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Abstract Background To date, although most thyroid carcinoma (THCA) achieves an excellent prognosis, some patients experience a rapid progression episode, even with differentiated THCA. Nodal metastasis is an unfavorable predictor. Exploring the underlying mechanism may bring a deep insight into THCA. Methods A total of 108 THCA from Chinese patients with next-generation sequencing (NGS) were recruited. It was used to explore the gene alteration spectrum of THCA and identify gene alterations related to nodal metastasis in papillary thyroid carcinoma (PTC). The Cancer Genome Atlas THCA cohort was further studied to elucidate the relationship between specific gene alterations and tumor microenvironment. A pathway enrichment analysis was used to explore the underlying mechanism. Results Gene alteration was frequent in THCA. BRAF, RET, POLE, ATM, and BRCA1 were the five most common altered genes. RET variation was positively related to nodal metastasis in PTC. RET variation is associated with immune cell infiltration levels, including CD8 naïve, CD4 T and CD8 T cells, etc. Moreover, Step 3 and Step 4 of the cancer immunity cycle (CIC) were activated, whereas Step 6 was suppressed in PTC with RET variation. A pathway enrichment analysis showed that RET variation was associated with several immune-related pathways. Conclusion RET variation is positively related to nodal metastasis in Chinese PTC, and anti-tumor immune response may play a role in nodal metastasis triggered by RET variation.

Abstract Background This study aimed to evaluate the efficacy of radiomics signatures derived from polyenergetic images (PEIs) and virtual monoenergetic images (VMIs) obtained through dual-layer spectral detector CT (DLCT). Moreover, it sought to develop a clinical-radiomics nomogram based on DLCT for predicting cancer stage (early stage: stage I-II, advanced stage: stage III-IV) in pancreatic ductal adenocarcinoma (PDAC). Methods A total of 173 patients histopathologically diagnosed with PDAC and who underwent contrast-enhanced DLCT were enrolled in this study. Among them, 49 were in the early stage, and 124 were in the advanced stage. Patients were randomly categorized into training (n = 122) and test (n = 51) cohorts at a 7:3 ratio. Radiomics features were extracted from PEIs and 40-keV VMIs were reconstructed at both arterial and portal venous phases. Radiomics signatures were constructed based on both PEIs and 40-keV VMIs. A radiomics nomogram was developed by integrating the 40-keV VMI-based radiomics signature with selected clinical predictors. The performance of the nomogram was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curves analysis (DCA). Results The PEI-based radiomics signature demonstrated satisfactory diagnostic efficacy, with the areas under the ROC curves (AUCs) of 0.92 in both the training and test cohorts. The optimal radiomics signature was based on 40-keV VMIs, with AUCs of 0.96 and 0.94 in the training and test cohorts. The nomogram, which integrated a 40-keV VMI-based radiomics signature with two clinical parameters (tumour diameter and normalized iodine density at the portal venous phase), demonstrated promising calibration and discrimination in both the training and test cohorts (0.97 and 0.91, respectively). DCA indicated that the clinical-radiomics nomogram provided the most significant clinical benefit. Conclusions The radiomics signature derived from 40-keV VMI and the clinical-radiomics nomogram based on DLCT both exhibited exceptional performance in distinguishing early from advanced stages in PDAC, aiding clinical decision-making for patients with this condition.

Abstract In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments in the current era, particularly the emerging integration of single-cell and spatiotemporal transcriptomics, have enabled a detailed molecular comprehension of the complex regulation of cell fate. The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine. Currently, single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors. Starting from the perspective of RNA sequencing technology, this review outlined the significance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, encompassing preclinical medicine and clinical applications. We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies, as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis, treatment, and drug resistance characteristics of prostate cancer. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer. Furthermore, we explore the potential clinical applications stemming from other single-cell technologies in this review, paving the way for future research in precision medicine.

