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Abstract Diabetic kidney disease (DKD) is the main cause of deaths due to diabetes mellitus (DM). Due to the complexity of its onset, it is difficult to achieve accurate prevention and treatment. The classically activated macrophage (M1) polarization is a crucial proinflammatory mechanism of DKD, while the interaction and cascade effects of oxidative stress and inflammatory response remain to be elucidated. A urine proteomic analysis of patients with DM indicated that peroxiredoxin 2 (PRDX2) had the higher abundance in DKD. We recently found that PRDX of parasitic protozoa Entamoeba histolytica, which was similar to human PRDX2 in amino acid sequence and spatial structure, could activate the inflammatory response of macrophages through toll-like receptor 4 (TLR4). Hence, our study was designed to explore the role of PRDX2 in chronic inflammation during DKD. Combined with in vivo and in vitro experiments, results showed that the PRDX2 was positively correlated with DKD progression and upregulated by high glucose or recombinant tumor necrosis factor-α in renal tubular epithelial cells; Besides, recombinant PRDX2 could promote M1 polarization of macrophages, and enhance the migration as well as phagocytic ability of macrophages through TLR4. In summary, our study has explored the novel role of PRDX2 in DKD to provide a basis for further research on the diagnosis and treatment of DKD.

Abstract Emergent superconductivity at the LaAlO3/KTaO3 interfaces exhibits a mysterious dependence on the KTaO3 crystallographic orientations. Here by soft X-ray angle-resolved photoemission spectroscopy, we directly resolve the electronic structure of the LaAlO3/KTaO3 interfacial superconductors and the non-superconducting counterpart. We find that the mobile electrons that contribute to the interfacial superconductivity show strong k ⊥ dispersion. Comparing the superconducting and non-superconducting interfaces, the quasi-three-dimensional electron gas with over 5.5 nm spatial distribution ubiquitously exists and shows similar orbital occupations. The signature of electron-phonon coupling is observed and intriguingly dependent on the interfacial orientations. Remarkably, the stronger electron-phonon coupling signature correlates with the higher superconducting transition temperature. Our observations help scrutinize the theories on the orientation-dependent superconductivity and offer a plausible and straightforward explanation. The interfacial orientation effect that can modify the electron-phonon coupling strength over several nanometers sheds light on the applications of oxide interfaces in general.

Abstract Background Hepatocellular carcinoma (HCC) is a common type of malignant tumor where the prognosis is dismal. Circular RNA (CircRNA) is a novel RNA that regulates downstream gene transcription and translation to influence the progression of HCC. However, the regulatory relationship that exists between E3 ligases, which is a class of post-translational modifying proteins, and circRNA remains unclear. Methods Based on the E3 ubiquitin ligase in the competitive endogenous RNA (ceRNA) network, a circRNA-regulated E3 ubiquitin ligase signature (CRE3UL) was developed. A CRE3UL signature was created using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis and merged it with clinicopathologic characteristics to generate a nomogram for prognosis prediction. The pRRophetic algorithm was utilized and immunological checkpoints were analyzed to compare the responses of patients in the high-risk group (HRG) and low-risk group (LRG) to targeted therapy and immunotherapy. Finally, experimental research will further elucidate the relationship between E3 ubiquitin ligase signature and HCC. Results HRG patients were found to have a worse prognosis than LRG patients. Furthermore, significant variations in prognosis were observed among different subgroups based on various clinical characteristics. The CRE3UL signature was identified as being an independent prognostic indicator. The nomogram that combined clinical characteristics and the CRE3UL signature was found to accurately predict the prognosis of HCC patients and demonstrated greater clinical utility than the current TNM staging approach. According to anticancer medication sensitivity predictions, the tumors of HRG patients were more responsive to gefitinib and nilotinib. From immune-checkpoint markers analysis, immunotherapy was identified as being more probable to assist those in the HRG. Conclusions We found a significant correlation between the CRE3UL signature and the tumor microenvironment, enabling precise prognosis prediction for HCC patients. Additionally, a nomogram was developed that performs well in predicting the overall survival (OS) of HCC patients. This provides valuable guidance for clinicians in devising specific personalized treatment strategies. Graphical Abstract

ABSTRACT: The size of the initial primordial follicle pool in the ovary depends on primordial follicle formation, which determines the female reproductive lifespan. However, the molecular regulation of primordial follicle formation in chickens remains unclear. In this study, the left ovaries of chickens were collected at 2 d posthatch (dph), 5.5 dph, and 10.5 dph to examine the formation of primordial follicles. Single-cell mRNA sequencing (scRNA-seq) and spatial transcriptomic analysis were performed to explore the ovarian microenvironment and identify regulatory pathways involved in the formation of primordial follicles in chickens. Histomorphological analysis of chicken ovary tissues revealed the presence of germ cell cysts at 1 dph, which began to disintegrate at 2 dph. Primordial follicles appeared at 5.5 dph and continued to develop into larger-diameter follicles. scRNA-seq and spatial transcriptomic analysis revealed 24 cellular clusters involved in chicken primordial follicle formation. The metabolic pathway of steroid hormone synthesis was found in pregranulosa and pretheca cells. Histological analysis showed that chicken ovaries did not form primordial follicles after the inhibition of the steroid hormone synthesis pathway by simvastatin or tamoxifen. In addition, mRNA transcriptomic and bioinformatics analyses revealed that GREB1 was a downstream gene of the steroid hormone synthesis pathway during the formation of chicken primordial follicles. This study provides a valuable foundation for investigating primordial follicle formation in avian species and optimizing their reproductive performance.

This article delves into the role of ChatGPT within the rapidly evolving field of artificial intelligence, especially highlighting its significant potential in nursing education. Initially, the paper presents the notable advancements ChatGPT has achieved in facilitating interactive learning and providing real-time feedback, along with the academic community’s growing interest in this technology. Subsequently, summarizing the research outcomes of ChatGPT’s applications in nursing education, including various clinical disciplines and scenarios, showcases the enormous potential for multidisciplinary education and addressing clinical issues. Comparing the performance of several Large Language Models (LLMs) on China’s National Nursing Licensure Examination, we observed that ChatGPT demonstrated a higher accuracy rate than its counterparts, providing a solid theoretical foundation for its application in Chinese nursing education and clinical settings. Educational institutions should establish a targeted and effective regulatory framework to leverage ChatGPT in localized nursing education while assuming corresponding responsibilities. Through standardized training for users and adjustments to existing educational assessment methods aimed at preventing potential misuse and abuse, the full potential of ChatGPT as an innovative auxiliary tool in China’s nursing education system can be realized, aligning with the developmental needs of modern teaching methodologies.

Leaf Area Index (LAI) is a critical vegetation structural parameter for characterizing vegetation canopy structure. Multiple LAI products derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) observations have made a noteworthy impact on global energy fluxes, climate change, and biogeochemistry research. It is essential to examine the long-term performance of global LAI products and quantitatively evaluate their quality. However, traditional methods, which often rely on single overall accuracy metrics, fail to assess the ability to capture vegetation's internal heterogeneity and temporal dynamics. This study introduces a new approach by combining spatial heterogeneity and temporal stability to assess product consistency, using MOD15A2H and MYD15A2H as examples. We observed that the local spatial heterogeneity (within 5 × 5 pixels) of the two products exhibited similar distribution pattern. The MYD15A2H LAI exhibits better time-series stability and lower spatially heterogeneous anomalous fluctuations in the tropical forest region. Both products demonstrate sustainable usability in the time series, and their spatial heterogeneity exhibit consistent trends. In conclusion, this study shows the comparability and stability of MOD15A2H and MYD15A2H in terms of the spatiotemporal variability of LAI. For differences stemming from unavoidable reflectivity issues, it is recommended to filter for high-quality inversion results or to utilize reliable reanalysis datasets.

