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Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Abstract Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.

Abstract Observational data suggest a link between gut microbiota and immune-related vasculitis, but causality remains unclear. A bidirectional mendelian randomization study was conducted using public genome-wide data. The inverse-variance-weighted (IVW) method identified associations and addressed heterogeneity.Families Clostridiaceae 1 and Actinomycetaceae correlated positively with granulomatosis with polyangiitis risk, while classes Lentisphaeria and Melainabacteria, and families Lachnospiraceae and Streptococcaceae showed negative associations. Behçet's disease was positively associated with the risk of family Streptococcaceae abundance. And other several gut microbiota constituents were identified as potential risk factors for immune-related vasculitis. Furthermore, combining positive association results from the IVW analysis revealed numerous shared gut microbiota constituents associated with immune-related vasculitis. MR analysis demonstrated a causal association between the gut microbiota and immune-related vasculitis, offering valuable insights for subsequent mechanistic and clinical investigations into microbiota-mediated immune-related vasculitis.

Abstract Objective Recent studies have indicated a potential association between giant cell arteritis (GCA) and diabetes mellitus, encompassing both type 1 diabetes (T1D) and type 2 diabetes (T2D). However, the exact nature of this relationship requires further investigation to be fully elucidated. Methods Genetic links between T1D/T2D and GCA were explored using data from genome-wide association studies available to the public, focusing on populations of European ancestry. We applied a bidirectional mendelian randomization (MR) approach to assess the potential association between these diseases. Confirmatory analyses, including additional datasets and a comprehensive meta-analysis, were utilized. The inverse-variance-weighted (IVW) method was applied to pinpoint heterogeneity and pleiotropy, while subsequent sensitivity analyses aimed to trace the origins of any heterogeneity. Results Initial analysis demonstrated a correlation between T1D and an elevated likelihood of developing GCA (IVW odds ratio = 1.33, with a 95% confidence interval of 1.22–1.46, and a P-value of 9.42E−10). The causal association was verified through four validation datasets and meta-analysis (all P-value

Background: Cannabidiol (CBD), extracted from Cannabis sativa, has anticancer, anti-inflammation, and analgesic effects. Nevertheless, its therapeutic effect and the mechanism by which it alleviates oral mucositis (OM) remain unclear. Aims: To explore the impact of CBD on OM in mice and on human oral keratinocyte (HOK) cells. Study Design: Expiremental study. Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, GeneCard, DisGeNET, and Gene Expression Omnibus databases were used to conduct therapeutic target gene screening for drugs against OM. Cytoscape software was used to build networks linking components, targets, and diseases. The STRING database facilitated analysis of intertarget action relationships, and the target genes were analyzed for Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Occurrence of serum inflammation-related factors, hematoxylin and eosin staining, and immunohistochemistry were used to assess OM injury. Cell proliferation, migration, pyroptosis, and apoptosis of HOK cells under different treatments were assessed. Molecular mechanisms were elucidated through western blot and quantitative real-time polymerase chain reaction analyses. Results: A total of 49 overlapping genes were pinpointed as potential targets, with NF-κB1, PIK3R1, NF-κBIA, and AKT1 being recognized as hub genes among them. Additionally, the PI3K/Akt/NF-κB and interleukin-17 signaling pathways were identified as relevant. Our in vivo experiments showed that CBD significantly reduced the proportion of lesion area, mitigated oral mucosal tissue lesions, and downregulated the expression levels of genes and levels of proteins, including NLRP3, P65, AKT, and PI3K. In vitro experiments indicated that CBD enhanced HOK cell proliferation and migration and reduced apoptosis through inhibition of the PI3K/Akt/NF-κB signaling pathway and pyroptosis. Conclusion: Our findings suggest a novel mechanism for controlling OM, in which CBD suppresses the PI3K/Akt/NF-κB signaling pathway and pyroptosis, thereby mitigating OM symptoms.

Abstract Glioma is the most common malignant tumor in the central nervous system, and its unique pathogenesis often leads to poor treatment outcomes and prognosis. In 2021, the World Health Organization (WHO) divided gliomas into five categories based on their histological characteristics and molecular changes. Non-coding RNA is a type of RNA that does not encode proteins but can exert biological functions at the RNA level, and long non-coding RNA (lncRNA) is a type of non-coding RNA with a length exceeding 200 nt. It is controlled by various transcription factors and plays an indispensable role in the regulatory processes in various cells. Numerous studies have confirmed that the dysregulation of lncRNA is critical in the pathogenesis, progression, and malignancy of gliomas. Therefore, this article reviews the proliferation, apoptosis, invasion, migration, angiogenesis, immune regulation, glycolysis, stemness, and drug resistance changes caused by the dysregulation of lncRNA in gliomas, and summarizes their potential clinical significance in gliomas.

Background: Cervical cancer is one of the most common gynecological malignancies worldwide. The incidence of cervical cancer ranks second for female malignancies in China. However, human papillomavirus (HPV) prevalence and genotype replacement for a long time in Beijing were not yet evaluated. Methods: Women patients who visited clinical departments, especially the gynecology department, were included in this study from 2014 to 2020. They suffered from different kinds of cervical abnormalities even cervical cancer. Thirteen types of HPV were detected in cervical samples by using multiple fluorescence polymerase chain reactions. All patients were divided into four groups according to age (15?30, 31?45, 46?60, and >60 years old). Results: The study included data from four certain years (2014, 2016, 2018, and 2020). Overall HPV prevalence was 18.0%, 16.7%, 21.9%, and 19.1%, respectively. Of the 13 genotypes, the top one infection type was HPV52, followed by HPV58 and HPV16 or HPV16 and HPV58 in different years. HPV56 prevalence raised from 2018, which replaced HPV39 into the top five list. Only HPV prevalence of 46?60 years age group declined, mainly resulting from the reduced prevalence of HPV39 and HPV58 (p < 0.001 and p = 0.020). The proportions of HPV dual-infection across the four years varied significantly in statistics (p = 0.001), whereas the most common dual-infection HPV39/68 disappeared after 2018. Conclusion: The prevalence of two HPV genotypes (HPV39 and HPV58) and dual-infection HPV39/68 showed a declining trend, especially in the 46?60 years age group. The trends need to be observed continuously.

ObjectiveCurrently, distinct use of clinical data, routine laboratory indicators or the detection of diabetic autoantibodies in the diagnosis and management of diabetes mellitus is limited. Hence, this study was aimed to screen the indicators, and to establish and validate a multifactorial logistic regression model nomogram for the non-invasive differential prediction of type 1 diabetes mellitus.MethodsClinical data, routine laboratory indicators, and diabetes autoantibody profiles of diabetic patients admitted between September 2018 and December 2022 were retrospectively analyzed. Logistic regression was used to select the independent influencing factors, and a prediction nomogram based on the multiple logistic regression model was constructed using these independent factors. Moreover, the predictive accuracy and clinical application value of the nomogram were evaluated using Receiver Operating Characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and clinical impact curves (CIC).ResultsA total of 522 diabetic patients were included in this study. These patients were randomized into training and validation sets in a 7:3 ratio. The predictors screened included age, prealbumin (PA), high-density lipoprotein cholesterol (HDL-C), islet cells autoantibodies (ICA), islets antigen 2 autoantibodies (IA-2A), glutamic acid decarboxylase antibody (GADA), and C-peptide levels. Based on these factors, a multivariate model nomogram was constructed, which had an Area Under Curve (AUC) of 0.966 and 0.961 for the training set and validation set, respectively. Subsequently, the calibration curves demonstrated a strong accuracy of the graph; the DCA and CIC results indicated that the graph could be used as a non-invasive valid predictive tool for the differential diagnosis of type 1 diabetes mellitus, clinically.ConclusionThe established prediction model combining patient’s age, PA, HDL-C, ICA, IA-2A, GADA, and C-peptide can assist in differential diagnosis of type 1 diabetes mellitus and type 2 diabetes mellitus and provides a basis for the clinical as well as therapeutic management of the disease.