Abstract Largely removed from anthropogenic delivery of nitrogen (N), Antarctica has notably low levels of nitrogen. Though our understanding of biological sources of ammonia have been elucidated, the microbial drivers of nitrate (NO3 −) cycling in coastal Antarctica remains poorly understood. Here, we explore microbial N cycling in coastal Antarctica, unraveling the biological origin of NO3 − via oxygen isotopes in soil and lake sediment, and through the reconstruction of 1968 metagenome-assembled genomes from 29 microbial phyla. Our analysis reveals the metabolic potential for microbial N2 fixation, nitrification, and denitrification, but not for anaerobic ammonium oxidation, signifying a unique microbial N-cycling dynamic. We identify the predominance of complete ammonia oxidizing (comammox) Nitrospira, capable of performing the entire nitrification process. Their adaptive strategies to the Antarctic environment likely include synthesis of trehalose for cold stress, high substrate affinity for resource utilization, and alternate metabolic pathways for nutrient-scarce conditions. We confirm the significant role of comammox Nitrospira in the autotrophic, nitrification process via 13C-DNA-based stable isotope probing. This research highlights the crucial contribution of nitrification to the N budget in coastal Antarctica, identifying comammox Nitrospira clade B as a nitrification driver.

Variations in the mechanical properties and pore structure of granulated blast furnace slag self-compacting concrete were studied. The grey correlation theory established the relationship between mechanical properties and pore structure. The test results show that with the continuous improvement of age, the mechanical properties decreased with the increase of sand replacement rate in the early stage. In the middle and late stages, the compressive strength and splitting tensile strength of granulated blast furnace slag self-compacting concrete are higher than those of ordinary self-compacting concrete, while the elastic modulus continues to decrease with increasing slag content. After standard curing, the change in the pore structure parameters of ordinary self-compacting concrete is relatively stable. The pore structure parameters of granulated blast furnace slag self-compacting concrete change significantly. Because granulated blast furnace slag has a certain hydraulicity, the strength and strength growth rate of granulated blast furnace slag self-compacting concrete are higher than those of ordinary self-compacting concrete, and the corresponding pore structure parameters change. Through grey correlation analysis, the specific surface area and average chord length structure of granulated blast furnace slag self-compacting concrete are essential factors affecting its mechanical properties.

BackgroundIgG4-related disease (IgG4-RD) was characterized by single or multiple masses in organs, which may mimic various inflammatory and malignant diseases. Here, we summarize 4 patients with aggressive manifestations of IgG4-RD that mimic nasopharynx cancer to provide some new sights for the diagnosis of IgG4-RD.Case summaryFour patients were included in our series. The age ranged from 53 to 64 years old, and the duration of the disease ranged from 4 to 6 months. The chief complaints included headache, rhinorrhea, or diplopia. All patients had more than 10 IgG4+ plasma cells/HPF in immunohistochemistry with plasma lgG4 levels ranging from 218 mg/dL to 765 mg/dL. All of them met the diagnostic criteria of lgG4-RD.ConclusionThe described case is highly similar to the clinical manifestations of nasopharyngeal carcinoma. Although pathology is the gold standard, there are still limitations. Serological IgG4 can help confirm the diagnosis. Timely diagnosis of IgG4-RD is of great significance in preventing secondary organ damage in patients with active diseases.

Introduction: Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody–drug conjugates (ADCs) are a novel class of targeted therapeutics that have demonstrated encouraging results for UC. Although there is a limited number of high-quality randomized control trials (RCTs) examining the use of ADCs in patients with UC, some prospective non-randomized studies of interventions (NRSIs) provide valuable insights and pertinent information. We aim to assess the efficacy and safety of ADCs in patients with UC, particularly those with locally advanced and metastatic diseases.Methods: A systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science databases to identify pertinent studies. Outcomes, such as the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and treatment-related adverse events (TRAEs), were extracted for further analyses.Results: Twelve studies involving 1,311 patients were included in this meta-analysis. In terms of tumor responses, the pooled ORR and DCR were 40% and 74%, respectively. Regarding survival analysis, the pooled median PFS and OS were 5.66 months and 12.63 months, respectively. The pooled 6-month PFS and OS were 47% and 80%, while the pooled 1-year PFS and OS were 22% and 55%, respectively. The most common TRAEs of the ADCs were alopecia (all grades: 45%, grades ≥ III: 0%), decreased appetite (all grades: 34%, grades ≥ III: 3%), dysgeusia (all grades: 40%, grades ≥ III: 0%), fatigue (all grades: 39%, grades ≥ III: 5%), nausea (all grades: 45%, grades ≥ III: 2%), peripheral sensory neuropathy (all grades: 37%, grades ≥ III: 2%), and pruritus (all grades: 32%, grades ≥ III: 1%).Conclusion: The meta-analysis in this study demonstrates that ADCs have promising efficacies and safety for patients with advanced or metastatic UC.Systematic review registration:https://www.crd.york.ac.uk/prospero/, identifier: CRD42023460232