Establishing an urban ecological network is a means to improve the ecological environment and enhance sustainable urban development amidst rapid urbanization. Based on the demand of eco-city, morphological spatial pattern analysis (MSPA), ecological regulation services value (ERSV), and landscape connectivity have been combined to identify ecological resources with high connectivity and ecological benefits in this study. Using the Minimum Cumulative Resistance (MCR) model, ecological corridors have been constructed and ecological critical nodes have been identified. In addition, the urban ecological network has then been optimized from the overall layout and local key nodes based on the circuit theory to balance the ecological livability and species diversity in the eco-city. The main conclusions could be demonstrated as follows: (1) 76.45% of the high ecological regulation service value areas have been identified as core areas. (2) The distribution of ecological corridors has been found uneven with significant disparities (3) The connectivity indices, especially the line point rate (β) index, have increased by 21.66%, while the robustness has increased by 75.44%. Overall, the combined methods have been used to establish and optimize the ecological network within the limited space to balance the ecological livability and biodiversity. The results of this study could provide a scientific reference for the optimization of urban ecological space and promote sustainable development in the eco-city.

Abstract T‐cell receptor (TCR) engineered T‐cell therapy, unlike chimeric antigen receptor T‐cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR‐T‐cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel “universal” TCR‐T “artificial antigen expression” technique that involves the delivery of the antigen to tumor cells using DSPE‐PEG‐NY‐ESO‐1157‐165 liposomes (NY‐ESO‐1 Lips) to express TCR‐T‐cell‐specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor‐specific cytotoxic T‐cell immune response. NY‐ESO‐1 TCR‐T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD‐1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY‐ESO‐1 Lips “cursed” tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR‐T in solid tumor treatment.

Abstract Perylenequinones (PQs) from bambusicolous Shiraia fungi serve as excellent photosensitizers for photodynamic therapy. However, the lower yield of PQ production in mycelium cultures is an important bottleneck for their clinical application. Light has long been recognized as a pivotal regulatory signal for fungal secondary metabolite biosynthesis. In this study, we explored the role of nitric oxide (NO) in the growth and PQ biosynthesis in mycelium cultures of Shiraia sp. S9 exposed to red light. The continuous irradiation with red light (627 nm, 200 lx) suppressed fungal conidiation, promoted hyphal branching, and elicited a notable increase in PQ accumulation. Red light exposure induced NO generation, peaking to 81.7 μmol/g FW on day 8 of the culture, with the involvement of nitric oxide synthase (NOS)- or nitrate reductase (NR)-dependent pathways. The application of a NO donor sodium nitroprusside (SNP) restored conidiation of Shiraia sp. S9 under red light and stimulated PQ production, which was mitigated upon the introduction of NO scavenger carboxy-PTIO or soluble guanylate cyclase inhibitor NS-2028. These results showed that red light-induced NO, as a signaling molecule, was involved in the regulation of growth and PQ production in Shiraia sp. S9 through the NO-cGMP-PKG signaling pathway. While mycelial H2O2 content exhibited no significant alternations, a transient increase of intracellular Ca2+ and extracellular ATP (eATP) content was detected upon exposure to red light. The generation of NO was found to be interdependent on cytosolic Ca2+ and eATP concentration. These signal molecules cooperated synergistically to enhance membrane permeability and elevate the transcript levels of PQ biosynthetic genes in Shiraia sp. S9. Notably, the combined treatment of red light with 5 μM SNP yielded a synergistic effect, resulting in a substantially higher level of hypocrellin A (HA, 254 mg/L), about 3.0-fold over the dark control. Our findings provide valuable insights into the regulation of NO on fungal secondary metabolite biosynthesis and present a promising strategy involving the combined elicitation with SNP for enhanced production of photoactive PQs and other valuable secondary metabolites in fungi. Graphical Abstract

The Special Issue “New Insights into Energy Economics and Sustainable Development” includes a total of eight papers, focusing on different problems related to energy economics and sustainable development [...]

With advanced digital technologies as the key support, many scholars and researchers have proposed various random warranty models by integrating mission cycles into the warranty stage. However, these existing warranty models are designed only from the manufacturer’s subjective perspective, ignoring certain consumer requirements. For instance, they overlook a wide range of warranty coverage, the pursuit of reliability improvement rather than mere minimal repair, and the need to limit the delay in repair. To address these consumer requirements, this paper proposes a novel random collaborative preventive maintenance warranty with repair-time threshold (RCPMW-RTT). This model incorporates terms that are jointly designed by manufacturers and consumers to meet specific consumer needs, thereby overcoming the limitations of existing warranty models. The introduction of a repair-time threshold aims to limit the time delay in repairing failures and to compensate for any losses incurred by consumers. Using probability theory, the RCPMW-RTT is evaluated in terms of cost and time, and relevant variants are derived by analyzing key parameters. As an exemplary representation of the RCPMW-RTT, two random replacement policies named the discrete random renewable back replacement (DRRBR) and the discrete random renewable front replacement (DRRFR) are proposed and modelled to ensure reliability after the expiration of the RCPMW-RTT. In both policies, product replacement is triggered either by the occurrence of the first extreme mission cycle or by reaching the limit on the number of non-extreme mission cycles, whichever comes first. Probability theory is used to present cost rates for both policies in order to determine optimal values for decision variables. Finally, numerical analysis is performed on the RCPMW-RTT to reveal hidden variation tendencies and mechanisms; numerical analysis is also performed on the DRRBR and the DRRFR. The numerical results show that the proposed random replacement policies are feasible and unique; the replacement time within the post-warranty coverage increases as the maintenance quality improves and the cost rate can be reduced by setting a smaller repair-time threshold.

Abstract The severity of osteoarthritis (OA) and cartilage degeneration is highly associated with synovial inflammation. Although recent investigations have revealed a dysregulated crosstalk between fibroblast‐like synoviocytes (FLSs) and macrophages in the pathogenesis of synovitis, limited knowledge is available regarding the involvement of exosomes. Here, increased exosome secretion is observed in FLSs from OA patients. Notably, internalization of inflammatory FLS‐derived exosomes (inf‐exo) can enhance the M1 polarization of macrophages, which further induces an OA‐like phenotype in co‐cultured chondrocytes. Intra‐articular injection of inf‐exo induces synovitis and exacerbates OA progression in murine models. In addition, it is demonstrated that inf‐exo stimulation triggers the activation of glycolysis. Inhibition of glycolysis using 2‐DG successfully attenuates excessive M1 polarization triggered by inf‐exo. Mechanistically, HIF1A is identified as the determinant transcription factor, inhibition of which, both pharmacologically or genetically, relieves macrophage inflammation triggered by inf‐exo‐induced hyperglycolysis. Furthermore, in vivo administration of an HIF1A inhibitor alleviates experimental OA. The results provide novel insights into the involvement of FLS‐derived exosomes in OA pathogenesis, suggesting that inf‐exo‐induced macrophage dysfunction represents an attractive target for OA therapy.

Background: We aim to investigate genes associated with myasthenia gravis (MG), specifically those potentially implicated in the pathogenesis of dilated cardiomyopathy (DCM). Additionally, we seek to identify potential biomarkers for diagnosing myasthenia gravis co-occurring with DCM. Methods: We obtained two expression profiling datasets related to DCM and MG from the Gene Expression Omnibus (GEO). Subsequently, we conducted differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) on these datasets. The genes exhibiting differential expression common to both DCM and MG were employed for protein-protein interaction (PPI), Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Additionally, machine learning techniques were employed to identify potential biomarkers and develop a diagnostic nomogram for predicting MG-associated DCM. Subsequently, the machine learning results underwent validation using an external dataset. Finally, gene set enrichment analysis (GSEA) and machine algorithm analysis were conducted on pivotal model genes to further elucidate their potential mechanisms in MG-associated DCM. Results: In our analysis of both DCM and MG datasets, we identified 2641 critical module genes and 11 differentially expressed genes shared between the two conditions. Enrichment analysis disclosed that these 11 genes primarily pertain to inflammation and immune regulation. Connectivity map (CMAP) analysis pinpointed SB-216763 as a potential drug for DCM treatment. The results from machine learning indicated the substantial diagnostic value of midline 1 interacting protein1 (MID1IP1) and PI3K-interacting protein 1 (PIK3IP1) in MG-associated DCM. These two hub genes were chosen as candidate biomarkers and employed to formulate a diagnostic nomogram with optimal diagnostic performance through machine learning. Simultaneously, single-gene GSEA results and immune cell infiltration analysis unveiled immune dysregulation in both DCM and MG, with MID1IP1 and PIK3IP1 showing significant associations with invasive immune cells. Conclusion: We have elucidated the inflammatory and immune pathways associated with MG-related DCM and formulated a diagnostic nomogram for DCM utilizing MID1IP1/PIK3IP1. This contribution offers novel insights for prospective diagnostic approaches and therapeutic interventions in the context of MG coexisting with DCM.

