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Yifang Li, Yanzhen Chen, Xing Tian, Shanshan Zhang, Jian Jiao Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, People’s Republic of ChinaCorrespondence: Jian JiaoDepartment of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, People’s Republic of ChinaTel +86 13756009567Fax +86 0431-84995850Email jjian@jlu.edu.cnObjective: Non-alcoholic fatty liver disease (NAFLD), previously thought to predominantly affect obese individuals, has also been shown to occur in subjects who have a relatively normal body mass index (BMI). Due to the normal BMI, non-obese NAFLD are easily to be ignored and eventually lead to potential liver injuries.Methods: A population-based cross-sectional study was conducted on 1608 cases with normal serum alanine aminotransferase (ALT) levels who were divided into an obese group (BMI ≥ 25 kg/m2) and a non-obese group (BMI < 25 kg/m2). NAFLD was diagnosed by ultrasound and Fibro Scan examination. Non-obese populations were divided into NAFLD group (CAP ≥ 240 db/m) and non-NAFLD group (CAP < 240 db/m). The incidence of NAFLD in the obese and non-obese populations and constituent ratios of genders, age, and serum levels of triglycerides (TG), cholesterol (CHOL), and blood glucose were compared. Risk factors of NAFLD in non-obese people were analyzed by multivariate logistics regression.Results: The occurrence of NAFLD was higher in the obese group than in the non-obese group, regardless of gender (P < 0.001). In the non-obese group, the occurrence of NAFLD in female patients was lower than that in male (P=0.001). The occurrence of NAFLD increased with age, with 50– 59 years being the peak age of incidence in both male and female. The peak age of NAFLD occurrence in non-obese male patients was more delayed than that in obese male patients. BMI (OR=1.311, P=0.000) and TG (OR=2.545, P=0.000) were risk factors for NAFLD in the non-obese population.Conclusion: Compared with obese population, the incidence of NAFLD in non-obese population was relatively low and more frequently in male than in female, the peak age of NAFLD occurrence in non-obese male patients was also delayed. BMI and TG should still be controlled to avoid the occurrence of NAFLD although the BMI of such patients is normal.Keywords: obese, non-obese, non-alcoholic liver disease, gender, characteristic

Qi-Xing Tian,1,* Zhi-Hui Zhang,1,* Qing-Lin Ye,1 Shen Xu,1 Qian Hong,1 Wei-Yang Xing,1 Lei Chen,1 De-Xin Yu,1 De-Xiang Xu,2,3 Dong-Dong Xie1 1Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 3Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: De-Xiang XuDepartment of Toxicology, Anhui Medical University, Hefei, 230032, People’s Republic of ChinaTel +86 138 6674 1832Email xudex@126.comDong-Dong XieDepartment of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of ChinaTel +86 138 6670 0010Email xiedd_urology@163.comPurpose: Gram-negative bacteria are usually found in prostate cancer (PCa) tissues. This study aims to investigate the role of lipopolysaccharide (LPS), a glycolipid compound found in the outer membrane of gram-negative bacteria, on the migration and invasion of PCa cells, and to evaluate the protective effect of melatonin.Materials and Methods: DU145, PC-3 and LNCaP cells were incubated with LPS in the presence or absence of melatonin. Wound healing and Transwell assays were used to analyze migration and invasion of PCa cells. RT-PCR and Western blotting were used to assess the mRNA and protein levels, respectively. Co-IP was used to analyze β-catenin ubiquitination.Results: Our results showed that LPS promoted migration and invasion of PCa cells. In addition, LPS stimulated inflammatory reaction and induced epithelial–mesenchymal transition (EMT) in PCa cells by activating several TLR4 downstream pathways. Specifically, LPS promoted NF-κB/IL-6/STAT3 signal transduction. In addition, LPS upregulated phosphorylation levels of cytoplasmic AKTSer473 and GSK-3βSer9. Moreover, LPS induced phosphorylation of GSK-3βSer9 in the “disruption complex”, and then inhibited phosphorylation and ubiquitination of cytoplasmic β-catenin, leading to β-catenin nuclear translocation. Interestingly, melatonin inhibited invasion and migration not only in LPS-stimulated but also in LPS-unstimulated PCa cells. Melatonin suppressed PCa cells migration and invasion by blocking EMT mediated by IL-6/STAT3, AKT/GSK-3β and β-catenin pathways.Conclusion: This study provides evidence that melatonin inhibits migration and invasion through blocking multiple TLR4 downstream EMT-associated pathways both in LPS-stimulated and -unstimulated PCa cells. Our results provide new insights into the role of bacterial infection in PCa metastasis and a potential therapeutic agent.Keywords: β-catenin, EMT, lipopolysaccharide, melatonin, prostate cancer

The motor and sensory systems work collaboratively to fulfill cognitive tasks, such as speech. For example, it has been hypothesized that neural signals generated in the motor system can transfer directly to the sensory system along a neural pathway (termed as motor-to-sensory transformation). Previous studies have demonstrated that the motor-to-sensory transformation is crucial for speech production. However, it is still unclear how neural representation dynamically evolves among distinct neural systems and how such representational transformation depends on task demand and the degrees of motor involvement. Using three speech tasks - overt articulation, silent articulation, and imagined articulation, the present fMRI study systematically investigated the representational formats and their dynamics in the motor-to-sensory transformation. Frontal-parietal-temporal neural pathways were observed in all three speech tasks in univariate analyses. The extent of the motor-to-sensory transformation network differed when the degrees of motor engagement varied among tasks. The representational similarity analysis (RSA) revealed that articulatory and acoustic information was represented in motor and auditory regions, respectively, in all three tasks. Moreover, articulatory information was cross-represented in the somatosensory and auditory regions in overt and silent articulation tasks. These results provided evidence for the dynamics and task-dependent transformation between representational formats in the motor-to-sensory transformation.

Purpose Metadherin (MTDH), as an oncogene, is associated with metastasis and poor prognosis. This study investigated MTDH expressions and development of gastric cancer (GC) cell phenotypes and the contribution of MTDH to epithelial-mesenchymal transition (EMT). Patients and methods MTDH expression was assayed in human GC cell lines and tumor tissue from 92 GC patients. Functional experiments were performed to characterize MTDH activity. Expressions of EMT-related proteins (vimentin and E-cadherin), phosphorylated β-catenin and β-catenin were assayed by immunohistochemistry, Western blotting, immunofluorescence, and co-immunoprecipitation, respectively. Results MTDH expressions were higher in GC tissue than that in gastric mucosa from the same patient. MTDH overexpression was correlated with metastasis and enhanced malignant GC phenotypes, i.e., proliferation, migration, invasiveness, and chemoresistance. MTDH overexpression was associated with expressions of vimentin, E-cadherin and cancer stem-cell biomarkers including CD44, CD133, and Oct4. MTDH complexed with β-catenin and decreased phosphorylated β-catenin levels to facilitate β-catenin translocation into the nucleus and expressions of downstream genes. Conclusion MTDH overexpression in GC cells is associated with EMT and development of cancer stem cell malignant phenotypes and affects the subcellular translocation of β-catenin. The results warrant investigation of the prognostic value of MTDH in GC and as a therapeutic target.

Background Anorectal melanoma (AM) is an extremely rare malignant tumor originating from anorectal melanocytes with a poor prognosis. AM has been reported to have a much lower incidence than cutaneous or choroid melanoma, accounting for 0.4%-1.6% of all melanomas. Case summary We report a 76-year-old female patient diagnosed with anorectal malignant melanoma by colonoscopy and biopsy. Intraoperative examination revealed two distinct anorectal tumors, one melanotic and another amelanotic, as well as two pigmented mucosal zones at the dentate line level. Abdominal perineal resection was performed. A pathological report confirmed all four lesions to be melanomas. Postoperatively, we followed an immunotherapy protocol targeting PD-1 (nivolumab). The patient had 24 mo of disease-free follow-up upon completion of nivolumab treatment. Conclusion This is the first reported case presenting coexistence of pigmented and unpigmented AMs in the same patient.