Abstract Perineural invasion (PNI) leads to the poor prognosis of head and neck squamous cancer (HNSCC) patients, but the mechanism of PNI remains unclear. Dickkopf‐1 (DKK1), a secretory protein in the Wnt signaling pathway, was found indeed upregulated in HNSCC cells and tissues. Higher expression of DKK1 was statistically relevant to T stage, N stage, PNI, and poor prognosis of HNSCC. DKK1 overexpression enhanced the migration abilities of cancer cells. Moreover, DKK1‐overexpressing cancer cells promoted cancer cells invasion of peripheral nerves in vitro and in vivo. Mechanistically, DKK1 could promote the PI3K–AKT signaling pathway. The migration abilities of neuroblastoma cells, which were enhanced by DKK1‐overexpressing HNSCC cell lines, could be reversed by an inhibitor of Akt (MK2206). The association of DKK1 with PNI was also confirmed in HNSCC samples. Variables, including T stage, N stage, DKK1 expression, and PNI, were used to establish a nomogram to predict the survival probability and disease‐free probability at 3 and 5 years. In summary, DKK1 can promote the PI3K–AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI.

Rationale and objectives: To investigate alterations in the brain structure in patients with Crohn's disease in activity (CD-A) and in remission (CD-R) compared to healthy controls (HCs) and explore the relationship between gray matter volume (GMV) and psychological disorders. Materials and methods: A total of 127 CD patients (62 CD-A, 65 CD-R) and 92 healthy controls (HCs) were enrolled and analyzed in this study. The Crohn's disease activity index (CDAI) was used as the grouping criteria. Voxel-based morphometry (VBM) was applied to investigate gray matter volume (GMV), white matter volume (WMV) and global cerebrospinal fluid (CSF) volume alterations. Pearson correlation analysis was used to evaluate the relationships. Results: The CSF volume was negatively correlated with the disease duration in CD-R. Increased GMV of CD was observed in the parahippocampal gyrus, precentral gyrus, precuneous cortex, and subcallosal cortex, decreased was located in the occipital pole, precentral gyrus, inferior temporal gyrus, middle frontal gyrus, angular gyrus, frontal pole, lateral occipital cortex, and lingual gyrus. The GMV in the right temporal pole, left precuneous cortex, and left cingulate gyrus had a positive correlation with erythrocyte and hemoglobin in CD groups. The GMV in the right frontal pole, right postcentral gyrus, and left cingulate gyrus had a negative correlation with somatization in the CD groups. The GMV in the right temporal pole had a negative correlation with psychoticism and other in the CD groups. The GMV in the left cingulate gyrus was positive with bowel symptoms and systemic symptoms in the CD groups. Conclusion: Alterations of GMV in CD-A and CD-R and associated correlation with psychological disorders may provide evidence for possible neuro-mechanisms of CD with psychological disorders.

