation broth can actively regulate the intestinal flora and improve liver inflammation. The underlying mechanism might be that the fermentation broth could enhance intestinal permeability and reduce the inflammatory signals and LPS transmitted through the gut-liver axis, thereby reducing the oxidative stress and inflammation of the liver caused by alcohol.

B3 is the most common subtype of blood group B in the Taiwanese population, and most of the B3 individuals in the Taiwanese population have the IVS3 + 5 G > A (rs55852701) gene variation. Additionally, a typical mixed field agglutination is observed when the B3 subtype is tested with anti-B antibody or anti-AB antibody. The molecular biology of the gene variation in the B3 subtype has been identified, however, the mechanism of the mixed field agglutination caused by the type B3 blood samples is still unclear. Therefore, the purpose of this study was to understand the reason for the mixed field agglutination caused by B3. A micro-droplet platform was used to observe the agglutination of type B and type B3 blood samples in different blood sample concentrations, antibody concentrations, and at reaction times. We found that the agglutination reaction in every droplet slowed down with an increase in the dilution ratio of blood sample and antibody, whether type B blood or type B3 blood was used. However, as the reaction time increased, the complete agglutination in the droplet was seen in type B blood, while the mixed field agglutination still occurred in B3 within 1 min. In addition, the degree of agglutination was similar in each droplet, which showed high reproducibility. As a result, we inferred that there are two types of cells in the B3 subtype that simultaneously create a mixed field agglutination, rather than each red blood cell carrying a small amount of antigen, resulting in less agglutination.

The activity of nanomaterials (NMs) in catalytically scavenging superoxide anions mimics that of superoxide dismutase (SOD). Although dozens of NMs have been demonstrated to possess such activity, the underlying principles are unclear, hindering the discovery of NMs as the novel SOD mimics. In this work, we use density functional theory calculations to study the thermodynamics and kinetics of the catalytic processes, and we develop two principles, namely, an energy level principle and an adsorption energy principle, for the activity. The first principle quantitatively describes the role of the intermediate frontier molecular orbital in transferring electrons for catalysis. The second one quantitatively describes the competition between the desired catalytic reaction and undesired side reactions. The ability of the principles to predict the SOD-like activities of metal-organic frameworks were verified by experiments. Both principles can be easily implemented in computer programs to computationally screen NMs with the intrinsic SOD-like activity., A general predicting theory for superoxide-dismutase mimicking nanomaterials is currently lacking. The present manuscript reports a density functional theory study on the superoxides dismutase-like activity of nanomaterials based on their electronic band structures and surface adsorption energies.

Mesenchymal stem cells (MSCs) are promising tools for cancer therapy, but there is a risk of malignant transformation in their clinical application. Our previous work revealed that the paracrine protein S100B in the glioma microenvironment induces malignant transformation of MSCs and upregulates intracellular S100B, which could affect cell homeostasis by interfering with p53. The purpose of this study was to investigate whether extracellular S100B can be internalized by MSCs and the specific endocytic pathway involved in S100B internalization. By using real-time confocal microscopy and structured illumination microscopy (SIM), we visualized the uptake of fluorescently labeled S100B protein (S100B-Alexa488) and monitored the intracellular trafficking of internalized vesicles. The results showed that S100B-Alexa488 was efficiently internalized into MSCs in a time-dependent manner and transported through endolysosomal pathways. After that, we used chemical inhibitors and RNA interference approaches to investigate possible mechanisms involved in S100B-Alexa488 uptake. The internalization of S100B-Alexa488 was inhibited by pitstop-2 or dyngo-4a treatment or RNA-mediated silencing of clathrin or dynamin, and the lipid raft-mediated endocytosis inhibitors nystatin and MβCD. In conclusion, our findings show that clathrin and lipid rafts contribute to the internalization of S100B-Alexa488, which provides promising interventions for the safe application of MSCs in glioma therapy.

