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Abstract Organoid technology provides a transformative approach to understand human physiology and pathology, offering valuable insights for scientific research and therapeutic development. Human gastric organoids, in particular, have gained significant interest for applications in disease modeling, drug discovery, and studies of tissue regeneration and homeostasis. However, the lack of standardized quality control has limited their extensive clinical applications. The “Human Gastric Organoids” is part of a series of guidelines for human gastric organoids in China, which establishes comprehensive standards on terminology, technical specifications, testing methods, inspection rules, usage instructions, labeling, transportation, and storage, developed by experts from the Chinese Society for Cell Biology and its branch societies. Released on October 29, 2024, this guideline aims to establish standardized protocols, enhance institutional practices, and promote international standardization for clinical and research applications of human gastric organoids.

Abstract Gastric cancer is one of the most common malignancies with poor prognosis. The use of organoids to simulate gastric cancer has rapidly developed over the past several years. Patient-derived gastric cancer organoids serve as in vitro models that closely mimics donor characteristics, offering new opportunities for both basic and applied research. The “Human Gastric Cancer Organoid” is part of a series of guidelines for human gastric cancer organoids in China, jointly drafted by experts from the Chinese Society for Cell Biology and its branches, and initially released on October 29, 2024. This standard outlines terminology, technical requirements, assessment protocols, and applies to production, evaluation procedures, and quality control for human gastric cancer organoids. The publication of this guideline aims to assist institutions in endorsing, establishing, and applying best practices, advancing the international standardization of human gastric cancer organoids for clinical development and therapeutic application.

Abstract The intestine, is responsible for food digestion, nutrient absorption, endocrine secretion, food residue excretion, and immune defense. These function performances are based on the intricate composition of intestinal epithelial cells, encompassing differentiated mature cells, rapidly proliferative cells, and intestinal stem cells. Although the characteristics of these cell types are well-documented, in-depth exploration of their representative markers and transcription factors is critical for comprehensive cell fate trajectory analysis. Here, we unveiled the feature genes in different cell types of the human and mouse gut through single-cell RNA sequencing analysis. Further, the locations of some specific transcription factors and membrane proteins were determined by immunofluorescence staining, and their role in regulating the proliferation and differentiation of intestinal epithelial cells were explored by CRISPR/Cas9 knockout. Therefore, this study not only reports new markers for various intestinal epithelial cell types but also elucidates the involvement of relevant genes in the determination of epithelial cell fate and maintenance of stem cell homeostasis, which facilitates the tracing and functional elucidation of intestinal epithelial cells.

Abstract The occurrence of multiple primary lung cancer (MPLC) has witnessed a significant surge in recent years within the Chinese population. MPLC is distinguished by its potential genetic susceptibility and notable genetic heterogeneity. Investigating the etiology of MPLC holds substantial clinical importance.The whole genome sequencing (WGS) and genome-wide linkage analysis were performed in a family affected by a dominant form of lung abnormalities. Specifically, five family members were diagnosed with MPLC, while nine members had pulmonary nodules and one normal member. To confirm the potential pathogenic germline mutations sites, Sanger sequencing was performed in an additional 162 MPLC family patients. Furthermore, molecular biology experiments were conducted to investigate the function and the mechanism of the identified pathogenic mutation site in lung cancer A549 and H322, both in vitro and in vivo. Linkage analysis revealed the presence of shared genomic regions among affected family members. Subsequent exome sequencing identified a deleterious variant within these linkage intervals, specifically a heterozygous mutation in ETS-oncogene transcription factors 4 (ETV4). This particular variant was found in affected family members at a rate of 13 out of 15 individuals. Furthermore, ETV4 P433L mutation could be detected in an additional MPLC family patients and mutation frequency was 3.7% (6 out of 162). The ETV4 P433L mutations site was introduced into lung cancer cell lines, resulting in altered migration and stem-like properties of the cancer cells. Further investigation revealed that the activation of the Wnt/β-catenin signaling pathway, which is associated with stemness, could be attributed to the presence of the ETV4 P433L mutation, suggesting its involvement in tumor promotion. A novel pathogenic germline mutation, ETV4 P433L, was identified in a dominant MPLC family, with a mutation rate of 3.7% among MPLC family patients. The ETV4 P433L mutation was found to impact the stem-like properties and migration of tumors through Wnt/β-catenin signaling pathway.

Abstract Introduction The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. Method We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. Results In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P

Summary: Glycine- and arginine-rich (GAR) motifs, commonly found in RNA-binding and -processing proteins, can be symmetrically (SDMA) or asymmetrically (ADMA) dimethylated at the arginine residue by protein arginine methyltransferases. Arginine-methylated protein motifs are usually read by Tudor domain-containing proteins. Here, using a GFP-Trap, we identify a non-Tudor domain protein, squamous cell carcinoma antigen recognized by T cells 3 (SART3), as a reader for SDMA-marked GAR motifs. Structural analysis and mutagenesis of SART3 show that aromatic residues lining a groove between two adjacent aromatic-rich half-a-tetratricopeptide (HAT) repeat domains are essential for SART3 to recognize and bind to SDMA-marked GAR motif peptides, as well as for the interaction between SART3 and the GAR-motif-containing proteins fibrillarin and coilin. Further, we show that the loss of this reader ability affects RNA splicing. Overall, our findings broaden the range of potential SDMA readers to include HAT domains.

