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Background: An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases, yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma (HCC) and biliary tract cancer (BTC). This study aims to explore the relationship between them using Mendelian randomization (MR) analysis method., Aim: To assess the relationship between gut microbiota and HCC and BTC., Methods: We obtained Genome-wide association study (GWAS) data for the gut microbiome from the intestinal microbiota genomic library (MiBioGen, https://mibiogen.gcc.rug.nl/). Additionally, we accessed data pertaining to HCC and BTC from the IEU open GWAS platform (https://gwas.mrcieu.ac.uk/). Our analysis employed fundamental instrumental variable analysis methods, including inverse-variance weighted, MR and Egger. To ensure the dependability of the results, we subjected the results to tests for multiple biases and heterogeneity., Results: During our investigation, we discovered 11 gut microbiota linked to an increased risk to BTC and HCC. The former included the genus Eubacterium hallii group ( P = 0.017), Candidatus Soleaferrea ( P = 0.034), Flavonifractor ( P = 0.021), Lachnospiraceae FCS020 ( P = 0.034), the order Victivallales ( P = 0.018), and the class Lentisphaeria ( P = 0.0.18). The latter included the genus Desulfovibrio ( P = 0.042), Oscillibacter ( P = 0.023), the family Coriobacteriaceae ( P = 0.048), the order Coriobacteriales ( P = 0.048), and the class Coriobacteriia ( P = 0.048). Furthermore, in BTC, we observed 2 protective gut microbiota namely the genus Dorea ( P = 0.041) and Lachnospiraceae ND3007 group ( P = 0.045). All results showed no evidence of multiplicity or heterogeneity., Conclusion: This study explores a causal link between gut microbiota and HCC and BTC. These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways, potentially informing therapeutic strategies., Competing Interests: Conflict-of-interest statement: The authors declare no potential conflicts of interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aim: Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains., Methods: A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini-mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test-revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation., Results: Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p < .05). Apathy of PBA-s was correlated to MMSE, animal VFT and Stroop-interference tests performance. Severity of motor symptoms, functional capacity, age, and age of motor symptom onset were correlated to all neuropsychological scores, whereas education attainment and diagnostic delay were correlated to most neuropsychological scores except TMT. Severity of motor symptoms, functional capacity, and education attainment showed independent predicting effect (p < .05) in diverse cognitive domains., Conclusion: Cognitive impairment was very common in Chinese HD patients at the first visit and worse in the patients in advanced phase. The severity of motor symptoms and functional capacity were correlated to the diverse cognitive domains., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

This study aimed to evaluate the cost-effectiveness of Chaiyin Granules compared with Oseltamivir Phosphate Capsules in the treatment of influenza(exogenous wind-heat syndrome). Based on a randomized, double-blind, positive drug parallel control clinical trial, this study evaluated the pharmacoeconomics of Chaiyin Granules with cost-effectiveness analysis method. A total of 116 patients with influenza from eight hospitals(grade Ⅱ level A above) in 6 cities were selected in this study, including 78 cases in the experimental group with Chaiyin Granules and Oseltamivir Phosphate Capsules placebo, and 38 cases in the control group with Oseltamivir Phosphate Capsules and Chaiyin Granules placebo. The total cost of this study included direct medical cost, direct non-medical cost, and indirect cost. The remission time of clinical symptoms, cure time/cure rate, antipyretic onset time/complete antipyretic time, viral nucleic acid negative rate, and traditional Chinese medicine(TCM) syndrome curative effect were selected as the effect indicators for cost-effectiveness analysis. Four-quadrant diagram was used to estimate the incremental cost-effectiveness ratio. The results showed that Chaiyin Granules were not inferior to Oseltamivir Phosphate Capsules in the remission time of clinical symptoms of influenza(3.1 d vs 2.9 d, P=0.360, non-inferiority margin was 0.5 d). Compared with Oseltamivir Phosphate Capsules, Chaiyin Granules would delay the remission time of clinic symptoms of influenza for 1 d, but could save 213.9 yuan. 1 d delay in cure time could save 149.3 yuan; 1% reduction in the cure rate could save 8.2 yuan; 1 d delay in antipyretic onset time could save 295.4 yuan; 1 d delay in complete antipyretic time could save 114.3 yuan; 1% reduction in the 5-day cure rate of TCM syndrome could save 19.2 yuan. Different from other indicators, there was no statistically significant difference between two groups in the effect of negative conversion rate of viral nucleic acid, but the cost was lower and the effect was superior, and the pharmacoeconomics was not different from that of Oseltamivir Phosphate Capsules in the field of influenza treatment.