This study evaluated the inhibition and interaction of Bacillus velezensis BvL03 as a probiotic agent against Aeromonas hydrophila. Strain BvL03 isolated from sediment samples of fish ponds had excellent antimicrobial activity against several fish pathogenic bacteria, especially Aeromonas, including A. hydrophila, A. veronii, A. caviae, and A. sobria. The successful amplification of lipopeptide antimicrobial chemical biosynthetic genes, including iturin family (ituA, ituB, and ituD), bacillomycin family (bacA, bacD, and bacAB), surfactin family (srfAB, srfC, and srfAA), and subtilosin family (albF and sunT) from the genome of BvL03 strain, confirmed its predominant antimicrobial activity. The challenge test suggested that BvL03 significantly decreased fish mortality when challenged with A. hydrophila, which had a cumulative mortality of 12.5% in the treatment group. Toxicity and hemolytic activity of A. hydrophila after co-cultured with BvL03 were relieved as confirmed by the cell experiments, when the initial inoculated concentration of BvL03 was 109 cfu/mL or higher. Moreover, the BvL03 strain labeled with GFP protein (BvL03-GFP) and AhX040 strain labeled with mCherry protein (AhX040-mCherry) were injected into grass carps. The fluorescence levels were monitored by using In Vivo Imaging System (IVIS), in which the green color was steadily increasing, whereas the red color was gradually weakening. Whole genome sequencing revealed that strain BvL03 possesses 15 gene clusters related to antibacterial compounds, including 5 NRPS gene clusters and 3 PKS gene clusters. These results suggested that B. velezensis BvL03 has the potential to be developed as a probiotic candidate against A. hydrophila infection in aquaculture.

Norisoprenoids are produced from carotenoids under oxidative degradation mediated by carotenoid cleavage dioxygenases (CCDs) and contribute to floral and fruity notes in grape berries and wine. The diversity of CCD substrates and products has been demonstrated by in vitro recombinant proteins extracted from Escherichia coli expressing CCD genes and of in vivo proteins in an E. coli system co-expressing genes for carotenoid synthesis and cleavage. In the current study, VvCCD1 and VvCCD4b were isolated from the cDNA library of Vitis vinifera L. cv. Cabernet Sauvignon and then transformed into carotenoid-accumulating recombinant Saccharomyces cerevisiae strains. The expression of the target genes was monitored during the yeast growth period, and the accumulation of carotenoids and norisoprenoids in the recombinant strains was measured. The results indicated that both of the VvCCDs cleaved β-carotene at the 7, 8 (7', 8') position into β-cyclocitral for the first time. Additionally, the two enzymes also degraded β-carotene at the 9, 10 (9', 10') position to generate β-ionone and cleaved lycopene at the 5, 6 (5', 6') position into 6-methyl-5-hepten-2-one. These findings suggested that the VvCCDs may possess more cleavage characteristics under the eukaryotic expression system in S. cerevisiae than the prokaryotic system in E. coli, which could better explain the biochemical functions of VvCCDs in grape berries.

To identify stable quantitative trait loci (QTLs) responsible for sheath blight resistance, a recombinant inbred line mapping population consisting of 219 lines was developed by crossing Lemont and Yangdao 4. Average disease rating, average lesion length, maximum disease rating and maximum lesion length were assayed in six different environments. A total of 128 minor effect QTLs were detected by multiple interval mapping. These QTLs explained less than 11.2% of the phenotypic variations individually, and 106 QTLs were clustered in 20 QTL-rich regions/putative loci. Significant QTL × environment interactions were detected at three putative loci (qSBR11.1, qSBR11.2 and qSBR11.3), indicating that these three loci were not stable. The other 17 stable loci (qSBR1.1, qSBR1.2, qSBR2.1, qSBR2.3, qSBR3.1, qSBR3.2, qSBR3.5, qSBR3.6, qSBR5.1, qSBR7.1, qSBR8.1, qSBR9.1, qSBR9.2, qSBR9.3, qSBR12.1, qSBR12.2 and qSBR12.4) provided a foundation for marker-assisted selection in breeding. Analysis of allelic effect on the 20 putative loci identified 7 highly stable loci, including qSBR3.2, qSBR7.1, qSBR8.1, qSBR9.2, qSBR9.3, qSBR12.1 and qSBR12.2. Keywords: Rice, Sheath blight resistance, Quantitative trait locus, Recombinant inbred line