Summary: Background: Recurrence following radical resection in patients with stage IB gastric cancer (GC) is not uncommon. However, whether postoperative adjuvant chemotherapy could reduce the risk of recurrence in stage IB GC remains contentious. Methods: We collected data on 2110 consecutive patients with pathologic stage IB (T1N1M0 or T2N0M0) GC who were admitted to 8 hospitals in China from 2009 to 2018. The survival of patients who received adjuvant chemotherapy was compared with that of postoperative observation patients using propensity score matching (PSM). Two survival prediction models were constructed to estimate the predicted net survival gain attributable to adjuvant chemotherapy. Findings: Of the 2110 patients, 1344 received adjuvant chemotherapy and 766 received postoperative observation. Following the 1-to-1 matching, PSM yielded 637 matched pairs. Among matched pairs, adjuvant chemotherapy was not associated with improved survival compared with postoperative observation (OS: hazard ratio [HR], 0.72; 95% CI, 0.52–1.00; DFS: HR, 0.91; 95% CI, 0.64–1.29). Interestingly, in the subgroup analysis, reduced mortality after adjuvant chemotherapy was observed in the subgroups with elevated serum CA19-9 (HR, 0.22; 95% CI, 0.08–0.57; P = 0.001 for multiplicative interaction), positive lymphovascular invasion (HR, 0.32; 95% CI, 0.17–0.62; P

Abstract With the rapid development of e-commerce, online reviews have become an important information source for consumers and e-commerce businesses. While the negative impact of deceptive online reviews has been well recognized, more research has to be done to help understand the linguistic manifestations of deceptive online reviews in order to help identify deceptive reviews and help increase the value and sustainability of e-commerce businesses. This study explores the linguistic manifestations of deceptive online reviews based on the reality monitoring theory, and then uses the data from Amazon.com online product reviews to examine perceptual cues, affective cues, detail cues, relevance cues, and cognitive cues of various deceptive online reviews. The results show that reviews for emotional catharsis are more extreme with affective cues, while perfunctory reviews often lack details with fewer prepositions and adjectives. In addition, deceptive reviews often lack relevance cues when these reviews are made to obtain the rewards provided by the vendors while paid posters tend to use more cognitive cues in deceptive reviews. Moreover, deceptive online reviews under all motives often lack perceptual cues. These findings provide a deeper understanding of the linguistic manifestations of deceptive online reviews and provide significant managerial implications for e-commerce businesses to employ high-quality online reviews for sustainable growth.

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms that consist of social deficits and repetitive behaviors. Unfortunately, no effective medication is available thus far to target the core symptoms of ASD, since the pathogenesis remains largely unknown. To investigate the pathogenesis of the core symptoms in ASD, we constructed Shank1 P1812L-knock-in (KI) mice corresponding to a recurrent ASD-related mutation, SHANK1 P1806L, to achieve construct validity and face validity. Shank1 P1812L-KI heterozygous (HET) mice presented with social deficits and repetitive behaviors without the presence of confounding comorbidities. HET mice also exhibited downregulation of metabotropic glutamate receptor (mGluR1) and associated signals, along with structural abnormalities in the dendritic spines and postsynaptic densities. Combined with findings from Shank1 R882H-KI mice, our study confirms that mGluR1-mediated signaling dysfunction is a pivotal mechanism underlying the core symptoms of ASD. Interestingly, Shank1 P1812L-KI homozygous (HOM) mice manifested behavioral signs of impaired long-term memory rather than autistic-like core traits; thus, their phenotype was markedly different from that of Shank1 P1812L-KI HET mice. Correspondingly, at the molecular level, Shank1 P1812L-KI HOM displayed upregulation of AMPA receptor (GluA2)-related signals. The different patterns of protein changes in HOM and HET mice may explain the differences in behaviors. Our study emphasizes the universality of mGluR1-signaling hypofunction in the pathogenesis of the core symptoms in ASD, providing a potential target for therapeutic drugs. The precise correspondence between genotype and phenotype, as shown in HOM and HET mice, indicates the importance of reproducing disease-related genotypes in mouse models.

SET and MYND domain protein 2 (SMYD2) can methylate histone H3 at lysine36 (H3K36) and some non-histone substrates to play a role in tumorigenesis. However, It is unclear how SMYD2 contributes to chronic kidney disease (CKD). Here, AZ505 or LLY507, which could inhibit SMYD2, were used in cisplatin-induced CKD to investigate the effects and possible mechanisms by which they might act. We found that high expression of SMYD2 in cisplatin-induced CKD. However, AZ505 or LLY507 can significantly inhibit its expression, improve renal function injury and fibrosis induced by cisplatin, inhibit the transition of epithelial cells to a fibrogenic phenotype and fibrosis-related proteins, inhibit the expression of Inflammatory Cytokines (such as IL-6 and TNF-α), And inhibit the phosphorylation of pro-fibrosis molecule Smad3 and signal transduction and transcription activator-3 (STAT3) and up-regulated the expression of renal protective factor Smad7. In cultured tubular epithelial cells, AZ505 also can inhibit the expression of EMT, fibrosis-related proteins, and inflammatory cytokines in cisplatin-induced tubular epithelial cells. Based on these findings, SMYD2 may be a critical regulator of cisplatin-induced CKD and targeted pharmacological inhibition of SMYD2 may prevent cisplatin-induced CKD through Smad3 or STAT3-related signaling pathways.

Protein palmitoylation, the most common and the only reversible post-translational lipid modification following protein translation, plays a pivotal role in the biochemical and physiological processes of both animals and plants. DHHC proteins, enriched with DHHC (Asp-His-His-Cys) domains, serve as catalyst for protein palmitoylation. However, research on DHHC in cotton remains scarce. This study conducted a systematic characterization and bioinformatics analysis on G. arboreum, G. raimondii, G. hirsutum, and G. barbadense, detecting 38, 37, 74, and 74 DHHC genes, respectively. Phylogenetic analysis categorized the DHHC gene family into six subgroups, consistent with previous evolutionary studies in Arabidopsis and rice. A further examination of protein structure revealed a correlation between genetic relatedness, structural similarity, and functional identity. Cis-element analysis identified elements predominantly associated with light response, stress, growth and development, and plant hormones. The integration of cotton seed development transcriptome, tissue expression pattern analysis, and population transcriptome data collectively suggests that Ghir_A05G027650 and Ghir_D05G027670 are promising candidate genes influencing seed development in upland cotton. Conversely, Gbar_A04G010750 and Gbar_A12G020520 emerge as potential candidates affecting both seed and fiber development in sea island cotton. These findings lay down a theoretical foundation for delving into the functional diversity of DHHC genes in cotton, thereby paving the way for the development of new breeding strategies and the optimization of cotton seed and fiber production, ultimately contributing to improved crop yield and quality.