In this study, the effects of laser power on the microstructure and mechanical properties of Inconel 718 formed by SLM were systematically studied. The results show that with the increase in laser power from 285 W to 360 W, the increase in working temperature in the molten pool promoted the evaporation of gas and the vaporization of the low-melting-point alloy components, and the relative density gradually increased from 99.31% to 99.79%. In addition, with the increase in laser energy density, the microstructure gradually coarsened from columnar dendrites to cellular crystals. The nano-hardness of the material decreased with the increase in laser power. The nano-hardness of four groups of samples from 285 W to 360 W decreased form 3.43 GPa to 2.09 GPa, and the elastic modulus decreased form 205.72 GPa to 199.91 GPa.

Abstract As an important part of the stomach, gastric antrum secretes gastrin which can regulate acid secretion and gastric emptying. Although most cell types in the gastric antrum are identified, the comparison of cell composition and gene expression in the gastric antrum among different species are not explored. In this study, we collected antrum epithelial tissues from human, pig, rat and mouse for scRNA-seq and compared cell types and gene expression among species. In pig antral epithelium, we identified a novel cell cluster, which is marked by high expression of AQP5, F3, CLCA1 and RRAD. We also discovered that the porcine antral epithelium has stronger immune function than the other species. Further analysis revealed that this may be due to the insufficient function of porcine immune cells. Together, our results replenish the information of multiple species of gastric antral epithelium at the single cell level and provide resources for understanding the homeostasis maintenance and regeneration of gastric antrum epithelium.

Abstract Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.

Abstract Organoids have attracted great interest for disease modelling, drug discovery and development, and tissue growth and homeostasis investigations. However, lack of standards for quality control has become a prominent obstacle to limit their translation into clinic and other applications. “Human intestinal organoids” is the first guideline on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods, inspection rules for human intestinal organoids, which is applicable to quality control during the process of manufacturing and testing of human intestinal organoids. It was originally released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of human intestinal organoids for applications.

Abstract Intestinal cancer is one of the most frequent and lethal types of cancer. Modeling intestinal cancer using organoids has emerged in the last decade. Human intestinal cancer organoids are physiologically relevant in vitro models, which provides an unprecedented opportunity for fundamental and applied research in colorectal cancer. “Human intestinal cancer organoids” is the first set of guidelines on human intestinal organoids in China, jointly drafted and agreed by the experts from the Chinese Society for Cell Biology and its branch society: the Chinese Society for Stem Cell Research. This standard specifies terms and definitions, technical requirements, test methods for human intestinal cancer organoids, which apply to the production and quality control during the process of manufacturing and testing of human intestinal cancer organoids. It was released by the Chinese Society for Cell Biology on 24 September 2022. We hope that the publication of this standard will guide institutional establishment, acceptance and execution of proper practocal protocols, and accelerate the international standardization of human intestinal cancer organoids for clinical development and therapeutic applications.

Fluorescent probes, typically based on the intramolecular charge transfer (ICT) mechanism, have received considerable research attention in cell detection due to their non-invasiveness, fast response, easy regulation, high sensitivity, and low damage tolerance for in vivo bio-samples. Generally, intracellular pH and biological species such as various gases, metal ions, and anions constitute the foundation of cells and participate in the basic physiological processes, whose abnormal level can lead to poisoning, cardiovascular disease, and cancer in living organisms. Therefore, monitoring of their quantity plays an essential role in understanding the status of organisms and preventing, diagnosing, and treating diseases. In the last decades, remarkable progress has been made in developing ICT probes for the detection of biological elements. In this review, we highlight the recent ICT probes focusing primarily on the detection of intracellular pH, various gases (H2S, CO, H2O2, and NO), metal ions (Cu2+, Hg2+, Pb2+, Zn2+, and Al3+), and anions (ClO−, CN−, SO32−, and F−). In addition, we discuss the issues and limitations of ICT-based fluorescent probes for in vivo detection and explore the clinical translational potential and challenges of these materials, providing valuable guidance and insights for the design of fluorescent materials.

