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Xiao-He Guo, Yan-Li Zhu, Lu Yang, Wen-Jing Li, Xue-Fang Du Department of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, People’s Republic of ChinaCorrespondence: Yan-Li Zhu, Department of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui District, Henan, 453100, People’s Republic of China, Tel +86 15036615840, Email huyanlizyl02@21cn.comObjective: This study aimed to assess the effects of multi-donor fecal microbiota transplantation (FMT) capsules combined with thalidomide on hormone-dependent ulcerative colitis (UC).Methods: A total of 59 patients with steroid-dependent UC treated at the Gastroenterology Department of the First Affiliated Hospital of Xinxiang Medical University between January 2017 and January 2019 were enrolled in this study. Using a random number table, the patients were divided into two groups: a group treated with FMT capsules (the FMT group) and a group treated with FMT capsules and thalidomide (the FMT+S group). Multi-donor FMT capsules were prepared, and all subjects and stool donors followed the FMT pathway for FMT transplantation. Each patient’s Mayo score, C-reactive protein (CRP) level, and level of fecal calprotectin before FMT treatment and at week 1 and week 13 after treatment were recorded. All patients were followed up for 15 weeks.Results: A total of 56.7% of the patients (34/59) achieved a therapeutic response at the end of the research period. Compared with the FMT group, the FMT+S group had better clinical benefit (P < 0.05). In the comparison of efficacy at week 1 and week 13 after treatment, the Mayo scores, calprotectin levels, and CRP indexes in the FMT+S group were better than those in the FMT group (P < 0.05). There were no serious adverse events in the treatment process or during follow-up.Conclusion: A combination of FMT capsules and thalidomide provides a treatment choice for patients with hormone-dependent UC, and it can be used as an adjuvant therapy. However, large-scale, multi-center, and prospective trials are required to further verify the reliability of this treatment.Keywords: fecal microbiota transplantation capsules, thalidomide, hormone-dependent ulcerative colitis

The Daya Bay experiment was the first to report simultaneous measurements of reactor antineutrinos at multiple baselines leading to the discovery of ν¯e oscillations over km-baselines. Subsequent data has provided the world's most precise measurement of sin22θ13 and the effective mass splitting Δmee2. The experiment is located in Daya Bay, China where the cluster of six nuclear reactors is among the world's most prolific sources of electron antineutrinos. Multiple antineutrino detectors are deployed in three underground water pools at different distances from the reactor cores to search for deviations in the antineutrino rate and energy spectrum due to neutrino mixing. Instrumented with photomultiplier tubes, the water pools serve as shielding against natural radioactivity from the surrounding rock and provide efficient muon tagging. Arrays of resistive plate chambers over the top of each pool provide additional muon detection. The antineutrino detectors were specifically designed for measurements of the antineutrino flux with minimal systematic uncertainty. Relative detector efficiencies between the near and far detectors are known to better than 0.2%. With the unblinding of the final two detectors' baselines and target masses, a complete description and comparison of the eight antineutrino detectors can now be presented. This paper describes the Daya Bay detector systems, consisting of eight antineutrino detectors in three instrumented water pools in three underground halls, and their operation through the first year of eight detector data-taking.

The Daya Bay experiment consists of functionally identical antineutrino detectors immersed in pools of ultrapure water in three well-separated underground experimental halls near two nuclear reactor complexes. These pools serve both as shields against natural, low-energy radiation, and as water Cherenkov detectors that efficiently detect cosmic muons using arrays of photomultiplier tubes. Each pool is covered by a plane of resistive plate chambers as an additional means of detecting muons. Design, construction, operation, and performance of these muon detectors are described.

A new measurement of the $\theta_{13}$ mixing angle has been obtained at theDaya Bay Reactor Neutrino Experiment via the detection of inverse beta decaystagged by neutron capture on hydrogen. The antineutrino events for hydrogencapture are distinct from those for gadolinium capture with largely differentsystematic uncertainties, allowing a determination independent of thegadolinium-capture result and an improvement on the precision of $\theta_{13}$measurement. With a 217-day antineutrino data set obtained with sixantineutrino detectors and from six 2.9 GW$_{th}$ reactors, the rate deficitobserved at the far hall is interpreted as $\sin^22\theta_{13}=0.083\pm0.018$in the three-flavor oscillation model. When combined with thegadolinium-capture result from Daya Bay, we obtain$\sin^22\theta_{13}=0.089\pm0.008$ as the final result for thesix-antineutrino-detector configuration of the Daya Bay experiment.

A new measurement of the $\theta_{13}$ mixing angle has been obtained at theDaya Bay Reactor Neutrino Experiment via the detection of inverse beta decaystagged by neutron capture on hydrogen. The antineutrino events for hydrogencapture are distinct from those for gadolinium capture with largely differentsystematic uncertainties, allowing a determination independent of thegadolinium-capture result and an improvement on the precision of $\theta_{13}$measurement. With a 217-day antineutrino data set obtained with sixantineutrino detectors and from six 2.9 GW$_{th}$ reactors, the rate deficitobserved at the far hall is interpreted as $\sin^22\theta_{13}=0.083\pm0.018$in the three-flavor oscillation model. When combined with thegadolinium-capture result from Daya Bay, we obtain$\sin^22\theta_{13}=0.089\pm0.008$ as the final result for thesix-antineutrino-detector configuration of the Daya Bay experiment.

A search for light sterile neutrino mixing was performed with the first 217 days of data from the Daya Bay Reactor Antineutrino Experiment. The experiment's unique configuration of multiple baselines from six 2.9 GW(th) nuclear reactors to six antineutrino detectors deployed in two near (effective baselines 512 m and 561 m) and one far (1579 m) underground experimental halls makes it possible to test for oscillations to a fourth (sterile) neutrino in the 10(-3) eV(2)

A measurement of the energy dependence of antineutrino disappearance at the Daya Bay reactor neutrino experiment is reported. Electron antineutrinos (ν¯(e)) from six 2.9  GW(th) reactors were detected with six detectors deployed in two near (effective baselines 512 and 561 m) and one far (1579 m) underground experimental halls. Using 217 days of data, 41 589 (203 809 and 92 912) antineutrino candidates were detected in the far hall (near halls). An improved measurement of the oscillation amplitude sin(2)2θ(13)=0.090(-0.009)(+0.008) and the first direct measurement of the ν¯(e) mass-squared difference |Δm(ee)2|=(2.59(-0.20)(+0.19))×10(-3)  eV2 is obtained using the observed ν¯(e) rates and energy spectra in a three-neutrino framework. This value of |Δm(ee)2| is consistent with |Δm(μμ)2| measured by muon neutrino disappearance, supporting the three-flavor oscillation model.

The Daya Bay Reactor Neutrino Experiment was designed to achieve a sensitivity on the value of sin22θ13 to better than 0.01 at 90% CL. The experiment consists of eight antineutrino detectors installed underground at different baselines from six nuclear reactors. With data collected with six antineutrino detectors for 55 days, Daya Bay announced the discovery of a non-zero value for sin22θ13 with a significance of 5.2 standard deviations in March 2012. The most recent analysis with 139 days of data acquired in a six-detector configuration yields sin22θ13=0.089±0.010(stat.)±0.005(syst.), which is the most precise measurement of sin22θ13 to date. © 2013.

We report an improved measurement of the neutrino mixing angle θ13 from the Daya Bay Reactor Neutrino Experiment. We exclude a zero value for sin22θ13 with a significance of 7.7 standard deviations. Electron antineutrinos from six reactors of 2.9 GW th were detected in six antineutrino detectors deployed in two near (flux-weighted baselines of 470 m and 576 m) and one far (1648 m) underground experimental halls. Using 139 days of data, 28909 (205308) electron antineutrino candidates were detected at the far hall (near halls). The ratio of the observed to the expected number of antineutrinos assuming no oscillations at the far hall is 0.944±0.007(stat.)±0.003(syst.). An analysis of the relative rates in six detectors finds sin22θ13=0. 089±0.010(stat.)±0.005(syst.) in a three-neutrino framework. © 2013 Chinese Physical Society and the Institute of High Energy Physics of the Chinese Academy of Sciences and the Institute of Modern Physics of the Chinese Academy of Sciences and IOP Publishing Ltd.