Point clouds are sets of points used to visualize three-dimensional (3D) objects. Point clouds can be static or dynamic. Each point is characterized by its 3D geometry coordinates and attributes such as color. High-quality visualizations often require millions of points, resulting in large storage and transmission costs, especially for dynamic point clouds. To address this problem, the moving picture experts group has recently developed a compression standard for dynamic point clouds called video-based point cloud compression (V-PCC). The standard generates two-dimensional videos from the geometry and color information of the point cloud sequence. Each video is then compressed with a video coder, which converts each frame into frequency coefficients and quantizes them using a quantization parameter (QP). Traditionally, the QPs are severely constrained. For example, in the low-delay configuration of the V-PCC reference software, the quantization parameter values of all the frames in a group of pictures are set to be equal. We show that the rate-distortion performance can be improved by relaxing this constraint and treating the QP selection problem as a multi-variable constrained combinatorial optimization problem, where the variables are the QPs. To solve the optimization problem, we propose a variant of the differential evolution (DE) algorithm. Differential evolution is an evolutionary algorithm that has been successfully applied to various optimization problems. In DE, an initial population of randomly generated candidate solutions is iteratively improved. At each iteration, mutants are generated from the population. Crossover between a mutant and a parent produces offspring. If the performance of the offspring is better than that of the parent, the offspring replaces the parent. While DE was initially introduced for continuous unconstrained optimization problems, we adapt it for our constrained combinatorial optimization problem. Also, unlike standard DE, we apply individual mutation to each variable. Furthermore, we use a variable crossover rate to balance exploration and exploitation. Experimental results for the low-delay configuration of the V-PCC reference software show that our method can reduce the average bitrate by up to 43% compared to a method that uses the same QP values for all frames and selects them according to an interior point method.

Abstract Background In China, the rising prevalence of high Body Mass Index (BMI) is linked to increasing health issues, including Alzheimer’s disease (AD). This study analyzes mortality trends related to AD and other dementias associated with high BMI from 1990 to 2019, considering age, period, and birth cohort effects, and forecasts future trends. Methods We analyzed mortality data for AD and other dementias linked to high BMI in Chinese residents from the Global Burden of Disease 2019 database. Using Joinpoint regression, we examined age-standardized mortality rate (ASMR) trends and calculated annual and average annual percentage changes (APC and AAPC). Age-period-cohort models provided deeper insights, with Bayesian models used to project future ASMR trends to 2042. Results From 1990 to 2019, the ASMR for AD and other dementias associated with high BMI in China showed an overall increasing trend. Females had a lower increase rate than males, yet their overall levels remained higher. Specifically, the ASMR for males increased by an average of 2.70% per year, peaking between 2006 and 2010, while for females, it increased by an average of 2.29% per year, also peaking in the same period. Age-period-cohort analysis revealed increasing mortality relative risk with age and period, but a decrease with birth cohort. Projections suggest a continued rise in ASMR by 2042, with rates for males and females expected to be 2.48/100,000 and 2.94/100,000, respectively. Conclusion The increasing mortality trend from AD and other dementias associated with high BMI highlights the urgent need for policy interventions focused on overweight prevention, particularly vital for addressing the health challenges in China’s aging population.

Abstract Background Intervertebral disc degeneration and sarcopenia are both age-related diseases without effective treatments. Their comorbidities may worsen the prognosis, and further studies on interaction and therapy are needed. The purpose of the study was to investigate the prevalence of sarcopenia in intervertebral disc degeneration, and to compare the characteristics of intervertebral disc degeneration with and without sarcopenia and effects of interferential current. Methods One hundred twenty disc degeneration patients were included from 2021 to 2022 in a single institute. Medical records, examination results and radiological reports were reviewed. Patients with sarcopenia were screened and grouped according to Asian Working Group for Sarcopenia 2019. VAS, ODI, SARC-F, SMI, gait speed (GS), grip strength, disc Pfirrmann grading, standard cross-sectional area (SCSA), degree of fatty infiltration (DFF), and nerve conduction velocity (NCV) were assessed before and after treatment. Results The prevalence of sarcopenia in intervertebral disc degeneration was 28.3%. The difference of VAS, ODI, disc Pfirrmann grading, SCSA, DFF and NCV between two groups were significant before intervention (P 0.05). Conclusion The prevalence of sarcopenia was high in intervertebral disc degeneration, and paravertebral muscles degeneration correlated with the degree of disc degeneration. Compared to those without sarcopenia, intervertebral disc degeneration patients with sarcopenia have more severe pain, poorer mobility and neurological function. Interferential current is effective in intervertebral disc degeneration patients and sarcopenia patients.

Abstract Background Cyclic Nucleotide-Binding Domain (CNBD)-family channels display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, the human Ether-a-go-go Related Gene (hERG) channel and the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel share high amino acid sequence similarity and identical domain structures. hERG conducts outward current and is activated by positive membrane potentials (depolarization), whereas HCN conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the “opposite” voltage-sensing properties of hERG and HCN remains unknown. Results We found the voltage-sensing domain (VSD) involves in modulating the gating polarity of hERG. We identified that a long-QT syndrome type 2-related mutation within the VSD, K525N, mediated an inwardly rectifying non-deactivating current, perturbing the channel closure, but sparing the open state and inactivated state. K525N rescued the current of a non-functional mutation in the pore helix region (F627Y) of hERG. K525N&F627Y switched hERG into a hyperpolarization-activated channel. The reactivated inward current induced by hyperpolarization mediated by K525N&F627Y can be inhibited by E-4031 and dofetilide quite well. Moreover, we report an extracellular interaction between the S1 helix and the S5-P region is crucial for modulating the gating polarity. The alanine substitution of several residues in this region (F431A, C566A, I607A, and Y611A) impaired the inward current of K525N&F627Y. Conclusions Our data provide evidence that a potential cooperation mechanism in the extracellular vestibule of the VSD and the PD would determine the gating polarity in hERG.