This study aims to present the optimum technological parameters of the hot forging process of aerospace bolts. Deformation-related parameters were determined according to the relevant conditions for commercial production of bolts. Deformation behavior and evolution of the microstructure of Waspaloy were systematically studied at temperature in the range of 1000–1120 °C and strain rate in the range of 0.01–10 s−1. The obtained results revealed the sensitivity of the flow stresses to the deformation parameters and stresses increased when deformed at lower temperatures or higher strain rates. At the high strain rates of 5–10 s−1, the flow curves exhibited a pronounced flow softening. The curves demonstrated a dynamic equilibrium at the low strain rates of 0.01–0.1 s−1. A constituent model of Waspaloy was established to describe the flow characteristic of Waspaloy. The microstructures showed that the grain refinement of DRX at low temperature (1000–1040 °C) was the main mechanism for microstructural evolution, while the grain growth kinetic was the dominant mechanism at high temperature (1080–1120 °C). The DRX kinetic model of this superalloy was established. Also, the constitutive and dynamic recrystallization models were used in the Deform-3D software for validation. The obtained results revealed that the simulation results matched well with the experimental results of grain sizes at different regions of the bolt specimens. The study can provide guidance to optimize technological parameters and predict the microstructure for commercial bolt forging.

Abstract Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by multiple genetic and environmental factors. Numerous genes are implicated in the etiology of IBD, but the diagnosis of IBD is challenging. Here, XGBoost, a machine learning prediction model, has been used to distinguish IBD from healthy cases following elaborative feature selection. Using combined unsupervised clustering analysis and the XGBoost feature selection method, we successfully identified a 32-gene signature that can predict IBD occurrence in new cohorts with 0.8651 accuracy. The signature shows enrichment in neutrophil extracellular trap formation and cytokine signaling in the immune system. The probability threshold of the XGBoost-based classification model can be adjusted to fit personalized lifestyle and health status. Therefore, this study reveals potential IBD-related biomarkers that facilitate an effective personalized diagnosis of IBD.

Occupational health risk assessments of exposure to VOCs still need to be extensively studied to improve the safety standards in the industry. Based on the monitoring of organic pollutants at various workstations in a truck tire factory in Jiangsu Province, both semi-quantitative and quantitative health risk assessment methods were employed to assess health risk levels. The findings indicated that VOCs were categorized into five classes, which included alkanes, aromatics, halocarbons, carbon disulfide, and oxygenated volatile organic compounds (OVOCs). The highest concentration of total volatile organic compounds (TVOCs) was found in shaping workshop; alkanes were the most abundant class (74.2%), followed by aromatics (24.02%) and OVOCs (1.96%). Although the results of the semi-quantitative risk assessment showed that most of the organic compounds had low R values, various kinds of VOCs were detected; particularly, many harmful organic compounds (such as toluene, ethyl benzene) were detected in all the sampling sites. The quantitative risk in the calendering and vulcanizing workshop exceeded the acceptable level; both the carcinogenic risk of ethylbenzene in the tire-strip storage room, and trichloroethylene and perchloroethylene in the calendering workshop were unacceptable. Thus, the calendering and vulcanizing processes in rubber tire manufacturing should be priority-controlled processes.

The poor prognosis of triple negative breast cancer (TNBC) results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis, which is associated with high recurrence and short overall survival. Here we developed a strategy by employing tumor-targeted self-assembled nanoparticles to coordinately regulate BACH1 (BTB domain and CNC homology 1) and mitochondrial metabolism. The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative (BD) were used to prepare nanoparticles (BH NPs) followed by the modification of chondroitin sulfate (CS) on the surface of BH NPs to achieve tumor targeting (CS/BH NPs). CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites, glycolysis and metastasis-associated proteins, which were related to the inhibition of BACH1 function. Meanwhile, decreased mitochondrial membrane potential, activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism. In a xenograft mice model of breast cancer, CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs. In sum, the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.

Abstract The intestinal epithelium is responsible for food digestion and nutrient absorption and plays a critical role in hormone secretion, microorganism defense, and immune response. These functions depend on the integral single-layered intestinal epithelium, which shows diversified cell constitution and rapid self-renewal and presents powerful regeneration plasticity after injury. Derailment of homeostasis of the intestine epithelium leads to the development of diseases, most commonly including enteritis and colorectal cancer. Therefore, it is important to understand the cellular characterization of the intestinal epithelium at the molecular level and the mechanisms underlying its homeostatic maintenance. Single-cell technologies allow us to gain molecular insights at the single-cell level. In this review, we summarize the single-cell RNA sequencing applications to understand intestinal cell characteristics, spatiotemporal evolution, and intestinal disease development.

The SMN protein recognizes symmetric dimethylarginine by its Tudor domain, and SMN deficiency leads to spinal muscular atrophy. Here, Liu et al. discover a small molecule that binds to the SMN Tudor domain and disrupts the interaction between SMN and RNA Polymerase II.

