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Neutrophil extracellular traps (NETs) promote neovascularization during the acute phase after ocular chemical injury, while the local inflammatory acidic environment delays post-injury repair. Currently, the mechanism of NETs promoting neovascularization has not been fully elucidated, and there is a lack of therapeutic strategies to effectively improve the local microenvironment for corneal repair. In this study, we validated the NETs-M2-angiogenic pathway after injury. Using transcriptomics sequencing and liquid-phase microarray assays, the intrinsic immune cascade mechanism of NETs inducing macrophage M2 polarization and releasing VEGF via PI3K/AKT was identified. Based on this pathology and the physiological need to improve the local inflammatory acidic environment and promote corneal repair, we organically integrated the alkaline ion-rich bioglass with the highly transmissive and highly adhesive filipin protein, and constructed NETs ablative gel eye drops (DMS) that can release DNase I and alkaline ions in a sustained manner. The eye drops restricted the inflammatory interaction of NETs with macrophages from the source, adhered to the corneal surface and continuously released alkaline ions to improve the local acidic inflammatory environment, providing a favorable immune microenvironment for corneal recovery. We established a cell co-culture system and a corneal alkali burn model to further validate the role of DMS in modulating the intrinsic immune cascade of neovascularization for corneal repair and the related mechanisms. In conclusion, based on the biological mechanism of NETs-M2-VEGF after corneal chemical injury, the present study designed eye drops for dual regulation of intrinsic immunity and the inflammatory acid environment, which not only further supplemented and improved the pathophysiological mechanism of corneal neovascularization after chemical injury, but also provided a new way of thinking about corneal regeneration after injury., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Road traffic injuries (RTIs) have been one of the most serious public health problems in China. The purpose of this study was to investigate the extent to which traffic investment affects traffic fatalities in China as well as regional differences., Methods: The cohort study analyzed the correlation between traffic investment and traffic fatalities, incorporating additional factors such as economic conditions, road infrastructure, population density, and lighting. The selected variables included the number of traffic fatalities, traffic investment, urban per capita road area, urban road length, road mileage, urban road lighting, population size, and per capita gross domestic product. Relevant data between 2004 and 2020 were collected for an analysis using a fixed effect regression model. A p < 0.05 is considered statistically significant. To reduce the heterogeneity caused by regional differences, the provinces were divided into 6 groups according to administrative districts, and the clustering standard error analysis was carried out., Results: Overall, there has been a significant improvement in road safety in China from 2004 to 2020, but some regions show an increase in traffic fatalities. The model reveals that traffic investment is significantly and positively correlated with the number of traffic fatalities. Holding all other factors constant, each 10,000 yuan increase in transport investment was associated with an average increase of 0.22 road traffic fatalities. In the analysis of regional differences, there was a significant positive correlation between traffic investment and traffic fatalities in the Northwest region and an increase of 10,000 yuan leads to an increase of 0.47. There was a significant negative correlation between road mileage, urban road lighting system, and population and traffic fatalities. For example, holding other factors constant, a 10,000 km reduction in road length would increase the number of traffic deaths by 45.56. The model results of urban per capita road area, urban road length, per capita gross domestic product, and the explained variables showed that p > 0.100, which was not statistically significant., Conclusions: Therefore, traffic investments are essential for governments to develop measures to enhance road safety and reduce the risk of road fatalities. Adjusting traffic road investment and other covariates is conducive to improving traffic safety and reducing the risk of road fatalities. The road safety situation in different regions of China varies greatly. Local governments should consider the actual conditions to provide better road safety configuration policies., (Copyright © 2024. Published by Elsevier B.V.)

The influence of annealing at various temperatures on the phase stability and microstructure of pulsed-wave laser mode (PW) 316L stainless steel fabricated via Directed Energy Deposition (DED) was systematically investigated. The microstructural alterations resulting from heat treatment were examined to clarify their influence on the mechanical properties of the specimens subjected to tensile loading. The results showed that cell size increased with annealing temperature, with the cellular microstructure disappearing at higher temperatures (T ≥ 1000 °C). A decrease in the mechanical strength of the specimens was observed as annealing temperature increased. Additionally, the influence of different laser pulse frequencies and duty cycles on residual stresses was examined, revealing that moderate laser frequencies and duty cycles effectively reduced residual stress levels.

Directed energy deposition with laser beam (DED-LB) components experience significant residual stress due to rapid heating and cooling cycles. Excessive residual tensile stress can lead to cracking in the deposited sample, resulting in service failure. This study utilized digital image correlation (DIC) and thermal imaging to observe the in situ temporal evolution of strain and temperature gradients across all layers of a deposited 316 L stainless steel thin wall during DED-LB. Both continuous-wave (CW) and pulsed-wave (PW) laser modes were employed. Additionally, the characteristics of thermal cracks and geometric dislocation density were examined. The results reveal that PW mode generates a lower temperature gradient, which in turn reduces thermal strain. In CW mode, the temperature-stress relationship curve of the additive manufacturing sample enters the "brittleness temperature zone", leading to the formation of numerous hot cracks. In contrast, PW mode samples are almost free of cracks, as the metal avoids crack-sensitive regions during solidification, thereby minimizing hot crack formation. Overall, these factors collectively contribute to reduced residual stress and improved mechanical properties through the adjustment of pulsed-wave laser deposition.

In the process of directed energy deposition (DED), the grain structure of the deposited samples is determined by two aspects. The first is the initial solidification grain structure; the second is the effect of the upper thermal cycle on the solidified grain structure of the lower layer. Dynamic recrystallization and grain growth can be activated under suitable strain and the temperature resulting from thermal cycles. The evolution of grain size and the geometric dislocation density (GND) of austenitic stainless steel 316 L under different strains and temperatures caused by thermal cycles was investigated. It is found that dynamic recrystallization requires an appropriate level of accumulated strain, temperature, and initial grain size. Under <2% accumulated strain and 400-1200 °C conditions caused by 30 layers of thermal cycles, fully dynamic recrystallization occurs with coarse initial grains (CIG), leading to the complete coarsening of grains. However, relatively fine initial grains (FIG) under the same conditions only display partial dynamic recrystallization. The next 2-4% strain and 400-700 °C by 60 layers of thermal cycles make up the driving force of fully dynamic recrystallization, and the grains coarsen completely. Larger accumulated strain (4-6%) and lower temperature (400-600 °C) by 90 layers of thermal cycles and FIG provide more nucleation sites for dynamic recrystallization, which leads to little coarsening of grains even after fully dynamic recrystallization. Temperature, accumulated strain, and the amount of δ-ferrite promote the formation of sub-grains during dynamic recrystallization caused by thermal cycles, which leads to the increase in GND.

As one of the two main histologic subtypes of gastric cancer (GC), diffuse-type gastric cancer (DGC) containing poorly cohesive gastric carcinoma (PCC) components has a worse prognosis and does not respond well to typical therapies. Despite the large number of studies revealing the complex pathogenic network of DGC, the molecular heterogeneity of DGC is still not fully understood. We obtained single-cell RNA-seq data and bulk data from the tumor immune single cell hub, the public gene expression omnibus, and the cancer genome atlas databases. A series of bioinformatics analyses were performed using R software. Immunofluorescence staining, hematoxylin and eosin staining, western blot, and functional experiments were used for experimental validation. Caudin-3, -4 and -7 were lowly expressed in DGC and their expression levels were further reduced in PCC. The PCC components were mainly located in the deeper layers of the DGC and had a high level of hypoxic Wnt/β-catenin signaling and stemness. We further identified Insulin Like Growth Factor Binding Protein 7 (IGFBP7) as a marker for PCC components in the deep layer. IGFBP7 is stimulated by hypoxia and promotes cancer cell invasiveness and reduced claudin expression. In addition, programmed death-1 ligand (PD-L1) was specifically expressed in the deep layer, reflecting deep layer-specific immunosuppression. The PCC components are predominantly situated in the deeper layers of DGC. Initial molecular characterization of these PCC components revealed distinct features, including low expression of claudin-3, -4, and -7, high expression of IGFBP7, and the presence of PD-L1. These molecular traits may partially account for the pronounced tumor heterogeneity observed in GC., (© 2024. The Author(s).)

