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Abstract. Background:. Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants. Methods:. A total of 3053 healthy Han Chinese adults (1922 women) aged 18–79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere–Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance. Results:. All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction

Abstract Group 3 innate lymphoid cells (ILC3) are crucial for maintaining mucosal homeostasis and regulating inflammatory diseases, but the molecular mechanisms governing their phenotype and function are not fully understood. Here, we show that ILC3s highly express Fcer1g gene, which encodes the antibody Fc-receptor common gamma chain, FcεR1γ. Genetic perturbation of FcεR1γ leads to the absence of critical cell membrane receptors NKp46 and CD16 in ILC3s. Alanine scanning mutagenesis identifies two residues in FcεR1γ that stabilize its binding partners. FcεR1γ expression in ILC3s is essential for effective protective immunity against bacterial and fungal infections. Mechanistically, FcεR1γ influences the transcriptional state and proinflammatory cytokine production of ILC3s, relying on the CD16-FcεR1γ signaling pathway. In summary, our findings highlight the significance of FcεR1γ as an adapter protein that stabilizes cell membrane partners in ILC3s and promotes anti-infection immunity.

Abstract ADGRF5 (GPR116) has been identified as a facilitator of breast cancer cell migration and metastasis, yet the underlying mechanisms remain largely elusive. Our current study reveals that the absence of ADGRF5 in breast cancer cells impairs extracellular matrix (ECM)-associated cell motility and impedes in vivo tumor growth. This correlates with heightened expression of matrix metalloproteinase 8 (MMP8), a well-characterized antitumorigenic MMP, and a shift in the polarization of tumor-associated neutrophils (TANs) towards the antitumor N1 phenotype in the tumor microenvironment (TME). Mechanistically, ADGRF5 inhibits ERK1/2 activity by enhancing RhoA activation, leading to decreased phosphorylation of C/EBPβ at Thr235, hindering its nuclear translocation and subsequent activation. Crucially, two C/EBPβ binding motifs essential for MMP8 transcription are identified within its promoter region. Consequently, ADGRF5 silencing fosters MMP8 expression and CXCL8 secretion, attracting increased infiltration of TANs; simultaneously, MMP8 plays a role in decorin cleavage, which leads to trapped-inactivation of TGF-β in the TME, thereby polarizing TANs towards the antitumor N1 neutrophil phenotype and mitigating TGF-β-enhanced cell motility in breast cancer. Our findings reveal a novel connection between ADGRF5, an adhesion G protein-coupled receptor, and the orchestration of the TME, which dictates malignancy progression. Overall, the data underscore ADGRF5 as a promising therapeutic target for breast cancer intervention.

Abstract According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR)

Abstract Background Ossification of ligamentum flavum (OLF) is a prevalent degenerative spinal disease, typically causing severe neurological dysfunction. Kruppel-like factor 5 (KLF5) plays an essential role in the regulation of skeletal development. However, the mechanism KLF5 plays in OLF remains unclear, necessitating further investigative studies. Methods qRT-PCR, immunofluorescent staining and western blot were used to measure the expression of KLF5. Alkaline Phosphatase (ALP) staining, Alizarin red staining (ARS), and the expression of Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcin (OCN) were used to evaluate the osteogenic differentiation. Luciferase activity assay and ChIP-PCR were performed to investigate the molecular mechanisms. Results KLF5 was significantly upregulated in OLF fibroblasts in contrast to normal ligamentum flavum (LF) fibroblasts. Silencing KLF5 diminished osteogenic markers and mineralized nodules, while its overexpression had the opposite effect, confirming KLF5’s role in promoting ossification. Moreover, KLF5 promotes the ossification of LF by activating the transcription of Connexin 43 (CX43), and overexpressing CX43 could reverse the suppressive impact of KLF5 knockdown on OLF fibroblasts’ osteogenesis. Conclusion KLF5 promotes the OLF by transcriptionally activating CX43. This finding contributes significantly to our understanding of OLF and may provide new therapeutic targets.

Abstract Internal N6-methyladenosine (m6A) modifications are among the most abundant modifications of messenger RNA, playing a critical role in diverse biological and pathological processes. However, the functional role and regulatory mechanism of m6A modifications in the immune response to Mycobacterium tuberculosis infection remains unknown. Here, we report that methyltransferase-like 14 (METTL14)-dependent m6A methylation of NAPDH oxidase 2 (Nox2) mRNA was crucial for the host immune defense against M. tuberculosis infection and that M. tuberculosis-secreted antigen EsxB (Rv3874) inhibited METTL14-dependent m6A methylation of Nox2 mRNA. Mechanistically, EsxB interacted with p38 MAP kinase and disrupted the association of TAB1 with p38, thus inhibiting the TAB1-mediated autophosphorylation of p38. Interaction of EsxB with p38 also impeded the binding of p38 with METTL14, thereby inhibiting the p38-mediated phosphorylation of METTL14 at Thr72. Inhibition of p38 by EsxB restrained liquid–liquid phase separation (LLPS) of METTL14 and its subsequent interaction with METTL3, preventing the m6A modification of Nox2 mRNA and its association with the m6A-binding protein IGF2BP1 to destabilize Nox2 mRNA, reduce ROS levels, and increase intracellular survival of M. tuberculosis. Moreover, deletion or mutation of the phosphorylation site on METTL14 impaired the inhibition of ROS level by EsxB and increased bacterial burden or histological damage in the lungs during infection in mice. These findings identify a previously unknown mechanism that M. tuberculosis employs to suppress host immunity, providing insights that may empower the development of effective immunomodulators that target M. tuberculosis.

Abstract Background The evasion of the immune response by tumor cells through programmed death-ligand 1 (PD-L1) has been identified as a factor contributing to resistance to radioimmunotherapy in lung cancer patients. However, the precise molecular mechanisms underlying the regulation of PD-L1 remain incompletely understood. This study aimed to investigate the role of cyclin-dependent kinase-like 1 (CDKL1) in the modulation of PD-L1 expression and the response to radioimmunotherapy in lung cancer. Methods The tumorigenic roles of CDKL1 were assessed via cell growth, colony formation, and EdU assays and an in vivo nude mouse xenograft model. The in vitro radiosensitization effect of CDKL1 was evaluated using a neutral comet assay, γH2AX foci formation analysis, and a clonogenic cell survival assay. The protein‒protein interactions were confirmed via coimmunoprecipitation and GST pulldown assays. The regulation of PD-L1 by CDKL1 was evaluated via chromatin immunoprecipitation (ChIP), real-time quantitative PCR, and flow cytometry analysis. An in vitro conditioned culture model and an in vivo C57BL/6J mouse xenograft model were developed to detect the activation markers of CD8+ T cells and evaluate the efficacy of CDKL1 overexpression combined with radiotherapy (RT) and an anti-PD-L1 antibody in treating lung cancer. Results CDKL1 was downregulated and suppressed the growth and proliferation of lung cancer cells and increased radiosensitivity in vitro and in vivo. Mechanistically, CDKL1 interacted with the transcription factor YBX1 and decreased the binding affinity of YBX1 for the PD-L1 gene promoter, which consequently inhibits the expression of PD-L1, ultimately leading to the activation of CD8+ T cells and the inhibition of immune evasion in lung cancer. Moreover, the combination of CDKL1 overexpression, RT, and anti-PD-L1 antibody therapy exhibited the most potent antitumor efficacy against lung cancer. Conclusions Our findings demonstrate that CDKL1 plays a crucial role in regulating PD-L1 expression, thereby enhancing the antitumor effects of radioimmunotherapy. These results suggest that CDKL1 may be a promising therapeutic target for the treatment of lung cancer.

