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Tangible programming combines the advantages of object manipulation with programmable hardware, which plays an essential role in improving programming skills. As a tool for ensuring the quality of projects and improving learning outcomes, the PDCA cycle strategy is conducive to cultivating reflective thinking. However, there is still a lack of empirical research on the effect of introducing the PDCA cycle strategy into programming education. In this study, using a PDCA cycle strategy, in a four-pronged model of "(P)draw up a plan, (D)assemble and programming, (C)test and debug, display and reflect (A)," and its effects on students' programming skills and their reflective thinking were explored. There were 65 children between the ages of 7 and 8 years participated in this study. There were 31 students in each of the experimental group and the control group. A combination of qualitative and quantitative research methods was adopted in this research, and students' programming processes and results were observed and counted. The study results revealed that after attending the 'Magic Card Robot' course that applied the PDCA cycle strategy, the experimental group students outperformed their counterparts in programming skills (sequencing, repetitive and conditional structures). Meanwhile, the experimental group students' reflective thinking levels were higher than those of the control group students. These findings imply that tangible programming education using the PDCA cycle strategy in the course has potential.

Abstract RNA surveillance systems degrade aberrant RNAs that result from defective transcriptional termination, splicing, and polyadenylation. Defective RNAs in the nucleus are recognized by RNA-binding proteins and MTR4, and are degraded by the RNA exosome complex. Here, we detect aberrant RNAs in MTR4-depleted cells using long-read direct RNA sequencing and 3′ sequencing. MTR4 destabilizes intronic polyadenylated transcripts generated by transcriptional read-through over one or more exons, termed 3′ eXtended Transcripts (3XTs). MTR4 also associates with hnRNPK, which recognizes 3XTs with multiple exons. Moreover, the aberrant protein translated from KCTD13 3XT is a target of the hnRNPK-MTR4-RNA exosome pathway and forms aberrant condensates, which we name KCTD13 3eXtended Transcript-derived protein (KeXT) bodies. Our results suggest that RNA surveillance in human cells inhibits the formation of condensates of a defective polyadenylated transcript-derived protein.

Abstract The advancement in extraterrestrial exploration has highlighted the crucial need for studying how the human cardiovascular system adapts to space conditions. Human development occurs under the influence of gravity, shielded from space radiation by Earth’s magnetic field, and within an environment characterized by 24-hour day-night cycles resulting from Earth’s rotation, thus deviating from these conditions necessitates adaptive responses for survival. With upcoming manned lunar and Martian missions approaching rapidly, it is essential to understand the impact of various stressors induced by outer-space environments on cardiovascular health. This comprehensive review integrates insights from both actual space missions and simulated experiments on Earth, to analyze how microgravity, space radiation, and disrupted circadian affect cardiovascular well-being. Prolonged exposure to microgravity induces myocardial atrophy and endothelial dysfunction, which may be exacerbated by space radiation. Mitochondrial dysfunction and oxidative stress emerge as key underlying mechanisms along with disturbances in ion channel perturbations, cytoskeletal damage, and myofibril changes. Disruptions in circadian rhythms caused by factors such as microgravity, light exposure, and irregular work schedules, could further exacerbate cardiovascular issues. However, current research tends to predominantly focus on disruptions in the core clock gene, overlooking the multifactorial nature of circadian rhythm disturbances in space. Future space missions should prioritize targeted prevention strategies and early detection methods for identifying cardiovascular risks, to preserve astronaut health and ensure mission success.

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

This paper aims to provide evidence on student teachers' perceptions of Flipped Classroom (FC) to help teacher educators (TEs) to make informed decisions about implementing FC and support student teachers to reflect on the value of FC in their teaching practice. FC, a pedagogical model requiring digital competence of students and teachers, has been a popular teaching approach for nearly two decades in K-12 and higher education. After the outbreak of Covid-19, more teachers have started to implement FC. In post-COVID-19, with the possibility of reusing video lectures made during the pandemic and the familiarity of digital skills to create digital lectures, a question for teachers is whether to continue with this approach. This paper follows an explanatory sequential mixed methods research approach. Insights from student teachers (STs) in the field of English as a foreign language (EFL) in Norway are the primary data, and surveys and focus group interviews are the main instruments to collect the data. FC's advantages and challenges perceived by STs are reported, and the possibility of STs becoming future flippers is explored. Findings from this paper indicate that STs would like to have more courses flipped in their studies, yet STs seem hesitant about flipping their courses in their teaching practice. STs also provide some practical suggestions on implementing the FC approach.