BackgroundThe previous studies have demonstrated that patients with Crohn’s disease in remission (CD-R) have abnormal alterations in brain function. However, whether brain function changes in patients with Crohn’s disease in activity (CD-A) and the relationship with CD-R are still unclear. In this study, we aimed to investigate whether the different levels of disease activity may differentially affect the brain function and to find the brain functional biomarker distinguishing patients with different disease stages by measuring the amplitude of low frequency fluctuations (ALFF).Methods121 patients with CD and 91 healthy controls (HCs) were recruited. The clinical and psychological assessment of participants were collected. The criteria for the disease activity were the Crohn’s disease activity index (CDAI) scores. CD-R refers to CD patients in remission which the CDAI score is less than 150. Conversely, CD-A refers to CD patients in activity which the CDAI score is ≥150. The ALFF was compared among three groups by performing one-way analysis of variance, followed by a post hoc two-sample t-test. Differences among the groups were selected as seeds for functional connectivity analyses. We also investigated the correlation among clinical, psychological scores and ALFF. Binary logistic regression analysis was used to examine the unique contribution of the ALFF characteristics of the disease stages.ResultsThere were widespread differences of ALFF values among the 3 groups, which included left frontal pole (FP_L), right supramarginal gyrus (SG_R), left angular gyrus (AG_L), right cingulate gyrus (CG_R), right intracalcarine cortex (IC_R), right parahippocampal gyrus (PG_R), right lingual gyrus (LG_R), right precuneous cortex (PC_R), left occipital fusiform gyrus (OFG_L). Significant brain regions showing the functional connections (FC) increased in FP_L, SG_R, PC_R and OFG_L between CD-A and HCs. The erythrocyte sedimentation rate had a negative correlation with the ALFF values in PC_R in the patients with CD. The phobic anxiety values had a negative correlation with the ALFF values in OFG_L. The psychoticism values had a negative correlation with ALFF values in the IC_R. And the hostility values had a positive correlation with the ALFF values in CG_R. Significant brain regions showing the FC increased in FP_L, SG_R, CG_R, PG_R, LG_R and OFG_L between CD-R and HCs. In binary logistic regression models, the LG_R (beta = 5.138, p = 0.031), PC_R (beta = 1.876, p = 0.002) and OFG_L (beta = 3.937, p = 0.044) was disease stages predictors.ConclusionThe results indicated the significance of the altered brain activity in the different disease stages of CD. Therefore, these findings present a potential identify neuroimaging-based brain functional biomarker in CD. Additionally, the study provides a better understanding of the pathophysiology of CD.

Glycyrrhetinic acid (GA) is a saponin compound, isolated from licorice (Glycyrrhiza glabra), which has been wildly explored for its intriguing pharmacological and medicinal effects. GA is a triterpenoid glycoside displaying an array of pharmacological and biological activities, including anti-inflammatory, anti-bacterial, antiviral and antioxidative properties. In this study, we investigated the underlying mechanisms of GA on acne vulgaris through network pharmacology and proteomics. After the intersection of the 154 drug targets and 581 disease targets, 37 therapeutic targets for GA against acne were obtained. A protein–protein interaction (PPI) network analysis highlighted TNF, IL1B, IL6, ESR1, PPARG, NFKB1, STAT3 and TLR4 as key targets of GA against acne, which is further verified by molecular docking. The experimental results showed that GA inhibited lipid synthesis in vitro and in vivo, improved the histopathological damage of skin, prevented mast cell infiltration and decreased the level of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6. This study indicates that GA may regulate multiple pathways to improve acne symptoms, and the beneficial effects of GA against acne vulgaris might be through the regulation of sebogenesis and inflammatory responses.

Background: To investigate the prognostic significance of systemic inflammation score (SIS) in upper tract urothelial carcinoma (UTUC) in patients undergoing radical nephroureterectomy (RNU). Methods: A total of 313 UTUC patients who underwent RNU at West China Hospital from May 2014 to June 2019 were retrospectively analyzed. The predictive value of SIS for relevant endpoints, including overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS), was assessed by Kaplan–Meier curves and the Cox proportional hazards model. Results: According to inclusion and exclusion criteria, 218 UTUC patients were ultimately included in this cohort study. Statistical analysis shows that increased SIS was significantly associated with higher TNM stage (p = 0.017), lower BMI (p = 0.037), absence of hemoglobin (p < 0.001), and pathologic necrosis (p = 0.007). Kaplan–Meier survival curves clearly visually stratified survival for the three outcomes. After adjusting for tumor grade, the multivariate Cox proportional hazards model results showed that SIS was an independent risk factor for poor OS and CSS (HR = 1.89, 95% CI: 1.11–3.21, p = 0.0183, HR = 1.89, 95% CI: 1.07–3.33, p = 0.0285) in the advanced group. Conclusions: SIS was an independent risk factor for OS and CSS after RNU in patients with high-grade UTUC. It may be a novel and conducive tool for preoperative risk stratification and guiding individualized therapy for high-risk UTUC patients.