Abstract The intermitochondrial cement (IMC) and chromatoid body (CB) are posited as central sites for piRNA activity in mice, with MIWI initially assembling in the IMC for piRNA processing before translocating to the CB for functional deployment. The regulatory mechanism underpinning MIWI translocation, however, has remained elusive. We unveil that piRNA loading is the trigger for MIWI translocation from the IMC to CB. Mechanistically, piRNA loading facilitates MIWI release from the IMC by weakening its ties with the mitochondria-anchored TDRKH. This, in turn, enables arginine methylation of MIWI, augmenting its binding affinity for TDRD6 and ensuring its integration within the CB. Notably, loss of piRNA-loading ability causes MIWI entrapment in the IMC and its destabilization in male germ cells, leading to defective spermatogenesis and male infertility in mice. Collectively, our findings establish the critical role of piRNA loading in MIWI translocation during spermatogenesis, offering new insights into piRNA biology in mammals.

Summary: Alternative polyadenylation (APA) is a critical post-transcriptional process that generates mRNA isoforms with distinct 3′ untranslated regions (3′ UTRs), thereby regulating mRNA localization, stability, and translational efficiency. Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Despite its recognized significance, the precise regulatory mechanisms governing cell-type-specific APA remain unclear. In this study, we uncover PQBP1 as an emerging APA regulator that actively maintains cell-specific APA profiles in neural progenitor cells (NPCs) and delicately manages the equilibrium between NPC proliferation and differentiation. Multi-omics analysis shows that PQBP1 directly interacts with the upstream UGUA elements, impeding the recruitment of the CFIm complex and influencing polyadenylation site selection within genes associated with the cell cycle. Our findings elucidate the molecular mechanism by which PQBP1 orchestrates dynamic APA changes during neurogenesis, providing valuable insights into the precise regulation of cell-type-specific APA and the underlying pathogenic mechanisms in neurodevelopmental disorders.

Semantic segmentation plays a significant role in parsing remote sensing images. However, mainstream segmentation models lack a thorough understanding of the complex structures and scale differences, and struggle to effectively locate and emphasize diverse edges. Aiming at these limitations, we propose a frequency-driven edge guidance network, named FDEG-Net, for semantic segmentation of remote sensing images. First, we design a joint sparse context aggregation module that integrates both dense local context and sparse long-range context to improve the analysis of intricate and multiscale objects. Second, an edge guidance module is developed for strong interclass edge acquisition. It applies a 2-D discrete wavelet transform, coefficient superposition method, and adaptive edge feature enhancement algorithm to reduce low-frequency information and highlight salient boundaries in spatial features. This module has two significant advantages. 1) The edge positions are defined in pixel intensity with high interpretability. 2) The modular design without additional edge labels is plug-and-play. The effectiveness and robustness of this module are validated through edge visualization results. The proposed FDEG-Net is evaluated on the Potsdam, Vaihingen, and GID datasets, demonstrating its excellent performance in accurately capturing the rich semantics of geographic space features.

Change detection (CD) is a significant branch of remote sensing image analysis. Its main distinction from general semantic segmentation lies in the input of bitemporal images. Recent CD methods have primarily focused on Euclidean space, disregarding the hidden non-Euclidean details due to the high imaging altitude and complex scenes in remote sensing imagery. This limitation hampers the model's performance. In recent years, hyperbolic space has gradually been introduced into deep learning as a classical non-Euclidean space. To explore the potential impact of hyperbolic information in CD, a hyperbolic-embedding-based Siamese network is proposed in this article. Specifically, we propose a hyperbolic similarity attention mechanism that can map deep features from bitemporal images into hyperbolic space, then establish the relationship between bitemporal features based on the hyperbolic distance, fully mining non-Euclidean information, and fusing features from both branches to enhance feature cohesiveness. Furthermore, we design a differential feature enhanced module in the decoder, which utilizes differential operations at multiple scales to highlight the essence of each layer's features and improve feature richness. Experimental results on two public very-high-resolution CD datasets demonstrate that the proposed network achieves better detection accuracy than other state-of-the-art CD methods.

Abstract In the context of electricity market, the heavy load of some inter‐provincial and intra‐provincial lines limits available transfer capability (ATC). As a series compensation device, static synchronous series compensator (SSSC) can reallocate the power flow of adjacent lines. In order to maximize the inter‐regional ATC, a two‐stage optimal SSSC allocation method considering the uncertainty and correlation of multi‐wind farm is proposed. Firstly, the initial wind power scenarios are generated based on latin hypercube sampling (LHS) and reduced by the improved iterative self‐organizing data analysis techniques algorithm (I‐ISODATA). Then, a multi‐objective optimization model is constructed with the maximum expected power flow transfer entropy (PFTE) and minimum expected SSSC investment cost in all typical wind power scenarios, and non‐dominated sorting genetic algorithm‐II (NSGA‐II) method is used to determine the location of SSSC. In addition, based on the reduced wind power scenarios, the ATC calculation model containing SSSC is constructed, and the modern interior point method is used to determine the control parameters and configuration capacity of SSSC. Finally, based on the improved IEEE39 and IEEE118 node systems, case study proves that the proposed model can determine the optimal SSSC configuration scheme and significantly improves the ATC.

Based on the emulsification/demulsification method, a gas chromatography tandem mass spectrometry method was established for the quantitative determination of 12 nitrosamines in milk. The optimization results of pretreatment conditions such as the type of filter membrane, the type of extractant and the number of extractions were as follows: The type of filter membrane was nylon, the extractant was acetonitrile, and the number of extractions was two times. After acetonitrile extraction, deproteinizing, and degreased by emulsification/demulsification, the samples were separated on the HP-INNOWAX chromatographic column. The content of nitrosamines was quantitatively determined by the internal standard method, using multi-reactive ion monitoring (MRM) mode. The results showed that the linear range of N-nitrosopyrrolidine (NPYR) was 2~100 ng/mL, and the linear range of the other nitrosamines was 1~100 ng/mL. All nitrosamines had good determination coefficient which was greater than 0.995. During the high, medium and low-level fortification experiments, the recovery rate ranged from 90.90% to 114.30%, the intra-day precision ranged from 1.76% to 7.62%, and the inter-day precision ranged from 2.75% to 7.71%. The limit of quantitation (LOQ) of N-nitrosopyrrolidine (NPYR) was 4 µg/kg, and the LOQ of other compounds was 2 µg/kg. The method was precise and accurate, that met the demand of accurately testing 12 nitrosamines in milk. The test results of the actual samples indicated that N-nitrosodiphenylamine (NDPhA) was detected in six milk samples, and the content ranged from 4.29 to 6.67 μg/kg.

