Identification of prognostic m6A modification patterns and score system in melanoma patients.

N6-methyladenosine (m6A) is the most common modification on RNAs and LncRNAs. It plays an important role in cancer stem cell differentiation, T cell differentiation, and immune homeostasis. In this study, we explored the potential roles of m6A modification of RNA in melanoma and investigated the immune cell infiltration in tumor microenvironment in diverse m6Aclusters and different m6Ascore groups. A consensus clustering algorithm determined m6A modification patterns based on 14 m6A regulators, and further explored the biological functions and the connection with TME. An m6A-related gene signature (m6Ascore) was constructed based on m6A-related genes using principal component analysis. Three m6A modification patterns were identified based on 14 m6A regulators, named as m6Aclusters A-C. The prognosis of m6Acluster A was more favorable than m6Aclusters B and C, and it was more closely associated with immune regulation. To quantify the m6A modification patterns of individual tumor, an m6Ascore was constructed, and patients were classified into high and low m6Ascore groups. The low m6Ascore group, which had a favorable prognosis, was more relevant to immunology. The expression of PD-L1 was higher and the immunophenoscore (IPS) revealed stronger response to immunotherapy in the low m6Ascore group. This study identified 3 m6A modification patterns with different immune characteristics and constructed an m6Ascore system to predict prognosis and immunogenicity of patients, which is conducive to clinical prognosis judgment and individual treatment.

Ferroptosis in liver cancer: a key role of post-translational modifications.

Ferroptosis is an emerging form of regulated cell death in an oxidative stress- and iron-dependent manner, primarily induced by the over-production of reactive oxygen species (ROS). Manipulation of ferroptosis has been considered a promising therapeutic approach to inhibit liver tumor growth. Nevertheless, the development of resistance to ferroptosis in liver cancer poses a significant challenge in cancer treatment. Post-translational modifications (PTMs) are crucial enzymatic catalytic reactions that covalently regulate protein conformation, stability and cellular activities. Additionally, PTMs play pivotal roles in various biological processes and divergent programmed cell death, including ferroptosis. Importantly, key PTMs regulators involved in ferroptosis have been identified as potential targets for cancer therapy. PTMs function of two proteins, SLC7A11, GPX4 involved in ferroptosis resistance have been extensively investigated in recent years. This review will summarize the roles of PTMs in ferroptosis-related proteins in hepatocellular carcinoma (HCC) treatment.

NK92 cells and peripheral blood NK cells respond oppositely upon dasatinib treatment.

Natural killer (NK) cell is a valuable tool for immunotherapy in cancer treatment, both the cultured cell line NK92 and primary NK cells are widely studied and used in research and clinical trials. Clinical observations witnessed the improvement of patients' NK cells in terms of cell counts and cytotoxic activity upon dasatinib treatment, an approved drug for chronic myeloid leukaemia and Ph+ acute lymphocytic leukaemia. Several studies supported the clinical observations, yet others argued a detrimental effect of dasatinib on NK cells. Due to the complex conditions in different studies, the definite influence of dasatinib on NK92 and primary NK cells remains to be settled. Here, we used a well-defined in vitro system to evaluate the effects of dasatinib on NK92 cells and peripheral blood (PB)-NK cells. By co-culturing NK cells with dasatinib to test the cell counts and target cell-killing activities, we surprisingly found that the chemical influenced oppositely on these two types of NK cells. While dasatinib suppressed NK92 cell proliferation and cytotoxic activity, it improved PB-NK-killing tumour cells. RNA sequencing analysis further supported this finding, uncovering several proliferating and cytotoxic pathways responding invertedly between them. Our results highlighted an intrinsic difference between NK92 and PB-NK cells and may build clues to understand how dasatinib interacts with NK cells in vivo.

1-Naphthaleneacetic Acid Improved the In Vitro Cell Culturing by Inhibiting Apoptosis.

