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The Zuojin Pill consists of Coptidis Rhizoma (CR) and Euodiae Fructus (EF). It has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. Alkaloids are considered to be its main pharmacologically active substances. The authors of the present study investigated the feasibility of preparing high purity total alkaloids (TAs) from CR and EF extracts separately and evaluated the effect for the treatment of bile reflux gastritis (BRG). Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. were used in the study. An optimized method for the enrichment and purification of TAs with macroporous resin was established. Furthermore, qualitative analysis by using ultra-high performance liquid chromatography coupled with electrospray ionization and quadrupole-time of flight mass spectrometry (UHPLC–ESI–QTOF-MS) was explored to identify the components of purified TAs. Thirty-one compounds, thirty alkaloids and one phenolic compound, were identified or tentatively assigned by comparison with reference standards or literature data. A method of ultra-high performance liquid chromatography coupled with diode array detector (UHPLC–DAD) for quantitative analysis was also developed. The contents of nine alkaloids were determined. Moreover, a rat model of BRG was used to investigate the therapeutic effect of the combination of purified TAs from CR and EF. Gastric pathologic examination suggested that the alkaloids’ combination could markedly attenuate the pathological changes of gastric mucosa.

The issue of insufficient physical activity(PA) among adolescents is increasingly prominent, and Physical literacy (PL) is considered an important determinant of PA. This study aimed to explore the interplay between school physical environment, classroom achievement emotions and PL among adolescents.1,020 junior and senior high school students from 12 schools in Liaoning Province participated in the study(mean age = 15.23 ± 1.63) years. The collected data were analyzed using SPSS 27.0 and AMOS26.0, independent sample t-tests, Pearson correlation, linear regression, structural equation model testing and mediation analysis were used to analyze the relationship between indicators. The findings indicated significant correlations existed among the school physical environment, classroom achievement emotions, and PL. Regression analyses showed that both the school physical environment and classroom achievement emotions significantly predicted PL. Structural equation modeling analysis demonstrated that the school physical environment directly influenced PL ( β  = 0.259, 95% CI [0.164, 0.370]. Furthermore, classroom achievement emotions mediated the indirect effect of the school physical environment on PL ( β   = 0.685, 95% CI [0.598, 0.774].This study provides evidence of the relationships among school physical environment, classroom achievement emotions, and PL. This study traces to the source both external environmental and internal psychological factors that promote adolescents’ PL. The findings suggest that creating diverse and suitable school physical environment, alongside positive classroom achievement emotions, constitutes an effective path for enhancing adolescents’ PL cultivation.

Over the years, microbiome research has achieved tremendous advancements driven by culture‐independent meta‐omics approaches. Despite extensive research, our understanding of the functional roles and causal effects of the microbiome on phenotypes remains limited. In this study, we focused on the rumen metaproteome, combining it with metatranscriptome and metabolome data to accurately identify the active functional distributions of rumen microorganisms and specific functional groups that influence feed efficiency. By integrating host genetics data, we established the potentially causal relationships between microbes‐proteins/metabolites‐phenotype, and identified specific patterns in which functional groups of rumen microorganisms influence host feed efficiency. We found a causal link between Selenomonas bovis and rumen carbohydrate metabolism, potentially mediated by bacterial chemotaxis and a two‐component regulatory system, impacting feed utilization efficiency of dairy cows. Our study on the nutrient utilization functional groups in the rumen of high‐feed‐efficiency dairy cows, along with the identification of key microbiota functional proteins and their potentially causal relationships, will help move from correlation to causation in rumen microbiome research. This will ultimately enable precise regulation of the rumen microbiota for optimized ruminant production. In this study, we focused on the rumen metaproteome, combining it with metatranscriptome and metabolome data to identify the active functional distributions of rumen microorganisms and specific functional groups that influence feed efficiency. By integrating host genetics data, we established potentially causal relationships between microbes, proteins/metabolites, and phenotypes. We identified specific patterns in which functional groups of rumen microorganisms influence host feed efficiency. We found a causal link between Selenomonas bovis and rumen carbohydrate metabolism, potentially mediated by bacterial chemotaxis and a two‐component regulatory system, impacting feed utilization efficiency in dairy cows. Our study on nutrient utilization functional groups in the rumen of high‐feed‐efficiency dairy cows, along with identifying key microbiota functional proteins and their potential causal relationships, will help move from correlation to causation in rumen microbiome research. This will enable precise regulation of the rumen microbiota for optimized ruminant production. Highlights We combined rumen metaproteome, metatranscriptome, and metabolome data to identify active functional distributions of rumen microorganisms influencing feed efficiency. By integrating host genetics data, we identified causal relationships between microbes, proteins/metabolites, and phenotypes. We found a causal link between Selenomonas bovis and rumen carbohydrate metabolism, suggesting its role in improving feed utilization efficiency in dairy cows.