Genetic variability has significant impacts on biological characteristics and pathogenicity of hepatitis B virus (HBV), in which the N-terminal sequence of the presurface 1 (preS1) region of HBV large surface protein (LHBs) displays genotype (GT) dependent genetic heterogeneity. However, the influence of this heterogeneity on its biological roles is largely unknown. By analyzing 6560 full-length genome sequences of GTA-GTH downloaded from HBVdb database, the preS1 N-terminal sequences were divided into four representative types, namely C-type (representative of GTA, GTB, and GTC), H-type (GTF and GTH), E-type (GTE and GTG), and D-type (GTD), respectively. We artificially substituted the preS1 N-termini of GTC and GTD plasmids or viral strains with each sequence of the four representative types. The roles of preS1 N-terminus on HBV replication, secretion and infectivity were investigated using HepG2 or HepG2-NTCP cells. In the transfection experiments, the results showed that the extracellular HBsAg levels and HBsAg secretion coefficients in D- and E-type strains were significantly higher than those in C- and H-type strains. D-type strain produced more extracellular HBV DNA than C-type strain. We further observed that D-, H-, and E-type strains increased the levels of intracellular replicative HBV DNAs, comparing with C-type strain. In the infection experiments, the levels of extracellular HBeAg, intracellular HBV total RNA and pgRNA/preC mRNA in D- and E-type strains were markedly higher than C and H-type ones. Our data suggest that the preS1 N-termini affect HBV replication, secretion and infectivity in a genotype dependent manner. The C- and H-type strains prefer to attenuate HBsAg secretion, while the strains of D- and E-type promoted infectivity. The existence and function of the intergenotypic shift of preS1 in naturally occurring recombination requires further investigation, as the data we acquired are mostly related to recombinant preS1 region between N-terminus of preS1 from genotypes A-H and the remaining preS1 portion of GTC or GTD.

Areca nut and Fuzhuan brick tea, a type of natural plant products, have obvious effects of fat reduction and weight loss; however, there is no report on their synergistic effect. This study investigated the effects of Fuzhuan brick tea supplemented with different concentrations of areca nut (5% (LAF), 10% (MAF), and 20% (HAF)) on serum and gut microbiota in Kunming (KM) mice. The results showed that Fuzhuan brick tea supplemented with areca nuts (AFTs) could reduce weight, prevent the accumulation of fat, inhibit the increase in the levels of serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, blood glucose, free fatty acid, insulin, and total bile acid, alleviate the decrease in high-density lipoprotein cholesterol level, and regulate the composition of gut microbiota by high-fat diet intervention. The HAF group with 20% areca nut content showed the best effect. These results could provide a novel approach to prevent obesity and hyperlipidemia. PRACTICAL APPLICATIONS: Consumption of areca nut and tea is widespread in Asia and other regions. As a controversial raw material, the damage due to areca nut to oral mucosa health has often aroused public concern and heated discussion; however, its medicinal value has been confirmed in terms of its pharmacological effects in various aspects. Fuzhuan brick tea, a type of traditional postfermented dark tea, has been confirmed to exert effects of antiobesity. Therefore, the areca nut and Fuzhuan brick tea, as a type of natural plant products, have obvious effects of fat reduction and weight loss; however, their synergistic effect has not been reported. To our knowledge, this study is the first to explore the effects of the Fuzhuan brick tea supplemented with areca nuts (AFTs) on serum and gut microbiota in mice. On the premise of exerting their beneficial effects (especially in terms of easing food stagnation and eliminating indigestion) and reducing their toxic and side effects, the effects of AFTs on health were further clarified, which could provide a novel direction for the development and utilization of areca nut. Moreover, our research would increase public understanding of areca nut and provide guidance to the Fuzhuan brick tea processing industry.

Clinical trials have reported that a four-oil intravenous lipid emulsion (SMOFlipid) play a positive role in immune function, but showed inconsistent outcomes compared to other lipid emulsions. A systematic review and meta-analysis was conducted to evaluate the effect of SMOFlipid on liver function, triglycerides (TG), inflammatory markers, and clinical outcomes in hospitalized adults after short-term use compared to others. A search of the PubMed, Medline, Embase, China National Knowledge Infrastructure, and Wanfang databases was performed to identify the included randomized controlled trials. Trials with adults who were administrated a short-term course of SMOFlipid were included. A meta-analysis on liver function markers, TG, inflammatory markers, and clinical outcomes was conducted. A total of 18 randomized controlled trials with 1188 patients were included. Compared to other lipid emulsions, SMOFlipid was associated with a significant reduction in ALT, AST, γ-glutamyltransferase, total bilirubin, TG, C-reactive protein and length of hospital stay. No effect on serum interleukin-6 levels or adverse events were observed. For adult patients, our meta-analysis indicated that SMOFlipid may be beneficial to the liver and prone to prevent hyperlipidemia. The SMOFlipid also shortened length of hospital stay.

Coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) may result in severe liver disease and frequent progression to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests that HBV replication is suppressed by replicating HCV and often rebounds after treatment with drugs against HCV. Thus, a highly efficient cell culture system permissive for HBV/HCV would facilitate investigation on the interaction and pathogenesis after coinfection. Here we reported a robust HBV/HCV coinfection cell culture model by overexpressing human sodium-taurocholate cotransporting polypeptide (NTCP), CD81 and Mir122 into HepG2 cells and investigated interactions between HBV and HCV. In this system, HepG2-NTCP/CD81/Mir122 cells not only supported robust infection and replication of HBV and HCV, but also allowed HBV/HCV coinfection in the single cell level. Our result showed cells with replicating HBV still supported HCV infection. However, HBV replication was suppressed by HCV through the inhibition of HBV core promoter and S promoter II activity, and this inhibition was attenuated by the interferon alpha (IFNα) treatment, suggesting HCV influence on HBV at transcriptional level. Coinfection of HBV/HCV in this system did not block IFN stimulated genes expression. Inhibition of HCV by direct-acting antiviral drugs restored HBV replication and expression of viral genes. Conclusions: HepG2-NTCP/CD81/Mir122 fully supports HBV/HCV coinfection, replication and interaction. This novel cell model offers a platform to advance our understanding of the molecular details of the interaction, pathogenesis and outcomes of HBV/HCV coinfection.

Turkish galls (TG) is a traditional Uygur medicine typically used in clinics for dental disease and chronic ulcerative colitis. In this study, a novel liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of gallic acid, methyl gallate, and 1,3,6-tri-O-galloyl-β-d-glucose in rat plasma, which are the major bioactive compounds of TG. After a feasible protein precipitation using acetonitrile for sample preparation, chromatographic separation was performed with a BDS Hypersil C18 column (2.1 × 100 mm, 5 μm) at 30°C, and water containing 10 mmol of ammonium acetate and acetonitrile was used as the mobile phase with a flow rate of 0.3 mL/min. The MS detector was operated in the selective reaction monitoring with negative-ionization mode. The results of the method validation, including selectivity, linearity, accuracy, precision, extraction recovery, matrix effect, and stability of the compounds in the biosamples, were all within the current acceptance criteria. The established method was successfully applied to the pharmacokinetics study of three analytes in rats after an oral administration of TG extract and laid the foundation for studying the active components and mechanism of TG in vivo.

Chewing of areca nuts is quite popular in various regions worldwide. Previous studies have demonstrated the pharmacological and toxicological effects of fresh areca nuts. However, processed areca nuts, which are popular in the Hunan province of China, have not been extensively studied for its biological effect. This study aimed at investigating the impact of the acrea nut extracts (ANE) prepared from the raw material, the semi-product, and the final product on the immune system and inflammation-related markers in the Kunming mice. The mice were assigned to seven different groups and administered different ANE at two concentrations (1X and 5X) for four weeks. Total body weight gain and organ coefficient of the liver, spleen, and kidney, as well as the immune system and inflammation-related markers were evaluated. The results revealed that processed areca nuts have a much milder effect on the mice immune system and some inflammatory markers than fresh areca nut in the Kunming mice. PRACTICAL APPLICATIONS: Chewing various forms of areca nuts is popular in China, Southeast Asia, and other regions. People from Hunan, China prefer to chew a processed areca nut, which has rarely been studied. This manuscript explores the effects of three kinds of areca nut extracts on the immune system- and inflammation-related indicators in Kunming mice. The obtained results revealed that processed areca nuts had significantly milder effects than the raw nut/nut extract, particularly on the body weight, immune responses, and inflammatory markers. The results of the present study provide some new directions for the areca nut industry and raise public awareness for the undesirable effects of areca nuts.