Immunotherapy has limited response rates in colorectal cancer (CRC) due to an immunosuppressive tumor microenvironment (TME). Combining transcriptome sequencing, clinical specimens, and functional experiments, we identified a unique group of CAF subpopulations (COX4I2 + ) with inhibited mitochondrial respiration and enhanced glycolysis. Through bioinformatics predictions and luciferase reporter assays, we determined that EBF1 can upstreamly regulate COX4I2 transcription. COX4I2 + CAFs functionally and phenotypically resemble myofibroblasts, are important for the formation of the fibrotic TME, and are capable of activating the M2 phenotype of macrophages. In vitro experiments demonstrated that COX4I2 + CAFs promote immunosuppressive TME by blocking CD8 + T cell infiltration and inducing CD8 + T cell dysfunction. Using multiple independent cohorts, we also found a strong correlation between the immunotherapy response rate of CRC patients and COX4I2 expression in their tumors. Our results identify a CAF subpopulation characterized by activation of the EBF1-COX4I2 axis, and this group of CAFs can be targeted to improve cancer immunotherapy outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The unique geographical and climatic conditions in the Three-River Headwaters Region gave birth to distinctive plant species and vegetation types. To reveal the spatial distribution of plant communities and soil habitats along the riparian zone of the Sanjiangyuan Region and their influencing mechanisms, 14 survey plots were set up （ten from the Yangtze River source, two from the Lancang River source, and two from the Yellow River source）, and the effects of soil nutrient characteristics （especially soil phosphorus morphology）, climate factors, and river topography on plant community characteristics were quantitatively analyzed. The results showed that the plant community composition in the riparian zone of the source of the three rivers was dominated by perennial herbs （72.2%）, followed by annual herbs （20.4%） and shrubs （7.4%）. The dominant plants were Stipa purpurea , Polygonum orbiculatum , Carex parvula , Potentilla anserina, and Gentiana straminea . The average plant coverage, Shannon-Wiener index, and Pielou index were （64.4% ±23.6%）, （1.31 ±0.42）, and （0.84 ±0.08）, respectively. The plant community diversity index was the highest in the Yangtze River source, followed by that in the Lancang River source, and the lowest in the Yellow River source. The soil pH of the riparian zone of the Yangtze River source was significantly higher than that of the Lancang River source, whereas the mean contents of organic matter, total nitrogen, and Fe-Al combined phosphorus were significantly lower than those of the Lancang River source. The calcium and magnesium-combined phosphorus was the main form of phosphorus in riparian soil （63.89%）. Temperature, soil organic phosphorus content, and pH had significant effects on plant composition in the riparian zone of the Three-River Headwaters Region, whereas soil calcium and magnesium-combined phosphorus content had significant effects on plant community diversities. These results may deepen the scientific understanding of the evolution trend and genetic mechanism of plant communities in the riparian zone of the Three-River Headwaters Region.

Radiotherapy (RT) is recognized as a primary treatment modality for Nasopharyngeal carcinoma (NPC). However, enhancing RT's targeting accuracy and selectivity remains a significant challenge. In this study, we present an innovative radiosensitizer, Gd-metal-organic framework (MOF)-based nanocarrier coated with indocyanine green (ICG) and red blood cell membrane (RBCM), designed to bypass immune clearance and achieve prolonged circulation within the bloodstream. This design significantly enhances tumor localization and systemic circulation, as evidenced by in vivo analyses. The strategic accumulation of the Gd-MOF-ICG nanocarrier at the tumor site facilitates precise tumor localization and sensitization to RT, leveraging the RBCM camouflage to enhance the tumor uptake potential. Our comprehensive study introduces a potent approach for optimizing RT in NPC treatment through this advanced theranostic nanoplatform, which combines material science with biomedical engineering to augment the effectiveness of RT and underscores the significance of precision in cancer therapy. This strategy offers a promising avenue for clinical application and further research in targeted cancer treatments., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential., Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle., Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation., Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Liu et al.)

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Connexin is a transmembrane protein involved in gap junctions (GJs) formation. Our previous study found that connexin 37 (Cx37), encoded by gap junction protein alpha 4 (GJA4), expressed on fibroblasts acts as a promoter of CRC and is closely related to epithelial-mesenchymal transition (EMT) and tumor immune microenvironment. However, to date, the mechanism concerning the malignancy of GJA4 in tumor stroma has not been studied., Methods: Hematoxylin-eosin (HE) and immunohistochemical (IHC) staining were used to validate the expression and localization of GJA4. Using single-cell analysis, enrichment analysis, spatial transcriptomics, immunofluorescence staining (IF), Sirius red staining, wound healing and transwell assays, western blotting (WB), Cell Counting Kit-8 (CCK8) assay and in vivo experiments, we investigated the possible mechanisms of GJA4 in promoting CRC., Results: We discovered that in CRC, GJA4 on fibroblasts is involved in promoting fibroblast activation and promoting EMT through a fibroblast-dependent pathway. Furthermore, GJA4 may act synergistically with M2 macrophages to limit T cell infiltration by stimulating the formation of an immune-excluded desmoplasic barrier. Finally, we found a significantly correlation between GJA4 and pathological staging (P < 0.0001) or D2 dimer (R = 0.03, P < 0.05)., Conclusion: We have identified GJA4 expressed on fibroblasts is actually a promoter of the tumor mesenchymal phenotype. Our findings suggest that the interaction between GJA4+ fibroblasts and M2 macrophages may be an effective target for enhancing tumor immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: The aim of the present study was to assess the clinical outcomes and prognostic factors of lung adenocarcinoma patients with brain metastases (BMs) after intracranial local therapy., Patients and Methods: A total of 83 lung adenocarcinoma patients with BMs who underwent craniotomy combined with radiotherapy or intracranial radiotherapy alone were retrospectively analyzed. The intracranial tumor response was determined according to the Response Assessment in Neuro-Oncology of Brain Metastases (RANO-BM) criteria. The median overall survival (OS), intracranial progression-free survival (iPFS), and related prognostic factors were analyzed with the Kaplan‒Meier estimator method and Cox proportional hazards regression model., Results: Among 83 patients, 20 patients received craniotomy combined with radiotherapy, and 63 patients received intracranial radiotherapy alone. Following intracranial local therapy, 11 patients (13.3%) achieved complete response (CR); among them, 8 patients underwent neurosurgical resection. In addition, 32 patients (38.55%) achieved partial response (PR), 32 patients (38.55%) experienced stable disease (SD), and 8 (9.6%) experienced progressive disease (PD). The median follow-up period was 25.4 months (range 0.8-49.6 months). The median follow-up time for the iPFS was 16.2 months (range 0.6-41.2 months). The median OS, iPFS were 28.2 months and 24.7 months. Epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) mutations (HR 3.216, 95% confidence interval (CI) 1.269-8.150, p = 0.014) and iPFS (HR 0.881, 95% CI 0.836-0.929, p < 0.001) were found to be beneficial factors for OS. An intracranial-tumor CR was associated with a longer iPFS (PR: HR 0.052, 95% CI 0.009-0.297, p = 0.001; SD: HR 0.081, 95% CI 0.025-0.259, p < 0.001; PD: HR 0.216, 95% CI 0.077-0.606, p = 0.004)., Conclusion: Prolonged iPFS was associated with better OS in lung adenocarcinoma patients with BMs following intracranial local therapy, and mutations of EGFR / ALK or an intracranial-tumor CR are independent prognostic factors for prolonged survival., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Shen et al.)

The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC., (© 2024. The Author(s).)

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity., (© 2024. The Author(s).)