Abstract Transforming growth factor beta (TGF‐β), a multifunctional cytokine, plays critical roles in immune responses. However, the precise role of TGF‐β in colitis and colitis‐associated cancer remains poorly defined. Here, it is demonstrated that TGF‐β promotes the colonic inflammation and related tumorigenesis in the absence of Smad family member 4 (Smad4). Smad4 loss in intestinal epithelium aggravates colitis and colitis‐associated neoplasia induced by dextran sulfate sodium (DSS) and azoxymethane/dextran sulfate sodium (AOM/DSS), leading to over‐activated immune responses and increased TGF‐β1 levels. In Smad4‐deficient organoids, TGF‐β1 stimulates spheroid formation and impairs intestinal stem cell proliferation and lineage specification. YAP, whose expression is directly upregulated by TGF‐β1 after Smad4 deletion, mediates the effect of TGF‐β1 by interacting with Smad2/3. Attenuation of YAP/TAZ prevents TGF‐β1‐induced spheroid formation in Smad4−/– organoids and alleviates colitis and colitis‐associated cancer in Smad4‐deficient mice. Collectively, these results highlight an integral role of the TGF‐β/Smad4 axis in restraining intestinal inflammation and tumorigenesis and suggest TGF‐β or YAP signaling as therapeutic targets for these gastrointestinal diseases intervention.

Healive® was the only Chinese WHO-prequalified inactivated vaccine for the hepatitis A virus, which has been widely used in national immunization programs in China. Long-term follow-up studies are needed to estimate the persistence of vaccine-induced antibody levels and the necessity for booster vaccines. During the trial, geometric mean concentrations (GMCs) and seroconversion rates (SRs) of anti-HAV antibodies were compared based on two different inactivated hepatitis A vaccines, Healive® and Havrix®. Four hundred children were randomly assigned to receive two doses of Healive® or Havrix® at 0 and 6 months. The current study assessed antibody persistence for both vaccines 15 years post-immunization. A mixed linear model was used to predict long-term antibody persistence. The GMCs were significantly higher for Healive® compared to Havrix® at 1, 6, 7, 66, 138 months (P

Abstract Animal models are widely used for biomedical studies and drug evaluation. The small intestine plays key roles in nutrient absorption, hormone secretion, microbiota defense and drug absorption and metabolism. Although the intestinal structure of mammals is conserved, the differences on epithelial cell composition, functional assignments and drug absorption among mammals are largely unknown. Here, cross-species analysis of single-cell transcriptomic atlas of the ileum epithelium from mouse, rat, pig, macaque and human reveals the conserved and differential cell types and functions among species, identifies a new CA7+ cell type in pig, macaque and human ileum, uncovers the distinct expression pattern in enterocytes, enteroendocrine cells and Paneth cells, and defines the conserved and species-specific intestinal stem cell signature genes. The examination of drug absorption across species suggests that drug metabolism in mouse ileum is closer to human while drug transport in macaque ileum is more similar to human. Together, our data provide the comprehensive information about cell composition and functional assignments in five species, and offer the valuable guidance for animal model selection and drug testing.

Summary: The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation and xenograft tumor growth. High PRMT1 protein expression is associated with elevated mTORC1 signaling in patients with HCC. Thus, our study dissects a phosphorylation- and arginine methylation-dependent regulatory mechanism of mTORC1 activation and tumor growth and provides a molecular basis to target this pathway for cancer therapy.

The sequence determinants governing CRISPR/Cas9 specificity are not fully understood. Here, the authors devise a high-throughput dual-target synthetic system to explore the sequence features associated with CRISPR/Cas9 off-target effect, reveal a set of sequence-dependent rules, and develop an off-target prediction model and a strategy for Cas9-based allele-specific editing.

Fluorescent materials have great potential for use in biomedical applications due to their ease of functionalization and tunable fluorescence color [...]

Abstract Pig and monkey are widely used models for exploration of human diseases and evaluation of drug efficiency and toxicity, but high cost limits their uses. Organoids have been shown to be promising models for drug test as they reasonably preserve tissue structure and functions. However, colonic organoids of pig and monkey are not yet established. Here, we report a culture medium to support the growth of porcine and monkey colonic organoids. Wnt signaling and PGE2 are important for long-term expansion of the organoids, and their withdrawal results in lineage differentiation to mature cells. Furthermore, we observe that porcine colonic organoids are closer to human colonic organoids in terms of drug toxicity response. Successful establishment of porcine and monkey colonic organoids would facilitate the mechanistic investigation of the homeostatic regulation of the intestine of these animals and is useful for drug development and toxicity studies.

