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Drawing on skill acquisition theory (DeKeyser, 2017) and the Information Feedforward and Feedback Loop model (de Bot, 1980), this study aimed to explore the effects of digital zoom technology as a visual reinforcement tool (VRT) in foreign language (FL) pronunciation instruction on learners' segmental production, and learners' attitudes toward and experience with it. The study was conducted during a two-week introductory FL Spvanish course with a cross-over design. In the experimental class, the teacher used a tablet to provide magnified visual feedforward for articulatory gestures during explicit instruction of target consonants that were new to Chinese learners, and the students used smartphone apps with digital zoom for augmented visual self-feedback during their practice. In the control class, the teacher adopted a traditional analytic-linguistic approach for explicit instruction and an audio-only intuitive-imitative approach for students' practice. The results of the production test show that the experimental group performed significantly better in the production of the postvocalic /[squat reversed esh]/ and the dental fricatives /[voiceless dental fricative]/ and /[voiced dental fricative]/, but not in the trill /r/. Interview data suggests that the VRT strategy was advantageous in directing the participants' attention to articulatory gestures, and that most students showed positive attitudes toward this new method.

Abstract Background Obesity and metabolic syndrome (MetS) have become urgent worldwide health problems, predisposing patients to unfavorable myocardial status and thyroid dysfunction. Low-carbohydrate diet (LCD) and time-restricted eating (TRE) have been confirmed to be effective methods for weight management and improving MetS, but their effects on the myocardium and thyroid are unclear. Methods We conducted a secondary analysis in a randomized clinical diet-induced weight-loss trial. Participants (N = 169) diagnosed with MetS were randomized to the LCD group, the 8 h TRE group, or the combination of the LCD and TRE group for 3 months. Myocardial enzymes and thyroid function were tested before and after the intervention. Pearson’s or Spearman’s correlation was assessed between functions of the myocardium and thyroid and cardiometabolic parameters at baseline. Results A total of 162 participants who began the trial were included in the intention-to-treat (ITT) analysis, and 57 participants who adhered to their assigned protocol were involved in the per-protocol (PP) analysis. Relative to baseline, lactate dehydrogenase, creatine kinase MB, hydroxybutyrate dehydrogenase, and free triiodothyronine (FT3) declined, and free thyroxine (FT4) increased after all 3 interventions (both analyses). Creatine kinase (CK) decreased only in the TRE (− 18 [44] U/L, P

Lentiviruses, with their high transduction efficiency and gene expression levels, are widely used as gene delivery vectors in the development of chimeric antigen receptor T cells (CAR-T) and other genetically modified cell therapies. Accurate determination of the lentiviral vector infectious titer is essential to ensure effective transduction and product consistency. In this study, we developed an efficient method for lentiviral vector titration based on digital droplet polymerase chain reaction (ddPCR) technology, enabling absolute quantification of the target gene. Benzonase treatment of non-transduced plasmids substantially shortened the experimental period, reducing cell culture duration from 10-14 days–3 days. The method was rigorously validated by assessing specificity, working range, limit of quantification, precision, accuracy, and robustness. This study demonstrates the feasibility of combining enzymatic digestion with ddPCR to quantify lentiviral vector infectious titer and provides a detailed and readily adaptable methodology for the scientific community.

Abstract TNF receptor superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF superfamily member 11 (TNFRSF11, RANKL) are overexpressed in many malignancies. However, the clinical importance of RANKL/RANK in colorectal cancer (CRC) is mainly unknown. We examined CRC samples and found that RANKL/RANK was elevated in CRC tissues compared with nearby normal tissues. A higher RANKL/RANK expression was associated with a worse survival rate. Furthermore, RANKL was mostly produced by regulatory T cells (Tregs), which were able to promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulated C-C motif chemokine ligand 20 (CCL20) production by CRC cells, leading to Treg recruitment and boosting tumor stemness and malignant progression. This recruitment process was accomplished by CCL20–CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest an important role of RANKL/RANK in CRC progression, offering a potential target for CRC prevention and therapy.

Abstract Background Despite advancements in school scoliosis screening (SSS), there are still no effective indicators to estimate the severity of spinal curvature. We aim to investigate the association between incorrect postures and curve magnitude of adolescent idiopathic scoliosis (AIS) among Chinese adolescents. Methods In this SSS program, we examined the incorrect posture, Adam’s forward bending test (FBT) results, and angle of trunk rotation (ATR) in adolescents. Those with suspected scoliosis were referred for a standing anteroposterior whole-spine radiography as outpatients. The radiographic data of 426 students with lateral Cobb angles were collected from 2016 to 2022 and the associations were studied using logistic regression (LR) models and receiver operating characteristic (ROC) curves. Results Univariate LR revealed that female gender [odds ratio (OR) = 2.92, 95% confidence interval (CI) 1.67–5.09, P

