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Antibodies targeting a tumor antigen, GD2, show some efficacy for neuroblastoma but induce severe neuropathic pain and peripheral neuropathy. Here the authors design a gated chimeric antigen receptor (CAR), using GD2 as the gate and another tumor antigen, B7H3, as the target, to find this GD2-B7H3 CAR capable of suppressing neuroblastoma in mouse models with little adverse effects.

This study aims to track college students' on-task rate during the teaching process and to analyze the influence of instructional strategies on on-task rate through the aspects of observable and internal engagement indicators. Thirty-six undergraduate students at a higher education institution in China participated in the study. Students' behaviors and their EEG signals were recorded from fifty-one learning activities. Analyses have been focused on identifying the determinants of student's engagement levels and revealing the impacts of behavioral sequences and cognitive sequences on student's engagement levels. The results show that: (1) instructional strategies, classroom behaviors, and cognitive states were significant predictors of students' on-task rate; (2) the continuity of classroom behaviors improved the on-task rate; and (3) the standard deviations of attention and cognitive load were positively correlated with the on-task rate. This study describes a case of integrating multimodal data analysis in classroom teaching and discusses practical implications for improving classroom teaching.

Population-specific profiling of mutations in cancer genes is of critical importance for the understanding of cancer biology in general as well as the establishment of optimal diagnostics and treatment guidelines for that particular population. Although genetic analysis of tumor tissue is often used to detect mutations in cancer genes, the invasiveness and limited accessibility hinders its application in large-scale population studies. Here, we used ultra-deep massive parallel sequencing of plasma cell free DNA (cfDNA) to identify the mutation profiles of 265 Vietnamese patients with advanced non-small cell lung cancer (NSCLC). Compared to a cohort of advanced NSCLC patients characterized by sequencing of tissue samples, cfDNA genomic testing, despite lower mutation detection rates, was able to detect major mutations in tested driver genes that reflected similar mutation composition and distribution pattern, as well as major associations between mutation prevalence and clinical features. In conclusion, ultra-deep sequencing of plasma cfDNA represents an alternative approach for population-wide genetic profiling of cancer genes where recruitment of patients is limited to the accessibility of tumor tissue site.

Abstract Background Recent advances in sequencing technologies and bioinformatics tools have allowed for large-scale microbiome studies that are rapidly advancing medical research. However, small changes in technique or analysis can significantly alter the results and lead to conflicting findings. Quantifying the technical versus biological variation expected in targeted 16S rRNA gene sequencing studies and how this variation changes with input biomass is critical to guide meaningful interpretation of the current literature and plan future research. Results Data were compiled from 469 sequencing libraries across 19 separate targeted 16S rRNA gene sequencing runs over a 2.5-year time period. Following removal of contaminant sequences identified from negative controls, 244 samples retained sufficient reads for further analysis. Coefficients of variation for intra- and inter-assay variation from repeated measurements of a bacterial mock community ranged from 8.7 to 37.6% (intra) and 15.6 to 80.5% (inter) for all but one genus of bacteria whose relative abundance was greater than 1%. Intra- versus inter-assay Bray-Curtis pairwise distances for a single stool sample were 0.11 versus 0.31, whereas intra-assay variation from repeat stool samples from the same donor was greater at 0.38 (Wilcoxon p = 0.001). A dilution series of the bacterial mock community was used to assess the effect of input biomass on variability. Pairwise distances increased with more dilute samples, and estimates of relative abundance became unreliable below approximately 100 copies of the 16S rRNA gene per microliter. Using this data, we created a prediction model to estimate the expected variation in microbiome measurements for given input biomass and relative abundance values. Conclusions Well-controlled microbiome studies are sufficiently robust to capture small biological effects and can achieve levels of variability consistent with clinical assays. Relative abundance is negatively associated with measures of variability and has a stronger effect on variability than does absolute biomass, suggesting that it is feasible to detect differences in bacterial populations in very low-biomass samples. Further, by quantifying the effect of biomass and relative abundance on compositional variability, we developed a tool for defining the expected variance in a given microbiome study.

Blended learning, integrating online and in-person components, has been increasingly adopted in higher education to enhance students' learning experience and outcomes. While the advantages of blended learning are well-evidenced, research has primarily focused on the online pre-learning component, neglecting the significance of in-class activities. In-class activities play a crucial role in affording active learning opportunities (e.g., discussion, elaboration), necessitating a systemic understanding of their dynamics. The purpose of this study was thus to systemically investigate college students' learning behaviors during in-class activities in a blended course. In-class activities were video-recorded and labelled manually following a coding scheme. By establishing a linear regression model, the study identified listening to the instructor's lecture and taking notes as two predictors of students' learning gains. Additionally, sequential patterns of learning behaviors during in-class activities were examined. The reciprocal interactions between students' behavior of listening to the lecture and their note-taking actions were noted. The findings of this study contributed to a systemic view of blended learning by shedding light on students' learning behaviors and their implications for instructional practice.