Perioperative immune function, postoperative cognitive function and prognosis are momentous issues for patients undergoing digestive tract cancer surgery. Studies have investigated the efficacy of dexmedetomidine (DEX) administration on these issues, but the results are inconsistent. Therefore, this meta-analysis aimed to summarize all the existing evidence and draw a conclusion more accurately on these associations. Trials were located through electronic searches of the PubMed, Embase, the Cochrane Library and Web of Science databases sources (from the establishment date of databases to April 2022). Bibliographies of the retrieved articles were checked. A total of 17 RCTs involving 1619 patients were included. The results showed that DEX decreased the level of C-reactive protein (SMD = -4.26, 95%CI: -6.16, -2.36), TNF-α (SMD = -4.22, 95%CI: -5.91, -2.54) and IL-6 (SMD = -2.71, 95%CI: -4.46, -0.97), and increased the level of IL-10 (SMD = 1.74, 95%CI: 0.25, 3.24). DEX also increased CD4+ T cells (SMD = 0.55, 95%CI: 0.29, 0.82) and CD4+/CD8+ ratio (SMD = 0.62, 95%CI: 0.24, 1.01). Thus, DEX was associated with alleviation of postoperative systemic inflammatory response and immune dysfunction. Furthermore, DEX increased mini-mental state examination scores at 12h (SMD = 1.10, 95%CI: 0.74,1.45), 24h (SMD = 0.85, 95%CI: 0.59, 1.11), 48h (SMD = 0.89, 95%CI: 0.50, 1.28) and 72h (SMD = 0.75, 95%CI: 0.38, 1.11) after surgery. DEX decreased the occurrence of postoperative cognitive dysfunction (POCD) at 24h (OR = 0.22, 95%CI: 0.11, 0.46) and 72h (OR = 0.39, 95%CI: 0.22, 0.68) after surgery. DEX decreased first flatus time (SMD = -1.55, 95%CI: -2.82, -0.27) and hospital stay (SMD = -1.23, 95%CI: -1.88, -0.59). Therefore, based on perioperative immune dysfunction alleviation, DEX attenuated POCD and potential neuroinflammation, improved postoperative recovery and clinical prognosis of patients undergoing digest tract cancer surgery. Further studies are necessary to elucidate the clinical application of DEX from an immunological perspective.

The pandemic of coronavirus disease 2019 (COVID-19) has already evoked massive influence. The global pandemic has been ravaging the whole world for a year, with the number of confirmed human infection cases over 150 million and a death toll exceeding 3 million. Although the genomic sequence of the cognate pathogen SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has been quickly determined, there are still many unknown aspects, including the virus origin and evolution trend, and the effectiveness of current vaccines and drugs against the mutating virus. This review summarizes current knowledge and advances about COVID-19, including virus origin, transmission and infection, with the aim to improve the understanding of COVID-19 and provide a new perspective for future studies.

Background: Hepatitis A vaccine has been used in mass and routine public vaccination programs in China. Long-term follow-up studies are required to determine the duration of protection and the need for booster vaccinations. Methods: A prospective, randomized, open-label clinical trial was performed to compare the geometric mean concentration (GMC) and seroprotection rates of anti-Hepatitis A virus (HAV) antibodies elicited by the inactivated vaccines Healive and Havrix. 400 healthy children were randomly assigned 3:1 ratio to receive two doses of Healive or Havrix at 0 and 6 months. Persistence of anti-HAV antibodies for 5 years post immunization has been reported The current study reports new data at 11 years post immunization for the purpose of showing antibody persistence. Sensitivity analyzes were performed to assess the results. In addition, predictions for long-term antibody persistence were performed using a statistical model. Two different serological assays were used that were shown to be 98.3% concordant for detecting anit-HAV antibody. Results: GMCs were significantly higher following Healive compared to Havrix at 1, 6, 7, 66, 112 and 138 months post-vaccination. In addition, the GMCs obtained using sensitivity analysis were very similar to those obtained using the original models. Prediction analysis indicated that the duration of protection for both vaccines was at least 30 years after immunization, with a lower limit of the 95% confidence interval for GMC of greater than 20mIU/mL. Conclusions: Healive is more immunogenic than Havrix in children at 11 years post full immunization. Prediction analysis indicated at least 30 years of antibody persistence for both vaccines.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here the authors performed multi-omics analysis of human samples to investigate the mutational landscape of PSC and show three subgroups of PSC with distinct biology, prognosis and potential therapeutic strategies.

Abstract Background Low‐dose computed tomography screening has been proved to reduce lung cancer mortality, however, the issues of high false‐positive rate and overdiagnosis remain unsolved. Risk prediction models for lung cancer that could accurately identify high‐risk populations may help to increase efficiency. We thus sought to develop a risk prediction model for lung cancer incorporating epidemiological and metabolic markers in a Chinese population. Methods During 2006 and 2015, a total of 122 497 people were observed prospectively for lung cancer incidence with the total person‐years of 976 663. Stepwise multivariable‐adjusted logistic regressions with Pentry = .15 and Pstay = .20 were conducted to select the candidate variables including demographics and metabolic markers such as high‐sensitivity C‐reactive protein (hsCRP) and low‐density lipoprotein cholesterol (LDL‐C) into the prediction model. We used the C‐statistic to evaluate discrimination, and Hosmer‐Lemeshow tests for calibration. Tenfold cross‐validation was conducted for internal validation to assess the model's stability. Results A total of 984 lung cancer cases were identified during the follow‐up. The epidemiological model including age, gender, smoking status, alcohol intake status, coal dust exposure status, and body mass index generated a C‐statistic of 0.731. The full model additionally included hsCRP and LDL‐C showed significantly better discrimination (C‐statistic = 0.735, P = .033). In stratified analysis, the full model showed better predictive power in terms of C‐statistic in younger participants (