Retroperitoneal liposarcoma (RLPS) is one of the most common subtypes of retroperitoneal soft tissue sarcomas and lacks effective treatment. This study aimed to provide a thorough profile of immune characteristics of RLPS. This study included 56 RLPS patients. Multisite tumor tissues were collected from 16 patients. Immunohistochemistry was carried out to identify CD4+, CD8+, FoxP3+, CD20+, or programmed cell death‐1 (PD‐1)+ tumor infiltrating lymphocytes (TILs) and Programmed cell death ligand‐1 (PD‐L1) expression in tumor tissues. Ultradeep sequencing of T‐cell receptor (TCR) β‐chain gene was carried out in 42 tumor samples as well as peripheral blood samples collected from 6 patients. In RLPS, TILs were distributed in 3 patterns and T cells were more prevalent than B cells. Generally, the proportion of TILs decreased and PD‐L1 expression increased with tumor progression. Patients with higher PD‐1/PD‐L1 expression tended to have poorer prognosis, whereas patients with tertiary lymphoid structure tended to have a favorable disease‐free survival. Although T‐cell clones in tumors were quite different from those in peripheral blood, TCR sequencing showed low TCR repertoire reads as well as polyclonal status within tumors, which indicated limited T cell response in the tumors. Both TILs distribution and TCR repertoires suggested spatial immune heterogeneity in RLPS. Our research described the immune landscape of RLPS, and suggested RLPS might be a kind of tumor with low T cell infiltration as well as great immune heterogeneity. Therefore, strategies that can facilitate lymphocytic infiltration and immune reactivity need to be developed in the future to improve the efficacy of immunotherapy.

Background: Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies. The incidence of CRC has been rapidly increasing in China. Transferrin receptor 1 (TfR1) is a key regulator of cellular iron homeostasis. Several studies have demonstrated TfR1 overexpression in a variety of human tumors, but the association between TfR1 and CRC remains unclear. Methods: TfR1 expression was evaluated in six CRC cell lines and tumor tissues. A total of 201 CRC patients were included for immunohistochemistry and 19 pairs of frozen tissues were used for real-time PCR. Cell proliferation, cell cycle, cell migration and invasion, and in vivo carcinogenesis were tested after downregulation of TfR1 by lentivirus. Protein microarray and Western blot analyses were used to explore the underlying mechanisms of TfR1 in CRC. Results: TfR1 expression was higher in CRC tissues than in normal tissues (57.2% vs 22.9%, P＜0.001). TfR1 expression was obviously higher in CRC tissues with well differentiation (P＝0.008), no lymph node metastasis (P＝0.002), no distant metastasis (P＝0.006), no vascular invasion (P＜0.001) and early TNM stage (P＝0.013). CRC patients with TfR1-positive expression had a better survival than those with TfR1-negative expression (P＝0.044). Downregulation of TfR1 expression inhibited cell proliferation, promoted cells from G1 phase to S phase and facilitated cell migration and invasion. Knockdown of TfR1 also suppressed tumor growth in BALB/C-nu mice. Protein microarray and Western blot analyses showed that the Janus protein tyrosine kinase/signal transducer and activator of transcription pathway was activated along with downregulation of TfR1 expression. Conclusion: Though TfR1 was overexpressed in colorectal cancer tissues, there was evidence that downregulation of TfR1 could promote cancer progression.

Infected bone defect healing is hindered by infection and compromised bone regenerative capacity. In this study, we designed a dual functional bone‐defect‐filling material with a sequential release system, that is, a burst release of a potent antibacterial agent, hydroxypropyltrimethyl ammonium chloride chitosan (HACC), followed by a controlled release of osteoinductive bone morphogenic protein (BMP2) to repair the infected bone defect. Minimum bactericidal concentration (MBC) of HACC against methicillin‐resistant Staphylococcus aureus was 40 μg/mL. HACC at 40 μg/mL did not affect preosteoblast proliferation and did not influence the BMP2‐induced alkaline phosphatase activity, osteocalcin expression, and matrix mineralization. in vitro release profile revealed burst release of HACC followed by a slow release of BMP2. in vivo bone formation was observed only in the BMP2‐containing groups. HACC did not influence of biomimetic calcium phosphate (BioCaP) resorption and BMP2‐induced bone formation. In conclusion, the optimized HACC/BMP2‐incorporated BioCaP complex showed strong antibacterial effect and robustly enhanced osteoinduction both in vitro and in vivo.