The protective effect of Schisandra chinensis water extract (SWE) on ethanol-induced neurotoxicity in Caenorhabditis elegans and the underlying mechanism were investigated. Young worms were exposed to ethanol or a mixture of ethanol and SWE for 24 hr. Locomotion ability, tissue ethanol concentration, free radical content, antioxidant enzyme activity, lifespan, and expression of key dopaminergic nervous system-related genes were evaluated. Ethanol affected the motion ability of worms and shortened their lifespan. Ethanol intake increased the tissue ethanol concentration, resulting in redox imbalance, and dopamine release and accumulation. SWE alleviated motility loss of C. elegans and extended their lifespan. It reduced the tissue ethanol concentration and free radical content, likely because it alleviated oxidative stress. Finally, SWE inhibited continuous dopamine excitement. These results suggest that SWE plays a protective role in dopaminergic neurons. It can be used to treat ethanol-induced neurotoxicity, and to investigate its potential mechanism. PRACTICAL APPLICATIONS: Schisandra chinensis is a traditional functional food that has protective effects on the liver and brain. Although S. chinensis is found in some anti-alcohol products, the effects of S. chinensis on neurological and behavioral disorders caused by alcohol are rarely reported. The manuscript explored the protective effect of SWE on ethanol-induced nerve injury in Caenorhabditis elegans, and we preliminarily discussed the underlying mechanism. The results suggested that SWE can alleviate ethanol-induced neurotoxicity. Meanwhile, the results provide a theoretical basis for better use of S. chinensis to develop products to antagonize the side effects of alcohol. In addition, the method of using C. elegans model to evaluate the protective effect of S. chinensis on ethanol-induced nerve injury can provide practical reference for the screening and utilization of other plant functional components.

Gallic acid (GA), a plant phenol found in fruits and vegetables, has been recently reported to attenuate ulcerative colitis (UC). However, the mechanism of GA in UC remains unknown. In this study, we investigated the therapeutic effects of GA on UC from the perspective of gut microbiota and supervised the metabolic alterations in vivo with 1H NMR-based metabolomics, which can provide a holistic view to understand the functions of GA in UC. Rats with dextra sulfate sodium (DSS)-induced colitis were rectally administrated with GA (6 mg kg-1) for 8 consecutive days. 16S gene sequencing was performed on feces samples to obtain bacterial community information. Urine and feces samples were analyzed with 1H NMR spectroscopy, and short chain fatty acids (SCFAs) in feces and colon contents were detected with gas chromatography. Our results showed that UC syndromes in the GA group were significantly attenuated. The microbial alterations in the DSS group were characterized by a decrease of probiotic bacteria, such as Lactobacillaceae and Prevotellaceae, and an increase of some pathogenic species, mainly in the Firmicutes and Proteobacteria phyla. GA treatment could modulate the microbiota composition towards a similar proportion to the control group. Metabolic data further revealed that the GA-induced metabolic changes focus on increasing carbohydrate metabolism (gluco-related metabolism) and bile acid (BA) metabolism and decreasing amino acid metabolism, which also provides evidence for alteration of the microbiota because these feces metabolites are by-products of interactions between the host and the microbiota. These findings demonstrate GA-induced alterations in metabolic and bacterial profiles in DSS-colitis, providing new insight into the attenuation of GA in UC.

Muscarinic acetylcholine receptor (mAChR) regulates many neurophysiological functions in insects. In this report, a full-length cDNA encoding an A-type mAChR was cloned from the oriental armyworm, Mythimna separata. Pharmacological properties studies revealed that nanomolar to micromolar concentrations of carbachol or muscarine induced an increase of intracellular Ca2+ concentration ([Ca2+] i ), with the EC50 values of 124.6 and 388.1 nM, respectively. The increases of [Ca2+] i can be greatly blocked by the antagonist atropine, with an IC50 value of 0.09 nM. The receptor mRNA is expressed in all developmental stages, with great differential expression between male and female adults. The tissue expression analysis identified novel target tissues for this receptor, including ovaries and Malpighian tubules. The distribution of Ms A-type mAChR protein in the male brain may suggest the neurophysiological roles that are mediated by this receptor. However, the receptor protein was found to be distributed on the membranes of oocytes that are not innervated by neurons at all. These results indicate that Ms A-type mAChR selectively mediates intracellular Ca2+ mobilization. And the high level of receptor protein in the membrane of oocytes may indicate a possible non-neuronal role of A-type mAChR in the reproductive system of M. separata.

Long-stamen chive (Allium macrostemon Bunge; AMB), which is prevalent in the Wuling Mountain area of China, is a characteristic food of the nation. In the study, we evaluated the as-yet-unknown nutritional value and antioxidant activity of fresh AMB. The free amino acid content, volatile components, and free radical-scavenging capacity of isolated organic sulfides were analyzed to evaluate the qualitative and physiological properties of fresh AMB. The plant was found to be rich in free essential amino acids and contain multiple flavor-imparting amino acids. The organic sulfides showed an apparent free radical-scavenging activity in vitro. Furthermore, these sulfides alleviated oxidative stress in Caenorhabditis elegans. Notably, the organic sulfides isolated from AMB enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase; improved motility; and extended the lifespan in oxidative stress-affected nematodes. In conclusion, our study indicates that AMB is a nutritious vegetable with potential to be developed as a functional food. PRACTICAL APPLICATIONS: Long-stamen chive is a wild edible vegetable belonging to the genus Allium (A. macrostemon Bunge; AMB). However, its quality and physiological properties have not been comprehensively investigated. Herein, we analyzed the free amino acid content, composition of volatile compounds, and potential antioxidative properties of AMB. Our results indicated that AMB is rich in essential amino acids, making it a highly nutritious food. Further analysis indicated that AMB contains a high proportion of organic sulfides, which have been previously been shown to have antioxidative properties. Together, our findings indicate that AMB contains important bioactive components and can be developed as a functional food or health supplement. Furthermore, our findings will enhance public awareness regarding this wild resource and provide new directions for the research and development of natural products derived from it.

Stocking density is one of the major factors affecting production and welfare of fish in aquaculture. This study investigated the effect of different stocking densities on growth, feed efficiency, blood biochemistry, histometric response, muscular composition, and flesh quality of channel catfish Ictalurus punctatus. Fish were cultured at low, medium, and high stocking density of 50, 150, and 300 fish m−3, respectively, for 60 days in the recirculating aquaculture system. Fish growth and feed efficiency significantly decreased with increasing stocking density. Serum concentrations of glucose, triglyceride, and total cholesterol, as well as the activities of both aspartate aminotransferase and alanine aminotransferase, significantly elevated as stocking density increased. High stocking density led to the decline in serum levels of thyroid hormones. The villi length and its number, as well as the size of goblet cells in the intestine, were negatively affected by high stocking density. There was a significant density-dependent decrease in muscular fat content, diameter of dorsal muscle fiber, intensity of muscular bundles, and percentage of muscular bundles area in dorsal muscle. However, the percentage of the intramuscular connective tissue showed a significant increase in fish reared at high stocking density. Fish stocked in high density exhibited the decrease in muscle pH, drip loss, and frozen leakage rate. Overall, the increased stocking density could cause the unfavorable impacts on growth, feed efficiency, histological change, and flesh quality of I. punctatus.

The way top-down and bottom-up processes interact to shape our perception and behaviour is a fundamental question and remains highly controversial. How early in a processing stream do such interactions occur, and what factors govern such interactions? The degree of abstractness of a perceptual attribute (for example, orientation versus shape in vision, or loudness versus sound identity in hearing) may determine the locus of neural processing and interaction between bottom-up and internal information. Using an imagery-perception repetition paradigm, we find that imagined speech affects subsequent auditory perception, even for a low-level attribute such as loudness. This effect is observed in early auditory responses in magnetoencephalography and electroencephalography that correlate with behavioural loudness ratings. The results suggest that the internal reconstruction of neural representations without external stimulation is flexibly regulated by task demands, and that such top-down processes can interact with bottom-up information at an early perceptual stage to modulate perception.

