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Abstract Background Neural stem cells (NSCs) are considered to be the most promising cell type for cell replacement therapy in neurodegenerative diseases. However, their low neuronal differentiation ratio impedes their application in such conditions. Elucidating the molecular mechanism of NSC differentiation may provide the necessary experimental basis for expanding their application. Previous studies have indicated that POU3F4 can induce neuronal differentiation of NSCs, this study aims to underly the possible exact mechanism of POU3F4 on the NSC differentiation and development. Methods NSCs were isolated and cultured from the hippocampus of neonatal mice. The frozen hippocampal sections were prepared for immunohistochemical staining. Synaptic development was assessed using electron microscopy. High-throughput sequencing was employed to analyze the gene expression profile following the overexpression of Brn4. Gene expression levels were determined through Western blotting and qRT-PCR. Cell cycle and differentiation were evaluated using flow cytometry and immunofluorescent staining. Results It was found that POU3F4 promoted the neuronal differentiation of hippocampal NSCs and synapse development, and inhibited NSC proliferation. POU3F4-deficient mice exhibited impairments in learning and memory. RNA sequencing and ChIP assays confirmed that Gli1 was downstream of POU3F4. Loss and gain function experiments indicated that Gli1 mediated POU3F4 promoting neuronal differentiation and synapse development. Forced expression of Gli1 in hippocampus improved learning and memory function of animal models. Conclusions The results suggest that POU3F4 and Gli1 promote neuronal differentiation and synaptic development of NSCs, and that Gli1 partially mediates the effects of POU3F4. Graphical abstract

Research has demonstrated that POU3F4 is integral to various cancers, in addition to its significance in inner ear development, pancreatic differentiation, as well as neural stem cell differentiation. Nevertheless, comprehensive pan-cancer analyses focusing on POU3F4 remain limited. This study aims to assess the prognostic value of POU3F4 in thirty-three cancers and explore its immune-related functions. Based on data from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genotype-Tissue Expression (GTE), and Gene Set Cancer Analysis (GSCA), we employed various bioinformatics approaches to investigate the potential carcinogenic effects of POU3F4. Our study encompassed DNA methylation, RNA methylation, tumor mutation burden (TMB), mismatch repair (MMR) genes, microsatellite instability (MSI), the relationship between POU3F4 and prognosis, and immune cell infiltration (ICI) across different tumors. The analysis revealed that POU3F4 expression is typically low in most cancers but is elevated in breast invasive carcinoma, glioblastoma multiforme (GBM), liver hepatocellular carcinoma, and thyroid carcinoma, with the highest levels in GBM. Additionally, POU3F4 expression correlates with cancer prognosis, either positively or negatively. The expression of POU3F4 demonstrated significant associations with MSI in four cancers and TMB in six cancers. POU3F4 expression was significantly linked to DNA methylation in 13 cancer types and RNA methylation in most cancers. It also correlated with the tumor immune microenvironment, immune-related genes, immune checkpoint inhibitors, and drug resistance in various cancers. In vitro experiments demonstrated that POU3F4 enhances cell viability, proliferation, and migration in GBM. Our findings indicate that, given its critical role in carcinogenesis and tumor immunity, POU3F4 serves as a prognostic marker in diverse malignancies.

BackgroundTraditionally, patients with microsatellite stability (MSS)/microsatellite instability-Low (MSI-L)/proficient mismatch repair (p-MMR) metastatic colorectal cancer (mCRC) have had poor benefit from immunotherapy. Therefore, how to enhance the response of immunotherapy is still a challenge for MSS/MSI-L/p-MMR CRC patient.Case presentationWe report a special case of a rectal cancer patient with programmed death-ligand 1 (PD-L1) negative expression, MSI-L/p-MMR, tumor mutational burden-low (TMB-L) and liver metastases, who partial response (PR) to immunotherapy after systemic therapy failure including chemotherapy, anti-angiogenesis therapy and stereotactic body radiation-therapy (SBRT). The computed tomography (CT) results showed that among three liver metastases had been reduction or disappearance after Tislelizumab treatment for three times. Besides, the carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) decrease and maintained at a low level for 3 months. The progression-free survival (PFS) of patient has exceeded 3 months.ConclusionsThis case indicates that the patient with MSI-L/p-MMR mCRC can respond to anti-PD-1 immunotherapy after systemic therapy. And the SBRT (targeting liver metastases) may a method for increase-sensitivity of immunotherapy in CRC patients with MSI-L/p-MMR.

