Exploring the impact of N4-acetylcytidine modification in RNA on non-neoplastic disease: unveiling its role in pathogenesis and therapeutic opportunities.

RNA modifications include not only methylation modifications, such as m6A, but also acetylation modifications, which constitute a complex interaction involving "writers," "readers," and "erasers" that play crucial roles in growth, genetics, and disease. N4-acetylcytidine (ac4C) is an ancient and highly conserved RNA modification that plays a profound role in the pathogenesis of a wide range of diseases. This review provides insights into the functional impact of ac4C modifications in disease and introduces new perspectives for disease treatment. These studies provide important insights into the biological functions of post-transcriptional RNA modifications and their potential roles in disease mechanisms, offering new perspectives and strategies for disease treatment.

Electroacupuncture improves the learning and memory abilities of rats with PSCI by attenuating the TLR4/NF-κB/NLRP3 signaling pathway on the hippocampal microglia.

This study aims to investigate how electroacupuncture regulates the learning and memory abilities of poststroke cognitive impairment (PSCI) rats through the TLR4/NF-κB/NLRP3 signaling pathway on the hippocampal microglia. Thirty male rats were randomly divided into three groups: sham surgery group, PSCI model group, and electroacupuncture group, with 10 rats in each group. Middle cerebral artery occlusion was used to establish the PSCI model. The Zea Longa method was used to score the rats' neurological function. Electroacupuncture was utilized for 21 days to improve PSCI. The learning and memory abilities of rats were tested using the Morris water maze. Hematoxylin-eosin staining and immunofluorescence were used to find the hippocampus' pathological changes. The concentration of interleukin-1ß, interleukin-6, tumor necrosis factor-α, and interleukin-18 were detected by ELISA. The mRNA expression levels of associated inflammatory corpuscles were measured by quantitative real-time PCR. The protein expression levels of TLR4, MyD88, NF-κB, and NLRP3 were measured using western blotting. Electroacupuncture improved not only the learning and memory abilities of PSCI rats but also hippocampal morphology. Electroacupuncture inhibited the activation of microglia and the TLR4/NF-κB/NLRP3 signaling pathway. Electroacupuncture also reduced proinflammatory factors and restrained the mRNA levels of NLRP3-associated inflammatory cytokines. Its mechanism was related to inhibiting the expression of the TLR4/NF-κB/NLRP3 signaling pathway, attenuating the release of inflammatory factors, and regulating the activation of hippocampal microglia in the brain.

Corrigendum: Identifying neutrophil-associated subtypes in ulcerative colitis and confirming neutrophils promote colitis-associated colorectal cancer.

[This corrects the article DOI: 10.3389/fimmu.2023.1095098.].

Identification and prognostic biomarkers among ZDHHC4/12/18/24, and APT2 in lung adenocarcinoma.