This study examines the development and effectiveness of four board games designed to promote cognitive learning activities and STEM education, focusing on kinematics and energy. We used the Engagement - Purpose - Deign - Prototype - Evaluation process to develop four board games. The study involved 53 senior high school students in Vietnam. We used a mixed methods approach to evaluate the impact of these board games on students' cognitive understanding and motivation in STEM education. Data collection included multiple-choice tests before and post-tests from the previous literature study to measure cognitive gains. We also surveyed students using 5-point Likert scales and open-ended questions to explore their motivation and engagement. Quantitative and qualitative analyses assessed whether board games significantly improved students' motivation and learning outcomes. These results suggest that integrating board games into STEM education can improve student engagement and understanding of STEM learning. In light of the results, we discussed the implications of the Engagement - Purpose - Deign - Prototype - Evaluation process and the effectiveness of four board games. [ABSTRACT FROM AUTHOR]

Introduction: The research on cancer patients returning to work in China is still in its infancy, and there is no research and discussion on the adaptability to returnto-work for cancer patients. It is critical to develop the Adaptability to Return-to-Work Scale (ARTWS) for cancer patients and evaluate its psychometric properties. Methods: The items of the initial scale were compiled based on the theoretical model and literature review results. Through two rounds of Delphi expert consultation (N = 15) and a pilot survey (N = 40), the initial scale was further checked and revised. Conduct a large sample survey (N = 376) and the construct validity and reliability of the ARTWS were assessed by confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Results: The final ARTWS consisted of 24 items. “Focusing on rehabilitation,” “Rebuilding Self-efficiency,” and “Adjusting plans” as common factors in determining adaptability to return to work for cancer patients, and the cumulative variance contribution rate for these three factors was 66.6%. The S-CVI of the total scale was 0.979. The Cronbach’s α coefficient was 0.937 and the 2-week test–retest reliability was 0.814. Discussion: ARTWS has good correlation validity and can be used as a tool to measure the adaptability of cancer patients’ return to work. The presentation of the manuscript in Research Square [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to identify predictors of remission or low disease activity (LDA) in patients with rheumatoid arthritis (RA) and low-ultrasound inflammation. Methods: A total of 80 patients with RA who fulfilled the 1987 ACR criteria for RA with a disease activity score of 28 joints (DAS28) > 3.2 were recruited. Over 1 year of therapy, we conducted blood tests every 6 months to examine erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), neuraminidase 3 (Neu3), and α-2,3-sialyltrasnferse I (ST3Gal-1) levels in B cells and monocytes. Additionally, we evaluated physical function by using the Health Assessment Questionnaire–Disability Index (HAQ-DI). Data on demographic and clinical parameters were collected, and musculoskeletal ultrasonography was performed twice a year on 12 specific joints to assess synovial changes. One year later, we compared all collected data and laboratory or ultrasound results between patients achieving remission or LDA and those who did not in order to determine the predictors. Results: Age, the presence or absence of rheumatoid factor, and the number of conventional disease-modifying anti-rheumatic drugs used were not correlated with remission or LDA for DAS28 or Simplified Disease Activity Index formulas. However, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores were associated with a higher likelihood of achieving remission or LDA for DAS28-ESR. Negative anticyclic citrullinated peptide (CCP) and low HAQ-DI scores were predictors of remission or LDA for DAS28-MCP-1. Interestingly, having less than two comorbidities is a good predictor of a combined remission/low disease activity state for SDAI and DAS28-MCP-1. Furthermore, Neu3 and ST3Gal-1 levels and ST3Gal-1/Neu3 ratios in B cells and monocytes had no significant correlation with total ultrasound scores. Nevertheless, monocyte ST3Gal-1 and Neu3 correlated significantly with DAS28-ESR >5.1 and DAS-MCP-1 >4.8 (both categories belong to high disease activity), respectively (rho = 0.609 with p = 0.012, and rho = 0.727 with p = 0.011, respectively). Monocyte ST3Gal-1/Neu3 ratios connected with DAS28-ESR >5.1 and 3.3 < SDAI ≦ 11 (low disease activity), respectively (rho = 0.662 with p = 0.005, and rho = 0.342 with p = 0.048, respectively). Conclusions: In patients with RA in Taiwan, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores are predictors of remission or LDA for DAS28-ESR, which differ from the predictors for DAS28-MCP-1. Moreover, monocyte ST3Gal-1, Neu3, and their ratios correlated with different disease activity categories of DAS28-ESR, DAS28-MCP-1, and SDAI scores. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the regulatory function of the non-coding microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) in alcoholic hepatitis (AH) and its potential mechanism associated with the mitogen-activated protein kinase (MAPK) signaling pathway. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured in a rat model of AH. The biological prediction website microRNA.org and dual-luciferase reporter gene assay were used to identify whether SOCS1 was a direct target of miR-155, and the effects of miR-155 and SOCS1 on the viability, cycle progression, and apoptosis of hepatic stellate cells were assessed using RT-qPCR, Western blot assay, MTT assay, Annexin V/PI double staining, and PI single staining. The levels of ALT, AST, MDA, and TBIL and the liver cell morphology were all prominently changed in AH model rats. miR-155 suppressed SOCS1 by specifically binding to SOCS1-3'-UTR to activate the MAPK signaling pathway. SOCS1 had low expression while miR-155 was highly expressed in AH rats. miR-155 promoted hepatic stellate cell viability and cycle progression and reduced cell apoptosis by silencing SOCS1. Together, we find that silenced miR-155 could upregulate SOCS1 and inactivate the MAPK signaling pathway, thereby inhibiting the proliferation of alcoholic hepatic stellate cells and promoting cell apoptosis. [ABSTRACT FROM AUTHOR]

