Two new jatrophane diterpenoids from Euphorbia helioscopia with activity towards autophagic flux.

Nine jatrophane diterpenoids were isolated from the whole plant Euphorbia helioscopia, including two new ones, helioscopnins A (1) and B (2). Comprehensive spectroscopic data analysis and ECD calculations elucidated their structures, including absolute configurations. All compounds were evaluated for bioactivity towards autophagic flux by flow cytometry using HM mCherry-GFP-LC3 cells. Compounds 1, 3, 4, 5, 8, and 9 significantly increased autophagic flux.

Deletion of Tgm2 suppresses BMP-mediated hepatocyte-to-cholangiocyte metaplasia in ductular reaction.

Transglutaminase 2 (Tgm2) plays an essential role in hepatic repair following prolonged toxic injury. During cholestatic liver injury, the intrahepatic cholangiocytes undergo dynamic tissue expansion and remodelling, referred to as ductular reaction (DR), which is crucial for liver regeneration. However, the molecular mechanisms governing the dynamics of active cells in DR are still largely unclear. Here, we generated Tgm2-knockout mice (Tgm2-/-) and Tgm2-CreERT2-Rosa26-mTmG flox/flox (Tgm2CreERT2-R26T/Gf/f) mice and performed a three-dimensional (3D) collagen gel culture of mouse hepatocytes to demonstrate how Tgm2 signalling is involved in DR to remodel intrahepatic cholangiocytes. Our results showed that the deletion of Tgm2 adversely affected the functionality and maturity of the proliferative cholangiocytes in DR, thus leading to more severe cholestasis during DDC-induced liver injury. Additionally, Tgm2 hepatocytes played a crucial role in the regulation of DR through metaplasia. We unveiled that Tgm2 regulated H3K4me3Q5ser via serotonin to promote BMP signalling activation to participate in DR. Besides, we revealed that the activation or inhibition of BMP signalling could promote or suppress the development and maturation of cholangiocytes in DDC-induced DR. Furthermore, our 3D collagen gel culture assay indicated that Tgm2 was vital for the development of cholangiocytes in vitro. Our results uncovered a considerable role of BMP signalling in controlling metaplasia of Tgm2 hepatocytes in DR and revealed the phenotypic plasticity of mature hepatocytes.

Cross-sectional study of pharmacovigilance knowledge, attitudes, and practices based on structural equation modeling and network analysis: a case study of healthcare personnel and the public in Yunnan Province.

Background: This study focuses on understanding pharmacovigilance knowledge, attitudes, and practices (KAP) in Yunnan Province, employing Structural Equation Modeling (SEM) and network analysis. It aims to evaluate the interplay of these factors among healthcare personnel and the public, assessing the impact of demographic characteristics to inform policy and educational initiatives. Methods: A cross-sectional survey was conducted in Yunnan, targeting healthcare personnel and the public. Data collection was through questionnaires, with subsequent analysis involving correlation matrices, network visualization, and SEM. The data analysis utilized SPSS 27.0, AMOS 26.0, and Gephi software for network analysis. Results: This study evaluated pharmacovigilance KAP among 209 public participants and 823 healthcare personnel, uncovering significant differences. Public respondents scored averages of 4.62 ± 2.70 in knowledge, 31.99 ± 4.72 in attitudes, and 12.07 ± 4.96 in practices, while healthcare personnel scored 4.38 ± 3.06, 27.95 ± 3.34, and 7.75 ± 2.77, respectively. Statistically significant correlations across KAP elements were observed in both groups, highlighting the interconnectedness of these factors. Demographic influences were more pronounced among healthcare personnel, emphasizing the role of professional background in pharmacovigilance competency. Network analysis identified knowledge as a key influencer within the pharmacovigilance KAP network, suggesting targeted education as a vital strategy for enhancing pharmacovigilance engagement. Conclusion: The research reveals a less-than-ideal state of pharmacovigilance KAP among both healthcare personnel and the public in Yunnan, with significant differences between the two groups. SEM and network analysis confirmed a strong positive link among KAP components, moderated by demographics like age, occupation, and education level. These insights emphasize the need to enhance pharmacovigilance education and awareness, thereby promoting safer drug use.