Background: Single nucleotide polymorphisms (SNPs), as the most abundant form of DNA variation in the human genome, contribute to age-related cataracts (ARC) development. Apoptosis of lens epithelial cells (LECs) is closely related to ARC formation. Insulin-like growth factor 1 (IGF1) contributes to cell apoptosis regulation. Moreover, IGF1 was indicated to exhibit a close association with cataract formation. Afterward, an investigation was conducted to examine the correlation between polymorphisms in IGF1 and the susceptibility to ARC., Methods: The present investigation was a case-control study. Venous blood draws were collected from the participants for DNA genotyping. Lens capsule samples were collected to detect mRNA and apoptosis. TaqMan RT-PCR was used to detect IGF1 polymorphism genotypes and qRT PCR was used to detect IGF1 mRNA levels in LECs. LEC apoptosis was evaluated through flow cytometry. The chi-square test was used to compare differences between ARCs and controls of each SNP., Results: We found that the G allele frequency in the IGF1 -rs6218 was higher in the ARCs than in the controls. Furthermore, it was observed that the rs6218 GG genotype exhibited a positive correlation to elevated levels of IGF1 mRNA in LECs. The IGF1 mRNA in the LECs and the apoptosis of LECs in nuclear type of ARCs (ARNC) was higher than the controls., Conclusion: The susceptibility to ARC was related to IGF1 -rs6218 polymorphism, and this polymorphism is associated with IGF1 expression at the mRNA level. Moreover, apoptosis in LECs of ARNCs was found to be increased., Competing Interests: The authors declare that they have no competing interests., (© 2024 Zou et al.)

Retinal vein occlusion (RVO) ranks as the second most prevalent retinal vascular disease, following diabetic retinopathy. Neutrophil extracellular traps (NETs) play an important role in vascular diseases. This study aimed to elucidate the relationship between NETs and RVO, and to discern the potential role of deoxyribonuclease I (DNase I) in the prevention and treatment of RVO through the modulation of NETs. We analyzed circulating NETs biomarkers, namely cell-free DNA (cf-DNA), myeloperoxidase (MPO)-DNA, and neutrophil elastase (NE), in 30 RVO patients and 30 healthy individuals. We established an RVO mouse model using a retinal laser, and the mice were categorized into two groups: the DNase I group and the control group. Retinal images were taken at predetermined time points, and the state of the retinal vessels was assessed. Both tissue and blood samples were harvested for analysis of NETs expression through methods such as western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Our finding indicate an increase in circulating NETs biomarkers in human and mouse RVO cases, while also verifying the presence of NETs in the retinal thrombus of the RVO model. Both in vitro and in vivo tests revealed that DNase I attenuated NETs formation. Moreover, DNase I injections led to diminished NETs biomarker levels and a reduced duration of the thrombus after the RVO model establishment. Consequently, DNase I, a well-established modulator of NETs formation, might exhibit protective properties in the prevention and treatment of RVO.

Selective transformations at the more sterically hindered sites of organic molecules represent a frontier in the ability to precisely modify molecules. The lack of effective synthetic methods stands in stark contrast to the large number of encumbered sites encountered in molecules of interest. Here, we demonstrate that 1,2-bis(boronates) undergo selective alkynylation and alkenylation at the more sterically hindered C-B bond. Our preliminary mechanistic studies disclosed that this reaction can proceed through two convergent pathways involving direct coupling of sterically encumbered site versus 1,2-boron migratory coupling. Notably, this method facilitated convenient access to alkenyl and alkynyl boron products, which can be diversified by an array of transformations.

Ethnopharmacological Relevance: Sargentodoxa cuneata (Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson, DXT)-Patrinia villosa(Patrinia villosa (Thunb.) Dufr, BJC) constitutes a commonly employed herb pair in Chinese medicine for colorectal cancer (CRC) treatment. Modern pharmacological investigations have revealed the anticancer activities of both Sargentodoxa cuneata and Patrinia villosa. Nevertheless, comprehensive studies are required to discern the specific antitumor active ingredients and mechanism of action when these two herbs are used in combination., Aim of the Study: Through the integration of network pharmacology, molecular docking techniques, experimental assays, and bioinformatics analysis, our study aims to forecast the active ingredients, potential targets, and molecular mechanisms underlying the therapeutic efficacy of this herb pair against CRC., Materials and Methods: Plant names (1, Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson; 2, Patrinia villosa (Thunb.) Dufr.) have been verified through WorldFloraOnline (www.worldFloraonline.org) and MPNs (http://mpns.kew.org). The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) were utilized for screening the active ingredients of the herb pair. The PharmMapper database was employed to predict the target proteins for each active ingredient. CRC-related targets were obtained from the Genecards database, Online Mendelian Inheritance in Man (OMIM) database, Disease Gene Network (DisGeNET) database, and Therapeutic Target Database (TTD). Common targets were identified by intersecting the target proteins of all active ingredients with CRC-related targets. Protein-protein interactions (PPI) for the common target proteins were constructed using the String database and Cytoscape 3.9.1 software. Network topology analysis facilitated the identification of core targets. These core targets were subjected to enrichment analysis of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) using the Metascape database. Molecular docking was performed using Discovery Studio 2019 to investigate the interactions between the active ingredients and core target proteins. The core targets were validated through bioinformatics analysis using GEPIA, HPA, and the cBioPortal database. Finally, a series of experiments were conducted to further validate the results in vitro., Result: A total of 15 active ingredients and 255 herb targets were identified, resulting in 66 common targets in conjunction with 6113 disease targets. The PPI analysis highlighted AKT1, EGFR, CASP3, SRC, and ESR1 as core targets. KEGG enrichment analysis indicated significant enrichment in the PI3K-AKT signaling pathway, a pathway associated with cancer. Molecular docking experiments confirmed favorable interactions between dihydroguaiaretic acid and the core target proteins (AKT1, EGFR, CASP3, and ESR1). Bioinformatics analysis revealed differential expression of EGFR and CASP3 in normal and CRC tissues. Cellular experiments further verified that dihydroguaiaretic acid induces apoptosis in colorectal cancer cells through the PI3K-AKT signaling pathway., Conclusion: Our network pharmacology study has elucidated that the Sargentodoxa cuneata-Patrinia villosa herb pair exerts the negative regulation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the induction of apoptosis in colorectal cancer cells. This research has predicted and validated the active ingredients, potential targets, and molecular mechanisms of Sargentodoxa cuneata-Patrinia villosa in the treatment of CRC, providing scientific evidence for the use of traditional Chinese medicine in managing CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Complementary treatment with valuable efficacy and less toxic or side effect is in urgent need for colorectal cancer (CRC) therapy. Yiqi Huayu Jiedu Decoction (YHJD) is a polyherbal formulation which has been applied in clinic to treat CRC for a long period of time. Nevertheless, the potential active ingredients and molecular mechanism remains to be further explored., Aim of the Study: To probe the effective compounds of YHJD and its underlying pharmacological effects. Moreover, the influence on liver metastasis of CRC as well as function of natural killer (NK) cells results from YHJD was investigated., Materials and Methods: The active ingredients and target genes of YHJD was examined through TCMSP databases. Compound-compound target network was performed by applying Cytoscape3.9.1 software. The CRC-related disease targets were explored via DisGeNET database. Venn database was used to find the common genes between CRC and YHJD. Protein-protein interaction network was established by STRING database. Biological process and signaling pathways potentially regulated by YHJD were evaluated by DAVID database. Western blot assay was then conducted to further investigate the effect of YHJD on PI3K-AKT signaling. The association between NK cells content and TNM or pathological stages of CRC was studied through TCGA database. The killing efficiency of NK cells was researched by CCK8 experiment. In vivo assay and HE staining were performed to assess the anti-liver metastasis effect of YHJD. The variation of NK cells content was authenticated by applying flow cytometry analysis., Results: We firstly found 176 active ingredients and 268 target genes of YHJD. Compound-compound target network was then established consisted of 455 nodes and 3989 edges. Then 707 disease targets associated with CRC were discovered and 42 common genes between CRC and YHJD were identified. Protein-protein interaction network was further constructed, among which 5 vital genes including TP53, AKT1, TNF, MYC and CCND1 were recognized. GO and KEGG analysis was performed to explore probable biological process and signaling pathways regulated by YHJD. Particularly, the ratio of p-PI3K/PI3K and p-AKT/AKT at protein level representing the activation of PI3K-AKT signaling could be suppressed by YHJD. In addition, bioinformatic analysis detected reduced NK cells content in CRC tissues, which gave rise to more advanced node, metastasis and pathological stages. We next presented that YHJD can improve the killing effect of NK cells on CRC. At meantime, YHJD was capable of suppressing liver metastasis of CRC in vivo as well as promoting the content of NK cells, while the improving effect was partially neutralized by anti-ASGM1., Conclusions: Our research indicates that YHJD can prohibit liver metastasis of CRC in vivo. The therapeutic effectiveness is linked to regulation of multiple targets and effector process, especially PI3K-AKT signaling as well as immune response dominated by NK cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: In the present study, we explored the role of N 6 -methyladenosine (m 6 A) modification of long non-coding RNAs (lncRNAs) and its association with ferroptosis in lens epithelium cells (LECs) of age-related cataract (ARC)., Methods: Through m 6 A RNA immunoprecipitation sequencing (m 6 A-RIP-seq) and RNA sequencing (RNA-seq), we identified m 6 A mediated and differentially expressed lncRNAs (dme-lncRNAs) in ARC patients. Based on bioinformatics analysis, we selected critical dme-lncRNAs and pathways associated with ARC formation to reveal their potential molecular mechanisms. The downregulation of glutathione peroxidase 4 (GPX4), a key component of ferroptosis, was confirmed by real-time RT-PCR (RT-qPCR) and Western blotting in age-related cortical cataract (ARCC) samples. Transmission electron microscopy was used to assess the change in mitochondrial in LECs., Results: The analysis revealed a total of 11,193 m 6 A peaks within lncRNAs, among which 7043 were enriched and 4150 were depleted. Among those, lncRNA ENST00000586817(upstream of the GPX4 gene) was not only significantly upregulated in the LECs of ARCC but also potentially augmented the expression of GPX4 through a cis mechanism. The expression of m 6 A-modified lncRNA (ENST00000586817) was correlated with that of GPX4 and was downregulated in ARC patients. The TEM results indicated significant mitochondrial changes in ARCC samples. GPX4 downregulation enhanced LEC ferroptosis and decreased viability via RSL3 in SRA01/04 cells., Conclusions: Our results provide insight into the potential function of m 6 A-modified lncRNAs. M 6 A-modified lncRNA ENST00000586817 might regulate the expression of GPX4 by a cis mechanism and be implicated in ferroptosis in ARCs., (© 2023. The Author(s).)

