Novel role of circRNAs in the drug resistance of gastric cancer: regulatory mechanisms and future for cancer therapy.

Cancer, including gastric cancer, has become a serious disease that jeopardizes public life. Currently, the main treatment methods are surgery, radiation therapy, and chemotherapy. One of the primary causes of death for patients with gastric cancer is drug resistance. Several mechanisms of anticancer drugs resistance have been reported, including changes in drugs transport and metabolism, mutations in drug targets, changes in DNA repair systems, inhibition of cell apoptosis and autophagy, gastric cancer stem cells, invasion and migration. It is becoming more widely known that non-coding RNAs, like circRNAs, play a critical role in the resistance of drugs used to treat gastric cancer. CircRNAs have a unique structure and function that is related to gastric cancer resistance, cell proliferation, apoptosis, autophagy, DNA repair systems, migration, and invasion. A clear understanding of the molecular mechanism of circRNAs mediated the resistance of gastric cancer drugs will open a new window for the treatment and management of gastric cancer. Therefore, in this review, we will summarize the current mechanism of drug resistance, and finally discuss the molecular mechanism of circRNAs in regulating the development of drug resistance in gastric cancer.

Exploration of the pneumocandin biosynthetic gene cluster based on efficient CRISPR/Cas9 gene editing strategy in Glarea lozoyensis.

Pneumocandin B0 (PB0) is a lipopeptide produced by the fungus Glarea lozoyensis. The existing challenges with the low-yield and the extended-fermentation cycle emphasize necessity for strain improvement. In this study, we optimized conditions to obtain high-quality protoplasts and screened effective selection markers, leading to the construction of three CRISPR/Cas9 gene editing systems. Utilizing a constitutive Cas9 expression recipient strain, combined with dual sgRNAs targeting, we achieved highly efficient editing of target genes. We successfully knocked out 10 genes within the pneumocandin putative biosynthetic gene cluster and analyzed their roles in PB0 production. Our findings reveal that 4 of 10 genes are directly involved in PB0 production. Specially, the deletion of gltrt or gl10050 resulted in reduced PB0 production, while the absence of glhyp or glhtyC led to the complete loss of PB0 biosynthesis. Notably, the deletion of glhyp caused the silencing of nearly all cluster genes, whereas overexpression of glhyp led to a 2.38-fold increase in PB0 production. Therefore, this study provides the first comprehensive exploration of the functions of 10 genes within the pneumocandin putative biosynthetic gene cluster. Our findings provide valuable technical strategies for constructing bioengineering strains with purposefully enhanced PB0 production.

A ubiquitin-mediated post-translational degradation of Cyp51A contributes to a novel azole resistance mode in Aspergillus fumigatus.

The airborne fungus Aspergillus fumigatus is a major pathogen that poses a serious health threat to humans by causing aspergillosis. Azole antifungals inhibit sterol 14-demethylase (encoded by cyp51A), an enzyme crucial for fungal cell survival. However, the most common mechanism of azole resistance in A. fumigatus is associated with the mutations in cyp51A and tandem repeats in its promoter, leading to reduced drug-enzyme interaction and overexpression of cyp51A. It remains unknown whether post-translational modifications of Cyp51A contribute to azole resistance. In this study, we report that the Cyp51A expression is highly induced upon exposure to itraconazole, while its ubiquitination level is significantly reduced by itraconazole. Loss of the ubiquitin-conjugating enzyme Ubc7 confers resistance to multiple azole antifungals but hinders hyphal growth, conidiation, and virulence. Western blot and immunoprecipitation assays show that deletion of ubc7 reduces Cyp51A degradation by impairing its ubiquitination, thereby leading to drug resistance. Most importantly, the overexpression of ubc7 in common environmental and clinical azole-resistant cyp51A isolates partially restores azole sensitivity. Our findings demonstrate a non-cyp51A mutation-based resistance mechanism and uncover a novel role of post-translational modification in contributing to azole resistance in A. fumigatus.

Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria.