TET2 regulation of alcoholic fatty liver via Srebp1 mRNA in paraspeckles.

Epigenetic modifications have emerged as key regulators of metabolism-related complex diseases including the alcoholic fatty liver disease (AFLD) prevalent chronic liver disorder with significant economic implications. Building upon previous research that emphasizes ten-eleven translocation (TET) proteins' involvement in adipocyte insulin sensitization and fatty acid oxidation, we explored the role of TET2 protein in AFLD pathogenesis which catalyzes 5-methylcytosine into 5-hydroxymethylcytosine in DNA/RNA. Our findings revealed that TET2 deficiency exacerbates AFLD progression. And TET2 influenced the expression and activity of sterol regulatory element binding protein 1 (SREBP1), a key regulator of hepatic lipid synthesis, by modulating Srebp1 mRNA retention. Employing RIP-qPCR and bisulfite sequencing techniques, we provided evidence of TET2-mediated epigenetic modifications on Srebp1 mRNA, thereby affecting lipid metabolism. Through elucidating the role of methylation in RNA nuclear retention via paraspeckles, our study enhances understanding of AFLD pathogenesis from an epigenetic perspective, paving the way for identifying potential therapeutic targets.

Comparison of Second-Generation Cryoballoon Ablation and Quantitative Radiofrequency Ablation Guided by Ablation Index for Atrial Fibrillation.

We compared the efficacy and complication rates of quantitative radiofrequency ablation guided by ablation index (RFCA-AI) with those of second-generation cryoballoon ablation (CBA-2). Consecutive patients (n = 230) with symptomatic atrial fibrillation (AF) undergoing a first ablation CBA-2 (92 patients) or RFCA-AI (138 patients) procedure were enrolled in this study. The late recurrence rate in the CBA-2 group was higher than that in the RFCA-AI group (P = .012). Subgroup analysis showed the same result in patients with paroxysmal AF (PAF) (P = .039), but no difference was found in patients with persistent AF (P = .21). The average operation duration in the CBA-2 group (85 [75-99.5] minutes) was shorter than that in the RFCA-AI group (100 [84.5-120] minutes) (P < .0001), but the average exposure time (17.36(13.87-22.49) vs 5.49(4.00-8.24) minutes) in the CBA-2 group and X-ray dose (223.25(149.15-336.95) vs 109.15(80.75-168.7) mGym) were significantly longer than those in RFCA-AI group (P < .0001). Multivariate logistic regression analysis showed that left atrial diameter (LAD), early recurrence, and methods of ablation (cryoballoon ablation) were independent risk factors for late recurrence after AF ablation. Early recurrence of AF and LAD were independent risk factors for predicting late recurrence after AF ablation.

E3 ubiquitin ligase NEDD4L inhibits epithelial-mesenchymal transition by suppressing the ß-catenin/HIF-1α positive feedback loop in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyp (CRSwNP) is a refractory inflammatory disease with epithelial-mesenchymal transition (EMT) as one of the key features. Since ubiquitin modification has been shown to regulate the EMT process in other diseases, targeting ubiquitin ligases may be a potential strategy for the treatment of CRSwNP. In this study we investigated whether certain E3 ubiquitin ligases could regulate the EMT process in CRSwNP, and whether these regulations could be the potential drug targets as well as the underlying mechanisms. After screening the potential drug target by bioinformatic analyses, the expression levels of three potential E3 ubiquitin ligases were compared among the control, eosinophilic nasal polyp (ENP) and non-eosinophilic nasal polyp (NENP) group in clinical samples, and the significant decrement of the expression level of NEDD4L was found. Then, IP-MS, bioinformatics and immunohistochemistry studies suggested that low NEDD4L expression may be associated with the EMT process. In human nasal epithelial cells (hNECs) and human nasal epithelial cell line RPMI 2650, knockdown of NEDD4L promoted EMT, while upregulating NEDD4L reversed this effect, suggesting that NEDD4L inhibited EMT in nasal epithelial cells. IP-MS and Co-IP studies revealed that NEDD4L mediated the degradation of DDR1. We demonstrated that NEDD4L inhibited the ß-catenin/HIF-1α positive feedback loop either directly (degrading ß-catenin and HIF-1α) or indirectly (mediating DDR1 degradation). These results were confirmed in a murine NP model in vivo. This study for the first time reveals the regulatory role of ubiquitin in the EMT process of nasal epithelial cells, and identifies a novel drug target NEDD4L, which has promising efficacy against both ENP and NENP by suppressing ß-catenin/HIF-1α positive feedback loop.