Hepatocellular carcinoma (HCC) is the most widespread histological form of primary liver cancer, and it faces great diagnostic and therapeutic difficulties owing to its tumor diversity. Herein, we aim to establish a unique prognostic molecular subtype (MST) and based on this to find potential therapeutic targets to develop new immunotherapeutic strategies. Using calcium channel molecules expression-based consensus clustering, we screened 371 HCC patients from The Cancer Genome Atlas to screen for possible MSTs. We distinguished core differential gene modules between varying MSTs, and Tumor Immune Dysfunction and Exclusion scores were employed for the reliable assessment of HCC patient immunotherapeutic response rate. Immunohistochemistry and Immunofluorescence staining were used for validation of predicted immunotherapy outcomes and underlying biological mechanisms, respectively. We identified two MSTs with different clinical characteristics and prognoses. Based on the significant differences between the two MSTs, we further identified Follistatin-like 3 (FSTL3) as a potential indicator of immunotherapy resistance and validated this result in our own cohort. Finally, we found that FSTL3 is predominantly expressed in HCC stromal components and that it is a factor in enhancing fibroblast-M2 macrophage signaling crosstalk, the function of which is relevant to the pathogenesis of HCC. The presence of two MSTs associated with the calcium channel phenotype in HCC patients may provide promising directions for overcoming immunotherapy resistance in HCC, and the promotion of FSTL3 expressed in stromal components for HCC hyperfibrosis may be responsible for the poor response rate to immunotherapy in Cluster 2 (C2) patients., (© 2023. The Author(s).)

A novel copper-catalyzed cross-coupling reaction of sulfinamides and aryl boronic acids is developed. The reaction is highly chemoselective and stereospecific, which allows mild synthesis of optically pure sulfoximines with broad scope and functional group tolerance. The utility of this method is demonstrated by the asymmetric synthesis of pharmaceutical intermediates.

We examine how cultural distance between sojourners' country of origin and their host country influences their engagement in intercultural exchange upon return. One might expect intercultural exchange to be much harder between culturally-distant countries than culturally-close ones, given that the former vary more in norms or expected behaviors from one's home country. Our novel theorizing, however, leads to precisely the opposite expectations. In particular, we hypothesized that cultural distance between the repatriates' home and host countries would be positively associated with being inspired by the host culture. In turn, this heightened inspiration would predict an increased sharing of knowledge about the host culture upon returning home (intercultural exchange). We combined measurement-of-mediation (Study 1) and experimental-causal-chain (Studies 2-3) approaches to test and confirm these hypotheses in three large samples of repatriates. We first examined whether cultural distance predicted greater intercultural exchange via repatriates' heightened inspiration (Study 1). We then tested the individual links in this postulated causal chain. In Study 2, a quasi-experiment, we examined the causal path from cultural distance to inspiration. In Study 3, we experimentally manipulated inspiration to test its causal effect on intercultural exchange. The findings advance theory and application around multicultural experience and intercultural exchange., (© 2023. Springer Nature Limited.)

This paper mainly analyzes the typical thermodynamic response (thermal history, thermal strain and residual stress) in a conventional continuous-wave (CW) laser during Directed Energy Deposition (DED). The influence of process parameters (laser power and scanning speed) on the temperature gradient in the heat-affected zone, thermal strain and residual stress are studied, and the corresponding relationship are established. The results show that a reduction in residual stress can be obtained by decreasing the temperature gradient. However, the method of reducing the temperature gradient by changing process parameters leads to low forming quality and low density. A pulse-wave laser (PW) is proposed to actively control the residual stress of the deposited sample. This laser mode can reduce not only the temperature gradient in the process of DED but also the in situ release of thermal stress, correspondingly greatly reducing the residual stress.

Sulfonyl and sulfonimidoyl fluorides are versatile substrates in organic synthesis and medicinal chemistry. However, they have been exclusively used as S(VI) + electrophiles for defluorinative ligations. Converting sulfonyl and sulfonimidoyl fluorides to S(VI) radicals is challenging and underexplored due to the strong bond dissociation energy of S VI -F and high reduction potentials, but once achieved would enable dramatically expanded synthetic utility and downstream applications. In this report, we disclose a general platform to address this issue through cooperative organosuperbase activation and photoredox catalysis. Vinyl sulfones and sulfoximines are obtained with excellent E selectivity under mild conditions by coupling reactions with alkenes. The synthetic utility of this method in the preparation of functional polymers and dyes is also demonstrated., (© 2023. Springer Nature Limited.)

Ocular alkali burns recruit neutrophils and triggers neutrophil extracellular trap (NET)-neovascularization cascade effects that limit ocular surface reconstruction and functional repair. However, effective inhibition of the release of neutrophil extracellular traps after a corneal chemical injury, coordination of intrinsic immunity with corneal repair, and exploration of more effective and non-invasive drug-delivery modes are still urgently needed. Using an in vitro coculture system, we found that an alkaline environment stimulates neutrophils to release NETs, which can be regulated by deoxyribonuclease I (DNase I). Inspired by this, we loaded DNase I, which effectively regulates NETs, onto chitosan nanoparticles and combined them with silk fibroin to construct a composite hydrogel that can sustainably regulate NETs. The hydrogel reduced neutrophil extracellular trap production by 50% and neovascularization by approximately 70% through sustained DNase I release after a corneal alkali burn. The complex hydrogel promotes ocular surface reconstruction by modulating the intrinsic immune-cascade neovascularization effect, providing a new research basis for the construction of nanobiomaterials that modulate pathological neovascularization.

