Adjudin improves beta cell maturation, hepatic glucose uptake and glucose homeostasis.

AIMS/HYPOTHESIS: Recovering functional beta cell mass is a promising approach for future diabetes therapies. The aim of the present study is to investigate the effects of adjudin, a small molecule identified in a beta cell screen using zebrafish, on pancreatic beta cells and diabetes conditions in mice and human spheroids. METHODS: In zebrafish, insulin expression was examined by bioluminescence and quantitative real-time PCR (qPCR), glucose levels were examined by direct measurements and distribution using a fluorescent glucose analogue, and calcium activity in beta cells was analysed by in vivo live imaging. Pancreatic islets of wild-type postnatal day 0 (P0) and 3-month-old (adult) mice, as well as adult db/db mice (i.e. BKS(D)-Leprdb/JOrlRj), were cultured in vitro and analysed by qPCR, glucose stimulated insulin secretion and whole mount staining. RNA-seq was performed for islets of P0 and db/db mice. For in vivo assessment, db/db mice were treated with adjudin and subjected to analysis of metabolic variables and islet cells. Glucose consumption was examined in primary human hepatocyte spheroids. RESULTS: Adjudin treatment increased insulin expression and calcium response to glucose in beta cells and decreased glucose levels after beta cell ablation in zebrafish. Adjudin led to improved beta cell function, decreased beta cell proliferation and glucose responsive insulin secretion by decreasing basal insulin secretion in in vitro cultured newborn mouse islets. RNA-seq of P0 islets indicated that adjudin treatment resulted in increased glucose metabolism and mitochondrial function, as well as downstream signalling pathways involved in insulin secretion. In islets from db/db mice cultured in vitro, adjudin treatment strengthened beta cell identity and insulin secretion. RNA-seq of db/db islets indicated adjudin-upregulated genes associated with insulin secretion, membrane ion channel activity and exocytosis. Moreover, adjudin promoted glucose uptake in the liver of zebrafish in an insulin-independent manner, and similarly promoted glucose consumption in primary human hepatocyte spheroids with insulin resistance. In vivo studies using db/db mice revealed reduced nonfasting blood glucose, improved glucose tolerance and strengthened beta cell identity after adjudin treatment. CONCLUSIONS/INTERPRETATION: Adjudin promoted functional maturation of immature islets, improved function of dysfunctional islets, stimulated glucose uptake in liver and improved glucose homeostasis in db/db mice. Thus, the multifunctional drug adjudin, previously studied in various contexts and conditions, also shows promise in the management of diabetic states. DATA AVAILABILITY: Raw and processed RNA-seq data for this study have been deposited in the Gene Expression Omnibus under accession number GSE235398 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235398 ).

Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

Identifying novel acute pancreatitis sub-phenotypes using total serum calcium trajectories.

BACKGROUND: Acute pancreatitis (AP) has heterogeneous clinical features, and identifying clinically relevant sub-phenotypes is useful. We aimed to identify novel sub-phenotypes in hospitalized AP patients using longitudinal total serum calcium (TSC) trajectories. METHODS: AP patients had at least two TSC measurements during the first 24 h of hospitalization in the US-based critical care database (Medical Information Mart for Intensive Care-III (MIMIC-III) and MIMIC-IV were included. Group-based trajectory modeling was used to identify calcium trajectory phenotypes, and patient characteristics and treatment outcomes were compared between the phenotypes. RESULTS: A total of 4518 admissions were included in the analysis. Four TSC trajectory groups were identified: "Very low TSC, slow resolvers" (n = 65; 1.4% of the cohort); "Moderately low TSC" (n = 559; 12.4%); "Stable normal-calcium" (n = 3875; 85.8%); and "Fluctuating high TSC" (n = 19; 0.4%). The "Very low TSC, slow resolvers" had the lowest initial, maximum, minimum, and mean TSC, and highest SOFA score, creatinine and glucose level. In contrast, the "Stable normal-calcium" had the fewest ICU admission, antibiotic use, intubation and renal replace treatment. In adjusted analysis, significantly higher in-hospital mortality was noted among "Very low TSC, slow resolvers" (odds ratio [OR], 7.2; 95% CI, 3.7 to 14.0), "moderately low TSC" (OR, 5.0; 95% CI, 3.8 to 6.7), and "Fluctuating high TSC" (OR, 5.6; 95% CI, 1.5 to 20.6) compared with the "Stable normal-calcium" group. CONCLUSIONS: We identified four novel sub-phenotypes of patients with AP, with significant variability in clinical outcomes. Not only the absolute TSC levels but also their trajectories were significantly associated with in-hospital mortality.