Abstract Background Cancer stem cells (CSCs) and long non-coding RNAs (lncRNAs) are known to play a crucial role in the growth, migration, recurrence, and drug resistance of tumor cells, particularly in triple-negative breast cancer (TNBC). This study aims to investigate stemness-related lncRNAs (SRlncRNAs) as potential prognostic indicators for TNBC patients. Methods Utilizing RNA sequencing data and corresponding clinical information from the TCGA database, and employing Weighted Gene Co-expression Network Analysis (WGCNA) on TNBC mRNAsi sourced from an online database, stemness-related genes (SRGs) and SRlncRNAs were identified. A prognostic model was developed using univariate Cox and LASSO-Cox analysis based on SRlncRNAs. The performance of the model was evaluated using Kaplan–Meier analysis, ROC curves, and ROC-AUC. Additionally, the study delved into the underlying signaling pathways and immune status associated with the divergent prognoses of TNBC patients. Results The research identified a signature of six SRlncRNAs (AC245100.6, LINC02511, AC092431.1, FRGCA, EMSLR, and MIR193BHG) for TNBC. Risk scores derived from this signature were found to correlate with the abundance of plasma cells. Furthermore, the nominated chemotherapy drugs for TNBC exhibited considerable variability between different risk score groups. RT-qPCR validation confirmed abnormal expression patterns of these SRlncRNAs in TNBC stem cells, affirming the potential of the SRlncRNAs signature as a prognostic biomarker. Conclusion The identified signature not only demonstrates predictive power in terms of patient outcomes but also provides insights into the underlying biology, signaling pathways, and immune status associated with TNBC prognosis. The findings suggest the possibility of guiding personalized treatments, including immune checkpoint gene therapy and chemotherapy strategies, based on the risk scores derived from the SRlncRNA signature. Overall, this research contributes valuable knowledge towards advancing precision medicine in the context of TNBC.

Abstract Background Immunosuppressive status is prevalent in cancer patients and increases the complexity of tumor immunotherapy. It has been found that Listeria-vectored tumor vaccines had the potential ability of two-side regulatory effect on the immune response during immunotherapy. Results The results show that the combined immunotherapy with the LM∆E6E7 and LI∆E6E7, the two cervical cancer vaccine candidate strains constructed by our lab, improves the antitumor immune response and inhibits the suppressive immune response in tumor-bearing mice in vivo, confirming the two-sided regulatory ability of the immune response caused by Listeria-vectored tumor vaccines. The immunotherapy reduces the expression level of myeloid-derived suppressor cells (MDSCs)-inducing factors and then inhibits the phosphorylation level of STAT3 protein, the regulatory factor of MDSCs differentiation, to reduce the MDSCs formation ability. Moreover, vaccines reduce the expression of functional molecules associated with MDSCs may by inhibiting the phosphorylation level of the JAK1-STAT1 and JAK2-STAT3 pathways in tumor tissues to attenuate the immunosuppressive function of MDSCs. Conclusions Immunotherapy with Listeria-vectored cervical cancer vaccines significantly reduces the level and function of MDSCs in vivo, which is the key point to the destruction of immunosuppression. The study for the first to elucidate the mechanism of breaking the immunosuppression.

Aim: To compare the dosimetric advantages and disadvantages between hybrid intensity-modulated radiation therapy (h-IMRT) and the volumetric modulated arc therapy (VMAT) technique in hypofractionated whole-breast irradiation (HF-WBI) for early-stage breast cancer (BC). Methods: The dose distribution of h-IMRT and VMAT plans was compared in 20 breast cancer patients. This comparison included evaluation of dosimetric parameters using dose volume histograms (DVHs) for the planning target volume (PTV) and organs-at-risk (OARs). Additionally, the study examined the normal tissue complication probability (NTCP), the second cancer complication probability (SCCP) and the tumor control probability (TCP) based on different models. Results: Significant differences were detected between the two plans, in terms of Machine units (MUs), the control points, 95 % volume (V95 %), dose homogeneity index (DHI) and conformity index (CI). The endpoint of grade II radiation pneumonitis and cardiac death due to ischemic heart disease were assessed. In h-IMRT plan, the NTCP values were marginally lower for radiation pneumonitis and slightly higher for cardiac death compared to VMAT plan, as determined by the Lyman–Kutcher–Burman model. The Schneider model was employed to predict the SCCP for both the bilateral lungs and contralateral breast, the results demonstrate that the h-IMRT plan outperforms the VMAT plan, with statistical significance. Additionally, the LQ-Poisson model was employed to forecast the TCP of the PTV, showing that the h-IMRT plan outperformed the VMAT plan (P > 0.05). Conclusion: The h-IMRT technique, offering superior dose coverage and better therapeutic efficacy with fewer side effects as calculated by models, is more suitable for HF-WBI compared to the VMAT technique.