In vitro cell culturing witnessed its applications in scientific research and industrial activities. Attempts to shorten the doubling time of cultured cells have never ceased. In plants, auxin is applied to promote plant growth, the synthetic derivative 1-Naphthaleneacetic acid (NAA) is a good example. Despite the auxin's naturally occurring receptors are not present in mammalian cells, studies suggested they may affect cell culturing. Yet the effects and mechanisms are still unclear. Here, an up to 2-fold increase in the yield of in vitro cultured human cells is observed. Different types of human cell lines and primary cells are tested and found that NAA is effective in all the cells tested. The PI staining followed by FACS suggested that NAA do not affect the cell cycling. Apoptosis-specific dye staining analysis implicated that NAA rescued cell death. Further bulk RNA sequencing is done and it is identified that the lipid metabolism-engaging and anti-apoptosis gene, ANGPTL4, is enhanced in expression upon NAA treatment. Studies on ANGPTL4 knockout cells indicated that ANGPTL4 is required for NAA-mediated response. Thus, the data identified a beneficial role of NAA in human cell culturing and highlighted its potency in in vitro cell culturing.

Symmetric inheritance of parental histones contributes to safeguarding the fate of mouse embryonic stem cells during differentiation.

Parental histones, the carriers of posttranslational modifications, are deposited evenly onto the replicating DNA of sister chromatids in a process dependent on the Mcm2 subunit of DNA helicase and the Pole3 subunit of leading-strand DNA polymerase. The biological significance of parental histone propagation remains unclear. Here we show that Mcm2-mutated or Pole3-deleted mouse embryonic stem cells (ESCs) display aberrant histone landscapes and impaired neural differentiation. Mutation of the Mcm2 histone-binding domain causes defects in pre-implantation development and embryonic lethality. ESCs with biased parental histone transfer exhibit increased epigenetic heterogeneity, showing altered histone variant H3.3 and H3K27me3 patterning at genomic sites regulating differentiation genes. Our results indicate that the lagging strand pattern of H3.3 leads to the redistribution of H3K27me3 in Mcm2-2A ESCs. We demonstrate that symmetric parental histone deposition to sister chromatids contributes to cellular differentiation and development.

Impaired histone inheritance promotes tumor progression.

Faithful inheritance of parental histones is essential to maintain epigenetic information and cellular identity during cell division. Parental histones are evenly deposited onto the replicating DNA of sister chromatids in a process dependent on the MCM2 subunit of DNA helicase. However, the impact of aberrant parental histone partition on human disease such as cancer is largely unknown. In this study, we construct a model of impaired histone inheritance by introducing MCM2-2A mutation (defective in parental histone binding) in MCF-7 breast cancer cells. The resulting impaired histone inheritance reprograms the histone modification landscapes of progeny cells, especially the repressive histone mark H3K27me3. Lower H3K27me3 levels derepress the expression of genes associated with development, cell proliferation, and epithelial to mesenchymal transition. These epigenetic changes confer fitness advantages to some newly emerged subclones and consequently promote tumor growth and metastasis after orthotopic implantation. In summary, our results indicate that impaired inheritance of parental histones can drive tumor progression.

A generalizable strategy for crosslinkable albumin-based hydrogels and application as potential anti-tumor nanoplatform.

Albumin-based hydrogels have emerged as promising nanoparticle systems for the effective delivery of hydrophobic anticancer drugs. Anti-cancer drugs often cause some adverse effects, such as toxicity and rapid clearance by mononuclear phagocytic systems. Herein, a new strategy of synthesizing N-hydroxysuccinimide (NHS)-activated linker to form crosslinkable albumin-based hydrogels (CABH) is reported. The CABH favored physiochemical characteristics improvement of doxorubicin (Dox) and drug release. The CABH was constructed depending on the crosslinking reaction between NHS activated glycerol and albumin. The size of CABH was approximately 200 nm examined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). It was found that the particle size and size distribution of the CABH remained stable in neutral PBS for 1 week. Dox loaded CABH would be controllably released in weak acidic environment verified by in vitro release and in vitro cell imaging. The Dox loaded hydrogel results in significant killing in the case of acidic culture medium. Our work provides a crosslinking method to formulate albumin nanoplatform and improve the size, stability, drug loading capacity and controlled release, which throws light on the potential application in drug delivery.

Large-Scale, Abrasion-Resistant, and Solvent-Free Superhydrophobic Objects Fabricated by a Selective Laser Sintering 3D Printing Strategy.