Unveiling the Occurrence and Non-Negligible Role of Amino Sugars in Waste Activated Sludge Fermentation by an Enriched Chitin-Degradation Consortium.

Polysaccharides in extracellular polymeric substances (EPS) can form a hybrid matrix network with proteins, impeding waste-activated sludge (WAS) fermentation. Amino sugars, such as N-acetyl-d-glucosamine (GlcNAc) polymers and sialic acid, are the non-negligible components in the EPS of aerobic granules or biofilm. However, the occurrence of amino sugars in WAS and their degradation remains unclear. Thus, amino sugars (∼6.0%) in WAS were revealed, and the genera of Lactococcus and Zoogloea were identified for the first time. Chitin was used as the substrate to enrich a chitin-degrading consortium (CDC). The COD balances for methane production ranged from 83.3 and 95.1%. Chitin was gradually converted to oligosaccharides and GlcNAc after dosing with the extracellular enzyme. After doing enriched CDC in WAS, the final methane production markedly increased to 60.4 ± 0.6 mL, reflecting an increase of ∼62%. Four model substrates of amino sugars (GlcNAc and sialic acid) and polysaccharides (cellulose and dextran) could be used by CDC. Treponema (34.3%) was identified as the core bacterium via excreting chitinases (EC 3.2.1.14) and N-acetyl-glucosaminidases (EC 3.2.1.52), especially the genetic abundance of chitinases in CDC was 2.5 times higher than that of WAS. Thus, this study provides an elegant method for the utilization of amino sugar-enriched organics.

Analysis of the efficacy of separation surgery for severe neurological compression in multiple myeloma: a retrospective analysis of 35 cases.

PURPOSE: To investigate the effectiveness and safety of separation surgery for Epidural Spinal Cord Compression (ESCC) graded ≥ 2 in patients with Multiple Myeloma (MM), analyze factors influencing surgical outcomes, and develop a preliminary treatment decision framework for these patients. METHODS: A retrospective analysis was conducted on clinical data from 35 MM patients who underwent separation surgery for ESCC graded ≥ 2 between 2013 and 2018. Patient data, including baseline information, surgical details, complications, and pre-operative as well as one-month post-operative efficacy evaluation indicators were recorded. Statistical analysis was performed on pre-operative and post-operative efficacy indicators to determine if there were significant improvements (p < 0.05). Ordered logistic regression was utilized to assess factors associated with an unfavorable post-operative quality of life outcome. RESULTS: Compared to pre-operative values, at one-month post-surgery, patients showed significant improvements in Frankel Score Classification (4 vs 5, p < 0.05), Karnofsky Performance Score (30 vs 70, p < 0.05), and Visual Analogue Scale (8 vs 3, p < 0.05). Complications occurred in 7 cases (20%). The number of segments with ESCC (OR = 0.171, p < 0.05) and pre-operative chemotherapy (OR = 5.202, p = 0.05) were identified as independent factors influencing patient outcomes. Patients with more than two vertebral segments with ESCC exhibited significantly worse post-operative conditions. CONCLUSIONS: Separation surgery effectively alleviates pain, improves neurological function, and enhances the quality of life in patients with ESCC graded ≥ 2 due to MM.

Which factors are associated with adverse prognosis in multiple myeloma patients after surgery? - preliminary establishment and validation of the nomogram.