Associations between Phthalate Metabolite Concentrations in Follicular Fluid and Reproductive Outcomes among Women Undergoing in Vitro Fertilization/Intracytoplasmic Sperm Injection Treatment.

BACKGROUND: Phthalates have been reported to impair fertility in various studies. However, evidence exploring the associations between phthalate metabolites in follicular fluid (FF) and reproductive outcomes is lacking. OBJECTIVES: To investigate the associations between phthalate metabolite concentrations in FF and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes among women recruited from a fertility clinic. METHODS: We included 641 women undergoing IVF/ICSI treatment from December 2018 to January 2020. The levels of eight phthalate metabolites, including monoethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), were quantified in FF collected on the oocyte retrieval day. Associations between quartiles of individual phthalate metabolite concentrations and nine IVF/ICSI outcomes, including oocyte yield, mature oocyte number, two distinct pronuclei (2PN) zygote number, fertilization rate, blastocyst formation rate, implantation, clinical pregnancy, miscarriage, and live birth, were estimated with generalized linear models. The effects of phthalate mixtures on IVF/ICSI outcomes were assessed using Bayesian kernel machine regression (BKMR) models. RESULTS: After adjusting for relevant confounders, elevated quartiles of MBzP, MEHHP, and MEHP in FF were inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes (all p for trends <0.10). In comparison with the lowest quartile, the highest quartile of molar sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP) was associated with a reduction of 9.1% [95% confidence interval (CI): -17.1%, -0.37%] and 10.3% (95% CI: -18.8%, -0.94%) in yielded oocyte and mature oocyte numbers, respectively. Furthermore, the BKMR models revealed inverse associations between phthalate mixtures and the numbers of retrieved oocytes and mature oocytes. We generally found null results for implantation, clinical pregnancy, miscarriage, and live birth. DISCUSSION: Certain phthalate metabolites in FF are inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes among women undergoing IVF/ICSI treatment. https://doi.org/10.1289/EHP11998.

Integrated investigation and discovery of therapeutic targets for 3-hydroxybakuchiol against diabetes based on molecular docking studies and cell experiments.

BACKGROUND: Diabetes mellitus is a prevalent endocrine condition. We aimed to investigate the anti-diabetic effects of 3-hydroxybakuchiol (HYD) by exploring its potential targets and molecular mechanisms through bioinformatics analysis and cell experiments. METHODS: We performed an extensive search and screening of HYD and its potential targets for diabetes mellitus across various databases. Enrichment analyses were conducted using the ClusterProfiler package. PPI networks of the identified genes were constructed using STRING, and topological analysis was performed to identify core targets. The results were further confirmed through molecular docking. To validate the findings of our bioinformatics analysis, we conducted cell experiments using insulin resistance-induced HepG2 cells and C2C12 cells. RESULTS: We discovered 260 common targets of HYD and diabetes mellitus, which were primarily related to the MAPK signaling pathway, PI3K-Akt signaling pathway, and endocrine resistance. A topological analysis of the PPI network identified four core targets (HSP90AA1, AKT1, SRC, and MAPK1). Molecular docking studies further confirmed the strong binding ability between HYD and these core targets. In cell experiments, we observed that HYD enhanced glucose uptake and suppressed gluconeogenesis in HepG2 cells and C2C12 cells. This resulted in an improvement in glucose metabolism, potentially through the regulation of the PI3K-Akt pathway. CONCLUSIONS: This study provides valuable insights into the pharmacological effects of HYD on diabetes mellitus, suggesting its potential as a promising treatment option for the disease.

