YTHDF1 promotes gallbladder cancer progression via post-transcriptional regulation of the m6A/UHRF1 axis.

Gallbladder cancer is a rare but fatal malignancy. However, the mechanisms underlying gallbladder carcinogenesis and its progression are poorly understood. The function of m6A modification and its regulators was still unclear for gallbladder cancer. The current study seeks to investigate the function of YTH m6A RNA-binding protein 1 (YTHDF1) in gallbladder cancer. Transcriptomic analysis and immunochemical staining of YTHDF1 in gallbladder cancer tissues revealed its upregulation compared to paracancerous tissues. Moreover, YTHDF1 promotes the proliferation assays, Transwell migration assays, and Transwell invasion assays of gallbladder cancer cells in vitro. And it also increased tumour growth in xenograft mouse model and metastases in tail vein injection model in vivo. In vitro, UHRF1 knockdown partly reversed the effects of YTHDF1 overexpression. Mechanistically, dual-luciferase assays proved that YTHDF1 promotes UHRF1 expression via direct binding to the mRNA 3'-UTR in a m6A-dependent manner. Overexpression of YTHDF1 enhanced UHRF1 mRNA stability, as demonstrated by mRNA stability assays, and Co-IP studies confirmed a direct interaction between YTHDF1 and PABPC1. Collectively, these findings provide new insights into the progression of gallbladder cancer as well as a novel post-transcriptional mechanism of YTHDF1 via stabilizing target mRNA.

AgNPs-Modified Polylactic Acid Microneedles: Preparation and In Vivo/In Vitro Antimicrobial Studies.

OBJECTIVE: To prepare polylactic acid microneedles (PLAMNs) with sustained antibacterial effect to avoid skin infection caused by traditional MNs-based biosensors. METHODS: Silver nanoparticles (AgNPs) were synthesized using an in-situ reduction process with polydopamine (PDA). PLAMNs were fabricated using the hot-melt method. A series of pressure tests and puncture experiments were conducted to confirm the physicochemical properties of PLAMNs. Then AgNPs were modified on the surface of PLAMNs through in-situ reduction of PDA, resulting in the formation of PLAMNs@PDA-AgNPs. The in vitro antibacterial efficacy of PLAMNs@PDA-AgNPs was evaluated using agar diffusion assays and bacterial liquid co-culture approach. Wound healing and simulated long-term application were performed to assess the in vivo antibacterial effectiveness of PLAMNs@PDA-AgNPs. RESULTS: The MNs array comprised 169 tiny needle tips in pyramidal rows. Strength and puncture tests confirmed a 100% puncture success rate for PLAMNs on isolated rat skin and tin foil. SEM analysis revealed the integrity of PLAMNs@PDA-AgNPs with the formation of new surface substances. EDS analysis indicated the presence of silver elements on the surface of PLAMNs@PDA-AgNPs, with a content of 14.44%. Transepidermal water loss (TEWL) testing demonstrated the rapid healing of micro-pores created by PLAMNs@PDA-AgNPs, indicating their safety. Both in vitro and in vivo tests confirmed antibacterial efficacy of PLAMNs@PDA-AgNPs. CONCLUSIONS: In conclusion, the sustained antibacterial activity exhibited by PLAMNs@PDA-AgNPs offers a promising solution for addressing skin infections associated with MN applications, especially when compared to traditional MN-based biosensors. This advancement offers significant potential for the field of MN technology.

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA-binding protein YT521-B homology domain-containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP-seq), m6A-modified RIP-seq, and RNA sequencing, which revealed that death-associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3'-UTR of DAPK3 mRNA and facilitates its degradation in an m6A-dependent manner. DAPK3 inhibition restores the tumor-suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A-dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.

The TGF-ß/miR-31/CEACAM1-S axis inhibits CD4+ CD25+ Treg differentiation in systemic lupus erythematosus.

