Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

Bicyclol Alleviates Atherosclerosis by Manipulating Gut Microbiota.

Atherosclerosis (AS) is associated with high morbidity and mortality, thus imposing a growing burden on modern society. Herb-derived bicyclol (BIC) is a versatile bioactive compound that can be used to treat AS. However, its efficacy in AS is not yet described. Here, it is shown that BIC normalizes gut microflora dysbiosis induced by a high fat diet in Apoe(-/-) mice. Metagenome-wide association study analysis verifies that the modulation on carbohydrate-active enzymes and short-chain fatty acid generating genes in gut flora is among the mechanisms. The gut healthiness, especially the gut immunity and integrity, is restored by BIC intervention, leading to improved systemic immune cell dynamic and liver functions. Accordingly, the endothelial activation, macrophage infiltration, and cholesterol ester accumulation in the aortic arch are alleviated by BIC to lessen the plaque onset. Moreover, it is proved that the therapeutic effect of BIC on AS is transmissible by fecal microbiota transplantation. The current study, for the first time, demonstrates the antiatherosclerotic effects of BIC and shows that its therapeutic value can at least partially be attributed to its manipulation of gut microbiota.

Efficacy and safety of bicyclol for treating patients with idiosyncratic acute drug-induced liver injury: A multicenter, randomized, phase II trial.

BACKGROUND AND AIMS: Evidence for using bicyclol in drug-induced liver injury (DILI) is limited. This study aimed to explore the efficacy and safety of bicyclol in acute DILI. METHODS: This was a multicenter, randomized, double-blinded, double-dummy, active-controlled, superiority and phase II trial. Patients with idiosyncratic acute DILI were randomized 1: 1:1 to low-dose bicyclol (25 mg times a day [TID]), high-dose bicyclol (50 mg TID) and polyene phosphatidylcholine (control) groups. The primary endpoint was the decrease from baseline in serum alanine aminotransferase (ALT) levels at post-treatment for 4 weeks. RESULTS: Overall, 241 patients were included in the full analysis set, with 81, 82 and 78 patients in the low-dose bicyclol, high-dose bicyclol, and control groups respectively. ALT levels decreased across groups (-249.2 ± 151.1, -273.6 ± 203.1, and -180.8 ± 218.2 U/L in the low-dose bicyclol, high-dose bicyclol and control groups, respectively; both p < .001, the bicyclol-dependent groups vs. control group). The ALT normalization rates at weeks 1, 2, 4, 6 and 8 were higher in the bicyclol-dependent groups than in the control group (p = .002 at week 1 and all p < .001 at weeks 2, 4, 6 and 8 respectively). The median times to ALT normalization in the low-dose bicyclol, high-dose bicyclol and control groups were 29, 16 and 43 days respectively. Adverse events, serious adverse events and adverse drug reactions were similar across groups. CONCLUSIONS: Bicyclol (25 and 50 mg TID) appeared efficacious and safe for treating idiosyncratic acute DILI, while bicyclol 50 mg TID showed higher efficacy. TRIAL REGISTRATION NUMBER: www. CLINICALTRIALS: gov (registration no. NCT02944552).

Shifting borders and migrant workers' im/mobility: The case of Taiwan during the COVID-19 pandemic.

The COVID-19 pandemic intensified border control and disrupted international labor migration, but the complex consequences for migrant workers, including deepened marginalization and countervailing opportunities, have yet to receive sufficient scrutiny. Drawing on the case of Taiwan, this article examines how a host country reorganizes the multiple layers of physical and social borders for the purpose of sanitization, leading to an entanglement of mobilities and immobilities in migrant workers' lives. I illustrate how bordering practices have had uneven impacts on Filipino and Indonesian migrant workers across different circumstances of risk management. The findings highlight the geographic scales and temporal changes of shifting borders, which involve the negotiation of social membership for migrant workers in relation to the public health crisis and labor market shortage.

Rethinking the migration-development nexus in the post-COVID-19 era.

This concluding article serves as an epilogue summing up key issues about migration, labor migrants and development amid a crisis of public health. We predict the forging of an age of sanitization in which different kinds of sanitizing policies will still be in place, especially in Asia, to deal with the sporadic changes of the pandemic. Sanitization politics will continue to intersect with different policy sectors and powers, which will extend beyond the medical understanding of a pandemic and blur the division between science and politics. It will have varied impacts on the migration regime and global governance as a whole.