Objectives: This study aimed to explore the synergistic interaction effect between hyperuricemia and hypertension towards chronic kidney disease in patients with type 2 diabetes., Methods: This research originates from a cross-sectional study performed in Zhejiang Province, Eastern China, between March and November 2018. The correlation between serum uric acid levels and the risk of chronic kidney disease was assessed using a restricted cubic spline model. An unconditional multivariable logistic regression model, along with an interaction table, was utilized to explore the potential interaction effect of hyperuricemia and hypertension towards chronic kidney disease., Results: 1,756 patients with type 2 diabetes were included in this study, the prevalence of chronic kidney disease (CKD) was 27.62% in this population. A U-shaped non-linear pattern emerged correlating serum uric acid (SUA) levels and CKD risk, indicating that both low and high SUA levels were linked to an increased CKD risk. This risk achieved its lowest point (nadir) at SUA approximately equals to 285μmol/L (p for trend <0.05). Once adjustments for age, gender, education level, abnormal fasting plasma glucose (FPG), abnormal hemoglobin A1c (HbA1c), abnormal total cholesterol (TC), abnormal high-density lipoprotein cholesterol (HDL-C), alcohol consumption and duration of diabetes were factored in, it was found that patients with both hyperuricemia and hypertension demonstrated a 5.42-fold (95% CI: 3.72-7.90) increased CKD risk compared to the reference group. The additive interaction between hyperuricemia and hypertension was statistically significant, as manifested by the following values: a relative excess risk due to interaction (RERI) of 2.57 (95% CI: 0.71-4.71), an attributable proportion due to interaction (AP) of 0.47 (95% CI: 0.14-0.64), and a synergy index (SI) of 2.39 (95% CI: 1.24-4.58). In contrast, there was no significant interaction effect in multiplicative scale., Conclusion: Hyperuricemia and hypertension may contribute additively to CKD, beyond their isolated impacts. Evaluating the risk of CKD in type 2 diabetes patients necessitates considering this potential interaction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Lu, Zhang, Xu, Du, Liang, Chen and Zhong.)

The progression of prostate cancer (PCa) leads to poor prognosis. However, the molecular mechanism of PCa is still not completely clear. This study aimed to elucidate the important role of centromere protein A (CENPA) in PCa. Large numbers of bulk RNA sequencing (RNA-seq) data and in-house immunohistochemistry data were used in analysing the expression level of CENPA in PCa and metastatic PCa (MPCa). Single-cell RNA-seq data was used to explore the expression status of CENPA in different prostate subpopulations. Enrichment analysis was employed to detect the function of CENPA in PCa. Clinicopathological parameters analysis was utilised in analysing the clinical value of CENPA. The results showed that CENPA was upregulated in PCa (standardised mean difference [SMD] = 0.83, p = 0.001) and MPCa (SMD = 0.61, p = 0.029). CENPA was overexpressed in prostate cancer stem cells (CSCs) with androgen receptor (AR) negative compared to epithelial cells with AR positive. CENPA may influence the development of PCa through affecting cell cycle. Patients with nodal metastasis had higher expression level of CENPA. And patients with high CENPA expression had poor disease-free survival. Taken together, Overexpression of CENPA may influence the development of PCa by regulating cell cycle and promoting metastasis., (© 2023 The Authors. IET Systems Biology published by John Wiley & Sons Ltd on behalf of The Institution of Engineering and Technology.)

The treatment of bone defects remains a significant challenge to be solved clinically. Immunomodulatory properties of orthopedic biomaterials have significance in regulating osteoimmune microenvironment for osteogenesis. A lactic acid-co-glycolic acid (PLGA) scaffold incorporates black phosphorus (BP) fabricated by 3D printing technology to investigate the effect of BP on osteoimmunomodulation and osteogenesis in site. The PLGA/BP scaffold exhibits suitable biocompatibility, biodegradability, and mechanical properties as an excellent microenvironment to support new bone formation. The studies' result also demonstrate that the PLGA/BP scaffolds are able to recruit and stimulate macrophages M2 polarization, inhibit inflammation, and promote human bone marrow mesenchymal stem cells (hBMSCs) proliferation and differentiation, which in turn promotes bone regeneration in the distal femoral defect region of steroid-associated osteonecrosis (SAON) rat model. Moreover, it is screened and demonstrated that PLGA/BP scaffolds can promote osteogenic differentiation by transcriptomic analysis, and PLGA/BP scaffolds promote osteogenic differentiation and mineralization by activating PI3K-AKT signaling pathway in hBMSC cells. In this study, it is shown that the innovative PLGA/BP scaffolds are extremely effective in stimulating bone regeneration by regulating macrophage M2 polarization and a new strategy for the development of biomaterials that can be used to repair bone defects is offered., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Chest tightness variant asthma (CTVA) was first reported and named by Chinese scholars in 2013. It is a new clinical type of asthma characterized by chest tightness as the only or primary symptom, without typical asthma manifestations such as recurrent wheezing and shortness of breath, and without wheezing sounds heard during lung auscultation. The overall epidemiological data on CTVA is currently unavailable. Its pathogenesis is similar to that of typical asthma, involving eosinophilic airway inflammation. Due to the lack of typical clinical manifestations, insufficient knowledge of this disease in some clinicians and some other reasons, CTVA is susceptible to misdiagnosis or missed diagnosis. Currently, the diagnostic criteria for CTVA are: chest tightness as the only or primary symptom, without typical asthma symptoms and signs such as wheezing and shortness of breath, and with any one of the objective indicators of variable airflow limitation. Effective anti-asthma treatment is required, and other diseases that cause chest tightness, such as cardiovascular, digestive, nervous, muscular, and mental diseases should be excluded. CTVA treatment follows that of typical asthma, but the specific treatment duration is uncertain and may require long-term management. Traditional Chinese medicine has shown some therapeutic effects on CTVA. Most CTVA patients have a good prognosis after active anti-asthma treatment. This paper analyzes and summarizes the research of CTVA in China from 2013 and provides new perspectives for further exploration of CTVA.

The circadian clock orchestrates a wide variety of physiological and behavioral processes, enabling animals to adapt to daily environmental changes, particularly the day-night cycle. However, the circadian clock's role in the developmental processes remains unclear. Here, we employ the in vivo long-term time-lapse imaging of retinotectal synapses in the optic tectum of larval zebrafish and reveal that synaptogenesis, a fundamental developmental process for neural circuit formation, exhibits circadian rhythm. This rhythmicity arises primarily from the synapse formation rather than elimination and requires the hypocretinergic neural system. Disruption of this synaptogenic rhythm, by impairing either the circadian clock or the hypocretinergic system, affects the arrangement of the retinotectal synapses on axon arbors and the refinement of the postsynaptic tectal neuron's receptive field. Thus, our findings demonstrate that the developmental synaptogenesis is under hypocretin-dependent circadian regulation, suggesting an important role of the circadian clock in neural development., (© 2023. The Author(s).)

Competing Interests: There are no conflicts of interest.

Background: Acid phosphatase type 6 (ACP6) is a mitochondrial lipid phosphate phosphatase that played a role in regulating lipid metabolism and there is still blank in the clinico-pathological significance and functional roles of ACP6 in human cancers. No investigations have been conducted on ACP6 in hepatocellular carcinoma (HCC) up to date., Methods: Herein, we appraised the clinico-pathological significance of ACP6 in HCC via organizing expression profiles from globally multi-center microarrays and RNA-seq datasets. The molecular basis of ACP6 in HCC was explored through multidimensional analysis. We also carried out in vitro and in vivo experiment on nude mice to investigate the effect of knocking down ACP6 expression on biological functions of HCC cells, and to evaluate the expression variance of ACP6 in xenograft of HCC tissues before and after the treatment of NC., Results: ACP6 displayed significant overexpression in HCC samples (standard mean difference (SMD) = 0.69, 95% confidence interval (CI) = 0.56-0.83) and up-regulated ACP6 performed well in screening HCC samples from non-cancer liver samples. ACP6 expression was also remarkably correlated with clinical progression and worse overall survival of HCC patients. There were close links between ACP6 expression and immune cells including B cells, CD8 + T cells and naive CD4 + T cells. Co-expressed genes of ACP6 mainly participated in pathways including cytokine-cytokine receptor interaction, glucocorticoid receptor pathway and NABA proteoglycans. The proliferation and migration rate of HCC cells transfected with ACP6 siRNA was significantly suppressed compared with those transfected with negative control siRNA. ACP6 expression was significantly inhibited by nitidine chloride (NC) in xenograft HCC tissues., Conclusions: ACP6 expression may serve as novel clinical biomarker indicating the clinical development of HCC and ACP6 might be potential target of anti-cancer effect by NC in HCC., (© 2022. The Author(s).)