S-palmitoylases and S-depalmitoylases are differentially expressed in various cancers and several malignant tumors and show a strong prognostic ability. Notwithstanding, the potential clinical impact of S-palmitoylases and S-depalmitoylases, particularly in the prognosis and progression of lung adenocarcinoma (LUAD), has not been clarified. Expression levels of S-palmitoylases and S-depalmitoylases in LUAD were investigated using TCGA. GEPIA was used to evaluate the mRNA levels of S-palmitoylases and S-depalmitoylases at different pathological stages. Metascape was used to investigate the biological significance of S-palmitoylases and S-depalmitoylases. The Kaplan-Meier plotter was used to analyze the prognostic value of S-palmitoylases and S-depalmitoylases. CBioportal was used to analyze gene alterations in S-palmitoylases and S-depalmitoylases. UALCAN was used to examine DNA promoter methylation levels of S-palmitoylases and S-depalmitoylases. Finally, we investigated the relationship between S-palmitoylases, S-depalmitoylases, and tumor-infiltrating immune cells using TIMER. Correlations with immune checkpoint-related genes were determined using the R packages reshape2, ggpubr, ggplot2, and corrplot. PCR was also performed to assess the degree of ZDHHC4/12/18/24 and APT2 transcript expression in lung adenocarcinoma and adjacent normal lung tissues. HPA was utilized to investigate protein levels of S-palmitoylases and S-depalmitoylases in LUAD and normal lung tissue. Our study found that ZDHHC2/3/4/5/6/7/9/12/13/16/18/20/21/23/24, APT1/2, PPT1, LYPLAL1, ABHD4/10/11/12/13 and ABHD17C mRNA expression was significantly upregulated in LUAD, whereas ZDHHC1/8/11/11B/14/15/17/19/22, ABHD6/16A and ABHD17A mRNA expression was significantly downregulated. The functions of the differentially expressed S-palmitoylases and S-depalmitoylases were mainly associated with protein-cysteine S-palmitoyltransferase and protein-cysteine S-acyltransferase activities. Patients with high expression of ZDHHC4/12/18/24, APT2, ABHD4, ABHD11 and ABHD12 had a shorter overall survival. Infiltration of six immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) was closely associated with the expression of ZDHHC4/12/18/24 and APT2. ZDHHC4/12/18/24 and APT2 positively correlated with the immune checkpoint-related gene CD276. We assessed the mRNA levels of ZDHHC4/12/18/24 and APT2 using qRT-PCR and found increased expression of ZDHHC4/12/18/24 in LUAD compared with healty control lung tissues. ZDHHC4/12/18/24, and APT2 are potential prognostic biomarkers of LUAD. Their expression levels could be related to the tumor microenvironment in LUAD.

A turn-on fluorescent probe for detecting and bioimaging of HOCl in inflammatory and liver disease models.

Hypochlorous acid (HOCl) is a common reactive oxygen species (ROS) associated with the development of liver, tumor, inflammatory, and other diseases. In this work, the turn-on fluorescent probe named (WZ-HOCl) with a naphthalimide structure was designed and synthesized to detect endogenous HOCl in disease models. WZ-HOCl can achieve a fast response to HOCl with good linearity in the range of 0-45 µM (LOD = 147 nM). The application of WZ-HOCl in bioimaging was investigated by constructing a series of cellular disease models, and the results showed that WZ-HOCl could sensitively detect endogenous HOCl in inflammatory and liver disease models. It can also be used to differentiate between hepatocytes and hepatoma cells. WZ-HOCl will provide new methods and ideas for fluorescent probes in detecting drug-induced liver injury, alcoholic and non-alcoholic steatohepatitis, and some inflammation-related diseases.

Single-cell RNA sequencing reveals cancer stem-like cells and dynamics in tumor microenvironment during cholangiocarcinoma progression.

Cholangiocarcinoma is a malignancy of the bile ducts that is driven by activities of cancer stem-like cells and characterized by a heterogeneous tumor microenvironment. To better understand the transcriptional profiles of cancer stem-like cells and dynamics in the tumor microenvironment during the progression of cholangiocarcinoma, we performed single-cell RNA analysis on cells collected from three different timepoints of tumorigenesis in a YAP/AKT mouse model. Bulk RNA sequencing data from TCGA (The Cancer Genome Atlas program) and ICGC cohorts were used to verify and support the finding. In vitro and in vivo experiments were performed to assess the stemness of cancer stem-like cells. We identified Tm4sf1high malignant cells as cancer stem-like cells. Across timepoints of cholangiocarcinoma formation in YAP/AKT mice, we found dynamic change in cancer stem-like cell/stromal/immune cell composition. Nevertheless, the dynamic interaction among cancer stem-like cells, immune cells, and stromal cells at different timepoints was elaborated. Collectively, these data serve as a useful resource for better understanding cancer stem-like cell and malignant cell heterogeneity, stromal cell remodeling, and immune cell reprogramming. It also sheds new light on transcriptomic dynamics during cholangiocarcinoma progression at single-cell resolution.

Laser-driven hierarchical "gas-needles" for programmable and high-precision proximity transfer printing of microchips.