The politics of sanitization: Pandemic crisis, migration and development in Asia-Pacific.

COVID-19 has resulted in new anxieties about the risks and dangers involved in human mobility and forced governments to simultaneously re-engineer policies for temporary health control and longer-term border-crossing and migration policies; characterized by the sanitization of space and mobility. This special issue considers the policies, including health and non-health measures, that have impacts on migrant workers and migration. While COVID control measures are often phrased in medical language and policy discourses, they often serve multiple goals including political and social control. The papers in this issue cover different places in Asia and the Pacific. We propose the "politics of sanitization" as a conceptual framework to examine the multiple dimensions of state governance and the variegated impacts upon migrants, including: (1) sanitizing space and borders, (2) stigmatization and sanitizing migrants' bodies, (3) sanitizing ethnic borders and the national body, and (4) reorganizing the borders of sanitization and membership of society.

Investigation of the pan-cancer property of FNDC1 and its molecular mechanism to promote lung adenocarcinoma metastasis.

BACKGROUND: Fibronectin type III domain containing 1 (FNDC1) has been associated with the metastasis of many tumors, but its function in lung cancer remains uncertain. METHODS: FNDC1 expression was analyzed in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), evaluate its prognostic value. Gene Set Enrichment Analysis (GSEA) enrichment analysis of differential expression of FNDC1 in lung cancer. The expression of FNDC1 was detected in five types of lung cancer cells, and screened to establish FNDC1 stable knockdown cell strains. To observe the migration and invasion ability of lung cancer cells after FNDC1 knockdown. Finally, we used rhIL-6 to interfere with the stable knockdown of FNDC1 in A549 cells and observed the recovery of migration and invasion. RESULT: Our results showed that FNDC1 expression was increased in 21 tumor tissues, including lung cancer, and was associated with poor prognosis in five cancers, including lung adenocarcinoma (LUAD) (P < 0.05). GSEA enrichment analysis showed that FNDC1 was related to the pathways involved the JAK-STAT signaling pathway. Stable knockdown of FNDC1 in A549 and H292 cells resulted in decreased migration and invasion ability of both cells, accompanied by decreased expression of MMP-2 and Snail, and a significant decline in the expression of p-JAK2 and p-STAT3. The suppressive effect of FNDC1 knockdown on lung cancer cell metastasis counteracted by the JAK-STAT agonist rhIL-6 were presented in the nude mouse metastatic tumor model. CONCLUSION: FNDC1 is implicated in poor prognosis of a diverse range of malignant tumors, which can promote metastasis and invasion of lung cancer through the JAK2-STAT3 signaling pathway.

Caffeinated Chewing Gum Improves Basketball Shooting Accuracy and Physical Performance Indicators of Trained Basketball Players: A Double-Blind Crossover Trial.

(1) Background: This study investigated the effects of caffeinated chewing gum on the basketball-specific performance of trained basketball players. A double-blind, randomized crossover design was employed. (2) Methods: Fifteen participants (age: 20.9 ± 1.0 years; height: 180.9 ± 5.4 cm; mass: 77.2 ± 7.5 kg; training age: 8.2 ± 0.3 years) were recruited and divided into a caffeine trial (CAF) and placebo trial (PL). The participants in the CAF trial chewed gum containing 3 mg/kg of caffeine for 10 min, while those in the PL trial chewed a placebo gum without caffeine. Following a 15 min rest, all the participants completed basketball-specific performance tests. (3) Results: The free throw accuracy for the CAF trial was significantly higher than that for the PL trial (CAF: 79.0 ± 4.31%; PL: 73.0 ± 9.16%; p = 0.012; Cohen's d = 0.94). Additionally, the CAF trial demonstrated significantly better performance in the 20 m segmented dash (CAF: 2.94 ± 1.12 s; PL: 3.13 ± 0.10 s; p < 0.001; Cohen's d =1.8) and squats (p < 0.05), and exhibited lower fatigue indexes (CAF: 3.6 ± 1.6%; PL: 5.2 ± 1.6%; p = 0.009; Cohen's d =1.0). (4) Conclusions: These findings suggest that chewing gum containing 3 mg/kg of caffeine offers moderate-to-large improvements in key performance aspects relevant to professionally trained basketball players.