Parsing continuous acoustic streams into perceptual units is fundamental to auditory perception. Previous studies have uncovered a cortical entrainment mechanism in the delta and theta bands (~1-8 Hz) that correlates with formation of perceptual units in speech, music, and other quasi-rhythmic stimuli. Whether cortical oscillations in the delta-theta bands are passively entrained by regular acoustic patterns or play an active role in parsing the acoustic stream is debated. Here we investigate cortical oscillations using novel stimuli with 1/f modulation spectra. These 1/f signals have no rhythmic structure but contain information over many timescales because of their broadband modulation characteristics. We chose 1/f modulation spectra with varying exponents of f, which simulate the dynamics of environmental noise, speech, vocalizations, and music. While undergoing magnetoencephalography (MEG) recording, participants listened to 1/f stimuli and detected embedded target tones. Tone detection performance varied across stimuli of different exponents and can be explained by local signal to noise ratio computed using a temporal window around 200 ms. Furthermore, theta band oscillations, surprisingly, were observed for all stimuli, but robust phase coherence was preferentially displayed by stimuli with exponents 1 and 1.5. We constructed an auditory processing model to quantify acoustic information on various timescales and correlated the model outputs with the neural results. We show that cortical oscillations reflect a chunking of segments, >200 ms. These results suggest an active auditory segmentation mechanism, complementary to entrainment, operating on a timescale of ~200 ms to organize acoustic information. This article is protected by copyright. All rights reserved.

AIM To investigate the protective effects of Foeniculum vulgare root bark (FVRB), a traditional Uyghur medicine, against carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. METHODS Mice were randomly divided into eight groups (n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected (i.p.) with 0.1% CCl4-olive oil mixture at 10 mL/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB (88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), hexadecenoic acid (HA), laminin (LN), glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in liver tissues were measured. Hematoxylin-eosin (H and E) staining and Masson trichrome (MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor β1 (TGF-β1), matrix metalloprotein 9 (MMP-9) and metallopeptidase inhibitor 1 (TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-β1 and alpha-smooth muscle actin (α-SMA) protein expression was measured by Western blot. RESULTS A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-β1, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl4-induced liver injury were confirmed by histopathological studies. Protein expression of TGF-β1 and α-SMA detected by Western blot was decreased by FVRB treatment. CONCLUSION Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice.

Traditional dry-cured pork, a meat product with a unique flavor and good chewability, occupies an important place in the Chinese market. However, the salt content of dry-cured pork is on the high side and long-term consumption of high-salt meat products is not good for human health. This study determined the role of salt in volatile organic substances and non-volatile taste components of dry-cured pork. Dry-cured pork samples with different salt content (0%, 1%, 3%, 5%, and 7%) were analyzed by electronic tongue for moisture content, pH, salt (NaCl) value, taste activity value, free amino acids, and taste components and by headspace-gas chromatography-ion mobility spectrometry for volatile organic components. The results showed that the moisture content of the tested samples decreased while the salt content increased. The highest amounts of free amino acids were found in dry-cured pork with 3% salt content (P

Increasing evidence suggests that infection promotes the initiation and progression of prostate cancer. This study investigated the effects of lipopolysaccharide (LPS), a major component of Gram-negative bacilli, on proliferation, migration and invasion of prostate cancer cells and the protective effects of 1α,25(OH)2D3 (calcitriol). PC-3 and DU145 cells were stimulated with LPS (2.0 μg/mL) in the presence or absence of 1α,25(OH)2D3 (100 nM). Our results shown that 1α,25(OH)2D3 reduced the proportion of S phase cells in LPS-stimulated PC-3 and DU145 cells, and down-regulated the nuclear protein levels of Cyclin D1 and PCNA in LPS-stimulated PC-3 cells. In addition, 1α,25(OH)2D3 inhibited migration and invasion, as determined by wound healing and transwell assay, in LPS-stimulated PC-3 and DU145 cells. Of interest, we observed that 1α,25(OH)2D3 inhibits NF-κB activation and subsequent synthesis and secretion of IL-6 and IL-8 by promoting VDR and NF-κB p65 interaction. Surprisingly, 1α,25(OH)2D3 blocks nuclear translocation of pSTAT3 by promoting physical interaction between VDR and pSTAT3 (Tyr705) in LPS-stimulated PC-3 and DU145 cells. These results suggest that 1α,25(OH)2D3 inhibits LPS-induced proliferation, migration and invasion in prostate cancer cells by directly and indirectly blocking STAT3 signal transduction.

Ancient Chinese poetry is constituted by structured language that deviates from ordinary language usage [1, 2]; its poetic genres impose unique combinatory constraints on linguistic elements [3]. How does the constrained poetic structure facilitate speech segmentation when common linguistic [4-8] and statistical cues [5, 9] are unreliable to listeners in poems? We generated artificial Jueju, which arguably has the most constrained structure in ancient Chinese poetry, and presented each poem twice as an isochronous sequence of syllables to native Mandarin speakers while conducting magnetoencephalography (MEG) recording. We found that listeners deployed their prior knowledge of Jueju to build the line structure and to establish the conceptual flow of Jueju. Unprecedentedly, we found a phase precession phenomenon indicating predictive processes of speech segmentation-the neural phase advanced faster after listeners acquired knowledge of incoming speech. The statistical co-occurrence of monosyllabic words in Jueju negatively correlated with speech segmentation, which provides an alternative perspective on how statistical cues facilitate speech segmentation. Our findings suggest that constrained poetic structures serve as a temporal map for listeners to group speech contents and to predict incoming speech signals. Listeners can parse speech streams by using not only grammatical and statistical cues but also their prior knowledge of the form of language. VIDEO ABSTRACT.

Cognitive models postulate that impaired source monitoring incorrectly weights the top-down prediction and bottom-up sensory processes and causes hallucinations. However, the underlying mechanisms of the interaction, such as whether the incorrectly weighting is ubiquitously on all levels of sensory features and whether different top-down processes have distinct effects in subgroups of schizophrenia are still unclear. This study investigates how multi-scale predictions influence perception of basic tonal features in schizophrenia. Sixty-three schizophrenia patients with and without symptoms of auditory verbal hallucinations (AVHs), and thirty healthy controls identified target tones in noise at the end of tone sequences. Predictions of different timescales were manipulated by either an alternating pattern in the preceding tone sequences (long-term regularity) or a repetition between the target tone and the tone immediately before (short-term repetition). The sensitivity index, d prime (d'), was obtained to assess the modulation of predictions on tone identification. Patients with AVHs showed higher d' when the target tones conformed to the long-term regularity of alternating pattern in the preceding tone sequence than when the target tones were inconsistent with the pattern. Whereas, the short-term repetition modulated the tone identification in patients without AVHs. Predictions did not influence tone identification in healthy controls. Our results suggest that impaired source monitoring in schizophrenia patients with AVHs heavily weights top-down predictions over bottom-up perceptual processes to form incorrect perception. The weighting function in source monitoring can extend to the processes of basic tonal features, and predictions at multiple timescales could differentially modulate perception in different clinical populations. The impaired interaction between top-down and bottom-up processes might underlie the development of hallucination symptoms in schizophrenia.