Despite convincing evidence suggesting that organizations benefit from employees' flow states, when and how work flow experience generates negative effects remain largely understudied. By integrating the spillover-crossover model and perseverative cognition theory, we established a model to explain how flow experience induces employees' positive rumination after work (i.e., problem-solving pondering), which ultimately results in work-family conflict. We proposed that mindfulness acts as a buffer factor in this process but further elucidated that work-family segmentation preference serves as a boundary that may alter or even completely reverse the original effects of mindfulness. Our experience sampling method yielded 1425 data points from 186 employees and their family members across 10 workdays in China, and multilevel analyses supported our propositions. We identified the mediating role of problem-solving pondering in transmitting the effects of flow to work-family conflict. Additionally, we confirmed the three-way interaction effect among mindfulness, segmentation preference, and flow. Specifically, the harmful effect of flow is assuaged when segmentation preference and mindfulness are both high. However, flow experience causes severe work-family conflict when mindfulness is high and segmentation preference is low. Theoretical and practical implications were discussed. [ABSTRACT FROM AUTHOR]

Background: Mufangji tang (MFJT) is composed of Ramulus Cinnamomi, Radix Ginseng, Cocculus orbiculatus (Linn.) DC., and Gypsum. In clinical settings, MFJT has been effectively employed in addressing a range of respiratory disorders, notably including pulmonary arterial hypertension (PAH). However, the mechanism of action of MFJT on PAH remains unknown. Methods: In this study, a monocrotaline-induced PAH rat model was established and treated with MFJT. The therapeutic effects of MFJT on PAH rat model were evaluated. Network pharmacology was conducted to screen the possible targets for MFJT on PAH, and the molecular docking between the main active components and the core targets was carried out. The key targets identified from network pharmacology were tested. Results: Results showed significant therapeutic effects of MFJT on PAH rat model. Analysis of network pharmacology revealed several potential targets related to apoptosis, inflammation, oxidative stress, and vascular remodeling. Molecular docking showed that the key components were well docked with the core targets. Further experimental validation results that MFJT treatment induced apoptosis (downregulated Bcl-2 levels and upregulated Bax levels in lung tissue), inhibited inflammatory response and oxdative stress (decreased the levels of IL-1β, TNF-α, inducible NOS, and malondialdehyde, and increased the levels of endothelial nitric oxide synthase, nitric oxide, glutathione and superoxide dismutase), reduced the proliferation of pulmonary arterial smooth muscle cells (downregulated ET-1 and β-catenin levels and ERK1/2 phosphorylation, increased GSK3β levels). Conclusion: Our study revealed MFJT treatment could alleviate PAH in rats via induction of apoptosis, inhibition of inflammation and oxidative stress, and the prevention of vascular remodeling. [ABSTRACT FROM AUTHOR]