Spatiotemporal profile and ecological impacts of major and trace elements in surface sediments of marginal seas of the Arctic and Northern Pacific Oceans.

The status and ecological impacts of sedimentary elements of the marginal seas of Arctic and Northern Pacific Oceans was investigated during 2016 to 2018 by using inductively coupled plasma mass spectrometry. Industrial (0.006 mg kg-1-64.6 g kg-1), precious (0.003-43.8 mg kg-1), rare earth (0.006-112.9 mg kg-1), and heavy metal (0.009-398.9 mg kg-1) elements showed spatial variation, and temporal uniformity. The results indicated ΣREEs and light REEs enrichment compared to chondrite and heavy REEs, respectively, while nonsignificant positive and negative δCe and δEu anomalies existed, respectively. High contamination and extreme enrichment of priority control, industrial (As, Mo, Re, Sb), precious (Au, Ir, Pd, Pt, and Ru) and RE elements indicated potential moderate to high ecological and biological risks. The study highlighted the ecological importance and fragile nature of these ecosystems and calls for an urgent action to ensure sustainability of these ecosystems.

Unraveling the Role of Microalgae in Mitigating Antibiotics and Antibiotic Resistance Genes in Photogranules Treating Antibiotic Wastewater.

Harnessing the potential of specific antibiotic-degrading microalgal strains to optimize microalgal-bacterial granular sludge (MBGS) technology for sustainable antibiotic wastewater treatment and antibiotic resistance genes (ARGs) mitigation is currently limited. This article examined the performance of bacterial granular sludge (BGS) and MBGS (of Haematococcus pluvialis, an antibiotic-degrading microalga) systems in terms of stability, nutrient and antibiotic removal, and fate of ARGs and mobile genetic elements (MGEs) under multiclass antibiotic loads. The systems exhibited excellent performance under none and 50 µg/L mixed antibiotics and a decrease in performance at a higher concentration. The MBGS showed superior potential, higher nutrient removal, 53.9 mg/L/day higher chemical oxygen demand (COD) removal, and 5.2-8.2% improved antibiotic removal, notably for refractory antibiotics, and the system removal capacity was predicted. Metagenomic analysis revealed lower levels of ARGs and MGEs in effluent and biomass of MBGS compared to the BGS bioreactor. Particle association niche and projection pursuit regression models indicated that microalgae in MBGS may limit gene transfers among biomass and effluent, impeding ARG dissemination. Moreover, a discrepancy was found in the bacterial antibiotic-degrading biomarkers of BGS and MBGS systems due to the microalgal effect on the microcommunity. Altogether, these findings deepened our understanding of the microalgae's value in the MBGS system for antibiotic remediation and ARG propagation control.

Associations between phthalate metabolites and cytokines in the follicular fluid of women undergoing in vitro fertilization.

Many studies have showed that phthalates have reproductive and embryonic toxicity, while the potential mechanisms are mostly unknown. Inflammation may play a mediating part in phthalate exposure and adverse reproductive endpoints. A cross-sectional survey was conducted to investigate the associations of phthalate metabolites with inflammatory cytokines in the follicular fluid (FF) of women undergoing in vitro fertilization (IVF). We determined the levels of eight phthalate metabolites and five cytokines in the FF of 76 women, including interleukin (IL)- 6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). The associations of individual phthalate exposure with cytokines in FF samples were explored by multiple linear regression. We further evaluated the combined effects of multiple phthalate exposures on FF levels of cytokines by using Bayesian kernel machine regression (BKMR) models. We found that there was a positive relationship between mono-ethyl phthalate (MEP) and IL-6 in the FF (percent change:12.4%; 95% CI: 1.3%, 24.9%). In contrast, elevated mono-benzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP) and %MEHP levels were associated with decreased MCP-1. In the BKMR models, phthalate metabolite mixtures were positively associated with TNF-α when the mixtures were lower than 65th percentile compared with their medians. In the stratified analyses, MEHP was inversely associated with MCP-1 among women with BMI ≥ 23 kg/m2 (test for interaction <0.05). Our results suggest that certain phthalate metabolites or their mixtures may alter levels of inflammatory cytokines in the FF, and further research is necessary to elucidate the mechanisms underlying the relationship between phthalates exposure, ovarian dysfunction and adverse pregnancy outcomes.

Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function.

BACKGROUND AND AIMS: Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9+ hepatocytes in response to the acute liver injury and repair are poorly understood. METHODS: In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H2O2) in order to induce cellular damage in an in vitro setting. RESULTS: We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H2O2-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. CONCLUSIONS: Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future.

Individual and joint associations of urinary phthalate metabolites with polycystic ovary and polycystic ovary syndrome: Results from the TREE cohort.

Phthalates are widespread endocrine disrupting chemicals that adversely affect female reproductive health. We aimed to investigate the individual and joint associations of phthalate exposures measured by repeated urinary metabolites with polycystic ovary (PCO) and polycystic ovary syndrome (PCOS) (96 PCO cases, 96 PCOS cases and 370 controls). In single-pollutant analyses, mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP) and the sum of di(2-ethylhexyl) phthalate (∑DEHP) were associated with increased prevalence of PCO. Mono(2-ethylhexyl) phthalate (MEHP), MBzP and ∑DEHP were associated with elevated prevalence of PCOS. In multiple-pollutant analyses, one-quartile increase of weighted quantile sum index in phthalate metabolite mixtures was associated with increased prevalence of PCO and PCOS, and MBzP was the most major contributor. Our findings suggest a potential role for phthalate exposures, both individually and in mixtures, in the development of PCO and PCOS.

MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation.

Male-specific lethal 1 (MSL1) is critical for the formation of MSL histone acetyltransferase complex which acetylates histone H4 Lys16 (H4K16ac) to activate gene expression. However, the role of MSL1 in liver regeneration is poorly understood. Here, this work identifies MSL1 as a key regulator of STAT3 and histone H4 (H4) in hepatocytes. MSL1 forms condensates with STAT3 or H4 through liquid-liquid phase separation to enrich acetyl-coenzyme A (Ac-CoA), and Ac-CoA in turn enhances MSL1 condensate formation, synergetically promoting the acetylation of STAT3 K685 and H4K16, thus stimulating liver regeneration after partial hepatectomy (PH). Additionally, increasing Ac-CoA level can enhance STAT3 and H4 acetylation, thus promoting liver regeneration in aged mice. The results demonstrate that MSL1 condensate-mediated STAT3 and H4 acetylation play an important role in liver regeneration. Thus, promoting the phase separation of MSL1 and increasing Ac-CoA level may be a novel therapeutic strategy for acute liver diseases and transplantation.

Diagnostic accuracy of interleukin-2 receptor in sarcoidosis: a systematic review and meta-analysis.

INTRODUCTION: Soluble interleukin-2 receptor (sIL-2 R), a valuable diagnostic biomarker for sarcoidosis, has been reported with variable results. Based on the literatures currently accessible, a systematic review and meta-analysis of the diagnostic performance of serum sIL-2 R for sarcoidosis were performed. METHODS: Relevant studies investigating sIL-2 R for sarcoidosis diagnosis in several databases were searched and data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled by STATA 16.0 software. Overall test performance was assessed using summary receiver operating characteristic curves and the area under the curve (AUC). Potential publication bias was assessed by Deeks test. RESULTS: We included eleven studies involving 1,424 subjects, with 1,099 cases of sarcoidosis and 325 of non-sarcoidosis. The pooled parameters of sIL-2 R in diagnosing sarcoidosis were summarized as follows: sensitivity, 0.85 (95% CI: 0.72-0.93); specificity, 0.88 (95% CI: 0.72-0.96); PLR, 7.3 (95% CI: 2.7-20.1); NLR, 0.17 (95% CI:0.08-0.36); DOR, 44 (95% CI: 8-231); and the AUC, 0.93 (95% CI: 0.90-0.95). No publication bias was identified (P = 0.64). CONCLUSIONS: Evidence suggests sIL-2 R performs well in diagnosing sarcoidosis. Nevertheless, results of sIL-2 R assay should be interpreted with other diagnostic examinations.