Previous studies have shown that the oncogene SEI1 is highly expressed in ovarian carcinomas, and promoting genomic instability. However, the molecular mechanism of SEI1 in promoting genomic instability remains unclear. We observed SEI1 overexpression in 30 of 46 cases of ovarian cancer compared to non-tumor tissues and the overexpression of SEI1 was positively associated with the tumor FIGO stage. Our functional studies revealed that overexpression of SEI1 could induce genomic instability and increased DNA strand breaks. In contrast, SEI1 co-localized with γH2AX and phosphorylated ATM and DNAPKcs in the nucleus. Furthermore, we found that overexpression of SEI1 induced translocation of the SEI1 protein from the cytoplasm to the nucleus; ATM and DNAPKcs were associated with the cytoplasm-to-nucleus translocation of SEI1. To further prove the correlation between the DNA damage response (DDR) and SEI1, we knocked down SEI1 expression in SEI1-transfected ovarian cancer cell lines. The expression of DDR proteins was significantly downregulated, and the number of micronuclei was significantly decreased. Together, these results define a new mechanism of SEI1 in the regulation of genomic stability and in the malignant progression of ovarian cancer.

Ethnopharmacological relevance Citrullus lanatus ssp. vulgaris var. megalaspermus Lin et Chao, was also known as watermelon belongs to family Cucurbitaceae, variously used as healthy food and in the treatment of liver and lungs problems. Currently, Citrullus lanatus has become a major economic crop of medicinal and edible effects with regional characteristics. Aim This study was designed to evaluate the hepatoprotective and antioxidant activity of the seed melon ( Citrullus lanatus ssp. vulgaris var. megalaspermus Lin et Chao) extract (SME) against carbon tetrachloride (CCl 4 ) induced hepatic fibrosis in mice. Materials and methods In this study, mice were randomly divided into 7 groups, including normal control, model, silymarin tablets as the positive control, SME 100, 200, 400, and 800 mg/kg. After 8 weeks, activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), hyaluronic acid (HA) and laminin (LN) were checked. The levels of antioxidant enzymes such as superoxide dismutase (SOD), glutataion (GSH) and glutathione peroxidase (GSH-Px) were determined after SME administration. The hydroxyproline (HYP) levels, malondialdehyde (MDA) levels and histopathologic examinations of hepatocyte fibrosis were also determined. Additionally, effects of SME on alpha-smooth muscle actin ( α -SMA) and transforming growth factor beta-1(TGF- β 1) protein expressions were determined. Results We found that SME could significantly lower the serum levels of hepatic enzyme markers AST, ALT, HA and LN ( P 0.01). Compared with the CCl 4 -only treatment group, levels of hepatic SOD and GSH-Px were significantly increased, and the MDA levels were remarkably decreased in mice treated by SME at medium dose (400 mg/kg) and high dose (800 mg/kg) ( P 0.01). A histological examination of the liver showed that lesions, including necrosis, lymphocyte infiltration and fatty degeneration, were partially healed by treatment with SME. The results of protein expressions studies displayed that SME could inhibit α -SMA and TGF- β 1 protein expression (P 0.01). Conclusion The present results suggested that protective effect of SME against CCl 4 -induced hepatic fibrosis may rely on its effect on reducing oxidative stress and improving drug metabolizing enzyme activity in liver.

Objectives: Compound MQA (1,5-O-dicaffeoyl-3-O-[4-malic acid methyl ester]-quinic acid) is a natural caffeoylquinic acid derivative isolated from Arctium lappa L. roots. This study aims to explore the neuroprotective effects of MQA against hydrogen peroxide (H2O2)-induced oxidative stress in SH-SY5Y neuroblastoma cells.Methods: The SH-SY5Y cells were divided into four groups, including control, 20 μM MQA, 200 μM H2O2, 200 μM H2O2 + 20 μM MQA groups. The effects of MQA on H2O2-induced cell death were measured by MTT and LDH assays. Hoechst 33342 and Annexin V-PI double staining were used to observed H2O2-induced apoptosis. Also, the effects of MQA on antioxidant system and mitochondrial pathway were explored. Further, steady-state phosphorylation levels of ERK1/2, Akt and GSK-3β were examined by Western blot analysis.Results: Pretreatment with MQA prevented cell death in SH-SY5Y cells exposed to 200 μM H2O2 for 3 h. Meanwhile, Hoechst 33342 and Annexin V-PI double staining showed that MQA attenuated H2O2-i...

Objective Neurodegenerative diseases, such as ischemia, traumatic injury, Alzheimer's disease, and Parkinson's disease are characterized by neuronal loss and dysfunction. It is known that glutamate-induced toxicity plays an important role in neurodegenerative diseases. Glutamate toxicity seems to be mediated by excessive influx of Ca2+ into neuronal cells through activation of N-methyl-D-aspartate (NMDA) receptor. To search for potential NMDA receptor inhibitors in traditional Chinese medicine. Methods A series of computer methods including drug-likeness evaluation, ADMET tests as well as molecular docking have been used. Results 1,5-O-dicaffeoyl-quinic acid was identified as NMDA receptor inhibitor by virtual screening. Its neuroprotective activity was further confirmed by in vitro test. 1,5-O-dicaffeoyl-quinic acid showed strong neuroprotection against NMDA-induced cell injury. Conclusion 1,5-O-Dicaffeoylquinic acid may be regarded as a potential NMDA receptor inhibitor for the prevention and treatment of neurodegenerative disorders.

To flexibly convey meaning, the human language faculty iteratively combines smaller units such as words into larger structures such as phrases based on grammatical principles. During comprehension, however, it remains unclear how the brain encodes the relationship between words and combines them into phrases. One hypothesis is that internal grammatical principles governing language generation are also used to parse the hierarchical syntactic structure of spoken language during comprehension. An alternative hypothesis suggests, in contrast, that decoding language during comprehension solely relies on statistical relationships between words or strings of words, i.e., the N-gram statistics, while grammatical rules are not used and no hierarchical linguistic structures are constructed. Here, we briefly review distinctions between rule-based hierarchical models and statistics-based linear string models for comprehension, and how the neurolinguistic approach can shed light on this debate. Recent neurolinguistic studies show that tracking of probabilistic relationships between words is not sufficient to explain cortical encoding of linguistic constituent structure and support the involvement of rule-based processing during language comprehension.

// Yantao Bao 1, * , Jia Liu 1, * , Jia You 1 , Di Wu 1 , Yang Yu 1, 2 , Chang Liu 1 , Lei Wang 1, 3 , Fei Wang 1 , Lu Xu 1 , Liqun Wang 1 , Nan Wang 1 , Xing Tian 1 , Falin Wang 1 , Hongbin Liang 1 , Yating Gao 1 , Xiaobo Cui 1 , Guohua Ji 1 , Jing Bai 1 , Jingcui Yu 4 , Xiangning Meng 1 , Yan Jin 1 , Wenjing Sun 1 , Xin-yuan Guan 5, 6 , Chunyu Zhang 1 , Songbin Fu 1, 7 1 Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 2 Department of Genetics and Eugenics, Maternity and Child Care Center of Qinghuangdao, Qinghuangdao, China 3 Genetic Diagnosis Center, First People's Hospital of Yunnan Province, Yunnan, China 4 Scientific Research Centre, Second Affiliated Hospital, Harbin Medical University, Harbin, China 5 Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China 6 State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China 7 Key Laboratory of Medical Genetics, Harbin Medical University, Heilongjiang Higher Education Institutions, Harbin, China * These authors contributed equally to this work Correspondence to: Songbin Fu, email: fusb@ems.hrbmu.edu.cn Chunyu Zhang, email: zhangcy@ems.hrbmu.edu.cn Keywords: Sei-1, in vivo passage, DMs, amplification, met Received: March 30, 2016 Accepted: July 19, 2016 Published: August 01, 2016 ABSTRACT Background: Sei-1 is an oncogene capable of inducing double minute chromosomes (DMs) formation. DMs are hallmarks of amplification and contribute to oncogenesis. However, the mechanism of Sei-1 inducing DMs formation remains unelucidated. Results: DMs formation significantly increased during serial passage in vivo and gradually decreased following culture in vitro . micro nuclei (MN) was found to be responsible for the reduction. Of the DMs-carrying genes, Met was found to be markedly amplified, overexpressed and highly correlated with DMs formation. Inhibition of Met signaling decreased the number of DMs and reduced the amplification of the DMs-carrying genes. We identified a 3.57Mb DMs representing the majority population, which consists of the 1.21 Mb AMP1 from locus 6qA2 and the 2.36 Mb AMP2 from locus 6qA2-3. Materials and Methods: We employed NIH-3T3 cell line with Sei-1 overexpression to monitor and characterize DMs in vivo and in vitro . Array comparative genome hybridization (aCGH) and fluorescence in situ hybridization (FISH) were performed to reveal amplification regions and DMs-carrying genes. Metaphase spread was prepared to count the DMs. Western blot and Met inhibition rescue experiments were performed to examine for involvement of altered Met signaling in Sei-1 induced DMs. Genomic walking and PCR were adopted to reveal DMs structure. Conclusions: Met is an important promotor of DMs formation.