Blended learning has been widely integrated in college-level computer science education. Despite evidence about benefits of blended learning, students' in-class activities remain underexplored. To afford effective blended learning experience, supporting students in both modalities is essential. This study thus took an initial step to fill the gap by investigating college students' in-class activities in a blended course from the perspective of attention. Using non-intrusive electroencephalography (EEG) instruments to collect attentional data, this study found students' attention in in-class activities positively correlated with their learning gains. Students' attention also varied across in-class activities, reaching a higher level in group discussions than in pre-tests and lectures. Linear regression analysis indicated students' length of time spent viewing online resources and their pre-test scores significantly predicted their in-class attention. The findings of the study provide insight into course design and facilitation for effective blended computer science courses.

Molecular and functional characterization of alveolar epithelial type I (AT1) cells has been challenging due to difficulty in isolating sufficient numbers of viable cells. Here we performed single-cell RNA-sequencing (scRNA-seq) of tdTomato+ cells from lungs of AT1 cell-specific Aqp5-Cre-IRES-DsRed (ACID);R26tdTomato reporter mice. Following enzymatic digestion, CD31-CD45-E-cadherin+tdTomato+ cells were subjected to fluorescence-activated cell sorting (FACS) followed by scRNA-seq. Cell identity was confirmed by immunofluorescence using cell type-specific antibodies. After quality control, 92 cells were analyzed. Most cells expressed ‘conventional’ AT1 cell markers (Aqp5, Pdpn, Hopx, Ager), with heterogeneous expression within this population. The remaining cells expressed AT2, club, basal or ciliated cell markers. Integration with public datasets identified three robust AT1 cell- and lung-enriched genes, Ager, Rtkn2 and Gprc5a, that were conserved across species. GPRC5A co-localized with HOPX and was not expressed in AT2 or airway cells in mouse, rat and human lung. GPRC5A co-localized with AQP5 but not pro-SPC or CC10 in mouse lung epithelial cell cytospins. We enriched mouse AT1 cells to perform molecular phenotyping using scRNA-seq. Further characterization of putative AT1 cell-enriched genes revealed GPRC5A as a conserved AT1 cell surface marker that may be useful for AT1 cell isolation.

Background: The SARS-CoV-2 virus has been a global public health threat since December 2019. This study aims to investigate the neurological characteristics and risk factors of coronavirus disease 2019 (COVID-19) in Taiwanese children, using data from a collaborative registry. Methods: A retrospective, cross-sectional, multi-center study was done using an online network of pediatric neurological COVID-19 cohort collaborative registry. Results: A total of 11160 COVID-19-associated emergency department (ED) visits and 1079 hospitalizations were analyzed. Seizures were the most common specific neurological symptom, while encephalitis and acute disseminated encephalomyelitis (ADEM) was the most prevalent severe involvement.In ED patients with neurological manifestations, severe neurological diagnosis was associated with visual hallucination, seizure with/without fever, behavior change, decreased GCS, myoclonic jerk, decreased activity/fatigue, and lethargy. In hospitalized patients with neurological manifestations, severe neurological diagnosis was associated with behavior change, visual hallucination, decreased GCS, seizure with/without fever, myoclonic jerk, fatigue, and hypoglycemia at admission. Encephalitis/ADEM was the only risk factor for poor neurological outcomes at discharge in hospitalized patients. Conclusion: Neurological complications are common in pediatric COVID-19. Visual hallucination, seizure, behavior change, myoclonic jerk, decreased GCS, and hypoglycemia at admission are the most important warning signs of severe neurological involvement such as encephalitis/ADEM.