Ultrafast Fabrication of H2SO4, LiCl, and Li2SO4 Gel Electrolyte Supercapacitors with Reduced Graphene Oxide (rGO)-LiMnOx Electrodes Processed Using Atmospheric-Pressure Plasma Jet.

Pastes containing reduced graphene oxide (rGO) and LiCl-Mn(NO3)2·4H2O are screen-printed on a carbon cloth substrate and then calcined using a nitrogen atmospheric-pressure plasma jet (APPJ) for conversion into rGO-LiMnOx nanocomposites. The APPJ processing time is within 300 s. RGO-LiMnOx on carbon cloth is used to sandwich H2SO4, LiCl, or Li2SO4 gel electrolytes to form hybrid supercapacitors (HSCs). The areal capacitance, energy density, and cycling stability of the HSCs are evaluated using electrochemical measurement. The HSC utilizing the Li2SO4 gel electrolyte exhibits enhanced electrode-electrolyte interface reactions and increased effective surface area due to its high pseudocapacitance (PC) ratio and lithium ion migration rate. As a result, it demonstrates the highest areal capacitance and energy density. The coupling of charges generated by embedded lithium ions with the electric double-layer capacitance (EDLC) further contributed to the significant overall capacitance enhancement. Conversely, the HSC with the H2SO4 gel electrolyte exhibits better cycling stability. Our findings shed light on the interplay between gel electrolytes and electrode materials, offering insights into the design and optimization of high-performance HSCs.

Contested skills and constrained mobilities: migrant carework skill regimes in Taiwan and Japan.

This article compares the paradoxical conditions of migrant care workers in two major receiving countries in Asia: Taiwan's policy regime has positioned live-in care workers as "unskilled" foreigners, who nevertheless have gained increasing desirability and mobility in the labor market. By contrast, Japan has maintained the regime of skilled migration but the recent expansion of the trainee program reinforces paternalistic control over migrant caregivers, who are considered culturally inadequate. Contesting the assumption that skills indicate desirability and mobility in the labor market, I argue that we must examine the context-dependent constitution of skills at the intersection of migration, care, and skill regimes. I propose a multifaced framework to examine how the state and intermediary agencies co-produce the skill regime of care migration, including the following dimensions: migrant skills as a political language and structure of governance, care work skills as social and cultural constructions, the infrastructure of recruitment and training, and the consequence of labor market mobility.

5 days of time-restricted feeding increases fat oxidation rate but not affect postprandial lipemia: a crossover trial.

Studies have revealed that time-restricted feeding affects the fat oxidation rate; however, its effects on the fat oxidation rate and hyperlipidemia following high-fat meals are unclear. This study investigated the effects of 5-day time-restricted feeding on the fat oxidation rate and postprandial lipemia following high fat meals. In this random crossover experimental study, eight healthy male adults were included each in the 5-day time-restricted feeding trial and the control trial. The meals of the time-restricted feeding trial were provided at 12:00, 16:00, and 20:00. The meals of the control trial were provided at 08:00, 14:00, and 20:00. The contents of the meals of both trials were the same, and the calories of the meals met the 24-h energy requirement of the participants. After 5 days of the intervention, the participants consumed high-fat meals on the sixth day, and their physiological changes were determined. The fasting fat oxidation rate (p < 0.001) and postprandial fat oxidation rate (p = 0.019) of the time-restricted feeding trial were significantly higher than those of the control trial. The 24-h energy consumption and postprandial triglyceride, blood glucose, insulin, glycerol, and free fatty acid concentrations of the two trials showed no significant differences (p > 0.05). The results revealed that 5 days of time-restricted feeding effectively increased the fasting and postprandial fat oxidation rate, but it did not affect postprandial lipemia.

Bicyclol ameliorates advanced liver diseases in murine models via inhibiting the IL-6/STAT3 signaling pathway.

Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases.

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis.

Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10-6] and to endoplasmic reticulum stress [p-value = 8.67 × 10-7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10-8], and responses to a redox state [p-value = 5.80 × 10-5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10-8] and an ATP metabolic process [p-value = 3.95 × 10-4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.

Correction to: DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation.

In the original publication of this article [1], labelling within Fig. 7a was incorrect. The updated figure is shown below, with 'DMT1' now corrected to read 'DNMT1'.

Erratum: Author correction to 'Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication' [Acta Pharmaceutica Sinica B 9 (2019) 769-781].