The electric fault arc, particularly the series arc, leads to plenty of electrical fire. The limitations of t previous studies include: (1) most existing research focused on gaseous atmospheres rather than solids materials, which is contrary to the actual demand; and (2) the studied external heat sources were restricted to cone heaters and flames, while the electric arc was seldom studied. To overcome these limitations, we developed an experimental platform to investigate the flame behavior when cable insulation material was ignited by the fault arc. We proposed a flame-extracting and noise-reduction algorithm to process the enormous number of photos shot by the high-speed camera. The main obtained findings were: (1) the appropriate size of the structuring element plays an essential role in filtering the flame region in the photos, too small a size resulted in the wrong recognition of incandescent particles, while too large a size made a jagged distortion; (2) the mean flame area increased as the system load grew; (3) The flame size became more prominent, and the flame appeared more frequently in specific locations when the system load increased. The in-depth understanding of flame behavior provided by this work will help to optimize the design of electric systems and disaster prevention reduction.

Performance analysis of connectivity-based geolocation in ultra-dense networks (UDNs) is a very important task. Although several performance analyses have been presented for range-free localization, determining the best achievable positioning accuracy of range-free localization remains an open problem. In this paper, we first derive the Cramer-Rao lower bound (CRLB) for the performance evaluation of range-free localization. All the current performance analyses in the literature for range-free localization are used to evaluate the real performance of a given algorithm, whereas the proposed CRLB provides a benchmark to evaluate the performance of any unbiased range-free location algorithm and determines the physical impossibility of the variance of an unbiased estimator being less than the bound. To the best of our knowledge, this is the first time in the literature that the CRLB for range-free localization has been derived. Second, the theoretical variance of centroid-based localization (CL) with an arbitrary node distribution is derived in this paper. In contrast to the existing theoretical variance of CL for uniform node distribution, the proposed theoretical variance can be used to evaluate the performance of CL in the case of an arbitrary node distribution. Additionally, characteristics of the proposed CRLB and theoretical variance are given in this paper. Finally, an optimal estimator based on a maximum likelihood estimator (MLE) is proposed to improve positioning accuracy. Since both prior information on the spatial node distribution and the connectivity property are effectively utilized in our algorithm, the proposed method performs better than the CL method and can asymptotically attain the CRLB.

Abstract Backgrounds The pulmonary ciliated muconodular papillary tumor (CMPT) is a very rare tumor with only several case reports in published literatures, and its clinicopathological features, standard treatment methods and prognosis has not been well defined. Methods Two cases of CMPT diagnosed and treated in our hospital and 39 cases reported in the published literature were analyzed retrospectively. Results The cohort of 41 CMPT patients comprised of 20 males and 21 females, aged 9–84 years. The diameter of the primary tumor was 0.3–4.5 cm. Most of these lesions were subsolid nodules, as observed on computed tomography and easily misdiagnosed as early lung adenocarcinoma. Tumors of 26 patients were stained by immunohistochemistry method, which revealed that CK7, CEA, and TTF-1 were positive and CK20 was negative in most patients. The results of gene alternation demonstrated mutations in EGFR, KRAS, and BRAF and ALK rearrangements in CMPT. All the patients underwent surgical treatment and did not receive postoperative adjuvant therapy. The follow-up duration was 0–120 months, and no case of tumor recurrence was found until the final follow-up. Conclusions The incidence of CMPT was low and rate of image misdiagnosis high. Immunohistochemistry is helpful for accurate diagnosis of CMPT. Sub-lobectomy may be proper and adjuvant treatment should be avoided since the disease is now prone to benign lesions. Furthermore, since the biological behavior of this tumor is not yet fully elucidated, additional case data are essential for accurate conclusions.

Abstract Alternative splicing (AS) and the regulation of AS by splicing factors play critical roles in cancer. Plant homeodomain (PHD)–finger domain protein PHF5A, a critical splicing factor involved in AS, has been demonstrated to play an oncogenic role in glioblastoma multiforme and breast cancer, but its biological function in lung cancer remains unclear. In the present study, we systematically analyzed the biological function and clinical relevance of PHF5A in non–small cell lung cancer (NSCLC). We found that PHF5A was significantly upregulated in NSCLC tumors compared with normal tissues in both TCGA data set and tissue microarrays. Upregulation of PHF5A was negatively correlated to the overall survival (OS) of lung adenocarcinoma (LUAD) patients. Loss‐of‐function and gain‐of‐function experiments confirmed that PHF5A functioned as an oncoprotein by promoting LUAD cell proliferation, migration and invasion, inducing G0/G1 cell cycle progression and inhibiting cisplatin–induced apoptosis. RNA–seq analysis identified many essential genes whose AS was dysregulated by PHF5A, including cell cycle–associated genes such as SKP2, CHEK2, ATR and apoptosis–associated genes such as API5 and BCL2L13. Additionally, pladienolide, a small molecular inhibitor of PHF5A, inhibited LUAD cell proliferation in a dose–dependent manner and induced AS changes similar to PHF5A knockdown. In conclusion, we validated that PHF5A played an oncogenic role via AS in LUAD and suggested that PHF5A might serve as a potential drug target with a promising anticancer therapeutic effect.