Manufacturing abrasion-resistant superhydrophobic matters is challenging due to the fragile feature of the introduced micro-/nanoscale surface roughness. Besides the long-term durability, large scale at meter level, and 3D complex structures are of great importance for the superhydrophobic objects used across diverse industries. Here it is shown that abrasion-resistant, half-a-meter scaled superhydrophobic objects can be one-step realized by the selective laser sintering (SLS) 3D printing technology using hydrophobic-fumed-silica (HFS)/polymer composite grains. The HFS grains serve as the hydrophobic guests while the sintered polymeric network provides the mechanical strength, leading to low-adhesion, intrinsic superhydrophobic objects with desired 3D structures. It is found that as-printed structures remained anti-wetting capabilities even after undergoing different abrasion tests, including knife cutting test, rude file grinding test, 1000 cycles of sandpaper friction test, tape test and quicksand impacting test, illustrating their abrasion-resistant superhydrophobic stability. This strategy is applied to manufacture a shell of the unmanned aerial vehicle and an abrasion-resistant superhydrophobic shoe, showing the industrial customization of large-scale superhydrophobic objects. The findings thus provide insight for designing intrinsic superhydrophobic objects via the SLS 3D printing strategy that might find use in drag-reduce, anti-fouling, or other industrial fields in harsh operating environments.

Depth and Video Segmentation Based Visual Attention for Embodied Question Answering.

Embodied Question Answering (EQA) is a newly defined research area where an agent is required to answer the user's questions by exploring the real-world environment. It has attracted increasing research interests due to its broad applications in personal assistants and in-home robots. Most of the existing methods perform poorly in terms of answering and navigation accuracy due to the absence of fine-level semantic information, stability to the ambiguity, and 3D spatial information of the virtual environment. To tackle these problems, we propose a depth and segmentation based visual attention mechanism for Embodied Question Answering. First, we extract local semantic features by introducing a novel high-speed video segmentation framework. Then guided by the extracted semantic features, a depth and segmentation based visual attention mechanism is proposed for the Visual Question Answering (VQA) sub-task. Further, a feature fusion strategy is designed to guide the navigator's training process without much additional computational cost. The ablation experiments show that our method effectively boosts the performance of the VQA module and navigation module, leading to 4.9 % and 5.6 % overall improvement in EQA accuracy on House3D and Matterport3D datasets respectively.

MARCH1 as a novel immune-related prognostic biomarker that shapes an inflamed tumor microenvironment in lung adenocarcinoma.

E3 ubiquitin ligases (E3s), the second most common cancer-related functional protein family, play vital roles in multiple tumors. However, their importance in prognosis and immunotherapy of lung adenocarcinoma (LUAD) is not clear. First, utilizing the data from The Cancer Genome Atlas (TCGA), we comprehensively assessed the expression profile and immunological association of 13 E3s in LUAD patients. Consequently, MARCH1 was considered a candidate for further study. Second, several algorithms were applied to assess the correlation between MARCH1 and immunological characteristics in the LUAD tumor microenvironment. Third, an immune risk score (IRS) was developed to predict the prognosis. Finally, the immunological relationship of MARCH1 in pan-cancer was also estimated. We found that E3s were disordered in LUAD. Among them, MARCH1 was positively correlated with most immunological characteristics, indicating that MARCH1 designed an inflamed TME in LUAD. Coincidently, LUAD with low MARCH1 expression had a poor prognosis and was not sensitive to immune checkpoint blockers. In addition, the IRS could accurately predict the prognosis. In pan-cancer, MARCH1 was also positively correlated with most immunological characteristics. In conclusion, MARCH1 could be a novel and promising biomarker for immune status and effectiveness of immunotherapy for LUAD patients.

Synthesis of flower-like MnO2 nanostructure with freshly prepared Cu particles and electrochemical performance in supercapacitors.