The mechanism by which transcription factor (TF) network instructs cell-type-specific transcriptional programs to drive primitive endoderm (PrE) progenitors to commit to parietal endoderm (PE) versus visceral endoderm (VE) cell fates remains poorly understood. To address the question, we analyzed the single-cell transcriptional signatures defining PrE, PE, and VE cell states during the onset of the PE-VE lineage bifurcation. By coupling with the epigenomic comparison of active enhancers unique to PE and VE cells, we identified GATA6, SOX17, and FOXA2 as central regulators for the lineage divergence. Transcriptomic analysis of cXEN cells, an in vitro model for PE cells, after the acute depletion of GATA6 or SOX17 demonstrated that these factors induce Mycn, imparting the self-renewal properties of PE cells. Concurrently, they suppress the VE gene program, including key genes like Hnf4a and Ttr, among others. We proceeded with RNA-seq analysis on cXEN cells with FOXA2 knockout, in conjunction with GATA6 or SOX17 depletion. We found FOXA2 acts as a potent suppressor of Mycn while simultaneously activating the VE gene program. The antagonistic gene regulatory activities of GATA6/SOX17 and FOXA2 in promoting alternative cell fates, and their physical co-bindings at the enhancers provide molecular insights to the plasticity of the PrE lineage. Finally, we show that the external cue, BMP signaling, promotes the VE cell fate by activation of VE TFs and repression of PE TFs including GATA6 and SOX17. These data reveal a putative core gene regulatory module that underpins PE and VE cell fate choice.

The Hippo pathway is known for its crucial involvement in development, regeneration, organ size control, and cancer. While energy stress is known to activate the Hippo pathway and inhibit its effector YAP, the precise role of the Hippo pathway in energy stress response remains unclear. Here, we report a YAP-independent function of the Hippo pathway in facilitating autophagy and cell survival in response to energy stress, a process mediated by its upstream components MAP4K2 and STRIPAK. Mechanistically, energy stress disrupts the MAP4K2-STRIPAK association, leading to the activation of MAP4K2. Subsequently, MAP4K2 phosphorylates ATG8-family member LC3, thereby facilitating autophagic flux. MAP4K2 is highly expressed in head and neck cancer, and its mediated autophagy is required for head and neck tumor growth in mice. Altogether, our study unveils a noncanonical role of the Hippo pathway in energy stress response, shedding light on this key growth-related pathway in tissue homeostasis and cancer.

Deep learning has been widely applied in the field of electrocardiogram (ECG) signal analysis due to its powerful data representation capability. However, supervised methods require a large amount of labeled data, and ECG data annotation is typically time-consuming and costly. Additionally, supervised methods are limited by the finite data types in the training set, resulting in limited generalization performance. Therefore, how to leverage massive unlabeled ECG signals for data mining and universal feature representation has become an urgent problem to be addressed. Self-supervised learning (SSL) is an effective approach to address the issue of missing annotated ECG data and improve the transfer ability of the model by learning generalized features from unlabeled data using pre-defined proxy tasks. However, existing surveys on self-supervised learning mostly focus on the domains of images or temporal signals, and there is a relative lack of comprehensive reviews on self-supervised learning in the ECG domain. To fill this gap, this paper provides a comprehensive review of advanced self-supervised learning methods used in the field of ECG. Firstly, a systematic summary and classification of self-supervised learning methods for ECG are presented, starting from two learning paradigms—contrastive and predictive. The basic principles of different categories of methods are elaborated, and the characteristics of each method are analyzed in detail, highlighting the advantages and limitations of each approach. Subsequently, a summary is provided for the commonly used datasets and application scenarios in ECG self-supervised learning, along with a review of data augmentation methods frequently applied in the ECG domain, offering a systematic reference for subsequent research. Finally, an in-depth discussion is presented on the current challenges of self-supervised learning within the ECG field, and future directions for the development of ECG self-supervised learning are explored, providing guidance for subsequent research in the field.

Abstract This study, using Jinan as a case study, systematically investigates the characteristics and geological genesis of loess-like silty clay in the middle and lower reaches of the Yellow River. The primary distribution of loess-like silty clay is revealed through field surveys, laboratory experiments, and previous literature reviews. The chemical and physical properties of the loess-like silty clay were examined, in addition to investigations into its mineral composition, microstructural characteristics, and engineering mechanical properties, in order to enhance comprehension of its attributes and formation mechanisms. The research suggests that the distinctive soil environment in the area has been influenced by numerous instances of the Yellow River overflow and channel shifts over its history, as well as the impacts of climate change, geological factors, and human activities. The primary sources of material for the loess-like silty clay consist of loess, Hipparion Red Clay, and paleosol layers. The discussion also addresses the impact of regional climate on the formation of mineral components. The aforementioned findings hold significant implications for advancing the understanding of historical climatic and paleogeographic shifts, as well as for addressing engineering challenges associated with the distribution of loess-like silty clay.

The Hippo pathway is an evolutionarily conserved pathway with crucial roles in development, organ size control, tissue homeostasis and cancer. Over two decades of research have elucidated the core Hippo pathway kinase cascade, but its precise organization has not been fully understood. In this issue of The EMBO Journal, Qi et al (2023) report a new model of two modules for the Hippo kinase cascade, providing new insights into this long-standing question.

