Exploring the Biomedical Potential of Terpenoid Alkaloids: Sources, Structures, and Activities.

Terpenoid alkaloids are recognized as a class of compounds with limited numbers but potent biological activities, primarily derived from plants, with a minor proportion originating from animals and microorganisms. These alkaloids are synthesized from the same prenyl unit that forms the terpene skeleton, with the nitrogen atom introduced through ß-aminoethanol, ethylamine, or methylamine, leading to a range of complex and diverse structures. Based on their skeleton type, they can be categorized into monoterpenes, sesquiterpenes, diterpenes, and triterpene alkaloids. To date, 289 natural terpenoid alkaloids, excluding triterpene alkaloids, have been identified in studies published between 2019 and 2024. These compounds demonstrate a spectrum of biological activities, including anti-inflammatory, antitumor, antibacterial, analgesic, and cardioprotective effects, making them promising candidates for further development. This review provides an overview of the sources, chemical structures, and biological activities of natural terpenoid alkaloids, serving as a reference for future research and applications in this area.

Research Progress on Sesquiterpene Compounds from Artabotrys Plants of Annonaceae.

Artabotrys, a pivotal genus within the Annonaceae family, is renowned for its extensive biological significance and medicinal potential. The genus's sesquiterpene compounds have attracted considerable interest from the scientific community due to their structural complexity and diverse biological activities. These compounds exhibit a range of biological activities, including antimalarial, antibacterial, anti-inflammatory analgesic, and anti-tumor properties, positioning them as promising candidates for medical applications. This review aims to summarize the current knowledge on the variety, species, and structural characteristics of sesquiterpene compounds isolated from Artabotrys plants. Furthermore, it delves into their pharmacological activities and underlying mechanisms, offering a comprehensive foundation for future research.

Mechanisms of Sepsis-Induced Acute Lung Injury and Advancements of Natural Small Molecules in Its Treatment.

Sepsis-induced acute lung injury (ALI), characterized by widespread lung dysfunction, is associated with significant morbidity and mortality due to the lack of effective pharmacological treatments available clinically. Small-molecule compounds derived from natural products represent an innovative source and have demonstrated therapeutic potential against sepsis-induced ALI. These natural small molecules may provide a promising alternative treatment option for sepsis-induced ALI. This review aims to summarize the pathogenesis of sepsis and potential therapeutic targets. It assembles critical updates (from 2014 to 2024) on natural small molecules with therapeutic potential against sepsis-induced ALI, detailing their sources, structures, effects, and mechanisms of action.

Electrolyte disorders induced by six multikinase inhibitors therapy for renal cell carcinoma: a large-scale pharmacovigilance analysis.

To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45-64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65-74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.

MEN1 is a regulator of alternative splicing and prevents R-loop-induced genome instability through suppression of RNA polymerase II elongation.

The fidelity of alternative splicing (AS) patterns is essential for growth development and cell fate determination. However, the scope of the molecular switches that regulate AS remains largely unexplored. Here we show that MEN1 is a previously unknown splicing regulatory factor. MEN1 deletion resulted in reprogramming of AS patterns in mouse lung tissue and human lung cancer cells, suggesting that MEN1 has a general function in regulating alternative precursor mRNA splicing. MEN1 altered exon skipping and the abundance of mRNA splicing isoforms of certain genes with suboptimal splice sites. Chromatin immunoprecipitation and chromosome walking assays revealed that MEN1 favored the accumulation of RNA polymerase II (Pol II) in regions encoding variant exons. Our data suggest that MEN1 regulates AS by slowing the Pol II elongation rate and that defects in these processes trigger R-loop formation, DNA damage accumulation and genome instability. Furthermore, we identified 28 MEN1-regulated exon-skipping events in lung cancer cells that were closely correlated with survival in patients with lung adenocarcinoma, and MEN1 deficiency sensitized lung cancer cells to splicing inhibitors. Collectively, these findings led to the identification of a novel biological role for menin in maintaining AS homeostasis and link this role to the regulation of cancer cell behavior.

Impaired function of dendritic cells within the tumor microenvironment.