Stromal antigen 1 (STAG1), a component of cohesion, is overexpressed in various cancers, but it is unclear whether it has a role in the transcriptional regulation of hepatocellular carcinoma (HCC). To test this hypothesis, here, we screened global HCC datasets and performed multiscale embedded gene co-expression network analysis to identify the potential functional modules of differentially expressed STAG1 co-expressed genes. The putative transcriptional targets of STAG1 were identified using chromatin immunoprecipitation followed by high-throughput DNA sequencing. The cohesin-associated gene score (CAGS) was quantified using the The Cancer Genome Atlas HCC cohort and single-sample gene set enrichment analysis. Distinct cohesin-associated gene patterns were identified by calculating the euclidean distance of each patient. We assessed the potential ability of the CAGS in predicting immune checkpoint blockade (ICB) treatment response using IMvigor210 and GSE78220 cohorts. STAG1 was upregulated in 3313 HCC tissue samples compared with 2692 normal liver tissue samples (standard mean difference = 0.54). A total of three cohesin-associated gene patterns were identified, where cluster 2 had a high TP53 mutated rate and a poor survival outcome. Low CAGS predicted a significant survival advantage but presaged poor immunotherapy response. Differentially expressed STAG1 co-expression genes were enriched in the mitotic cell cycle, lymphocyte activation, and blood vessel development. PDS5A and PDGFRA were predicted as the downstream transcriptional targets of STAG1. In summary, STAG1 is significantly upregulated in global HCC tissue samples and may participate in blood vessel development and the mitotic cell cycle. A cohesin-associated gene scoring system may have potential to predict the ICB response., (© 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Microglia are the resident immune cells in the brain. It is well known that brain injury can activate the microglia and induce its directional migration towards the injury sites for exerting immune functions. While extracellular ATP released from the injury site mediates the directionality of activated microglia's migration, what endows activated microglia with migration capability remains largely unexplored. In the present study, we used the larval zebrafish as an in vivo model to visualize the dynamics of both morphology and Ca 2+ activity of microglia during its migration evoked by local brain injury. We found that, in response to local injury, activated microglia exhibited an immediate Ca 2+ transient and later sustained Ca 2+ bursts during its migration towards the local injury site. Furthermore, suppression of Ca 2+ activities significantly retarded microglial cell migration. Thus, our study suggests that intracellular Ca 2+ activity is required for activated microglia's migration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V.)

Frontal fibrosing alopecia (FFA) is a primary patterned cicatricial alopecia that mostly affects postmenopausal women and causes frontotemporal hairline regression and eyebrow loss. Although the incidence of FFA has increased worldwide over the last decade, its etiology and pathology are still unclear. We cover the latest findings on its pathophysiology, including immunomodulation, neurogenic inflammation, and genetic regulation, to provide more alternatives for current clinical treatment. A persistent inflammatory response and immune privilege (IP) collapse develop and lead to epithelial hair follicle stem cells (eHFSCs) destruction and epithelial-mesenchymal transition (EMT) in the bulge area, which is the key process in FFA pathogenesis. Eventually, fibrous tissue replaces normal epithelial tissue and fills the entire hair follicle (HF). In addition, some familial reports and genome-wide association studies suggest a genetic susceptibility or epigenetic mechanism for the onset of FFA. The incidence of FFA increases sharply in postmenopausal women, and many FFA patients also suffer from female pattern hair loss in clinical observation, which suggests a potential association between FFA and steroid hormones. Sun exposure and topical allergens may also be triggers of FFA, but this conjecture has not been proven. More evidence and cohort studies are needed to help us understand the pathogenesis of this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miao, Jing, Du, Mao, Yang and Lv.)

Diutina catenulata ( Candida catenulata ) is an ascomycete yeast species widely used in environmental and industrial research and capable of causing infections in humans and animals. At present, there are only a few studies on D. catenulata , and further research is required for its more in-depth characterization and analysis. Eleven strains of D. catenulata collected from China Hospital Invasive Fungal Surveillance Net (CHIF-NET) and the CHIF-NET North China Program were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry and internal transcribed spacer sequencing. The antifungal susceptibility of the Diutina catenulata strains was tested using the Clinical and Laboratory Standards Institute broth microdilution method and Sensititre YeastOne™. Furthermore, ERG11 and FKS1 were sequenced to determine any mutations related to azole and echinocandin resistance in D. catenulata . All isolates exhibited low minimum inhibitory concentration (MIC) values for itraconazole (0.06-0.12 μg/ml), posaconazole (0.06-0.12 μg/ml), amphotericin B (0.25-1 μg/ml), and 5-flucytosine (range, <0.06-0.12 μg/ml), whereas four isolates showed high MICs (≥4 μg/ml) for echinocandins. Strains with high MIC values for azoles showed common ERG11 mutations, namely, F126L/K143R. In addition, L139R mutations may be linked to high MICs of fluconazole. Two amino acid alterations reported to correspond to high MIC values of echinocandin, namely, F621I (F641) and S625L (S645), were found in the hot spot 1 region of FKS1 . In addition, one new amino acid alteration, I1348S (I1368), was found outside of the FKS1 hot spot 2 region, and its contribution to echinocandin resistance requires future investigation. Diutina catenulata mainly infects patients with a weak immune system, and the high MIC values for various antifungals exhibited by these isolates may represent a challenge to clinical treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Zhang, Fan, Hou, Liu, Huang, Kang, Zhang, Zhang, Yang, Li, Wang, Guo, Sun, Chen, Zou, Du, Pan, Li, He and Xu.)

Objective: To investigate the clinical significance of human leukocyte antigen (HLA)-E levels in oesophageal squamous cell carcinoma (ESCC)., Methods: The levels of HLA-E immunostaining in ESCC lesions and 47 corresponding adjacent normal tissues were measured using immunohistochemistry. The correlation between the levels of immunostaining and clinical parameters was analysed., Results: This study analysed 110 paraffin-embedded primary tumour lesions and 47 case-controlled paracancerous tissues that were surgically resected from 110 patients with ESCC. Positive immunostaining for HLA-E was observed in 88.2% (97 of 110) of ESCC lesions and 29.8% (14 of 47) of normal oesophageal tissues. There was no correlation between HLA-E immunostaining in ESCC lesions and clinicopathological characteristics such as lymph node metastasis, tumour-node-metastasis stage and differentiation grade. Kaplan-Meier survival analysis revealed a significantly better prognosis in patients with higher levels of HLA-E immunostaining than in those with lower levels of HLA-E immunostaining; overall survival was 28.6 months (95% confidence interval [CI], 23.2, 34.0) versus 15.3 months (95% CI, 11.5, 19.1), respectively. Furthermore, multivariate analysis showed that the HLA-E level was an independent prognostic factor in patients with ESCC., Conclusion: A higher level of HLA-E immunostaining was associated with favourable survival in patients with ESCC.

Background: The immunoregulatory functions of regulatory T cells (Tregs) in the development and progression of some chronic infectious diseases are mediated by immune checkpoint molecules and immunosuppressive cytokines. However, little is known about the immunosuppressive functions of Tregs in human brucellosis, which is a major burden in low-income countries. In this study, expressions of immune checkpoint molecules and Treg-related cytokines in patients with acute and chronic Brucella infection were evaluated to explore their impact at different stages of infection., Methods: Forty patients with acute brucellosis and 19 patients with chronic brucellosis admitted to the Third People's Hospital of Linfen in Shanxi Province between August 2016 and November 2017 were enrolled. Serum and peripheral blood mononuclear cells were isolated from patients before antibiotic treatment and from 30 healthy subjects. The frequency of Tregs (CD4 + CD25 + FoxP3 + T cells) and expression of CTLA-4, GITR, and PD-1 on Treg cells were detected by flow cytometry. Levels of Treg-related cytokines, including IL-35, TGF-β1, and IL-10, were measured by customised multiplex cytokine assays using the Luminex platform., Results: The frequency of Tregs was higher in chronic patients than in healthy controls (P = 0.026) and acute patients (P = 0.042); The frequency of CTLA-4 + Tregs in chronic patients was significantly higher than that in healthy controls (P = 0.011). The frequencies of GITR + and PD-1 + Tregs were significantly higher in acute and chronic patients than in healthy controls (P < 0.05), with no significant difference between the acute and chronic groups (all P > 0.05). Serum TGF-β1 levels were higher in chronic patients (P = 0.029) and serum IL-10 levels were higher in acute patients (P = 0.033) than in healthy controls. We detected weak correlations between serum TGF-β1 levels and the frequencies of Tregs (R = 0.309, P = 0.031) and CTLA-4 + Tregs (R = 0.302, P = 0.035)., Conclusions: Treg cell immunity is involved in the chronicity of Brucella infection and indicates the implication of Tregs in the prognosis of brucellosis. CTLA-4 and TGF-β1 may contribute to Tregs-mediated immunosuppression in the chronic infection stage of a Brucella infection., (© 2021. The Author(s).)