BACKGROUND: To investigate the prognosis of patients with Multiple Myeloma (MM) after surgery, analyze the risk factors leading to adverse postoperative outcomes, and establish a nomogram. METHODS: Clinical data from 154 patients with MM who underwent surgery at our institution between 2007 and 2019 were retrospectively analyzed. Assessing and comparing patients' pain levels, quality of life, and functional status before and after surgery (P < 0.05) were considered statistically significant. The Kaplan-Meier survival curve was used to estimate the median survival time. Adverse postoperative outcomes were defined as worsened symptoms, lesion recurrence, complication grade ≥ 2, or a postoperative survival period < 1 year. Logistic regression analysis was used to determine the prognostic factors. Based on the logistic regression results, a nomogram predictive model was developed and calibrated. RESULTS: Postoperative pain was significantly alleviated in patients with MM, and there were significant improvements in the quality of life and functional status (P < 0.05). The median postoperative survival was 41 months. Forty-nine patients (31.8%) experienced adverse postoperative outcomes. Multivariate logistic regression analysis identified patient age, duration of MM, International Staging System, preoperative Karnofsky Performance Status, and Hb < 90 g/L as independent factors influencing patient prognosis. Based on these results, a nomogram was constructed, with a C-index of 0.812. The calibration curve demonstrated similarity between the predicted and actual survival curves. Decision curve analysis favored the predictive value of the model at high-risk thresholds from 10% to-69%. CONCLUSION: This study developed a nomogram risk prediction model to assist in providing quantifiable assessment indicators for preoperative evaluation of surgical risk.

High levels of mitochondrial dynamics, autophagy, and apoptosis contribute to stable testicular status in hibernating Daurian ground squirrels.

Daurian ground squirrels (Spermophilus dauricus) experience various stress states during winter hibernation, but the impact on testicular function remains unclear. This study focused on the effects of changes in testicular autophagy, apoptosis, and mitochondrial homeostasis signaling pathways at various stages on the testes of Daurian ground squirrels. Results indicated that: (1) During winter hibernation, there was a significant increase in seminiferous tubule diameter and seminiferous epithelium thickness compared to summer. Spermatogonia number and testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were higher during inter-bout arousal, suggesting that the testes remained stable during hibernation. (2) An increased number of mitochondria with intact morphology were observed during hibernation, indicating that mitochondrial homeostasis may contribute to testicular stability. (3) DNA fragmentation was evident in the testes during the hibernation and inter-bout arousal stages, with the highest level of caspase3 enzyme activity detected during inter-bout arousal, together with elevated levels of Bax/Bcl-2 and Lc3 II/Lc3 I, indicating an up-regulation of apoptosis and autophagy signaling pathways during hibernation. (4) The abundance of DRP1, MFF, OPA1, and MFN2 proteins was increased, suggesting an up-regulation of mitochondrial dynamics-related pathways. Overall, testicular autophagy, apoptosis, and mitochondrial homeostasis-related signaling pathways were notably active in the extreme winter environment. The well-maintained mitochondrial morphology may favor the production of reproductive hormones and support stable testicular morphology.

Preparation, characterization, and anticancer effects of an inclusion complex of coixol with ß-cyclodextrin polymers.

CONTEXT: Coix [Coix lacryma-jobi L. var. mayuen (Roman.) Stapf (Poaceae)], a crop of medicinal and edible significance, contains coixol, which has demonstrated anticancer properties. However, the limited solubility of coixol restricts its potential therapeutic applications. OBJECTIVE: This study prepared a water-soluble coixol-ß-cyclodextrin polymer (CDP) inclusion compound and evaluated its anticancer effect. MATERIALS AND METHODS: The coixol-CDP compound was synthesized through a solvent-stirring and freeze-drying technique. Its coixol content was quantified using HPLC, and its stability was tested under various conditions. The anticancer effects of the coixol-CDP compound (4.129, 8.259, 16.518, and 33.035 mg/L for 24, 48, and 72 h) on the proliferation of non-small cell lung cancer (NSCLC) A549 cells were evaluated using an MTT assay; cell morphology was examined by Hoechst nuclear staining; apoptosis and cell cycle was detected by flow cytometry; and the expression of apoptosis-related proteins was assessed by Western blots. RESULTS: The water-soluble coixol-CDP inclusion compound was successfully prepared with an inclusion ratio of 86.6% and an inclusion yield rate of 84.1%. The coixol content of the compound was 5.63% and the compound remained stable under various conditions. Compared to coixol alone, all 24, 48, and 72 h administrations with the coixol-CDP compound exhibited lower IC50 values (33.93 ± 2.28, 16.80 ± 1.46, and 6.93 ± 0.83 mg/L) in A549 cells; the compound also showed stronger regulatory effects on apoptosis-related proteins. DISCUSSION AND CONCLUSIONS: These findings offer a new perspective for the potential clinical application of Coix in NSCLC therapy and its future research.