Dendritic cells (DCs), a class of professional antigen-presenting cells, are considered key factors in the initiation and maintenance of anti-tumor immunity due to their powerful ability to present antigen and stimulate T-cell responses. The important role of DCs in controlling tumor growth and mediating potent anti-tumor immunity has been demonstrated in various cancer models. Accordingly, the infiltration of stimulatory DCs positively correlates with the prognosis and response to immunotherapy in a variety of solid tumors. However, accumulating evidence indicates that DCs exhibit a significantly dysfunctional state, ultimately leading to an impaired anti-tumor immune response due to the effects of the immunosuppressive tumor microenvironment (TME). Currently, numerous preclinical and clinical studies are exploring immunotherapeutic strategies to better control tumors by restoring or enhancing the activity of DCs in tumors, such as the popular DC-based vaccines. In this review, an overview of the role of DCs in controlling tumor progression is provided, followed by a summary of the current advances in understanding the mechanisms by which the TME affects the normal function of DCs, and concluding with a brief discussion of current strategies for DC-based tumor immunotherapy.

Psychiatric adverse reactions to non-selective RET multi-kinase inhibitors: a large-scale pharmacovigilance analysis.

Objective: The development of non-selective multi-kinase inhibitors (MKIs) has improved the. survival outcomes of patients with cancers. Psychiatric disorders represent an MKIs related AE of particular concern, as they are often ignored and may harm the patient's personal and social functioning. Therefore, we use the public database to describe and evaluate psychiatric adverse events related to various non-selective RET MKIs. Provide evidence for optimizing drug administration in the clinic. Methods: We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System FDA Adverse Event Reporting System in an observational and retrospective manner. Selecting psychiatric AEs to non-selective RET multikinase inhibitors (sorafenib, lenvatinib, vandetanib, cabozantinib, and sunitinib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of psychiatric related induced by non-selective RET MKIs between January 2004 and September 2022. Results: As of September 2022, 1,108 non-selective RET MKIs ICSRs were related to psychiatric AEs. 706 were ADR ICSRs, and 402 were non-ADR ICSRs. There were more ADR cases in males (69.5%), and 71.8% of the cases were submitted from North America. The age group most frequently affected by psychiatric ADRs was individuals aged 50-64 years for sorafenib, whereas 65-74 years for sunitinib, cabozantinib, and lenvatinib. In all psychiatric ADRs ICSRs, excluding missing data (n = 329), the most common adverse outcome was hospitalization (260/377, 69.0%), and the most serious was death (100/377, 26.5%). What calls for special attention is that the percentage of death rate for sunitinib was highest (24/54, 44.4%) in sunitinib-related psychiatric ADRs ICSRs, (excluding missing data, n = 44), followed by lenvatinib (4/14, 28.6%). Based on ROR, PRR, BCPNN, and MGPS methods, sorafenib, sunitinib, cabozantinib, and lenvatinib are significantly associated with all ADRs, the strongest association was the association between cabozantinib and feeding disorder. Conclusion: Despite the limitations, our study found that, except for vandetanib, other four drugs have been reported to have significant psychiatric side effects. Clinicians need to recognize and monitor these potentially fatal adverse events. If it is suitable for treatment with vandetanib, doctors should choose vandetanib for treatment.

Disability weight measurement for the severity of different diseases in Wuhan, China.

