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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.

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 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 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.

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.

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.

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.

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.

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 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.

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.

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.

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 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.

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.

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

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.

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 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.

In this work, the thermal behavior, soft magnetic properties, and structure of Fe86−xP11C2B1Wx (x = 0, 0.1, 0.2, 0.4, 0.6, 0.8, 1, 2, and 4) amorphous alloys were researched by several experimental methods and ab initio molecular dynamics. The addition of W improved the thermal stability of the alloy system when the first onset crystallization temperature (Tx1) increased from 655 K to 711 K, significantly reduced the coercivity Hc, and decreased the saturation magnetization Bs. The Fe85.6P11C2B1W0.4 alloy showed optimal soft magnetic performance, with low Hc of 1.4 A/m and relatively good Bs of 1.52 T. The simulation results suggested that W atoms increased the distance of the neighboring Fe-Fe pair, reduced the coordination number, narrowed the gap between the spin-up and spin-down electrons of each atom, and decreased the average magnetic moment of the Fe atoms. This work demonstrates a micro-alloying strategy to greatly reduce Hc while maintaining high Bs.

Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can no longer recognize PRMT5-catalyzed methylarginine marks. Quantitative PCR analysis of normal, KO, and KI liver samples revealed a role for the SND1 Tudor domain in regulating the expression of genes encoding major acute phase proteins, which could provide mechanistic insight into SND1 function in a tumor setting. Prior studies indicated that ectopic overexpression of SND1 in the mouse liver dramatically accelerates the development of diethylnitrosamine (DEN)-induced HCC. Thus, we tested the combined effects of DEN and SND1 loss or mutation on the development of HCC. We found that both Snd1 KO and Snd1 KI mice were partially protected against malignant tumor development following exposure to DEN. These results support the development of small molecule inhibitors that target the SND1 Tudor domain or the use of upstream PRMT5 inhibitors, as novel treatments for HCC. [ABSTRACT FROM AUTHOR]

Synaptic vesicle (SV) endocytosis is a critical and well-regulated process for the maintenance of neurotransmission. We previously reported that synaptotagmin-11 (Syt11), an essential non-Ca21-binding Syt associated with brain diseases, inhibits neuronal endocytosis (Wang et al., 2016). Here, we found that Syt11 deficiency caused accelerated SV endocytosis and vesicle recycling under sustained stimulation and led to the abnormal membrane partition of synaptic proteins in mouse hippocampal boutons of either sex. Furthermore, our study revealed that Syt11 has direct but Ca2+-independent binding with endophilin A1 (EndoA1), a membrane curvature sensor and endocytic protein recruiter, with high affinity. EndoA1-knockdown significantly reversed Syt11-KO phenotype, identifying EndoA1 as a main inhibitory target of Syt11 during SV endocytosis. The N-terminus of EndoA1 and the C2B domain of Syt11 were responsible for this interaction. A peptide (amino acids 314-336) derived from the Syt11 C2B efficiently blocked Syt11-EndoA1 binding both in vitro and in vivo. Application of this peptide inhibited SV endocytosis in WT hippocampal neurons but not in EndoA1-knockdown neurons. Moreover, intracellular application of this peptide in mouse calyx of Held terminals of either sex effectively hampered both fast and slow SV endocytosis at physiological temperature. We thus propose that Syt11 ensures the precision of protein retrieval during SV endocytosis by inhibiting EndoA1 function at neuronal terminals. [ABSTRACT FROM AUTHOR]