Abstract Background The role of the membrane-associated RING-CH (MARCH) family in carcinogenesis has been widely studied, but the member of this family, RNF173, has not yet been thoroughly explored in the context of hepatocellular carcinoma (HCC). Methods With the use of an HCC tissue microarray and IHC staining, we aim to determine the differential expression of RNF173 in HCC patients and its clinical significance. The biological role of RNF173 is investigated through in vitro and in vivo experiments. RNA sequencing, mass spectrometry, and immunoprecipitation are performed to uncover the underlying mechanism of RNF173's impact on the development of HCC. Results The mRNA and protein levels of RNF173 were significantly lower in HCC tissues than in normal tissues. HCC patients with low RNF173 expression had shorter overall survival and recurrence-free survival, and RNF173 was significantly correlated with tumor number, tumor capsule, tumor differentiation, and BCLC stage. In addition, in vitro and in vivo experiments showed that RNF173 downregulation exacerbated tumor progression, including migration, invasion, and proliferation. GRB2 is a key molecule in the RAF/MEK/ERK pathway. RNF173 inhibits the RAF/MEK/ERK signaling by ubiquitinating and degrading GRB2, thereby suppressing HCC cell proliferation, invasion and migration. Combining clinical samples, we found that HCC patients with high RNF173 and low GRB2 expression had the best prognosis. Conclusion RNF173 inhibits the invasion and metastasis of HCC by ubiquitinating and degrading GRB2, thereby suppressing the RAF/MEK/ERK signaling pathway. RNF173 is an independent risk factor for the survival and recurrence of HCC patients. RNF173 may serve as a novel prognostic molecule and potential therapeutic target for HCC. Video Abstract Graphical Abstract Graphical abstract Model of RNF173 on RAF/MEK/ERK signaling. RNF173 knockdown resulted in impaired ubiquitination and degradation of GRB2, leading to the activation of the RAF/MEK/ERK signaling pathway and promotion of invasion and metastasis in HCC cells.

Abstract Objective To isolate a prevalent G9P[8] group A rotavirus (RVA) (N4006) in China and investigate its genomic and evolutionary characteristics, with the goal of facilitating the development of a new rotavirus vaccine. Methods The RVA G9P[8] genotype from a diarrhea sample was passaged in MA104 cells. The virus was evaluated by TEM, polyacrylamide gel electrophoresis, and indirect immunofluorescence assay. The complete genome of virus was obtained by RT-PCR and sequencing. The genomic and evolutionary characteristics of the virus were evaluated by nucleic acid sequence analysis with MEGA ver. 5.0.5 and DNASTAR software. The neutralizing epitopes of VP7 and VP4 (VP5* and VP8*) were analyzed using BioEdit ver. 7.0.9.0 and PyMOL ver. 2.5.2. Results The RVA N4006 (G9P[8] genotype) was adapted in MA104 cells with a high titer (105.5 PFU/mL). Whole-genome sequence analysis showed N4006 to be a reassortant rotavirus of Wa-like G9P[8] RVA and the NSP4 gene of DS-1-like G2P[4] RVA, with the genotype constellation G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1 (G9P[8]-E2). Phylogenetic analysis indicated that N4006 had a common ancestor with Japanese G9P[8]-E2 rotavirus. Neutralizing epitope analysis showed that VP7, VP5*, and VP8* of N4006 had low homology with vaccine viruses of the same genotype and marked differences with vaccine viruses of other genotypes. Conclusion The RVA G9P[8] genotype with the G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1 (G9P[8]-E2) constellation predominates in China and may originate from reassortment between Japanese G9P[8] with Japanese DS-1-like G2P[4] rotaviruses. The antigenic variation of N4006 with the vaccine virus necessitates an evaluation of the effect of the rotavirus vaccine on G9P[8]-E2 genotype rotavirus.

Kiwifruit, a nutrient-dense fruit, has become increasingly popular with consumers in recent decades. However, kiwifruit trees are prone to stunted growth after a few years of planting, called early tree decline. In this study, melatonin (MT), pollen polysaccharide (SF), 14-hydroxyed brassinosteroid (14-HBR) were applied alone or in combination to investigate their influence on plant growth, nutrition absorption and rhizosphere bacterial abundance in kiwifruit seedlings. The results revealed that MT, SF and 14-HBR alone treatments significantly increased leaf chlorophyll content, photosynthetic capacity and activities of dismutase and catalase compared with the control. Among them, MT treatment significantly increased the dry root biomass by 35.7%, while MT+14-HBR treatment significant enhanced the dry shoot biomass by 36.9%. Furthermore, both MT and MT+14-HBR treatments markedly improved the activities of invertase, urease, protease and phosphatase in soil, as well as the abundance of Proteobacteria and Acidobacteria in rhizosphere microorganisms based on 16S rDNA sequencing. In addition, MT treatment improved the content of available K and organic matter in soil, and increased the uptake of P, K and Fe by seedlings. In summary, 14-HBR and MT combined had the best effect on promoting rhizosphere bacterial distribution, nutrient absorption and plant growth. These findings may provide valuable guidance for solving growth weakness problem in kiwifruit cultivation.

Primary dysmenorrhea is a common gynecological disease with typical clinical symptoms and diverse treatment methods. Acupoint patch therapy is one of the traditional external treatments of traditional Chinese medicine, with a long history, and has been widely used in the treatment of many diseases in China. Graphene nuangong acupoint plaster (GNGAP) developed based on traditional acupoints and new materials have been used in the clinical treatment of primary dysmenorrhea, and satisfactory therapeutic effects have been achieved. However, the underlying mechanisms of GNGAP still need further investigation. In this study, we used estradiol benzoate combined with oxytocin intraperitoneally to establish dysmenorrhea model rats, and observed the torsion response, uterine organ coefficients, prostaglandin levels and metabolite changes of rats with dysmenorrhea model after the intervention of GNGAP, to elucidate the mechanism of the effect of GNGAP. Compared with normal rats, the dysmenorrhea model rats exhibited increased writhing response and latency time, increased uterine organ coefficient, and significant changes in 79 metabolites. Twenty-three significantly enriched pathways were discovered, including amino acid metabolism, arachidonic acid metabolism, pyrimidine metabolism, and ovarian steroidogenesis, which may be involved in the pathogenesis of primary dysmenorrhea. Compared with the model group, the torsion response, latency time and uterine organ coefficient of rats in the acupoint patch group were significantly improved, and nine uterine metabolites were significantly altered, among which metabolites such as 4-pyridoxic acid, d-glucarate and Phenol were identified as potential biomarkers for the therapeutic effects of GNGAP. Vitamin B6 metabolism, Ascorbate and aldarate metabolism and Tyrosine metabolism were enriched in nine metabolic pathways. These findings contribute to the screening study of potential pathological metabolic pathways in primary dysmenorrhea. Additionally, they reveal the biological effects of GNGAP in the treatment of primary dysmenorrhea at the metabolite level.

Abstract The interplay between immune cells/macrophages and fibroblast‐like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single‐cell RNA sequencing (scRNA‐seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients’ synovial macrophage infiltration and polarization. In addition, the yes‐associated protein 1 (YAP1)/thioredoxin‐interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)‐dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule‐1 (ICAM‐1) which may subsequently fine‐tune the infiltration of M1‐polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane‐camouflaged Verteporfin (Vt)‐loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1‐polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

Summary: Current diagnostic methods for diabetic nephropathy (DN) lack precision, especially in early stages and monitoring progression. This study aims to find potential biomarkers for DN progression and evaluate their accuracy. Using serum samples from healthy controls (NC), diabetic patients (DM), early-medium stage DN (DN-EM), and late-stage DN (DN-L), researchers employed quantitative proteomics and Mfuzz clustering analysis revealed 15 proteins showing increased expression during DN progression, hinting at their biomarker potential. Combining Mfuzz clustering with weighted gene co-expression network analysis (WGCNA) highlighted five candidates (HMGB1, CD44, FBLN1, PTPRG, and ADAMTSL4). HMGB1 emerged as a promising biomarker, closely correlated with renal function changes. Experimental validation supported HMGB1’s upregulation under high glucose conditions, reinforcing its potential as an early detection biomarker for DN. This research advances DN understanding and identifies five potential biomarkers, notably HMGB1, as a promising early monitoring target. These findings set the stage for future clinical diagnostic applications in DN.