Oxidatively generated DNA damage mediates the associations of exposure to phthalates with uterine fibroids and endometriosis: Findings from TREE cohort.

BACKGROUND: Epidemiological studies on phthalate exposures in associations with uterine fibroids (UF) and endometriosis (EMT) are inconsistent. The underlying mechanisms are poorly understood. OBJECTIVES: To investigate the relationships of urinary phthalate metabolites with UF and EMT risks, and further to examine the mediating role of oxidative stress. METHODS: This study included 83 and 47 women separately diagnosed with UF and EMT, as well as 226 controls from the Tongji Reproductive and Environmental (TREE) cohort. Two spot urine samples from each woman were analyzed for two oxidative stress indicators and eight urinary phthalate metabolites. Unconditional logistic regression models or multivariate regression models were fitted to evaluate the associations among phthalate exposures, oxidative stress indicators, and the risks of UF and EMT. The potential mediating role of oxidative stress was estimated by the mediation analyses. RESULTS: We observed that each ln-unit increase in urinary mono-benzyl phthalate (MBzP) concentrations was associated with increased UF risk [adjusted OR (aOR): 1.56, 95% CI: 1.20, 2.02], and that each ln-unit increase in urinary MBzP (aOR: 1.48, 95% CI: 1.09, 1.99), mono-isobutyl phthalate (MiBP) (aOR: 1.83, 95% CI: 1.19, 2.82), and mono-2-ethylhexyl phthalate (MEHP) (aOR: 1.66, 95% CI: 1.19, 2.31) concentrations were associated with increased EMT risk (all FDR-adjusted P < 0.05). Moreover, we observed that all tested urinary phthalate metabolites were positively associated with two oxidative stress indicators [4-hydroxy-2-nonenal-mercapturic acid (4-HNE-MA) and 8-hydroxy-2-deoxyguanosine (8-OHdG)], in which 8-OHdG was associated with increased risks of UF and EMT (all FDR-adjusted P < 0.05). The mediation analyses showed that 8-OHdG mediated the positive relationships of MBzP with UF risk, and of MiBP, MBzP, and MEHP with EMT risk, with the estimated intermediary proportion ranging from 32.7% to 48.1%. CONCLUSIONS: Oxidatively generated DNA damage may mediate the positive associations of certain phthalate exposures with the risks of UF and EMT. However, further investigation is warranted to confirm these findings.

Research on the Efficacy of Ganpu Vine Tea in Inhibiting Uric Acid Production.

Ganpu vine tea is a new type of health care citrus fruit tea made from citrus shell, Pu-er tea, and vine tea baked as raw materials. In this study, the in vitro uric acid synthase inhibition system and hyperuric acid cell model were constructed to appraise the uric acid lowering efficacy of Ganpu vine tea, traditional Ganpu tea, and vine tea. Results showed that in the uric acid synthase inhibition system, the aqueous extract can inhibite the puric metabolically related enzymes, such as adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and xanthine oxidase (XOD). The ability of the aqueous extract to inhibit the above enzyme was as follows: vine tea > Ganpu vine tea > Ganpu tea; all teas had a strong effect on XOD inhibition. The hyperuric acid cell model test showed that the aqueous extract inhibited uric acid production through accumulating inosine and hypoxanthine and hindering xanthine synthesis. The uric acid reductive ability was as follows: Vine tea > Ganpu vine tea > Ganpu tea. The inhibition of enzymes related to uric acid synthesis and the inhibition of uric acid production were significantly enhanced through adding vine tea to Ganpu tea. It also shows that flavonoids are the main factor driving this ability because they are the main active ingredients in these botanical drinks.