Abstract Background For patients with multilevel degenerative cervical myelopathy, laminectomy and posterior cervical fusions (PCF) with instrumentation are widely accepted techniques for symptom relief. However, hardware failure is not rare and results in neck pain or even permanent neurological lesions. There are no in-depth studies of hardware-related complications following laminectomy and PCF with instrumentation. Methods The present study was a retrospective, single centre, observational study. Patients who underwent laminectomy and PCF with instrumentation in a single institution between January 2019 and January 2021 were included. Patients were divided into hardware failure and no hardware failure group according to whether there was a hardware failure. Data, including sex, age, screw density, end vertebra (C7 or T1), cervical sagittal alignment parameters (C2-C7 cervical lordosis, C2-C7 sagittal vertical axis, T1 slope, Cervical lordosis correction), regional Hounsfield units (HU) of the screw trajectory and osteoporosis status, were collected and compared between the two groups. Results We analysed the clinical data of 56 patients in total. The mean overall follow-up duration was 20.6 months (range, 12–30 months). Patients were divided into the hardware failure group (n = 14) and no hardware failure group (n = 42). There were no significant differences in the general information (age, sex, follow-up period) of patients between the two groups. The differences in fusion rate, fixation levels, and screw density between the two groups were not statistically significant (p > 0.05). The failure rate of fixation ending at T1 was lower than that at C7 (9% vs. 36.3%) (p = 0.019). The regional HU values of the pedicle screw (PS) and lateral mass screw (LMS) in the failure group were lower than those in the no failure group (PS: 267 ± 45 vs. 368 ± 43, p = 0.001; LMS: 308 ± 53 vs. 412 ± 41, p = 0.001). The sagittal alignment parameters did not show significant differences between the two groups before surgery or at the final follow-up (p > 0.05). The hardware failure rate in patients without osteoporosis was lower than that in patients with osteoporosis (14.3% vs. 57.1%) (p = 0.001). Conclusions Osteoporosis, fixation ending at C7, and low regional HU value of the screw trajectory were the independent risk factors of hardware failure after laminectomy and PCF. Future studies should illuminate if preventive measures targeting these factors can help reduce hardware failure and identified more risk factors, and perform long-term follow-up.

Abstract Background To find out if three-dimensional printing (3DP) off-the-shelf (OTS) prosthesis is superior to titanium mesh cages in anterior cervical corpectomy and fusion (ACCF) when treating single-segment degenerative cervical spondylotic myelopathy (DCSM). Methods DCSM patients underwent ACCF from January 2016 to January 2019 in a single center were included. Patients were divided into the 3DP group (28) and the TMC group (23). The hospital stays, operation time, intraoperative blood loss, and the cost of hospitalization were compared. The Japanese Orthopedic Association (JOA) scores and Neck Disability Index (NDI) were recorded pre-operatively, 1 day, 3, 6, 12, and 24 months post-operatively. Radiological data was measured to evaluate fusion, subsidence, and cervical lordosis. Patients were sent with SF-36 to assess their health-related quality of life (HRQoL). Results The differences in operative time, intraoperative blood loss, and hospital stay were not statistically significant between groups (p > 0.05). Postoperative dysphagia occurred in 2 cases in the 3DP group and 3 cases in the TMC group, which all relieved one week later. The difference in improvement of JOA and NDI between the two groups was not statistically significant (p > 0.05). No hardware failure was found and bony fusion was achieved in all cases except one in the 3DP group. The difference in cervical lordosis (CL), fused segmental angle (FSA), mean vertebral height (MVH), and subsidence rates between groups at each follow-up time point was not statistically significant and the results of the SF-36 were similar (p > 0.05). The total cost was higher in the 3DP group with its higher graft cost (p

ABSTRACT: Wooden breast (WB) is a myopathy mainly affecting pectoralis major (PM) muscle in modern commercial broiler chickens, causing enormous economic losses in the poultry industry. Recent studies have observed hepatic and PM muscle injury in broilers affected by WB, but the relationships between WB and the 2 tissues are mostly unclear. In the current study, the RNA-seq raw data of PM muscle and liver were downloaded from GSE144000, and we constructed the gene coexpression networks of PM muscle and liver to explore the relationships between WB and the 2 tissues using the weighted gene coexpression network analysis (WGCNA) method. Six and 2 gene coexpression modules were significantly correlated with WB in the PM muscle and liver networks, respectively. TGF-beta signaling, Toll-like receptor signaling and mTOR signaling pathways were significantly enriched in the genes within the 6 gene modules of PM muscle network. Meanwhile, mTOR signaling pathway was significantly enriched in the genes within the 2 gene modules of liver network. In the consensus gene coexpression network across the 2 tissues, salmon module (r = −0.5 and p = 0.05) was significantly negatively correlated with WB, in which Toll-like receptor signaling, apoptosis, and autophagy pathways were significantly enriched. The genes related with the 3 pathways, myeloid differentiation primary response 88 (MYD88), interferon regulatory factor 7 (IRF7), mitogen-activated protein kinase 14 (MAPK14), FBJ murine osteosarcoma viral oncogene homolog (FOS), jun proto-oncogene (JUN), caspase-10, unc-51 like autophagy activating kinase 2 (ULK2) and serine/threonine kinase 11 (LKB1), were identified in salmon module. In this current study, we found that the signaling pathways related with cell inflammation, apoptosis and autophagy might influence WB across 2 tissues in broilers.

Key Clinical Message Colorectal cancer is the third most common malignancy worldwide, with an increasing incidence. Colonic metastasis is a rare occurrence; thus, misdiagnosis is common. Immunohistochemistry facilitates accurate diagnosis and subsequent management. Abstract Most cancers in the colon are primary colorectal cancers, however metastasis from another primary is possible, albeit rare. Endometrial cancer metastasis to the colon is a rare occurrence and is only described in a handful of cases. We describe a rare case of metastatic endometrial cancer in the colon presenting 5 years post radical hysterectomy and adjuvant radiotherapy in a 62‐year‐old female. She presented with a 1‐week history of right upper quadrant pain, with no other associated symptoms. She was presumed to have a primary colorectal cancer based on her colonoscopy and CT findings; later proven otherwise by immunohistochemistry (IHC). Endometrial cancer metastasis to the colon is rare, thus misdiagnosis can easily occur. Currently, there are 6 similar cases reported in the literature, all occurring in the absence of colorectal endometriosis. This case illustrates the relative importance of considering colon as a potential site for metastasis of endometrial cancer and the utility of IHC in aiding diagnosis and guiding further management.

Sarcopenia is a condition characterized by age-related loss of muscle mass and strength. Increasing evidence suggests that patients with sarcopenia have higher rates of coronavirus 2019 (COVID-19) infection and poorer post-infection outcomes. However, the exact mechanism and connections between the two is unknown. In this study, we used high-throughput data from the GEO database for sarcopenia (GSE111016) and COVID-19 (GSE171110) to identify common differentially expressed genes (DEGs). We conducted GO and KEGG pathway analyses, as well as PPI network analysis on these DEGs. Using seven algorithms from the Cytoscape plug-in cytoHubba, we identified 15 common hub genes. Further analyses included enrichment, PPI interaction, TF-gene and miRNA-gene regulatory networks, gene-disease associations, and drug prediction. Additionally, we evaluated immune cell infiltration with CIBERSORT and assessed the diagnostic accuracy of hub genes for sarcopenia and COVID-19 using ROC curves. In total, we identified 66 DEGs (34 up-regulated and 32 down-regulated) and 15 hub genes associated with sarcopenia and COVID-19. GO and KEGG analyses revealed functions and pathways between the two diseases. TF-genes and TF-miRNA regulatory network suggest that FOXOC1 and hsa-mir-155-5p may be identified as key regulators, while gene-disease analysis showed strong correlations with hub genes in schizophrenia and bipolar disorder. Immune infiltration showed a correlation between the degree of immune infiltration and the level of infiltration of different immune cell subpopulations of hub genes in different datasets. The ROC curves for ALDH1L2 and KLF5 genes demonstrated their potential as diagnostic markers for both sarcopenia and COVID-19. This study suggests that sarcopenia and COVID-19 may share pathogenic pathways, and these pathways and hub genes offer new targets and strategies for early diagnosis, effective treatment, and tailored therapies for sarcopenia patients with COVID-19.

Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) prescribed to patients diagnosed with insomnia, which can achieve excellent therapeutic outcomes. As positively modulating the γ-aminobutyric acid (GABA) type A receptors (GABAARs) is the most effective strategy to manage insomnia, this study aimed to investigate whether the activation of GABAARs is involved in the anti-insomnia effect of HWD. We assessed the metabolites of HWD using LC/MS and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and tested the pharmacological activity in vitro and in vivo using whole-cell patch clamp and insomnia zebrafish model. In HEK293 cells expressing α1β3γ2L GABAARs, HWD effectively increased the GABA-induced currents and could induce GABAAR-mediated currents independent of the application of GABA. In the LC-MS (QToF) assay, 31 metabolites were discovered in negative ion modes and 37 metabolites were found in positive ion modes, but neither three selected active metabolites, Danshensu, Coptisine, or Dihydromyricetin, showed potentiating effects on GABA currents. 62 active metabolites of the seven botanical drugs were collected based on the TCMSP database and 19 of them were selected for patch-clamp verification according to the virtual docking simulations and other parameters. At a concentration of 100 μM, GABA-induced currents were increased by (+)-Cuparene (278.80% ± 19.13%), Ethyl glucoside (225.40% ± 21.77%), and β-Caryophyllene (290.11% ± 17.71%). In addition, (+)-Cuparene, Ethyl glucoside, and β-Caryophyllene could also serve as positive allosteric modulators (PAMs) and shifted the GABA dose-response curve (DRC) leftward significantly. In the PCPA-induced zebrafish model, Ethyl glucoside showed anti-insomnia effects at concentrations of 100 μM. In this research, we demonstrated that the activation of GABAARs was involved in the anti-insomnia effect of HWD, and Ethyl glucoside might be a key metabolite in treating insomnia.

Abstract Objective The aim of the present study was to investigate the therapeutic effect of ammidin on hypoxia/reoxygenation (H/R) injury in primary neonatal rat cardiomyocytes by observing the role of ferroptosis in the process of H/R injury, and to verify its target and regulatory signaling pathways. Methods The network pharmacology analysis was used to predict the biological processes, core targets and related signaling pathways of Angelica dahurica in the treatment of ferroptosis. Cell viability was assessed using live cell imaging and cell counting kit-8. Lactate dehydrogenase (LDH), reactive oxygen species (ROS) production, and malondialdehyde (MDA), superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) content were determined to assess the level of ferroptosis. Western blotting was performed to measure protein expression. Results Network pharmacology predicted that Acyl-CoA synthetase long chain family member 4 (ACSL4) was highly associated with myocardial H/R injury in the intersection of Angelica dahurica and ferroptosis. The top three active components of Angelica dahurica were found to be mandenol, alloisoimperatorin and ammidin, among which ammidin was found to have the strongest binding to the target proteins of the ACSL4/AMPK/mTOR pathway. H/R reduced the viability of cardiomyocytes, while the inhibition of ferroptosis by ferrostatin-1 alleviated the H/R-induced inhibition of cardiomyocyte viability. This was evidenced by the increased cell viability, SOD release, MMP level and glutathione peroxidase 4 (GPX4) protein expression, as well as the decreased LDH and MDA release and ROS production and ACSL4 protein expression (P

Abstract This study examined the associations between emerging lipid biomarkers (small dense low‐density lipoprotein cholesterol [sdLDL‐C), lipoprotein(a) [Lp(a)], and free fatty acids [FFA]), two ratios (sdLDL‐C/LDL‐C and the triglyceride–glucose [TyG) index), and the Gensini score (GS) in patients with premature coronary artery disease (PCAD) in relation to the extent of coronary stenosis. The authors evaluated a cohort of 2952 individuals undergoing coronary angiography (CAG), encompassing those with PCAD (n = 1749), late‐onset coronary artery disease (LCAD; n = 328), and non‐coronary artery disease (non‐CAD; n = 575). Noteworthy differences were observed in the levels of the novel lipid biomarkers and ratio indexes among the PCAD, LCAD, and non‐CAD groups (p 40) in PCAD patients, as evidenced by the ROC analysis. In conclusion, sdLDL‐C, Lp(a), FFA, and the sdLDL‐C/LDL‐C and TyG indexes have considerable potential as risk and diagnostic markers for coronary artery stenosis in individuals afflicted with PCAD.

Abstract The demand for high‐resolution videos has been consistently rising across various domains, propelled by continuous advancements in societal. Nonetheless, limitations in imaging and economic factors often result in obtaining low‐resolution images. The currently available space‐time video super‐resolution methods often fail to fully exploit the information existing within the spatio‐temporal domain. To address this problem, the issue is tackled by conceptualizing the input low‐resolution video as a cuboid structure. An innovative methodology called “Cuboid‐Net”, which incorporates a multi‐branch convolutional neural network, is introduced. Cuboid‐Net is designed to collectively enhance the spatial and temporal resolutions of videos, enabling the extraction of rich and meaningful information across both spatial and temporal dimensions. Specifically, the input video is taken as a cuboid to generate different directional slices as input for different branches of the network. The proposed network contains four modules, that is, a multi‐branch‐based hybrid feature extraction module, a multi‐branch‐based reconstruction module, a first‐stage quality enhancement module, and a second‐stage cross frame quality enhancement module for interpolated frames only. Experimental results demonstrate that the proposed method is not only effective for spatial and temporal super‐resolution of video but also for spatial and angular super‐resolution of light field.

Ethylene is the main factor controlling fruit ripening of pear (Pyrus ussuriensis). Ethylene production rate is negatively correlated with fruit shelf life; therefore, it is important to decrease the ethylene levels for optimal fruit storage. Here, we observed that blue light treatment could inhibit ethylene production and promote the expression of ELONGATED HYPOCOTYL 5 (PuHY5), a basic leucine zipper domain (bZIP) transcription factor. The following studies showed that PuHY5 could bind to the promoter of ACC synthase 1 (PuACS1), a rate-limiting enzyme in ethylene biosynthesis, and inhibit its expression. For pears in which PuHY5 was silenced, the ethylene production and PuACS1 expression were much higher than those in the control fruit. These results demonstrated that blue light inhibited ethylene production through the induction of PuHY5 in pear. Our finding provides a new method for prolonging fruit shelf life.

A full triangular chiral (Tri-Chi) honeycomb, combining a honeycomb structure with triangular chiral configuration, notably impacts the Poisson’s ratio (PR) and stiffness. To assess the random vibration properties of a composite sandwich panel with a Tri-Chi honeycomb core (CSP-TCH), a two-dimensional equivalent Reissner–Mindlin model (2D-ERM) was created using the variational asymptotic method. The precision of the 2D-ERM in free and random vibration analysis was confirmed through numerical simulations employing 3D finite element analysis, encompassing PSD curves and RMS responses. Furthermore, the effects of selecting the model class were quantified through dynamic numerical examples. Modal analysis revealed that the relative error of the first eight natural frequencies predicted by the 2D-ERM consistently remained below 7%, with the modal cloud demonstrating high reliability. The PSD curves and their RMS values closely aligned with 3D finite element results under various boundary conditions, with a maximum error below 5%. Key factors influencing the vibration characteristics included the ligament–rib angle of the core layer and layup modes of the composite facesheets, while the rib-to-ligament thickness ratio and the aspect ratio exert minimal influence. The impact of the ligament–rib angle on the vibration properties primarily stems from the significant shift in the core layer’s Poisson’s ratio, transitioning from negative to positive. These findings offer a rapid and precise approach for optimizing the vibration design of CSP-TCH.