[This corrects the article DOI: 10.1016/j.apsb.2019.01.013.].

DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation.

BACKGROUND: The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear. METHODS: HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo. RESULTS: We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells. CONCLUSIONS: The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b-mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.

Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication.

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.

Characterization of a carbonyl-conjugated polyene precursor in 10-membered enediyne biosynthesis.

We have characterized a linear carbonyl-conjugated polyene generated by the iterative polyketide synthase (CalE8) involved in the biosynthesis of the 10-membered enediyne core of calicheamicin. The results provide insight into the mysterious biosynthetic mechanism of the unique enediyne. The carbonyl-conjugated polyene differs from the precursor for 9-membered enediyne, suggesting that the divergence of enediyne biosynthesis starts at the PKS stage.

TGF-ßI Regulates Cell Migration through Pluripotent Transcription Factor OCT4 in Endometriosis.

Transforming growth factor (TGF-ß)/TGF-ß receptor signal is known to promote cell migration. Up-regulation of TGF-ß in serum/peritoneal fluid and increased levels of pluripotent transcription factor OCT4 in endometriotic tissues are frequently observed in patients with endometriosis. However, the mechanisms underlying how TGF-ß/TGF-ß receptor and OCT4 affect endometriotic cell migration still remain largely unknown. Therefore, endometriotic tissue with high cell migratory capacity were collected from patients with adenomyotic myometrium (n = 23) and chocolate cyst (n = 24); and endometrial tissue with low cell migratory capacity in normal endometrium or hyperplastic endometrium (n = 8) were collected as the controls. We found the mRNA levels of TGF-ß receptor I (TGF-ß RI) and OCT4 were significantly higher in the high-migratory ectopic endometriotic tissues than those of the low-migratory normal or hyperplastic endometrium. Positive correlations between TGF-ß RI and OCT4, and either TGF-ß RI or OCT4 with migration-related genes (SNAIL, SLUG and TWIST) regarding the mRNA levels were observed in human endometriotic tissues. TGF-ßI dose-dependently increased the gene and protein levels of OCT4, SNAIL and N-Cadherin (N-CAD) and silencing of endogenous OCT4 significantly suppressed the TGF-ßI-induced expressions of N-CAD and SNAIL in primary human endometriotic stromal cells and human endometrial carcinoma cell lines RL95-2 and HEC1A. Furthermore, TGF-ßI significantly increased the migration ability of endometriotic cells and silencing of OCT4 dramatically suppressed the TGF-ßI-induced cell migration activity evidenced by wound-closure assay, transwell assay, and confocal image of F-actin cellular distribution. In conclusion, the present findings demonstrate that the niche TGF-ß plays a critical role in initiating expressions of pluripotent transcription factor OCT4 which may contribute to the ectopic endometrial growth by stimulating endometrial cell migration. These findings would be useful for developing therapeutic strategies targeting TGF-ß-OCT4 signaling to prevent endometriosis in the future.

Application of ARIMA model in predicting monthly incidence of syphilis / 西安交通大学学报(医学版)

Objective To explore the value of the autoregressive integrated moving average model (ARIMA) applied to predict monthly incidence of syphilis so as to provide basis for prevention and control of syphilis . Methods Eviews 8 .0 was used to establish the ARIMA model based on the data of monthly incidence of syphilis in China from January 2009 to December 2015 .Then the data of the first half of 2016 were used to verify the predicted results .The predictions were evaluated by RMSE ,MAE ,MAPE and MRE models .Then the monthly incidence of syphilis in the second half of 2016 was predicted .Results The optimal model for the monthly incidence of syphilis from January 2009 to June 2016 was the model of ARIMA (2 ,1 ,1) × (0 ,1 ,1)12 ,its equation was (1 - B)(1 - B12 ) (1+0 .820 B)(1+0 .566 B2 ) x2t = (1+0 .365 B) (1+0 .897 B12 )εt ,its parameters are as follows :R2 =0 .832 ,RMSE=0 .181 ,MAE=0 .118 ,MAPE=5 .088 .The predicted monthly incidence values (10-5 ) of the second half of 2016 were 3 .124 ,3 .008 ,2 .906 ,2 .691 ,2 .714 ,and 2 .717 .Conclusion ARIMA model has a relatively good prediction precision .Therefore , it can make short-term prediction based on the evolution trend of monthly incidence of syphilis in China .