Transcatheter arterial radioembolization (TARE) is of great significance for the treatment of advanced hepatocellular carcinoma (HCC). However, the existing radioembolic microspheres still have problems such as non-degradability, non-uniform size, and inability to directly monitor in vivo, which hinders the development of TARE. In this paper, a novel radioembolic agent, 131 I-labeled methacrylated gelatin microspheres ( 131 I-GMs), is prepared for the treatment of HCC. Water-in-oil (W/O) emulsion templates are prepared by a simple one-step microfluidic method to obtain methacrylated gelatin microspheres (GMs) after UV irradiation. A series of GMs with uniform and controllable size is obtained by adjusting the flow rate of each fluid. Both air-dried and freeze-dried GMs can quickly restore their original shape and size, and still have good monodispersity, elasticity, and biocompatibility. The radiolabeling experiments show that 131 I can efficiently bind to GMs by chloramine-T method, and the obtained 131 I-GMs have good radioactive stability in vitro. The results of in vivo TARE treatment in rats show that 131 I-GMs can be well retained in the hepatic artery and have a good inhibitory effect on the progression of liver cancer, showing the potential for the treatment of HCC., (© 2023 Wiley-VCH GmbH.)

Controllable mass production of monodisperse droplets plays a key role in numerous fields ranging from scientific research to industrial application. Microfluidic ladder networks show great potential in mass production of monodisperse droplets, but their design with uniform microflow distribution remains challenging due to the lack of a rational design strategy. Here an effective design strategy based on backstepping microflow analysis (BMA) is proposed for the rational development of microfluidic ladder networks for mass production of controllable monodisperse microdroplets. The performance of our BMA rule for rational microfluidic ladder network design is demonstrated by using an existing analogism-derived rule that is widely used for the design of microfluidic ladder networks as the control group. The microfluidic ladder network designed by the BMA rule shows a more uniform flow distribution in each branch microchannel than that designed by the existing rule, as confirmed by single-phase flow simulation. Meanwhile, the microfluidic ladder network designed by the BMA rule allows mass production of droplets with higher size monodispersity in a wider window of flow rates and mass production of polymeric microspheres from such highly monodisperse droplet templates. The proposed BMA rule provides new insights into the microflow distribution behaviors in microfluidic ladder networks based on backstepping microflow analysis and provides a rational guideline for the efficient development of microfluidic ladder networks with uniform flow distribution for mass production of highly monodisperse droplets. Moreover, the BMA method provides a general analysis strategy for microfluidic networks with parallel multiple microchannels for rational scale-up.

The oxygen reduction reaction (ORR) activity of the Fe/N/Carbon catalysts derived from the pyrolysis of zeolitic-imidazolate-framework-8 (ZIF-8) has been still lower than that of commercial Pt-based catalysts utilized in the proton exchange membrane fuel cells (PEMFCs) due to low density of accessible active sites. In this study, an efficient carbon-supporting strategy is developed to enhance the ORR efficiency of the ZIF-derived Fe/N/Carbon catalysts by increasing the accessible active site density. The enhancement lies in (i) improving the accessibility of active sites via converting dodecahedral particles to graphene-like layered materials and (ii) enhancing the density of FeN x active sites via suppressing the formation of nanoparticles as well as providing extra spaces to host active sites. The optimized and efficient Fe/N/Carbon catalyst shows a half-wave potential ( E 1/2 ) of 0.834 V versus reversible hydrogen electrode in acidic media and produces a peak power density of 0.66 W cm -2 in an air-fed PEMFC at 2 bar backpressure, outperforming most previously reported Pt-free ORR catalysts. Finally, the general applicability of the carbon-supporting strategy is confirmed using five different commercial carbon blacks. This work provides an effective route to derive Fe/N/Carbon catalysts exhibiting a higher power density in PEMFCs.