Micro-transfer printing (µTP) techniques are essential for advanced electronics. However, current contact/noncontact µTP techniques fail to simultaneously achieve high selectivity and transfer accuracy. Here, a laser projection proximity transfer (LaserPPT) technique is presented, which assembles the microchips in an approach-and-release manner, combining high-precision parallelism with individual chip control. An embedded carbon layer with a thin gas layer is generated by an ultraviolet laser, followed by absorbing heat from the infrared laser, to enable the sequential expansion of hierarchical "gas-needles." The level 1 large gas-needle with a substantially growing height can reduce the gap between the microchip and the receiver. Then, the level 2 small gas-needles enable the gentle release of a chip. Therefore, the LaserPPT can obtain a strong adhesion modulation (~1000 times), excellent size scalability (<100 micrometers), and high transfer accuracy of ~4 micrometers. Last, the assembly of a micro-light-emitting diode display demonstrates the capabilities for deterministic assembly of microarrays.

Aire drives steroid hormone biosynthesis by medullary thymic epithelial cells.

Thymic epithelial cells (TECs) produce glucocorticoids, which antagonize negative selection of autoreactive thymocytes and promote a competent T cell antigen-specific repertoire. To characterize their source, we generated a knock-in reporter mouse in which endogenous Cyp11b1, the final enzyme in de novo production of active glucocorticoids, was fluorescently tagged with mScarlet. Here, we find that Cyp11b1 is expressed in medullary TECs (mTECs) but not cortical TECs or other cells in the thymus. A distinct characteristic of mTECs is the presence of Aire, a transcription factor that drives expression of tissue-restricted antigens (TRAs) important for establishing immune tolerance. Cyp11b1 expression was highest in Aire+ mTECs, lower in post-Aire mTECs, and absent in mTECs of Aire-deficient mice. Transcriptomic analyses found that multiple enzymatic biosynthetic pathways are expressed specifically in mTECs and are also Aire dependent. In particular, we found that the thymus expresses messenger RNA for enzymes that catalyze production of many bioactive steroids and that glucocorticoids and sex steroids were secreted by cultured thymi. Expression of the transcripts for these genes and production of their final steroid products were markedly reduced in the absence of Aire. Thus, in addition to its well-established role in inducing TRAs that promote negative selection, Aire has an additional and contrary function of inducing glucocorticoids that antagonize negative selection, which together may expand and enhance the TCR repertoire. Furthermore, because Aire drives expression of multiple enzymes responsible for production of other non-gene-encoded bioactive molecules, it might have yet other roles in thymus development and function.

Anti-Cancer Activity of Verteporfin in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a heterogenous malignancy that arises from the biliary epithelium and has a poor clinical prognosis. The Hippo/yes-associated protein (YAP) pathway has been reported to affect various aspects of tumorigenesis, with high expression of YAP1 being negatively associated with survival in CCA patients. Thus, we investigated the antitumoral effect of verteporfin, a YAP1 pathway inhibitor, in YAP1/AKT hydrodynamic tail vein injected murine models. We also used flow cytometry and single-cell RNA sequencing (scRNA-seq) to analyze the change in the immune cell profile and malignant cell stemness following verteporfin treatment. Our results demonstrated reduced liver weight and tumor formation in verteporfin-treated groups compared to that of a vehicle-treated group. Immune cell profiling through flow cytometry showed that relative to the vehicle, verteporfin induced a higher ratio of tumor-associated macrophage (TAM) M1/M2 and increased the percentage of activated CD8 T cell population (CD8+CD25+ and CD8+CD69+). scRNA-seq analysis showed significantly increased TAM M1 populations following verteporfin treatment and decreased proportions of stem-like cells within the malignant cell population. In summary, this study indicates that in CCA YAP/AKT murine models, verteporfin reduces tumorigenesis by polarizing anti-tumoral TAM and activating CD8 T cells and decreasing stem-like malignant cell proportions in the tumor microenvironment.

CT synthesis from multi-sequence MRI using adaptive fusion network.

