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This study investigates the role of a collaboration script, the Funnel Model, in supporting students' computer-supported collaborative scientific argumentation, and how the students appropriated the collaboration script in scientific argumentation. In this exploratory case study, a class of 33 Secondary grade four students went through four phases of computer-supported collaborative argumentation activity scripted by the Funnel Model: individual ideation, intra-group synergy, inter-group critique and intra-group refinement. Multiple sources of data were collected including student-generated artefacts online at different phases of collaboration, and the post-intervention interviews with the students. The results show that the Funnel Model facilitated students' computer-supported collaborative argumentation. The students' levels of content mastery, motivation, classroom culture and time allocated for classroom participation affect students' appropriation of the script for effective collaborative argumentation.

Existing studies have evidenced that mobile-assisted vocabulary learning, which allows students to create artefacts and engage in productive skills, can help them in vocabulary learning. However, there remains little research and validated approaches for designing seamless vocabulary learning experiences for young learners. In this paper, a seamless vocabulary learning system was specifically designed for young learners. The study involved three classes of primary 2 students to investigate the learning effectiveness of seamless vocabulary learning, with a focus on analyzing student-generated artefacts. The results validated the effectiveness of seamless vocabulary learning for young learners, emphasizing the importance of strengthening the connection between home-based learning and classroom-based learning. The study also indicated the pivotal role of providing students with opportunities to improve their artefacts constantly across different learning contexts.

Abstract Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells (ECs) that play an important role in liver development and regeneration. Additionally, it is involved in various pathological processes, including steatosis, inflammation, fibrosis and hepatocellular carcinoma. However, the rapid dedifferentiation of LSECs after culture greatly limits their use in vitro modeling for biomedical applications. In this study, we developed a highly efficient protocol to induce LSEC-like cells from human induced pluripotent stem cells (hiPSCs) in only 8 days. Using single-cell transcriptomic analysis, we identified several novel LSEC-specific markers, such as EPAS1, LIFR, and NID1, as well as several previously revealed markers, such as CLEC4M, CLEC1B, CRHBP and FCN3. These LSEC markers are specifically expressed in our LSEC-like cells. Furthermore, hiPSC-derived cells expressed LSEC-specific proteins and exhibited LSEC-related functions, such as the uptake of acetylated low density lipoprotein (ac-LDL) and immune complex endocytosis. Overall, this study confirmed that our novel protocol allowed hiPSCs to rapidly acquire an LSEC-like phenotype and function in vitro. The ability to generate LSECs efficiently and rapidly may help to more precisely mimic liver development and disease progression in a liver-specific multicellular microenvironment, offering new insights into the development of novel therapeutic strategies.

Abstract Background Non‐alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, which is commonly associated with NAFLD. Adenosine‐to‐inosine editing, catalysed by adenosine deaminase acting on RNA (ADAR), is an important post‐transcriptional modification of genome‐encoded RNA transcripts. Three ADAR gene family members, including ADAR1, ADAR2 and ADAR3, have been identified. However, the functional role of ADAR2 in obesity‐associated NAFLD and sarcopenia remains unclear. Methods ADAR2+/+/GluR‐BR/R mice (wild type [WT]) and ADAR2−/−/GluR‐BR/R mice (ADAR2 knockout [KO]) were subjected to feeding with standard chow or high‐fat diet (HFD) for 20 weeks at the age of 5 weeks. The metabolic parameters, hepatic lipid droplet, grip strength test, rotarod test, muscle weight, fibre cross‐sectional area (CSA), fibre types and protein associated with protein degradation were examined. Systemic and local tissues serum amyloid A1 (SAA1) were measured. The effects of SAA1 on C2C12 myotube atrophy were investigated. Results ADAR2 KO mice fed with HFD exhibited lower body weight (−7.7%, P

Abstract Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2−/−/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD–induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3β pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.