Four types of flowerlike manganese dioxide in nano scale was synthesized via a liquid phase method in KMnO4-H2SO4 solution and Cu particles, wherein the effect of Cu particles was investigated in detail. The obtained manganese dioxide powder was characterized by XRD, SEM and TEM, and the supercapacity properties of MnO2 electrode materials were measured. The results showed that doping carbon black can benefit to better dispersion of copper particles, resulting in generated smaller size of Cu particles, and the morphology of MnO2 nanoparticles was dominated by that of Cu particles. The study of MnO2 synthesis by different sources of Cu particles showed that the size of MnO2 particles decreased significantly with freshly prepared fine copper powder compared with using commercial Cu powder, and the size of MnO2 particles can be further reduced to 120 nm by prepared Cu particles with smaller size. Therefore, it was suggested that the copper particles served as not only the reductant and but also the nuclei centre for the growth of MnO2 particles in synthesis process MnO2, and that is the reason how copper particles worked on the growth of flower-like MnO2 and electrochemical property. In the part of investigation for electrochemical property, the calculated results of b values indicated that the electrode materials have pseudo capacitance property, and the highest specific capacitance of 197.2 F g-1 at 2 mV s-1 and 148 F/g at 1 A/g were obtained for MCE electrode materials (MnO2 was synthesized with freshly prepared copper particles, where carbon black was used and dispersed in ethanol before preparation of Cu particles). The values of charge transfer resistance in all types of MnO2 materials electrodes were smaller than 0.08 Ω. The cycling retention of MCE material electrode is still kept as 93.8% after 1000 cycles.

Emerging Roles of lncRNAs Regulating RNA-Mediated Type-I Interferon Signaling Pathway.

The type-I interferon (IFN-I) signaling pathway plays pivot roles in defending against pathogen invasion. Exogenous ssRNA and dsRNA could be immunogenic. RNA-mediated IFN signaling is extensively studied in the field. The incorrect functioning of this pathway leads to either autoimmune diseases or suffering from microorganism invasion. From the discrimination of "self" and "non-self" molecules by receptors to the fine-tune modulations in downstream cascades, all steps are under the surveillance featured by complex feedbacks and regulators. Studies in recent years highlighted the emerging roles of long noncoding RNAs (lncRNAs) as a reservoir for signaling regulation. LncRNAs bind to targets through the structure and sequence, and thus the mechanisms of action can be complex and specific. Here, we summarized lncRNAs modulating the RNA-activated IFN-I signaling pathway according to the event order during the signaling. We hope this review help understand how lncRNAs are participating in the regulation of IFN-I signaling.

MicroRNA-23a-3p influences the molecular mechanism of gastric cancer cells via CCL22/PI3K/Akt axis.

A great many microRNAs (miRNAs) have been reported to play different roles in human cancers, including gastric cancer (GC). However, the specific character of miR-23a-3p in GC has not been elucidated. This study was to explore the function of miR-23a-3p in GC. The results manifested that miR-23a-3p was down-regulated in GC and patients with reduced miR-23a-3p had poor prognosis. Functional experiments assured that elevated miR-23a-3p refrained GC proliferation, invasion, migration, PIK3/Akt phosphorylation and apoptosis, while knockdown miR-23a-3p accelerated the growth of GC. Double luciferase report experiments manifested that miR-23a-3p targeted CCL22 expression. Functional rescue experiments affirmed that the repression of elevated miR-23a-3p on GC was reversed by simultaneous augmented CCL22. In vivo, elevated miR-23a-3p restrained the volume and tumor of GC and reduced the expression of CCL22 and phosphorylated PIK3/Akt, while knockdown miR-23a-3p motivated tumor growth. In conclusion, the results of this study indicate that miR-23a-3p plays a repressive role in GC, and affects the progression of GC via down-regulating CCL22 and blocking PI3K/AKT signal transduction pathway, which may offer a new molecular target for clinical treatment of GC.

Progressive Self-Guided Loss for Salient Object Detection.

We present a simple yet effective progressive self-guided loss function to facilitate deep learning-based salient object detection (SOD) in images. The saliency maps produced by the most relevant works still suffer from incomplete predictions due to the internal complexity of salient objects. Our proposed progressive self-guided loss simulates a morphological closing operation on the model predictions for progressively creating auxiliary training supervisions to step-wisely guide the training process. We demonstrate that this new loss function can guide the SOD model to highlight more complete salient objects step-by-step and meanwhile help to uncover the spatial dependencies of the salient object pixels in a region growing manner. Moreover, a new feature aggregation module is proposed to capture multi-scale features and aggregate them adaptively by a branch-wise attention mechanism. Benefiting from this module, our SOD framework takes advantage of adaptively aggregated multi-scale features to locate and detect salient objects effectively. Experimental results on several benchmark datasets show that our loss function not only advances the performance of existing SOD models without architecture modification but also helps our proposed framework to achieve state-of-the-art performance.