[Abstract]: Objective: This study evaluates the efficacy of imiquimod liposome gel (IMQ-Lips gel) to prevent and treat hypertrophic scars (HS). Methods: On the basis of an orthogonal L9 (34) design, IMQ-Lips formulations were optimized using the film dispersion-pH gradient method. The optimal parameters were phospholipid–cholesterol (3 : 1), lipid-to-drug ratio (8 : 1), and a vitamin E of 5 mg. The in vitro transdermal experiment and rabbit HS model were used to evaluate the pharmacodynamics in vitro and in vivo. Results: IMQ-Lips has good physical and chemical properties, with an encapsulation rate of 81.2% ± 1.9%, an average diameter of (347 ± 21) nm, and a zeta potential of (–12.19 ± 1.7) mV. In vitro transdermal penetration tests showed that IMQ-Lips gel enhanced skin retention and reduced transdermal delivery compared with IMQ gel. The rabbit HS model further revealed that IMQ-Lips gel treatment reduced scar formation by inhibiting overproliferation of fibroblasts and reducing interleukin-4 levels. Conclusion: Taken together, these data suggest that IMQ-Lips gel represents a potential therapeutic approach for HS treatment.

[Abstract]: Objective: Network pharmacology techniques were used to predict the key active compounds and targets of Tongxie Yaofang decoction in treating ulcerative colitis (UC) and exploring the potential multicomponent, multitarget, and multipathway mechanism. Also, peroxisome proliferator-activated receptor-γ (PPAR-γ) in cancer pathways was selected for animal testing. Methods: The chemical components of the four herbs in Tongxie Yaofang decoction were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), whereas the other relevant information was obtained from the literature. Targets of the active compounds were obtained from the TCMSP and Swiss Target Prediction. Meanwhile, the UC targets were searched and screened from GeneCards and DisGeNET and intersected with targets of the active compounds in Tongxie Yaofang decoction. The obtained common targets were imported into the STRING database to build the target protein-protein interaction network. Cytoscape software was used to construct the network diagram of single herb-active compounds-targets of Tongxie Yaofang decoction. The common targets of the drug and disease received the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the biological functions and metabolic pathways of the drug and predict its potential mechanism of action in treating UC. Molecular docking was conducted for the top 3 and 5 relevant proteins using AutoDock software and verified in animal testing: UC rat models were established and received 22 g/kg alcohol extract of Tongxie Yaofang decoction through intragastric administration for 28 days. The colonic mucosa damage index was assessed. PPAR-γ protein expression was detected by immunohistochemistry. Results: Fifty-three UC-related potential active compounds and 168 potential targets were obtained. Paeoniflorin in Radix Paeoniae Alba and wogonin in Radix Sileris might be the key compounds of Tongxie Yaofang decoction in treating UC. Cyclooxygenase-2 (PTGS2), the most highly associated with active compounds, might be an important therapeutic target. GO and KEGG enrichment analyses showed that the efficacy of Tongxie Yaofang decoction involved various molecular functions and biological processes and might achieve the collaborative treatment for UC through multiple pathways, such as cancer pathways, tumor necrosis factor signaling pathway, Toll-like receptor signaling pathway, and phosphatidylinositol 3-kinase/Akt signaling pathway. The molecular docking results demonstrated that active compounds had a favorable binding activity with the target AR. Tongxie Yaofang decoction could significantly increase PPAR-γ expression in UC rats (P < 0.05), verifying part of the predicting outcomes of network pharmacology. Conclusion: Tongxie Yaofang decoction is featured with the multicomponent, multitarget, multipathway collaborative treatment for UC. This study has predicted the potential active compounds and key targets and preliminarily clarified the potential material base for the efficacy and mechanism of this drug.