Current research reports that lactate affects Treg metabolism, although the precise mechanism has only been partially elucidated. In this study, we presented evidence demonstrating that elevated lactate levels enhanced cell proliferation, suppressive capabilities, and oxidative phosphorylation (OXPHOS) in human Tregs. The expression levels of Monocarboxylate Transporters 1/2/4 (MCT1/2/4) regulate intracellular lactate concentration, thereby influencing the varying responses observed in naive Tregs and memory Tregs. Through mitochondrial isolation, sequencing, and analysis of human Tregs, we determined that Alpha-1,3-Mannosyl-Glycoprotein 2-Beta-N-Acetylglucosaminyltransferase (MGAT1) served as the pivotal driver initiating downstream N-glycosylation events involving progranulin (GRN) and hypoxia-upregulated 1 (HYOU1), consequently enhancing Treg OXPHOS. The mechanism by which MGAT1 was upregulated in mitochondria depended on elevated intracellular lactate that promoted the activation of XBP1s, which, in turn, supported MGAT1 transcription as well as the interaction of lactate with the translocase of the mitochondrial outer membrane 70 (TOM70) import receptor, facilitating MGAT1 translocation into mitochondria. Pre-treatment of Tregs with lactate reduced mortality in a xenogeneic graft-versus-host disease (GvHD) model. Together, these findings underscored the active regulatory role of lactate in human Treg metabolism through the upregulation of MGAT1 transcription and its facilitated translocation into the mitochondria.

Lower Serum ATG7 Levels Linked to Insulin Resistance in Women with Polycystic Ovary Syndrome.

BACKGROUND Previous studies have suggested that autophagy, a cellular process regulated by ATG7, plays a critical role in ovarian physiology and pathology. In this study, our objective was to examine ATG7 levels in women with and without polycystic ovary syndrome (PCOS) and to explore potential associations between serum ATG7 levels and PCOS. MATERIAL AND METHODS The study included 188 women diagnosed with PCOS, matched with an equal number of healthy women for comparison. Serum levels of ATG7 were determined using the ELISA technique, and the difference was assessed using an independent samples t test. The association between ATG7 serum levels and the risk of developing PCOS was evaluated by using a multivariable logistic regression model. Additionally, the potential of ATG7 to predict PCOS was investigated through logistic regression and receiver operating characteristic (ROC) analysis. RESULTS Our study found that women with PCOS had significantly lower serum ATG7 levels than their healthy counterparts. Lower ATG7 levels were associated with a higher risk of developing PCOS after adjusting for various confounding variables. The combination of ATG7 with HOMA-IR performed well in predicting PCOS, with an AUC of 92.3%, a sensitivity of 88.3%, and a specificity of 85.3%. CONCLUSIONS Our study found that serum ATG7 levels were significantly lower in women with PCOS and were associated with an increased risk of developing PCOS. This suggests that ATG7 could potentially serve as a biomarker for diagnosing and managing PCOS.

Review of Baduanjin and resistance exercise for the mental health of patients with hematologic malignancies.

Patients with hematological tumors experience physical and psychological stress, and negative psychological states. Baduanjin, an emerging psychological rehabilitation method combined with resistance exercise, has received widespread attention. This study reviews the current status of the application of Baduanjin combined with resistance exercise in improving the negative psychological state of patients with hematological tumors and discusses its problems and prospects. Through a literature review and comprehensive analysis, the application of Baduanjin and resistance exercise in the psychological rehabilitation of patients with hematological tumors was identified and evaluated. The results showed that Baduanjin with resistance exercise had a positive effect on improving negative psychological states of patients with hematological tumors, which can alleviate anxiety, depression, and other adverse emotions, and improve quality of life. However, there is a lack of unified and standardized exercise intervention programs for practical application, and patient participation and compliance must be improved. Baduanjin combined with resistance exercise can potentially improve the negative psychological status of patients with hematological tumors; however, it is still necessary to further standardize and improve the exercise program improving patient participation and compliance. Future studies should strengthen theoretical exploration and empirical research, providing more effective psychological rehabilitation strategies for patients with hematological tumors.

Extraction-Free Testing for SARS-CoV-2 in Nasal Swab and Saliva Samples on a Single High-Throughput Platform.

The COVID-19 pandemic introduced an urgent need for rapid and high-throughput testing for SARS-CoV-2. RNA extraction is a major bottleneck for RT-qPCR. We describe a semi-automated, extraction-free RT-qPCR assay for detection of SARS-CoV-2 in nasal swab and saliva samples on a single platform. With a limit of detection of 4 copies/mL, this laboratory developed test performed equivalently to established methods requiring nucleic acid extraction. Five technologists staffing two shifts per day (80 person-hours) processed more than 400,000 samples over 10 months. Patients opted to provide nasal swab samples (83.6%) more frequently than saliva (16.4%), creating the added challenge of producing swab collection kits. Real-world testing data indicated a higher frequency of SARS-CoV-2 detection in saliva (10.1%) compared to nasal swab (7.7%). This cost-effective and quickly scalable approach is suitable for pandemic preparedness planning related to surveillance and diagnostic testing.

Observation of monopole topological mode.