Summary: Male infertility is a recognized side effect of chemoradiotherapy. Extant spermatogonial stem cells (SSCs) may act as originators for any subsequent recovery. However, which type of SSCs, the mechanism by which they survive and resist toxicity, and how they act to restart spermatogenesis remain largely unknown. Here, we identify a small population of Set domain-containing protein 4 (Setd4)-expressing SSCs that occur in a relatively dormant state in the mouse seminiferous tubule. Extant beyond high-dose chemoradiotherapy, these cells then activate to recover spermatogenesis. Recovery fails when Setd4+ SSCs are deleted. Confirmed to be of fetal origin, these Setd4+ SSCs are shown to facilitate early testicular development and also contribute to steady-state spermatogenesis in adulthood. Upon activation, chromatin remodeling increases their genome-wide accessibility, enabling Notch1 and Aurora activation with corresponding silencing of p21 and p53. Here, Setd4+ SSCs are presented as the originators of both testicular development and spermatogenesis recovery in chemoradiotherapy-induced infertility.

Abstract Background The relationship between vitamin D status and mortality among adults with hypertension remains unclear. Methods This prospective cohort study involved a sample of 19,500 adults with hypertension who participated in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. We utilized a weighted COX proportional hazard model to assess the association between vitamin D status and mortality. This statistical model calculates hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI). Results The study indicated that lower serum 25(OH)D concentration was associated with an increased risk of all-cause mortality among individuals with hypertension. Specially. Those with concentrations between 25.0 and 49.9 nmol/L (HR = 1.71, 95%CI = 1.22–2.40) and less than 25.0 nmol/L (HR = 1.97, 95%CI = 1.15–3.39) had higher hazard ratios for all-cause mortality. Individuals with hypertension who took vitamin D supplements had a lower risk of all-cause mortality, but not the risk of CVD mortality (HR 0.75, 95%CI 0.54–1.03), compared to those who did not supplement (HR = 0.76, 95%CI = 0.61–0.94). Subgroup analysis further revealed that vitamin D supplementation was associated with a reduced risk of all-cause mortality among individuals without diabetes (HR = 0.65, 95%CI = 0.52–0.81) and individuals without CVD (HR = 0.75, 95%CI = 0.58–0.97), and a decreased risk of CVD mortality among individuals without diabetes (HR = 0.63, 95%CI = 0.45–0.88) and without CVD (HR = 0.61, 95%CI = 0.40–0.92). Furthermore, higher-dose vitamin D supplementation was also associated with a greater reduction in all-cause mortality among hypertensive individuals, and there was the potential synergistic effect of combining normal-dose calcium and vitamin D supplementation, showing a superior effect on mortality compared to low-dose supplementation in adults with hypertension. Conclusions This prospective cohort study demonstrated a significant association between lower serum 25 (OH)D concentration and increased all-cause mortality among adults with hypertension. Furthermore, the study found that vitamin D supplementation had a strong and significantly positive correlation with reduced all-cause and CVD mortality among hypertensive individuals without diabetes or CVD. This positive correlation suggests that vitamin D supplementation could potentially be an effective strategy to reduce the risk of mortality in this specific group of people.

Background Cardiac aging represents an independent risk factor for aging‐associated cardiovascular diseases. Although evidence suggests an association between NOD‐, LRR‐, and pyrin domain–containing protein 3 (NLRP3) inflammasome formation and numerous cardiovascular diseases, its role in cardiac aging remains largely unclear. Methods and Results The longevity of mice with wild‐type and NLRP3 knockout (NLRP3−/−) genotypes was assessed, with or without d‐galactose treatment. Cardiac function was evaluated using echocardiography, and cardiac histopathology was examined through hematoxylin and eosin and Masson's trichrome staining. Senescence‐associated β‐galactosidase (SA‐β‐gal) staining was employed to detect cardiac aging. Western blotting was used to assess aging‐related proteins (p53, p21) and pyroptosis‐related proteins. Additionally, dihydroethidium staining, lactate dehydrogenase release, and interleukin‐1β ELISA assays were performed, along with measurements of total superoxide dismutase and malondialdehyde levels. In vitro, H9c2 cells were exposed to d‐galactose for 24 hours in the absence or presence of N‐acetyl‐l‐cysteine (reactive oxygen species inhibitor), BAY‐117082 (nuclear factor κ‐light‐chain enhancer of activated B cells inhibitor), MCC950 (NLRP3 inhibitor), and VX‐765 (Caspase‐1 inhibitor). Immunofluorescence staining was employed to detect p53, gasdermin D, and apoptosis‐associated speck‐like protein proteins. Intracellular reactive oxygen species levels were assessed using fluorescence microscopy and flow cytometry. Senescence‐associated β‐galactosidase staining and Western blotting were also employed in vitro for the same purpose. The results showed that NLRP3 upregulation was implicated in aging and cardiovascular diseases. Inhibition of NLRP3 extended life span, mitigated the aging phenotype, improved cardiac function and blood pressure, ameliorated lipid metabolism abnormalities, inhibited pyroptosis in cardiomyocytes, and ultimately alleviated cardiac aging. In vitro, the inhibition of reactive oxygen species, nuclear factor κ‐light‐chain enhancer of activated B cells, NLRP3, or caspase‐1 attenuated NLRP3 inflammasome‐mediated pyroptosis. Conclusions The reactive oxygen species/nuclear factor κ‐light‐chain enhancer of activated B cells/NLRP3 signaling pathway loop contributes to d‐galactose–treated cardiomyocyte senescence and cardiac aging.