BACKGROUND: Measurement of the Chinese burden of disease with disability-adjusted life-years (DALYs) requires disability weight (DW) that quantify health losses for all non-fatal consequences of disease and injury. The Global Burden of Disease (GBD) 2013 DW study indicates that it is limited by lack of geographic variation in DW data and by the current measurement methodology. We aim to estimate DW for a set of health states from major diseases in the Wuhan population. METHODS: We conducted the DW measurement study for 206 health states through a household survey with computer-assisted face-to-face interviews and a web-based survey. Based on GBD 2013 DW study, paired comparison (PC) and Population health equivalence (PHE) method was used and different PC/PHE questions were randomly assigned to each respondent. In statistical analysis, the PC data was analyzed by probit regression. The probit regression results will be anchored by results from the PHE data analyzed by interval regression on the DW scale units between 0 (no loss of health) and 1 (loss equivalent to death). RESULTS: A total of 2610 and 3140 individuals were included in the household and web-based survey, respectively. The results from the total pooled data showed health state "mild anemia" (DW = 0.005, 95% UI 0.000-0.027) or "allergic rhinitis (hay fever)" (0.005, 95% UI 0.000-0.029) had the lowest DW and "heroin and other opioid dependence, severe" had the highest DW (0.699, 95% UI 0.579-0.827). A high correlation coefficient (Pearson's r = 0.876; P < 0.001) for DWs of same health states was observed between Wuhan's survey and GBD 2013 DW survey. Health states referred to mental symptom, fatigue, and the residual category of other physical symptoms were statistically significantly associated with a lower Wuhan's DWs than the GBD's DWs. Health states with disfigurement and substance use symptom had a higher DW in Wuhan population than the GBD 2013 study. CONCLUSIONS: This set of DWs could be used to calculate local diseases burden for health policy-decision in Wuhan population. The DW differences between the GBD's survey and Wuhan's survey suggest that there might be some contextual or culture factors influencing assessment on the severity of diseases.

Moderating effects of humanistic care and socioeconomic status on the relationship among pain intensity, psychological factors, and psychological function in adults with cancer pain from a province of China: A cross-sectional study.

Objective: The objective of this study is to explore whether humanistic care practiced by clinical pharmacists and socioeconomic status moderate the associations among pain intensity, psychological factors (catastrophizing and resilience), and psychological function (depression and anxiety) in cancer patients with low levels of education and income in the Shanxi province in the Northwest of China. Methods: Our sample comprised 123 adult inpatients with cancer pain. Demographic variables were obtained from the Hospital Information System of The Second Hospital of Shanxi Medical University. Pain intensity, psychological factors, and psychological functions were evaluated with four scales, and humanistic care was practiced with a part of the patients by clinical pharmacists. First, univariate analyses were conducted, followed by moderating effect models. Results: The incidence of depression and anxiety in patients with cancer pain in our sample were 48.78 and 41.46%, respectively. Low levels of psychological resilience (63.37, SD 21.74) were in this study. Pain intensity was significantly associated with humanistic care and anxiety. Humanistic care practiced by clinical pharmacists moderated not only the association between resilience and pain intensity but also the association between pain intensity and anxiety. Education levels moderated the relationship between pain intensity and the psychological factors of catastrophizing and resilience. Income levels moderated the association between resilience and anxiety. Conclusion: Humanistic care is essential in moderating the association among pain intensity, psychological factors, and psychological functions in Chinese cancer patients, especially those from lower-level counties and rural areas. Furthermore, socioeconomic statuses, such as education level and income, cannot easily change quickly. Still, proper humanistic care can relieve pain more effectively, reminding us that medical staff should implement effective personalized interventions to reduce patients' pain intensity.

Hydrogel-Encapsulated Engineered Microbial Consortium as a Photoautotrophic "Living Material" for Promoting Skin Wound Healing.

Genetically modified engineered microorganisms have been encapsulated in hydrogels and used as "living materials" for the treatment of skin diseases. However, their applications are often limited by the epidermal dry, nutrient-poor environment and cannot maintain functions stably for an expected sufficient time. To solve this problem, a photoautotrophic "living material" containing an engineered microbial consortium was designed and fabricated. The engineered microbial consortium comprised Synechococcus elongatus PCC7942 for producing sucrose by photosynthesis and another heterotrophic engineered bacterium (Escherichia coli or Lactococcus lactis) that can utilize sucrose for the growth and secretion of functional biomolecules. These engineered microorganisms in the "living material" were proved to function stably for a longer time than only individual microbes. Subsequently, CXCL12-secreting engineered L. lactis was used to construct the "living material", and its effect on promoting wound healing was verified in a full-thickness rat-skin defect model. The wounds treated by our hydrogel-encapsulated engineered microbial consortium (HeEMC) healed faster, with a wound area ratio of only 13.2% at day 14, compared to the remaining 62.6, 51.4, and 40.8% of the control, PEGDA, and PEGDA/CS groups, respectively. In conclusion, we established an efficient living material HeEMC to offer promising applications in the treatment of skin diseases.