Helicobacter pylori-induced protein tyrosine phosphatase receptor type C as a prognostic biomarker for gastric cancer.

BACKGROUND: Helicobacter pylori (H. pylori) infection is closely associated with the tumorigenesis of gastric cancer. The aim of the present study was to identify the key regulator in H. pylori-related gastric cancer and to study the expression level and clinical value of the indicated key regulator in gastric cancer. METHODS: The GSE6143 dataset was used to identify differentially expressed genes (DEGs) with limma R package, and enrichment analysis was done using the Metascape web-based portal. The protein-protein interaction analysis was done using Search Tool for the Retrieval of Interacting Genes/Proteins. Gastric adenocarcinoma AGS and BGC-823 cells were treated with H. pylori strain 26695 to construct the in vitro H. pylori infection model, and quantitative reverse transcription polymerase chain reaction was used to analyze the mRNA levels of indicated genes. The correlation analysis between two genes in gastric cancer was done by GEPIA. Furthermore, the PTPRC expression by pathological features analysis was conducted in UALCAN, an easy to use, interactive web-portal (http://ualcan.path.uab.edu). The survival analysis for gastric cancer, based on PTPRC expression levels, was done using the Kaplan-Meier plotter. RESULTS: DEGs in gastric mucosa with or without H. pylori infection were identified and enriched in immune-related pathways and cancer pathways. The protein-protein interaction analysis confirmed the enrichment analysis of gene ontology. H. pylori strain 26695 exposure also confirmed the alteration of gene expression levels in AGS and BGC-823 cells. PTPRC was co-expressed with CSF2RB and TNFRSF7, indicating a significant positive correlation in gastric cancer. PTPRC was overexpressed in gastric cancer, and the overexpression of PTPRC was positively correlated with the progression of gastric cancer. Furthermore, the high expression of PTPRC could act as a poor prognostic factor for gastric cancer patients, especially for those at advanced stage. CONCLUSIONS: H. pylori-induced PTPRC is overexpressed in gastric cancer, and the overexpression of PTPRC is positively associated with the development of gastric cancer. The high expression of PTPRC could serve as poor prognostic biomarker for gastric cancer patients, especially for those at advanced stage. H. pylori-induced PTPRC is a prognostic biomarker for gastric cancer.

Targeting FGFR in non-small cell lung cancer: implications from the landscape of clinically actionable aberrations of FGFR kinases.

OBJECTIVE: Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in diverse cancer types, including non-small cell lung cancer (NSCLC). The frequency of FGFR aberrations in Chinese NSCLC patients is therefore of great clinical significance. METHODS: A total of 10,966 NSCLC patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing were reviewed. Patients' clinical characteristics and treatment histories were also evaluated. RESULTS: FGFR aberrations, including mutations, fusions, and gene amplifications, were detected in 1.9% (210/10,966) of the population. FGFR abnormalities were more frequently observed in lung squamous cell carcinomas (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9,596). FGFR oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were male lung squamous cell carcinoma patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus highlighting a potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in such patients. Furthermore, FGFR fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including 9 FGFR3-TACC3, 1 FGFR2-INA, 1 novel FGFR4-RAPGEFL1, and 1 novel fusion between the FGFR1 and SLC20A2 5'-untranslated regions, which may have caused FGFR1 overexpressions. Concomitant EGFR mutations or amplifications were observed in 6 patients, and 4 patients received anti-EGFR inhibitors, in whom FGFR fusions may have mediated resistance to anti-EGFR therapies. FGFR amplification was detected in 24 patients, with the majority being FGFR1 amplifications. Importantly, FGFR oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events. CONCLUSIONS: We report the prevalence of FGFR anomalies in a large NSCLC population, including mutations, gene amplifications, and novel FGFR fusions.