Background: Hepatocellular carcinoma (HCC) remains one of the most common malignant neoplasms. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a key role in the lipid remodelling and is correlated with various neoplasms. Nonetheless, the biological functions and molecular mechanisms of LPCAT1 underlying HCC remain obscure., Methods: In the present study, we investigated the role of LPCAT1 in the progression of HCC. In-house RT-qPCR, tissue microarrays, and immunohistochemistry were performed to detect the expression levels and the clinical value of LPCAT1 in HCC. External datasets were downloaded to confirm the results. Proliferation, migration, invasiveness, cell cycle, and apoptosis assays were conducted to reveal the biological effects LPCAT1 has on SMMC-7721 and Huh7 cells. HCC differentially expressed genes and LPCAT1 co-expressed genes were identified to explore the molecular mechanisms underlying HCC progression., Results: LPCAT1 showed upregulated expression in 3715 HCC specimens as opposed to 3105 non-tumour specimens. Additionally, LPCAT1 might be an independent prognostic factor for HCC. LPCAT1-knockout hampered cellular proliferation, migration, and metastasis in SMMC-7721 and Huh7 cells. More importantly, the cell cycle and chemical carcinogenesis were the two most enriched signalling pathways., Conclusions: The present study demonstrated that increased LPCAT1 correlated with poor prognosis in HCC patients and fuelled HCC progression by promoting cellular growth, migration, and metastasis., (© 2021. The Author(s).)

Objective: Low back pain is a leading cause of disabilities worldwide, and intervertebral disc degeneration (IVDD)-related disorders have been recognised as one of the main contributors. Nevertheless, the underlying mechanism has not yet been fully understood. The aim of this study was to investigate the role of the miR-133a-5p/FBXO6 axis in the regulation of IVDD., Methods: RT-qPCR, WB and IHC were performed to assess the expression of FBXO6 in human IVD tissues. Nucleus pulposus (NP) cells were treated with IL-1β to induce IVDD cellular model. Silence of FBXO6 was achieved using specific siRNAs. CCK-8 assay, flow cytometry, TUNEL assay, RT-qPCR and WB were used to evaluate the role and mechanism of FBXO6 in the process of IVDD. Online tools, GSE datasets and RT-qPCR were used to search the candidate miRNAs targeting FBXO6. The direct binding sites between FBXO6 and miR-133a-5p were further verified by a dual luciferase assay. RT-qPCR, WB and rescue experiments were conducted to identify the regulatory function of miR-133a-5p on the expression of aggrecan, collagen Ⅱ, MMP3, ADAMTS5, IL-6 and COX2. In addition, the role of the NF-κB pathway in regulating miR-133a-5p was studied using lentiviral shRNA, WB and RT-qPCR., Results: Results showed that FBXO6 mainly expressed in the NP tissue of IVD and the expression of FBXO6 decreased with the process of IVDD as well as under IL-1β stimulation. The silence of FBXO6 led to the decreased expression of aggrecan and collagen Ⅱ and the increased expression of MMP3, ADAMTS5, IL-6 and COX2, which further induced the degeneration of NP cells. The bioinformatic analysis showed that miR-133a-5p was the candidate miRNA targeting FBXO6. miR-133a-5p was upregulated in IVDD tissues and significantly inhibited the expression of FBXO6. The inhibition of miR-133a-5p ameliorated the acceleration of IVDD induced by the silence of FBXO6 in vitro. Moreover, it was demonstrated that IL-1β regulated the expression of the miR-133a-5p/FBXO6 axis via the NF-κB pathway in NP cells., Conclusion: miR-133a-5p was upregulated by IL-1β to aggravate intervertebral disc degeneration via sponging FBXO6. Inhibiting miR-133a-5p expression or rescuing FBXO6 expression may be promising strategies for the treatment of IVDD., The Translational Potential of This Article: This study suggests that the miR-133a-5p/FBXO6 axis could regulate NP cells proliferation, apoptosis, synthesis and degradation of extracellular matrix, which provides a promising therapeutic target and strategy for the treatment of IVDD., Competing Interests: The authors have no conflicts of interest to disclose in relation to this article., (© 2021 The Authors.)

BACKGROUND Hepatocellular carcinoma (HCC) causes a heavy disease burden worldwide. Cell division cycle 45 (Cdc45) and its encoding gene (CDC45) have been studied for a long time, but their expression patterns and roles in liver carcinogenesis and advanced HCC deterioration are still incompletely understood. This study integrated tissue microarray and bioinformatics analyses to explore the expression and clinical value of CDC45 and Cdc45 in HCC. MATERIAL AND METHODS In HCC, the expression and relationships with clinic-pathological parameters of CDC45 and Cdc45 were investigated by integrating the RNA-sequencing data, downloaded from The Cancer Genome Atlas and Oncomine databases, and tissue microarray with immunohistochemistry staining. Co-expressed genes and genetic alterations of CDC45 separately obtained from Oncomine and cBioPortal databases were identified to shed light on the potential mechanisms of CDC45 in HCC. RESULTS CDC45 and Cdc45 were both overexpressed in HCC tissues, and the CDC45 level progressively increased from stage I to III. The survival outcomes of the group with high CDC45 expression were significantly worse compared with the group with low expression. Amplification and deep deletion were 2 major significant alteration types in HCC patients, and the outcomes were worse in patients with altered versus unaltered CDC45. NUDT1, E2F1, CCNE2, MCM5, and CENPM were identified as the most significantly co-expressed genes. CONCLUSIONS CDC45 and Cdc45 were both upregulated in HCC, and increased expression levels and genetic alternations of CDC45 were correlated with worse prognosis in HCC patients. CDC45 may promote HCC by co-expressing with NUDT1, E2F1, CCNE2, MCM5, and CENPM.

During development, endothelial tip cells (ETCs) located at the leading edge of growing vascular plexus guide angiogenic sprouts to target vessels, and thus, ETC pathfinding is fundamental for vascular pattern formation in organs, including the brain. However, mechanisms of ETC pathfinding remain largely unknown. Here, we report that Piezo1-mediated Ca 2+ activities at primary branches of ETCs regulate branch dynamics to accomplish ETC pathfinding during zebrafish brain vascular development. ETC branches display spontaneous local Ca 2+ transients, and high- and low-frequency Ca 2+ transients cause branch retraction through calpain and branch extension through nitric oxide synthase, respectively. These Ca 2+ transients are mainly mediated by Ca 2+ -permeable Piezo1 channels, which can be activated by mechanical force, and mutating piezo1 largely impairs ETC pathfinding and brain vascular patterning. These findings reveal that Piezo1 and downstream Ca 2+ signaling act as molecular bases for ETC pathfinding and highlight a novel function of Piezo1 and Ca 2+ in vascular development., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Previous studies showed that soluble IL-2Rα is an important marker of cellular immune activation and might be a marker of treatment efficacy for children with brucellosis. However, data regarding adult patients with brucellosis were unknown. The aim of study was to explore the potential role of serum sIL-2Rα evaluating treatment responses in adult patients with brucellosis, and T cell immune status was also examined., Methods: During January 2016-April 2017, 30 patients with acute brucellosis from the Third People's Hospital of Linfen in Shanxi Province and Beijing Di Tan Hospital, and 28 healthy controls were included in this study. Peripheral blood samples were collected before and after six weeks of antibiotic treatment. Serum sIL-2Rα levels were measured by enzyme-linked immunosorbent assay, and the percentage of Th1, Th2, Tc1, Tc2, and Tregs was detected by flow cytometry after intracellular staining for cytokines (interferon-γ and interleukin-4) and Foxp3 in T lymphocytes from peripheral blood. The obtained data were analyzed with Wilcoxon ranked sum tests for paired values, Mann-Whitney U-tests for comparisons between patients and healthy controls, and Spearman rank tests for correlation analyses., Results: Serum sIL-2Rα levels were significantly higher in patients than in controls (P = 0.001). A significant decline was observed in patients after the cessation of treatment (P < 0.001) and return to normal (P > 0.05). Th1, Tc1, Th2, and Tc2 cell frequencies were higher in patients than in healthy subjects (P < 0.05), while the Th1/Th2 and Tc1/Tc2 ratios were significantly lower (P = 0.0305 and 0.0005, respectively) and returned to normal levels after treatment. In patients with acute brucellosis, serum sIL-2Rα levels were negatively correlated with the Th1/Th2 ratio (r = - 0.478, P = 0.028), Tc1/Tc2 ratio (r = - 0.677, P = 0.001), and Tc1 percentage (r = - 0.516, P = 0.017). Serum sIL-2Rα and Tc2 percentages were positively correlated (r = 0.442, P = 0.045)., Conclusions: Based on the correlations with Th1/Th2 and Tc1/Tc2 ratios, serum sIL-2Rα levels may reflect the immune response status. sIL-2Rα may be a marker for therapeutic efficacy in acute brucellosis.