OBJECTIVE: To investigate a method using multi-sequence magnetic resonance imaging (MRI) to synthesize computed tomography (CT) for MRI-only radiation therapy. APPROACH: We proposed an adaptive multi-sequence fusion network (AMSF-Net) to exploit both voxel- and context-wise cross-sequence correlations from multiple MRI sequences to synthesize CT using element- and patch-wise fusions, respectively. The element- and patch-wise fusion feature spaces were combined, and the most representative features were selected for modeling. Finally, a densely connected convolutional decoder was applied to utilize the selected features to produce synthetic CT images. MAIN RESULTS: This study includes a total number of 90 patients' T1-weighted MRI, T2-weighted MRI and CT data. The AMSF-Net reduced the average mean absolute error (MAE) from 52.88-57.23 to 49.15 HU, increased the peak signal-to-noise ratio (PSNR) from 24.82-25.32 to 25.63 dB, increased the structural similarity index measure (SSIM) from 0.857-0.869 to 0.878, and increased the dice coefficient of bone from 0.886-0.896 to 0.903 compared to the other three existing multi-sequence learning models. The improvements were statistically significant according to two-tailed paired t-test. In addition, AMSF-Net reduced the intensity difference with real CT in five organs at risk, four types of normal tissue and tumor compared with the baseline models. The MAE decreases in parotid and spinal cord were over 8% and 16% with reference to the mean intensity value of the corresponding organ, respectively. Further, the qualitative evaluations confirmed that AMSF-Net exhibited superior structural image quality of synthesized bone and small organs such as the eye lens. SIGNIFICANCE: The proposed method can improve the intensity and structural image quality of synthetic CT and has potential for use in clinical applications.

Identifying neutrophil-associated subtypes in ulcerative colitis and confirming neutrophils promote colitis-associated colorectal cancer.

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of the intestinal mucosa, the incidence of which has increased worldwide. There is still a lack of clear understanding of the pathogenesis of ulcerative colitis that ultimately leads to colitis-associated colorectal cancer. Method: We download UC transcriptome data from the GEO database and pass the limma package in order to identify differentially expressed genes. Gene Set Enrichment Analysis (GSEA) was used to identify potential biological pathways. We identified immune cells associated with UC by CIBERSORT and Weighted co-expression network analysis (WGCNA). We used validation cohorts and mouse models to verify the expression of the hub genes and the role of neutrophils. Result: We identified 65 differentially expressed genes in UC samples and healthy controls. GSEA, KEGG, and GO analyses displayed that DEGs were enriched in immune-related pathways. CIBERSORT analysis revealed increased infiltration of neutrophils in UC tissues. The red module, obtained by WGCNA analysis, was considered to be the most relevant module for neutrophils.Based on neutrophil-associated differentially expressed genes, UC patients were classified into two subtypes of neutrophil infiltration. We discovered that the highly neutrophil-infiltrated subtype B of UC patients had a higher risk of developing CAC. Five genes were identified as biomarkers by searching for DEGs between distinct subtypes. Finally, using the mouse model, we determined the expression of these five genes in the control, DSS, and AOM/DSS groups. The degree of neutrophil infiltration in mice and the percentage of MPO and pSTAT3 expression in neutrophils were analyzed by flow cytometry. In the AOM/DSS model, MPO and pSTAT3 expressions were significantly increased. Conclusions: These findings suggested neutrophils might promote the conversion of UC into CAC. These findings improve our understanding of the pathogenesis of CAC and provide new and more effective insights into the prevention and treatment of CAC.

Unveiling the dynamics of antibiotic resistome, bacterial communities, and metals from the feces of patients in a typical hospital wastewater treatment system.