Asymmetric cross-couplings based on 1,2-carbon migration from B-ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2-boron shift have remained to be unaddressed synthetic challenge. Here, Ir-catalyzed asymmetric allylic alkylation enabled by 1,2-boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis-boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities., (© 2023 Wiley-VCH GmbH.)

Water quality is directly linked to drinking water safety for millions of people receiving the water. The Danjiangkou Reservoir is the main water source for the Middle Route of the South-to-North Water Diversion Project (MR-SNWDP), located in the vicinity of Henan and Hubei provinces in China. Aquatic microorganisms are key indicators of biologically assessing and monitoring the water quality of the reservoir as they are sensitive to environmental and water quality changes. This study aimed to investigate the spatiotemporal variations in bacterioplankton communities during wet (April) and dry (October) seasons at eight monitoring points in Hanku reservoir and five monitoring points in Danku reservoir. Each time point had three replicates, labeled as wet season Hanku (WH), wet season Danku (WD), dry season Hanku (DH), and dry season Danku (DD) of Danjiangkou Reservoir in 2021. High-throughput sequencing (Illumina PE250) of the 16S rRNA gene was performed, and alpha (ACE and Shannon) and beta (PCoA and NDMS) diversity indices were analyzed. The results showed that the dry season (DH and DD) had more diverse bacterioplankton communities compared to the wet season (WH and WD). Proteobacteria, Actinobacteria, and Firmicutes were the most abundant phyla, and Acinetobacter, Exiguobacterium, and Planomicrobium were abundant in the wet season, while polynucleobacter was abundant in the dry season. The functional prediction of metabolic pathways revealed six major functions including carbohydrate metabolism, membrane transport, amino acid metabolism, signal transduction, and energy metabolism. Redundancy analysis showed that environmental parameters greatly affected bacterioplankton diversity during the dry season compared to the wet season. The findings suggest that seasonality has a significant impact on bacterioplankton communities, and the dry season has more diverse communities influenced by environmental parameters. Further, the relatively high abundance of certain bacteria such as Acinetobacter deteriorated the water quality during the wet season compared to the dry season. Our findings have significant implications for water resource management in China, and other countries facing similar challenges. However, further investigations are required to elucidate the role of environmental parameters in influencing bacterioplankton diversity in order to devise potential strategies for improving water quality management in the reservoir.

The prevalence of obesity and diabetes mellitus (DM) has been consistently increasing worldwide. Sharing powerful genetic and environmental features in their pathogenesis, obesity amplifies the impact of genetic susceptibility and environmental factors on DM. The ectopic expansion of adipose tissue and excessive accumulation of certain nutrients and metabolites sabotage the metabolic balance via insulin resistance, dysfunctional autophagy, and microbiome-gut-brain axis, further exacerbating the dysregulation of immunometabolism through low-grade systemic inflammation, leading to an accelerated loss of functional β-cells and gradual elevation of blood glucose. Given these intricate connections, most available treatments of obesity and type 2 DM (T2DM) have a mutual effect on each other. For example, anti-obesity drugs can be anti-diabetic to some extent, and some anti-diabetic medicines, in contrast, have been shown to increase body weight, such as insulin. Meanwhile, surgical procedures, especially bariatric surgery, are more effective for both obesity and T2DM. Besides guaranteeing the availability and accessibility of all the available diagnostic and therapeutic tools, more clinical and experimental investigations on the pathogenesis of these two diseases are warranted to improve the efficacy and safety of the available and newly developed treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ruze, Liu, Zou, Song, Chen, Xu, Yin and Xu.)

Difenoconazole is a type of triazole fungicide that is widely used in the treatment of plant diseases. Triazole fungicides have been shown in several studies to impair the development of the nervous system in zebrafish embryos. There is still little known about difenoconazole-induced neurotoxicity in fish. In this study, zebrafish embryos were exposed to 0.25, 0.5, and 1 mg/L of difenoconazole solution until 120 h post-fertilization (hpf). The difenoconazole-exposed groups showed concentration-dependent inhibitory tendencies in heart rate and body length. Malformation rate and spontaneous movement of zebrafish embryos increased, and the locomotor activity decreased in the highest exposure group. The content of dopamine and acetylcholine was reduced significantly in difenoconazole treatment groups. The activity of acetylcholinesterase (AChE) was also increased after treatment with difenoconazole. Furthermore, the expression of genes involved in neurodevelopment was remarkably altered, which corresponded with the alterations of neurotransmitter content and AChE activity. These results indicated that difenoconazole might affect the development of the nervous system through influencing neurotransmitter levels, enzyme activity, and the expression of neural-related genes, ultimately leading to abnormal locomotor activity in the early stages of zebrafish.

The tumor microenvironment (TME) contains complex components, of which the most well-known one is the tumor-associated fibroblast (CAF) that participates in the development and progression of tumors. A high abundance of CAFs implies that tumor stroma is also abundant and often predicts a poor prognosis, especially in terms of immunotherapeutic resistance. In this study, DAZ interacting zinc finger protein 1 (DZIP1) was identified to be upregulated in CAFs and malignant epithelial cells based on single-cell sequencing. Furthermore, results from The Cancer Genome Atlas database showed that this gene was highly positively associated with the mesenchymal phenotype in gastric cancer (GC). In addition, molecular experiments verified that DZIP1 directly promoted the proliferation of CAFs and enhanced the epithelial-mesenchymal transition (EMT) of GC cells to drive angiogenesis. Also, the upregulated DZIP1 in GC cells was found to directly promote invasion and metastasis. Finally, multiplex immunofluorescence and immunohistochemistry showed that DZIP1 was correlated with the immunosuppressive microenvironment of GC and resulted in a poor response to immunotherapy. Overall, our findings suggest that DZIP1 is expressed in both tumor parenchyma and mesenchyme and that it is involved in shaping the immunosuppressive microenvironment and inducing EMT by participating in tumor-stromal signaling crosstalk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The Proteasome (PSM) is a large multi-catalytic protease complex consisting of a 20S core particle and a 19S regulatory particle whose main function is to accept and degrade ubiquitinated substrates, are now considered as one of the potential regulators of tumor proliferation, and stemness maintenance. However, to date, studies on the relationship between PSM and hepatocellular carcinoma (HCC) are limited., Methods: This study used a bioinformatics approach combining validation experiments to investigate the biological mechanisms that may be related with PSM. A series of experiments in vivo and in vitro were performed to explore the function of the 26S proteasome non-ATPase regulatory subunit 13 (PSMD13) in HCC., Results: HCC patients can be divided into two clusters. Cluster 1 (C1) patients having a significantly worse prognosis than Cluster (C2). Two subtypes had significant differences in proliferation-related signaling. In particular, the frequency of TP53 mutation was significantly higher in C1 than in C2. In addition, PSM-associated genes were highly consistent with the expression of DNA repair-related signatures, suggesting a potential link between PSM and genomic instability. We also found that downregulation of PSMD13 expression significantly inhibited stemness of tumor cells and impaired the Epithelial mesenchymal transition (EMT) process. Finally, the correlation between the PSMD13 and Ki67 was found to be strong., Conclusion: PSM is a valid predictor of prognosis and therapeutic response in patients with HCC disease. Furthermore, PSMD13 may be a potential therapeutic target., Competing Interests: The authors declare no conflicts of interest., (© 2023 Huang et al.)