Abstract Diabetes mellitus remains a major global health issue, and great attention is directed at natural therapeutics. This systematic review aimed to assess the potential of flavonoids as antidiabetic agents by investigating their inhibitory effects on α-glucosidase and α-amylase, two key enzymes involved in starch digestion. Six scientific databases (PubMed, Virtual Health Library, EMBASE, SCOPUS, Web of Science, and WHO Global Index Medicus) were searched until August 21, 2022, for in vitro studies reporting IC50 values of purified flavonoids on α-amylase and α-glucosidase, along with corresponding data for acarbose as a positive control. A total of 339 eligible articles were analyzed, resulting in the retrieval of 1643 flavonoid structures. These structures were rigorously standardized and curated, yielding 974 unique compounds, among which 177 flavonoids exhibited inhibition of both α-glucosidase and α-amylase are presented. Quality assessment utilizing a modified CONSORT checklist and structure–activity relationship (SAR) analysis were performed, revealing crucial features for the simultaneous inhibition of flavonoids against both enzymes. Moreover, the review also addressed several limitations in the current research landscape and proposed potential solutions. The curated datasets are available online at https://github.com/MedChemUMP/FDIGA . Graphical Abstract

Ewing sarcoma family tumors (ESFT) are aggressive bone and soft tissue tumors that express EWS-ETS fusion genes as driver mutations. Although the histogenesis of ESFT is controversial, mesenchymal (MSC) and/or neural crest (NCSC) stem cells have been implicated as cells of origin. For the current study we evaluated the consequences of EWS-FLI1 expression in human embryonic stem cell-derived NCSC (hNCSC). Ectopic expression of EWS-FLI1 in undifferentiated hNCSC and their neuro-mesenchymal stem cell (hNC-MSC) progeny was readily tolerated and led to altered expression of both well established as well as novel EWS-FLI1 target genes. Importantly, whole genome expression profiling studies revealed that the molecular signature of established ESFT is more similar to hNCSC than any other normal tissue, including MSC, indicating that maintenance or reactivation of the NCSC program is a feature of ESFT pathogenesis. Consistent with this hypothesis, EWS-FLI1 induced hNCSC genes as well as the polycomb proteins BMI-1 and EZH2 in hNC-MSC. In addition, up-regulation of BMI-1 was associated with avoidance of cellular senescence and reversible silencing of p16. Together these studies confirm that, unlike terminally differentiated cells but consistent with bone marrow-derived MSC, NCSC tolerate expression of EWS-FLI1 and ectopic expression of the oncogene initiates transition to an ESFT-like state. In addition, to our knowledge this is the first demonstration that EWS-FLI1-mediated induction of BMI-1 and epigenetic silencing of p16 might be critical early initiating events in ESFT tumorigenesis.

Developmental delay (DD) has a great impact on children at the developmental stage, and is often manifested by varying degrees of motor delays, intellectual disabilities, and other defects [...]

Quiz question annotation aims to assign the most relevant knowledge point to a question, which is a key technology to support intelligent education applications. However, the existing methods only extract the explicit semantic information that reveals the literal meaning of a question, and ignore the implicit knowledge information that highlights the knowledge intention. To this end, an innovative dual-channel model, the Semantic-Knowledge Mapping Network (S-KMN) is proposed to enrich the question representation from two perspectives, semantic and knowledge, simultaneously. It integrates semantic features learning and knowledge mapping network (KMN) to extract explicit semantic features and implicit knowledge features of questions,respectively. Designing KMN to extract implicit knowledge features is the focus of this study. First, the context-aware and sequence information of knowledge attribute words in the question text is integrated into the knowledge attribute graph to form the knowledge representation of each question. Second, learning a projection matrix, which maps the knowledge representation to the latent knowledge space based on the scene base vectors, and the weighted summations of these base vectors serve as knowledge features. To enrich the question representation, an attention mechanism is introduced to fuse explicit semantic features and implicit knowledge features, which realizes further cognitive processing on the basis of understanding semantics. The experimental results on 19,410 real-world physics quiz questions in 30 knowledge points demonstrate that the S-KMN outperforms the state-of-the-art text classification-based question annotation method. Comprehensive analysis and ablation studies validate the superiority of our model in selecting knowledge-specific features.

Abstract The purpose of this study aimed to analyze the process of online collaborative problem solving (CPS) via brain-to-brain synchrony (BS) at the problem-understanding and problem-solving stages. Aiming to obtain additional insights than traditional approaches (survey and observation), BS refers to the synchronization of brain activity between two or more people, as an indicator of interpersonal interaction or common attention. Thirty-six undergraduate students participated. Results indicate the problem-understanding stage showed a higher level of BS than the problem-solving stage. Moreover, the level of BS at the problem-solving stage was significantly correlated with task performance. Groups with all high CPS skill students had the highest level of BS, while some of the mixed groups could achieve the same level of BS. BS is an effective indicator of CPS to group performance and individual interaction. Implications for the online CPS design and possible supports for the process of online CPS activity are also discussed.