The tradeoffs between the spatial and temporal resolutions for the remote sensing instruments limit their capacity to monitor the eutrophic status of inland lakes. Spatiotemporal fusion (STF) provides a cost-effective way to obtain remote sensing data with both high spatial and temporal resolutions by blending multisensor observations. However, remote sensing reflectance (Rrs) over water surface with a relatively low signal-to-noise ratio is prone to be contaminated by large uncertainties in the fusion process. To present a comprehensive analysis on the influence of processing and modeling errors, we conducted an evaluation study to understand the potential, uncertainties, and limitations of using STF for monitoring chlorophyll a (Chla) concentration in an inland eutrophic water (Chaohu Lake, China). Specifically, comparative tests were conducted on the Sentinel-2 and Sentinel-3 image pairs. Three typical STF methods were selected for comparison, i.e., Fit-FC, spatial and temporal nonlocal filter-based fusion model, and the flexible spatiotemporal data fusion. The results show as follows: (a) among the influencing factors, atmospheric correction uncertainties and geometric misregistration have larger impacts on the fusion results, compared with radiometric bias between the imaging sensors and STF modeling errors; and (b) the machine-learning-based Chla inversion accuracy of the fusion data [R2 = 0.846 and root mean square error (RMSE) = 17.835 μg/l] is comparable with that of real Sentinel-2 data (R2 = 0.856 and RMSE = 16.601 μg/l), and temporally dense Chla results can be produced with the integrated Sentinel-2 and fusion image datasets. These findings will help to provide guidelines to design STF framework for monitoring aquatic environment of inland waters with remote sensing data.

Douyin is the Chinese version of TikTok. Using Douyin at bedtime is a very common behavior among Douyin users. However, the reasons why users like using Douyin before sleep are yet unclear. We conducted a cross-section survey from January 1st to January 16th, 2023 to capture data to examine the associations of depression, anxiety, life satisfaction, well-being, loneliness, and physical activity with Douyin usage at bedtime. The mediation role of insomnia in these associations was examined. A total of 3,392 participants who met the inclusion criteria were included for analysis. Our structural equation modeling analysis showed that depression on (β = 0.08; p

Sour cherry (Prunus cerasus L.) is an important allotetraploid cherry species that evolved in the Caspian Sea and Black Sea regions from a hybridization of the tetraploid ground cherry (Prunus fruticosa Pall.) and an unreduced pollen of the diploid sweet cherry (P. avium L.) ancestor. Details of when and where the evolution of this species occurred are unclear, as well as the effect of hybridization on the genome structure. To gain insight, the genome of the sour cherry cultivar ‘Schattenmorelle’ was sequenced using Illumina NovaSeqTM and Oxford Nanopore long-read technologies, resulting in a ~629-Mbp pseudomolecule reference genome. The genome could be separated into two subgenomes, with subgenome PceS_a originating from P. avium and subgenome PceS_f originating from P. fruticosa. The genome also showed size reduction compared to ancestral species and traces of homoeologous sequence exchanges throughout. Comparative analysis confirmed that the genome of sour cherry is segmental allotetraploid and evolved very recently in the past.

In China, county-level regions play a pivotal role in achieving dual carbon goals. In this study, we analyzed the spatiotemporal characteristics of carbon balance coefficients for counties in Jiangsu Province from 2000 to 2021. The logarithmic mean Divisia index decomposition method explored the factors influencing county-level carbon balance. The findings indicated that CO2 emissions in Jiangsu Province increased from 192 million tons in 2001 to 637 million tons in 2011 and exhibited a small fluctuation from 2012 to 2021. A “higher in the south, lower in the north” distribution pattern emerged, with high CO2 emission areas concentrated in the economically developed south. Vegetative carbon sequestration increased from 142 million tons in 2000 to 171 million tons in 2021 with a “higher boundary and lower at the center” distribution pattern. High carbon sequestration areas were mainly in regions with abundant natural resources and vegetation. The number of counties experiencing carbon imbalance rose from 63 in 2000 to 95 in 2021, with a spatial distribution similar to high carbon emissions. Economic development and urbanization accelerated carbon imbalance, whereas technological advancement and reduced regional carbon fixation pressure effectively alleviated it. Pursuing of dual carbon goals can be supported by reducing emissions and increasing carbon sinks.

Background: Propofol combined with alfentanil is suitable for intravenous anesthesia for day-case hysteroscopy. Objective: To investigate the median effective dose (ED 50 ) and 95% effective dose (ED 95 ) of alfentanil compounded with propofol for day-case hysteroscopy. Design: In all, 29 patients who volunteered for painless hysteroscopy in 2022 were recruited. 1.5 mg/kg propofol was given as a sedative to all patients. The trial was conducted using the modified Dixon sequential method, with an initial dose of 10 μg/kg of alfentanil, and the subject’s alfentanil dose depended on whether the prior hysteroscopy had failed, which was defined as inadequate cervical dilatation and hysteroscope placement with the patient exhibiting body movement, frowning, or a MOAA/S score >1. If the hysteroscopy failed (i.e. a positive response), the subsequent subject’s alfentanil dosage was raised, and conversely (i.e. a negative response), the dose was decreased, with the adjacent dose ratio always being 1:1.2. The formal test begins with the first crossover wave and lasts until seven crossover waves materialize. Methods: The probit method was used to calculate the ED 50 , ED 95 , and corresponding 95% confidence intervals (CIs) of alfentanil compounded with propofol for hysteroscopy. Results: The ED 50 and ED 95 of alfentanil combined with propofol for day-case hysteroscopy were 5.701 (95% CI: 3.841–7.069) μg/kg and 8.817 (95% CI: 7.307–20.868) μg/kg, respectively. Conclusion: Alfentanil at 8.817 μg/kg in conjunction with propofol is a successful and safe approach for day-case painless hysteroscopy. Trial registration: The trial registry name: Modified sequential method to determine the half-effective dose of alfentanil compounded with propofol for ambulatory hysteroscopy. The URL of registration is https://www.chictr.org.cn/showproj.html?proj=171786 , where the full trial protocol can be accessed. Registration number: ChiCTR2200061619.

Due to their tailorable morphology, silica nanoparticles (SNPs) have recently attracted widespread attention because they can be used in many emerging areas. Over the past decade, important work has been done on novel processing methodologies to prepare SNPs, which have resulted in better control over the size, shape, porosity, and notable improvements in their physio-chemical properties. Microemulsions are a simple and widely used method of preparing silica nanoparticles. The method, however, still has several flaws, such as the inability to produce the expected silica nanoparticles even under carefully designed synthesis conditions. In order to effectively use silica nanoparticles (SNs) in catalyst, adsorption, polymer filler, optical devices, bio-imaging, drug delivery, and biomedical applications, it is becoming more and more crucial to have good control over their morphology, particle size, uniformity, and dispersity. It is therefore desirable to monitor the synthesis process in real time to unravel the mechanisms behind the formation of silica nanoparticles and to promote their controllable synthesis. It has always been a hot topic in nano science to apply microemulsions using different types of surfactants to inorganic nanomaterials. Despite this, very few studies have been performed on polymer-based microemulsions based on different ionic surfactants and their relative dielectric spectroscopy (DS). This review examines various synthesis techniques for producing well-dispersed SNs and hollow silica nanoparticles (HSNs) with adjustable dimensions ranging from a few to hundreds of nanometers of various mesostructures.