One water-soluble polysaccharide (AAP), with a molecular weight of 6.3 × 104 Da, was isolated from Artemisia annua L. Structrual analysis indicated that AAP was found to be a 1, 3-α-linked and 1, 3, 6-α-linked Glcp backbone, with a branch of 1, 6-α-linked Glcp and terminal 1-linked-L-Rhap along the main chain in a ratio of 1: 1: 1: 1. MTT assay showed that AAP reduced the cell viability of HepG2 cells in a concentration-dependent manner. DAPI staining and Flow cytometric analysis revealed that AAP suppressed cells proliferation, not most at least via inducing p65-dependent mitochondrial signaling pathway, as evidenced by more activation of caspase-3 and -9, down-regulation of Bcl-2 protein, up-regulation of Bax protein and release of cytochrome c from mitochondria into cytosol, as well as suppression of the nuclear factor-κB (NF-κB) p65. These data confirmed AAP inhibits HepG2 cell growth via inducing caspase-dependent mitochondrial apoptosis and inhibition of NF-κB p65.

Tiller angle, controlled by quantitative trait loci (QTL), is crucial for achieving ideal plant architecture in rice, which affects its final yield values. It is important to understand the genetic mechanisms underlying tiller angle when breeding new plant-type varieties. To uncover the genetic regulation mechanisms in cultivated rice, we performed QTL analysis using a recombinant inbred line (RIL) mapping population consisting of 219 lines developed by crossing two rice cultivars, Lemont and Yangdao4. The angle between the side tiller (ST) and the horizontal ground was measured as a tiller angle-related trait in QTL analysis. Twenty-three QTLs responsible for ST-ground angle were detected using multiple interval mapping in four mapping environments. A major QTL, qTA9, was detected on chromosome 9, which explained 12.9, 39.8, 37.9, and 28.3% of the phenotypic variation in the four mapping environments, respectively. Another QTL, qTA8, with a relatively large effect, was detected on chromosome 8. The other 21 QTLs explained

The transfer of misfolded α-Synuclein (α-Syn) from cell to cell as a prion protein is important in α-Synucleinopathies. Extraneous α-Syn induces apoptosis of dopaminergic neurons by causing mitochondrial dysfunction. However, the mechanism by which α-Syn disrupts the mitochondrial function is still unclear. In the present study, we used a gene microarray and western blotting analysis to show that the expression of mitochondrially encoded cytochrome c oxidase subunit 2 (MT-CO2, COXII) increased significantly in SH-SY5Y cells stimulated by α-Syn for 24 h. Furthermore, the decline in ATP levels, the decreased mitochondrial membrane potential, and the enhanced reactive oxygen species in cells treated by α-Syn was reversed by inhibiting MT-CO2 gene expression. Subsequently, we observed that upregulation of MT-CO2 contributed to the release of cytochrome c and altered the levels of certain mitochondria-localized proteins, such as BCL2 family proteins. Therefore, we hypothesized that after being transferred into dopaminergic neurons, α-Syn injures mitochondria via activating MT-CO2. Our results suggested the initial step of the process by which α-Syn injures dopaminergic neurons and provides new therapeutic targets for α-Syn associated neurodegenerative disorders.

We investigated the antifungal susceptibility profiles of 207 independent Candida albicans strains isolated from patients with vulvovaginal candidiasis (VVC) in Xinjiang Province of China. Using CLSI M27-A3 and M27-S4 guidelines, anidulafungin and micafungin were the most active drugs against C. albicans showing an MIC50/MIC90 corresponding to 0.016/0.0313 µg/mL, followed by caspofungin (0.25/0.25 µg/mL), posaconazole (0.125/0.5 µg/mL), ravuconazole (0.063/1 µg/mL), itraconazole (0.125/1 µg/mL), amphotericine B (0.5/1 µg/mL), isavuconazole (0.063/2 µg/mL), 5-flucytosine (1/2 µg/mL), voriconazole (0.125/4 µg/mL), and fluconazole (0.5/4 µg/mL). 96.1% (199)–100.0% (207) isolates were sensitive to the three echinocandins tested, amphotericine B and 5-flucytosine. The in vitro activity of triazoles against all isolates tested was variable; itraconazole and voriconazole had reduced the activity to almost half of the isolates (55.1% (114) and 51.2% (106) susceptible, respectively). Fluconazole was active against 76.3% (158) isolates tested. The new triazoles ravuconazole, isavuconazole and posaconazole showed good in vitro potency against 89.9% (186)–95.2% (197) of isolates with the geometric mean MIC (µg/mL) of 0.10, 0.12 and 0.14 µg/mL, respectively. In conclusion, our study indicates that for effective management of systemic candidiasis in Xinjiang Province of China, it is important to determine the susceptibility profiles of isolated C. albicans from patients with VVC.