IMP‐3 expression is a poor prognostic factor of melanomas and it promotes melanoma cell migration and invasion by a pathway modulating HMGA2 mRNA expression. We tried to identify other putative targets of IMP‐3. We identified putative IMP‐3‐binding RNAs, including AKT1, MAPK3, RB1 and RELA, by RNA immunoprecipitation coupled with next‐generation sequencing. IMP‐3 overexpression increased AKT and RELA levels in MeWo cells. siRNAs against AKT1 and RELA inhibited MeWo/Full‐length IMP‐3 cell migration. IMP‐3 knockdown of A2058 cells decreased AKT1 and RELA expression and lowered migration ability. Co‐transfection of A2058 cells with AKT1‐ or RELA‐expressing plasmids with IMP‐3 siRNA restored the inhibitory effects of IMP‐3 knockdown on migration. HMGA2 did not influence AKT1 and RELA expression in melanoma cells. Human melanoma samples with high IMP‐3 levels also showed high HMGA2, AKT1 and RELA expression. Our results show that IMP‐3 enhances melanoma cell migration through the regulation of the AKT1 and RELA axis. [ABSTRACT FROM AUTHOR]

Abstract Considering the effect of SIRT1 on improving myocardial fibrosis and GAS5 inhibiting occurrence and development of myocardial fibrosis at the cellular level, the aim of the present study was to investigate whether LncRNA GAS5 could attenuate cardiac fibrosis through regulating mir-217/SIRT1, and whether the NLRP3 inflammasome activation was involved in this process. Isoprenaline (ISO) was given subcutaneously to the male C57BL/6 mice to induce myocardial fibrosis and the AAV9 vectors were randomly injected into the left ventricle of each mouse to overexpress GAS5. Primary myocardial fibroblasts (MCFs) derived from neonatal C57BL/6 mice and TGF-β1 were used to induce fibrosis. And the GAS5 overexpressed MCFs were treated with mir-217 mimics and mir-217 inhibitor respectively. Then the assays of expression levels of NLRP3, Caspase-1, IL-1β and SIRT1 were conducted. The findings indicated that the overexpression of GAS5 reduced the expression levels of collagen, NLRP3, Capase-1, IL-1β and SIRT1 in ISO treated mice and TGF-β1 treated MCFs. However, this effect was significantly weakened after mir-217 overexpression, but was further enhanced after knockdown of mir-217. mir-217 down-regulates the expression of SIRT1, leading to increased activation of the NLRP3 inflammasome and subsequent pyroptosis. LncRNA GAS5 alleviates cardiac fibrosis induced via regulating mir-217/SIRT1 pathway.

Stroke represents a significant threat to global human health, characterized by high rates of morbidity, disability, and mortality. Predominantly, strokes are ischemic in nature. Ischemic stroke (IS) is influenced by various cell death pathways, notably autophagy and ferroptosis. Recent studies have increasingly highlighted the interplay between autophagy and ferroptosis, a process likely driven by the accumulation of reactive oxygen species (ROS). Post-IS, either the inhibition of autophagy or its excessive activation can escalate ROS levels. Concurrently, the interaction between ROS and lipids during ferroptosis further augments ROS accumulation. Elevated ROS levels can provoke endoplasmic reticulum stress-induced autophagy and, in conjunction with free iron (Fe2+), can trigger ferroptosis. Moreover, ROS contribute to protein and lipid oxidation, endothelial dysfunction, and an inflammatory response, all of which mediate secondary brain injury following IS. This review succinctly explores the mechanisms of ROS-mediated crosstalk between autophagy and ferroptosis and the detrimental impact of increased ROS on IS. It also offers novel perspectives for IS treatment strategies.

Biodiversity of local communities has been found to generally decrease with elevation. However, the elevational patterns of intraspecific genetic diversity remain unclear, especially in passive dispersers and species with short life histories. In this study, we investigated the populations of a tropical dominant Cladoceran, Diaphanosoma dubium, along elevation in the largest watershed of South China. The studied populations were grouped into four regional groups based on elevation and habitat connectivity. No significant elevation pattern was observed for mitochondrial genetic diversity, but nuclear diversity was influenced by habitat type. The haplotype network showed a radial pattern with a common haplotype at the centre, and many private haplotypes existed in each regional group. Four clusters of D. dubium populations were identified and exactly corresponding to the four investigated regions, indicating a strong spatial genetic structure. Weak but significant isolation by distance (IBD) supported the critical role of environmental selection with elevation. Precipitation significantly explained population genetic variation at the watershed scale. Bidirectional gene flow was a common pattern that occurred among the four regional groups. Our results highlight that habitat selection with gene flow plays an important role in shaping the genetic pattern of tropical freshwater Cladocera along an elevational gradient.