Aberrant expression of deubiquitinases (DUBs) is significantly associated with tumorigenesis. However, the precise impact of deubiquitination on the tumour microenvironment (TME) and immunotherapy in hepatocellular carcinoma (HCC) remains unclear. In this study, we comprehensively characterized the transcriptional and genetic alterations of 26 overall survival (OS)-related DUBs in HCC. The consensus clustering algorithm was used to identify patients with distinct deubiquitination patterns. We then established a DUBscore model using the principal component analysis (PCA) algorithm to quantify the deubiquitination patterns of individual HCC patients. Finally, we performed weighted gene coexpression network analysis (WGCNA) to identify the key DUBs. Consequently, three distinct deubiquitination patterns were identified, each showing significant differences in the characteristics of the TME, immune response, and clinical prognosis. Further analysis revealed that the DUBscore was an independent prognostic factor and could predict the response to immunotherapy for patients with HCC. Ultimately, BRCC3 was identified as a key DUB based on the DUBscore, which was significantly overexpressed in tumour tissues, as confirmed by qRT‒PCR and immunohistochemistry (IHC). We analysed the distribution and expression of BRCC3 in various types of immune cells using single-cell RNA sequencing (scRNA-seq). In conclusion, our study revealed the crucial role of deubiquitination patterns in shaping TME complexity and diversity. A more personalized and effective antitumour immunotherapy strategy can be developed by utilizing the DUBscore model to identify deubiquitination patterns in individual HCC patients. Our findings also highlight that BRCC3 may serve as a potential therapeutic target in HCC and a predictive marker for immunotherapeutic response.

This paper investigates a warm standby repairable retrial system with two types of components and a single repairman, where type 1 components have priority over type 2 in use. Failure and repair times for each type of component are assumed to be exponential distributions. The retrial feature is considered and the retrial time of each failed component is exponentially distributed. By using Markov process theory and matrix-analytic method, the system steady-state probabilities are derived, and the system steady-state availability and some steady-state performance indices are obtained. Using the Bayesian approach, the system parameters can be estimated. The cost-benefit ratio function of the system is constructed based on the failed components and repairman's states. Numerical experiments are given to evaluate the effect of each parameter on the system steady-state availability and optimize the system cost-benefit ratio with repair rate as a decision variable.

Abstract Clear cell renal cell carcinoma (ccRCC) is a main subtype of renal cancer, and advanced ccRCC frequently has poor prognosis. Many studies have found that lipid metabolism influences tumor development and treatment. This study was to examine the prognostic and functional significance of genes associated with lipid metabolism in individuals with ccRCC. Using the database TCGA, differentially expressed genes (DEGs) associated with fatty acid metabolism (FAM) were identified. Prognostic risk score models for genes related to FAM were created using univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Our findings demonstrate that the prognosis of patients with ccRCC correlate highly with the profiles of FAM-related lncRNAs (AC009166.1, LINC00605, LINC01615, HOXA-AS2, AC103706.1, AC009686.2, AL590094.1, AC093278.2). The prognostic signature can serve as an independent predictive predictor for patients with ccRCC. The predictive signature's diagnostic effectiveness was superior to individual clinicopathological factors. Between the low- and high-risk groups, immunity research revealed a startling difference in terms of cells, function, and checkpoint scores. Chemotherapeutic medications such lapatinib, AZD8055, and WIKI4 had better outcomes for patients in the high-risk group. Overall, the predictive signature can help with clinical selection of immunotherapeutic regimens and chemotherapeutic drugs, improving prognosis prediction for ccRCC patients.

Abstract Background Perylenequinones from Shiraia fruiting bodies are excellent photosensitizers and widely used for anti-cancer photodynamic therapy (PDT). The lower yield of Shiraia perylenequinones becomes a significant bottleneck for their medical application. Branched-chain amino acids (BCAAs) not only serve as important precursors for protein synthesis, but also are involved in signaling pathway in cell growth and development. However, there are few reports concerning their regulation of fungal secondary metabolism. In present study, the eliciting effects of BCAAs including l-isoleucine (l-Ile), l-leucine (l-Leu) and l-valine (l-Val) on Shiraia perylenequinone production were investigated. Results Based on the analysis of the transcriptome and amino acid contents of Shiraia in the production medium, we revealed the involvement of BCAAs in perylenequinone biosynthesis. The fungal conidiation was promoted by l-Val treatment at 1.5 g/L, but inhibited by l-Leu. The spore germination was promoted by both. The production of fungal perylenequinones including hypocrellins A (HA), HC and elsinochromes A-C (EA–EC) was stimulated significantly by l-Val at 1.5 g/L, but sharply suppressed by l-Leu. After l-Val treatment (1.5 g/L) in Shiraia mycelium cultures, HA, one of the main bioactive perylenequinones reached highest production 237.92 mg/L, about 2.12-fold than that of the control. Simultaneously, we found that the expression levels of key genes involved in the central carbon metabolism and in the late steps for perylenequinone biosynthesis were up-regulated significantly by l-Val, but most of them were down-regulated by l-Leu. Conclusions Our transcriptome analysis demonstrated that BCAA metabolism was involved in Shiraia perylenequinone biosynthesis. Exogenous BCAAs exhibit contrasting effects on Shiraia growth and perylenequinones production. l-Val could promote perylenequinone biosynthesis via not only enhancing the central carbon metabolism for more precursors, but also eliciting perylenequinone biosynthetic gene expressions. This is the first report on the regulation of BCAAs on fungal perylenequinone production. These findings provided a basis for understanding physiological roles of BCAAs and a new avenue for increasing perylenequinone production in Shiraia mycelium cultures. Graphical Abstract

Abstract Background Risk prediction rules are important to establish appropriate treatment and management strategy for patients with different risk classification of pulmonary embolism (PE). Neutrophils are considered to be related to PE as an essential marker of inflammation. However, few studies have reported the association between neutrophil levels and risk classification of acute PE (APE). The aim of this study was to investigate the role of neutrophil levels upon admission in the assessment of risk classification of APE. Methods A total of 299 consecutive APE patients and 90 patients without APE confirmed by computed tomographic pulmonary angiography were retrospectively screened. APE patients were stratified into two subgroups according to clinical guidelines: low- (n = 233) and intermediate- and high-risk (n = 60) APE. Results The neutrophil levels in intermediate- and high-risk APE patients were significantly higher compared to low-risk APE or non-APE patients (P

The incidence of depression has been steadily rising in recent years, making it one of the most prevalent mental illnesses. As the pursuit of novel antidepressant drugs captivates the pharmaceutical field, the therapeutic efficacy of Traditional Chinese Medicine (TCM) has been widely explored. Chaihu (Bupleurum) has been traditionally used for liver conditions such as hepatitis, liver inflammation, liver fibrosis, and liver cancer. It is believed to have hepatoprotective effects, promoting liver cell regeneration and protecting against liver damage. In addition, Bupleurum has also been used as a Jie Yu (depression-relieving) medicine in China, Japan, Republic of Korea, and other Asian countries for centuries. This review article aims to summarize the research conducted on the antidepressant properties and mechanisms of Bupleurum, as well as discuss the potential of TCM formulas containing Bupleurum. This review highlights various antidepressant ingredients isolated from Bupleurum, including saikosaponin A, saikosaponin D, rutin, puerarin, and quercetin, each with distinct mechanisms of action. Additionally, Chinese herb prescriptions and extracts containing Bupleurum, such as Chaihu Shugansan, Xiaoyaosan, and Sinisan, are also included due to their demonstrated antidepressant effects. This review reveals that these Bupleurum compounds exhibit antidepressant effects through the regulation of neurotransmitter mechanisms (such as 5-HT and DA), the NMDA (N-methyl-D-aspartate) system, brain-derived neurotrophic factor (BDNF), and other intracellular signaling pathways. Collectively, this comprehensive review provides insights into the multiple applications of Bupleurum in the treatment of depression and highlights its potential as an alternative or complementary approach to traditional therapies. However, it is essential to consider the potential adverse effects and clinical restrictions of Bupleurum despite its promising potential. Further research is needed to elucidate its specific mechanisms of action and evaluate its effectiveness in human subjects.