Tubiechong (Eupolyphaga sinensis) is an important material used in traditional Chinese medicine (TCM). However, the immunoregulation effects of E. sinensis Lyophilized Powder (ESL) are uncl...

Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2–4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and—in the case of PDAC—the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface—where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth—is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities. In an inducible mouse model of pancreatic ductal adenocarcinoma, the signalling defect that underlies 90% of these tumours causes increased cell-surface expression of syndecan 1, leading to misregulation of macropinocytosis, and linking the defective signalling with nutrient-salvage pathways.

Expression of cytochrome P450s (P450s) is regulated by epigenetic factors, such as DNA methylation, histone modifications, and noncoding RNAs through different mechanisms. Among these factors, long noncoding RNAs (lncRNAs) have been shown to play important roles in the regulation of gene expression; however, little is known about the effects of lncRNAs on the regulation of P450 expression. The aim of this study was to explore the role of lncRNAs in the regulation of P450 expression by using human liver tissues and hepatoma Huh7 cells. Through lncRNA microarray analysis and quantitative polymerase chain reaction in human liver tissues, we found that the lncRNA hepatocyte nuclear factor 1 alpha antisense 1 (HNF1α-AS1), an antisense RNA of HNF1α, is positively correlated with the mRNA expression of CYP2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 as well as pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Gain- and loss-of-function studies in Huh7 cells transfected with small interfering RNAs or overexpression plasmids showed that HNF1α not only regulated the expression of HNF1α-AS1 and P450s, but also regulated the expression of CAR, PXR, and aryl hydrocarbon receptor (AhR). In turn, HNF1α-AS1 regulated the expression of PXR and most P450s without affecting the expression of HNF1α, AhR, and CAR. Moreover, the rifampicin-induced expression of P450s was also affected by HNF1α and HNF1α-AS1. In summary, the results of this study suggested that HNF1α-AS1 is involved in the HNF1α-mediated regulation of P450s in the liver at both basal and drug-induced levels.

Objective We attempt to investigate the biological function of the discoidin, complement C1r/C1s,Uegf, and Bmp1 and Limulus factor C, Coch, and Lgl domain-containing 2 (DCBLD2) in glioblastoma, as well as its effect on the epithelial-mesenchymal transition (EMT) process. Methods The public expression data of glioblastoma samples and normal brain samples from The Cancer Genome Atlas database, Genotype-Tissue Expression database and Chinese Glioma Genome Atlas database were used to analyze the expression of DCBLD2 and its relationship with the survival of patients with glioblastoma. Quantitative real-time PCR and western blot were used to evaluate mRNA and protein levels of DCBLD2. Cell viabilities were tested using Cell Counting Kit-8 and clone formation assays. Cell invasive and migratory abilities were measured by transwell assays. Results DCBLD2 expression was upregulated in glioblastoma and has a significantly positive correlation with the WHO classification. In addition, high expression of DCBLD2 was closely correlated with poor prognosis in primary and recurrent patients with glioblastoma. What is more, we found that knockdown of DCBLD2 notably reduced the cell proliferative, invasive and migratory capacities by elevating the expression of E-cadherin and inhibiting the expression of vimentin, snail, slug and twist. However, overexpression of DCBLD2 presented the opposite results. Conclusion The current study reveals that high expression of DCBLD2 is closely related to poor prognosis in glioblastoma and can significantly enhance the tumor cell viability and metastasis by activating the EMT process, suggesting that DCBLD2 may be a possible biomarker for glioblastoma treatment.

Rice sheath blight (SB) disease is a global issue that causes great yield losses each year. To explore whether SB field resistance can be predicted, 273 rice genotypes were inoculated and evaluated for SB field resistance across nine environments from 2012 to 2019 to identify loci associated with SB resistance by association mapping. A total of 80 significant marker–trait associations were detected in nine environments, among which six loci (D130B, D230A, D304B, D309, D427A, and RM409) were repeatedly detected in at least two environments. A linear regression model for predicting SB lesion length was developed using genotypic data of these six loci and SB field resistance data of the 273 rice genotypes: y = 34.44 – 0.56x, where y is the predicted value of lesion length, and x is the total genotypic value of the six loci. A recombinant inbred line (RIL) population consisting of 219 lines that was grown in six environments (from 2013 to 2018) for evaluation of SB field resistance was used to check the prediction accuracy of the prediction model. The average absolute error between the predicted lesion length and real lesion length for the RIL population was 6.67 cm. The absolute errors between predicted and real lesion lengths were