Abstract Background TAMs (tumor-associated macrophages) infiltration promotes the progression of esophageal cancer (EC). However, the underlying mechanisms remain unclear. Methods Abnormal expression of LINC01592 from EC microarrays of the TCGA database was analyzed. LINC01592 expression level was validated in both EC cell lines and tissues. Stable LINC01592 knockdown and overexpression of EC cell lines were established. In vitro and in vivo trials were conducted to test the impact of LINC01592 knockdown and overexpression on EC cells. RNA binding protein immunoprecipitation (RIP), RNA pulldown assays, and Immunofluorescence (IF) were used to verify the combination of E2F6 and LINC01592. The combination of E2F6 and NBR1 was verified through the utilization of ChIP and dual luciferase reporter assays. Results LINC01592 is carried and transferred by exosomes secreted by M2-TAMs to tumor cells. The molecular mechanism underlying the promotion of NBR1 transcription involves the direct binding of LINC01592 to E2F6, which facilitates the nuclear entry of E2F6. The collaborative action of LINC01592 and E2F6 results in improved NBR1 transcription. The elevation of NBR1 binding to the ubiquitinated protein MHC-I via the ubiquitin domain caused a higher degradation of MHC-I in autophagolysosomes and a reduction in MHC-I expression on the exterior of cancerous cell. Consequently, this caused cancerous cells to escape from CD8+ CTL immune attack. The tumor-promoting impacts of LINC01592, as well as the growth of M2-type macrophage-driven tumors, were significantly suppressed by the interruption of E2F6/NBR1/MHC-I signaling through the effect of siRNA or the corresponding antibody blockade. Significantly, the suppression of LINC01592 resulted in an upregulation of MHC-I expression on the tumor cell membrane, thereby enhancing the efficacy of CD8+ T cell reinfusion therapy. Conclusions The investigation conducted has revealed a significant molecular interaction between TAMs and EC via the LINC01592/E2F6/NBR1/MHC-I axis, which facilitates the progression of malignant tumors. This suggests that a therapeutic intervention targeting this axis may hold promise for the treatment of the disease.

Abstract Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression. Neoadjuvant chemoimmunotherapy (NACI) has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism behind this clinical response is unknown. The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting NACI response in advanced HNSCC. Methods We performed combined single‐cell RNA sequencing (scRNA‐seq) and multiplex immunofluorescence (mIHC) staining with tumor samples derived from NACI‐treated HNSCC patients to identify a new tumor‐infiltrating cell (TIL) subtype, CD103+CD8+ TILs, associated with clinical response, while both in vitro and in vivo assays were carried out to determine its antitumor efficiency. The regulatory mechanism of the CD103+CD8+ TILs population was examined by performing cell‐cell interaction analysis of the scRNA‐seq data and spatial analysis of the mIHC images. Results We established intratumoral CD103+CD8+ TILs density as a determinant of NACI efficacy in cancers. Our scRNA‐seq results indicated that the population of CD103+CD8+ TILs was dramatically increased in the responders of NACI‐treated HNSCC patients, while mIHC analysis confirmed the correlation between intratumoral CD103+CD8+ TILs density and NACI efficacy in HNSCC patients. Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI. Functional assays showed that CD103+CD8+ TILs were tumor‐reactive T cells, while programmed cell death protein‐1 (PD‐1) blockade enhanced CD103+CD8+ TILs cytotoxicity against tumor growth in vivo. Mechanistically, targeting the triggering receptor expressed on myeloid cells 2‐positive (TREM2+) macrophages might enhance the population of CD103+CD8+ TILs and facilitate antitumor immunity during NACI treatment. Conclusions Our study highlights the impact of intratumoral CD103+CD8+ TILs density on NACI efficacy in different cancers, while the efforts to elevate its population warrant further clinical investigation.

Abstract Understanding of the molecular drivers of lineage diversification and tissue patterning during primary germ layer development requires in-depth knowledge of the dynamic molecular trajectories of cell lineages across a series of developmental stages of gastrulation. Through computational modeling, we constructed at single-cell resolution, a spatio-temporal transcriptome of cell populations in the germ-layers of gastrula-stage mouse embryos. This molecular atlas enables the inference of molecular network activity underpinning the specification and differentiation of the germ-layer tissue lineages. Heterogeneity analysis of cellular composition at defined positions in the epiblast revealed progressive diversification of cell types. The single-cell transcriptome revealed an enhanced BMP signaling activity in the right-side mesoderm of late-gastrulation embryo. Perturbation of asymmetric BMP signaling activity at late gastrulation led to randomization of left-right molecular asymmetry in the lateral mesoderm of early-somite-stage embryo. These findings indicate the asymmetric BMP activity during gastrulation may be critical for the symmetry breaking process.

In order to meet the requirements of automatic mapping of the smart substation models, based on the application requirements of the smart substation model construction and automatic model association configuration, the automatic generation technology of smart station diagram models is studied, and the automatic correlation modeling method and wiring diagram generation technology of primary and secondary equipment models based on the automatic matching of predefined correlation models are proposed. Support the realization of the goal of effective configuration and efficient application of the secondary system model of the smart substation.

Respiratory syncytial virus (RSV) is a serious human respiratory pathogen that commonly affects children, older adults, and immunocompromised individuals. At present, the design of licensed vaccines focuses on the incorporation of the pre-fusion protein (PreF protein) of RSV, as this protein has the ability to induce antibodies that offer a high level of protection. Moreover, the G protein contains the CX3C motif that binds the chemokine receptor CX3CR1 in respiratory epithelial cells, which plays an essential role in viral infection. Therefore, incorporating the G antigen into vaccine design may prove more advantageous for RSV prevention. In this study, we developed a human adenoviral vector-based RSV vaccine containing highly neutralizing immunogens, a modified full-length PreF protein fused with the central conserved peptides of the G protein (Gcc) from both RSV subgroups trimerized via a C-terminal foldon, and evaluated its immune response in mice through intranasal (i.n.) immunization. Our results showed that immunization with Ad5-PreF-Qa-Gcc elicited a balanced Th1/Th2 immune response and robust mucosal immunity with higher neutralizing antibody titers against RSV Long and RSV B1. Importantly, immunization with Ad5-PreF-Qa-Gcc enhanced CD4+ CD25+ FoxP3+ Treg cell response and protected the mice against RSV infection. Our data demonstrate that the combination of Gcc and the PreF antigen is a viable strategy for developing effective RSV vaccines.

Abstract Objective Buccal mucosa cancer (BMC) is one of the most common oral cancers and has poor prognosis. The study aimed to develop and validate nomograms for predicting the 1‐, 3‐, and 5‐year overall survival (OS) and cancer‐specific survival (CSS) of BMC patients. Methods We collected and reviewed information on BMC patients diagnosed between 2004 and 2019 from the Surveillance Epidemiology and End Results database. Two nomograms were developed and validated to predict the OS and CSS based on predictors identified by univariate and multivariate Cox regression. An extra external validation was further performed using data from Sun Yat‐sen Memorial Hospital (SYSMH). Results A total of 3154 BMC patients included in this study were randomly assigned to training and validation groups in a 2:1 ratio. Independent prognostic predictors were identified, confirmed, and fitted into nomograms for OS and CSS, respectively. The C‐indices are 0.767 (Training group OS), 0.801 (Training group CSS), 0.763 (Validation group OS), and 0.781 (Validation group OS), respectively. Moreover, the nomograms exhibited remarkable precision in forecasting and significant clinical significance, as evidenced by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analyses (DCA). The final validation using our data from SYSMH also showed high accuracy and substantial clinical benefits within the nomograms. The C‐indices are 0.849 (SYSMH group OS) and 0.916 (SYSMH group CSS). These indexes are better than tumor, node, and metastasis stage based on prediction results. Conclusions The nomograms developed with great performance predicted 1‐, 3‐, and 5‐year OS and CSS of BMC patients. Use of the nomograms in clinical practices shall bring significant benefits to BMC patients.