Background: Intestinal inflammation is a common digestive tract disease, which is usually treated with hormone medicines. Hormone medicines are effective to some extent, but long-term use of them may bring about many complications., Aim: To explore the protective effects of panax notoginseng saponin (PNS) against dextran sulfate sodium (DSS)-induced intestinal inflammatory injury through phosphoinositide-3-kinase protein kinase B (PI3K/AKT) signaling pathway inhibition in rats., Methods: Colitis rat models were generated via DSS induction, and rats were divided into control (no modeling), DSS, DSS + PNS 50 mg/k, and DSS + PNS 100 mg/kg groups. Then, the intestinal injury, oxidative stress parameters, inflammatory indices, tight junction proteins, apoptosis, macrophage polarization, and TLR4/AKT signaling pathway in colon tissues from rats in each of the groups were detected. The PI3K/AKT signaling pathway in the colon tissue of rats was blocked using the PI3K/AKT signaling pathway inhibitor, LY294002., Results: Compared with rats in the control group, rats in the DSS group showed significantly shortened colon lengths, and significantly increased disease activity indices, oxidative stress reactions and inflammatory indices, as well as significantly decreased expression of tight junction-associated proteins. In addition, the DSS group showed significantly increased apoptotic cell numbers, and showed significantly increased M1 macrophages in spleen and colon tissues. They also showed significantly decreased M2 macrophages in colon tissues, as well as activation of the PI3K/AKT signaling pathway (all P < 0.05). Compared with rats in the DSS group, rats in the DSS + PNS group showed significantly lengthened colon lengths, decreased disease activity indices, and significantly alleviated oxidative stress reactions and inflammatory responses. In addition, this group showed significantly increased expression of tight junction-associated proteins, significantly decreased apoptotic cell numbers, and significantly decreased M1 macrophages in spleen and colon tissues. This group further showed significantly increased M2 macrophages in colon tissues, and significantly suppressed activation of the PI3K/AKT signaling pathway, as well as a dose dependency (all P < 0.05). When the PI3K/AKT signaling pathway was inhibited, the apoptosis rate of colon tissue cells in the DSS + LY294002 group was significantly lower than that of the DSS group ( P < 0.05)., Conclusion: PNS can protect rats against DSS-induced intestinal inflammatory injury by inhibiting the PI3K/AKT signaling pathway, and therefore may be potentially used in the future as a drug for colitis., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Ulcerative colitis (UC) is a main form of inflammatory bowel disease. Due to complicated etiology and a high rate of recurrence, it is quite essential to elucidate the underlying mechanism of and search for effective therapeutic methods for UC., Aim: To investigate the effects of astragalus polysaccharides (APS) combined with matrine on UC and associated lung injury., Methods: UC was induced in rats by colon mucosal tissue sensitization combined with trinitro-benzene-sulfonic acid-ethanol. Then, the effects of the treatments of salazopyrine, APS, matrine, and APS combined with matrine on histopathological changes of lung and colon tissues, disease activity index (DAI), colon mucosal damage index (CMDI), serum endotoxin (ET) level, serum diamine oxidase (DAO) activity, the contents of tumor necrosis factor-α and interleukin-1β, and the activities of myeloperoxidase, superoxide dismutase, and malondialdehyde in lung tissues, as well as the protein expression of zonula occludens (ZO)-1, Occludin, and trefoil factor 3 (TFF3) were detected in UC rats., Results: The treatments of salazopyrine, APS, matrine, and APS combined with matrine reduced DAI scores and improved histopathological changes of colon and lung tissues, as well as decreased CMDI scores, ET levels, and DAO activities in UC rats. Moreover, in lung tissues, inflammatory response and oxidative stress injury were relieved after the treatments of salazopyrine, APS, matrine, and APS combined with matrine in UC rats. Furthermore, the expression of ZO-1, Occludin, and TFF3 in lung and colon tissues was increased after different treatments in UC rats. Notably, APS combined with matrine exerted a better protective effect against UC and lung injury compared with other treatments., Conclusion: APS combined with matrine exert a synergistic protective effect against UC and lung injury, which might be associated with regulating TFF3 expression., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To identify the abnormal regional spontaneous brain activity associated with relapsing-remitting multiple sclerosis (RRMS) using fractional amplitude of low-frequency fluctuation (fALFF) analysis and their relationships with clinical features. Methods: A total of 26 RRMS (11 males, 15 females; age, 36.58 ± 10.82 years) and 27 status-matched healthy group (HGs; 12 males, 15 females; age, 35.85 ± 12.05 years) underwent an Expanded Disability Status Scale (EDSS) examination. fALFF was applied to evaluate the abnormal regional brain activity associated with RRMS. Pearson's correlation analysis was applied to calculate the correlations between the signal values of brain areas that exhibited abnormal fALFF values and clinical features. Receiver operating characteristic (ROC) curve was performed to evaluate the sensitivity and specificity of those altered brain areas to distinguish between RRMS and HGs. Results: Compared with HGs, RRMS exhibited higher fALFF in the right cerebellum posterior lobe, left orbitofrontal cortex, left dorsolateral prefrontal cortex, bilateral supplementary motor area, and right fusiform gyrus and lower fALFF values in the left hippocampus and right precuneus. ROC revealed that these areas showed two good and five fair AUC values (0.77 ± 0.03, 0.729~0.822). However, four combinations with more than five brain regions received the same best discriminatory power with a sensitivity of 96.3% and a specificity of 88.5%. EDSS revealed a negative correlation with supplementary motor area ( r = -0.395, p = 0.046). Conclusions: RRMS is associated with abnormal regional brain activity deficits of motor- and cognitive-related areas. The fALFF parameter may serve as a potential biological marker to discriminate between the two groups., (Copyright © 2019 Du, Liu, Hua and Wu.)

The surface modification of nanoparticles (NPs) can enhance cellular and intracellular targeting. A new type of polyamine-modified gold NPs (AuNPs) are designed and synthesized, which can be selectively absorbed onto the cell membrane. AuNPs with an average diameter of 4.0 nm were prepared and modified with polyamine (R-4C) through amidation. In order to detect the distribution of NPs within cells by fluorescence imaging, AuNP@MPA-R-4C was functionalized with fluorescein isothiocyanate (FITC). The fluorescence-labled NPs AuNP@MPA-R-4C-FITC demonstrated minimal cytotoxicity in several cell lines. Both confocal laser scanning microscopy and transmission electron microscopy demonstrated that AuNP@MPA-R-4C-FITC was distributed on the cell membrane. Compared with the free organic dye, the modified AuNPs showed significantly increased accumulation on the cell membrane after treatment for only 10 min. These results suggested that AuNP@MPA-R-4C-FITC can be used as a bioprobe targeting the cell membrane for various biological applications., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Introduction: Achieving efficacious and safe treatments for unstable angina pectoris (UAP) is still a challenging clinical problem. The availability of different oral Chinese patent medicines frequently poses a practical challenge to clinicians, namely, which one to choose as first-line regimen for treatment. This study aims to examine the comparative effectiveness and safety of oral Chinese patent medicines for UAP on the national essential drugs list of China., Methods and Analysis: We will conduct a network meta-analysis (NMA) of all randomised controlled trials to evaluate the use of oral Chinese patent medicines as adjuvant for the treatment of UAP. We will explore eight electronic databases from their inception to June 2018 and search for grey literature. Primary outcomes include mortality and the cardiovascular events. Secondary outcomes include: (1) symptom improvement; (2) ECG improvement; (3) frequency of acute angina attack; (4) duration of angina; (5) adverse effects. Two independent authors will screen titles and abstracts, review full texts, extract data, assess the risk of bias using the Cochrane risk of bias tool and assess the quality of evidence and strength of the recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). If adequate data are available, NMA will be performed with Bayesian analysis methods., Ethics and Dissemination: The NMA will help us to reduce the uncertainty of interventions and help clinicians to make optimal and more accurate therapeutic decisions for adults with UAP. Therefore, we will publish the findings of this study in a peer-reviewed journal. No ethics approval is necessary for this study based on the nature of its design., Trial Registration Number: CRD42018092822., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