What enables the mental activities of thinking verbally or humming in our mind? We hypothesized that the interaction between motor and sensory systems induces speech and melodic mental representations, and this motor-to-sensory transformation forms the neural basis that enables our verbal thinking and covert singing. Analogous with the neural entrainment to auditory stimuli, participants imagined singing lyrics of well-known songs rhythmically while their neural electromagnetic signals were recorded using magnetoencephalography (MEG). We found that when participants imagined singing the same song in similar durations across trials, the delta frequency band (1–3 Hz, similar to the rhythm of the songs) showed more consistent phase coherence across trials. This neural phase tracking of imagined singing was observed in a frontal-parietal-temporal network: the proposed motor-to-sensory transformation pathway, including the inferior frontal gyrus (IFG), insula (INS), premotor area, intra-parietal sulcus (IPS), temporal-parietal junction (TPJ), primary auditory cortex (Heschl’s gyrus [HG]), and superior temporal gyrus (STG) and sulcus (STS). These results suggest that neural responses can entrain the rhythm of mental activity. Moreover, the theta-band (4–8 Hz) phase coherence was localized in the auditory cortices. The mu (9–12 Hz) and beta (17–20 Hz) bands were observed in the right-lateralized sensorimotor systems that were consistent with the singing context. The gamma band was broadly manifested in the observed network. The coherent and frequency-specific activations in the motor-to-sensory transformation network mediate the internal construction of perceptual representations and form the foundation of neural computations for mental operations., What enables our mental activities for thinking verbally or humming in our mind? Using an imagined singing paradigm with magnetoencephalography recordings, this study shows that neural oscillations in the motor-to-sensory transformation network tracked inner speech and covert singing.

Emerging evidence implicates gut microbiota have an important role in ulcerative colitis (UC). Previous study indicated that Evodiamine (EVO) can alleviate colitis through downregulating inflammatory pathways. However, specific relationship between EVO-treated colitis relief and regulation of gut microbiota is still unclear. Here, our goal was to determine the potential role of gut microbiota in the relief of UC by EVO. By using pathology-related indicators, 16S rRNA sequencing and metabolomics profiling, we assessed the pharmacological effect of EVO on dextran sulfate sodium (DSS)-induced colitis rats as well as on the change of gut microbiota and metabolism. Fecal derived from EVO-treated rats was transplanted into colitis rats to verify the effect of EVO on gut microbiota, and 'driver bacteria' was found and validated by 16S rRNA sequencing, metagenome and qRT-PCR. The effect of Lactobacillus acidophilus (L. acidophilus) was investigated by vivo experiment, microbiota analysis, Short-chain fatty acids (SCFAs) quantification and colon transcriptomics. EVO reduced the susceptibility to DSS-induced destruction of epithelial integrity and severe inflammatory response, and regulated the gut microbiota and metabolites. Fecal Microbiota Transplantation (FMT) alleviated DSS-induced colitis, increased the abundance of L. acidophilus and the level of acetate. Furthermore, gavaged with L. acidophilus reduced pro-inflammatory cytokines, promoted the increase of goblet cells and the secretion of antimicrobial peptides, regulated the ratio of Firmicutes/Bacteroidetes and increased the level of acetate. Our results indicated that EVO mitigation of DSS-induced colitis is associated with increased in L. acidophilus and protective acetate production, which may be a promising strategy for treating UC.

A rising amount of evidences show that gut microbiota is an important factor in mediating the growth of ulcerative colitis (UC), the major product of colon bacteria fermentation butyrate as mediator have effects on the mucosal immune system by expanding regulatory T cells (Treg) in the colon. Turkish galls, an insect gall parasitized on the tree branches of Quercus infectoria Oliv., exhibiting the promising prospect in treating the remedy of UC by regulating the bacteria, whereas its mechanism remains unclear. Here, this work found that three types of gut bacteria collaborating to improve DSS-induced UC in mice after Turkish galls intervention, including putative SCFAs-producing bacteria (PCPB), anti-inflammatory bacteria and harmful bacteria. The Helicobacter, Bilophila, Acinetobacter and Odoribacter, which belong to the harmful bacteria were dramatically increased in UC group, whereas the harmful bacteria were reduced after treatment with Turkish galls. The Allobaculum, Bacteriodes, Blautia, Butyricimonas, belonging to PCPB, were significantly increased after Turkish galls and butyrate intervention, and we also observed that the concentration of butyrate increased with the grows of PCPB. The Bifidobacterium, Lactococcus, which belong to the anti-inflammatory bacteria, were also significantly increased after Turkish galls intervention. Meanwhile, rectal administration of Turkish galls and butyrate could increase mucosa inflammation and diarrhea. The expression of cytokines in the colon was improved by butyrate and Turkish galls treatment group. The percentage of Treg out of CD4+ population was evaluated by flow cytometry after Turkish galls and butyrate intervention. The results suggested that Turkish galls alleviated UC by modulating three types of the gut microbiota, and butyrate may be used to relieve inflammatory. This study may help us to understand the mechanism of Turkish galls in treating UC from the perspective of intestinal flora and also offered a mechanism reference for UC treatment using an insect gall in rich of polyphenolic compounds.

Anisodus acutangulus is a Solanaceae perennial plant, which is endemic to China and classified as an endangered species. In this study, we have sequenced the complete chloroplast genome of A. acutangulus, which is 156,079 bp in length, containing a large single-copy (LSC) region of 86,526 bp, a small single-copy (SSC) region of 17,741 bp and comprises a pair of inverted repeat regions (IRs) of 25,906 bp. Totally 134 genes were annotated, including 87 protein-coding genes, 39 tRNA genes, and 8 rRNA genes. Its overall GC content is 37.6%. Phylogenetic analysis using total chloroplast genome DNA sequence of 21 species revealed that A. acutangulus was closely related to Hyoscyamus niger with 100% bootstrap value.

Background The relationship between phospholipase C ε‐1 (PLCE1) rs2274223 variant and digestive tract cancer remains inconclusive despite extensive investigations. Therefore, we performed this meta‐analysis to obtain a more credible conclusion. Methods PubMed, Medline, and Embase were systematic searched. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results A total of 27 studies were finally included. Pooled analyses suggested that PLCE1 rs2274223 variant was significantly correlated with the likelihood of esophageal cancer (dominant model: p

Although growing evidence has demonstrated that the long non-coding RNA DLEU1 is involved in the progression of various cancers, its functional role and underlying mechanisms have not been explored in cervical cancer (CC). In this study, we found that DLEU1 was up-regulated in both CC tissues and CC cell lines, and overexpression of DLEU1 was significantly correlated with shorter patient survival. Knockdown of DLEU1 suppressed CC cell proliferation and invasion, whereas overexpression of DLEU1 promoted the proliferation and invasion of CC cells. Bioinformatics analysis was used to elucidate the potential correlation between DLEU1 and miR-381. Moreover, qRT-PCR analysis, luciferase reporter assay and RNA immunoprecipitation assay confirmed that DLEU1 inhibited the expression of miR-381, and revealed a direct interaction between DLEU1 and miR-381. In addition, we demonstrated that miR-381 directly targeted HOXA13 in CC cells. The restoration of HOXA13 expression reversed DLEU1 knockdown or miR-381 overexpression-mediated suppression of cell proliferation and invasion. These results suggested that DLEU1 can promote CC cell proliferation and invasion via the miR-381/HOXA13 axis.