Recent studies suggest that the cell-to-cell spread of pathological α-synuclein (α-syn) plays important roles in the development of Parkinson’s disease (PD). PD patients who carry α-syn gene mutations often have an earlier onset and more severe clinical symptoms and pathology than sporadic PD cases who carry the wild-type (WT) α-syn gene. However, the molecular mechanism by which α-syn gene mutations promote PD remains unclear. Here, we hypothesized that pathogenic mutations facilitate the intercellular transfer and cytotoxicity of α-syn, favoring an early disease onset and faster progression. We investigated the effects of eight known pathogenic mutations in human α-syn (A18T, A29S, A30P, E46K, H50Q, G51D, A53E, and A53T) on its pathological transmission in terms of secretion, aggregation, intracellular level, cytotoxicity, seeding, and induction of neuroinflammation in SH-SY5Y neuroblastoma cells, cultured rat neurons, and microglia, and the rat substantia nigra pars compacta. We found that 2 of the 8 mutations (H50Q and A53T) significantly increased α-syn secretion while 6 mutations (A18T, A29S, A30P, G51D, A53E, and E46K) tended to enhance it. In vitroα-syn aggregation experiments showed that H50Q promoted while G51D delayed aggregation most strongly. Interestingly, 3 mutations (E46K, H50Q, and G51D) greatly increased the intracellular α-syn level when cultured cells were treated with preformed α-syn fibrils (PFFs) compared with the WT, while the other 5 had no effect. We also demonstrated that H50Q, G51D, and A53T PFFs, but not E46K PFFs, efficiently seeded in vivo and acutely induced neuroinflammation in rat substantia nigra pars compacta. Our data indicate that pathogenic mutations augment the prion-like spread of α-syn at different steps and blockade of this pathogenic propagation may serve as a promising therapeutic intervention for PD.

Background: The identification of prognostic markers for non-small-cell lung carcinoma (NSCLC) is needed for clinical practice. The metabolism-reprogramming marker ketohexokinase (KHK)-A and acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659 (ACSS2 pS659) play important roles in tumorigenesis and tumor development. However, the clinical significance of KHK-A and ACSS2 pS659 in NSCLC is largely unknown.Methods: The expression levels of KHK-A and ACSS2 pS659 were assessed by immunohistochemistry analyses of surgical specimens from 303 NSCLC patients. The prognostic values of KHK-A and ACSS2 pS659 were evaluated by Kaplan–Meier methods and Cox regression models.Results: The expression levels of KHK-A and ACSS2 pS659 were significantly higher in NSCLC tissues than those in adjacent non-tumor tissues (P < 0.0001). KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 were inversely correlated with overall survival in NSCLC patients (P < 0.001). The multivariate analysis indicated that KHK-A or ACSS2 pS659 and KHK-A/ACSS2 pS659 were independent prognostic biomarkers for NSCLC (P = 0.008 for KHK-A, P < 0.001 for ACSS2 pS659, and P < 0.001 for KHK-A/ACSS2 pS659). Furthermore, the combination of KHK-A and ACSS2 pS659 can be used as a prognostic indicator for all stages of NSCLC.Conclusions: KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 can be used as prognostic markers for NSCLC. Our findings highlight the important role of metabolic reprogramming in NSCLC progression.

P1B-type ATPases, known as heavy metal ATPases (HMAs), play an important role in the control of cadmium (Cd) accumulation in plants. In this study, a total of 12 ZmHMA genes were identified in the maize genome and particularly classified into six clusters based on their phylogenetic relationship and motif compositions. Furthermore, the expression patterns of different ZmHMA genes varied with developmental stages, and were tissue specific under normal conditions. ZmHMA2 and ZmHMA3 genes exhibited significant up-regulation under Cd treatment. Eventually, the association analysis between 103 inbred lines and alleles in ZmHMA2 and ZmHMA3 revealed that one insertion–deletion (InDel) in the intron from ZmHMA2 was associated with leaf Cd concentration under low Cd condition at the seedling stage. Twenty polymorphisms in ZmHMA3 were significantly associated with leaf Cd concentration under various Cd levels at seedling and maturing stages. Five single nucleotide polymorphisms (SNPs) and two InDels of these significantly associated polymorphic loci from ZmHMA3 caused the amino acid substitutions and insertion or deletion events. Importantly, the proteins encoded by ZmHMA2 and ZmHMA3 genes were located in the plasma membrane. This comprehensive analysis will provide an important theoretical basis for future functional verification of ZmHMA genes to unravel the mechanisms of Cd accumulation in leaves of maize. Additionally, the favorable alleles in ZmHMA3 will lay a foundation for the marker-assisted selection of low Cd accumulation in maize.