Background & Aims: Dysfunction of the intestinal epithelial barrier comprising the junctional complex of tight junctions and adherent junctions leads to increased intestinal permeability, which is a major cause of uncontrolled inflammation related to inflammatory bowel disease (IBD). The NAD+-dependent deacetylase SIRT1 is implicated in inflammation and the pathologic process of IBD. We aimed to elucidate the protective role and underlying mechanism of SIRT1 in cell-cell junction and intestinal epithelial integrity. Methods: The correlation of SIRT1 expression and human IBD was analyzed by GEO or immunohistochemical analyses. BK5.mSIRT1 transgenic mice and wild-type mice were given dextran sodium sulfate (DSS) and the manifestation of colitis-related phenotypes was analyzed. Intestinal permeability was measured by FITC-dextran and cytokines expression was analyzed by quantitative polymerase chain reaction. The expression of the cell junction–related proteins in DSS-treated or SIRT1-knockdown Caco2 or HCT116 cells was analyzed by Western blotting. The effects of nicotinamide mononucleotide in DSS-induced mice colitis were investigated. Correlations of the SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin pathway with human IBD samples were analyzed. Results: Reduced SIRT1 expression is associated with human IBD specimens. SIRT1 transgenic mice exhibit much-reduced manifestations of DSS-induced colitis. The activation of SIRT1 by nicotinamide mononucleotide bolsters intestinal epithelial barrier function and ameliorates DSS-induced colitis in mice. Mechanistically, DSS downregulates SiRT1 expression, leading to destabilization of β-TrCP1 and upregulation of Snail1, accompanied by reduced expression of E-cadherin, Occludin, and Claudin-1, consequently resulting in increased epithelial permeability and inflammation. The deregulated SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin pathway correlates with human IBD. Conclusions: SIRT1 is pivotal in maintaining the intestinal epithelial barrier integrity via modulation of the β-TrCP1-Snail1-E-cadhein/Occludin/Claudin-1 pathway.

Aiming at the weak performance of chaotic light output in semiconductor laser systems, the study designed a power control algorithm for semiconductor laser drive systems based on linear self-disturbance rejection control. Then the optimization parameters and scope were determined, and multi-objective optimization and direction preference algorithms were introduced. A chaotic optical performance optimization model based on improved multi-objective genetic algorithm was constructed using adaptive functions as evaluation indicators. These results confirmed that the larger the bandwidth of the controller, the faster the response speed of the resonant converter, but the stability was poor. When the input voltage underwent a sudden change, the current ripple coefficient of the PID algorithm was 0.55%. The linear active disturbance rejection control algorithm could ensure that the voltage and current maintained at the set values, and the output current of the algorithm was more stable when the load underwent sudden changes. The directional preference algorithm could further provide more valuable solutions on the basis of adaptive genetic algorithms. When the peak value of the autocorrelation function was equal to 0.2, the delay characteristics of chaotic light were effectively suppressed, having strong signal bandwidth and complexity. In summary, the constructed model has good application effects in optimizing chaotic optical performance and has certain positive significance for communication security.

Abstract The Mulibrey (Muscle–liver–brain–eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FIN major (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

Abstract During embryo development, DNA methylation is established by DNMT3A/3B and subsequently maintained by DNMT1. While much research has been done in this field, the functional significance of DNA methylation in embryogenesis remains unknown. Here, we establish a system of simultaneous inactivation of multiple endogenous genes in zygotes through screening for base editors that can efficiently introduce a stop codon. Embryos with mutations in Dnmts and/or Tets can be generated in one step with IMGZ. Dnmt-null embryos display gastrulation failure at E7.5. Interestingly, although DNA methylation is absent, gastrulation-related pathways are down-regulated in Dnmt-null embryos. Moreover, DNMT1, DNMT3A, and DNMT3B are critical for gastrulation, and their functions are independent of TET proteins. Hypermethylation can be sustained by either DNMT1 or DNMT3A/3B at some promoters, which are related to the suppression of miRNAs. The introduction of a single mutant allele of six miRNAs and paternal IG-DMR partially restores primitive streak elongation in Dnmt-null embryos. Thus, our results unveil an epigenetic correlation between promoter methylation and suppression of miRNA expression for gastrulation and demonstrate that IMGZ can accelerate deciphering the functions of multiple genes in vivo.

Objective: Evaluate the impact of adjusting the overall dose, Gypsum Fibrosum [Mineral; Gypsum] (ShiGao, SG) dose, and Prunus armeniaca L. [Rosaceae; Semen Armeniacae Amarum] (KuXingRen, KXR) dose on the efficacy of MaXingShiGan Decoction (MXSG) in treating children with bronchial pneumonia (Wind-heat Blocking the Lung), in order to provide strategy supported by high-quality evidence for the selection of rational clinical doses of MXSG.Methods: Based on the basic dose of MXSG, we conducted three randomized, double-blind, dose parallel controlled, multicenter clinical trials, involving adjustments to the overall dose, SG dose, and KXR dose, and included 120 children with bronchial pneumonia (Wind-heat Blocking the Lung) respectively. And the patients were divided into low, medium, and high dose groups in a 1:1:1 ratio, with 40 cases in each group. The intervention period lasted for 10 days. The primary outcome was the clinical cured rate, while the secondary outcomes included the effectiveness in alleviating major symptoms of bronchial pneumonia (including fever, cough, dyspnea, and phlegm congestion). And the occurrence of adverse events was recorded.Results: We first recorded and analyzed the baseline characteristics of the three studies, including age, gender, height, and so on. The results indicated that there were no significant differences among the dose groups within each study. For the study adjusting the overall dose of MXSG, the results showed that both the medium-dose group and high-dose group had significantly higher clinical cured rates compared to the low-dose group (Chi-square value 9.01, p = 0.0111). However, there was no significant benefit between the high-dose group and the medium-dose group (81.58% vs. 81.08%). Regarding phlegm congestion, excluding fever, cough, and dyspnea, both the medium-dose group and high-dose group had significantly higher clinical cured rates than the low-dose group (Chi-square value 6.31, p = 0.0426), and there was no significant benefit between the high-dose group and the medium-dose group (69.23% vs. 75.00%). A total of 5 adverse events were observed, of which only 1 case in the medium-dose group was possibly related to the experimental medication. For the study adjusted the SG dose in MXSG, the results showed that the high-dose group had the highest clinical cured rate, but the inter-group difference was not statistically significant (Chi-square value 3.36, p = 0.1864). The area under the curve (AUC) for cough in the medium-dose group was significantly lower than in the low-dose group and high-dose group (F-test value 3.14, p = 0.0471). Although no significant differences were observed in fever and dyspnea among the groups, the AUC in the high-dose group was lower than in the medium-dose and low-dose groups. In comparing the complete defervescence time, both the high-dose group (p < 0.0001) and the medium-dose group (p = 0.0015) achieved faster than the low-dose group. The high-dose group slightly outperformed the medium-dose group (0.50 (0.50, 0.80) vs. 0.80 (0.40, 1.40)), although the difference was not significant. In the medium-dose group, 1 adverse event was observed, but it was not related to the experimental medication. For the study adjusted the KXR dose in MXSG, the results showed that both the medium-dose group and high-dose group had significantly higher cured rates compared to the low-dose group (Chi-square value 47.05, p < 0.0001). However, there was no significant benefit comparing the high-dose group to the medium-dose group (90.00% vs. 92.50%). Regarding clinical symptoms, the results indicated that for cough (F-test value 3.16, p = 0.0460) and phlegm congestion (F-test value 3.84, p = 0.0243), the AUC for both the medium-dose group and high-dose group were significantly lower than in the low-dose group. Although there was benefit in the high-dose group compared to the medium-dose group, it was not statistically significant. No adverse events were observed during the study period.Conclusion: The synthesis of the three conducted clinical studies collectively indicates that for children with bronchial pneumonia (Wind-heat Blocking the Lung), the basic clinical dose of MXSG may represents an optimal intervention dose based on the accumulated clinical experience of doctors. If the dose is insufficient, the clinical effects might be compromised, but using a higher dose does not significantly enhance benefits. Concerning different symptoms, increasing the overall formula’s dose has a favorable impact on improving phlegm congestion, increasing the SG is effective in improving symptoms such as fever, cough, and dyspnea, while higher dose of KXR is effective in alleviating cough and phlegm congestion. These findings suggest that for MXSG, achieving the optimal intervention dose is crucial to achieve better clinical efficacy. For the SG and KXR, if certain symptoms are more severe, increasing the dose can be considered within safe limits, can lead to significant clinical benefits in symptom improvement. This also explains why the dose of MXSG might vary among clinical doctors, while maintaining a balance between safety and effectiveness. Of course, our study is still exploratory clinical trials, and further studies are needed to confirm our findings.Clinical Trial Registration:https://www.chictr.org.cn/index.html; Identifier: ChiCTR-TRC-13003093, ChiCTR-TRC-13003099.