Auditory hallucinations are the most common psychiatric symptoms of schizophrenia with high recurrence and refractoriness. Transcranial direct current stimulation (tDCS), a novel, non-invasion and affordable brain stimulation technique, has been recently applying on the schizophrenia patients to treat the auditory hallucinations. To analyze the efficacy of tDCS treatment on such symptoms and to reveal its potential working mechanisms, we carried out a structured literature search in PubMed, Embase and Cochrane Library database up to May 12, 2018. Five studies that met inclusion criteria with a total of 137 patients were included in this meta-analysis. After pooling all the data, we found that there was no significant effect between active group and sham group of tDCS (p = 0.18). When we removed one study that did not collaboratively stimulate the frontal-temporal sites, the active tDCS group marks a significant improvement of therapeutic effect compared with sham group (p = 0.007). Our findings suggested that tDCS could be a promising tool to alleviate auditory hallucinations, provided that the simulation sites and protocols are targeting at the sensorimotor frontal-parietal network.

Turkish galls have been reported to exhibit remedial effects in ulcerative colitis (UC). However, the active constituents of Turkish galls for the treatment of UC remain unclear. The objective of this study was to screen for anti-inflammatory active constituents and clarify their associated molecular mechanisms. Therefore, systems pharmacology was developed to predict the relationship between constituents and the corresponding targets as well as pathways. In addition, mass spectrometry-guided preparative chromatography technique was used for preparing constituents to evaluate the anti-inflammatory activities and the therapeutic efficacy against UC. In silico, active constituents exhibited a remedial effect on UC possibly by regulating multiple pathways and attacking multiple targets, of which those involved mainly in the NF-κB pathway were selected for verification. In vitro, 5 categories of constituents were screened as active constituents by comparing the cytotoxicity and detecting the level of the pro-inflammatory factors of 9 category constituents. In vivo, dextran sulfate sodium (DSS)-induced UC was significantly ameliorated in active constituents-fed mice. The results indicated that the active fraction comprising methyl gallate, digallic acid, di-O-galloyl-β-d-glucose, and tri-O-galloyl-β-d-glucose primarily contributed to the treatment of UC. Moreover, active fraction could also inhibit the phosphorylation level of IKKβ, thus inhibiting the downstream NF-κB signaling pathway. The approach developed in this study not only clarifies the anti-inflammation effect of Turkish galls but also provides a beneficial reference for the discovery of the base material and functional mechanism of this herbal medicine.

Action and perception interact in complex ways to shape how we learn. In the context of language acquisition, for example, hand gestures can facilitate learning novel sound-to-meaning mappings that are critical to successfully understanding a second language. However, the mechanisms by which motor and visual information influence auditory learning are still unclear. We hypothesize that the extent to which cross-modal learning occurs is directly related to the common representational format of perceptual features across motor, visual, and auditory domains (i.e., the extent to which changes in one domain trigger similar changes in another). Furthermore, to the extent that information across modalities can be mapped onto a common representation, training in one domain may lead to learning in another domain. To test this hypothesis, we taught native English speakers Mandarin tones using directional pitch gestures. Watching or performing gestures that were congruent with pitch direction (e.g., an up gesture moving up, and a down gesture moving down, in the vertical plane) significantly enhanced tone category learning, compared to auditory-only training. Moreover, when gestures were rotated (e.g., an up gesture moving away from the body, and a down gesture moving toward the body, in the horizontal plane), performing the gestures resulted in significantly better learning, compared to watching the rotated gestures. Our results suggest that when a common representational mapping can be established between motor and sensory modalities, auditory perceptual learning is likely to be enhanced.

Previous studies in speech production and acquisition have mainly focused on how feedback vs. goals and feedback vs. prediction regulate learning and speech control. The present study investigated the less studied mechanism–prediction vs. goals in the context of adult Mandarin speakers’ acquisition of non-native sounds, using an auditory feedback masking paradigm. Participants were asked to learn two types of non-native vowels: /ø/ and /ɵ/—the former being less similar than the latter to Mandarin vowels, either in feedback available or feedback masked conditions. The results show that there was no significant improvement in learning the two targets when auditory feedback was masked. This suggests that motor-based prediction could not directly compare with sensory goals for adult second language acquisition. Furthermore, auditory feedback can help achieve learning only if the competition between prediction and goals is minimal, i.e., when target sounds are distinct from existing sounds in one’s native speech. The results suggest motor-based prediction and sensory goals may share a similar neural representational format, which could result in a competing relation in neural recourses in speech learning. The feedback can conditionally overcome such interference between prediction and goals. Hence, the present study further probed the functional relations among key components (prediction, goals and feedback) of sensorimotor integration in speech learning.

Electroencephalography (EEG) provides high temporal resolution cognitive information from non-invasive recordings. However, one of the common practices-using a subset of sensors in ERP analysis is hard to provide a holistic and precise dynamic results. Selecting or grouping subsets of sensors may also be subject to selection bias, multiple comparison, and further complicated by individual differences in the group-level analysis. More importantly, changes in neural generators and variations in response magnitude from the same neural sources are difficult to separate, which limit the capacity of testing different aspects of cognitive hypotheses. We introduce EasyEEG, a toolbox that includes several multivariate analysis methods to directly test cognitive hypotheses based on topographic responses that include data from all sensors. These multivariate methods can investigate effects in the dimensions of response magnitude and topographic patterns separately using data in the sensor space, therefore enable assessing neural response dynamics. The concise workflow and the modular design provide user-friendly and programmer-friendly features. Users of all levels can benefit from the open-sourced, free EasyEEG to obtain a straightforward solution for efficient processing of EEG data and a complete pipeline from raw data to final results for publication.

Clinically, postoperative adhesions are common and serious complications, which almost always happen after abdominal or pelvic surgery. The adhesion development process is accompanied by increased inflammatory cell infiltration and oxygen-free radical production. In this study, the naturally occurring antioxidative and anti-inflammatory compounds extracted from Turkish galls by ethyl acetate (GEA) were encapsulated into an injectable and biodegradable thermosensitive hydrogel. Antiadhesion efficacy of the barrier system (GEA-NP/H) was tested on a rat peritoneum injury-cecum abrasion model. Upon injection, the mildly viscous liquid formed a potent physical barrier over the injured cecum and peritoneum without any additional cross-linkers or light sources. Once formed, GEA-NP/H acted as a durable wound dressing for more than 5 days, as well as a sustained drug depot of GEA. The polymer hydrogel can be degraded and absorbed gradually. After 14 days, severe adhesion occurred among rats treated with normal saline and GEA-loaded nanoparticles (GEA-NP). Whereas, frequency of score 1 adhesion among the blank hydrogel group is 30%, and 90% of the rats from GEA-NP/H group exhibited no adhesion. In addition, pathological sections and scanning electron microscopy assay demonstrated that operative defects treated with GEA-NP/H suffered from mild oxidative stress and inflammatory damages at early days after injury, as well as accelerated wound healing and more mature mesothelial cell deposition at the 14th day in contrast to the blank hydrogel treatment. Therefore, the study provided an available biodegradable hydrogel barrier to effectively prevent postsurgical adhesion.

Gray mold of tomato is caused by the pathogen Botrytis cinerea. MicroRNAs play a crucial role in the biotic and abiotic stress responses of plants and regulate their targets by gene silencing. miR394 is an ancient and conserved miRNA in plants, and it participates in the regulation of plant development and stress responses. In our previous study, miR394 was found to respond to B. cinerea infection in tomato, but the roles and regulatory mechanisms of miR394 in B. cinerea-infected tomato remain unclear. miR394 was down-regulated in tomato in response to B. cinerea infection, showing an expression pattern opposite to the previous finding that miR394 was up-regulated in tomato cv. Jinpeng 1 infected by B. cinerea. We obtained transgenic Arabidopsis overexpressing miR394, which resulted in low expression levels of its target LEAF CURLING RESPONSIVENESS (LCR). Leaf lesion size and trypan blue staining showed that miR394 overexpression led to increased sensitivity of transgenic Arabidopsis to B. cinerea compared to wild type. We also detected changes in the expression levels of stress-related miRNAs, including miR159, miR156, miR168, and miR172. In the transgenic plants, it indicated potential cross talk between these miRNAs and miR394, except for miR159. miR394 also enhanced the expression of ARGONAUTE 1 (AGO1), DSRNA-BINDING PROTEIN 4 (DRB4) and the RNA-binding protein gene DAWDLE (DDL), which are involved in the pathways of miRNA biosynthesis and regulation, suggesting that miR394 overexpression has a feedback effect on these genes. Our data indicate that overexpression of miR394 in Arabidopsis increased the susceptibility of plants to B. cinerea by affecting the expression of its target gene LCR along with a number of key genes involved in plant miRNA metabolism (AGO1). Thus, miR394 is a negative regulator of Arabidopsis resistance to B. cinerea infection by targeting LCR.