Pancreatic β-cell function impairment and insulin resistance are central to the development of obesity-related type 2 diabetes mellitus (T2DM). Bariatric surgery (BS) is a practical treatment approach to treat morbid obesity and achieve lasting T2DM remission. Traditionally, sustained postoperative glycemic control was considered a direct result of decreased nutrient intake and weight loss. However, mounting evidence in recent years implicated a weight-independent mechanism that involves pancreatic islet reconstruction and improved β-cell function. In this article, we summarize the role of β-cell in the pathogenesis of T2DM, review recent research progress focusing on the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on pancreatic β-cell pathophysiology, and finally discuss therapeutics that have the potential to assist in the treatment effect of surgery and prevent T2D relapse., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Zou, Ruze and Xu.)

poorly cohesive (PC) gastric cancer (GC) (PC-GC) is a distinct histological subtype of GC and is defined as a tumor consisting of isolated or small clusters of tumor cells with poorly differentiated and metastatic characteristics. According to multiple studies, PC-GC is intrinsically heterogeneous, with mesenchymal variants being the most aggressive. However, to date, the molecular mechanisms associated with PC-GC are still not fully understood. This study investigated the role of the USP51/ZEB1/ACTA2 axis in promoting GC metastasis. Single-cell sequencing revealed that E-box binding homeobox 1 (ZEB1) expression was significantly increased in a subpopulation of low-adherent cells and was an independent prognostic factor in GC patients. Furthermore, the bulk transcriptome analysis revealed a significant positive correlation between Ubiquitin Specific Peptidase 51 (USP51), ZEB1, and Actin Alpha 2 (ACTA2), and our data further confirmed that all three were highly co-localized in PC-GC tissues. According to the findings of in vitro and in vivo experiments, USP51 was able to maintain ZEB1 expression to promote ACTA2 transcription, thereby activating the mesenchymal phenotype of GC cells and promoting tumor metastasis. Moreover, USP51 could recruit and activate stromal cells, including M2-like macrophages and fibroblasts, through cancer cells. Clinical data suggested that overexpression of USP51 predicts that patients have difficulty benefiting from immunotherapy and is associated with immune-exclusion tumor characteristics. Collectively, the findings of this study shed light on a key mechanism by which elevated USP51 expression induces Epithelial-mesenchymal transition (EMT) in GC cells, hence facilitating GC cell proliferation, survival, and dissemination. In this view, USP51/ZEB1/ACTA2 may serve as a candidate therapeutic target against GC metastasis., Competing Interests: Declaration of competing interest The Authors declare no Competing Financial or NonFinancial Interests. All authors contributed to data analysis, drafting, or revising of the article; agree on the journal to which the article is being submitted; provided final approval of the version to be published; and agree to be accountable for all aspects of the work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We identify three themes in the current research on nostalgia and acculturation. First, different types of nostalgia (i.e., home-culture and host-culture nostalgia) have distinct effects on immigrants' and sojourners' identification with home or host culture, affecting the integration of home and host cultural identities. Second, nostalgia during acculturation plays a crucial role in facilitating self-continuity among immigrants and sojourners moving across different cultures. Third, nostalgia affects the majority-group members' attitude towards immigrants and sojourners in the host culture. We conclude by highlighting three challenges for future research on nostalgia and acculturation: the content of types of nostalgia, the moderating role of individual differences, and the functions of nostalgia at various acculturation stages., Competing Interests: Conflict of interest Nothing declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rationale: We describe a case of insulinoma located extremely close to the accessory pancreatic duct (APD), but away from the main pancreatic duct (MPD). Previous studies showed insulinoma enucleation is a safe procedure for small benign tumors >3 mm distant from the MPD. However, in this case enucleation of the tumor led to unanticipated APD injury and grade B post-operative pancreatic fistula (POPF). We provide detailed records of clinical management and argue that enucleation of tumors near APD needs to be carefully weighed., Patient Concerns: The patient experienced a sudden increase of abdominal drain fluid and prolonged drainage time after a regular insulinoma enucleation surgery., Diagnosis: APD damage during the enucleation., Interventions: Drain fluid amylase concentration were regularly recorded and prolonged somatostatin analogs were administered., Outcomes: Amount of abdominal drain gradually decreased and the drain tube was removed on postoperative 37., Lessons: Benign pancreatic tumor close to the APD need to be evaluated carefully and clinical evidence is warranted to affirm the necessity of placing a pancreatic duct stent before the surgery., Competing Interests: The authors have conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Current evidence suggests that the hypoxic tumor microenvironment further aggravates tumor progression, leading to poor therapeutic outcomes. There is as yet no biomarker capable of evaluating the hypoxic state of the tumor. The cytochrome c oxidase (COX) subunit is crucial to the mitochondrial respiratory chain., Methods: We investigated the potential oncogenic role of COX subunit 4 isoform 2 gene (COX4I2) in colorectal cancer (CRC) by least absolute shrinkage and selection operator (LASSO) and COX regression analysis to examine whether COX4I2 overexpression can predict colorectal cancer (CRC) prognosis. The association of COX4I2 levels with clinical features and its biological actions were evaluated both in vitro and in vivo., Results: Our analysis showed that elevated COX4I2 levels were correlated with poor clinical outcomes. We also observed that that COX4I2 may be involved in epithelial-mesenchymal transition, activation of cancer-related fibroblasts and angiogenesis in relation to fibroblast growth factor 1., Conclusions: The COX4I2 level may be a predictor of outcome in CRC and may represent a novel target for treatment development., (© 2022. The Author(s).)

Robotic distal pancreatectomy (RDP) has become a routine procedure in many pancreatic centers. This study aimed to describe a single-center experience with RDP since the first case, identify the learning curves of operation time and complication rate, and discuss the safety and feasibility of RDP., Methods: We collected and retrospectively analyzed the single-center surgical experience of 301 patients undergoing RDP at Peking Union Medical College Hospital (PUMCH) between 2012 and 2022 and described the change in operation proficiency and occurrence of perioperative complications in this observational study. The learning curve was assessed using the cumulative sum method., Results: We observed a three-phase pattern of RDP learning with operation time, complications, and postoperative pancreatic fistula as indicators and a two-phase pattern for spleening-preserving success. The mean operation time was 3.9 hours. The incidence rate of clinically significant postoperative pancreatic fistula (CRPOPF) was 17.9% and overall Clavien-Dindo complication rate (≥3) was 16.6%. The change of postoperative complicate rate was correlated with percentage of malignant cases., Conclusion: In the last decade, an evident decrease was seen in operation time, complication rate, and an increase in the spleen-preserving rate of distal pancreatectomy. With proper training, RDP is a safe and feasible procedure., Competing Interests: The authors declare that they have no conflicts of interest. Editor note: Wenming Wu is an Editorial Board member of Journal of Pancreatology. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editorial Board member and their research groups., (Copyright © 2022 The Chinese Medical Association, Published by Wolters Kluwer Health, Inc.)

Background: Helicases have been classified as a class of enzymes that determine the stability of the cellular genome. There is growing evidence that helicases can help tumor cells resist drug killing by repairing Deoxyribose Nucleic Acid (DNA) or stabilizing transcription, which may contribute to the understanding of drug resistance. Currently, identifying cancer biomarkers among helicases and stratifying patients according to helicase activity will be able to guide treatment well., Methods: We clustered 371 hepatocellular carcinoma (HCC) patients from The Cancer Genome Atlas (TCGA) by consensus clustering based on helicase expression profiles to identify potential molecular subtypes. The Multiscale Embedded Gene Co-Expression Network Analysis (MEGENA) algorithm was used to find core differential gene modules between different molecular subtypes, and single-cell analysis was utlized to explore the potential function of hub gene. Immunohistochemical (IHC) staining was used to verify the diagnostic value of DDX56 and its ability to reflect the proliferation efficiency of cancer cells., Results: We identified two subtypes associated with helicase. High helicase subtype was associated with poor clinical outcome, massive M0 macrophage infiltration, and highly active cell proliferation features. In addition, we identified a new biomarker, DDX56 , which has not been reported in HCC, was highly expressed in HCC tissues, associated with poor prognosis, and was also shown to be associated with high cell proliferative activity., Conclusion: In conclusion, based on helicase expression profiles, we have developed a new classification system for HCC, which is a proliferation-related system, and has clinical significance in evaluating prognosis and treating HCC patients, including immunotherapy and chemotherapy. In addition, we identified a new biomarker, DDX 56 , which is overexpressed in HCC tissues, predicts a poor prognosis and is a validated index of tumor cell proliferation., Competing Interests: The authors declare no conflicts of interest in relation to this work., (© 2022 Yin et al.)