With the elderly population rapidly growing, the prevalence of Parkinson's disease (PD) is quickly increasing because neurodegenerative disorders are usually late-onset. Herbal medicines and formula are adjuvant therapies of conventional PD agents, which result in serious side effects with long-term use. This study evaluated the neuroprotective effects of DA-9805, a standardized herbal formula that consists of an ethanolic extract of Moutan Cortex Radix, Angelica Dahuricae Radix, and Bupleuri Radix against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in vitro and in vivo. In PC12 cells, DA-9805 at concentrations of 1 and 10 μg/mL ameliorated cell viability, which was reduced by 6-OHDA. In addition, DA-9805 activated the extracellular-regulated kinase-nuclear transcription factor-erythroid 2-related factor 2 pathway, subsequently stimulating antioxidative enzymes such as NAD(P)H:quinone oxidoreductase 1 and catalase and suppressing apoptosis. Furthermore, DA-9805 prevented 6-OHDA-induced movement impairment, as well as a decrease of dopaminergic neurons and dopamine transmission in rodents. Taken together, these results suggest that the mixed herbal formula DA-9805 may be a pharmaceutical agent for preventing or improving PD., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Anisodamine is used for the treatment of reperfusion injury in various organs. In this study, we investigated the effectiveness and mechanisms of action of anisodamine in promoting recovery from glycerol-induced acute kidney injury (AKI)., Methods: We compared the protective effects of atropine and anisodamine in the rat model of glycerol-induced AKI. We examined signaling pathways involved in oxidative stress, inflammation and apoptosis, as well as expression of kidney injury molecule-1 (KIM-1). Renal injury was assessed by measuring serum creatinine and urea, and by histologic analysis. Rhabdomyolysis was evaluated by measuring creatine kinase levels, and oxidative stress was assessed by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) levels in kidney tissues. Inflammation was assessed by quantifying interleukin 6 (IL-6) and CD45 expression. Apoptosis and necrosis were evaluated by measuring caspase-3 (including cleaved caspase 3) and RIP3 levels, respectively., Results: Glycerol administration resulted in a higher mean histologic damage score, as well as increases in serum creatinine, urea, creatine kinase, reactive oxygen species (ROS), MDA, IL-6, caspase-3 and KIM-1 levels. Furthermore, glycerol reduced kidney tissue SOD activity. All of these markers were significantly improved by anisodamine and atropine. However, the mean histologic damage score and levels of urea, serum creatinine, creatine kinase, ROS and IL-6 were lower in the anisodamine treatment group compared with the atropine treatment group., Conclusion: Pretreatment with anisodamine ameliorates renal dysfunction in the rat model of glycerol-induced rhabdomyolytic kidney injury by reducing oxidative stress, the inflammatory response and cell death.

Background: Halofuginone, which is the main active ingredient of Dichroa fabrifuga, was used to inhibit the synthesis of type I collagen and played increasingly important roles in tumor therapy. This study aims to investigate the protective effects of halofuginone on human umbilical vein endothelial cells (HUVECs) from H2O2-induced apoptosis and oxidative stress., Methods: Propidium iodide and Annexin-V double staining assay was used to measure the apoptosis. Cell viability assay, the measurements of reactive oxygen species (ROS) parameters malondialdehyde and superoxide dismutase, western-blot assays, and quantitative PCR were used to elucidate the effects and mechanisms of halofuginone in protecting H2O2-induced injury., Results: The results showed that halofuginone counteracted H2O2-induced cell viability decline and PCNA downregulation. Furthermore, halofuginone decreased ROS levels and protected HUVECs from H2O2-induced apoptosis. In detail, it showed that H2O2 induced a transient activation of Mitogen-activated protein kinases members ERK1/2 and p38, whereas induced a sustained activation of c-Jun N-terminal kinase (JNK), which play dominant roles in triggering apoptosis. Inhibition of JNK activation also inhibited H2O2-mediated apoptosis. Finally, it was shown that halofuginone upregulated VEGF expressions, which functioned by inhibiting sustained JNK activation, thus protecting HUVECs., Conclusion: Halofuginone has powerful effects in protecting HUVECs from H2O2-induced apoptosis, via upregulating VEGF and inhibiting overactivated JNK phosphorylation. Halofuginone might be a promising preventive drug for cardiovascular diseases.

Moutan cortex, Angelica Dahurica root, and Bupleurum root are traditional herbal medicines used in Asian countries to treat various diseases caused by oxidative stress or inflammation. Parkinson's disease (PD) has been associated with mitochondrial dysfunction, but no effective treatment for mitochondrial dysfunction has yet been identified. In this study we investigated the neuroprotective effects of the triple herbal extract DA-9805 in experimental models of PD. DA-9805 was prepared by extracting three dried plant materials (Moutan cortex, Angelica Dahurica root, and Bupleurum root in a 1:1:1 mixture) with 90% ethanol on a stirring plate for 24 h at room temperature and fingerprinted using high-performance liquid chromatography. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP + ), which both exert neurotoxic effects on dopaminergic neurons by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) complex I, were used to make experimental models of PD. In MPP + -treated SH-SY5Y cells, DA-9805 ameliorated the suppression of tyrosine hydroxylase expression and mitochondrial damage on OXPHOS complex 1 activity, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and oxygen consumption rate. In the MPTP-induced subacute PD model mice, oral administration of DA-9805 recovered dopamine content as well as bradykinesia, as determined by the rotarod test. DA-9805 protected against neuronal damage in the substantia nigra pars compacta (SNpc) and striatum. In both in vitro and in vivo models of PD, DA-9805 normalized the phosphorylation of AKT at S473 and T308 on the insulin signaling pathway and the expression of mitochondria-related genes. These results demonstrate that the triple herbal extract DA-9805 showed neuroprotective effects via alleviating mitochondria damage in experimental models of PD. We propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics for PD.

Purpose: Oxidative stress was significantly associated with the development of malignancies. The purpose of this study was to evaluate the significance of serum total oxidant/antioxidant status in operable advanced gastric cancer patients., Materials and Methods: A total of 284 patients who underwent curative resection for primary stage III gastric cancer were enrolled. Total oxidant status, total antioxidant status, and oxidative stress index (OSI) were evaluated within 24 hours before surgery, and compared with 120 healthy donors. The correlation between the OSI and survival outcome was analyzed by the Kaplan-Meier method with log-rank test and Cox's regression methods, respectively., Results: Mean OSI of gastric cancer patients was higher than healthy controls (1.41±0.96 vs 0.78±0.42, P <0.001). All patients were stratified into two groups using the optimal cutoff value (1.42) of OSI using a sensitivity of 94.1% and a specificity of 64.0% as optimal conditions from receiver operating curve analysis. Patients with an OSI ≥1.42 had poorer mean overall survival (45.6 vs 29.8 months, P =0.022) and mean recurrence-free survival (43.3 vs 28.1 months, P =0.011) than patients with an OSI <1.42 in univariate analysis, and OSI was also confirmed as an independent predictor for survival for gastric cancer in multivariate analysis (hazard ratio, 0.541; 95% CI: 0.127-1.102; P =0.01)., Conclusion: Preoperative OSI can be considered as an independent prognostic factor for operable and advanced gastric cancer., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The retinotectal synapse in larval zebrafish, combined with live time-lapse imaging, provides an advantageous model for study of the development and remodelling of central synapses in vivo. In previous studies, these synapses were labelled by transient expression of fluorescence-tagged synaptic proteins, which resulted in the dramatic variation of labelling patterns in each larva. Here, using GAL4-Upstream Activating Sequence (GAL4-UAS) methodology, we generated stable transgenic lines, which express EGFP-tagged synaptophysin (a presynaptic protein) in retinal ganglion cells (RGCs), to reliably label the pre-synaptic site of retinotectal synapses. This tool avoids the variable labelling of RGCs that occurs in transient transgenic larvae. We obtained several stable transgenic lines that differ consistently in the number of labelled RGCs. Using stable lines that consistently had a single labelled RGC, we could trace synaptogenic dynamics on an individual RGC axonal arbor across different developmental stages. In the stable lines that consistently had multiple labelled RGCs, we could simultaneously monitor both pre- and post-synaptic compartments by combining transient labelling of post-synaptic sites on individual tectal neurons. These tools allowed us to investigate molecular events underlying synaptogenesis and found that the microRNA-132 (miR-132) is required for developmental synaptogenesis. Thus, these transgenic zebrafish stable lines provide appropriate tools for studying central synaptogenesis and underlying molecular mechanisms in intact vertebrate brain.