Background The clinical response rate to immune checkpoint blockade (ICB) therapy in melanoma remains low, despite its widespread use. Circular non-coding RNAs (circRNAs) are known to play a crucial role in cancer progression and may be a key factor limiting the effectiveness of ICB treatment. Methods The circRNAs that were downregulated after coadministration compared with single administration of PD-1 inhibitor administration were identified through RNA-seq and Ribo-seq, and thus the circPIAS1 (mmu_circ_0015773 in mouse, has_circ_0008378 in human) with high protein coding potential was revealed. Fluorescence in situ hybridization (FISH) assays were conducted to determine the localization of circPIAS1 in human and mouse melanoma cells, as well as its presence in tumor and adjacent tissues of patients. Validation through dual-luciferase reporter assay and LC–MS/MS confirmed the ability of circPIAS1 to encode a novel 108 amino acid polypeptide (circPIAS1-108aa). Specific antisense oligonucleotides (ASOs) targeting the junction site of circPIAS1 were developed to reduce its intracellular levels. Proliferation changes in melanoma cells were assessed using CCK8, EdU, and colony formation assays. The impact of circPIAS1-108aa on the ferroptosis process of melanoma cells was studied through GSH, MDA, and C11-BODIPY staining assays. Western Blot, Immunoprecipitation (IP), and Immunoprecipitation-Mass Spectrometry (IP-MS) techniques were employed to investigate the impact of circPIAS1-108aa on the P-STAT1/SLC7A11/GPX4 signaling pathway, as well as its influence on the balance between STAT1 SUMOylation and phosphorylation. Additionally, a melanoma subcutaneous transplanted tumor mouse model was utilized to examine the combined effect of reducing circPIAS1 levels alongside PD-1 inhibitor. Results Compared with the group treated with PD-1 inhibitor alone, circPIAS1 was significantly down-regulated in the coadministration group and demonstrated higher protein coding potential. CircPIAS1, primarily localized in the nucleus, was notably upregulated in tumor tissues compared to adjacent tissues, where it plays a crucial role in promoting cancer cell proliferation. This circRNA can encode a unique polypeptide consisting of 108 amino acids, through which it exerts its cancer-promoting function and impedes the effectiveness of ICB therapy. Mechanistically, circPIAS1-108aa hinders STAT1 phosphorylation by recruiting SUMO E3 ligase Ranbp2 to enhance STAT1 SUMOylation, thereby reactivating the transduction of the SLC7A11/GPX4 signaling pathway and restricting the immunogenic ferroptosis induced by IFNγ. Furthermore, the combination of ASO-circPIAS1 with PD-1 inhibitor effectively inhibits melanoma growth and significantly enhances the efficacy of immune drugs in vivo. Conclusions Our study uncovers a novel mechanism regarding immune evasion in melanoma driven by a unique 108aa peptide encoded by circPIAS1 in melanoma that dramatically hinders immunogenic ferroptosis triggered by ICB therapy via modulating the balance between SUMOylation and phosphorylation of STAT1. This work reveals circPIAS1-108aa as a critical factor limiting the immunotherapeutic effects in melanoma and propose a promising strategy for improving ICB treatment outcomes.