The TBC (Tre-2/Bub2/Cdc16, TBC) structural domain is now considered as one of the factors potentially regulating tumor progression. However, to date, studies on the relationship between TBC structural domains and tumors are limited. In this study, we identified the role of TBC1 domain family member 8 (TBC1D8) as an oncogene in colorectal cancer (CRC) by least absolute shrinkage and selection operator (LASSO) and Cox regression analysis, showing that TBC1D8 may independently predict CRC outcome. Functional enrichment and single-cell analysis showed that TBC1D8 levels were associated with hypoxia. TBC1D8 levels were also positively correlated with M2 macrophage infiltration, which may have a complex association with hypoxia. Taken together, these results show that the TBC1D8 gene is involved in colorectal carcinogenesis, and the underlying molecular mechanisms may include hypoxia and immune cell infiltration., (© 2022. The Author(s).)

Magnaporthe oryzae secretes several effectors that modulate and hijack rice processes to colonize host cells, but the underlying mechanisms remain unclear. We report on a novel cytoplasmic effector MoIug4 that targets the rice ethylene pathway as a transcription repressor to subvert host immunity. We found that MoIug4 binds to the promoter of the host OsEIN2 gene that encodes a central signal transducer in the ethylene-signaling pathway. We also identified a MoIug4 interacting protein, OsAHL1, which acts as an AT-hook motif-containing protein binding to the A/T-rich promoter regions. Our knockout and overexpression studies showed that OsAHL1 positively regulates plant immunity in response to M. oryzae infection. OsAHL1 exhibits transcriptional regulatory activities by binding the OsEIN2 promoter region, similar to MoIug4. Intriguingly, we found that MoIug4 exhibits a higher binding affinity than OsAHL1 to the OsEIN2 promoter, suggesting differential regulatory specificities. These results revealed a counter-defense strategy by which the pathogen effector suppresses the activation of host defense genes by interfering with host transcription activator functions., (© 2022 The Authors. New Phytologist © 2022 New Phytologist Foundation.)

Colon adenocarcinoma (COAD) accounts for 95% of colon cancer cases, with the 5-year survival rate significantly affected by local or distant metastases. Yiqi Jianpi Huayu Jiedu decoction (YJHJD), based on the theory of "nourish qi, invigorate the spleen, remove blood stasis, and detoxify", has long been applied and shown to be remarkable in the prevention and treatment of gastrointestinal tumors. However, the underlying therapeutic mechanisms of YJHJD have not been fully elucidated. Herein, we first confirmed hsa-miR-374a-3p as a tumor suppressor based on its lower expression in the plasma of patients with COAD with liver metastasis and association with more advanced local progression. We also verified WNT3 as a potential target of hsa-miR-374a-3p and observed its increased expression in COAD tissues. Furthermore, we showed that the hsa-miR-374a-3p/Wnt3/β-catenin axis was responsible for epithelial-mesenchymal transition (EMT) and cellular plasticity in COAD, as well as poorer patient prognosis. Our results showed that YJHJD inhibited motility and colony potential in vitro , as well as liver metastasis of COAD in vivo . Moreover, YJHJD induced a reversal of EMT and cellular plasticity-related molecular expression, increased hsa-miR-374a-3p, and decreased Wnt3 and β-catenin levels. In addition, silencing of hsa-miR-374a-3p weakened YJHJD inhibition, whereas the β-catenin inhibitor XAV939 partially repaired it. Taken together, these results demonstrated that YJHJD suppressed the EMT and cellular plasticity of COAD by regulating hsa-miR-374a-3p/Wnt3/β-catenin signaling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhuang, Zhou, Liu, Wang, Qian, Zou, Peng, Xue, Jin and Wu.)

Background: The goal of the current research was to investigate circATXN7 expression in esophageal cancer (EC) and its impact on the proliferation, migration, and invasion of EC cells., Methods: Determination of circATXN7 expression in esophageal cancer tissues and adjacent tissueswas carried out using quantitative reverse transcription polymerase chain reaction (qRT-PCR), and we further analyzed the correlation between patients' clinical characteristics and circATXN7 expression. EC cell lines (EC-9706, Eca-109, TE-1, KYSE-30, and KYSE-150) and normal esophageal cell line (HET-1A) were cultured, and circATXN7 expression was detected by qRT-PCR. The lowest circATXN7-containing Eca-109 cells were selected to be transfected with an overexpressing lentiviral vector (circATXN7). EC-9706 cells with the highest expression of circATXN7 were selected for transfection with knockdown vectors [short hairpin RNA (shRNA)#1 and shRNA#2] of the circATXN7 sequence. Cell proliferation was determined via MTT assay. The formation of cell clones was investigated via colony formation assay. Transwell migration assay was utilized to determine cell migration and invasion ability., Results: Significantly higher levels of circATXN7 were observed in EC tissues compared with paracancerous tissues (P<0.01), and circATXN7 expression level showed a significant correlation with the tumor/lymph nodes/metastasis (TNM) stage and metastasis of lymph nodes (P<0.05). Among all esophageal cell lines, EC-9706 had the highest expression level and Eca-109 had the lowest expression level. The MTT assay revealed that circATXN7 overexpression could significantly promote the proliferation of Eca-109 cells, while circATXN7 knockdown was capable of significantly inhibiting EC cell proliferation. The colony formation experiments revealed a significant increase in the number of clones in the circATXN7 overexpression model and a significant decrease in the circATXN7 knockdown model. The results of transwell migration experiments suggested that circATXN7 overexpression could promote EC cell invasion and migration, while knockdown of circATXN7 expression was associated with significant inhibition of the invasion and migration of these cells., Conclusions: CircATXN7 exerted a critical role in the incidence and progression of EC. This study identified a novel molecular target and established a theoretical basis for the early detection and treatment of EC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-481/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: As one of the most immunogenic malignancies, skin cutaneous melanoma (SKCM) is mainly characterized by a high prevalence in immune-compromised patients and a brisk lymphocyte infiltration in the tumor microenvironment (TME). However, to date, studies on deubiquitination in SKCM are still very limited., Methods: Public data with regard to this study in SKCM patients were acquired from The Cancer Genome Atlas (TCGA) and the Gene-Expression Omnibus (GEO) databases. We stratified TCGA-SKCM cases using consensus clustering and identified independent prognostic factors in deubiquitinating enzymes encoding genes (DECGs) by LASSO-Cox analysis. USP35 transcriptome level was examined using public data and validated by Immunohistochemical (IHC) staining at the protein level. Enrichment analysis was used to explore the potential functions of USP35 , and the TISCH database, providing further evidence at the single-cell level. The CIBERSORT algorithm was used to assess the relationship between USP35 and the immune microenvironment, and IHC was used to further evaluate the relationship between USP35 and immunotherapy response. Finally, we used the cBioPortal and the Methsurv database to analyze the significance of genomic alterations of USP35 in melanoma., Results: Our results showed that DECGs can be effectively used to stratify SKCM patients, suggesting their potential significance in the development of SKCM. Furthermore, USP35 overexpression was significantly associated with an unfavorable prognosis. We further revealed that USP35 may be involved in the activation of TORC1 signaling. Most importantly, USP35 was found to be significantly associated with an immunosuppressive TME, both in terms of negative correlation with the abundance of infiltrating CD8+ T cells and in terms of the fact that patients with high USP35 expression may benefit less from immunotherapy than those with low USP35 expression., Conclusion: Deubiquitinating enzymes are of great importance in the diagnosis and treatment of SKCM, and USP35 is an extremely promising target for immunotherapy., Competing Interests: The authors have declared no conflicts of interest., (© 2022 Zhang et al.)