Abstract Previous studies suggested odor stimulation may influence feeding of premature neonates. Therefore, this systematic review and meta-analysis of randomized controlled trials was conducted to assess the effect of human milk odor stimulation on feeding of premature infants. All randomized controlled trials related to human milk odor stimulation on feeding in premature infants published in PubMed, Cochrane, Library, Medline, Embase, Web of science databases and Chinese biomedical literature databases, China National Knowledge Infrastructure, China Science and Technology Journal Database (VIP) and Wanfang Chinese databases were searched, and The Cochrane Handbook 5.1.0 was used to evaluate the quality and authenticity of the literature. Relevant information of the included studies was extracted and summarized, and the evaluation indexes were analyzed using ReviewManager5.3. The retrieval time was from the establishment of the database to July 28, 2022.12 articles were assessed for eligibility, and six randomized controlled studies were eventually included in the meta-analysis (PRISMA). A total of 6 randomized controlled studies with 763 patients were finally included in the study, and the quality evaluation of literatures were all grade B. Human milk odor stimulation reduced the transition time to oral feeding in premature infants [SMD = − 0.48, 95% CI (− 0.69, − 0.27), Z = 4.54, P

Rubus fructus, the dried fruit of Rubus chingii Hu, is a versatile medicinal and edible plant. In this review, we used “Rubus chingii” or “Fupengzi” as the keyword and collected relevant information from classical Chinese herbal texts, PubMed, Web of Science, China National Knowledge Infrastructure database, and patent websites. An ethnopharmacological survey shows that R. chingii Hu belongs to a class of Rubus plants known for nourishing the kidneys and liver, consolidating essence, reducing urine, and improving vision. R. chingii is rich in flavonoids, phenolic compounds, terpenes, amino acids, and vitamins. Currently, ellagic acid and kaempferol-3-O-rutinoside are used as quality markers of R. chingii. Modern medical research indicates that it has multiple functional activities, including antioxidation/anti-aging, blood glucose regulation, immune enhancement, growth promotion, reproductive support, regulation of intestinal flora, and improvement of gastrointestinal function. Due to its numerous health benefits, various health products such as canned foods, fruit wine, fruit vinegar, beverages, teas, jams, and other foods have been developed worldwide. In summary, this review provides a comprehensive and up-to-date overview of the ethnopharmacology, phytochemistry, quality control, functions, and food application of R. chingii, contributing to the advancement of health food and medical development related to this plant.

Histone acetylation is a pivotal epigenetic modification that controls chromatin structure and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confine the utilization of the zygotic genome remain to be elucidated. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from mid-blastula and onward. The recruitment of Hdac1 to the genome at blastula is instructed maternally. Cis-regulatory modules (CRMs) bound by Hdac1 possess epigenetic signatures underlying distinct functions. We highlight a dual function model of Hdac1 where Hdac1 not only represses gene expression by sustaining a histone hypoacetylation state on inactive chromatin, but also maintains gene expression through participating in dynamic histone acetylation-deacetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities, both in time and space. Taken together, our study reveals a comprehensive role for Hdac1 during early vertebrate embryogenesis.

Emerging studies highlight the Hippo pathway as an important player in organ size control, tissue homeostasis, regeneration, development, and diseases, but our understanding of its roles and regulations remains incomplete. Our recent work reported a functional interplay between the Hippo pathway and heavy metals, providing new insights into this key signaling pathway.

Background: There is still no study on the use of the SARC-CalF questionnaire for older critically ill patients. Moreover, there is limited evidence on whether a combination of sarcopenia and frailty can provide incremental improvements in risk stratification for older critically ill patients. Methods: A total of 653 patients older than 60 years were recruited. We used the clinical frailty scale (CFS) and SARC-CalF questionnaire to assess the frailty status and sarcopenia risk, respectively, of older patients shortly after admission to the ICU. The effect of frailty and sarcopenia risk on ICU mortality and 30-day mortality was evaluated. Results: A total of 147 (22.5%) patients died in the ICU, and 187 (28.6%) patients died within 30 days after ICU admission. The CFS score was associated with increased ICU mortality [per 1-score increase: odds ratio (OR) = 1.222, 95% confidential interval (CI): 1.003–1.489] and 30-day mortality (per 1-score increase: OR = 1.307, 95% CI: 1.079–1.583). The SARC-CalF score was also associated with increased ICU mortality (per 1-score increase: OR = 1.204, 95% CI: 1.120–1.294) and 30-day mortality (per 1-score increase: OR = 1.247, 95% CI: 1.163–1.337). The addition of the CFS + SARC-CalF score to Acute Physiology and Chronic Health Evaluation (APACHE) II improved discrimination and reclassified ICU and 30-day mortality risk. Conclusions: Sarcopenia risk assessed by the SARC-CalF questionnaire provided independent prognostic information for older critically ill patients. A combination of sarcopenia and frailty improved the prediction of mortality for older critically ill patients and thus might be useful in the clinical decision-making process.