In 2011, DEHP (plasticizer) was reported to illegally be added in food and beverage products in Taiwan, which caused great concerns about food safety worldwide. DHEP has multiple toxic effects to human and animals such as endocrine disruption, cardiotoxicity, reproductive function, and development defects. However, the toxic effects of DEHP on mammalian oocyte quality are still unclear. SinceMEHP is the active metabolite of DEHP in vivo, in this study we used porcine oocyte asmodel to explore the effects of MEHP on oocyte maturation and we also studied the effects of melatonin administration on MEHP exposure-induced meiosis defects. Our results showed that exposure to MEHP significantly decreased the polar body extrusion rate in porcine oocytes. Further study showed that cell cycle progression, meiotic spindle organization, and actin assembly were all disturbed after MEHP exposure. Moreover, the DNA and histone methylation levels were also affected, showing with altered 5mC and H3K4me2 levels. These results indicated thatMEHP affected porcine oocytematuration, while MEHP exposure-induced meiotic defects were all remarkably ameliorated by the administration of melatonin in porcine oocytes. We further tried to explore the causes of MEHP toxicity on oocytes, and we found that MEHP exposure resulted in significant elevations of oxidative stress and induced early apoptosis as well as elevated autophagy, while melatonin administration could reduce these. Taken together, our results indicated that MEHP exposure induced deterioration of oocyte quality, whereas melatonin supplement showed amelioration on oocyte maturation through its rescue effects on oocyte oxidative stress-mediated apoptosis and autophagy. Summary Sentence Melatonin supplement rescued cell cycle and cytoskeleton defects through ameliorating oxidative stress-mediated apoptosis/autophagy in MEHP-exposed porcine oocytes.

Rumen bacteria produce volatile fatty acids which exert a far-reaching influence on hepatic metabolism, mammary gland metabolism, and animal production. In the current study, 32 heritable and 674 nonheritable bacterial taxa at species level were identified, and shown to have different microbiability (overall community contribution) and mean microbiability (the average of a single taxon’s contribution) for lactation performance. Recent studies have reported that some rumen microbes are heritable. However, it is necessary to clarify the functions and specific contributions of the heritable rumen microbes to cattle phenotypes (microbiability) in comparison with those that are nonheritable. This study aimed to identify the distribution and predicted functions of heritable and nonheritable bacterial taxa at species level in the rumen of dairy cows and their respective contributions to energy-corrected milk yield, protein content and yield, and fat content and yield in milk. Thirty-two heritable and 674 nonheritable bacterial taxa were identified at species level, and the functional analysis revealed that predicted microbial functions for both groups were mainly enriched for energy, amino acid, and ribonucleotide metabolism. The mean microbiability (to reflect a single taxon’s contribution) of heritable bacteria was found to range from 0.16% to 0.33% for the different milk traits, whereas the range for nonheritable bacteria was 0.03% to 0.06%. These findings suggest a strong contribution by host genetics in shaping the rumen microbiota, which contribute significantly to milk production traits. Therefore, there is an opportunity to further improve milk production traits through attention to host genetics and the interaction with the rumen microbiota. IMPORTANCE Rumen bacteria produce volatile fatty acids which exert a far-reaching influence on hepatic metabolism, mammary gland metabolism, and animal production. In the current study, 32 heritable and 674 nonheritable bacterial taxa at species level were identified, and shown to have different microbiability (overall community contribution) and mean microbiability (the average of a single taxon’s contribution) for lactation performance. The predicted functions of heritable and nonheritable bacterial taxa also differed, suggesting that targeted nutritional and genetic breeding approaches could be used to manipulate them to improve dairy cow performance.