[Research progress in chemical constituents, pharmacological effects, and clinical application of Curcuma wenyujin and prediction of its quality markers].

Curcuma wenyujin, as one of the eight Daodi-herbs in Zhejiang province, is widely used. It has the effects of eliminating stasis and dissipating mass, moving Qi and activating blood, and clearing heart and relieving depression. Modern studies have shown that it has anti-tumor, anti-inflammatory, anti-oxidation, anti-thrombus and liver-protecting effects and mainly contains sesquiterpenoids, monoterpenoids, diterpenoids, and curcumins. This paper reviews the research progress in the chemical constituents and pharmacological effects of C. wenyujin in the last decade, discusses the modern clinical applications combined with the traditional efficacy, and predicts its quality markers(Q-markers) from plant consanguinity, medicinal properties, efficacy, processing and measurability of chemical components based on the theory of Q-markers, so as to provide a reference for the establishment of a scientific quality evaluation system and the research and application of this herb in the future.

Tea intake and total body bone mineral density of all ages: a Mendelian randomization analysis.

Background: There is increasing evidence indicating that tea intake affects bone mineral density levels; however, the causality between tea intake and bone mineral density is inconclusive. This study aimed to assess the causal relationship between tea intake and total body bone mineral density (TB-BMD) through two-sample Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR approach to estimate the potential causal effects of tea intake on TB-BMD at all ages in a European population. The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs), identified from a genome-wide association meta-analysis of tea intake (N = up to 447,485 individuals) and from the GEnetic Factors for OSteoporosis (GEFOS) Consortium's genome-wide association meta-analysis (N = up to 56,284 individuals), with baseline data collected in 2018 and populations derived from the European ancestry. The association between each SNP and TB-BMD was weighted by its association with tea intake, and estimates were combined mainly using an inverse-variance weighted meta-analysis. In addition, we explored the potential causal effects between green tea intake, herbal tea intake, and TB-BMD. Results: The MR analysis revealed that genetically determined tea intake exerts a causal impact on TB-BMD, with an odds ratio (OR) of 1.204 (95% CI: 1.062-1.366, p = 0.004), especially in the age group of 45-60 years (OR = 1.360, 95% CI: 1.088-1.700, p = 0.007). No horizontal pleiotropy and heterogeneity were observed. However, there was no causal effect of tea intake on TB-BMD in the age groups of 0-15, 15-30, 30-45, and over 60 years. In the subgroup analysis, when green tea intake was regarded as the exposure factor, no salient associations were found between green tea consumption and TB-BMD (IVW p = 0.368). Similarly, there was also no causal association between herbal tea intake and TB-BMD (IVW p = 0.264). Conclusion: The findings of this study support the evidence that tea consumption increases bone density and reduces the risk of osteoporosis in the age group of 45-60 years within the European population.

Cognitively motivated or emotionally charged? Issue-switching mechanism of second screening-facilitated political participation during the 2022 COVID-19 waves in China.