Fate tracking reveals differences between Reelin+ hepatic stellate cells (HSCs) and Desmin+ HSCs in activation, migration and proliferation.

The activation of hepatic stellate cells (HSCs) is the main cause of liver fibrogenesis in response to different etiologies of chronic liver injuries. HSCs are heterogeneous, but the lack of specific markers to distinguish different HSC subset hinders the development of targeted therapy for liver fibrosis. In this study, we aim to reveal new HSC subsets by cell fate tracking. We constructed a novel ReelinCreERT2 transgenic mouse model to track the fate of cells expressing Reelin and their progeny (Reelin+ cells). And we investigated the property of Reelin+ cells, such as differentiation and proliferation, in hepatotoxic (carbon tetrachloride; CCl4 ) or cholestatic (bile duct ligation; BDL) liver injury models by immunohistochemistry. Our study revealed that Reelin+ cells were a new HSC subset. In terms of activation, migration, and proliferation, Reelin+ HSCs displayed different properties from Desmin+ HSCs (total HSCs) in cholestatic liver injury model but shared similar properties to total HSCs in hepatotoxic liver injury model. Besides, we did not find evidence that Reelin+ HSCs transdifferentiated into hepatocytes or cholangiocytes through mesenchymal-epithelial transition (MET). In this study, our genetic cell fate tracking data reveal that ReelinCreERT2-labelled cells are a new HSC subset, which provides new insights into targeted therapy for liver fibrosis.

Clustering ensemble in scRNA-seq data analysis: Methods, applications and challenges.

With the rapid development of single-cell RNA-sequencing techniques, various computational methods and tools were proposed to analyze these high-throughput data, which led to an accelerated reveal of potential biological information. As one of the core steps of single-cell transcriptome data analysis, clustering plays a crucial role in identifying cell types and interpreting cellular heterogeneity. However, the results generated by different clustering methods showed distinguishing, and those unstable partitions can affect the accuracy of the analysis to a certain extent. To overcome this challenge and obtain more accurate results, currently clustering ensemble is frequently applied to cluster analysis of single-cell transcriptome datasets, and the results generated by all clustering ensembles are nearly more reliable than those from most of the single clustering partitions. In this review, we summarize applications and challenges of the clustering ensemble method in single-cell transcriptome data analysis, and provide constructive thoughts and references for researchers in this field.

Examining the associations between urban bus drivers' rule violations and crash frequency using observational data.

Urban bus crashes have been an increasing concern in China thanks to the expansion of urban bus systems. Bus drivers' rule violation behavior appears to be an important factor of bus crashes. However, existing studies rely heavily on questionnaire survey of rule violation behaviors, which may suffer from self-reporting bias. Using observational data of 1,356 bus drivers from onboard video recordings, this paper develops a random parameter zero-inflated Poisson model (with heterogeneity in means and variances) to uncover the relationship between drivers' rule violation behaviors and bus crashes. Model results show that rule violation behaviors such as using a cell phone, driving outside the bus lane, and touching solid line with wheel while driving significantly correlate with crash frequencies with large marginal effects, whereas some other violation behaviors (e.g., running red lights, changing lanes suddenly) show a minor role. This finding highlights the importance of differentiating various rule violations when examining bus crashes instead of aggregating them altogether. Furthermore, the effects of rule violation behavior show substantial heterogeneity. For example, the association between not yielding to pedestrians and bus crashes is enhanced when drivers also show records of touching solid line with wheel while driving, driving outside the bus lane, or are internally trained. Findings of this study provide insights for countermeasures to improve bus safety by targeting critical bus driver groups with specific rule violations, and inform future research to collect observational data on drivers' rule violation behaviors.