ObjectiveThis study aimed to determine whether patients with disorders of consciousness (DoC) could experience neural entrainment to individualized music, which explored the cross-modal influences of music on patients with DoC through phase-amplitude coupling (PAC). Furthermore, the study assessed the efficacy of individualized music or preferred music (PM) versus relaxing music (RM) in impacting patient outcomes, and examined the role of cross-modal influences in determining these outcomes.MethodsThirty-two patients with DoC [17 with vegetative state/unresponsive wakefulness syndrome (VS/UWS) and 15 with minimally conscious state (MCS)], alongside 16 healthy controls (HCs), were recruited for this study. Neural activities in the frontal–parietal network were recorded using scalp electroencephalography (EEG) during baseline (BL), RM and PM. Cerebral-acoustic coherence (CACoh) was explored to investigate participants’ abilitiy to track music, meanwhile, the phase-amplitude coupling (PAC) was utilized to evaluate the cross-modal influences of music. Three months post-intervention, the outcomes of patients with DoC were followed up using the Coma Recovery Scale-Revised (CRS-R).ResultsHCs and patients with MCS showed higher CACoh compared to VS/UWS patients within musical pulse frequency (p = 0.016, p = 0.045; p

Aims: To identify and analyze genes closely related to the progression of nonalcoholic steatohepatitis (NASH) by employing a combination of single-cell RNA sequencing and machine-learning algorithms. Main methods: Single-cell RNA sequencing (scRNA-seq) analysis was performed to find the cell population with the most significant differences between the Chow and NASH groups. This approach was used to validate the developmental trajectory of this cell population and investigate changes in cellular communication and important signaling pathways among these cells. Subsequently, high dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA) was used to find the key modules in NASH. Machine learning analyses were performed to further identify core genes. Deep learning techniques were applied to elucidate the correlation between core genes and immune cells. The accuracy of this correlation was further confirmed using deep learning techniques, specifically Convolutional Neural Networks. Key findings: By comparing scRNA-seq data between the Chow and NASH groups, we have observed a notable distinction existing in the Kupffer cell population. Signaling interactions between hepatic macrophages and other cells were significantly heightened in the NASH group. Through subsequent analysis of macrophage subtypes and key modules, we identified 150 genes tightly associated with NASH. Finally, we highlighted the 16 most significant core genes using multiple iterations of machine learning. Furthermore, we pointed out the close relationship between core genes and immune cells. Significances: Using scRNA-seq analysis and machine learning, we can distinguish NASH-related genes from large genetic datasets, providing theoretical support in finding potential targets for the development of novel therapies.

Environmental and sustainability education cannot disconnect itself from politics. In order to achieve sustainable societies, we need approaches that educate students capable of coping with the political complexities of environmental issues in a civic environmental context. This study proposes a pluralistic environmental citizenship approach based on the exploration of a 13-month long curriculum case study that engaged Taiwanese youth in deliberating over a highly controversial wetland policy related to their community. By tracing five focal students' learning trajectories in depth, this study revealed that students conceptualize their roles toward a "pluralistic environmental citizenship" including four elements: conception of community, conception of environment, legal and institutional knowledge, and pluralistic values. This study showcases the potential power of integrating deliberative pedagogies in place-based education and how they can enrich environmental citizenship education.