Targeting inflammatory macrophages rebuilds therapeutic efficacy of DOT1L inhibition in hepatocellular carcinoma.

Epigenetic reprogramming is a promising therapeutic strategy for aggressive cancers, but its limitations in vivo remain unclear. Here, we showed, in detailed studies of data regarding 410 patients with human hepatocellular carcinoma (HCC), that increased histone methyltransferase DOT1L triggered epithelial-mesenchymal transition-mediated metastasis and served as a therapeutic target for human HCC. Unexpectedly, although targeting DOT1L in vitro abrogated the invasive potential of hepatoma cells, abrogation of DOT1L signals hardly affected the metastasis of hepatoma in vivo. Macrophages, which constitute the major cellular component of the stroma, abrogated the anti-metastatic effect of DOT1L targeting. Mechanistically, NF-κB signal elicited by macrophage inflammatory response operated via a non-epigenetic machinery to eliminate the therapeutic efficacy of DOT1L targeting. Importantly, therapeutic strategy combining DOT1L-targeted therapy with macrophage depletion or NF-κB inhibition in vivo effectively and successfully elicited cancer regression. Moreover, we found that the densities of macrophages in HCC determined malignant cell DOT1L-associated clinical outcome of the patients. Our results provide insight into the crosstalk between epigenetic reprogramming and cancer microenvironments and suggest that strategies to influence the functional activities of inflammatory cells may benefit epigenetic reprogramming therapy.

The dark side of university student entrepreneurship: Exploration of Chinese universities.

The dark side of entrepreneurship, especially the dark side of student entrepreneurship, has received little attention from academia. This study tries to examine the dark side of entrepreneurship among students in Chinese universities. Employing qualitative method by conducting semi-structured interview with students at the universities. Our study identifies the unproductive and destructive factors that drive the dark side of student entrepreneurship. Entrepreneurship costs that accompany students in the process of entrepreneurship are usually time pressure, academic conflict, and even health damage. There is a huge discrepancy between the knowledge given to students by universities and the knowledge required for entrepreneurship, and college students frequently lack entrepreneurial knowledge and business logic. In China, the use of inappropriate policy tools has decoupled the student entrepreneurship policies it pursues from the purpose the policies are supposed to serve. In so doing, this study contributes to the micro-level of the notion of the dark side of student entrepreneurship.

LincRNA RMRP Regulates Phenylephrine-induced Cardiomyocyte Hypertrophy by Means of Targeting miR-1.

ABSTRACT: Cardiac hypertrophy is a feature of hypertrophic cardiomyopathy (HCM), which could lead to heart failure and other cardiovascular diseases. Cardiomyocyte hypertrophy (CH) is the primary characteristic of cardiac hypertrophy. Long noncoding RNA (lncRNA, lincRNA) plays an important role in CH. In this study, the expression of linc-RMRP and its correlation with cardiac hypertrophy were analyzed in cardiac tissues of patients with HCM. Real-time qPCR and western blotting measured the expressions of lincf-RMRP, miR-1, and hypertrophic marker genes. RNA pulldown and luciferase reporter gene assays were performed to validate the combination between linc-RMRP and miR-1. We confirmed that Linc-RMRP was upregulated in both cardiac hypertrophy tissues and phenylephrine (PE)-induced CH cells, and the cells presented hypertrophic features, enlarged cell surface area and volume, elevated total protein contents, and increased expressions of ANP, BNP, ß-MHC, and activated p70S6K and 4EBP1. Bioinformatic analysis found that linc-RMRP directly bonds to miR-1. RNA pulldown, mutation, and luciferase reporter gene assays verified this combination. Silencing linc-RMRP significantly attenuated hypertrophic responses induced by PE while the expression of miR-1 was released. However, the transfection of miR-1 inhibitor reversed the effects of linc-RMRP knockdown exerted on PE-treated cardiomyocytes. In summary, our study identified the modulatory role linc-RMRP played in regulating PE-induced CH by means of binding miR-1, and this might provide a new target for cardiac hypertrophy therapy.