BackgroundPremature ventricular contractions (PVCs) are relatively common arrhythmias in the pediatric population, with implications that range from benign to potentially life-threatening. The management of PVCs in children poses unique challenges, and recent advancements in diagnostic and therapeutic options call for a comprehensive review of current practices.MethodsThis review synthesizes the latest literature on pediatric PVCs, focusing on publications from the past decade. We evaluate studies addressing the epidemiology, pathophysiology, diagnosis, and treatment of PVCs in children, including pharmacological, non-pharmacological, and invasive strategies.ResultsThe review identifies key advancements in the non-invasive detection of PVCs, the growing understanding of their genetic underpinnings, and the evolving landscape of management options. We discuss the clinical decision-making process, considering the variable significance of PVCs in different pediatric patient subgroups, and highlight the importance of individualized care. Current guidelines and consensus statements are examined, and areas of controversy or limited evidence are identified.ConclusionsOur review underscores the need for a nuanced approach to PVCs in children, integrating the latest diagnostic techniques with a tailored therapeutic strategy. We call for further research into long-term outcomes and the development of risk stratification tools to guide treatment. The potential of emerging technologies and the importance of multidisciplinary care are also emphasized to improve prognoses for pediatric patients with PVCs.

Currently, China's building materials market is large and the supply and demand transactions are very frequent, which requires us to have a comprehensive understanding of the supply and demand transactions of building materials. Based on complex network theory, this paper constructs a complex network model of supply and demand of building materials. And the Louvain algorithm is also improved to identify and characterize the network community relations based on the characteristics of this network. This paper also applies prefabricated components as an example for empirical research and obtains the following findings: (1) From 2017 to 2022, large- and medium-sized communities in the network gradually increase while small communities gradually decrease; the internal connectivity of large communities is higher than that of small communities; and the regional network also has the structural characteristics of the network. (2) The characteristics of geographic agglomeration gradually emerge in the individual communities in the supply–demand network of prefabricated components with the passage of time. Most of these communities are bounded by provinces, and large-scale communities are distributed in the eastern and southern coastal areas. Thus, this paper visualizes the supply and demand of construction materials to provide a theoretical basis and methodological support for the supply and demand of construction materials and the development of the construction industry.

Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to actin molecules. Consequently, this leads to a reduction in actin polymerization. Mechanistically, Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin, diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels. These alterations in actin dynamics result in inhibited cell cycle progression, increased apoptosis, and decreased proliferation of colonic epithelial cells, thereby exacerbating colitis development and progression. In contrast, the silencing of circNlgn or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization, enhanced cell survival, and reduced apoptosis and ultimately improves the outcome of colitis in vivo. Interestingly, nuclear actin polymerization is highly related with expression of PIAS3, which modulates signal transducer and activator of transcription 3 and NF-κB activity in colitis. Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerative colitis clinical intervention.

BackgroundThe etiology of recurrent spontaneous abortion (RSA) remains elusive despite specific investigations affirming the association between RSA and thyroid autoimmunity (TAI). This study explores the immunological and metabolic profiles of RSA patients exhibiting positive thyroid antibodies and their connection with the rates of first-trimester miscarriage and live births. The aim is to provide further guidance for clinical interventions.MethodsA retrospective analysis included 478 women with RSA. Thyroid profile, thyroid peroxidase antibodies, and anti-thyroglobulin antibodies were measured in all participants. The clinical characteristics and pregnancy outcomes of RSA women were compared between thyroid autoimmunity (TAI)-positive and TAI-negative patients. Significant factors associated with adverse pregnancy outcomes and risk prediction models were explored in TAI-positive patients. Correlation analysis was used to identify specific metabolic or immune biomarkers associated with thyroid autoantibodies.ResultsThe prevalence of TAI was 18.6%. Compared with women without TAI, the thyroid-stimulating hormone (TSH) concentration of TAI-positive RSA was significantly higher (2.80 ± 2.98 vs 1.89 ± 1.17, p=0.006). After 28 weeks, the live birth rate of the TAI-positive group was lower than that of the TAI-negative group, with statistical significance (p

Abstract Background Hydrogen-rich water (HRW) has been shown to prevent cognitive impairment caused by ionizing radiation. This study aimed to investigate the pharmacological effects and mechanisms of HRW on ionizing radiation by coupling the brain metabolomics and biological target network methods. Methods and results HRW significantly improves the cognitive impairment in rats exposed to ionizing radiation. Based on metabolomics and biological network results, we identified 54 differential metabolites and 93 target genes. The KEGG pathway indicates that glutathione metabolism, ascorbic acid and aldehyde acid metabolism, pentose and glucuronic acid interconversion, and glycerophospholipid metabolism play important roles in ionizing radiation therapy. Conclusion Our study has systematically elucidated the molecular mechanism of HRW against ionizing radiation, which can be mediated by modulating targets, pathways and metabolite levels. This provides a new perspective for identifying the underlying pharmacological mechanism of HRW.

Objective: This study aimed to explore the clinical value of thin slice computed tomography (CT) plain scan in the analysis of CT features of vascular abnormalities associated with coronavirus disease 2019 (COVID-19). Materials and methods: A total of 73 patients with COVID-19 confirmed by the Department of Infection of Beijing Shijitan Hospital from December 5, 2022 to December 17, 2022, were included in the study. Chest thin CT plain scan images showed that the lesions involved blood vessels were retrospectively collected. All patients had complete chest thin CT plain scan and relatively complete clinical data. According to age (>60 and ≤60 years), the patients were divided into the young and elderly groups. The chest imaging manifestations of all patients were observed and statistically analyzed between different age groups. Results: Among the 73 patients with COVID-19, the imaging indexes with statistical significance between the young and elderly groups were as follows: the distribution of the lesion around the central blood vessel, size of the lesion (10~30 mm), size of the lesion (>30 mm), percentage of the lesion to the volume of the lung lobe (≤30), percentage of the lesion to the volume of the lung lobe (>50) (white lung), shape of the lesion was large, the dominant type of the lesion was acinar, vascular distortion, vascular margin fuzzy, and tree-bud sign thick fiber rope. Conclusion: (1) Chest thin-slice CT plain scan can identify the number, location, involved location, scope, vascular abnormality, and pathological type of COVID-19-related vascular abnormality, which has certain significance for the qualitative and differential diagnosis of COVID-19 vascular abnormality. (2) The chest thin CT plain scan is of great significance for finding elderly patients with COVID-19 involving blood vessels. (3) COVID-19-related "blood vessel thickening" can be caused by either the diameter of the blood vessel itself or the inflammatory edema of the perivascular interstitium.