Bacterial pathogens and antibiotic resistance genes (ARGs) are extensively disseminated into the environment via hospital wastewater (HWW), as it contains large quantities of feces from resident patients. However, studies on the antibiotic resistome and pathogenic bacteria from the gut of resident patients within the hospital wastewater treatment plant (hWWTP) are limited. Here, we examined and compared the occurrence and abundance of ARGs, mobile genetic elements (MGEs), metals, and bacterial communities from the feces of patients in a typical hWWTP system and determined the pathogenic hosts responsible for transferring ARGs. There were 176 ARGs and 43 MGEs detected in the feces of hospitalized patients, 129 genes were persistent, and 88 genes were enriched after HWW treatment, particularly for the blaVEB, blaNDM, and class 1 integron (intI1), with an average of 659-fold, 202-fold, and seven-fold enrichment, respectively. MGEs, especially Is613, in the feces of hospitalized patients were exceptionally abundant and even surpassed the abundance of total ARGs, which explained the persistence of ARGs in hWWTPs due to possible gene mobilization events. Bacteroidetes and Firmicutes were the most abundant phyla in these feces, accounting for 81 % of the total gut microbiota, while Epsilonbacteraeota and Proteobacteria dominated the hWWTPs. Additionally, 54 possible bacterial pathogens were found in the hospital environment, including four "ESKAPE" pathogens and 14 cancer-related pathogens. Many of them were strongly associated with different types of ARGs. Notably, Bacteroides was the major potential ARG-harboring pathogenic genus, as determined by the network analysis, and was highly abundant after the treatment. The altered microbial community was the major contributing factor shaping antibiotic resistome. This study might provide a comprehensive insight into the distribution profiles of ARGs and pathogens from the gut of inpatients throughout the HWW treatment system, which could be used as a reference for optimizing HWW treatment and monitoring public risk.

Murine allogeneic CAR T cells integrated before or early after posttransplant cyclophosphamide exert antitumor effects.

Relapse limits the therapeutic efficacy both of chimeric antigen receptor (CAR) T cells and allogeneic hematopoietic cell transplantation (allo-HCT). Patients may undergo these therapies sequentially to prevent or treat relapsed malignancy. However, direct integration of the 2 therapies has been avoided over concerns for potential induction of graft-versus-host disease (GVHD) by allogeneic CAR T cells. We have shown in murine T-cell-replete MHC-haploidentical allo-HCT that suppressive mechanisms induced immediately after posttransplant cyclophosphamide (PTCy), given on days +3/+4, prevent GVHD induction by alloreactive T cells infused as early as day +5. Therefore, we hypothesized that allogeneic CAR T cells given in a similarly integrated manner in our murine MHC-haploidentical allo-HCT model may safely exert antitumor effects. Indeed, allogeneic anti-CD19 CAR T cells given early after (day +5) PTCy or even prior to (day 0) PTCy cleared leukemia without exacerbating the cytokine release syndrome occurring from the MHC-haploidentical allo-HCT or interfering with PTCy-mediated GVHD prevention. Meanwhile, CAR T-cell treatment on day +9 or day +14 was safe but less effective, suggesting a limited therapeutic window. CAR T cells infused before PTCy were not eliminated, but surviving CAR T cells continued to proliferate highly and expand despite PTCy. In comparison with infusion on day +5, CAR T-cell infusion on day 0 demonstrated superior clinical efficacy associated with earlier CAR T-cell expansion, higher phenotypic CAR T-cell activation, less CD4+CD25+Foxp3+ CAR T-cell recovery, and transcriptional changes suggesting increased activation of CD4+ CAR T cells and more cytotoxic CD8+ CAR T cells. This study provides mechanistic insight into PTCy's impact on graft-versus-tumor immunity and describes novel approaches to integrate CAR T cells and allo-HCT that may compensate for deficiencies of each individual approach.

Epidemiological investigation of lower respiratory tract infections during influenza A (H1N1) pdm09 virus pandemic based on targeted next-generation sequencing.