Facing towards the Carbon Neutrality goal by 2060, renewable energy sources are boosted in China in the past decade. Either these renewables or power systems are sensitive and vulnerable to natural disasters, such as wildfire and typhoon. In this paper, a fire spot identification algorithm is proposed for wildfire disaster occurred in transmission line corridors based on Fengyun-3E (FY-3E). It mitigates the effect of large observation of solar zenith angle, as well as changes of satellite views, on the infrared channel detection. And cloud information under complex atmospheric conditions is analyzed to extract the cloud pixel fire spot, which decreases false ratio of fire-spot alerts. According to the analysis of hybrid pixel linear spectrums, the fire-spot detection sensitivity of FY-3E is four times as that of geostationary meteorological satellites. The effectiveness of the proposed algorithm was confirmed by an application in the Shanxi province power grid of State Grid in China. It shows that and the FY-3E has a superiority in wildfire monitoring for power system in terms of fire detection sensitivity, spatial range accuracy, and positioning accuracy. Compared to geostationary meteorological satellites, the fire locating accuracy of FY-3E is increased by more than one-fold. This research can assist the operation and maintenance departments of transmission lines to rapidly detect wildfire, thereby reducing the damage of wildfires on the power grid.

Abstract Chromosomes occupy discrete spaces in the interphase cell nucleus, called chromosome territory. The structural and functional relevance of chromosome territory remains elusive. We fused chromosome 15 and 17 in mouse haploid embryonic stem cells (haESCs), resulting in distinct changes of territories in the cognate chromosomes, but with little effect on gene expression, pluripotency and gamete functions of haESCs. The karyotype-engineered haESCs were successfully implemented in generating heterozygous (2n = 39) and homozygous (2n = 38) mouse models. Mice containing the fusion chromosome are fertile, and their representative tissues and organs display no phenotypic abnormalities, suggesting unscathed development. These results indicate that the mammalian chromosome architectures are highly resilient, and reorganization of chromosome territories can be readily tolerated during cell differentiation and mouse development.

Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.

The complexity and strong spatial and temporal characteristics of municipal solid waste (MSW) have made resource utilization a major challenge in establishing the life-cycle model of MSW. Based on the planning of the domestic “dual-carbon” target and the current status of the structural transformation of resource utilization, this paper summarizes the physicochemical properties of MSW in China by component, species, and region. The aim is to identify the physicochemical components of MSW in different regions of China, drawing on the research findings of various scholars. A total of 159 sets of MSW data were collected, including 90 sets of physical composition and 69 sets of elemental composition. These data were used to calculate the calorific value of MSW and determine the energy-recovery and power-generation potentials before and after MSW classification. The analysis estimates the volume of MSW requiring removal in different regions of China in 2021 and assesses the effectiveness of the energy-recovery potential (ERP) and power-generation potential (PGP) before and after MSW classification in these regions. The aim is to offer insightful guidance and recommendations for municipal waste-treatment strategies tailored to the diverse regions of China.

Abstract Tumor‐associated macrophage (TAM) infiltration facilitates glioma malignancy, but the underlying mechanisms remain unclear. Herein, it is reported that TAMs secrete exosomal LINC01232 to induce tumor immune escape. Mechanistically, LINC01232 is found to directly bind E2F2 and promote E2F2 entry into the nucleus; the two synergistically promots the transcription of NBR1. The increase in binding between NBR1 binding and the ubiquitinating MHC‐I protein through the ubiquitin domain causes an increase in the degradation of MHC‐I in autophagolysosomes and a decrease in the expression of MHC‐I on the surface of tumor cells, which in turn led to tumor cell escape from CD8+ CTL immune attack. Disruption of E2F2/NBR1/MHC‐I signaling with shRNAs or blockade with the corresponding antibodies largely abolishes the tumor‐supportive effects of LINC01232 and inhibits tumor growth driven by M2‐type macrophages. Importantly, knockdown of LINC01232 enhances the expression of MHC‐I on the surface of tumor cells and improves the response to reinfusion with CD8+ T cells. This study reveals the existence of critical molecular crosstalk between TAMs and glioma mediates through the LINC01232/E2F2/NBR1/MHC‐I axis to support malignant tumor growth, indicating that targeting this axis may have therapeutic potential.

Cancer cells downregulate surface expression of major histocompatibility complex I (MHC-I) for immune evasion. Here, the authors show that rapid mitochondrial fission activates the ER-stress response leading to reduced MHC-I complex formation and cell surface expression in solid cancer cells; moreover inhibition of mitochondrial fission increases the immune-mediated anticancer response in murine models.

The acrosome is a membranous organelle positioned in the anterior portion of the sperm head and is essential for male fertility. Acrosome biogenesis requires the dynamic cytoskeletal shuttling of vesicles toward nascent acrosome which is regulated by a series of accessory proteins. However, much remains unknown about the molecular basis underlying this process. Here, we generated Ssh2 knockout (KO) mice and HA-tagged Ssh2 knock-in (KI) mice to define the functions of Slingshot phosphatase 2 (SSH2) in spermatogenesis and demonstrated that as a regulator of actin remodeling, SSH2 is essential for acrosome biogenesis and male fertility. In Ssh2 KO males, spermatogenesis was arrested at the early spermatid stage with increased apoptotic index and the impaired acrosome biogenesis was characterized by defective transport/fusion of proacrosomal vesicles. Moreover, disorganized F-actin structures accompanied by excessive phosphorylation of COFILIN were observed in the testes of Ssh2 KO mice. Collectively, our data reveal a modulatory role for SSH2 in acrosome biogenesis through COFILIN-mediated actin remodeling and the indispensability of this phosphatase in male fertility in mice.