BackgroundPrevious studies have suggested an association between gut microbiota and primary biliary cholangitis (PBC). Nonetheless, the causal relationship between gut microbiota and PBC risk remains unclear.MethodsA bidirectional two-sample Mendelian Randomization (MR) study was employed using summary statistical data for gut microbiota and PBC from the MiBioGen consortium and Genome-Wide Association Studies (GWAS) database to investigate causal relationships between 211 gut microbiota and PBC risk. Inverse variance weighted (IVW) method was the primary analytical approach to assess causality, and the pleiotropy and heterogeneity tests were employed to verify the robustness of the findings. Additionally, we performed reverse MR analyses to investigate the possibility of the reverse causal association.ResultsThe IVW method identified five gut microbiota that demonstrated associations with the risk of PBC. Order Selenomonadales [odds ratio (OR) 2.13, 95% confidence interval (CI) 1.10–4.14, p = 0.03], Order Bifidobacteriales (OR 1.58, 95% CI 1.07–2.33, p = 0.02), and Genus Lachnospiraceae_UCG_004 (OR 1.64, 95%CI 1.06–2.55, p = 0.03) were correlated with a higher risk of PBC, while Family Peptostreptococcaceae (OR 0.65, 95%CI 0.43–0.98, p = 0.04) and Family Ruminococcaceae (OR 0.33, 95%CI 0.15–0.72, p = 0.01) had a protective effect on PBC. The reverse MR analysis demonstrated no statistically significant relationship between PBC and these five specific gut microbial taxa.ConclusionThis study revealed that there was a causal relationship between specific gut microbiota taxa and PBC, which may provide novel perspectives and a theoretical basis for the clinical prevention, diagnosis, and treatment of PBC.

IntroductionInflammatory cell infiltration is a novel hallmark of diabetic kidney disease (DKD), in part, by activated macrophages. Macrophage-to-tubular epithelial cell communication may play an important role in renal fibrosis. Circular RNAs (circRNAs) have been reported in the pathogenesis of various human diseases involving macrophages activation, including DKD. However, the exact mechanism of circRNAs in macrophage infiltration and renal fibrosis of DKD remains obscure.MethodsIn our study, a novel circRNA circUBXN7 was identified in DKD patients using microarray. The function of circUBXN7 in vitro and in vivo was investigated by qRT-PCR, western blot, and immunofluorescence. Finally, a dual-luciferase reporter assay, ChIP, RNA pull-down, RNA immunoprecipitation and rescue experiments were performed to investigate the mechanism of circUBXN7.ResultsWe demonstrated that the expression of circUBXN7 was significantly upregulated in the plasma of DKD patients and correlated with renal function, which might serve as an independent biomarker for DKD patients. According to investigations, ectopic expression of circUBXN7 promoted macrophage activation, EMT and fibrosis in vitro, and increased macrophage infiltration, EMT, fibrosis and proteinuria in vivo. Mechanistically, circUBXN7 was transcriptionally upregulated by transcription factor SP1 and could reciprocally promote SP1 mRNA stability and activation via directly binding to the m6A-reader IGF2BP2 in DKD.ConclusionCircUBXN7 is highly expressed in DKD patients may provide the potential biomarker and therapeutic target for DKD.

In order to solve the problem of uneven distribution of traffic and traffic congestion in the toll plaza of the smart expressway, the measure of opening tidal lanes was proposed under the premise of certain spatial resources, and the optimal number of open lanes was explored. Taking the Xiong′an North mainline toll station of Jingxiong Smart Expressway as the research object, the tidal traffic flow characteristics of the lanes was analyzed and the feasibility of setting tidal lanes was demonstrated; The tidal coefficients of 06,07,07,08 and 09 were selected, and the traffic volume was divided into six grades of A—F, and the VISSIM toll station simulation model was established; Taking the morning peak of the toll station as an example, the simulation results such as traffic volume of each simulation scheme were analyzed to determine the number of tidal lanes to be opened under different traffic flow states. The results show that with the toll station exit as the main traffic flow direction, it is appropriate to open one tidal lane when the tidal coefficient is 07 and the traffic volume is C—F level and the tidal coefficient is 09 and the traffic volume is B level; When the tidal coefficient is 08 and 09, 2 and 3 tidal lanes are opened under C—F traffic volume respectively; in other cases, no tidal lane is opened. Relying on the Xiong′an North mainline toll station of the Jingxiong Smart Expressway with commuting function, studying the optimal number of opening tidal lanes can provide a reference for the regulation and control of the entrance and exit lanes of smart expressway, and has practical significance for improving its traffic capacity and efficiency.

Abstract Background It has been hypothesized that higher growth differentiation factor 15 (GDF15) level and lower testosterone/ estradiol (T/E) ratio are associated with major depressive disorder (MDD), yet the underlying effect of serum GDF15 on hinting the T/E ratio imbalance is not fully understood. We observed the correlation between serum T/E ratio and circulating GDF15 in male depressed cohort. Methods The sample consisted of participants (aged 18 ~ 65 years) from the Renmin Hospital of Wuhan University with MDD (n = 412) defined according to a Structured Clinical Interview for DSM-V (SCID), and male healthy controls (n = 137). Serum levels of testosterone, estradiol, and depression risk biomarkers (thyroid hormone, lipids, hs-CRP, Tenascin-C [TNC], GDF15, KLF4, Gas6, and sgp130) were measured. The associations among log-transformed T/E ratio and these biomarkers were analyzed using univariate correlation analysis, category analyses, and linear regression adjusting for standard risk factors. Results Of the sample, 36.89% had lower T/E ratio ( 20:1). After multivariable adjustment, T/E ratio was negatively associated with GDF15 (-0.095 [95% CI -0.170 ~ -0.023] standard deviation [SD] change per SD increase in lg[T/E], P = 0.015) and inversely related to TNC (-0.085 [95% CI -0.167 ~ 0.003] standard deviation [SD] change per SD increase in lg[T/E], P = 0.048). Serum T/E ratio was negatively associated with GDF15 level in both FT3, TSH and HDL strata, whereas this association was not observed in TNC. In T/E ratio strata analyses, there is a significant and negative correlation among T/E ratio and GDF15 in depressive patients with sex hormone imbalance, yet this relationship was not investigated in patients with sex hormone balance. Conclusion In our community-based observation, circulating GDF-15 level was greatly and inversely associated with serum T/E ratio, indicating that higher GDF-15 alerts sex hormone imbalance in patients with MDD.

Context Ranunculus ternatus Thunb (Ranunculaceae), (RTT) is used clinically for the treatment of tuberculosis or as tumour adjuvant therapy, but its potential effect on diabetic nephropathy (DN) has not been studied. Objective To investigate the effect of RTT extract in renal fibrosis of DN. Materials and methods C57BL/6 mice were randomly divided into four groups (n = 12). Diabetes mellitus (DM) mice were induced by streptozotocin (STZ, 55 mg/kg/day) for five consecutive days and treated by RTT extract (2 g/kg). Afterward, blood glucose, HE and Masson staining were assayed. The expression levels of Vimentin, ɑ-SMA, TNF-ɑ, NF-κB p-p65, NF-κB p65, SMYD2, H3K36me3, H3K4me3 were determined by western blots. Firbronectin was respectively assayed by western blot and immunofluorescent staining. Results RTT extract significantly ameliorated renal injury and renal fibrosis in the renal tissue of STZ-induced diabetic mice as demonstrated by the decreased expression level of Fibronectin (65%), Vimentin and α-SMA (75% & 53%). In addition, the levels of TNF-α (57%), NF-κB p-p65 and NF-κB p65 (35% & 25%) were elevated in the DN mice. Importantly, these were alleviated after RTT extract treatment. Moreover, we observed that the protein levels of SMYD2 (30%), H3K36me3 and H3K4me3 (53% & 75%) were reduced in DN mice after treatment with RTT extract. Discussion and conclusions RTT extract mediates antifibrotic effects and anti-inflammatory responses in STZ-induced DN mainly through suppressing SMYD2 activation and H3K36me3 and H3K4me3 protein expression. RTT extract might have therapeutic potential against high glucose-induced nephropathy.