Background: Co-infection has been a significant contributor to morbidity and mortality in previous influenza pandemics. However, the current influenza A (H1N1) pdm09 virus pandemic, as the first major outbreak following the SARS-CoV-2 pandemic, may differ epidemiologically. Further investigation is necessary to understand the specific features and impact of this influenza A pandemic. Study design: We conducted a retrospective cohort study at a Chinese hospital between January and April 2023, focusing on patients with lower respiratory tract infections. Pathogen detection employed targeted next-generation sequencing (tNGS) on bronchoalveolar lavage fluid (BALF) or sputum samples. Results: This study enrolled 167 patients with lower respiratory tract infections, and the overall positivity rate detected through tNGS was around 80%. Among them, 40 patients had influenza A (H1N1) pdm09 virus infection, peaking in March. In these patients, 27.5% had sole infections, and 72.5% had co-infections, commonly with bacteria. The frequently detected pathogens were Aspergillus fumigatus, SARS-CoV-2, and Streptococcus pneumoniae. For non-influenza A virus-infected patients, the co-infection rate was 36.1%, with 42.3% having SARS-CoV-2. Patients with influenza A virus infection were younger, had more females and diabetes cases. Among them, those with sole infections were older, with less fever and asthma but more smoking history. Regarding prognosis, compared to sole influenza A virus infection, co-infected patients demonstrated higher 21-day recovery rates and a higher incidence of heart failure. However, they exhibited lower proportions of respiratory failure, acute kidney failure, septic shock, and hospital stays lasting more than 10 days. Interestingly, patients with non-influenza A virus infection had a significantly lower 21-day recovery rate. Correlation analysis indicated that the 21-day recovery rate was only associated with influenza A (H1N1) pdm09 virus. Conclusion: During the current pandemic, the influenza A (H1N1) pdm09 virus may have been influenced by the SARS-CoV-2 pandemic and did not exhibit a strong pathogenicity. In fact, patients infected with influenza A virus showed better prognoses compared to those infected with other pathogens. Additionally, tNGS demonstrated excellent detection performance in this study and showed great potential, prompting clinical physicians to consider its use as an auxiliary diagnostic tool.

SLC2As as diagnostic markers and therapeutic targets in LUAD patients through bioinformatic analysis.

Facilitative glucose transporters (GLUTs), which are encoded by solute carrier 2A (SLC2A) genes, are responsible for mediating glucose absorption. In order to meet their higher energy demands, cancer cells are more likely than normal tissue cells to have elevated glucose transporters. Multiple pathogenic processes, such as cancer and immunological disorders, have been linked to GLUTs. Few studies, meanwhile, have been conducted on individuals with lung adenocarcinoma (LUAD) to evaluate all 14 SLC2A genes. We first identified increased protein levels of SLC2A1, SLC2A5, SLC2A6, and SLC2A9 via HPA database and downregulated mRNA levels of SLC2A3, SLC2A6, SLC2A9, and SLC2A14 by ONCOMINE and UALCAN databases in patients with LUAD. Additionally, lower levels of SLC2A3, SLC2A6, SLC2A9, SLC2A12, and SLC2A14 and higher levels of SLC2A1, SLC2A5, SLC2A10, and SLC2A11 had an association with advanced tumor stage. SLC2A1, SLC2A7, and SLC2A11 were identified as prognostic signatures for LUAD. Kaplan-Meier analysis, Univariate Cox regression, multivariate Cox regression and ROC analyses further revealed that these three genes signature was a novel and important prognostic factor. Mechanistically, the aberrant expression of these molecules was caused, in part, by the hypomethylation of SLC2A3, SLC2A10, and SLC2A14 and by the hypermethylation of SLC2A1, SLC2A2, SLC2A5, SLC2A6, SLC2A7, and SLC2A11. Additionally, SLC2A3, SLC2A5, SLC2A6, SLC2A9, and SLC2A14 contributed to LUAD by positively modulating M2 macrophage and T cell exhaustion. Finally, pathways involving SLC2A1/BUB1B/mitotic cell cycle, SLC2A5/CD86/negative regulation of immune system process, SLC2A6/PLEK/lymphocyte activation, SLC2A9/CD4/regulation of cytokine production might participate in the pathogenesis of LUAD. In summary, our results will provide the theoretical basis on SLC2As as diagnostic markers and therapeutic targets in LUAD.