Abstract Background RNA adenosine modifications, which are primarily mediated by “writer” enzymes (RMWs), play a key role in epigenetic regulation in various biological processes, including tumorigenesis. However, the expression and prognostic role of these genes in osteosarcoma (OS) remain unclear. Methods Univariate and multivariate Cox analyses were used to construct the RMW signature for OS using Target datasets. RMW expression in OS tissue was detected by qPCR analysis. Xcell and GSVA were used to determine the relationship between RMWs and immune infiltration. The DGIdb and CMap databases were used for drug prediction. In vivo and in vitro experiments showed that strophanthidin elicited antitumor activity against OS. Results A 3-RMW (CSTF2, ADAR and WTAP) prognostic signature in OS was constructed using the Target dataset and verified using GEO datasets and 63 independent OS tissues via qPCR analysis. High-risk OS patients had poor overall survival, and the prognostic signature was an independent prognostic factor for OS. Functional studies showed that tumour-, metabolism-, cell cycle- and immune-related pathways were related to high risk. Next, we found that RMW-derived high-risk patients exhibited increased infiltration of M2 macrophages and cDCs. Furthermore, we predicted the potential drugs for OS using the DGIdb and CMap databases. In vivo and in vitro experiments showed that strophanthidin elicited antitumor activity against OS by repressing cell growth and inducing cell cycle arrest at the G1 phase. Conclusion The 3-RWM-based prognostic signature established in this study is a novel gene signature associated with immune infiltration, and strophanthidin was identified as a candidate therapy for OS by repressing OS cell growth and the cell cycle.

In order to investigate the influence of different package materials on the flavor quality of cucumbers during postharvest storage at (13±2) ℃, three different treatments consisting of perforated polyethylene packaging bags 0.03 mm in thickness, perforated polyethylene 0.07 mm packaging bags in thickness and no package were evaluated. The volatile organic compounds (VOCs) in the cucumbers were analyzed by using chromatography-ion mobility spectrometry (GC-IMS), and multivariate analysis was then performed. The results showed that a total of 60 volatiles were identified in the cucumber samples, which could be generally classified into 2 hydrocarbons, 14 alcohols, 13 aldehydes, 13 ketones, 8 esters, 5 acids, 3 ethers, one pyrazine, and one furan compound. A clear separation between the experimental groups was achieved in the multivariate analysis. A panel of 19 volatile compounds with P 1 were suggested as potential markers for the discrimination of cucumbers treated with different packing materials, these 19 volatile compounds are acetone, 3-hydroxybutan-2-one, 3-pentanone, 2,3-butanedione, butanone, methyl isobutyl ketone, 2-pentanone, 2-hexanone, methylpropanal, butyraldehyde, butanal, pentanal, 3-methylbutanal, 1-propanol, 3-methyl-3-buten-1-ol, 2-methylbutan-1-ol, isobutanol, pentan-1-ol, 1-butanol, and ethyl acetate. During storage, the aldehydes of the main aroma of unpackaged cucumber decreased more obviously, and produced some ketones, esters, ethers, and other volatile metabolites, indicating that the loss of the unique aroma of cucumber in unpackaged was serious, while the aldehydes of the main aroma of cucumber in perforated passive modified atmosphere packaging decreased slowly, and the substances such as 3-hydroxy-2-butanone produced due to microbial growth increased less. Overall, perforated polyethylene 0.07 mm in thickness is recommended as a relatively efficient material to maintain the flavor quality of cucumbers. The findings were expected to facilitate the development and application of these package materials in the large-scale storage of cucumbers.

The application and development of a wide-area measurement system (WAMS) has enabled many applications and led to several requirements based on dynamic measurement data. Such data are transmitted as big data information flow. To ensure effective transmission of wide-frequency electrical information by the communication protocol of a WAMS, this study performs real-time traffic monitoring and analysis of the data network of a power information system, and establishes corresponding network optimization strategies to solve existing transmission problems. This study utilizes the traffic analysis results obtained using the current real-time dynamic monitoring system to design an optimization strategy, covering the optimization in three progressive levels: the underlying communication protocol, source data, and transmission process. Optimization of the system structure and scheduling optimization of data information are validated to be feasible and practical via tests.

CEP128 is a centrosomal protein important for the organization of centriolar microtubules. Here, the authors show that a CEP128 variant observed in human male siblings causes reduced sperm counts and morphologically abnormal sperm when modeled in mice, suggesting a role for CEP128 in male fertility.

Abstract Background Most of the microRNAs (MiRs) involved in myogenesis are transcriptional regulated. The role of MiR biogenesis in myogenesis has not been characterized yet. RNA‐binding protein Musashi 2 (Msi2) is considered to be one of the major drivers for oncogenesis and stem cell proliferation. The functions of Msi2 in myogenesis have not been explored yet. We sought to investigate Msi2‐regulated biogenesis of MiRs in myogenesis and muscle stem cell (MuSC) ageing. Methods We detected the expression of Msi2 in MuSCs and differentiated myotubes by quantitative reverse transcription PCR (RT‐qPCR) and western blot. Msi2‐binding partner human antigen R (HuR) was identified by immunoprecipitation followed by mass spectrometry analysis. The cooperative binding of Msi2 and HuR on MiR7a‐1 was analysed by RNA immunoprecipitation and electrophoresis mobility shift assays. The inhibition of the processing of pri‐MiR7a‐1 mediated by Msi2 and HuR was shown by Msi2 and HuR knockdown. Immunofluorescent staining, RT‐qPCR and immunoblotting were used to characterize the function of MiR7a‐1 in myogenesis. Msi2 and HuR up‐regulate cryptochrome circadian regulator 2 (Cry2) via MiR7a‐1 was confirmed by the luciferase assay and western blot. The post‐transcriptional regulatory cascade was further confirmed by RNAi and overexpressing of Msi2 and HuR in MuSCs, and the in vivo function was characterized by histopathological and molecular biological methods in Msi2 knockout mice. Results We identified a post‐transcription regulatory cascade governed by a pair of RNA‐binding proteins Msi2 and HuR. Msi2 is enriched in differentiated muscle cells and promotes MuSC differentiation despite its pro‐proliferation functions in other cell types. Msi2 works synergistically with another RNA‐binding protein HuR to repress the biogenesis of MiR7a‐1 in an Msi2 dose‐dependent manner to regulate the translation of the key component of the circadian core oscillator complex Cry2. Down‐regulation of Cry2 (0.6‐fold, vs. control, P