Aims: To investigate the therapeutic effect of acupuncture on acute inflammatory nerve root injury by regulating lymphatic function. Main methods: A mouse model of L5 nerve root compression was used to simulate acute nerve root injury. After modeling, acupuncture treatment was given each day for one week. Pain thresholds were assessed before and after modeling and treatment. Immunofluorescence staining was performed to observe the distribution astrocytes and neurons in the lumbar spinal cord, the innervation rate of neuromuscular junctions (NMJs), lymphatic endothelial cells (LECs) of lumbar aortic lymph nodes, and the percentage of M1 macrophages. The number of each type of immune cells in the lumbar aortic lymph nodes (LALNs) was measured by flow cytometry. Key findings: The model group showed a significant decrease in pain threshold in the affected lower limb, while acupuncture treatment was able to significantly increase it. Acupuncture significantly repaired astrocytes and neurons in the lumbar spinal cord of the compressed segment, increased the innervation rate of nerve endings at NMJs, reduced LECs in the LALNs, reduced the proportion of M1 macrophages in the LALNs, and significantly reduced mononuclear neutrophils and monocytic neutrophils. Significance: Acupuncture can reduce pain, promote nerve repair in mice with acute nerve root injury, and suppress immune responses in lumbar aortic lymph nodes.

With the development of the social economy, research on stock market prediction is in full swing. However, the fluctuations in stock price and returns are influenced by many factors, including political policies, market environment, investor psychology, and so on. The traditional analysis method, based on subjective experience, requires significant time and effort, and its prediction accuracy is often poor. Now, the application of machine learning algorithms to predict stock returns has become a hot topic among scholars. This article comprehensively analyzes the advantages and disadvantages of support vector machine (SVM), tree-based algorithms, and neural network algorithms in processing tabular data and time series data. It proposes a hybrid model based on the deep neural network (DNN) and TabNet models, combining the strengths of the DNN and tree-based models. In the model training stage, two neural networks are established to accept the inputs of ID features and numerical features, respectively, and multiple fully connected layers are used to complete the construction of the DNN model. The TabNet is implemented based on the attention transformer and feature transformer, and the prediction results of the two models are fused. The proposed model has a best Pearson correlation coefficient (PCC) value and a lowest root mean square error (RMSE) value at the same time, because the hybrid algorithm performs particularly well on large data sets with the least feature engineering and has strong interpretability, such as quantifying the contribution of different features in the model, it has certain theoretical significance and wide application value.

BackgroundCirculating metabolites, which play a crucial role in our health, have been reported to be disordered in basal cell carcinoma (BCC). Despite these findings, evidence is still lacking to determine whether these metabolites directly promote or prevent BCC’s progression. Therefore, our study aims to examine the potential effects of circulating metabolites on BCC progression.Material and methodsWe conducted a two−sample Mendelian randomization (MR) analysis using data from two separate genome-wide association studies (GWAS). The primary study included data for 123 blood metabolites from a GWAS with 25,000 Finnish individuals, while the secondary study had data for 249 blood metabolites from a GWAS with 114,000 UK Biobank participants.GWAS data for BCC were obtained from the UK Biobank for the primary analysis and the FinnGen consortium for the secondary analysis. Sensitivity analyses were performed to assess heterogeneity and pleiotropy.ResultsIn the primary analysis, significant causal relationships were found between six metabolic traits and BCC with the inverse variance weighted (IVW) method after multiple testing [P < 4 × 10−4 (0.05/123)]. Four metabolic traits were discovered to be significantly linked with BCC in the secondary analysis, with a significance level of P < 2 × 10−4 (0.05/249). We found that all the significant traits are linked to Polyunsaturated Fatty Acids (PUFAs) and their degree of unsaturation.ConclusionOur research has revealed a direct link between the susceptibility of BCC and Polyunsaturated Fatty Acids and their degree of unsaturation. This discovery implies screening and prevention of BCC.

Abstract Background Antidepressants, noninvasive brain stimulation (NIBS), and their combination are commonly used in routine clinical practice. Nevertheless, there is a continuous dispute regarding whether the effectiveness of NIBS in combination with antidepressants exceeds that of antidepressants alone. This meta-analysis aimed to evaluate the existing evidence and draw a definitive conclusion on this issue. Methods We conducted a comprehensive search of five databases: Embase, PubMed, Web of Science, SinoMed, and the Cochrane Database of Randomized Controlled Trials. The search was conducted until October 6, 2023. The primary outcomes were the pre- and post-intervention depression and anxiety scores. Secondary outcomes included dropout rates, response rates, and certain levels of neurotransmitters [ 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma-aminobutyric acid (GABA)] at the end of the intervention. Subgroup, meta-regression, and sensitivity analyses were performed to explore the sources of heterogeneity. The data were analysed using R 4.2.2. Results We included 18 RCTs [1357 participants; 11 studies used repetitive transcranial magnetic stimulation (rTMS) and 7 studies used transcranial direct current stimulation (tDCS)]. The follow-up duration varied from two weeks to three months. Overall, whether in combination with rTMS or tDCS, antidepressants proved more effective in alleviating depressive symptoms compared to when used as monotherapy. However, this advantage was not evident during the follow-up period. (p > 0.05). And the combination's efficacy in improving anxiety was found to be lacking. Post-treatment serum levels of 5-HT, DA, and GABA were higher in the rTMS group were higher than antidepressant medication group (p

Abstract Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).