Among the many far-reaching consequences of the potential existence of a magnetic monopole, it induces a topological zero mode in the Dirac equation, which was derived by Jackiw and Rebbi 48 years ago and has been elusive ever since. Here, we show that the monopole and multi-monopole solutions can be constructed in the band theory by gapping the three-dimensional Dirac points in hedgehog mass configurations. We then experimentally demonstrate such a monopole bound state in an optimized Dirac acoustic crystal structurally modulated in full solid angles. The monopole mode exhibits the optimal scaling behavior - whose modal spacing is inversely proportional to the cubic root of the modal volume. This work completes the kink-vortex-monopole zero-mode trilogy and paves the way for exploring higher-dimensional bulk-topological-defect correspondence.

POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis. DESIGN: In this study, to systematically investigate the characteristics of cancer-associated fibroblast (CAF) subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by CAF subsets, we generated an HCC atlas by compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify the specific CAF subsets in the TME that determine the efficacy of immunotherapy in HCC patients. RESULTS: Our findings highlight the pivotal role of POSTN+ CAFs as potent immune response barriers at specific tumor locations, as they hinder effective T-cell infiltration and decrease the efficacy of immunotherapy. Additionally, we elucidated the interplay between POSTN+ CAFs and SPP1+ macrophages, whereby the former recruits the latter and triggers increased SPP1 expression via the IL-6/STAT3 signaling pathway. Moreover, we demonstrated a spatial correlation between POSTN+ CAFs and SPP1+ macrophages, revealing an immunosuppressive microenvironment that limits the immunotherapy response. Notably, we found that patients with elevated expression levels of both POSTN+ CAFs and SPP1+ macrophages achieved less therapeutic benefit in an immunotherapy cohort. CONCLUSION: Our research elucidates light on the role of a particular subset of CAFs in immunotherapy resistance, emphasizing the potential benefits of targeting specific CAF subpopulations to improve clinical responses to immunotherapy.

ESF1 positively regulates MDM2 and promotes tumorigenesis.

Eighteen S rRNA factor 1 (ESF1) is a predominantly nucleolar protein essential for embryogenesis. Our previous studies have suggested that Esf1 is a negative regulator of the tumor suppressor protein p53. However, it remains unclear whether ESF1 contributes to tumorigenesis. In this current research, we find that increased ESF1 expression correlates with poor survival in multiple tumors including pancreatic cancer. ESF1 is able to regulate cell proliferation, migration, DNA damage-induced apoptosis, and tumorigenesis. Mechanistically, ESF1 physically interacts with MDM2 and is essential for maintaining the stability of MDM2 protein by inhibiting its ubiquitination. Additionally, ESF1 also prevented stress-induced stabilization of p53 in multiple cancer cells. Hence, our findings suggest that ESF1 is a potent regulator of the MDM2-p53 pathway and promotes tumor progression.

The differentiation of Lgr5+ progenitor cells on nanostructures of self-assembled silica beads.

Supporting cells(SCs) have been demonstrated to be a reliable source for regenerating hair cells(HCs). Previous research has reported that Lgr5+ SCs can regenerate HCs both in vitro and in vivo. However, there is limited knowledge about the impact of the material on Lgr5+ cells. In this study, Lgr5+ cells were isolated from neonatal Lgr5-EGFP-CreERT2 transgenic mice by flow cytometry and then plated on self-assembled silica beads (SB). Lgr5+ cell differentiation was observed by immunofluorescence. We found that in the direct differentiation assay, the SB group generated more hair cells than the control group(*p < 0.05). Especially in the SB group, Lgr5+ progenitors generated significantly more Myo7a+ HCs outside of the colony than in the control group(**p < 0.01). In the sphere differentiation assay, we found that the diameter of spheres in the SB group was significantly larger compared to those of the control group(**p < 0.01). However, the difference in the ratio of myo7a+ cell counts was not obvious(P>0.05). The experiment proved that the self-assembled silica beads could promote the differentiation of Lgr5+ progenitors in vitro. Our findings implicate that nanostructures of self-assembled silica beads can be used as vectors for stem cell research in the inner ear.

Core-Shell Gel Nanofiber Scaffolds Constructed by Microfluidic Spinning toward Wound Repair and Tissue Regeneration.