Eliciting national and subnational sets of disability weights in mainland China: Findings from the Chinese disability weight measurement study.

Background: The disability weight (DW) quantifies the severity of health states from disease sequela and is a pivotal parameter for disease burden calculation. We conducted a national and subnational DW measurement in China. Methods: In 2020-2021, we conducted a web-based survey to assess DWs for 206 health states in 31 Chinese provinces targeting health workers via professional networks. We fielded questions of paired comparison (PC) and population health equivalence (PHE). The PC data were analysed by probit regression analysis, and the regression results were anchored by results from the PHE responses on the DW scale between 0 (no loss of health) and 1 (health loss equivalent to death). Findings: We used PC responses from 468,541 respondents to estimate DWs of health states. Eight of 11 domains of health had significantly negative coefficients in the regression of the difference between Chinese and Global Burden of Disease (GBD) DWs, suggesting lower DW values for health states with mention of these domains in their lay description. We noted considerable heterogeneity within domains, however. After applying these Chinese DWs to the 2019 GBD estimates for China, total years lived with disability (YLDs) increased by 14·9% to 177 million despite lower estimates for musculoskeletal disorders, cardiovascular diseases, mental disorders, diabetes and chronic kidney disease. The lower estimates of YLDs for these conditions were more than offset by higher estimates of common, low-severity conditions. Interpretation: The differences between the GBD and Chinese DWs suggest that there might be some contextual factors influencing the valuation of health states. While the reduced estimates for mental disorders, alcohol use disorder, and dementia could hint at a culturally different valuation of these conditions in China, the much greater shifts in YLDs from low-severity conditions more likely reflects methodological difficulty to distinguish between health states that vary a little in absolute DW value but a lot in relative terms. Funding: This work was supported by the National Natural Science Foundation of China [grant number 82173626], the National Key Research and Development Program of China [grant numbers 2018YFC1315302], Wuhan Medical Research Program of Joint Fund of Hubei Health Committee [grant number WJ2019H304], and Ningxia Natural Science Foundation Project [grant number 2020AAC03436].

Impact of Particulate Matter on Hospitalizations for Respiratory Diseases and Related Economic Losses in Wuhan, China.

Background: Prior studies have reported the effects of particulate matter (PM) on respiratory disease (RD) hospitalizations, but few have quantified PM-related economic loss in the central region of China. This investigation aimed to assess the impacts of PM pollution on the risk burden and economic loss of patients admitted with RD. Methods: Daily cases of RD admitted to the hospital from 1 January 2015 to 31 December 2020 were collected from two class-A tertiary hospitals in Wuhan, China. Time series analysis incorporated with a generalized additive model (GAM) was adopted to assess the impacts of fine particulate matter (PM2.5) and inhalable particulate matter (PM10) exposures on patients hospitalized with RD. Stratified analyses were performed to investigate underlying effect modification of RD risk by sex, age, and season. The cost of illness (COI) approach was applied to evaluate the related economic losses caused by PM. Results: A total of 51,676 inpatients with a primary diagnosis of RD were included for the analysis. PM2.5 and PM10 exposures were associated with increased risks of hospitalizations for RD. Subgroup analysis demonstrated that men and children in the 0-14 years age group were more vulnerable to PM, and the adverse effects were promoted by low temperature in the cold season. A 152.4 million China Yuan (CNY) economic loss could be avoided if concentrations of PM2.5 and PM10 declined to 10 and 20 µg/m3, respectively. Conclusions: PM2.5 and PM10 concentrations were positively associated with RD hospitalization. Men and children were more vulnerable to PM. Effective air pollution control measures can reduce hospitalizations significantly and save economic loss substantially.

TRIM33 Modulates Inflammation and Airway Remodeling of PDGF-BB-Induced Airway Smooth-Muscle Cells by the Wnt/ß-Catenin Pathway.