Defects causing concomitant loss of CD25 expression in regulatory T cells (Tregs) have been identified in systemic lupus erythematosus (SLE). However, the cause of this deficiency is not fully understood. Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), an immune co-receptor, contributes to general T-cell function and activation. Our previous study revealed that CEACAM1 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from patients with SLE. However, its role remains unclear. Herein, we confirmed CEACAM1, especially CEACAM1-S, was upregulated in PBMCs from patients with SLE. CEACAM1-S over-expression inhibits CD4+ CD25+ Treg differentiation, whereas knockdown of CEACAM1 had the opposite effect in vitro. CEACAM1-S is the target of miR-31. MiR-31 mimic inhibits CEACAM1 expression and enhances CD4+ CD25+ Treg differentiation, which was reversed by CEACAM1-S over-expression. Moreover, the circulating TGF-ß level was upregulated in SLE patients and TGF-ß reduced miR-31 expression via enhancing NF-κB activity. Importantly, CEACAM1 and TGF-ß mRNA levels were downregulated, while the miR-31 level and the abundance of CD4+ CD25+ Tregs were increased in inactive patients compared with that in patients with active SLE. In addition, CEACAM1-S expression was positively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, while CD4+ CD25+ Treg abundance and miR-31 level were negatively correlated with the SLEDAI score. In conclusion, reduced activity of miR-31 by TGF-ß, via the inhibition of NF-ᴋB, acted to inhibit the differentiation of CD4+ CD25+ Tregs by directly targeting CEACAM1-S and to promote autoimmunity.

Improving Chinese electronic medical record retrieval by field weight assignment, negation detection, and re-ranking.

The technique of information retrieval has been widely used in electronic medical record (EMR) systems. It's a pity that most existing methods have not considered the structures and language features of Chinese EMRs, which affects the performance of retrieval. To improve accuracy and comprehensiveness, we propose an improved algorithm of Chinese EMR retrieval. First, the weights of fields in Chinese EMRs are assigned based on the corresponding importance in clinical applications. Second, negative relations in EMRs are detected, and the retrieval scores of negative terms are adjusted accordingly. Third, the retrieval results are re-ranked by expansion terms and time information to enhance the recall without decreasing precision. Experiment results show that the improved algorithm increases the precision and recall significantly, which shows that the algorithm takes a full account of the characteristics of Chinese EMRs and fits the needs for clinical applications.

Rho-kinase inhibitor attenuates airway mucus hypersecretion and inflammation partly by downregulation of IL-13 and the JNK1/2-AP1 signaling pathway.

We measured the effect of Rho-kinase on inflammation and mucus hypersecretion in the airways of mouse models of asthma. Additionally, we aimed to determine if these effects were the result of JNK 1/2-AP1 pathway inhibition.We sensitized and challenged female C57BL/6 mice using house dust mites (HDM) followed by treatment with an inhibitor of Rho-kinase. Lung tissue was harvested to evaluate inflammation and mucus secretion in the airways of asthma mice. Cytokine expression in broncho-alveolar lavage fluid (BALF) was established by ELISA and airway responsiveness, and was determined by the invasive lung function test. JNK1/2, p-JNK1/2, AP-1, and p-AP-1 protein expression was determined by Western blot analysis. Asthma model mice that were treated with Rho-kinase inhibitor showed a significantly decrease in inflammation score, inflammatory cells, and airway responsiveness. Additionally, we found that IL-13 expressions in BALF and mucus secretion were decreased in HDM-challenged mice treated with Rho-kinase inhibitor. Furthermore, Rho-kinase inhibitor treatment decreased the expression of JNK1/2 and AP-1 phosphorylation. Our findings indicated that the Rho-kinase inhibitor decreased HDM-induced mucus secretion as well as airway inflammation in asthma mice through regulation of the JNK1/2-AP-1 pathway.

LDK378 inhibits the recruitment of myeloid-derived suppressor cells to spleen via the p38-GRK2-CCR2 pathway in mice with sepsis.

Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cells that are persistently increased in abundance and associated with adverse clinical outcomes in sepsis. Here, we investigated the therapeutic potential of an anaplastic lymphoma kinase inhibitor, LDK378, in cecal ligation and puncture (CLP)-induced polymicrobial sepsis and examined its effects on the recruitment of MDSCs. LDK378 significantly improved the survival of CLP-induced polymicrobial septic mice, which was paralleled by reduced organ injury, decreased release of inflammatory cytokines and decreased recruitment of MDSCs to the spleen. Importantly, LDK378 inhibited the migration of MDSCs to the spleen by blocking the CLP-mediated upregulation of CC chemokine receptor 2 (CCR2), a chemokine receptor critical for the recruitment of MDSCs. Mechanistically, LDK378 treatment blocked the CLP-induced CCR2 upregulation of MDSCs via partially inhibiting the phosphorylation of p38 and G-protein-coupled receptor kinase-2 (GRK2) in bone marrow MDSCs of septic mice. Furthermore, in vitro experiments also showed that lipopolysaccharide (LPS)-induced migration of MDSCs was similarly owing to the activation of GRK2 and upregulation of CCR2 by LPS, whereas the treatment with LDK378 partially blocked the LPS-induced phosphorylation of p38 and GRK2 and decreased the expression of CCR2 on the cell surface, therefore leading to the suppression of MDSC migration. Together, these findings unravel a novel function of LDK378 in the host response to infection and suggest that LDK378 could be a potential therapeutic agent for sepsis.

Visible-Light Direct Conversion of Ethanol to 1,1-Diethoxyethane and Hydrogen over a Non-Precious Metal Photocatalyst.

Converting renewable biomass and their derivatives into chemicals and fuels has received much attention to reduce the dependence on fossil resources. Photocatalytic ethanol dehydrogenation-acetalization to prepare value-added 1,1-diethoxyethane and H2 was achieved over non-precious metal CdS/Ni-MoS2 catalyst under visible light. The system displays an excellent production rate and high selectivity of 1,1-diethoxyethane, 52.1 mmol g-1 h-1 and 99.2 %, respectively. In-situ electron spin resonance, photoluminescence spectroscopy and transient photocurrent responses were conducted to investigate the mechanism. This study provides a promising strategy for a green application of bioethanol.

Facet-selective charge carrier transport, deactivation mechanism and stabilization of a Cu2O photo-electro-catalyst.

A facet-dependent photo-deactivation mechanism of Cu2O was verified and reported, which is caused by the facet-dependent charge carrier transport. During irradiation, the {100} and {110} crystal facets are selectively corroded by the photo-generated holes, while the {111} facets are comparatively stable.

Evaluation of the radiosensitizing effect of MEK inhibitor KZ-001 on non-small cell lung cancer cells in vitro.

Background: Non-small cell lung cancer (NSCLC) has a poor prognosis and usually presents resistance against radiotherapy. MEK inhibitors have been proven to possess a radiosensitization effect. The compound KZ-001 as a particular MEK inhibitor is superior to the listed MEK inhibitor AZD6244. Objective: To investigate whether KZ-001 could enhance the radiosensitivity of NSCLC cell lines in vitro. Methods: MTT and colony formation assay were used to evaluate the radiosensitivity effect of KZ-001. Immunofluorescence, cell cycle, apoptosis staining, and western blot experiments were used to explore the radiosensitivity mechanism. Results: KZ-001 significantly decreased A549 cell viability at 6 Gy and 8 Gy radiation doses and caused the radiosensitivity at 1 Gy, 4 Gy, and 6 Gy in colony formation experiments. The A549 apoptosis ratio induced by irradiation (IR) combined with KZ-001 increased significantly in comparison with that by IR monotherapy (10.57% vs. 6.23%, P = 0.0055). The anti-apoptosis marker Bcl-XL was found downregulated in KZ-001 and IR-treated A549/H460 cells, but apoptosis marker Bax was downregulated in H460. Extracellular regulated protein kinases (ERK1/2) phosphorylation of H460 cells could be blocked both by IR alone and IR combined with KZ-001. IR combined with KZ-001 is able to inhibit ERK activation of A549 cells apparently. KZ-001 increased the proportion of G2 phase in irradiated cells from 21.24% to 32.22%. KZ-001 could also significantly increase the double-strand break damage cell ratio to more than 30% compared to the irradiation alone group. Conclusions: MEK1/2 inhibitor KZ-001 is a potential radiosensitizer for clinical applications.