Background: The main pathological feature of diabetic cardiomyopathy (DCM) caused by diabetes mellitus is myocardial fibrosis. According to recent studies in cardiology, it has been suggested that spermidine (SPD) has cardioprotective properties. Aims: To explore the role and mechanism of SPD in alleviating myocardial fibrosis of DCM. Study Design: In vivo and in vitro study. Methods: Type 2 diabetic mice and primary neonatal mouse cardiac fibroblasts (CFs) were selected. Measurements of serum-related markers, echocardiographic analysis, and immunohistochemistry were used to evaluate myocardial fibrosis injury and the effects of SPD. The proliferation and migration of CFs undergoing different treatments were studied. Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction were used to demonstrate molecular mechanisms. Results: In vivo immunoblotting analysis indicated a downregulation of ornithine decarboxylase and an upregulation of SPD/spermine N1-acetyltransferase. We observed cardiac dysfunction in diabetic mice after 12 weeks. However, the administration of exogenous SPD improved cardiac function, decreased collagen deposition, and reduced myocardial tissue damage. mRNA expression levels of NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-17A, and IL-18 were increased and suppressed in the myocardium of db/db mice upon treatment with SPD. SPD inhibited the proliferation, migration, and collagen secretion of high-glucose-treated fibroblasts in vitro. SPD inhibits the activation of the TGF-β1/Smad signaling pathway and decreases collagen deposition by reducing pyroptosis and Smad-7 ubiquitination levels. Conclusion: Based on our findings, SPD may have potential applications in protecting against the deterioration of cardiac function in patients with DCM due to a significant new mechanism for diabetic myocardial fibrosis that we discovered.

Abstract Background Luminal breast cancer (BC) is the predominant subtype of breast cancer with a sustained risk of late recurrence and death. Understanding the molecular mechanisms for the oncogenesis of luminal BC would improve the prognosis for this large subset of patients. SPDEF was reported to be dysregulated in breast cancers. However, the biological functions and underlying molecular mechanism of SPDEF in luminal BC remains largely unknown. The aim of the present study was to elucidate the potential roles of SPDEF underlying subtype-specific functions in BC, especially in luminal subtypes. Methods The expressions and clinicopathological characteristics of SPDEF in luminal BC patients were evaluated bioinformatically. In vitro and in vivo assays were performed to investigate the oncogenic function and stemness maintenance of SPDEF in luminal BC. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were conducted to determine the transcription regulation of GALNT7 by SPDEF. GALNT7 levels in serum from luminal BC patients were further detected by enzyme-linked immunosorbent assay (ELISA). Results SPDEF is markedly upregulated in luminal BC and positively associated with tumor progression and poor prognosis. Furthermore, we confirmed that SPDEF enhanced the proliferation, migration, invasion and stemness of luminal BC cells in vitro as well the tumorigenicity in vivo. Mechanistically, we demonstrated the stimulative effect of SPDEF on the progression and stemness of luminal BC, which is mediated by its directly transcriptional target GALNT7. Clinically, we verified that the GALNT7 can be used as a noninvasive diagnostic marker. Noteworthy, the combined detection of serum GALNT7 and traditional tumor markers can enhance diagnostic accuracy thus is of vital importance in the early diagnosis of luminal BC. Conclusions Our study reveals a novel mechanism by which SPDEF transcriptionally activates GALNT7 via directly binding to its promoter to promote cell proliferation, motility and stemness, and led to luminal BC tumorigenesis and poor prognosis.

Abstract Background To investigate the effect of intraoperative goal-directed fluid therapy (GDFT) combined with enhanced recovery after surgery (ERAS) program on postoperative complications in elderly patients undergoing thoracoscopic pulmonary resection. Methods Patients, more than 60 years old, undergoing thoracoscopic pulmonary resection for non-small cell lung cancer were randomly divided into GDFT group and restrictive fluid therapy (RFT) group. ERAS program was implemented in all patients. In GDFT group, the intraoperative fluid management was guided by stroke volume variation (SVV), cardiac index (CI), and mean arterial pressure (MAP) and maintained the SVV 2.5 L/min/m2, and MAP > 65 mmHg. In RFT group, fluid maintenance with 2 ml/kg/h of balanced crystalloid solution, norepinephrine was used to maintain MAP > 65 mmHg. The incidence of postoperative acute kidney injury (AKI) and pulmonary and cardiac complications was compared. Results Two-hundred seventy-six patients were enrolled and randomly divided into two groups (138 in each group). Compared to RFT group, the total intraoperative infusion volume, colloids infusion volume, and urine output were more; the dosage of norepinephrine was lower in GDFT group. Although there were no significant differences of postoperative AKI (GDFT vs RFT; 4.3% vs 8%; P = 0.317) and composite postoperative complications (GDFT vs RFT; 66 vs 70) between groups, but the postoperative increase degree of serum creatinine was lower in GDFT group than that in RFT group (GDFT vs RFT; 91.9 ± 25.2 μmol/L vs 97.1 ± 17.6 μmol/L; P = 0.048). Conclusions Under ERAS program, there was no significant difference of AKI incidence between GDFT and RFT in elderly patients undergoing thoracoscopic pulmonary resection. But postoperative increase degree of serum creatinine was lower in GDFT group. Trial registration Registered at ClinicalTrials.gov, NCT04302467 on 26 February 2020.

Managing chronic non-healing wounds presents a significant clinical challenge due to their frequent bacterial infections. Mesoporous silica-based materials possess robust wound-healing capabilities attributed to their renowned antimicrobial properties. The current study details the advancement of mesoporous silicon-loaded MnO and CaO molecules (HMn-Ca) against bacterial infections and chronic non-healing wounds. HMn-Ca was synthesized by reducing manganese chloride and calcium chloride by urotropine solution with mesoporous silicon as the template, thereby transforming the manganese and calcium ions on the framework of mesoporous silicon. The developed HMn-Ca was investigated using scanning electron microscopy (SEM), transmission electron microscope (TEM), ultraviolet-visible (UV-visible), and visible spectrophotometry, followed by the determination of Zeta potential. The production of reactive oxygen species (ROS) was determined by using the 3,3,5,5-tetramethylbenzidine (TMB) oxidation reaction. The wound healing effectiveness of the synthesized HMn-Ca is evaluated in a bacterial-infected mouse model. The loading of MnO and CaO inside mesoporous silicon enhanced the generation of ROS and the capacity of bacterial capture, subsequently decomposing the bacterial membrane, leading to the puncturing of the bacterial membrane, followed by cellular demise. As a result, treatment with HMn-Ca could improve the healing of the bacterial-infected wound, illustrating a straightforward yet potent method for engineering nanozymes tailored for antibacterial therapy.

Fiber metal laminated sandwich tubes are made up of alternating fiber-reinforced composite and metal layers. Fiber metal laminated tubes have the advantages of the high strength and high stiffness of fiber and the toughness of metal, so they have become an excellent load-bearing and energy-absorbing, lightweight structure. Due to the complexity of the fiber layup, it is difficult to establish an analytical model of the relevant structural properties. In this work, introducing the number and volume fraction of fiber layup, based on the modified rigid–plastic model, an analytical model is established for low-velocity impacts on sandwich tubes with fiber metal laminated tubes, which provided a theoretical basis for the design of fiber–metal composite tubes. In addition, a numerical simulation was conducted for low-velocity impacts on clamped rectangular sandwich tubes with fiber metal laminated (FML) tubes and a foam core. By comparing the results obtained from the theoretical analysis and numerical calculations, it is shown that the analytical results can reasonably agree with the numerical results. The influences of the metal volume fraction (MVF), the strength ratio factor of the FML metal layer to the FML composite layer, and the relative strength of the foam on the dynamic response of the rectangular sandwich tubes with FML tubes and a metal foam core (MFC) are discussed. It is shown that by increasing the fiber content and fiber strength of the FML tubes and the foam strength, the load-carrying and energy-absorbing capacity of the rectangular sandwich tubes can be effectively improved, especially by changing the fiber properties. In addition, present analytical solutions can be applied to make predictions about the dynamic response of the rectangular sandwich tubes with FML tubes and MFC during impacts with low-velocity and reasonably heavy-mass.