Abstract Background Exosomes secreted from stem cells exerted salutary effects on the fibrotic liver. Herein, the roles of exosomes derived from human embryonic stem cell (hESC) in anti-fibrosis were extensively investigated. Compared with two-dimensional (2D) culture, the clinical and biological relevance of three-dimensional (3D) cell spheroids were greater because of their higher regeneration potential since they behave more like cells in vivo. In our study, exosomes derived from 3D human embryonic stem cells (hESC) spheroids and the monolayer (2D) hESCs were collected and compared the therapeutic potential for fibrotic liver in vitro and in vivo. Results In vitro, PKH26 labeled-hESC-Exosomes were shown to be internalized and integrated into TGFβ-activated-LX2 cells, and reduced the expression of profibrogenic markers, thereby regulating cellular phenotypes. TPEF imaging indicated that PKH26-labeled-3D-hESC-Exsomes possessed an enhanced capacity to accumulate in the livers and exhibited more dramatic therapeutic potential in the injured livers of fibrosis mouse model. 3D-hESC-Exosomes decreased profibrogenic markers and liver injury markers, and improved the level of liver functioning proteins, eventually restoring liver function of fibrosis mice. miRNA array revealed a significant enrichment of miR-6766-3p in 3D-hESC-Exosomes, moreover, bioinformatics and dual luciferase reporter assay identified and confirmed the TGFβRII gene as the target of miR-6766-3p. Furthermore, the delivery of miR-6766-3p into activated-LX2 cells decreased cell proliferation, chemotaxis and profibrotic effects, and further investigation demonstrated that the expression of target gene TGFβRII and its downstream SMADs proteins, especially phosphorylated protein p-SMAD2/3 was also notably down-regulated by miR-6766-3p. These findings unveiled that miR-6766-3p in 3D-hESC-Exosomes inactivated SMADs signaling by inhibiting TGFβRII expression, consequently attenuating stellate cell activation and suppressing liver fibrosis. Conclusions Our results showed that miR-6766-3p in the 3D-hESC-Exosomes inactivates smads signaling by restraining TGFβRII expression, attenuated LX2 cell activation and suppressed liver fibrosis, suggesting that 3D-hESC-Exosome enriched-miR-6766-3p is a novel anti-fibrotic therapeutics for treating chronic liver disease. These results also proposed a significant strategy that 3D-Exo could be used as natural nanoparticles to rescue liver injury via delivering antifibrotic miR-6766-3p. Graphical Abstract

The solid-state fermentation process of strongly flavored Baijiu is complicated by the co-fermentation of many different microorganisms in the fermentation pools. The traditional fermentation pools of strong flavor Baijiu are sealed with mud, and this sealed-pit mud is not easy to maintain; therefore, the pit cap is prone to cracks and to caving in. The destruction of the sealed-pit mud may lead to instability in the composition and an abundance of microorganisms in the fermentation process that results in fluctuations of product quality. Thus, the production method of replacing the mud cap with a new steel cap is gradually attracting the attention of scientific and technical workers in the industry. However, so far, there have been relatively few reports on the use of steel lids for sealing pits for fermentation and brewing. In this study, the volatile flavor components of 270 Baijiu samples from mud-sealing and steel-sealing pits of a Chinese Baijiu distillery were studied qualitatively and quantitatively using Gas Chromatography–Mass Spectrometry (Abbreviated as GC-MS). Our statistical methods included Hierarchical Cluster Analysis (Abbreviated as HCA), Principal Component Analysis (Abbreviated as PCA), and Discriminant Analysis (Abbreviated as DA). A statistical analysis was carried out on the yield of strongly flavored Baijiu, and we made a comprehensive evaluation of the Baijiu produced under the two pit-sealing modes with regard to flavor and economic efficiency. The yield of strong flavored Baijiu was 6.7% higher with steel-sealing pits compared with mud-sealing pits. Cluster analysis categorized the strongly flavored Baijiu samples into two categories initially: (1) samples produced using mud-sealing pits and (2) samples using steel-sealing pits. Our analysis also indicated that the 28 compounds used for quantification were selected correctly. Surprising to the experimental staff, the overall score for the steel-sealing pits was greater than that of the mud-sealing pits based on PCA. Using DA, the prediction results were 100% accurate. In summary, through a comparative analysis of the flavor and yield, which are the two main factors that affect the quality of Baijiu in a distillery, and systematic combination at both experimental and theoretical levels, the differences between the Baijiu production by steel-sealing and the traditional mud-sealing were clear. Regardless of the impact of age, the detectable flavor components of Baijiu from the mud-steeling pits were very consistent with those of the steel-sealing pits in terms of richness or concentration. However, steel-sealing pits were significantly superior to mud-sealing pits with respect to output, consistency in quality, and cost (human and economic) savings.

MeCP2 mutations can cause Rett syndrome, a severe childhood neurological disorder. Here the authors show that MeCP2 mediates the higher-order assembly of a large splicing complex Rbfox/LASR, which is disrupted in the mouse models of Rett syndrome.

Application of adenine base editors (ABE) has been precluded by low activity. Here the authors show the generation of a human cell based ABE directional screening system and identification of ABE variant (NG-ABEmax-KR) exhibiting a significant increase in activity for human and mouse genome manipulation.

Abstract Sensory nerves are long being recognized as collecting units of various outer stimuli; recent advances indicate that the sensory nerve also plays pivotal roles in maintaining organ homeostasis. Here, this study shows that sensory nerve orchestrates intervertebral disc (IVD) homeostasis by regulating its extracellular matrix (ECM) metabolism. Specifically, genetical sensory denervation of IVD results in loss of IVD water preserve molecule chondroitin sulfate (CS), the reduction of CS bio‐synthesis gene chondroitin sulfate synthase 1 (CHSY1) expression, and dysregulated ECM homeostasis of IVD. Particularly, knockdown of sensory neuros calcitonin gene‐related peptide (CGRP) expression induces similar ECM metabolic disorder compared to sensory nerve denervation model, and this effect is abolished in CHSY1 knockout mice. Furthermore, in vitro evidence shows that CGRP regulates nucleus pulposus cell CHSY1 expression and CS synthesis via CGRP receptor component receptor activity‐modifying protein 1 (RAMP1) and cyclic AMP response element‐binding protein (CREB) signaling. Therapeutically, local injection of forskolin significantly attenuates IVD degeneration progression in mouse annulus fibrosus puncture model. Overall, these results indicate that sensory nerve maintains IVD ECM homeostasis via CGRP/CHSY1 axis and promotes IVD repair, and this expands the understanding concerning how IVD links to sensory nerve system, thus shedding light on future development of novel therapeutical strategy to IVD degeneration.

Quantitative measuring the population-level diversity-scaling of human microbiomes is different from conventional approach to traditional individual-level diversity analysis, and it is of obvious significance. For example, it is well known that individuals are of significant heterogeneity with their microbiome diversities, and the population-level analysis can effectively capture such kind of individual differences. Here we reanalyze a dozen datasets of 2,115 human breast milk microbiome (BMM) samples with diversity-area relationship (DAR) to tackle the previous questions. Our focus on BMM is aimed to offer insights for supplementing the gut microbiome research from nutritional perspective. DAR is an extension to classic species-area relationship, which was discovered in the 19th century and established as one of a handful fundamental laws in community ecology. Our DAR modeling revealed the following numbers, all approximately: (i) The population-level potential diversity of BMM is 1,108 in terms of species richness (number of total species), and 67 in terms of typical species. (ii) On average, an individual carry 17% of population-level diversity in terms of species richness, and 61% in terms of typical species. (iii) The similarity (overlap) between individuals according to pair-wise diversity overlap (PDO) should be approximately 76% in terms of total species, and 92% in terms of typical species, which symbolizes the inter-individual heterogeneity. (iv) The average individual (alpha-) diversity of BMM is approximately 188 (total-species) and 37 (typical-species). (v) To deal with the potential difference among 12 BMM datasets, we conducted DAR modeling separately for each dataset, and then performed permutation tests for DAR parameters. It was found that the DAR scaling parameter that measures inter-individual heterogeneity in diversity is invariant (constant), but the population potential diversity is different among 30% of the pair-wise comparison between 12 BMM datasets. These results offer comprehensive biodiversity analyses of the BMM from host individual, inter-individual, and population level perspectives.