This study proposes an adaptive distributed Student’s t extended Kalman filter (EKF) using Allan variance for ultrawide-band (UWB) localization. First of all, we model the state equation using the target’s position and velocity in east and north directions and the measurement equation by using distance between the UWB base station (BS) and the target object. Then, the adaptive distributed filter employs a federation structure: A local t EKF is designed to estimate the target’s position by fusing the distance between the UWB base station and the target object. The main filter fuses the local filter’s outputs and computes the final output. For the local t EKF, in order to overcome the problem that noise in the Kalman method is assumed to be white noise and difficult to adapt to practical application environments, the t distribution is used to model noise. Meanwhile, Allan variance is calculated to assist the local filter, which improves the adaptive ability. Experimental results show that the proposed method effectively enhances navigation accuracy compared to the distributed EKF.

Dihydroxyacid dehydratase (DHAD), a key enzyme in branched-chain amino acid synthesis in plants, is a promising yet unexploited herbicide target. Inspired by the natural DHAD inhibitor aspterric acid, we design benzoxazinone derivatives with α-hydroxycarboxylic acid moieties as potential inhibitors and develop an eco-friendly α-C(sp³)-H hydroxylation method for accessing carbonyl compounds. Among the derivatives, 7-fluoro-2-hydroxy-3-oxo-4-propyne-3,4-dihydro-2 H -benzo[ b ][1,4]oxazine-2-carboxylic acid ( I-6e) completely inhibits Arabidopsis thaliana germination and suppress six weed species by > 50%, with 100% efficacy against Avena fatua and Setaria viridis at 150 g ai/ha. This broad-spectrum activity and rice crop safety highlight its potential as an herbicide lead compound. Compound I-6e exhibits stronger affinity for DHAD ( K d  = 1 µM) than that of the natural substrate ( K d  = 5.39 µM). The 2.19 Å cocrystal structure of the At DHAD– I-6e complex reveals a unique binding mechanism, confirming the critical role of the α-hydroxycarboxylic acid scaffold. This study provides a blueprint for rational DHAD inhibitor design. Dihydroxyacid dehydratase (DHAD) is an essential enzyme for the synthesis of branched-chain amino acids in plants. Here, the authors rationally design a range of DHAD inhibitors as herbicides and present the crystal structure of a lead compound in complex with Arabidopsis DHAD.

Ferroptosis is a newly discovered type of cell death mediated by iron-dependent lipid peroxide. The disturbance of iron metabolism, imbalance of the amino acid antioxidant system, and lipid peroxide accumulation are considered distinct fingerprints of ferroptosis. The dysregulation of ferroptosis has been intensively studied in recent years due to its participation in various diseases, including cancer, kidney injury, and neurodegenerative diseases. Notably, increasing evidence indicates that ferroptosis plays different roles in a wide spectrum of liver diseases. On the one hand, inhibiting ferroptosis may counteract the pathophysiological progression of several liver diseases, such as alcoholic liver injury, nonalcoholic steatosis hepatitis and fibrosis. On the other hand, inducing ferroptosis may restrict the emergence of secondary resistance to current medicines, such as sorafenib, for hepatocellular carcinoma (HCC) therapy. Here, we summarize the biological characteristics and regulatory signalling pathways of ferroptosis involved in liver disease. The current available medical agents targeting ferroptosis, including inducers or inhibitors applied in liver diseases, are also reviewed. This work aims to provide new insight into the emerging role of pathogenesis and therapeutic approaches for liver diseases.

This paper studies the joint distribution of the default and prepayment losses for a large portfolio of loans, based on a bottom-up approach. The repayment behaviors of loans in the portfolio are determined by both systematic and idiosyncratic risk factors and are conditionally independent given the systematic factors. The joint two-dimensional limit distributions of the portfolio default and prepayment losses are obtained, including the strong law of large numbers and the central limit theorem. A numerical study for the portfolio losses is performed for some simplified models. Finally, we conduct the empirical analysis on the residential mortgage-backed security (RMBS) based on Freddie Mac’s dataset. The empirical results reveal the impacts of different factors on the default and prepayment behaviors, and the distributions of the portfolio losses are simulated based on empirical estimation results to show its difference with the log-normal distributions.