Abstract Small bowel vascular malformation disease (SBVM) commonly causes obscure gastrointestinal bleeding (OGIB). However, the pathogenetic mechanism and the role of lncRNAs in SBVM remain largely unknown. Here, we found that hypoxia and low-glucose environments co-augment angiogenesis and existed in SBVM. Mechanistically, hypoxia and low-glucose environments supported angiogenesis via activation of hypoxia and glucose deprivation-induced lncRNA (HGDILnc1) transcription by increasing binding of the NeuroD1 transcription factor to the HGDILnc1 promoter. Raised HGDILnc1 acted as a suppressor of α-Enolase 1 (ENO1) small ubiquitin-like modifier modification (SUMOylation)-triggered ubiquitination, and an activator of transcription of Aldolase C (ALDOC) via upregulation of Histone H2B lysine 16 acetylation (H2BK16ac) level in the promoter of ALDOC, and consequently promoting glycolysis and angiogenesis. Moreover, HGDILnc1 was clinically positively correlated with Neurogenic differentiation 1 (NeuroD1), ENO1, and ALDOC in SBVM tissues, and could function as a biomarker for SBVM diagnosis and therapy. These findings suggest that hypoxia and low-glucose environments were present in SBVM tissues, and co-augmented angiogenesis. Hypoxia and low-glucose environments co-induced HGDILnc1, which is higher expressed in SBVM tissue compared with normal tissue, could promoted glycolysis and angiogenesis.

Abstract Background Some studies have examined the relationship between internalization of media appearance ideals and eating disorders. However, few have discussed the relationship between eating disorder tendencies. To fill this research gap, this study was to explore the influencing mechanisms of internalization of media appearance ideals on adolescents’ eating disorder tendencies in Chinese cultural context. Method The Sociocultural Attitudes Towards Appearance Questionnaire, Eating Attitude Test-26, Physical Self-Description Questionnaire, Body Image Depression Questionnaire and Multidimensional Scale of Perceived Social Support were employed in this study to investigate 1523 adolescents. The collected data were analyzed using SPSS 26.0 and AMOS 24.0. Result The results showed that: (1) internalization of media appearance ideals had a significant positive predictive effect on adolescents’ eating disorder tendencies; (2) internalization of media appearance ideals significantly influenced adolescents’ eating disorder tendencies through the mediating role of body esteem and body image disturbance respectively, and also influenced eating disorder tendencies through the chain mediating of both; and (3) social support played a moderating role between body image disturbance and eating disorder tendency. Conclusion Our findings suggest distinct pathways through which internalization of media appearance ideals may influence adolescents’ eating disorder tendencies. It is suggested that reducing body image disturbance and enhancing social support can help reducing eating disorder tendency.

Exopolysaccharides (EPS) are natural high polymers metabolized into the extracellular space by lactic acid bacteria during their growth. EPS have a broad spectrum of biological activities including antitumor, antioxidant, cholesterol-lowering, and intestinal microflora balance promoting functions. They can also be used as a food thickening agent, emulsifier, and stabilizer. Weissella, which was discovered recently, has a strong ability to produce EPS. This article mainly reviews the sources of Weissella and the synthesis pathway, classification, functions and application in fermented foods of EPS produced by Weissella. Hopefully, this review will provide a scientific basis for the processing and application of EPS from Weissella.

Background: This study aimed to explore the expression level and transcriptional regulation mechanism of Extra Spindle Pole Bodies Like 1 (ESPL1) in bladder cancer (BC). Methods: A multicentre database of samples (n = 1391) was assayed for ESPL1 mRNA expression in BC and validated at the protein level by immunohistochemical (IHC) staining of in-house samples (n = 202). Single-cell sequencing (scRNA-seq) analysis and enrichment analysis explored ESPL1 distribution and their accompanying molecular mechanisms. ATAC-seq, ChIP-seq and Hi-C data from multiple platforms were used to investigate ESPL1 upstream transcription factors (TFs) and potential epigenetic regulatory mechanisms. Immune-related analysis, drug sensitivity and molecular docking of ESPL1 were also calculated. Furthermore, upstream microRNAs and the binding sites of ESPL1 were predicted. The expression level and early screening efficacy of miR-299-5p in blood (n = 6625) and tissues (n = 537) were examined. Results: ESPL1 was significantly overexpressed at the mRNA level (p