Arginine methylation is an essential post-translational modification (PTM) deposited by protein arginine methyltransferases (PRMTs) and recognized by Tudor domain-containing proteins. Of the nine mammalian PRMTs, PRMT5 is the primary enzyme responsible for the deposition of symmetric arginine methylation marks in cells. The staphylococcal nuclease and Tudor domain-containing 1 (SND1) effector protein is a key reader of the marks deposited by PRMT5. Both PRMT5 and SND1 are broadly expressed and their deregulation is reported to be associated with a range of disease phenotypes, including cancer. Hepatocellular carcinoma (HCC) is an example of a cancer type that often displays elevated PRMT5 and SND1 levels, and there is evidence that hyperactivation of this axis is oncogenic. Importantly, this pathway can be tempered with small-molecule inhibitors that target PRMT5, offering a therapeutic node for cancer, such as HCC, that display high PRMT5–SND1 axis activity. Here we summarize the known activities of this writer–reader pair, with a focus on their biological roles in HCC. This will help establish a foundation for treating HCC with PRMT5 inhibitors and also identify potential biomarkers that could predict sensitivity to this type of therapy.

Background/Aims: Diabetic cardiomyopathy (DCM) represents the major cause of morbidity and mortality among diabetics. Exercise has been reported to be effective to protect the heart from cardiac injury during the development of DCM. However, the potential cardioprotective effect of exercise in advanced DCM remains unclear. Methods: Seven-week old male C57BL/6 wild-type or db/db mice were either subjected to a running exercise program for 15 weeks or kept sedentary. Cardiac function, myocardial apoptosis and fibrosis, and mitochondrial biogenesis were examined for evaluation of cardiac injury. Results: A reduction in ejection fraction and fractional shortening in db/db mice was significantly reversed by exercise training. DCM induced remarkable cardiomyocyte apoptosis and increased ratio of Bax/Bcl-2 at the protein level. Meanwhile, DCM caused slightly myocardial fibrosis with elevated mRNA levels of collagen I and collagen III. Also, DCM resulted in a reduction of mitochondrial DNA (mtDNA) replication and transcription, together with reduced mtDNA content and impaired mitochondrial ultrastructure. All of these changes could be abolished by exercise training. Furthermore, DCM-associated inhibition of PGC-1α and Akt signaling was significantly activated by exercise, indicating that exercise-induced activation of PGC-1α and Akt signaling might be responsible for mediating cardioprotective effect of exercise in DCM. Conclusion: Exercise preserves cardiac function, prevents myocardial apoptosis and fbrosis, and improves mitochondrial biogenesis in the late stage of DCM. Exercise-induced activation of PGC-1α and Akt signaling might be promising therapeutic targets for advanced DCM.

Mg-Zn-Ca amorphous alloys are considered as potential bone implants. A large number of works have focused on the alloys under free corrosion environment. However, the real service environment of bone implants is a kind of chemistry-mechanics interactive environment in which the materials not only suffer corrosion by body fluids but also bear applied force induced by body movement. In order to imitate the real service environment, surface morphologies and mechanical properties of Mg-Zn-Ca amorphous alloys were studied under different chemistry-mechanics interactive environments in this paper. It was found that cracks and Ca/Mg phosphates formed on the surface of amorphous alloys. The compressive strength of the alloys decreased seriously but could still reach an acceptable value to avoid material failure. Fan-shaped patterns found on all the samples implied that brittle fracture was the main fracture form. Moreover, vein-like patterns could still be found in some areas, showing a locally plastic deformation. This was the reason why the alloy could maintain a high compressive strength after severe and interactive treatments. The study could guide related works in the establishment of experimental environments in the future, which will facilitate a more accurate biomedical evaluation of bone implants.

Cortical neurons implement a high frequency-specific modulation of subcortical nuclei that includes the cochlear nucleus. Anatomical studies show that corticofugal fibers terminating in the auditory thalamus and midbrain are mostly ipsilateral. Differently, corticofugal fibers terminating in the cochlear nucleus are bilateral, which fits to the needs of binaural hearing that improves hearing quality. This leads to our hypothesis that corticofugal modulation of initial neural processing of sound information from the contralateral and ipsilateral ears could be equivalent or coordinated at the first sound processing level.With the focal electrical stimulation of the auditory cortex and single unit recording, this study examined corticofugal modulation of the ipsilateral cochlear nucleus. The same methods and procedures as described in our previous study of corticofugal modulation of contralateral cochlear nucleus were employed simply for comparison. We found that focal electrical stimulation of cortical neurons induced substantial changes in the response magnitude, response latency and receptive field of ipsilateral cochlear nucleus neurons. Cortical stimulation facilitated auditory response and shortened the response latency of physiologically matched neurons whereas it inhibited auditory response and lengthened the response latency of unmatched neurons. Finally, cortical stimulation shifted the best frequencies of cochlear neurons towards those of stimulated cortical neurons.Our data suggest that cortical neurons enable a high frequency-specific remodelling of sound information processing in the ipsilateral cochlear nucleus in the same manner as that in the contralateral cochlear nucleus.