Single-cell sequencing reveals the landscape of the tumor microenvironment in a skeletal undifferentiated pleomorphic sarcoma patient.

Skeletal undifferentiated pleomorphic sarcoma (SUPS) is an invasive pleomorphic soft tissue sarcoma with a high degree of malignancy and poor prognosis. It is prone to recur and metastasize. The tumor microenvironment (TME) and the pathophysiology of SUPS are barely described. Single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect the landscape of human diseases at an unprecedented resolution, particularly in diseases lacking animal models, such as SUPS. We performed scRNA-seq to analyze tumor tissues and paracancer tissues from a SUPS patient. We identified the cell types and the corresponding marker genes in this SUPS case. We further showed that CD8+ exhausted T cells and Tregs highly expressed PDCD1, CTLA4 and TIGIT. Thus, PDCD1, CTLA4 and TIGIT were identified as potential targets in this case. We applied copy number karyotyping of aneuploid tumors (CopyKAT) to distinguish malignant cells from normal cells in fibroblasts. Our study identified eight malignant fibroblast subsets in SUPS with distinct gene expression profiles. C1-malignant Fibroblast and C6-malignant Fibroblast in the TME play crucial roles in tumor growth, angiogenesis, metastasis and immune response. Hence, targeting malignant fibroblasts could represent a potential strategy for this SUPS therapy. Intervention via tirelizumab enabled disease control, and immune checkpoint inhibitors (ICIs) of PD-1 may be considered as the first-line option in patients with SUPS. Taken together, scRNA-seq analyses provided a powerful basis for this SUPS treatment, improved our understanding of complex human diseases, and may afforded an alternative approach for personalized medicine in the future.

Multifunctional hybrid hydrogel with transparency, conductivity, and self-adhesion for soft sensors using hemicellulose-decorated polypyrrole as a conductive matrix.

Polymers with high conductivity and cross-linking ability are ideal materials for the preparation of conductive hydrogels for application in wearable electronic devices. However, the fabrication of conductive polymer-incorporated hydrogels with good synergistic properties remains a great challenge due to the hydrophobicity and opacity of conjugated π conductive polymers. In this study, a multifunctional hybrid hydrogel was prepared by incorporating hemicellulose-decorated polypyrrole (H/PPY), polyvinyl alcohol (PVA), and tannic acid (TA) into a polyacrylamide (PAM) network. The addition of excess ammonium persulfate (APS) in the process of gelation not only initiated the polymerization of PAM but also resulted in the change of the hydrogel from opaque to transparent by continuously breaking and reducing the size of the PPY particles. The hybrid hydrogel exhibited high transparency and conductivity, good adhesion ability and mechanical performance, and high resistance strain sensitivity and could accurately monitor the strain signals of the index finger and elbow flexion and pulse beat during rest and exercise, which has promising potential for use in wearable or implantable smart sensor devices, electronic skins, and artificial intelligence applications.

DLGAP1-AS2 promotes human colorectal cancer progression through trans-activation of Myc.

Substantial evidence suggests that non-coding RNA plays a vital role in human cancer, especially long non-coding RNA (lncRNA) with a length greater than 200nt. Herein, we found a lncRNA facilitating human colorectal cancer (CRC) progression. DLGAP1-AS2 was significantly increased in CRC tissues and cell lines. Knockdown of DLGAP1-AS2 inhibited CRC cell proliferation, migration, invasion in vitro, and tumor growth in vivo. The subcellular localization of DLGAP1-AS2 was translocated from the cytoplasm of normal cells to the nucleus of CRC cells due to reduced levels of N6-methyladenosine (m6A) modification. Further, through the screening of a series of signal pathways, we found that Myc pathway was involved in the effect of DLGAP1-AS2. Silencing of DLGAP1-AS2 markedly reduced Myc mRNA and protein levels. Blockade of Myc effectively abolished the enhanced aggressive behaviors of CRC cells caused by DLGAP1-AS2 overexpression. Mechanistically, DLGAP1-AS2 directly bound CTCF, a well-known transcriptional repressor of Myc, resulting in reduced binding of CTCF on Myc promoter and activating Myc transcription. The second hairpin structure of DLGAP1-AS2 was critical for the interaction between DLGAP1-AS2 and CTCF in the nucleus. Taken together, our study reveals the oncogenic regulatory axis of DLGAP1-AS2/CTCF/Myc in CRC, implying a promising targeted therapy for clinical application.