Disulfidptosis, an innovative type of controlled cellular death linked to metabolic dysfunction, has garnered attention. However, there is limited knowledge regarding the involvement of disulfidptosisrelated lnRNAs (DRlncRNAs) in laryngeal squamous cell carcinoma (LSCC). The objective of our team in this study seeks to establish a DRlncRNAs signature, investigate their prognostic value in LSCC, and explore their associations with immune cell subpopulations, biological signaling pathways, and exploring implications for drug sensitivity. We accessed LSCC patients’ RNA-seq data and pertinent clinical data for subsequent further analysis from The Cancer Genome Atlas (TCGA) portal. A literature search was conducted focusing on disulfidptosis-related genes. Pearson correlation coefficients were calculated to identify DRlncRNAs. Differential expression analysis of lncRNAs was performed. Utilizing univariate Cox regression analysis, we identified disulfidptosis-associated prognostic lncRNAs. The LASSO-Cox regression analysis was employed to refine this set of lncRNAs and construct a disulfidptosis-related lncRNAs signature. Various statistical techniques were employed to appraise model predictive performance. Subsequently, risk groups were stratified based on the risk score derived from the DRlncRNAs signature. The superiority of the risk score in prognostication over traditional clinicopathological features in LSCC patients was demonstrated. Evident distinctions emerged between risk groups, particularly in immune cell subpopulations like activated mast cells, eosinophils, and activated NK cells. Finally, the low-risk group demonstrated reduced IC50 values for specific chemotherapeutics like cisplatin and gemcitabine. The in vitro experiments indicated differential behavior of our DRlncRNAs. The DRlncRNAs signature can serve as a robust biomarker with the ability to predict both prognosis and therapeutic responses among patients with LSCC.

Objectives: The positive effects of tea on Alzheimer's disease (AD) have increasingly captured researchers' attention. Nevertheless, the quantitative comprehensive analysis in the relevant literatur is lack. This paper aims to thoroughly examine the current research status and hotspots from 2014 to 2023, providing a valuable reference for subsequent research. Methods: Documents spanning from 2014 to 2023 were searched from the Web of Science, and the R software, VOSviewer, and Citespace software were used for analysis and visualization. Results: A total of 374 documents were contained in the study. The rate of article publications exhibited a consistent increase each year from 2014 to 2023. Notably, China emerged as the leading country in terms of published articles, followed by the United States and India. Simultaneously, China is also in a leading position in cooperation with other countries. Molecules emerged as the most frequently published journal, while the Journal of Alzheimer's Disease secured the top spot in terms of citations. The identified main keywords included oxidative stress, amyloid, epigallocatechin gallate, and green tea polyphenol, among others. These focal areas delved into the antioxidative and anti-amyloid aggregation actions of tea's polyphenolic components. Furthermore, the particularly way in which epigallocatechin gallate delivers neuroprotective outcomes by influencing molecules related to AD represents a focal point of research. Conclusion: The increasing attention from researchers on the role of tea in ameliorating AD positions it as a hot spot in the development of anti-AD drugs in the development of future. Through our generalized analysis of the current landscape and hotspots regarding tea's application in AD, this study provides an estimable reference for future research endeavors.

AimsThis study aims to explore the gender differences in cognitive improvements after two months of atypical antipsychotic treatment in first episode schizophrenia (FES).Methods82 patients with FES, including 50 male patients and 32 female patients, were enrolled in the present study. Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) were respectively conducted to evaluate the clinical symptoms and cognitive function of patients with FES at baseline and after treatment. Repeated measure ANOVA was performed to compare gender differences in cognitive domains scores between baseline and 2-month follow-up. Stepwise liner regression model was performed to explore the effect factors of cognitive improvements in patients.ResultsThere was no significant difference in age of onset, education years, PANSS scores, duration of untreated psychosis and Olanzapine equivalent doses between male and female patients (all p > 0.05). In the comparisons of cognition function, male patients exhibited better performance in social cognition compared with female patients at baseline (t = 3.20, p < 0.05). After treatment, improvements of attention/vigilance and working memory were both found in male patients and female patients (attention/vigilance, F = 11.867, p < 0.05; working memory, F = 18.265, p < 0.05). In addition, improvement of speed of information processing was only found in female patients (F = 11.65, p < 0.01). Significant interaction between time and gender was found in speed information of processing (F = 4.140, p = 0.045). Stepwise liner regression model revealed that improvements of negative symptoms promote improvements of cognitive function in female patients (all p < 0.05).ConclusionsOur findings revealed gender differences of cognitive improvements in patients with FES after 2-month treatment. It provides new evidence for gender differences in cognitive symptoms of schizophrenia, and also provides preliminary clues for further individualized cognitive intervention strategies.