Human hair and street dust from rural and urban areas in Chongqing were collected to analyze Organophosphate esters (OPEs) and phthalate esters (PAEs). Concentrations of OPEs in urban hair were significantly higher than those in rural hair, whereas PAEs concentrations in rural hair were significantly higher than those in urban hair. Different composition patterns of OPEs were observed in rural and urban hair, where tris (2-chloroisopropyl) phosphate (TCIPP), tris (butyl) phosphate (TNBP) and triphenyl phosphate (TPHP) were the dominating analogues in rural hair, accounting for 62.1% of the OPEs burden, and tris (methylphenyl) phosphate (TMPP) exhibited a high contribution in urban hair, responsible for 51.3% of total OPEs, which differed from the composition profiles in corresponding street dust. Analogous composition patterns of PAEs were found in hair of both areas. Di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DNBP), diisobutyl phthalate (DIBP) and diethyl phthalate (DEP) were the most abundant analogues in hair samples, while DEHP was the predominant analogue in dust samples. No clear tendency was obtained between the increasing ages and the concentrations of both compounds. Most OPEs and PAEs congeners showed significantly positive correlation with one another in rural hair. On the contrary, different correlation patterns were observed in urban hair for OPEs and PAEs, indicating multiple or additional sources existed in urban areas. Significant correlations of OPEs and PAEs were found between hair and corresponding street dust samples, but poor correlations of OPEs and PAEs were observed between rural hair and rural indoor dust, suggesting that street dust may be a predominant exogenous source for human exposure to OPEs and PAEs in this area., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Traditional Chinese medicine (TCM) is commonly used for smoking cessation in China. The aim of this study is to perform a comprehensive literature search to identify clinical studies on TCM therapies for smoking cessation., Methods: Publications of randomized controlled trials, controlled clinical studies, cohort studies, case-control studies, case series and case reports, reviews and cross-sectional studies on smoking cessation using TCM therapies were retrieved from seven databases from their inception to February 2017. The following data were extracted and analyzed: study type, year of publication, language, country or region, journals, participants, intervention and comparison, and outcome., Results: In total, 260 publications on TCM therapies for smoking cessation were identified from 1980 to 2016, including 52 randomized clinical trials, 7 controlled clinical studies, 1 cohort study, 110 case series, 18 case reports, 50 narrative reviews, 17 systematic reviews, and 5 cross-sectional studies. Of these, 68.5% (178) were published in Chinese and the remaining published in English. Mainland China (n=129, 49.6%) was the leading country in this field, followed by USA (n=27, 10.4%) and UK (n=25, 9.6%). A total of 36 645 participants from 40 countries with age ranging from 12 to 86 years were involved in 188 clinical studies (excluding reviews and cross-sectional studies). The most commonly reported therapies were auricular acupressure (25, 13.3%), body acupuncture (14, 7.4%), and body acupuncture plus auricular acupressure (14, 7.4%). Composite outcomes were most frequently reported (110, 58.5%)., Conclusions: A substantial number of clinical studies have been conducted and published on TCM therapy for smoking cessation, mainly focusing on acupuncture stimulation techniques. The findings suggest that future research should pay more attention to acupuncture for smoking cessation., Competing Interests: Each of the authors has completed and submitted an ICMJE form for disclosure of potential conflicts of interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work.

Background: Severe acute pancreatitis (SAP) is characterized by the noxious combination of severe systemic inflammation and hypoperfusion and oxidative stress. Ischemia-modified albumin (IMA) was recognized as a novel marker of oxidative stress and ischemia. The purpose of this study was to evaluate serum IMA level in patients with SAP and analyze its prognostic significance. Methods: A total of 72 patients with SAP were enrolled. Serum IMA level was measured within 24 hours of the onset of SAP, and baseline characteristics were recorded. The BISAP, APACHE II and SOFA scores were calculated. Multivariate logistic regression and receiver operating characteristic curve analyses were used to evaluate predictive ability of LMA for in-hospital mortality of SAP. Kaplan-Meier analysis was further used to compare in-hospital mortality difference between high LMA and low LMA. Results: The overall in-hospital mortality rate of all 72 SAP patients was 23.6%. Non-survivor group had higher serum IMA (107.2±10.8 VS 88.4±11.9, P<0.05) than survivor group. Otherwise, the optimal cutoff levels for the IMA predicting in-hospital mortality of patients with SAP was 112 U/ml using a sensitivity of 77.4% and a specificity of 76.2% as optimal conditions (AUC, 0.734; 95% CI: 0.615-0.852; P=0.002). IMA level also was confirmed as an independent prognostic factor for SAP in multivariate analysis. Patient with high IMA level (≥112 U/ml) had poorer survival rate than low IMA (<112 U/ml) in log-rank test of Kaplan-Meier survival analysis (P<0.05). Conclusions: Serum IMA level can be considered as an independent predictor for in-hospital mortality of patients with SAP., Competing Interests: None., (IJCEP Copyright © 2017.)

Background: The associations of occupational activity (OA), commuting, leisure-time physical activity (LTPA), and sitting with overweight/obesity in working adults are controversial. This study explored these factors with the risk of overall and abdominal overweight/obesity in a Chinese working population and whether these associations differ by gender., Methods: A cross-sectional study was conducted. Data analysis was done among 6739 employed participants. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the studied associations., Results: For male employees, those with heavy OA had a lower overall (OR 0.76; 95% CI, 0.62-0.93) and abdominal (OR 0.76; 95% CI, 0.62-0.93) overweight/obesity risk than those with light OA. Those with LTPA ≥150 min/week had a lower risk of overall (OR 0.73; 95% CI, 0.56-0.96) and abdominal (OR 0.70; 95% CI, 0.53-0.91) overweight/obesity than those with LTPA <150 min/week. Men with leisure-sitting time <2.5 h/day had a significantly lower risk of abdominal overweight/obesity than those sitting ≥4 h/day (OR 0.80; 95% CI, 0.65-0.99). And men who cycled to/from work had a lower risk of overall (OR 0.69; 95% CI, 0.53-0.90) and abdominal overweight/obesity (OR 0.71; 95% CI, 0.54-0.92) than passive transports. However, the above significant associations disappeared among female employees., Conclusions: Heavy OA, cycling to/from work, and LTPA were associated with lower risk of overall or abdominal overweight/obesity in male employees. Reducing leisure sitting time can also help male employees reduce the risk of abdominal overweight/obesity. More research on gender disparity in the risk of overweight and obesity should be done., (Copyright © 2017. Production and hosting by Elsevier B.V.)

Vascular integrity helps maintain brain microenvironment homeostasis, which is critical for the normal development and function of the central nervous system. It is known that neural cells can regulate brain vascular integrity. However, due to the high complexity of neurovascular interactions involved, understanding of the neural regulation of brain vascular integrity is still rudimentary. Using intact zebrafish larvae and cultured rodent brain cells, we find that neurons transfer miR-132, a highly conserved and neuron-enriched microRNA, via secreting exosomes to endothelial cells (ECs) to maintain brain vascular integrity. Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular endothelial cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase (eef2k). Disruption of neuronal miR-132 expression or exosome secretion, or overexpression of vascular eef2k impairs VE-cadherin expression and brain vascular integrity. Our study indicates that miR-132 acts as an intercellular signal mediating neural regulation of the brain vascular integrity and suggests that the neuronal exosome is a novel avenue for neurovascular communication.