Objectives: This study aimed to identify predictors of remission or low disease activity (LDA) in patients with rheumatoid arthritis (RA) and low-ultrasound inflammation. Methods: A total of 80 patients with RA who fulfilled the 1987 ACR criteria for RA with a disease activity score of 28 joints (DAS28) > 3.2 were recruited. Over 1 year of therapy, we conducted blood tests every 6 months to examine erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), monocyte chemotactic protein-1 (MCP-1), neuraminidase 3 (Neu3), and α-2,3-sialyltrasnferse I (ST3Gal-1) levels in B cells and monocytes. Additionally, we evaluated physical function by using the Health Assessment Questionnaire–Disability Index (HAQ-DI). Data on demographic and clinical parameters were collected, and musculoskeletal ultrasonography was performed twice a year on 12 specific joints to assess synovial changes. One year later, we compared all collected data and laboratory or ultrasound results between patients achieving remission or LDA and those who did not in order to determine the predictors. Results: Age, the presence or absence of rheumatoid factor, and the number of conventional disease-modifying anti-rheumatic drugs used were not correlated with remission or LDA for DAS28 or Simplified Disease Activity Index formulas. However, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores were associated with a higher likelihood of achieving remission or LDA for DAS28-ESR. Negative anticyclic citrullinated peptide (CCP) and low HAQ-DI scores were predictors of remission or LDA for DAS28-MCP-1. Interestingly, having less than two comorbidities is a good predictor of a combined remission/low disease activity state for SDAI and DAS28-MCP-1. Furthermore, Neu3 and ST3Gal-1 levels and ST3Gal-1/Neu3 ratios in B cells and monocytes had no significant correlation with total ultrasound scores. Nevertheless, monocyte ST3Gal-1 and Neu3 correlated significantly with DAS28-ESR >5.1 and DAS-MCP-1 >4.8 (both categories belong to high disease activity), respectively (rho = 0.609 with p = 0.012, and rho = 0.727 with p = 0.011, respectively). Monocyte ST3Gal-1/Neu3 ratios connected with DAS28-ESR >5.1 and 3.3 < SDAI ≦ 11 (low disease activity), respectively (rho = 0.662 with p = 0.005, and rho = 0.342 with p = 0.048, respectively). Conclusions: In patients with RA in Taiwan, male sex, low CRP levels, low ESR levels, and low HAQ-DI scores are predictors of remission or LDA for DAS28-ESR, which differ from the predictors for DAS28-MCP-1. Moreover, monocyte ST3Gal-1, Neu3, and their ratios correlated with different disease activity categories of DAS28-ESR, DAS28-MCP-1, and SDAI scores.

The vascular endothelium acts as a dynamic interface between blood and tissue. TNF-α, a major regulator of inflammation, induces endothelial cell (EC) transcriptional changes, the overall response dynamics of which have not been fully elucidated. In the present study, we conducted an extended time-course analysis of the human EC response to TNF, from 30 min to 72 h. We identified regulated genes and used weighted gene network correlation analysis to decipher coexpression profiles, uncovering two distinct temporal phases: an acute response (between 1 and 4 h) and a later phase (between 12 and 24 h). Sex-based subset analysis revealed that the response was comparable between female and male cells. Several previously uncharacterized genes were strongly regulated during the acute phase, whereas the majority in the later phase were IFN-stimulated genes. A lack of IFN transcription indicated that this IFN-stimulated gene expression was independent of de novo IFN production. We also observed two groups of genes whose transcription was inhibited by TNF: those that resolved toward baseline levels and those that did not. Our study provides insights into the global dynamics of the EC transcriptional response to TNF, highlighting distinct gene expression patterns during the acute and later phases. Data for all coding and noncoding genes is provided on the Web site (http://www.endothelial-response.org/). These findings may be useful in understanding the role of ECs in inflammation and in developing TNF signaling-targeted therapies., (Copyright © 2023 The Authors.)