A Knock-In Mouse Model of Thymoma With the GTF2I L424H Mutation.

INTRODUCTION: The pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. Nevertheless, the precise role of this mutation in tumorigenesis of thymic epithelial cells is unclear. METHODS: To investigate the role of GTF2I L424H mutation in thymic epithelial cells in vivo, we generated and characterized a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. Digital spatial profiling was performed on thymomas and normal thymic tissues with GeoMx-mouse whole transcriptome atlas. Immunohistochemistry staining was performed using both mouse tissues and human thymic epithelial tumors. RESULTS: We observed that the Gtf2i mutation impairs development of the thymic medulla and maturation of medullary thymic epithelial cells in young mice and causes tumor formation in the thymus of aged mice. Cell cycle-related pathways, such as E2F targets and MYC targets, are enriched in the tumor epithelial cells. Results of gene set variation assay analysis revealed that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in the thymomas of the knock-in mice, which mirrors the human counterparts in The Cancer Genome Atlas database. Immunohistochemistry results revealed similar expression pattern of epithelial cell markers between mouse and human thymomas. CONCLUSIONS: We have developed and characterized a novel thymoma mouse model. This study improves knowledge of the molecular drivers in thymic epithelial cells and provides a tool for further study of the biology of thymic epithelial tumors and for development of novel therapies.

Protective Effect of Nalbuphine Combined With Dexmedetomidine on the Lungs of Children With Atelectasis and Foreign Body in the Bronchus During the Perioperative Period.

Objective: The present study aims to explore the protective effect of nalbuphine combined with dexmedetomidine on the lungs of children with atelectasis who have a foreign body in a bronchus during the perioperative period. Methods: A total of 180 patients whose computed tomography scan showed atelectasis and a foreign body in a bronchus were randomly divided into three groups: group C (conventional anesthesia group), group D (dexmedetomidine group), and group N + D (nalbuphine combined with the dexmedetomidine group). The following indicators were recorded: 1) heart rate (HR) and mean arterial pressure (MAP) prior to induction (T0), at bronchoscope placement (T1), at intubation after surgery (T2), at tube removal (T3), 10 min after tube removal (T4), 20 min after tube removal (T5), and at awaking (T6); 2) monocyte toll-like receptors (TLRs) TLR⁃2, TLR⁃4, tumor necrosis factor α, interleukin 6, oxygenation index, and the B-line sum at T0, T3, 2 h (T7), and 24 h (T8) after tube removal; and 3) hospital stay after surgery. Results: Compared with group C, in group D and group N + D, 1) the HR and MAP at T1∼T6 were lower; 2) the inflammatory factor indicator and B-line sum were lower, and the oxygenation index was higher at T7 and T8; 3) the agitation and cough scores were decreased during tube removal; and 4) the Ramsay sedation score was higher, and ventilator weaning time was shortened at T4∼T6 (p < 0.05). Compared with group D, in group N + D, 1) the inflammatory factor indicator and B-line sum were lower at T8; 2) the oxygenation index was higher (p < 0.05). Compared with groups C and D, in group N + D, the length of hospital stay was decreased (p < 0.05). Conclusion: In patients with atelectasis and a foreign body in a bronchus during the perioperative period, nalbuphine combined with dexmedetomidine may be capable of reducing the oxidative stress response, improving the oxygenation index, decreasing the pulmonary fluid content, protecting the lung, and facilitating postoperative recovery.