Fabrication of Antibacterial Sponge Microneedles for Sampling Skin Interstitial Fluid.

Microneedles (MNs) have recently garnered extensive interest concerning direct interstitial fluid (ISF) extraction or their integration into medical devices for continuous biomarker monitoring, owing to their advantages of painlessness, minimal invasiveness, and ease of use. However, micropores created by MN insertion may provide pathways for bacterial infiltration into the skin, causing local or systemic infection, especially with long-term in situ monitoring. To address this, we developed a novel antibacterial sponge MNs (SMNs@PDA-AgNPs) by depositing silver nanoparticles (AgNPs) on polydopamine (PDA)-coated SMNs. The physicochemical properties of SMNs@PDA-AgNPs were characterized regarding morphology, composition, mechanical strength, and liquid absorption capacity. The antibacterial effects were evaluated and optimized through agar diffusion assays in vitro. Wound healing and bacterial inhibition were further examined in vivo during MN application. Finally, the ISF sampling ability and biosafety of SMNs@PDA-AgNPs were assessed in vivo. The results demonstrate that antibacterial SMNs enable direct ISF extraction while preventing infection risks. SMNs@PDA-AgNPs could potentially be used for direct sampling or combined with medical devices for real-time diagnosis and management of chronic diseases.

The implication of pyroptosis in cancer immunology: Current advances and prospects.

Pyroptosis is a regulated cell death pathway involved in numerous human diseases, especially malignant tumors. Recent studies have identified multiple pyroptosis-associated signaling molecules, like caspases, gasdermin family and inflammasomes. In addition, increasing in vitro and in vivo studies have shown the significant linkage between pyroptosis and immune regulation of cancers. Pyroptosis-associated biomarkers regulate the infiltration of tumor immune cells, such as CD4+ and CD8+ T cells, thus strengthening the sensitivity to therapeutic strategies. In this review, we explained the relationship between pyroptosis and cancer immunology and focused on the significance of pyroptosis in immune regulation. We also proposed the future application of pyroptosis-associated biomarkers in basic research and clinical practices to address malignant behaviors. Exploration of the underlying mechanisms and biological functions of pyroptosis is critical for immune response and cancer immunotherapy.

A fluorescent probe of N'-formyl-rhodamine B hydrazide: structure and spectral properties of protonation behaviour.

The title compound is an "off-on" rhodamine probe. It exhibits strong pH dependence and responds to protons. The optimized geometries and energies calculation of the protonation were determined at the B3LYP level using DFT. The theoretical results are in good agreement with the single crystal analysis and the spectral results.

Impact of COVID-19 on Food Security in Ethiopia.

Since the outbreak of COVID-19, its effects on different aspects of life have been subject to much research, including food security, a domain that has been of special concern in many low-income countries. Ethiopia has been facing many challenges related to food security for decades via drought, famine, and conflict. Within this context, this case study assessed the impact of the COVID-19 pandemic on food security in Ethiopia. Results show that the ongoing pandemic has negatively impacted different regions and at-risk groups in a heterogeneous manner. This has been mainly through disruptions in the Ethiopian food value chain and the relative failure of social security programmes to address the losses generated by COVID-19. The population in the capital city, Addis Ababa, was able to maintain the same level of food security despite income losses caused by the COVID-19 pandemic. However, at-risk groups such as refugees, internally displaced persons (IDPs), and conflict affected regions were seen to suffer significantly from food insecurity exacerbated by COVID-19. Furthermore, this paper particularly emphasizes the importance of considering contextual factors other than COVID-19, such as conflicts or climate change, when discussing the state of food security in Ethiopia.