This study seeks to understand students' perceptions of self-agency and how they demonstrate their agency by engaging in discussions of a highly controversial wetland policy facing their community. Five focal students participating in this 13-month long curriculum were selected for further explorations. We traced their learning trajectories to explore how students perceive their own roles in coping with this environmental controversy. Our data included student interviews at three different learning phases and recordings of in-class deliberative activities. The results revealed that students were more aware of their own agency as they navigated the contesting viewpoints among stakeholders. Three themes were generated to explain this change: adults' business, family communication, and empowerment through civic action. This study showcases that engaging students in deliberations about environmental controversies has the potential to make them more aware of their own agency and become agentic citizens in addressing contentious environmental issues.

Abstract During maternal‐to‐zygotic transition (MZT) in the embryo, mRNA undergoes complex post‐transcriptional regulatory processes. However, it is unclear whether and how alternative splicing plays a functional role in MZT. By analyzing transcriptome changes in mouse and human early embryos, dynamic changes in alternative splicing during MZT are observed and a previously unnoticed process of zygotic splicing activation (ZSA) following embryonic transcriptional activation is described. As the underlying mechanism of RNA splicing, splicing factors undergo dramatic maternal‐to‐zygotic conversion. This conversion relies on the key maternal factors BTG4 and PABPN1L and is zygotic‐transcription‐dependent. CDK11‐dependent phosphorylation of the key splicing factor, SF3B1, and its aggregation with SRSF2 in the subnuclear domains of 2‐cell embryos are prerequisites for ZSA. Isoforms generated by erroneous splicing, such as full‐length Dppa4, hinder normal embryonic development. Moreover, alternative splicing regulates the conversion of early embryonic blastomeres from totipotency to pluripotency, thereby affecting embryonic lineage differentiation. ZSA is an essential post‐transcriptional process of MZT and has physiological significance in generating new life. In addition to transcriptional activation, appropriate expression of transcript isoforms is also necessary for preimplantation embryonic development.

Summary: The serine/threonine protein phosphatase family involves series of cellular processes, such as pre-mRNA splicing. The function of one of its members, protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G), remains unclear in hepatocellular carcinoma (HCC). Our results demonstrated that PPM1G was significantly overexpressed in HCC cells and tumor tissues compared with the normal liver tissues at both protein and RNA levels. High PPM1G expression is associated with shorter overall survival (p

Introduction: The R-loop is a naturally formed three-strand nucleic acid structure that recently has been reported to participate in multiple biological processes and helped answer some previously unexplained scientific questions. Meiosis process involves multiple chromatin-related events such as DNA double-stranded breaks (DSB) formation, repairing and transcriptional dynamics. Objectives: Explore the regulatory roles and physiological functions of R-loops in the mammalian meiosis process. Methods: In our study, using genome-wide S9.6 CUT & Tag seq, we first mapped the genomic distribution and dynamic changes of R-loop during the meiotic process in mice, from spermatogonia to secondary spermatocytes. And we further explore the role of R-loop in physiological conditions by constructing conditional knockout mice of Rnaseh1, which deleted the R-loop endonuclease before meiosis entry. Results: R-loop predominantly distributes at promoter-related regions and varies across different meiotic stages. By joint analysis with the corresponding transcriptome, we found that the R-loop was closely related to transcription during the meiotic process. The high frequency of promoter-related R-loop in meiotic cells is usually accompanied by high transcription activity, and we further verified this in the leptotene/zygotene to the pachytene transition process. Moreover, the lack of RNase H1 caused sterility in male mice with R-loop accumulation and abnormal DSB repair in spermatocytes. Further analysis showed that abnormal R-loop accumulation in the leptotene/zygotene stages influenced transcriptional regulation in the pachytene stage. Conclusion: The mutual regulation of the R-loop and transcription plays an essential role in spermatogenesis. And R-loop is also important for the normal repair process of DSB during meiosis.