Exploring Strategies for Improving Green Open Spaces in Old Downtown Residential Communities from the Perspective of Public Health to Enhance the Health and Well-Being of the Aged.

Based on the trend of global aging, people are paying more and more attention to the health of the elderly and the improvement of green open spaces. However, few studies have focused on strategies to improve green spaces in response to this trend. Especially, with the outbreak of COVID-19, an urgent need to develop a sustainable system strategy to improve the health of the elderly in residential communities in old districts has emerged. Traditional improvement strategies based on current situation evaluation often focus on the most prominent practical problems. Therefore, the objective of this study was to provide theoretical research and practical improvement strategies for green open spaces in old downtown residential communities to improve the health and well-being of the elderly. In response to this problem, this research proposes an alternative method based on causality (FDM-DANP-mV model), by extracting 23 green open space elements that affect the health of the elderly and dividing them into three dimensions, to form a preliminary evaluation framework. On this basis, the more effective and feasible standard elements are screened out, and the influence relationship behind the elements is clarified. Then, the sustainable development strategy is systematically discussed in three practical cases. This allows for the analysis of the present situation to not only identify the current significant problems but also to capture the source of the influence behind the real problems based on the clarification of the dominant influence relationship. The actual value of this study is to provide a key design decision basis for the improvement of the green open spaces in old downtown residential communities, aiming at avoiding waste to the greatest extent under the premise of limited resources and gradually promoting the improvement of the urban built environment to promote the health and well-being of the elderly.

Prognostic value of immune cell infiltration in bladder cancer: A gene expression-based study.

The present study aimed to analyse the relationship between tumour-infiltrating immune cells (TIICs) and the prognosis of bladder cancer (BC). In the present study, an established computational method (CIBERSORT) was used to analyse the gene expression profile of BC from 409 patients to infer the number of infiltrating immune cells among 22 immune cell subsets. The relationship between each cell type and overall survival (OS) was further analysed. Single-sample GSEA and ESTIMATE algorithms were performed to evaluate the composition of immune microenvironment in each immune cluster. A significant difference in immune cell infiltration between BC and bladder tissue was observed. Increased natural killer and CD8+ T cell infiltration was associated with longer OS, whereas a higher percentage of M0 macrophages among the total immune cells was associated with shorter OS. The number of M0 macrophages increased with increasing BC stage, whereas the percentage of activated memory CD4+ and CD8+ T cells decreased. Patients with BC were divided into three subgroups by hierarchical cluster analysis of immune cells, and each cluster was associated with distinct survival and immune characteristics. The data indicated differences in the cellular composition of TIICs in patients with BC. Moreover, these TIICs were shown to be potential drug targets and reliable prognostic indicators.

SUMOylated PRC1 controls histone H3.3 deposition and genome integrity of embryonic heterochromatin.

Chromatin integrity is essential for cellular homeostasis. Polycomb group proteins modulate chromatin states and transcriptionally repress developmental genes to maintain cell identity. They also repress repetitive sequences such as major satellites and constitute an alternative state of pericentromeric constitutive heterochromatin at paternal chromosomes (pat-PCH) in mouse pre-implantation embryos. Remarkably, pat-PCH contains the histone H3.3 variant, which is absent from canonical PCH at maternal chromosomes, which is marked by histone H3 lysine 9 trimethylation (H3K9me3), HP1, and ATRX proteins. Here, we show that SUMO2-modified CBX2-containing Polycomb Repressive Complex 1 (PRC1) recruits the H3.3-specific chaperone DAXX to pat-PCH, enabling H3.3 incorporation at these loci. Deficiency of Daxx or PRC1 components Ring1 and Rnf2 abrogates H3.3 incorporation, induces chromatin decompaction and breakage at PCH of exclusively paternal chromosomes, and causes their mis-segregation. Complementation assays show that DAXX-mediated H3.3 deposition is required for chromosome stability in early embryos. DAXX also regulates repression of PRC1 target genes during oogenesis and early embryogenesis. The study identifies a novel critical role for Polycomb in ensuring heterochromatin integrity and chromosome stability in mouse early development.