Background: The long non-coding RNA (lncRNA) RP9 pseudogene (RP9P) is a pseudogene-derived lncRNA that has never been reported in cancer, and its function underlying tumorigenesis in colorectal cancer (CRC) remains unknown., Methods: RP9P and miR-133a-3p were filtered through bioinformatics analysis. The level of RP9P, miR-133a-3p, and FOXQ1 in CRC cell lines was detected by real-time PCR. Cell Counting Kit-8 and flow cytometric analyses were used to detect cell proliferation and apoptosis, respectively. Interactions between RP9P, miR-133a-3p, and FOXQ1 were confirmed by a dual-luciferase reporter assay., Results: RP9P was overexpressed in CRC compared to normal control tissues and cells. Knockdown of RP9P inhibited CRC cell viability. RP9P directly interacted with miR-133a-3p, and miR-133a-3p downregulation abrogated the tumor-suppressing effect of RP9P knockdown. miR-133a-3p directly targeted FOXQ, which was positively regulated by RP9P. RP9P knockdown decreased FOXQ1 expression levels in CRC cells by directly targeting miR-133a-3p via a sponge mechanism. In addition, in vivo experiments in a xenograft model revealed that downregulated RP9P expression inhibited CRC cell tumorigenesis., Conclusion: RP9P promotes colorectal cancer progression by regulating the miR-133a-3p/FOXQ1 axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Liu, Lin, Yang, Wu, Xue, Zou and Qian.)

Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti-cancer drugs are severely restricted from reaching the tumour site. Cell-penetrating peptides (CPPs) are typically made up of 5-30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti-cancer treatment strategies, serving as an excellent potential choice for oncology treatment. However, their drawbacks, such as the lack of cell specificity, short duration of action, poor stability in vivo, compatibility problems (i.e. immunogenicity), poor therapeutic efficacy and formation of unwanted metabolites, have limited their further application in cancer treatment. The cellular uptake mechanisms of CPPs involve mainly endocytosis and direct penetration, but still remain highly controversial in academia. The CPPs-based drug delivery strategy could be improved by clever design or chemical modifications to develop the next-generation CPPs with enhanced cell penetration capability, stability and selectivity. In addition, some recent advances in targeted cell penetration that involve CPPs provide some new ideas to optimise CPPs., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Gap junctions, as one of the major ways to maintain social connections between cells, are now considered as one of the potential regulators of tumor metastasis. However, to date, studies on the relationship between gap junctions and colorectal cancer (CRC) are limited., Methods: We synthesized connexins-coding gene expression data from public Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatics analysis was performed using R software and several database resources such as MEXPRESS database, Gene Set Cancer Analysis (GSCA) database, Human Protein Atlas (HPA) database, Tumor Immune Single Cell Hub (TISCH) database, Search Tool for Retrieval of Gene Interaction Relationships (STRING), and Cytoscape software, etc., to investigate the biological mechanisms that may be involved in connexins. Immunofluorescence and immunohistochemical staining were used to validate the expression and localization of GJA4., Results: We found that CRC patients can be divided into two connexin clusters and that patients in cluster C1 had shorter survival than in cluster C2. The infiltration of M1 macrophages and NK cells was lower in cluster C1, while the levels of M2 macrophages and immune checkpoints were higher, indicating an immunosuppressed state in cluster C1. In addition, the epithelial-mesenchymal transition (EMT) phenotype was significantly activated in cluster C1. We observed that GJA4 was up-regulated in colorectal cancer tissues, which was related to poor prognosis. It was mainly expressed in fibroblasts, but the expression levels in normal intestinal epithelial cells were low. Finally, we found that GJA4 was associated with M2 macrophages and may be a potential immunosuppressive factor., Conclusion: We found that there is a significant correlation between abnormal connexins expression and patients' prognosis, and connexins play an important role in stromal-tumor interactions. Connexins, especially GJA4, can help enhance our understanding of tumor microenvironment (TME) and may guide more effective immunotherapeutic strategies., Competing Interests: The authors declare no conflicts of interest., (© 2022 Liu et al.)

Compost-based organic fertilizers made from animal manures may contain high levels of antibiotic resistance genes (ARGs). However, the factors affecting the abundance and profile of ARGs in organic fertilizers remain unclear. We conducted a national-wide survey in China to investigate the effect of material type and composting process on ARG abundance in commercial organic fertilizers and quantified the contributions of bacterial composition and mobile genetic elements (MGEs) to the structuring of ARGs, using quantitative PCR and Illumina sequencing of 16S rRNA gene amplicons. The tetracycline, sulfonamide, aminoglycoside and macrolide resistance genes were present at high levels in all organic fertilizers. Seven ARGs that confer resistance to clinically important antibiotics, including three β-lactam resistance genes, three quinolone resistance genes and the colistin resistance gene mcr-1, were detected in 8 - 50% the compost samples, whereas the vancomycin resistance gene vanC was not detected. Raw material type had a significant (p < 0.001) effect on the ARG abundance, with composts made from animal feces except some cattle feces generally having higher loads of ARGs than those from non-animal raw materials. Composting process type showed no significant (p > 0.05) effect on ARG abundance in the organic fertilizers. MGEs exerted a greater influence on ARG composition than bacterial community, suggesting a strong mobility of ARGs in the organic fertilizers. Our study highlights the need to manage the risk of ARG dissemination from agricultural wastes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Mechanical ventilation (MV) can provoke acute lung injury (ALI) by increasing inflammation activation and disrupting the barrier in lung tissues even causing death. However, the inflammation-related molecules and pathways in MV-induced ALI remain largely unknown. Hence, the purposes of this study are to examine the role and mechanism of a novel inflammation-related molecule, leukotriene B4 (LTB4), in ALI., Methods: The functions of LTB4 in one-lung ventilation (OLV) model were detected by the loss-of-function experiments. H&E staining was used to examine the pathologic changes of lung tissues. Functionally, PLC ε -1 knockdown and Toll-like receptor 4 (TLR4)/NF- κ B pathway inhibitor were used to detect the regulatory effects of LTB4 on the phospholipase C ε (PLC ε -1)/TLR4/nuclear factor-kappa B (NF- κ B) pathway. The levels of genes and proteins were determined by RT-qPCR and western blotting assay. The levels of inflammation cytokines and chemokines were measured by ELISA., Results: Here, we found LTA4H, leukotriene B (4) receptor 1 (BLT1), LTB4, and PLC ε -1 upregulated in OLV rats and associated with inflammatory activation and lung permeability changes of lung tissues. Inhibition of LTB4 alleviated the OLV-induced ALI by inhibiting inflammatory activation and lung permeability changes of lung tissues. For mechanism analyses, LTB4 promoted OLV-induced ALI by activating the PLC ε -1/TLR4/NF- κ B pathway., Conclusion: LTB4 induced ALI in OLV rats by activating the PLC ε -1/TLR4/NF- κ B pathway. Our findings might supply a new potential therapeutic for OLV-induced ALI., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Jing Luo et al.)

Alcoholic abuse is one of the most serious causes of liver diseases worldwide. Although detailed molecular pathogenesis of alcohol-induced liver damages remains elusive with intensive debates, it has been widely recognized that hepatic damage caused by free radicals generated from alcohol metabolism is one of the most critical factors for alcohol-induced liver diseases. Betulinic acid is a potent antioxidant with additional known pharmacological safety characteristics and minimal toxicity. However, poor solubility limited its usage. In this study, we assessed the efficacy of BAN, a betulinic acid and nucleoside hybrid with good water solubility, in reversing acute liver damages using an established alcohol overdose animal model. The results indicated that BAN is an extremely promising therapeutic agent against acute alcohol-induced liver damage. BAN effectively protects liver from alcohol damage by reducing serum ALT level by up to 47%, as well as liver oxidative stress indicated by significantly increased SOD, CAT, and GSH-Px levels. Moreover, hepatic FXR activation and a corresponding downstream anti-oxidative stress transcriptional cascade including Nrf2, HO-1, and NOQ1 induce the protective role of BAN. On the other hand, BAN administration also leads to increase cellular autophagy response, as indicated by the key ATG protein activation. We concluded that BAN, comparing with Betulinic acid, prevents acute alcohol-induced liver damages more effectively, with the dual mechanisms of neutralizing oxidative stress and promoting autophagy., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)