This study examines the effects of mass media and mobile media on civil behaviors in China during COVID-19 outbreaks. It explores the media practices of the Chinese public and the psychological mechanisms that led to their protests and boycotts against the government's COVID policies. Chinese official media has a reputation for depoliticizing natural disasters and censoring the online mobilization of collective actions. Based on previous research and theories regarding media multitasking and political communication, this study demonstrates the psychological mechanism by which a special type of media multitasking-second screening-contributed to political participation in a politically restrictive environment. This study contributes to existing research on media multitasking by proposing a unique theoretical framework that entails an issue-based typology of second screening. The framework expands knowledge by highlighting the importance of issue-switching and investigating its psychological influence on political participation. Previous studies have primarily focused on device-switching and its effects, so this study offers fresh insights in this field. Drawing on a nationwide online survey (N = 1180) conducted during the late-2022 wave of COVID-19 in China, this study reveals that second screening on official televised COVID-19 news can elicit simultaneous issue-switching among Chinese audiences: from the de-politicalized COVID-19 propaganda toward politics. Further, second screening on different issues (i.e., politics vs. health sciences) may instigate political participation through cognitive and emotion channels differently. That is, both political efficacy (cognitive) and negative emotions (emotion) facilitate the process, with the former making a greater contribution.

A moderated chain mediation model examining the relation between smartphone addiction and intolerance of uncertainty among master's and PhD students.

The theories of relational regulation and compensatory Internet use suggest that intolerance of uncertainty influences smartphone addiction (SPA), which in turn is influenced by other aspects. This study used previous results to examine how intolerance of uncertainty affects SPA in PhD and master's degree programs. A convenience sample comprising 1727 master's and PhD students (99.9 %; 50.7 % female; Mage = 27.71; SD = 3.80; range = 21-43) was recruited. Using established questionnaires, we measured SPA, anxiety, positive coping style, perceived social support, and intolerance of uncertainty. The results demonstrated that intolerance of uncertainty positively affects SPA in terms of predictive power. Furthermore, anxiety and positive coping style mediate that link in a cascade fashion. A greater SPA indicates that the individual is less likely to use a positive coping style, has a higher anxiety level, and has a lower tolerance for uncertainty. While thinking about how intolerance of uncertainty affects anxiety and positive coping style, perceived social support mediates the relationship. Intolerance of uncertainty has less impact on anxiety and positive coping style when perceived social support is high. These results indicate the possibility of examining SPA prevention and intervention from several angles. Therefore, emotional regulation, which modifies anxiety and the tendency to use a positive coping style, may reduce the impact of intolerance of uncertainty on SPA. Another successful strategy for reducing smartphone addiction is to provide social support from loved ones and the community at large.

Industrial hemp (Cannabis sativa L.) can utilize and remediate soil strongly contaminated with Cu, As, Cd, and Pb by phytoattenuation.

Industrial hemp (Cannabis sativa L.) has great application potential in heavy metal-polluted soils owing to its safe non-food utilization. However, the fate of heavy metals in different varieties of hemp planted in strongly contaminated natural soils remains unknown. Here, we investigated the growth, heavy metal uptake, distribution, and transfer of nine hemp varieties in soils strongly contaminated with Cu, As, Cd, and Pb. Hemp variety and metal type were the main factors affecting the growth and heavy metal uptake in hemp. The nine hemp varieties grew well in the contaminated soils; however, differences existed among the varieties. The biomass of Z3 reached 5669.1 kg hm-1, whereas that of Yunma No. 1 was only 51.8 % of Z3. The plant height, stalk diameter, and stalk bark thickness of Z3 were greater than those of the other varieties, reaching 168 cm, 9.2 mm, and 0.56 mm, respectively. Permanova's analysis revealed that the total effects of Cu, As, Cd, and Pb on the growth of the nine hemp varieties reached 60 %, with leaf As having the greatest effect, reaching 16 %. , Even in strongly contaminated soils, the nine varieties showed poor Cu, As, Cd, and Pb uptake. Most of the Cu, As, Cd, and Pb were retained in the root, reaching 57.7-72.4, 47.6-64.7, 76.0-92.9, and 70.0-87.8 %, respectively. Overall, the Cu, As, Cd, and Pb uptake of Wanma No.1 was the highest among the nine varieties, whereas that of Guangxi Bama was the lowest. These results indicate that hemp is a viable alternative for phytoattenuation in soils contaminated with heavy metals because of its ability to tolerate and accumulate Cu, As, Cd, and Pb in its roots, and Guangxi Bama is superior to the other varieties considering the safe utilization of hemp products.

Molecular fragmentation as a crucial step in the AI-based drug development pathway.