Based on complex network theory, this paper establishes a Boolean competitive relationship network model and a weighted competitive relationship network model for building material enterprises based on big data and performs empirical analyses with construction prefabricated component (PC) enterprises in the Beijing–Tianjin–Hebei region as research samples. Results show the competitive relationship network of PC enterprises in the Beijing–Tianjin–Hebei region is characterised by the development of a small-world network, and its cumulative degree and out-degree (in-degree) intensity distributions are single-scale networks with fast-decaying tails. The network has strong network clustering and assortativity, and it can truly reflect the competitive status and dynamics of the enterprises.

Deep learning has demonstrated unparalleled performance in various industries [...]

Abstract Background The prognostic value of in-hospital hemoglobin drop in non-overt bleeding patients with acute myocardial infarction (AMI) admitted to the intensive care unit (ICU) remains insufficiently investigated. Methods A retrospective analysis was performed based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. 2,334 ICU-admitted non-overt bleeders diagnosed with AMI were included. In-hospital hemoglobin values (baseline value on admission and nadir value during hospitalization) were available. Hemoglobin drop was defined as a positive difference between admission and in-hospital nadir hemoglobin. The primary endpoint was 180-day all-cause mortality. The time-dependent Cox proportional hazard models were structured to analyze the connection between hemoglobin drop and mortality. Results 2,063 patients (88.39%) experienced hemoglobin drop during hospitalization. We categorized patients based on the degree of hemoglobin drop: no hemoglobin drop (n = 271), minimal hemoglobin drop (

Abstract Background Sarcopenia and osteoporosis are common diseases that predominantly affect older individuals. The interaction between muscle and skeleton exerts pivotal roles in bone remodeling. This study aimed to explore the function of myoblast-derived exosomal Prrx2 in osteogenic differentiation and its potential mechanisms. Methods Exosomes were isolated from myogenic differentiated C2C12 cells. qRT-PCR and Western blotting were used to determine target molecule expression. Osteogenic differentiation of BMSCs was evaluated by Alizarin red staining, ALP activity and levels of OCN, OPN, RUNX2, and BMP2. Dual-luciferase reporter assay, RIP, and ChIP assays were performed to verify the interaction between molecules. The nuclear translocation of YAP1 was observed by immunofluorescence staining. In vivo osteoporotic model was established by ovariectomy in mice. Bone loss was examined using HE staining. Results Prrx2 expression was elevated in myogenic differentiated C2C12 cells and their exosomes. Myoblast-derived exosomal Prrx2 enhanced osteogenic differentiation of BMSCs. Delivering exosomal Prrx2 directly bond to MIR22HG promoter and promoted its transcription and expression. MIR22HG enhanced expression and nuclear translocation of YAP via sponging miR-128, thus facilitating BMSC osteogenic differentiation. Knockdown of exosomal Prrx2 suppressed osteogenic differentiation, which could be abolished by MIR22HG overexpression. Similarly, miR-128 inhibitor or YAP overexpression reversed the inhibitory effect of MIR22HG depletion or miR-128 mimics on osteogenic differentiation. Finally, myoblast-derived exosomal Prrx2 alleviated osteoporosis in mice via up-regulating MIR22HG and activating the Hippo pathway. Conclusion Myoblast-derived exosomal Prrx2 contributes to transcriptional activation of MIR22HG to activate YAP pathway via sponging miR-128, thereby facilitating osteogenic differentiation of BMSCs.

Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations. Improving its targeting of FGFR2 fusions remains an unmet clinical need due to its pan selectivity and resistance. Here, we report a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting the chimeric site in FGFR2-AHCYL1 (F-A Cho-HDO) that accumulates in ICC through endocytosis of low-density lipoprotein receptor (LDLR), which is highly expressed in both human and murine ICC. F-A Cho-HDO was determined to be a highly specific, sustainable, and well-tolerated agent for inhibiting ICC progression through posttranscriptional suppression of F-A in ICC patient-derived xenograft mouse models. Moreover, we identified an EGFR-orchestrated bypass signaling axis that partially offset the efficacy of F-A Cho-HDO. Mechanistically, EGFR-induced STAT1 upregulation promoted asparagine (Asn) synthesis through direct transcriptional upregulation of asparagine synthetase (ASNS) and dictated cell survival by preventing p53-dependent cell cycle arrest. Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.

Aims: This study was designed to investigate the role of pericytes in the pathogenesis of perioperative neurocognitive disorder (PND). Methods: In this study, we established a PND model via sevoflurane anesthesia and tibial fracture surgery in 2-month-old and 16-month-old male C57BL/6 mice. On the third postoperative day, the mice were subjected to behavioral testing or sacrificed to collect brain tissue. The progression of hippocampal blood–brain barrier (BBB) disruption and neuroinflammation was detected using transmission electron microscope and immunofluorescence. We also used western blotting to measure the levels of plasma-derived protein immunoglobulin G (IgG) and albumin in the hippocampus to assess the leakage of the BBB. Results: Aged mice did not experience age-related cognitive decline and BBB disruption compared with younger mice but only increased glial cell activity. Anesthesia/Surgery damaged cognitive function, reduced pericyte coverage, decreased the length of capillaries and levels of occludin and claudin-5, destroyed the structure of the BBB, exacerbated IgG and albumin accumulation in the hippocampus, and enhanced the activation of microglia and astrocytes in the hippocampus of aged mice. However, these negative effects did not occur in young mice. Conclusion: Our study showed that the loss of pericytes led to increased BBB permeability and neuroinflammation after anesthesia/surgery in aged mice, ultimately resulting in cognitive dysfunction.

Background: Regarding past epidemiological studies, there has been disagreement over whether type 1 diabetes (T1DM) is one of the risk factors for dental caries. The purpose of this study was to determine the causative links between genetic susceptibility to T1DM, glycemic traits, and the risk of dental caries using Mendelian randomization (MR) approaches.Methods: Summary-level data were collected on genome-wide association studies (GWAS) of T1DM, fasting glucose (FG), glycated hemoglobin (HbA1c), fasting insulin (FI), and dental caries. MR was performed using the inverse-variance weighting (IVW) method, and sensitivity analyses were conducted using the MR-Egger method, weighted median, weighted mode, replication cohort, and multivariable MR conditioning on potential mediators.Results: The risk of dental caries increased as a result of genetic susceptibility to T1DM [odds ratio (OR) = 1.044; 95% confidence interval (CI) = 1.015–1.074; p = 0.003], with consistent findings in the replication cohort. The relationship between T1DM and dental caries was stable when adjusted for BMI, smoking, alcohol intake, and type 2 diabetes (T2DM) in multivariable MR. However, no significant correlations between the risk of dental caries and FG, HbA1c, or FI were found.Conclusion: These results indicate that T1DM has causal involvement in the genesis of dental caries. Therefore, periodic reinforcement of oral hygiene instructions must be added to the management and early multidisciplinary intervention of T1DM patients, especially among adolescents and teenagers, who are more susceptible to T1DM.