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of cardiovascular disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (QH536) showed an EC 50 of 0.22 μΜ in promoting HMGCR degradation, which was about 2 times more potent than HMG499 (EC 50  = 0.43 μM). Interestingly, 29 was different from HMG499, it had no side-effect of inducing cholesterol accumulation in cells. Mechanistic studies disclosed that 29 could significantly decrease statin-induced accumulation of HMGCR protein via ubiquitination and degradation of HMGCR through ubiquitin-proteasome pathway and inhibit the cholesterol biosynthesis in cells. Therefore, these heterocyclic ring-fused analogs could be used as promising leads for the development of new types of agents against CVD. Furthermore, 29 also lowered cholesterol levels and suppressed TGFβ1-induced proliferation of LX-2 hepatic stellate cells in a dose-dependent manner. In particular, 29 not only decreased the NASH associated fibrotic mRNA and protein expression of α-SMA, COL1A1, TIMP1 and TGFβ1 but also suppressed cholesterol levels and inflammatory genes of TNF-α, IL-6 an IL-1β in RAW264.7 macrophage cells, indicating that 29 may bring therapeutic benefit to treat NASH., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The objective of this study was to investigate the effects of dietary energy levels and rumen-protected lysine supplementation on serum free fatty acid levels, β-hydroxybutyrate levels, dry matter (DM) intake, and milk production and composition. Treatments were arranged in a 2 × 2 factorial design with 2 dietary energy levels [high net energy for lactation (NE L ) = 1.53 Mcal/kg of DM vs. low NE L = 1.37 Mcal/kg of DM; HE vs. LE) fed either with rumen-protected lysine (bypass lysine; 40 g/cow per day) or without rumen-protected lysine (control). Sixty-eight third-lactation Holstein dairy cows entering their fourth lactation were randomly allocated to 4 treatments groups: HE with bypass lysine, HE without bypass lysine, LE with bypass lysine, and LE without bypass lysine. Groups were balanced based upon their expected calving date, previous milk yields, and body condition score. All cows were fed the same diet (NE L = 1.34 Mcal/kg of DM) during the dry period prior to the trial. Rumen-protected lysine was top-dressed on a total mixed ration to deliver 9.68 g/d of metabolizable lysine to pre- and postpartum cows. After calving, all cows received the same TMR (1.69 Mcal/kg of DM). Blood samples were collected at -21, -14, -7, 0, 3, 7, 14, and 21 d relative to calving, and free fatty acids and β-hydroxybutyrate concentrations were measured. Amount of feed offered and orts were collected and measured for individual cows 4 d/wk. Milk samples were collected once per week following calving, and milk composition was analyzed. Feeding high NE L to close-up cows decreased the concentrations of free fatty acid and β-hydroxybutyrate in prepartum cows but not in postpartum cows. Addition of rumen-protected lysine increased postpartum DM intake, and decreased serum free fatty acid and β-hydroxybutyrate concentrations. Neither energy nor rumen-protected lysine supplementation nor their interaction affected milk yield or fat or lactose yields. However, cows in the group receiving HE with bypass lysine tended to produce more milk compared with other groups and had a lower blood β-hydroxybutyrate concentration postpartum. These results indicate that feeding a high-energy diet together with rumen-protected lysine improved DM intake and lowered serum free fatty acid and β-hydroxybutyrate concentrations in transition cows., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Herein we screened our small synthetic library of diterpenoid analogs for hit compounds on promoting testosterone synthesis and the methylpyrimidine ring-fused diterpenoid analog 7 was obtained as the hit. Based on the hit, a series of derivatives were designed, synthesized and evaluated