The AI-based small molecule drug discovery has become a significant trend at the intersection of computer science and life sciences. In the pursuit of novel compounds, fragment-based drug discovery has emerged as a novel approach. The Generative Pre-trained Transformers (GPT) model has showcased remarkable prowess across various domains, rooted in its pre-training and representation learning of fundamental linguistic units. Analogous to natural language, molecular encoding, as a form of chemical language, necessitates fragmentation aligned with specific chemical logic for accurate molecular encoding. This review provides a comprehensive overview of the current state of the art in molecular fragmentation. We systematically summarize the approaches and applications of various molecular fragmentation techniques, with special emphasis on the characteristics and scope of applicability of each technique, and discuss their applications. We also provide an outlook on the current development trends of molecular fragmentation techniques, including some potential research directions and challenges.

The choice of ultra-low attachment plates impacts primary human and primary canine hepatocyte spheroid formation, phenotypes, and function.

Organotypic three-dimensional liver spheroid cultures in which hepatic cells retain their molecular phenotype and functionality have emerged as powerful tools for preclinical drug development. In recent years a multitude of culture systems have been developed; however, a thorough side-by-side benchmarking of the different methods is lacking. Here, we compared the performance of ten different 96- and 384-well microplate types to support spheroid formation and long-term culture. Specifically, we evaluated differences in spheroid formation kinetics, viability, functionality, expression patterns, and their utility for hepatotoxicity assessments using primary human hepatocytes (PHH) and primary canine hepatocytes (PCH). All 96-well plates enabled formation of PHH liver spheroids, albeit with differences between plates in spheroid size, geometry, and reproducibility. Performance of different 384-wells was less consistent. Only 6/10 microplates supported the formation of PCH aggregates. Interestingly, even if PCH aggregates in these six microplates were more loosely packed than PHH spheroids, they maintained their function and were compatible with long-term pharmacological and toxicological assays. Overall, Corning and Biofloat plates showed the best performance in the formation of both human and canine liver spheroids with highest viability, most physiologically relevant phenotypes, superior CYP activity and lowest coefficient of variation in toxicity assays. The presented data constitutes a valuable resource that demonstrates the impacts of current ultra-low attachment plates on liver spheroid metrics and can guide evidence-based plate selection. Combined, these results have important implications for the cross-comparison of different studies and can facilitate the standardization and reproducibility of three-dimensional liver culture experiments.

Moderating effect of negative emotion differentiation in chronic stress and fatigue among Chinese employees.

Introduction: According to the reactivity hypothesis and the diathesis-stress model, repeated activation of the stress system has a negative effect on health, and this effect may differ because of individual characteristics. Thus, the present study explores the effect of chronic stress on fatigue and investigates its mechanism. Methods: A questionnaire survey of 288 participants selected from the northwest part of China was conducted (13.89% females; ages ranged from 18 to 34 years, with M ± SD = 23.14 ± 3.79 years) on chronic stress, fatigue, depression, anxiety, and negative emotion differentiation. SPSS 28.0 was used to process descriptive statistics and correlation analysis and the PROCESS macro was used to analyze the moderated chained multi-mediation. Results: Chronic stress was found to be positively correlated with fatigue, depression, and anxiety; depression and anxiety played a chained multi-mediating role between chronic stress and fatigue, and negative emotion differentiation played a moderating role in the chained multi-mediation model. Discussion: Compared with depression, anxiety plays a more important role in the influence of chronic stress on fatigue. Therefore, it is necessary to pay more attention to anxiety symptoms and take appropriate intervention measures. Negative emotion differentiation plays a moderating role. Improving negative emotion differentiation through mindfulness and adaptive emotion regulation is an effective way to reduce the influence of chronic stress on fatigue.

Phytoremediation and environmental effects of three Amaranthaceae plants in contaminated soil under intercropping systems.