Background: Evidence on the interrelations between cigarette smoking and a cluster of lifestyle behaviors is scarce for the Chinese youth population. This study is conducted to identify the associations between cigarette smoking and multiple health-related behaviors in a Chinese sample of adolescents., Methods: We used data from 2012 Zhejiang Youth Risk Behavior Survey, which is a school-based survey of 19,542 adolescents that assess risk behaviors using a self-reported questionnaire. The interrelations of cigarette smoking with lifestyle behaviors were investigated using logistic regression models., Results: Cigarette smoking was significantly inversely associated with breakfast (AOR = 0.58), vegetables (AOR = 0.81), fruits (AOR = 0.81), milk consumption (AOR = 0.69) and attending physical education classes (AOR = 0.69), while positively associated with soft drinks (AOR = 2.05), fast food consumption (AOR = 1.21), muscle strengthening activity (AOR = 1.67), computer use (AOR = 1.93) and alcohol drinking (AOR = 5.40)., Conclusions: The results suggested that cigarette smoking was associated with a cluster of health-related behaviors in adolescents, which should be considered in health promotion interventions to target multiple health behaviors.

Objective: The efficacy of growth hormone (GH) co-treatment within a GnRH agonist long regimen, in women with a normal ovarian response to controlled ovarian hyperstimulation (COH), for IVF was assessed., Methods: This retrospective clinical trial was performed in a private-assisted reproduction centre. The study involved 1114 patients who responded normally to high-dose gonadotropin treatment. The study group of 556 patients was given in a daily subcutaneous injection of 4.5 IU of GH co-treatment, starting from the initial day of gonadotropin treatment and lasting for 5 days. The control group of 558 patients received the same treatment protocol without the GH co-treatment. The participants were further divided into two subgroups: age ≥35 years and age <35 years. The primary endpoint of the study was IVF-ET outcomes., Results: The demographic characteristics did not significantly differ between the groups. The implantation rate (36.7 vs. 20.4 %, P < 0.05) and clinical pregnancy rate (57.3 vs. 30.1 %, P < 0.05) were significantly higher in the study group than in the control group. An analysis using a multivariate logistic regression model showed that GH was a significant factor for predicting pregnancy outcomes (OR 3.125, 95 % CI 2.441-4.000). Furthermore, for the ≥35-year-old group, the endometrial thickness was significantly greater (11.99 ± 2.21 vs. 11.62 ± 2.45, P < 0.05) in the study group than in the control group; in contrast, for the <35-year-old group, the high-quality embryo rate was significantly higher (71.7 vs. 68.3 %, P < 0.05) in the study group than in the control group., Conclusion: Our study showed that co-treatment with GH in a GnRH agonist long protocol in patients who responded normally while undergoing IVF-ET could increase the implantation and pregnancy rates.

Microglia, immune cells of the brain, originate from erythromyeloid precursors, far from the central nervous system. Xu et al. (2016) in this issue of Developmental Cell and Casano et al. (2016) recently in Cell Reports show that apoptotic neurons act as bait to "trap" microglia into colonizing the developing brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hailey-Hailey disease (HHD) is an autosomal dominant disorder in which the ATP2C1 gene has been implicated. Many mutations of this gene have been detected in HHD patients. To analyze such mutations in HHD and summarize all those identified in Chinese patients with this disease, we examined four familial and two sporadic cases and searched for case reports and papers by using the Chinese Biological Medicine Database and PubMed. HHD diagnoses were made based on clinical features and histopathological findings. Polymerase chain reaction and direct sequencing of the ATP2C1 gene were performed using blood samples from HHD patients, unaffected family members, and 120 healthy individuals. Three mutations were identified, including the recurrent mutation c.2126C>T (p.Thr709Met), and two novel missense mutations, c.2235&#95;2236insC (p.Pro745fs*756) and c.689G>A (p.Gly230Asp). Considering our data, 81 different mutations have now been reported in Chinese patients with HHD. In cases of misannotation or duplication, previously published mutations were renamed according to a complementary DNA reference sequence. These mutations are scattered throughout the ATP2C1 gene, with no evident hotspots or clustering. It is of note that some reported "novel" mutations were in fact found to be recurrent. Our findings expand the range of known ATP2C1 sequence variants in this disease.

Objectives: To find extracellular biocatalysts that can specifically and efficiently remove the C-7 xylosyl group from 7-xylosyltaxanes., Results: A Cellulosimicrobium cellulans strain F16 that can remove the C-7 xylosyl group from 7-xylosyltaxanes was isolated from the root soil of an old Taxus yunnanensis tree. Using corn cob as sole carbon source, the maximum 7-xylosyl-10-deacetylpaclitaxel β-xylosidase activity of 9.6 U l(-1) was achieved. The β-xylosidase could be trapped by a ceramic tubular membrane (pore size 50 nm), and exhibited an apparent molecular weight much greater than 500 kDa. Under optimized conditions, 3.75 l cell-free culture medium transformed 2 grams 7-xylosyltaxane mixtures to their corresponding aglycones within 3 h, with a conversion >98%., Conclusion: This is the first report that C. cellulans can produce extracellular β-xylosidases capable of removing the C-7 xylosyl group from 7-xylosyltaxanes.

Aim: To compare the histological outcome of chronic hepatitis B (CHB) patients treated with entecavir (ETV) or lamivudine (LAM)-based therapy., Methods: We conducted a retrospective analysis of data from 42 CHB patients with advanced fibrosis (baseline Ishak score ≥ 2) or cirrhosis who were treated with ETV or LAM-based therapy in Beilun People's Hospital, Ningbo between January 2005 and May 2012. The patients enrolled were more than 16 years of age and underwent a minimum of 12 mo of antiviral therapy. We collected data on the baseline characteristics of each patient and obtained paired liver biopsies pre- and post-treatment. The Knodell scoring system and Ishak fibrosis scores were used to evaluate each example. An improvement or worsening of necroinflammation was defined as ≥ 2-point change in the Knodell inflammatory score. The progression or regression of fibrosis was defined as ≥ 1-point change in the Ishak fibrosis score. The continuous variables were compared using t-test or Mann-Whitney test, and the binary variables were compared using χ(2) test or Fisher's exact test. The results of paired liver biopsies were compared with a Wilcoxon signed rank test., Results: Nineteen patients were treated with ETV and 23 patients were treated with LAM therapy for a mean duration of 39 and 42 mo, respectively. After long-term antiviral treatment, 94.74% (18/19) of the patients in the ETV arm and 95.65% (22/23) in the LAM arm achieved an HBV DNA level less than 1000 IU/mL. The majority of the patients (94.74% in the ETV arm and 73.91% in the LAM arm) had normalized ALT levels. The median Knodell necroinflammatory score decreased from 11 to 0 in the patients receiving ETV, and the median Knodell score decreased from 9 to 3 in the patients receiving LAM (P = 0.0002 and < 0.0001, respectively). The median Ishak fibrosis score showed a 1-point reduction in ETV-treated patients and a 2-point reduction in LAM-treated patients (P = 0.0019 and 0.0205, respectively). The patients receiving ETV showed a more significant improvement in necroinflammation than the LAM-treated patients (P = 0.0003). However, there was no significant difference in fibrotic improvement between the two arms. Furthermore, two patients in each arm achieved a fibrosis score of 0 post-treatment, which indicates a full reversion of fibrosis after antiviral therapy., Conclusion: CHB patients with advanced fibrosis or cirrhosis benefit from antiviral treatment. ETV is superior to LAM therapy in improving necroinflammatory but not fibrotic outcome.

In order to attenuate the bitter taste and improve the aroma of the summer tieguanyin oolong tea from the Chinese Anxi county, the effects of processing treatment with exogenous laccase and α-galactosidase on tea sensory quality and related compounds were investigated. The solutions of laccase and/or α-galactosidase were sprayed on the tea leaves before the first drying process. The sensory evaluation results showed that the sensory quality of the tea was significantly enhanced with the enzymatic treatment. The combined application of laccase at 8.25 and α-galactosidase at 22 U per kg of fresh tea shoots achieved the most satisfying sensory quality. Further analysis of flavour-related constituents was carried out by HPLC and GC-MS. The HPLC analysis showed that the contents of catechins and total polyphenols were reduced, compared to the untreated group, by 11.9 and 13.3% respectively, and the total soluble sugars and water extract content were increased by 19.4 and 6.6% respectively, after the treatment with both enzymes. The decrease of catechins and total polyphenols reduced the bitterness and astringency of the summer tea, while the increase of total soluble sugars and water extract content improved the sweetness and mellow taste. The aromatic compound data from GC-MS showed that the total essential oil content in these tea samples co-treated with laccase and α-galactosidase increased significantly, in which aldehydes, alcohols, esters and alkenes increased by 23.28, 37.05, 20.10 and 38.99%, respectively. Our data suggest that the exogenous enzymatic treatment can enhance the summer oolong tea quality, especially its taste and aroma.