Abstract Background Xylan, the major constituent of hemicellulose, is composed of β-(1,4)-linked xylopyranosyl units that for the backbone, with side chains formed by other chemical moieties such as arabinose, galactose, mannose, ferulic acid and acetyl groups. Acetyl xylan esterases and α-l-arabinofuranosidases are two important accessory enzymes that remove side chain residues from xylan backbones and may act in synergy with other xylanolytic enzymes. Compared with enzymes possessing a single catalytic activity, multifunctional enzymes can achieve lignocellulosic biomass hydrolysis using a less complex mixture of enzymes. Results Here, we cloned an acetyl xylan esterase (PcAxe) from Penicillium chrysogenum P33 and expressed it in Pichia pastoris GS115. The optimal pH and temperature of the recombinant PcAxe (rPcAxe) for 4-nitrophenyl acetate were 7.0 and 40 °C, respectively. rPcAxe is stable across a broad pH range, retaining 100% enzyme activity om pH 6–9 after a 1 h incubation. The enzyme tolerates the presence of a wide range of metal ions. Sequence alignment revealed a GH62 domain exhibiting α-l-arabinofuranosidase activity with pH and temperature optima of pH 7.0 and 50 °C, in addition to the expected esterase domain. rPcAxe displayed significant synergy with a recombinant xylanase, with a degree of synergy of 1.35 for the hydrolysis of delignified corn stover. Release of glucose was increased by 51% from delignified corn stover when 2 mg of a commercial cellulase was replaced by an equivalent amount of rPcAxe, indicating superior hydrolytic efficiency. Conclusions The novel bifunctional enzyme PcAxe was identified in P. chrysogenum P33. rPcAxe includes a carbohydrate esterase domain and a glycosyl hydrolase family 62 domain. This is the first detailed report on a novel bifunctional enzyme possessing acetyl xylan esterase and α-l-arabinofuranosidase activities. These findings expand our current knowledge of glycoside hydrolases and pave the way for the discovery of similar novel enzymes.

Ground subsidence caused by collapse leads to suspension or subsidence of the pipe, resulting in the stress concentration. It is a significant factor being a threat to safe operation of the pipeline. Based on Pasternak’s beam-on-elastic-foundation theory, this study presents a mechanical model of interaction between the buried suspended pipeline and the soil, which considers the effect of the beam width. The pipeline was modeled as a buried part and a suspended part. According to the compatibility conditions of suspended and nonsuspended parts, this paper solved differential equations describing the deflection of pipeline and derived the formulas of deflection and internal force. This solution involves whole cases of the Pasternak model. Connecting to the pipeline operation status, the formulas of piping stress were deduced by piping stress analysis. Meanwhile, piping stress analysis can define the scope of application of the model. Compared with the measured values and results of the Winkler model, the calculated results of the Pasternak model are more accurate and suitable for predicting the behavior of the pipeline in the limit state. In addition, according to normalized analysis of main affecting factors which comprise the pipe material, pipe dimension, pipe depth, and length of collapse, it was also found that the length of collapse dominates the stability of the pipeline.