Background: As one of the most commonly used Chinese medicine formula in the manage of respiratory diseases, Maxing Ganshi Decoction (MGD) has been demonstrated to improve the clinical symptoms of pneumonia. To evaluate the efficacy and safety of MGD in treating children with community-acquired pneumonia (CAP), we conducted the clinical trial.Methods: A randomized, double-blind, placebo-controlled, multicenter trial was conducted in 3 study sites in Tianjin, China. MDG or placebo were randomly given to patients aged 3–6 years with onset of CAP within 48 h. Changes in disease efficacy during the study period (which was measured as recovery, significant effect, improvement and no effect) was evaluated as the primary outcome. Time from enrollment to fever resolution was assessed as the secondary outcome. The adverse event was analyzed as safety evaluation.Results: A total of 71 patients (36 in MGD and 35 in placebo) were randomized and completed the whole study. The patient demographics and other characteristics at baseline were similar between the 2 groups (p > 0.05). After 10 days of intervention, the proportion of recovered and significant effective patients was increased significantly in the MGD group (34.85% [95% CI, 12.44%–57.26%]; p < 0.05) compared with the control group. Besides, the symptom score of the MGD group was lowered significantly (p < 0.001). The estimated time to fever resolution in the MGD group was also reduced compared with the control group (p < 0.05). During the whole study, no side effects were observed in both MGD and control groups.Conclusion: MGD was effective in improving disease efficacy, clinical symptoms and reducing time to fever resolution in patients with childhood CAP, which suggested that MGD may be used as an alternative therapy in the treatment of childhood CAP.Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=5612, identifier 13003955.

Study DesignBibliometric analysis.ObjectiveAnterior cervical discectomy and fusion (ACDF) is a typical surgical method in spine surgery and has progressed significantly in the last several decades. The purpose of this study is to determine how the 100 most-cited original articles on ACDF have been the most influential in this field by identifying and analyzing them.MethodsThe articles on ACDF were identified by searching the Thomson ISI Web of Science database on 30 May 2022. The 100 most-cited articles were selected according to specific criteria. The data extracted from the articles included title, publication date, total citations, journal name, first author, institutions, and keywords.ResultsThe total number of citations was 13,181, with a mean number of 131.81 ± 100.18. The publication dates ranged from 1994 to 2018. Most of these articles originated in the United States (68%) and were published in the 2000s (32%) and 2010s (48%). Spine published most of the articles (30%), followed by the Journal of Neurosurgery-Spine (16%), Spine Journal (14%), and European Spine Journal (13%). The most prolific author was Dr. Todd J Albert (n = 7), with 1,312 citations. The Texas Back Institute was the most productive institution (n = 10). The keywords ACDF, cervical spine, cervical spine, and fusion showed the highest degree of centrality.ConclusionOne hundred top-cited articles on ACDF were identified and analyzed in this study. We demonstrate that ACDF is a growing and popular area of research, with the focus of research varying through timeline trends. This will provide a comprehensive and detailed basis for spine surgeons to make clinical decisions and assimilate the research focus of cervical spine surgery.

Abstract Background Protein C receptor (Procr) has recently been shown to mark resident adult stem cells in the mammary gland, vascular system, and pancreatic islets. More so, high Procr expression was also detected and used as indicator for subsets of triple-negative breast cancers (TNBCs). Previous study has revealed Procr as a target of Wnt/β-catenin signaling; however, direct upstream regulatory mechanism of Procr remains unknown. To comprehend the molecular role of Procr during physiology and pathology, elucidating the upstream effectors of Procr is necessary. Here, we provide a system for screening negative regulators of Procr, which could be adapted for broad molecular analysis on membrane proteins. Results We established a screening system which combines CRISPR-Cas9 guided gene disruption with fluorescence activated cell sorting technique (FACS). CommaDβ (murine epithelial cells line) was used for the initial Procr upstream effector screening using lentiviral CRISPR-gRNA library. Shortlisted genes were further validated through individual lentiviral gRNA infection followed by Procr expression evaluation. Adam17 was identified as a specific negative inhibitor of Procr expression. In addition, MDA-MB-231 cells and Hs578T cells (human breast cancer cell lines) were used to verify the conserved regulation of ADAM17 over PROCR expression. Conclusion We established an efficient CRISPR-Cas9/FACS screening system, which identifies the regulators of membrane proteins. Through this system, we identified Adam17 as the negative regulator of Procr membrane expression both in mammary epithelial cells and breast cancer cells.

Past research illustrated that leaders could restrict followers’ deviance by reinforcing social norms of appropriate behaviors. Nevertheless, we submit that this understanding is incomplete without considering the effects of leaders on followers’ self-sanctions given that most undesirable behaviors are controlled internally. This research argues that interactional justice is an effective strategy for leaders to enhance followers’ self-sanctions. Leaders’ interactional justice provides personalized information and dyadic treatment that indirectly reduce employees’ deviance by restraining followers’ moral disengagement. Besides, this study examines the social sanction role of ethical leadership. Ethical leaders highlight the importance of adherence to collective norms, which influence the relationship between followers’ moral disengagement and deviance. By identifying the different pathways via which they influence followers’ moral disengagement, we integrate interactional justice and ethical leadership into one theoretical framework. Our predictions are supported by data analyses of 220 samples from a multi-wave and -source field study. This integrative framework contributes to a comprehensive understanding of how leaders restrict employees’ deviance.

Telomeres attach to the nuclear envelope to facilitate homolog pairing during meiosis prophase I. Here, the authors show that SUN1 and SPDYA interact, and demonstrate that this interaction is important for telomere structure and function, and essential to mice gametogenesis.

ObjectiveTo investigate whether TCF7+ T cells constitute an important factor to improve the existing postoperative prediction model for patients with oral squamous cell carcinoma.MethodTCF7+ T cells were detected in the tissues of 167 OSCC patients by multiplex immunofluorescence. The percentage of TCF7+ T cells was transformed into a dichotomous variable, combined with the clinicopathological data for the OSCC patients, and then subjected to univariate and multivariate analyses. The derived independent predictors were then incorporated into risk models to analyze their relationship with the prognosis of patients.ResultsThe high TCF7+ group had a better prognosis than the low TCF7+ group (OS: p

BackgroundAn innovative prone cervical spine surgical position using a body-shape plaster bed with skull traction (BSPST) was compared with the traditional prone surgical position with horseshoe headrests.MethodsA total of 47 patients, undergoing posterior cervical spine surgery for cervical spine fracture, were retrospectively classified into two groups, the BSPST group (n = 24) and the traditional group (n = 23), and underwent a posterior instrumented fusion with or without decompression. Multiple indicators were used to evaluate the advantages of the BSPST compared with the traditional position.ResultsAll the operations went smoothly. The mean recovery rate was 56.30% in the BSPST group and 48.55% in the traditional group (p = 0.454), with no significant difference. The intraoperative blood loss (177.5 ml vs. 439.1 ml, p = 0.003) and the total incidence of complications (8.3 vs. 47.8%, p = 0.004) were significantly less in the BSPST group than in the traditional group. In addition, the BSPST position provided a greater comfort level for the operators and allowed convenient intraoperative radiography.ConclusionsThis is the first study to describe a combined body-shape plaster bed and skull traction as an innovative cervical spine-prone surgical position that is simple, safe, and stable, intraoperative traction direction adjustable, reproducible, and economical for posterior cervical spine fracture surgery, and potentially other cervical and upper dorsal spine surgeries in the prone position. Additionally, this position provides the surgeons with a comfortable surgical field and can be easily achieved in most orthopedic operation rooms.