Summary: Both therapeutic hypothermia and neural stem cells (NSCs) transplantation have shown promise in neuroprotection and neural repair after brain injury. However, the effects of therapeutic hypothermia on neuronal differentiation of NSCs are not elucidated. In this study, we aimed to investigate whether mild hypothermia promoted neuronal differentiation in cultured and transplanted human NSCs (hNSCs). A significant increase in neuronal differentiation rate of hNSCs was found when exposed to 35°C, from 33% to 45% in vitro and from 7% to 15% in vivo. Additionally, single-cell RNA sequencing identified upregulation of RNA-binding motif protein 3 (RBM3) in neuroblast at 35°C, which stabilized the SRY-box transcription factor 11 (SOX11) mRNA and increased its protein expression, leading to an increase in neuronal differentiation of hNSCs. In conclusion, our study highlights that mild hypothermia at 35°C enhances hNSCs-induced neurogenesis through the novel RBM3-SOX11 signaling pathway, and provides a potential treatment strategy in brain disorders.

Abstract Background The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. Results Here, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions. Conclusions Our study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.

Tangshan, a major industrial and agricultural center in northern China, frequently experiences significant PM2.5 pollution events during winter, impacting its large population. These pollution episodes are influenced by multi–scale meteorological processes, though the complex mechanisms remain not fully understood. This study integrates surface PM2.5 concentration data, ground-based and upper–air meteorological observations, and ERA5 reanalysis data from 2015 to 2019 to explore the interactions between local planetary boundary layer (PBL) structures and large-scale atmospheric processes driving PM2.5 pollution in Tangshan. The results indicate that seasonal variations in PM2.5 pollution levels are closely linked to changes in PBL thermal stability. During winter, day–to–day increases in PM2.5 concentrations are often tied to atmospheric warming above 1500 m, as enhanced thermal inversions and reduced PBL heights lead to pollutant accumulation. Regionally, this aloft warming is driven by a high-pressure system at 850 hPa over the southern North China Plain, accompanied by prevailing southwesterly winds. Additionally, southwesterly winds within the PBL can transport pollutants from the adjacent Beijing–Tianjin–Hebei region to Tangshan, worsening pollution. Simulations from the chemical transport model indicate that regional pollutant transport can contribute to approximately half of the near-surface PM2.5 concentration under the unfavorable synoptic conditions. These findings underscore the importance of multi-scale meteorology in predicting and mitigating severe wintertime PM2.5 pollution in Tangshan and surrounding regions.

Plant architecture and leaf color are important factors influencing cotton fiber yield. In this study, based on genetic analysis, stem paraffin sectioning, and phytohormone treatments, we showed that the dwarf-red (DR) cotton mutant is a gibberellin-sensitive mutant caused by a mutation in a single dominant locus, designated GhDR. Using bulked segregant analysis (BSA) and genotyping by target sequencing (GBTS) approaches, we located the causative mutation to a ~197-kb genetic interval on chromosome A09 containing 25 annotated genes. Based on gene annotation and expression changes between the mutant and normal plants, GH_A09G2280 was considered to be the best candidate gene responsible for the dwarf and red mutant phenotypes. A 2-nucleotide deletion was found in the coding region of GhDR/GH_A09G2280 in the DR mutant, which caused a frameshift and truncation of GhDR. GhDR is a homolog of Arabidopsis AtBBX24, and encodes a B-box zinc finger protein. The frameshift deletion eliminated the C-terminal nuclear localization domain and the VP domain of GhDR, and altered its subcellular localization. A comparative transcriptome analysis demonstrated downregulation of the key genes involved in gibberellin biosynthesis and the signaling transduction network, as well as upregulation of the genes related to gibberellin degradation and the anthocyanin biosynthetic pathway in the DR mutant. The results of this study revealed the potential molecular basis by which plant architecture and anthocyanin accumulation are regulated in cotton.

Deficiency in regulatory T cells (Tregs) is an important mechanism underlying the pathogenesis of pediatric aplastic anemia, but its specific mechanism is unclear. In our study, we aimed to investigate whether IL-2/STAT5 can regulate the proliferation of Tregs in aplastic anemia (AA) by regulating their expression of B lymphocyte-induced mature protein-1 (BLIMP-1) or interferon regulatory factor 4 (IRF4). Through clinical research and animal experiments, we found that poor activation of the IL-2/STAT5 signaling pathway may leads to low expression of BLIMP-1 in Tregs of children with AA, which leads to defects in the differentiation and proliferation of Tregs in AA. In AA model mice, treatment with IL-2c reversed the decrease in Treg proportions and reduction in Blimp-1 expression in Tregs by increasing the phosphorylation of Stat5 in Tregs. In AA, deficiency of IRF4 expression in Tregs is closely related to the deficiency of Tregs, but is not regulated by the IL-2/STAT5 pathway.