Growing demand for wound care resulting from the increasing chronic diseases and trauma brings intense pressure to global medical health service system. Artificial skin provides mechanical and microenvironmental support for wound, which is crucial in wound healing and tissue regeneration. However, challenges still remain in the clinical application of artificial skin since the lack of the synergy effect of necessary performance. In this study, a multi-functional artificial skin is fabricated through microfluidic spinning technology by using core-shell gel nanofiber scaffolds (NFSs). This strategy can precisely manipulate the microstructure of artificial skin under microscale. The as-prepared artificial skin demonstrates superior characteristics including surface wettability, breathability, high mechanical strength, strain sensitivity, biocompatibility and biodegradability. Notably, this artificial skin has the capability to deliver medications in a controlled and sustained manner, thereby accelerating the wound healing process. This innovative approach paves the way for the development of a new generation of artificial skin and introduces a novel concept for the structural design of the unique core-shell gel NFSs.

A novel cancer-associated fibroblast signature for kidney renal clear cell carcinoma via integrated analysis of single-cell and bulk RNA-sequencing.

Cancer-associated fibroblasts (CAFs), integral components of the tumor microenvironment, play a pivotal role in tumor proliferation, metastasis, and clinical outcomes. However, its specific roles in Kidney Renal Clear Cell Carcinoma (KIRC) remain poorly understood. Employing the established Seurat single-cell analysis pipeline, we identified 21 CAFs marker genes. Subsequently, a prognostic signature consisting of 6 CAFs marker genes (RGS5, PGF, TPM2, GJA4, SEPT4, and PLXDC1) was developed in a cohort through univariate and LASSO Cox regression analyses. The model's efficacy was then validated in an external cohort, with a remarkable predictive performance in 1-, 3-, and 5-year. Patients in the high-risk group exhibited significantly inferior survival outcomes (p < 0.001), and the risk score was an independent prognostic factor (p < 0.05). Distinct differences in immune cell profiles and drug susceptibility were observed between the two risk groups. In KIRC, the PGF-VEGFR1 signaling pathway displayed a notable increase. PGF expression was significantly elevated in tumor tissues, as demonstrated by quantitative real-time polymerase chain reaction. In vitro, transwell assays and CCK8 revealed that recombinant-PGF could enhance the capability of cell proliferation, migration, and invasion in 769P and 786-O cells. This study firstly developed a novel predictive model based on 6 CAFs genes for KIRC. Additionally, PGF may present a potential therapeutic target to enhance KIRC treatment.

Flavonoid as a Potent Antioxidant: Quantitative Structure-Activity Relationship Analysis, Mechanism Study, and Molecular Design by Synergizing Molecular Simulation and Machine Learning.

In this work, a quantitative structure-antioxidant activity relationship of flavonoids was performed using a machine learning (ML) method. To achieve lipid-soluble, highly antioxidant flavonoids, 398 molecular structures with various substitute groups were designed based on the flavonoid skeleton. The hydrogen dissociation energies (ΔG1, ΔG2, and ΔG3) related to multiple hydrogen atom transfer processes and the solubility parameter (δ) of flavonoids were calculated using molecular simulation. The group decomposition results and the calculated antioxidant parameters constituted the ML data set. The artificial neural network and random forest models were constructed to predict and analyze the contribution of the substitute groups and positions to the antioxidant activity. The results showed the hydroxyl group at positions B4', B5', and B6' and the branched alkyl group at position C3 in the flavonoid skeleton were the optimal choice for improving antioxidant activity and compatibility with apolar organic materials. Compared to the pyrogallol group-grafted flavonoid, the designed potent flavonoid decreased ΔG1 and δ by 2.2 and 15.1%, respectively, while ΔG2 and ΔG3 kept the favorable lower values. These findings suggest that an efficient flavonoid prefers multiple ortho-phenolic hydroxyl groups and suitable sites with hydrophobic groups. The combination of molecular simulation and the ML method may offer a new research approach for the molecular design of novel antioxidants.

Single-cell analysis reveals hypoxia-induced immunosuppressive microenvironment in intrahepatic cholangiocarcinoma.

The role of hypoxia in the tumor microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains unclear. Here, we generated a comprehensive atlas of the entire tumor microenvironment and delineated the multifaceted cell-cell interactions to decipher hypoxia-induced pro-tumor immune suppression. We discovered hypoxia is significantly associated with iCCA progression via the activation of HIF1A expression. Moreover, hypoxia-dependent PPARγ-mediated fatty acid oxidation in APOE+ TAMs promoted M2 macrophage polarization by activating the HIF1A-PPARG-CD36 axis. These polarized APOE+ TAMs recruited Treg cell infiltration via the CCL3-CCR5 pair to form an immunosuppressive microenvironment. APOE+ TAMs tended to co-localize spatially with Treg cells in the malignant tissue based on spatial transcriptome data and immunofluorescence analysis results. We identified tumor-reactive CXCL13+ CD8-PreTex with specific high expression of ENTPD1 and ITGAE, which acted as precursors of CD8-Tex and had higher cytotoxicity, lower exhaustion, and more vigorous proliferation. Consequently, CXCL13+ CD8-PreTex functioned as a positive regulator of antitumor immunity by expressing the pro-inflammatory cytokines IFNG and TNF, associated with a better survival outcome. Our study reveals the mechanisms involved in hypoxia-induced immunosuppression and suggests that targeting precursor-exhausted CXCL13+CD8+ T cells might provide a pratical immunotherapeutic approach.