The damage of proximal tubular epithelial cells (PTECs) is considered a central event in the pathogenesis of chronic kidney disease (CKD) and deregulated repair processes of PTECs result in epithelial–mesenchymal transition (EMT), which in turn aggravates tubular injury and kidney fibrosis. In this study, we firstly revealed that the reduction of TTC36 is associated with unilateral ureteral obstruction (UUO)-induced CKD; besides, ablation of TTC36 attenuated tubular injury and subsequent EMT in UUO-treated mice kidneys. Consistently, TTC36 overexpression promoted EMT in TGF-β1-induced HK2 cells. Moreover, TTC36 elevated the protein expression of CEBPB, which was involved in the regulation of TGF-β/SMAD3 signaling, and augmented SMAD3 signaling and downstream genetic response were reduced by CEBPB silencing. Collectively, our results uncovered that TTC36 deficiency plays a protective role in tubular injury and renal fibrosis triggered by UUO; further, TTC36 overexpression exacerbated TGF-β/SMAD3 signaling via elevating the stability of SMAD3 and CEBPB, suggesting that TTC36 inhibition may be a potential strategy in the therapy of obstructive nephropathy.

Background: Whether proximal gastrectomy (PG) can be applied to patients with proximal advanced gastric cancer (AGC) remains controversial. We aimed to explore the oncological safety of PG for proximal AGC in this study. Methods: 452 patients undergoing surgery for proximal AGC in the Affiliated Cancer Hospital of Nanjing Medical University were enrolled in this study. 329 patients with AGC were finally analyzed, of which 254 patients underwent total gastrectomy (TG) and 75 patients underwent PG. We used propensity score-matched (PSM) analysis to reduce biases. Results: After PSM, 67 patients with proximal AGC were included in the PG group and TG group, respectively. The estimated 5-year OS rates for TG and PG group after PSM were 64.3% and 74.9%, respectively, and no significant difference in OS existed between the two groups (p = 0.275). Multivariate analysis showed that PG was not an independent prognostic factor. Incidence of metastasis in No.5 or 6 lymph node (LN) station was significantly higher in the patients with pathological T4 and Borrmann III tumors (9.9% and 10.6%) than those with pathological T2/3 and Borrmann I/II tumors (2.2% and 3.3%). No metastasis was observed in No.5 or 6 LN station in patients with pathological T2/3 tumors or Borrmann I/II tumors when tumor size was ≤4 cm. Conclusions: PG is a reasonable choice for patients with selected proximal AGC, especially for those with tumors of size ≤4 cm, Borrmann type I/II, and pathological T2/3. Future prospective randomized trials should be conducted first in patients with these specific proximal tumors.

Quantification of vitamin K1 in serum is still quite a challenge for most analytical laboratories. For long, protein precipitation (PP) coupled with liquid–liquid extraction (LLE) or solid phase extraction (SPE) is the only choice for sample preparation before LC-MS/MS analysis. The objective of this study is to establish a novel method for the simple and rapid quantification of K1. To this end, three issues are illuminated in the first place: (i) the release efficiency of K1 is influenced by the type of precipitator and the volume ratio of serum to precipitator during PP; (ii) the absolute recovery of K1 will be compromised by the partition effect during extraction; (iii) the volume of injected serum per run should be proper rather than high to prevent the potential ion suppression effect. Benefitting from these findings, a single-step PP method is developed for K1 quantification for the first time. For pretreatment, isopropanol (100 μL), instead of the frequently used methanol, ethanol and acetonitrile, is utilized to release K1 from serum (25 μL), which realize the excellent release efficiency (>90%) and dilution effect (1:4) simultaneously. After validation, the method can provide favorable accuracy (91.5–112.2%) and precision (less than13.5%) in the wide concentration range (0.1–2.5 ng/mL). As a result, such method may provide a feasible and high-throughput alternative for evaluating K1 status in practice.

Cerebral ischemia–reperfusion injury (CIRI) is a series of cascade reactions that occur after blood flow recanalization in the ischemic zone in patients with cerebral infarction, causing an imbalance in intracellular homeostasis through multiple pathologies such as increased oxygen free radicals, inflammatory response, calcium overload, and impaired energy metabolism, leading to mitochondrial dysfunction and ultimately apoptosis. Rescue of reversibly damaged neurons in the ischemic hemispheric zone is the key to saving brain infarction and reducing neurological deficits. Complex and active neurological functions are highly dependent on an adequate energy supply from mitochondria. Mitochondrial biogenesis (MB), a process that generates new functional mitochondria and restores normal mitochondrial function by replacing damaged mitochondria, is a major mechanism for maintaining intra-mitochondrial homeostasis and is involved in mitochondrial quality control to ameliorate mitochondrial dysfunction and thus protects against CIRI. The main regulator of MB is peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which improves mitochondrial function to protect against CIRI by activating its downstream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) to promote mitochondrial genome replication and transcription. This paper provides a theoretical reference for the treatment of neurological impairment caused by CIRI by discussing the mechanisms of mitochondrial biogenesis during cerebral ischemia–reperfusion injury.

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

Primordial germ cells (PGCs) play a crucial role in preserving poultry genetic resources and conducting transgenic research. A system for the rapid isolation of PGCs from single chicken embryonic blood was established in this paper. We found that PGCs can migrate to the lower layer of chicken embryonic fibroblasts (CEFs) through pores smaller than their diameter, while blood cells cannot, when co-cultured with CEFs of passages two to three. Based on the characteristics of PGCs, we developed a new PGC isolation method (cell culture insert/CEF adhesion method) that utilizes a 3 μm cell culture insert and CEFs of passages two to three. Using this method, approximately 700 PGCs can be isolated from the blood of a single chicken embryo at Hamburger and Hamilton (H&H) stage 17 of development. The separation rate achieved was 87.5%, with a separation purity of 95%. The separation rate of this method was 41.4% higher than the common Percoll density gradient centrifugation method and 33.6% higher than lysis with ACK buffer. PGCs isolated from embryonic blood could proliferate 37-fold within 2 weeks when cultured in a feeder-free culture system. They also continued to express the SSEA-1 and DAZL proteins and retained the ability to migrate in vivo. Overall, PGCs separated using cell culture inserts/CEF adhesion method retain their stem cell characteristics and migration ability. PGCs also exhibit good proliferation efficiency, making them suitable for subsequent transgenic experiments or genetic resource preservation.

Background and aimsAs a result of increasing numbers of studies most recently, mitophagy plays a vital function in the genesis of cancer. However, research on the predictive potential and clinical importance of mitophagy-related genes (MRGs) in hepatocellular carcinoma (HCC) is currently lacking. This study aimed to uncover and analyze the mitophagy-related diagnostic biomarkers in HCC using machine learning (ML), as well as to investigate its biological role, immune infiltration, and clinical significance.MethodsIn our research, by using Least absolute shrinkage and selection operator (LASSO) regression and support vector machine- (SVM-) recursive feature elimination (RFE) algorithm, six mitophagy genes (ATG12, CSNK2B, MTERF3, TOMM20, TOMM22, and TOMM40) were identified from twenty-nine mitophagy genes, next, the algorithm of non-negative matrix factorization (NMF) was used to separate the HCC patients into cluster A and B based on the six mitophagy genes. And there was evidence from multi-analysis that cluster A and B were associated with tumor immune microenvironment (TIME), clinicopathological features, and prognosis. After then, based on the DEGs (differentially expressed genes) between cluster A and cluster B, the prognostic model (riskScore) of mitophagy was constructed, including ten mitophagy-related genes (G6PD, KIF20A, SLC1A5, TPX2, ANXA10, TRNP1, ADH4, CYP2C9, CFHR3, and SPP1). ResultsThis study uncovered and analyzed the mitophagy-related diagnostic biomarkers in HCC using machine learning (ML), as well as to investigate its biological role, immune infiltration, and clinical significance. Based on the mitophagy-related diagnostic biomarkers, we constructed a prognostic model(riskScore). Furthermore, we discovered that the riskScore was associated with somatic mutation, TIME, chemotherapy efficacy, TACE and immunotherapy effectiveness in HCC patients.ConclusionMitophagy may play an important role in the development of HCC, and further research on this issue is necessary. Furthermore, the riskScore performed well as a standalone prognostic marker in terms of accuracy and stability. It can provide some guidance for the diagnosis and treatment of HCC patients.