Asthma is a chronic airway disease involving airway inflammation and remodeling. Studies showed that tripartite motif-containing protein 33 (TRIM33) regulated natural immunity, inflammation, and pulmonary fibrosis. However, the role and regulatory mechanism of TRIM33 in children's asthma are unclear. In this study, the TRIM33 expressions in serum samples and platelet-derived growth factor BB (PDGF-BB)-induced airway smooth-muscle cells (ASMCs) were evaluated. A gain-of-function experiment was performed, and cell proliferation and migration were detected using CCK-8 and wound healing assays. Besides, the protein levels of EMT biomarkers and airway-remodeling markers were determined by Western blot assay. ELISA analyzed the contents of IL-1ß, IL-6, and TNF-α in the supernatant. The modulation of Smad4 expression and subsequent activation of Wnt/ß-catenin by TRIM33 were also assessed. We found that TRIM33 was downregulated in the serum from children who were asthma patients and PDGF-BB-induced ASMCs. TRIM33 overexpression showed decrease of PDGF-BB-induced ASMC proliferation and migration. Moreover, the augment of TRIM33 reduced the PDGF-BB-induced cell EMT and airway-remodeling marker levels and suppressed the secretions of inflammatory cytokines in PDGF-BB-induced ASMCs. Additionally, TRIM33 overexpression inhibited activation of Wnt/ß-catenin via reducing Smad4 expression to regulate asthma inflammation and airway remodeling. All in all, our study revealed that TRIM33 expression was downregulated in children who were asthma patients and PDGF-BB-induced ASMCs. TRIM33 modulated PDGF-BB-induced inflammation and airway remodeling of ASMCs by the Wnt/ß-catenin pathway via regulating Smad4, which may provide a new treatment direction for asthma.

c-Myc-driven glycolysis polarizes functional regulatory B cells that trigger pathogenic inflammatory responses.

B cells secreting IL-10 functionally are recognized as functional regulatory B (Breg) cells; however, direct evidence concerning the phenotype, regulation, and functional and clinical relevance of IL-10-secreting Breg cells in humans is still lacking. Here, we demonstrate that, although IL-10 itself is anti-inflammatory, IL-10+ functional Breg cells in patients with systemic lupus erythematosus (SLE) display aggressive inflammatory features; these features shift their functions away from inducing CD8+ T cell tolerance and cause them to induce a pathogenic CD4+ T cell response. Functional Breg cells polarized by environmental factors (e.g., CPG-DNA) or directly isolated from patients with SLE mainly exhibit a CD24intCD27-CD38-CD69+/hi phenotype that is different from that of their precursors. Mechanistically, MAPK/ERK/P38-elicited sequential oncogenic c-Myc upregulation and enhanced glycolysis are necessary for the generation and functional maintenance of functional Breg cells. Consistently, strategies that abrogate the activity of ERK, P38, c-Myc, and/or cell glycolysis can efficiently eliminate the pathogenic effects triggered by functional Breg cells.

How Do Mobile Social Apps Matter for College Students' Satisfaction in Group-Based Learning? The Mediation of Collaborative Learning.

Recently, many universities apply mobile tools to teaching practices. For instance, some teachers may set up groups on mobile social apps and assign course tasks and advise college students to submit papers online. Nevertheless, how these mobile social apps affect teaching practices, especially the process of students' satisfaction needs to be further explored. To fill this research gap, we build a theoretical model of how mobile social apps' functions affect course satisfaction from the perspective of Media Richness theory and the Uses and Gratifications (U and G) theory. A total of 186 valid questionnaires from college students in China were collected, and a structural equation model was built to test our research model. The results show that as: (1) only the communication function has positive impacts on knowledge sharing, while the impact of the information storing function and information distribution function on knowledge sharing is not significant; (2) knowledge sharing does not affect course satisfaction in a direct way, but it can act indirectly through promoting collaborative learning, which shows the mediating role of collaborative learning. The theoretical implications and practical implications of the study are discussed.

PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma.

OBJECTIVE: Patients with increased PD-L1+ host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1+ host cells in hepatocellular carcinoma (HCC). DESIGN: A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1+ cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies. RESULTS: We demonstrate that PD-L1+ host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRhighCD86high glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2+ glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties. CONCLUSIONS: Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.