Background/Aims: Traditional cardiovascular (CV) risk factors (RFs) and their management targets may not be applicable to specific medical subpopulations, particularly dialysis patients. This study aimed to evaluate the dose-response association between measurements of RFs, cardiovascular mortality, and potential metabolic targets among Chinese patients initializing peritoneal dialysis (PD). Methods: Risk-set sampling was applied to two population based 1: 10 case-control studies of incident PD patients, matched by age, sex and the year of initialisation of PD: a main sample (204 cases and 2,040 controls) and a replication sample (81 cases and 810 controls). The dose-response association between continuous measurements of CV RFs (blood pressure, fasting glucose, body mass index, total cholesterol, phosphate and ejection fraction) at baseline and the 2-year CV mortality were analyzed using conditional Logistic regression. The final threshold was chosen based upon a significant break in the regression coefficients and achievement of the minimum Bayesian information criterion (BIC). Results: A linear relationship was identified between fasting glucose and CV mortality. Non-linear associations between other measurements and CV mortality suggested potential metabolic treatment intensification thresholds as < 145/92mmHg for blood pressure, < 1.70mmol/L for phosphate, 24 kg/m2 for body mass index, 4.6mmol/L for total cholesterol, and > 60% for ejection fraction respectively. Conclusion: Our findings highlight the potential importance of more intensive glucose management, anti-hypertensive treatment and dietary management among PD patients. We recommend that the clinical relevance of these epidemiological associations be tested using randomized controlled trials of multifaceted interventions.

Background/Aims: Cerebrovascular disease (CeVD) is one of the leading causes of death in patients initialising peritoneal dialysis (PD). Currently there is no risk score to predict the future risk of CeVD on entry into PD. This study aimed to derive and validate a risk prediction model for CeVD mortality in 2 years after the initialisation of PD. Methods: All patients registered with the Henan Peritoneal Dialysis Registry (HPDR) between 2007 and 2014 were included. Multivariable logistic regression modelling was applied to derive the risk score. All accessible clinical measurements were screened as potential predictors. Internal validation through bootstrapping was applied to test the model performance. Results: The absolute risk of CeVD mortality was 2.9%. Systolic and diastolic blood pressure, total cholesterol, phosphate, and sodium concentrations were the strongest predictors of CeVD mortality in the final risk score. Good model discrimination with C statistics above 0.70 and calibration of agreed observed and predicted risks were identified in the model. Conclusion: The new risk score, developed and validated using clinical measurements that are accessible on entry into PD, could be used clinically to screen for patients at high risk of CeVD mortality. Such patients might benefit from therapies reducing the incidence of CeVD related events.

The most critical attribute of human language is its unbounded combinatorial nature: smaller elements can be combined into larger structures based on a grammatical system, resulting in a hierarchy of linguistic units, e.g., words, phrases, and sentences. Mentally parsing and representing such structures, however, poses challenges for speech comprehension. In speech, hierarchical linguistic structures do not have boundaries clearly defined by acoustic cues and must therefore be internally and incrementally constructed during comprehension. Here we demonstrate that during listening to connected speech, cortical activity of different time scales concurrently tracks the time course of abstract linguistic structures at different hierarchical levels, e.g. words, phrases, and sentences. Critically, the neural tracking of hierarchical linguistic structures is dissociated from the encoding of acoustic cues as well as from the predictability of incoming words. The results demonstrate that a hierarchy of neural processing timescales underlies grammar-based internal construction of hierarchical linguistic structure.

Background/Aims: During peritoneal equilibrium test (PET), intermediate measures of Dt/P (dialysate/plasma creatinine ratio), D0/P, D2/P and D4/P ratios might provide additional information regarding a patient’s cardiovascular mortality. We aimed to characterise heterogeneity of dialysate creatinine response patterns based on three ratios and compare cardiovascular mortality risks by response patterns. Methods: 3,477 patients initialising peritoneal dialysis (PD) between 2007-2015 were measured D0/P, D2/P and D4/P at baseline and 2-year cardiovascular mortality was defined as the primary outcome. Latent class mixed-effect models were fitted to identify distinct patterns of dialysate creatinine response. Multivariable Logistic regression model with adjustment of cardiometabolic factors were used to compare cardiovascular mortality by latent classes. Results: The 1st latent class including 36% of participants was characterised by consistently increasing and high Dt/P ratios both at 2-hour and 4-hour. The 2nd class including 61% of participants characterised by sharply increased ratio at 2-hour and slightly increased ratio at 4-hour. The 3rd class included 3% of participants with decreased ratio at 2-hour and increased ratio at 4-hour. Comparing the 1st class, the lower cardiovascular mortality risk was identified in the 2nd and 3rd class with adjusted odds ratio 0.65 (95% confidence interval: 0.62-0.69) and 0.48 (0.41-0.57), respectively. Conclusion: Patients with decreased Dt/P ratio between 0-hour and 2-hour and low ratios at 2-hour and 4-hour tend to have low cardiovascular mortality. Latent class analysis seems to be a promising method to reveal unidentified subgroups that do not fit into the risk category defined by Dt/P ratio at 4-hour.

Catechin exhibits antimicrobial activity against various microorganisms, such as EHEC O157:H7. This study reports the bactericidal effect of catechin on EHEC O157:H7 in simulated human gastrointestinal environment and the underlying antibacterial mechanism. Bacteriostasis test results showed that the minimum bactericidal concentration of catechin for EHEC O157:H7 was 5 g/L. The bactericidal effect of catechin in the gastrointestinal juice became more significant with increased culture time, and catechin exhibited a synergistic effect with bile salt in inhibiting EHEC O157:H7. Changes in the profile of protein expression in EHEC O157:H7 in response to catechin intervention were investigated. Two-dimensional electrophoresis identified 34 proteins with significantly altered expression. A total of 2 and 12 proteins were upregulated and downregulated, respectively. However, 20 proteins disappeared. No new protein was expressed compared with the control. Hence, catechin intervention resulted in diverse changes in the expression of proteins associated with cell structure and genetic information processing. Catechin could cause the disappearance of certain proteins or the destruction of certain peptides. These processes lead to the inhibition of EHEC O157: H7 cells.

Sei-1 is a potential oncogene that plays an important role in promoting genomic instability. Double minute chromosomes (DMs) are hallmarks of gene amplification and contribute to tumorigenesis. Defects in the DNA double-strand break (DSB) repairing pathways can lead to gene amplification. To date, the mechanisms governing the formation of DMs induced by Sei-1 are not fully understood. We established DMs induced by Sei-1 in the NIH-3T3 cell line. RNA-sequencing was used to identify key characteristics of differentially expressed genes. Metaphase spreads were used to calculate DM numbers. Immunofluorescence was employed to detect γH2AX foci. Western blot and Akt pathway inhibition experiments were performed to reveal the role of the PI3K/Akt/BRCA1-Abraxas pathway in Sei-1-induced DMs. Luciferase reporter assay was employed to explore the regulatory mechanisms between Sei-1 and BRCA1. DM formation was associated with a deficiency in DSB repair. Based on this finding, activation of the PI3K/Akt/BRCA1-Abraxas pathway was found to increase the DM population with passage in vivo, and inhibition resulted in a reduction of DMs. Apart from this, it was shown for the first time that Sei-1 could directly regulate the expression of BRCA1. Our results suggest that the PI3K/Akt/BRCA1-Abraxas pathway is responsible for the formation of DMs induced by Sei-1.