Intercropping is a widely used agricultural system; however, the effect of intercropping between accumulator plants on phytoextraction in heavy metal-contaminated soils remains unknown. Here, a field experiment was conducted to investigate the phytoextraction efficiency and related environmental effects of three Amaranthaceae plants (Amaranthus hypochondriacus, Celosia argentea, and Pfaffia glomerata) using mono- and intercropping models. In monocropping, the total biomass of A. hypochondriacus was only 51.2 % of that of C. argentea. Compared with monocropping, intercropping reduced the fresh weight per plant of A. hypochondriacus by 53.0 % (intercropping with C. argentea) and 40.5 % (intercropping with P. glomerata) but increased the biomass per plant of C. argentea and P. glomerata by 128.2 and 14.2 %, respectively. The Cd uptake of the three plants in the monocropping models showed the following trend: C. argentea > P. glomerata > A. hypochondriacus. Interplanting A. hypochondriacus and C. argentea further increased the phytoextraction efficiency by 361.2 % (compared with A. hypochondriacus monocropping) and 52.0 % (compared with C. argentea monocropping). Soil exchangeable Cd, Pb, Cu, Zn, K, and P, soil N-NO3- and N-NH4+, soil common bacteria and arbuscular mycorrhiza (AM) fungi, and soil total organic carbon (TOC) play key roles in Cd and Pb uptake by the three accumulator plants (p < 0.05). The biomass of common bacteria, Gm+, Gm- bacteria, fungi, AM fungi, and actinomycetes increased with the three accumulators planted in the mono- and intercropping models. Compared with C. argentea monocropping, the biomass of soil microbes in the rhizosphere soil was obviously increased in the intercropping A. hypochondriacus and C. argentea models. These results suggest that interplanting A. hypochondriacus and C. argentea can increase Cd removal efficiency from Cd-contaminated soils, and this model could be recommended to remediate Cd-contaminated soils on a field scale.

Stability Analysis of Sampled-Data Systems Based on Sawtooth-Characteristic-Based Hierarchical Integral Inequality.

The aim of this article is to investigate the stability of sampled-data systems (SDSs) by introducing a sawtooth-characteristic-based hierarchical integral inequality (SCBHII) and to obtain the maximum allowable sampling period that maintains the stability of the system. First, by associating the sawtooth characteristics of the input delay in SDSs with free matrices, an SCBHII is proposed; its accuracy improves as the hierarchy increases. Subsequently, a high-order two-sided looped-functional, which considers both the sampling multi-integral states and the sawtooth pattern, is introduced to cater to the aforementioned inequality. In addition, the system variables are augmented by sawtooth pattern-related terms, which eliminates the need for additional secondary processing when determining the negative-definiteness of derivatives with high-order terms. By combining the high-order two-sided looped-functional with the proposed SCBHII, a stability criterion for SDSs with reduced conservatism is achieved, presented in the form of linear matrix inequalities. The proposed inequality technique and the stability criterion are shown to be effective and superior through three numerical examples and a real-world simplified power market model.

Sawtooth-characteristic-based free matrix integral inequality and its application to sampled-data systems.

The focus of this article is to present a sawtooth-characteristic-based free-matrix integral inequality and to discuss its application to sampled-data systems (SDSs). Firstly, the free matrix, which is associated with the sawtooth characteristic of the input delay, is presented and incorporated into the integral inequality. In the development of inequality techniques, this is the first time that a free matrix has been associated with the sawtooth characteristic. On this basis, a corresponding sawtooth-characteristic-based free-matrix integral inequality is established, enabling estimation of the integral quadratic terms of the Lyapunov-Krasovskii functional (LKF) derivative. To overcome the challenges posed by second-order terms resulting from the proposed integral inequality, augmented system variables associated with the sawtooth characteristic are also introduced. Thus, the complicated calculation arising from second-order terms and the conservatism caused by the quadratic estimation of the LKF can be avoided. Finally, through the utilization of the sawtooth-characteristic-based free-matrix integral inequality, stability criteria with less conservatism are derived for the SDSs in the form of linear matrix inequalities. The superiority of the proposed approach is illustrated through two numerical examples and a simplified sampled-data based power market.

Cholangiocyte organoids to study drug-induced injury.

BACKGROUND: Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. METHODS: Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. RESULTS: CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. CONCLUSION: These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.