Objectives: To explore the relationship between the distance from the lower edge of the gestational sac to the internal cervical os in early pregnancy and placenta previa. Material and methods: A prospective cohort study of women who underwent pregnancy examination in Weifang People's Hospital or Sunshine Union Hospital from January 2020 to June 2021. The distance from the lower edge of the gestational sac to the internal cervical os was measured at 5--6 weeks' gestation. There were 86 women with distance < 2.5 cm, and 105 women with distance ≥ 2.5 cm were randomly selected. There were 92 cases of scarred uterus and 99 cases of non-scarred uterus among the 191 women. They were divided into six groups according to the distance: (1) < 1.0 cm; (2) 1.0 cm to < 1.5 cm; (3) 1.5 cm to < 2.0 cm; (4) 2.0 cm to < 2.5 cm; (5) 2.5 cm to < 3.0 cm; (6) ≥ 3.0 cm. All included women were followed-up during pregnancy and pregnancy outcome, and the likelihood ratio of different distances in early pregnancy was calculated and risk stratification was performed, and ROC curve was constructed. Results: There were 15 women in the included studies who were lost to follow-up, 47 had a scarred uterus with placenta previa and 29 had a non-scarred uterus with placenta previa after delivery at 28 weeks or later. The distance from the lower edge of the gestational sac to the internal cervical os in early pregnancy of the scarred uterus < 1.5 cm, and the likelihood ratio was ∞; and the distance ≥ 3.0 cm, the likelihood ratio was 0. The distance from the lower edge of the non-scarred gestational sac to the internal cervical os < 1.0 cm, and the likelihood ratio was ∞; and the distance ≥ 3.0 cm, the likelihood ratio was 0. The ROC curve showed that when the area AUC under the curve was 87%, the optimal diagnostic cut-off value was 2.4 cm. Conclusions: When the distance from the lower edge of the gestational sac to the internal cervical os was < 1.5 cm and the distance between the non-scarred uterus was < 1.0 cm, it eventually developed into placenta previa; the distance from the lower edge of the gestational sac to the internal cervical os in the first trimester of pregnancy between the scarred uterus and the non-scarred uterus was ≥ 3.0 cm, and it would hardly develop into placenta previa. When the distance from the lower edge of the gestational sac to the internal cervical os in early pregnancy was ≤ 2.4 cm, it could be used as a predictor of placenta previa. [ABSTRACT FROM AUTHOR]

The genome of Schizophyllum commune encodes a diverse repertoire of degradative enzymes for plant cell wall breakdown. Recent comparative genomics study suggests that this wood decayer likely has a mode of biodegradation distinct from the well-established white-rot/brown-rot models. However, much about the extracellular enzyme system secreted by S. commune during lignocellulose deconstruction remains unknown and the underlying mechanism is poorly understood. In this study, extracellular proteins of S. commune colonizing Jerusalem artichoke stalk were analyzed and compared with those of two white-rot fungi Phanerochaete chrysosporium and Ceriporiopsis subvermispora and a brown-rot fungus Gloeophyllum trabeum. Results: Under solid-state fermentation (SSF) conditions, S. commune displayed considerably higher levels of hydrolytic enzyme activities in comparison with those of P. chrysosporium, C. subvermispora and G. trabeum. During biodegradation process, this fungus modified the lignin polymer in a way which was consistent with a hydroxyl radical attack, similar to that of G. trabeum. The crude enzyme cocktail derived from S. commune demonstrated superior performance over a commercial enzyme preparation from Trichoderma longibrachiatum in the hydrolysis of pretreated lignocellulosic biomass at low enzyme loadings. Secretomic analysis revealed that compared with three other fungi, this species produced a higher diversity of carbohydrate-degrading enzymes, especially hemicellulases and pectinases acting on polysaccharide backbones and side chains, and a larger set of enzymes potentially supporting the generation of hydroxyl radicals. In addition, multiple non-hydrolytic proteins implicated in enhancing polysaccharide accessibility were identified in the S. commune secretome, including lytic polysaccharide monooxygenases (LPMOs) and expansin-like proteins. Conclusions: Plant lignocellulose degradation by S. commune involves a hydroxyl radical-mediated mechanism for lignocellulose modification in parallel with the synergistic system of various polysaccharide-degrading enzymes. Furthermore, the complex enzyme system of S. commune holds significant potential for application in biomass saccharification. These discoveries will help unveil the diversity of natural lignocellulose-degrading mechanisms, and advance the design of more efficient enzyme mixtures for the deconstruction of lignocellulosic feedstocks. [ABSTRACT FROM AUTHOR]