Aging is the largest risk factor of major human diseases. Long noncoding RNAs (lncRNAs) as the key regulatory elements have shown a strong impact on multiple biological processes as well as human disease mechanisms. However, the roles of lncRNAs in aging/healthy aging processes remain largely unknown. Centenarians are good models for healthy aging studies due to avoiding major chronic diseases and disabilities. To illustrate their ubiquitous nature in the genome and the ‘secrets’ of healthy aging regulation from the perspective of lncRNAs, peripheral blood samples from two regions consisting 76 centenarians (CENs), 54 centenarian-children (F1) and 41 spouses of centenarian-children (F1SP) were collected for deep RNA-seq. We identified 11 CEN-specific lncRNAs that is particularly expressed in longevous individuals. By kmers clustering, hundreds of human lncRNAs show similarities with CEN-specific lncRNAs, especially with ENST00000521663 and ENST00000444998. Using F1SP as normal elder controls (age: 59.9 ± 6.6 years), eight lncRNAs that are differentially expressed in longevous elders (CEN group, age: 102.2 ± 2.4 years) were identified as candidate aging/health aging–related lncRNAs (car-lncs). We found that the expression of eight car-lncs in human diploid fibroblasts displayed dynamic changes during cell passage and/or H2O2/rapamycin treatment; of which, overexpression either of THBS1-IT1 and THBS1-AS1, two lncRNAs that highly expressed in CENs, can remarkably decrease p16, p21 and the activity of senescent related β-galactosidase, suggesting that THBS1-IT1 and THBS1-AS1 can inhibit cellular senescence. We provided the first comprehensive analysis of lncRNA expression in longevous populations, and our results hinted that dysregulated lncRNAs in CENs are potential protective factors in healthy aging process.

The small changes in concentration of unsaturated fatty acids (UFAs) cause a significant influence on the aromatic component of wines. In this work, the effect of UFAs mixture (including linoleic, oleic, and α-linolenic acids) addition on intra-metabolites and aromatic compounds of two Saccharomyces cerevisiae strain EC1118 and BDX were investigated in red wine fermentation, respectively. The results showed that the pre-fermentative addition of UFAs significantly modified the physiological and energetic state of cells, and affected the levels of intra-metabolites in glycolysis pathway and TCA cycle, redox balance, ATP pool, fatty acids, and amino acids metabolism, which consequently altered the chemical and volatile composition of the wines. Different with the control wine, the wines produced by UFAs addition were characterized with higher amounts of glycerol, C6-alcohols and higher alcohols, and lower levels of acetic acid, medium-chain fatty acids, and acetate esters. Interestingly, the production of ethyl esters showed opposite profiles in different strains due to the distinct expression of EEB1, indicating that the effect of UFAs on ethyl esters syntheses is strain-specificity. Our results highlighted the effectiveness of modulating UFAs content in shaping aroma characteristics, and verified that fine adjusting the content of UFAs combined with inoculating proper yeast is a promising strategy to modulate the aromatic quality of wine, which probably provides an alternative approach to meet the expectations of wine consumers for diverse aromatic qualities.

Gene expression profiles of blood can reflect the physiopathologic status of the immune system. The dynamic microRNA (miRNA) expression profiles of peripheral blood from pigs at different developmental stages, and how differential expression of miRNAs might relate to immune system development, are unknown. In this study, peripheral blood samples taken at five developmental stages were used to construct 15 miRNA libraries (three biological replicates/stage): 0 days (newborn), 30 days (weaning), 60 days (weaned), and 180 and 360 days (puberty). We identified 295 known mature miRNAs. Hierarchical clustering of the miRNA expression profile showed significant differences between individuals at the neonatal and postnatal stages. Functional enrichment analysis revealed that miRNAs differentially expressed between pairwise comparisons of the developmental stages were over-represented in immune-related pathways such as toll-like receptor signaling. The time-course of expression of the over-representated miRNAs exhibited a pattern of steady decline over time, for both the complete miRNA compendium and immune-related miRNAs. We identified six marker miRNAs that were highly negatively correlated with chronologic age and enriched for genes involved in immune-related pathways. This study of a peripheral blood miRNA transcriptome offers insight into immune system development in swine and provides a resource for pig genome annotation.