Mutations in the master hematopoietic transcription factor GATA1 are often associated with functional defects in erythropoiesis and megakaryopoiesis. In this study, we identified a novel GATA1 germline mutation (c.1162delGG, p.Leu387Leufs*62) in a patient with congenital anemia and occasional thrombocytopenia. The C-terminal GATA1, a rarely studied mutational region, undergoes frameshifting translation as a consequence of this double-base deletion mutation. To investigate the specific function and pathogenic mechanism of this mutant, in vitro mutant models of stable re-expression cells were generated. The mutation was subsequently validated to cause diminished transcriptional activity of GATA1 and defective differentiation of erythroid and megakaryocytes. Using proximity labeling and mass spectrometry, we identified selective alterations in the proximal protein networks of the mutant, revealing decreased binding to a set of normal GATA1-interaction proteins, including the essential co-factor FOG1. Notably, our findings further demonstrated enhanced recruitment of the protein arginine methyltransferase PRMT6, which mediates histone modification at H3R2me2a and represses transcription activity. We also found an enhanced binding of this mutant GATA1/PRMT6 complex to the transcriptional regulatory elements of GATA1’s target genes. Moreover, treatment of the PRMT6 inhibitor MS023 could partially rescue the inhibited transcriptional and impaired erythroid differentiation caused by the GATA1 mutation. Taken together, our results provide molecular insights into erythropoiesis in which mutation leads to partial loss of GATA1 function and the broader role of PRMT6 and its inhibitor MS023 in congenital anemia, highlighting PRMT6 binding as a negative factor of GATA1 transcriptional activity in aberrant hematopoiesis.

Abstract Iron single‐atom nanozymes represent a promising artificial enzyme with superior activity owing to uniform active sites that can precisely mimic active center of nature enzymes. However, current synthetic strategies are hard to guarantee each active site at single‐atom state. In this work, an erythrocyte‐templated strategy by utilizing intrinsic hemin active center of hemoglobin as sing‐atom source for nanozyme formation is developed. By combining cell fixation, porous salinization, and high‐temperature carbonization, erythrocytes are successfully served as uniform templates to synthesize nanozymes with fully single‐atom FeN4 active sites which derived from hemin of hemoglobin, resulting in an enhanced peroxidase (POD)‐like activity. Interestingly, the catalytic activity of erythrocyte‐templated nanozyme (ETN) shows dependence on animal species, among which murine ETN performed superior catalytic efficiency. In addition, the as‐prepared ETNs display a honeycomb‐like network structure, serving as a sponge to accelerate hemostasis based on the interactions with prothrombin and fibrinogen. These features enable ETN to effectively kill methicillin‐resistant Staphylococcus aureus (MRSA) by combining POD‐like catalysis with near‐infrared (NIR) induced photothermal effect, and subsequently suitable to promote wound healing. This study provides a proof‐of‐concept for facile fabrication of multifunctional nanozymes with uniform single‐atom active sites by utilizing intrinsic iron structure characteristics of biogenic source like erythrocytes.

Summary: The molecular mechanism of ibrutinib-induced atrial fibrillation (AF) remains unclear. We here demonstrate that treating rats with ibrutinib for 4 weeks resulted in the development of inducible AF, left atrial enlargement, atrial fibrosis, and downregulation of connexin expression, which were associated with C-terminal Src kinase (CSK) inhibition and Src activation. Ibrutinib upregulated angiotensin-converting enzyme (ACE) protein expression in human pulmonary microvascular endothelial cells (HPMECs) by inhibiting the PI3K-AKT pathway, subsequently increasing circulating angiotensin II (Ang II) levels. However, the expression of ACE and Ang II in the left atria was not affected. Importantly, we observed that perindopril significantly mitigated ibrutinib-induced left atrial remodeling and AF promotion by inhibiting the activation of the ACE and its downstream CSK-Src signaling pathway. These findings indicate that the Ibrutinib-induced activation of the ACE contributes to AF development and could serve as a novel target for potential prevention strategies.

Objective: To study the role and mechanism of chloride channel-3 (ClC-3) in the formation of hypertrophic scar by constructing ClC-3 interference vectors and examining their effects on human hypertrophic scar fibroblasts (HSFB). Methods: Human HSFB and human normal skin fibroblasts (NSFB) were used in this study, and ClC-3 interference vectors were constructed to transfect cells. ClC-3 inhibitors NPPB and Tamoxifen were used to treat cells. Cell migration and the expression of TGF-β/Smad, CollagenⅠ,CollagenⅢ were examined to explore the role of ClC-3 in the formation of hypertrophic scar. Results: Compared with the normal skin tissue, the positive expression of ClC-3 and TGF–β in the scar tissue was significantly increased. The relative expression of ClC-3 and TGF-β1 in HSFB cells was higher than that in NSFB cells. Interfering with the expression of CLC-3 can inhibit the migration of HSFB cells and the expression of TGF- β/Smad, CollagenⅠ/Ⅲ. The experiment of HSFB cells treated by CLC-3 inhibitors can also obtain similar results. Conclusion: Inhibiting CLC-3 can reduce the formation of hypertrophic scars.