Ferroptosis-Related Gene MT1G as a Novel Biomarker Correlated With Prognosis and Immune Infiltration in Colorectal Cancer.

Ferroptosis, a newly discovered way of cell death, has been proved to be involved in the oncogenesis and development of cancers, including colorectal cancer (CRC). Here, by identifying the differentially expressed genes (DEGs) from three CRC transcriptome microarray datasets (GSE20842, GSE23878, and GSE25070), we found that the expression of MT1G was significantly decreased in CRC tissues, and the patients with a high level of MT1G displayed a poor prognosis. Quantitative PCR (qPCR) further confirmed the downregulated MT1G in two CRC cells, HCT8 and HCT116. The colony-forming assay indicated that the MT1G overexpression exhibited a remarkable inhibition of cell proliferation in HCT8 and HCT116 cells. In addition, we explored the co-expressed genes of MT1G to gain a better understanding of its potential signaling pathways. Aberrantly expressed MT1G also affected the immune response of CRC patients. Collectively, these findings might deepen our comprehension on the potential biological implications of MT1G in CRC.

Identification and validation of a novel pyroptosis-related lncRNAs signature associated with prognosis and immune regulation of hepatocellular carcinoma.

Pyroptosis is an inflammatory form of cell death triggered by certain inflammasomes. However, research concerning pyroptosis-related lncRNAs in hepatocellular carcinoma (HCC) remains scarce. This study aims to explore the prognostic pyroptosis-related long non-coding RNAs (lncRNAs) of HCC patients. Data of 373 HCC patients were obtained from the TCGA database. The entire cohort was randomly divided into a training cohort and a validation cohort in a 2:1 ratio. Pyroptosis-related lncRNAs were identified by the Pearson correlation analysis with reported pyroptosis-related genes. LASSO Cox regression was used to construct the signature. A prognostic signature consisting of nine pyroptosis-related lncRNAs was identified, and patients with lower risk scores had a better prognosis than those with higher risk scores. Multivariate Cox regression analysis showed that the signature was an independent risk factor for prognosis in both the training and validation cohorts. In the training cohort, the area under the signature curve reached 0.8043 at 1-year, 0.7878 at 2-year, and 0.8118 at 3-year; in the validation cohort, it reached 0.7315 at 1-year, 0.7372 at 2-year, and 0.7222 at 3-year. Gene set enrichment analysis (GSEA) suggested associations between the signature and several immune-related pathways. The expression of multiple immune checkpoints was also increased in the high-risk group, including PD-1, PD-L1, CTLA4, B7-H3, VSIR, LAG3, and TIGIT. A novel pyroptosis-related lncRNA signature, which may be associated with tumor immunity and potentially serve as an indicator for immunotherapy, has been identified to precisely predict the prognosis of HCC patients.

Porous Carbon Nanofibers Derived from Silk Fibroin through Electrospinning as N-Doped Metal-Free Catalysts for Hydrogen Evolution Reaction in Acidic and Alkaline Solutions.

Water electrolysis is considered as one promising strategy for hydrogen production, and thus, preparing electrocatalysts of superior efficiency and low cost for a hydrogen evolution reaction (HER) in a wide pH range is of paramount importance. In this research, N-doped porous carbon nanofibers derived from silk fibroin by KCl chemical activation are successfully synthesized as the metal-free catalyst for the HER under both acidic and alkaline conditions. After chemical activation of KCl, hierarchical porous structures are formed. Besides, it is found that the concentration of KCl in the electrospun membrane will affect the maintenance of the fibrous morphology for the carbonized samples due to the destruction of ß-sheets in silk fibroin induced by KCl. The specific surface area of the optimized sample, 4%-SPCNF, increased by nearly nine times compared with that without activation because of the hierarchical pores and large through pores between fibers. Meanwhile, the porosity increases from 59.87 to 80.28% due to the existence of through pores. Moreover, the 4%-SPCNF has remarkable stability and durability since the carbon substrate is resistant against the corrosion of the electrolyte. Our work provides insights into the design and engineering of silk fibroin-derived carbon nanofibers for metal-free catalysts of the HER under acidic and alkaline conditions.