for their effects on testosterone secretion in mouse Leydig TM3 cells. Most of the derivatives showed better activity in promoting testosterone synthesis than the positive control compound icariin, among which compound 17 has optimal activity and little cytotoxicity. Preliminary mechanism studies indicated that 17 significantly promoted the expression of testosterone synthesis-related marker genes (StAR, 3β-HSD and CYP11A1). Further studies showed that 17 provided sufficient steroid materials for testosterone synthesis by stimulating autophagy in Leydig cells. Thus compound 17 emerged as a potential lead compound for further development of therapeutics for late onset of hypogonadism (LOH)., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Maintaining the appropriate number of mitochondrial DNA (mtDNA) molecules is crucial for supporting mitochondrial metabolism and function in both plant and animal cells. For example, a substantial decrease in mtDNA levels occurs as a key part of pollen development. The molecular mechanisms regulating mtDNA copy number are largely unclear, particularly with regard to those that reduce mtDNA levels. Here, we identified and purified a 20-kD endonuclease, M20, from maize ( Zea mays ) pollen mitochondria. We found M20 to be an His-Asn-His/Asn (H-N-H/N) nuclease that degrades linear and circular DNA in the presence of Mg 2+ or Mn 2+ Arabidopsis ( Arabidopsis thaliana ) AtM20, which shared high sequence similarity with maize M20, localized to the mitochondria, had a similar H-N-H/N structure, and degraded both linear and circular DNA. AtM20 transcript levels increased during pollen development, in parallel with a rapid reduction in mtDNA. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 genome-editing techniques were used to generate knockout lines of AtM20 ( atm20 ), which exhibited a significant delay in the reduction in mtDNA levels in pollen vegetative cells but normal mtDNA levels in somatic cells. The delayed reduction in pollen mtDNA levels was rescued by the transgenic expression of AtM20 in atm20 plants. This study thus uncovers an endonucleolytic DNase in plant mitochondria and its crucial role in reducing mtDNA levels, pointing to the complex mechanism regulating mtDNA levels in plants., (© 2018 American Society of Plant Biologists. All rights reserved.)

Inexpensive and simple non-invasive indexes for predicting liver inflammation are urgently required, but have been poorly studied in chronic hepatitis B (CHB) patients with alanine transaminase (ALT) ≤2 times the upper limit of normal (ULN). A total of 356 CHB patients with ALT ≤2 ULN who presented at Huashan Hospital (n=181) and the First Hospital of Quanzhou (n=175) were enrolled and randomly divided into an experimental assessment cohort (n=238) and validation cohort (n=118) at a ratio of 2:1. Histological analysis of liver tissue was performed to determine the pathological stage according to the Scheuer scoring system. For the experimental assessment cohort, univariate and multivariate analysis identified aspartate aminotransferase (AST) and albumin (ALB) as independent predictors of liver necroinflammation [liver necroinflammation grade (G)≥2] in patients with ALT ≤2 ULN. Therefore, a novel index, the AST-to-ALB ratio (ATAR), was proposed, which had a better diagnostic performance [area under receiver operating characteristic curve (AUC)=0.721] than that of ALB (AUC=0.632; P=0.039 vs. ATAR) and AST (AUC=0.682; P=0.082 vs. ATAR). In the validation cohort, the AUC of ATAR (0.728) to identify patients with a G≥2 was slightly greater than that of AST (0.660; P=0.149 vs. ATAR) and ALB (0.672; P=0.282 vs. ATAR). Furthermore, a similar diagnostic superiority was also demonstrated in patients with ALT ≤1 ULN. Thus, ATAR may be a promising non-invasive surrogate marker for liver necroinflammation CHB patients with ALT ≤2 ULN and thereby determine whether anti-viral treatment should be initiated.