As a key factor in tumorigenesis, progression, recurrence and metastasis, the biological properties, metabolic adaptations and immune escape mechanisms of CSCs are the focus of current oncological research. CSCs possess self-renewal, multidirectional differentiation and tumorigenicity, and their mechanisms of action can be elucidated by the clonal evolution, hierarchical model and the dynamic CSCs model, of which the dynamic model is widely recognized due to its better explanation of the function and origin of CSCs. The origin hypothesis of CSCs involves cell-cell fusion, horizontal gene transfer, genomic instability and microenvironmental regulation, which together shape the diversity of CSCs. In terms of classification, CSCs include primary CSCs (pri-CSCs), precancerous stem cells (pre-CSCs), migratory CSCs (mig-CSCs), and chemo-radiotherapy-resistant CSCs (cr-CSCs and rr-CSCs), with each type playing a specific role in tumor progression. Surface markers of CSCs, such as CD24, CD34, CD44, CD90, CD133, CD166, EpCAM, and LGR5, offer the possibility of identifying, isolating, and targeting CSCs, but the instability and heterogeneity of their expression increase the difficulty of treatment. CSCs have adapted to their survival needs through metabolic reprogramming, showing the ability to flexibly switch between glycolysis and oxidative phosphorylation (OXPHOS), as well as adjustments to amino acid and lipid metabolism. The Warburg effect typifies their metabolic profiles, and altered glutamine and fatty acid metabolism further contributes to the rapid proliferation and survival of CSCs. CSCs are able to maintain their stemness by regulating the metabolic networks to maintain their stemness characteristics, enhance antioxidant defences, and adapt to therapeutic stress. Immune escape is another strategy for CSCs to maintain their survival, and CSCs can effectively evade immune surveillance through mechanisms such as up-regulating PD-L1 expression and promoting the formation of an immunosuppressive microenvironment. Together, these properties reveal the multidimensional complexity of CSCs, underscoring the importance of a deeper understanding of the biology of CSCs for the development of more effective tumor therapeutic strategies. In the future, therapies targeting CSCs will focus on precise identification of surface markers, intervention of metabolic pathways, and overcoming immune escape, with the aim of improving the relevance and efficacy of cancer treatments, and ultimately improving patient prognosis.

IntroductionPeach (Prunus persica) has a high nutritional and economic value. However, its overgrowth can lead to yield loss. Regulating the growth of peach trees is challenging. The small auxin-up RNA (SAUR) gene family is the largest family of auxin-responsive genes, which play important roles in plant growth and development. However, members of this gene family are rarely reported in peach.MethodsIn this study, we measured leaf area, chlorophyll and lignin content to detect the role of PpSAUR5 on growth through transgenic Arabidopsis.ResultsPpSAUR5 responds to auxin and gibberellin, promoting and inhibiting the synthesis of gibberellin and auxin, respectively. The heterologous transformation of PpSAUR5 in Arabidopsis led to enhanced growth of leaves and siliques, lightening of leaf color, decrease in chlorophyll content, increase in lignin content, abnormalities in the floral organs, and distortion of the inflorescence axis. Transcriptome data analysis of PpSAUR5 overexpression and wild-type lines revealed 854 differentially expressed genes (DEGs). GO and KEGG analyses showed that the DEGs were primarily involved in biological processes, such as cellular processes, metabolic processes, response to stimuli, and catalytic activity. These genes were mainly enriched in pathways, such as phenylalanine biosynthesis, phytohormone signaling, and MAPK signaling.DiscussionIn summary, these results suggested that PpSAUR5 might regulate tree vigor by modulating the synthesis of auxin and gibberellin. Future studies can use PpSAUR5 as a candidate gene to elucidate the potential regulatory mechanisms underlying peach tree vigor.

Surgery is the primary treatment of choice for tumours, and improves prognosis, prolongs survival and is potentially curative. Previous studies have described the effects of anaesthesia and changes in the neuroendocrine, circulatory and sympathetic nervous systems on postoperative cancer progression. There is growing evidence that intraoperative blood loss is an independent prognostic factor for tumour recurrence, postoperative inflammation is a predictor of cancer prognosis, and immunosuppressive status correlates with the degree of surgical damage. This paper outlines the potential mechanisms by which blood loss, surgical trauma and postoperative immunosuppressive status contribute to tumour growth and recurrence by reducing intraoperative haemorrhage and perioperative immunotherapy, thereby reducing tumour growth and recurrence, and improving long-term prognosis.