Decoding Roles of Exosomal lncRNAs in Tumor-Immune Regulation and Therapeutic Potential.

Exosomes are nanovesicles secreted into biofluids by various cell types and have been implicated in different physiological and pathological processes. Interestingly, a plethora of studies emphasized the mediating role of exosomes in the bidirectional communication between donor and recipient cells. Among the various cargoes of exosomes, long non-coding RNAs (lncRNAs) have been identified as crucial regulators between cancer cells and immune cells in the tumor microenvironment (TME) that can interfere with innate and adaptive immune responses to affect the therapeutic efficiency. Recently, a few major studies have focused on the exosomal lncRNA-mediated interaction between cancer cells and immune cells infiltrated into TME. Nevertheless, a dearth of studies pertains to the immune regulating role of exosomal lncRNAs in cancer and is still in the early stages. Comprehensive mechanisms of exosomal lncRNAs in tumor immunity are not well understood. Herein, we provide an overview of the immunomodulatory function of exosomal lncRNAs in cancer and treatment resistance. In addition, we also summarize the potential therapeutic strategies toward exosomal lncRNAs in TME.

The Roles of Drug Metabolism-Related ADH1B in Immune Regulation and Therapeutic Response of Ovarian Cancer.

Background: The different pharmacological effects of drugs in different people can be explained by the polymorphisms of drug metabolism-related genes. Emerging studies have realized the importance of drug metabolism-related genes in the treatment and prognosis of cancers, including ovarian cancer (OV). In this study, using comprehensive bioinformatics and western blot, we identified that the drug metabolism-related gene, ADH1B, was significantly down-regulated in OV cells and tissues. The patients with a high level of ADH1B presented a good prognosis. We also found a negative correlation between ADH1B expression and the activity of chemotherapeutic agents, such as cyclophosphamide. In addition, positive correlations were observed between ADH1B expression and multiple immune checkpoints, including LAG3 and HAVCR2. The immune infiltration analysis further indicated that aberrantly expressed ADH1B might have important roles in regulating the infiltration of macrophages and neutrophils in OV tissues. Then, the co-expression analysis was conducted and the top three enriched KEGG pathways were spliceosome, RNA transport, and DNA replication. In conclusion, the drug metabolism-related gene ADH1B and its interactive network play an essential role in the immune regulation and therapeutic response and maybe identified as promising therapeutic targets for OV patients.

Downregulated exosome-associated gene FGF9 as a novel diagnostic and prognostic target for ovarian cancer and its underlying roles in immune regulation.

Exosome has been demonstrated to be secreted from cells and seized by targeted cells. Exosome could transmit signals and exert biological functions in cancer progression. Nevertheless, the underlying mechanisms of exosome in ovarian cancer (OC) have not been fully explored. In this study, we wanted to explore whether Fibroblast growth factor 9 (FGF9), as an exosome-associated gene, was importantly essential in OC progression and prognosis. Firstly, comprehensive bioinformatics platforms were applied to find that FGF9 expression was lower in OC tissues compared to normal ovarian tissues. Meanwhile, downregulated FGF9 displayed favorable prognostic values in OC patients. The gene enrichment of biological functions indicated that abnormally expressed FGF9 could be involved in the OC-related immune signatures, such as immunoinhibitors and chemokine receptors. Taken together, these findings could provide a novel insight into the significance of FGF9 in OC progress and supply a new destination of FGF9-related immunotherapy in clinical treatment.