Abstract Hydrogels are prevailing drug delivery depots to improve antitumor efficacy and reduce systemic toxicity. However, the application of conventional free drug‐loaded hydrogel is hindered by poor drug penetration in solid tumors. Here, an injectable ferritin‐based nanocomposite hydrogel is constructed to facilitate tumor penetration and improve cancer chemoimmunotherapy. Specifically, doxorubicin‐loaded human ferritin (Dox@HFn) and oxidized dextran (Dex‐CHO) are used to construct the injectable hydrogel (Dox@HFn Gel) through the formation of pH‐sensitive Schiff‐base bonds. After peritumoral injection, the Dox@HFn Gel is retained locally for up to three weeks, and released intact Dox@HFn gradually, which can not only facilitate tumor penetration through active transcytosis but also induce immunogenic cell death (ICD) to tumor cells to generate an antitumor immune response. Combining with anti‐programmed death‐1 antibody (αPD‐1), Dox@HFn Gel induces remarkable regression of orthotopic 4T1 breast tumors, further elicits a strong systemic anti‐tumor immune response to effectively suppress tumor recurrence and lung metastasis of 4T1 tumors after surgical resection. Besides, the combination of Dox@HFn GelL with anti‐CD47 antibody (αCD47) inhibits postsurgical tumor recurrence of aggressive orthotopic glioblastoma tumor model and significantly extends mice survival. This work sheds light on the construction of local hydrogels to potentiate antitumor immune response for improved cancer therapy.

BackgroundDiabetic nephropathy (DN) is one of the most prevalent and severe microvascular complications of type 2 diabetes (T2DM). However, little is currently known about the pathogenesis and its associated risk factors in DN. The present study aims to investigate the potential risk factors of DN in patients with T2DM.MethodsA total of 6,993 T2DM patients, including 5,089 participants with DN and 1,904 without DN, were included in this cross-sectional study. Comparisons between the two groups (DN vs. non-DN) were carried out using Student’s t-test, Mann-Whitney U-test, or Pearson’s Chi-squared test. Spearman’s correlation analyses were performed to assess the correlations of serum lipids and indicators of renal impairment. Logistic regression models were applied to assess the relationship between blood lipid indices and the presence of DN.ResultsT2DM patients with DN were older, and had a longer duration of diagnosed diabetes compared to those without DN. Of note, the DN patients also more likely develop metabolic disorders. Among all serum lipids, Lipoprotein(a) [Lp(a)] was the most significantly correlated indicators of renal impairment. Moreover, univariate logistic regression showed that elevated Lp(a) level was associated with an increased risk of DN. After adjusted for confounding factors, including age, gender, duration of T2DM, BMI, SBP, DBP and lipid-lowering drugs usage, Lp(a) level was independently positively associated with the risk of DN [odds ratio (OR):1.115, 95% confidence interval (CI): 1.079-1.151, P=6.06×10-11].ConclusionsOverall, we demonstrated that serum Lp(a) level was significantly positively associated with an increased risk of DN, indicating that Lp(a) may have the potential as a promising target for the diagnosis and treatment of diabetic nephropathy.

In this study, blueberry pulp was used as the material to promote the release of bound polyphenols into free polyphenols by enzymatic transformation. The antioxidant activities of different forms of polyphenols were investigated. With the conversion rate of free polyphenols as the index, the optimal combination of different enzymes was screened. The single-factor test and the Box-Behnken response surface test were used to determine the optimal enzymatic hydrolysis parameters. The antioxidant activity was measured by FRAP and ABTS assays. The results showed that the optimal enzymatic hydrolysis conditions were as follows: Complex enzyme was composed of pectinase and cellulase with a ratio of 4:6, the dosage of complex enzyme was 2.8%, the hydrolysis temperature was 50 ℃, and the hydrolysis time was 124 min. Compared with the control group, the conversion rate of free polyphenols in enzymatic blueberry pulp was 83.47%, which was increased by 9.96%. The content of free polyphenols in enzymatic blueberry pulp (343.58 mg GAE/100 g FW) was increased by 27.67%, and the content of bound polyphenols (68.03 mg GAE/100 g FW) was decreased by 29.84%. The results of antioxidant activity revealed that the FRAP and ABTS antioxidant capacity of free polyphenols extract in enzymatic blueberry pulp was elevated by 15.45% and 27.25%, respectively. The FRAP and ABTS antioxidant capacity of total polyphenols in enzymatic blueberry pulp was increased by 6.81% and 15.62%, respectively. These results indicates that enzymatic hydrolysis promotes the transformation of free polyphenols in blueberry pulp and enhanced the antioxidant capacity of blueberry pulp, which provides a theoretical basis for the development and processing of functional activity for blueberry products.