Emotional sociology applied: predictive influence of affective neuroscience personality traits on Chinese preschool teachers' performance and wellbeing.

Background: The interplay between teaching engagement and performance has garnered attention in both theoretical and empirical research, primarily due to its influence on student academic achievement, teacher well-being, and the realization of institutional goals. This is especially pertinent in the realm of preschool education, where the scope of learning extends beyond academic content to encompass the broader socialization of children. Drawing from Affective Neuroscience research, this study investigates the role of affective tendencies as mediators in the relationship between work engagement and job performance. Objective: The primary aim of this research is to examine a chain mediation model that hypothesizes the predictive role of teacher engagement. This model posits the intermediary influence of four basic emotions-CARING, SEEKING, ANGER, and FEAR-followed by the mediating effect of job satisfaction on teacher job performance. Method: The study utilized a sample of 842 Chinese preschool teachers. Data were collected through an online questionnaire, employing a time-lagged design. The analysis was conducted using Model 80 of the PROCESS Macros. Results: The findings reveal that both positive and negative emotions significantly predict teachers' job satisfaction. However, job satisfaction does not influence job performance. The analysis confirmed the direct and total effects of teacher engagement, as well as the indirect effects, particularly through the positive emotion of Caring. Implications: The results are instrumental in informing and refining interventions designed to enhance teacher engagement and performance, underscoring the importance of emotional factors in the educational environment.

Tumor-resident microbiota contributes to colorectal cancer liver metastasis by lactylation and immune modulation.

The role of tumor-resident microbiota in modulating tumor immunity remains unclear. Here, we discovered an abundance of intra-tumoral bacteria, such us E.coli, residing and resulting in Colorectal cancer liver metastasis (CRLM). E.coli enhanced lactate production, which mediated M2 macrophage polarization by suppressing nuclear factor-κB -gene binding (NF-κB) signaling through retinoic acid-inducible gene 1 (RIG-I) lactylation. Lactylation of RIG-I suppressed recruitment of NF-κB to the Nlrp3 promoter in macrophages, thereby reducing its transcription. This loss of Nlrp3 affected the immunosuppressive activities of regulatory T cells (Tregs) and the antitumor activities of and CD8+ T cells. Small-molecule compound screening identified a RIG-I lactylation inhibitor that suppressed M2 polarization and sensitized CRLM to 5-fluorouracil (5-FU). Our findings suggest that tumor-resident microbiota may be a potential target for preventing and treating CRLM.

[Expression and Clinical Significance of LINC00475 in Multiple Myeloma].

OBJECTIVE: To investigate the relative expression level and clinical significance of LINC00475 in serum of patients with multiple myeloma (MM). METHODS: The expression of LINC00475 in serum of 108 MM patients and five MM cell lines including RPMI 8226, NCI-H929, U266, OPM2 and CAG were detected by real-time fluorescence quantitative PCR. The diagnostic value of LINC00475 in MM was evaluated by receiver operating characteristic (ROC) curve analysis. The correlation of LINC00475 with patients' characteristics was analyzed. RESULTS: Compared with control groups, the expression of LINC00475 was up-regulated in serum of MM patients and MM cell lines (all P < 0.05). ROC curve analysis showed that the optimal cut-off value of LINC00475 was 262.4, the area under curve (AUC) was 0.924(95%CI : 0.884-0.964), and sensitivity and specificity was 83.3% and 91.7%, respectively, which indicated that LINC00475 had good evaluation value in MM patients. Compared with low-LINC00475 expression group, patients in high-LINC00475 expression group had higher levels of ß2microglobulin (ß2-MG) and Cystatin C (Cys-C) but lower albumin (ALB) (all P < 0.05). Compared with MM patients with International Staging System (ISS) stage I, the expression level of LINC00475 was significantly higher in patients with stage II and III (both P < 0.05). CONCLUSION: LINC00475 is helpful to distinguish MM patients from healthy adults, which is correlated with the prognostic indicators such as ß2-MG, ALB, and ISS stage.