Abstract Background Left-behind adolescents (LBAs) are adolescents aged 11–18 years who are separated from their parents and left behind in local cities by one or both parents for a period of more than 6 months. LBAs in rural areas are likely to engage in aggressive behavior, which can affect interpersonal relationships, reduce academic performance, and even lead to anxiety and depression. To our knowledge, no studies have examined the mediating effect of resilience and self-esteem on the relationship between negative life events and aggression among Chinese rural LBAs. Therefore, this study aimed to explore the relationship between negative life events and aggression among Chinese rural LBAs and how self-esteem and resilience mediate the association. Methods Using a stratified random sampling method, 1344 LBAs in Hunan Province of China were investigated. Information was collected by a self-designed sociodemographic questionnaire, Adolescent Self-Rating Life Events Checklist, Resilience Scale Chinese Adolescent, Rosenberg Self-Esteem Scale and Aggression Scales to assess the psychology of LBAs. Data analysis was conducted using descriptive statistics, Pearson correlation, and regression analysis to estimate direct and indirect effects using bootstrap analysis. Results Negative life events were significantly related to self-esteem (r = − 0.338), resilience (r = − 0.359), and aggression (r = 0.441). Aggression was directly affected by self-esteem (β = − 0.44) and resilience (β = − 0.34). Negative life events were not only directly related to aggression (β = 0.34, 95% CI: 0.275 ~ 0.398) but also showed an indirect effect on aggression through self-esteem and resilience. The direct effect, total effect and indirect effect of negative life events on aggression through self-esteem and resilience were 0.3364, 0.4344 and 0.0980, respectively. The mediating effect of self-esteem and resilience accounted for 22.56% of the relationship between negative life events and aggression. Conclusions We found that self-esteem and resilience mediated most negative life events on aggression. It is imperative for educators and families to improve LBAs’ self-esteem and resilience to reduce the occurrence of aggression. Future intervention studies should be designed to strengthen self-esteem and resilience.

Vascular injury following traumatic knee injury quoted in the literature ranges from 3.3 to 65%, depending on the magnitude and pattern of the injury. Timely recognition is crucial to ensure the revascularization is done within 6 to 8 hours from the time of injury to avoid significant morbidity, amputation, and medicolegal ramifications. We present a case of an ischemic limb following delayed diagnosis of popliteal artery injury after knee dislocation. Even though we have successfully repaired the popliteal artery, the evolving ischemia over the distal limb poses a reconstruction challenge. Multiple surgical debridement procedures were performed to control the local tissue infection. Free tissue transfer with chimeric latissimus dorsi flap was done to resurface the defect. However, the forefoot became gangrenous despite a free muscle flap transfer. His limb appeared destined for amputation in the vicinity of tissue and recipient vessels, but we chose to use a cross-leg free flap as an option for limb salvage.

Abstract Background Serum lipids variations are closely related to the sepsis progression; however, their value for patients with pyogenic liver abscesses (PLA) has rarely been studied. We investigated the serum lipid level variations in patients with PLA and its predictive value to the disease. Methods The study included 328 patients with PLA hospitalized in the First Affiliated Hospital of Nanjing Medical University from January 2017 to December 2021; 35 (10.67%) in the severe group (SG) and 293 (89.33%) in the non-severe group (nSG). Their clinical records were analyzed retrospectively, and dynamic curves were drawn to clarify the changes in different indicators during the course of the disease. Results High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a) (Lp(a)) in the SG were significantly lower than those in nSG (P

As grid interfaces of renewable resources in weak grids, voltage source converters (VSCs) commonly cause low-frequency and sub-synchronous frequency oscillation issues that are mainly related to dc-link voltage control (DVC) and phase-locked loop (PLL). To investigate these oscillation issues, many scholars have proposed frequency-domain methods with different input-output variables. However, selecting improper input-output variables may lead to incorrect analysis results, which has rarely been discussed. To fill this gap, we propose a method for identifying VSC-induced oscillation modes and choosing the proper input-output variables for stability margin assessment. First, this study proposes a three-terminal admittance model suitable for analyzing both DVC- and PLL-dominated modes. This proposed model can also be evaluated for “black-boxed” VSCs. On this basis, we reveal that different admittance channels reflect different input-output characteristics, and two admittance-based stability criteria are proposed for DVC- and PLL-dominated modes. Moreover, a sensitivity indicator-based method and a corresponding approachable small-signal stability assessment procedure are proposed to identify the proper input-output variables for these two oscillation modes. The validity of the analysis results is verified through simulations in MATLAB/Simulink.

Diabetic cardiomyopathy (DCM) is a serious complication and death cause of diabetes mellitus (DM). Recent cardiology studies suggest that spermidine (SPD) has cardioprotective effects. Here, we verified the hypothesis of SPD’s protective effects on DCM. Therefore, db/db mice and primary neonatal mouse cardiomyocytes were used to observe the effects of SPD. Immunoblotting showed that ornithine decarboxylase (ODC) and SPD/spermine N1-acetyltransferase (SSAT) were downregulated and upregulated in the myocardium of db/db mice, respectively. We found that diabetic mice showed cardiac dysfunction in 12 weeks. Conversely, exogenous SPD could improve cardiac functions and reduce the deposition of collagens, myocardial damage, reactive oxygen species (ROS) levels, and endoplasmic reticulum stress (ERS) in diabetic mouse hearts. Our results also demonstrated that cardiomyocytes displayed ferroptosis and then activated Pannexin-1 expression, which resulted in the increase of the extracellular adenosine triphosphate (ATP). Subsequently, increased ATP as a paracrine molecule combined to purinergic receptor P2X7 to activate ERK1/2 signaling pathway in cardiomyocytes and activated NCOA4-mediated ferroptinophagy to promote lipid peroxidation and ferroptosis. Interestingly, SPD could reverse these molecular processes. Our findings indicate an important new mechanism for DCM and suggest that SPD has potential applicability to protect against deterioration of cardiac function with DCM.

As the highest prevalence and mortality, malignant lung carcinoma is still regarded to be an unabating cancer until now. Besides, mesoporous nanocarrier-based therapeutics delivery system has drawn plenty of attention and Co3O4 nanoparticles have been demonstrated intrinsic Fenton-like activity which is much higher than analogous synthesized Fe3O4. In this work, in order to precisely diagnose and effectively eliminate lung tumor cells, we have synthesized mesoporous hollowed Co3O4 nanocarriers with ICG loading and surface grafting of RGD peptides. We have demonstrated that the biodegradable nanoplatform is a promising NIR II fluorescent contrast agent for accurately delineating tumor counters and phototheranostic agent with photo-heat conversion efficiency as ∼59.93% under 808 nm light exposure. More importantly, the corresponded hyperthymia progressively potentiates the ROS production via Co ions catalyzation. Our Co-based nanocomposite could efficaciously suppress the tumorigenesis both in vitro and in vivo accompanied by 808 nm laser illumination. In summary, all data highlights the potency of biodegradable Co-based mesoporous nanocarriers as contrast agents for multimodal imaging and photothermal augmented ROS amplification for efficient lung tumor inhibition.

Background: Xin-tong-tai Granule (XTTG), a traditional Chinese medicine, has been used to treat atherosclerosis (AS), but its mechanism is poorly understood. Intriguingly, oxidative stress has been recognized as vital factors in the treatment of atherosclerosis. Purpose: This study aims to explore the potential mechanism of XTTG for treating AS. Methods: An in-vivo model of AS was established by feeding ApoE-/- mice with a high-fat diet (HFD), and the Human Aortic Vascular Smooth Muscle Cells (HAVSMCs) were induced by oxidized low-density lipoprotein (ox-LDL) in vitro. After treatment, the blood lipid levels and pathological aortic changes of each group were observed, and the cell proliferation and lipid droplet aggregation in each group were evaluated. The oxidative stress indicators such as malondialdehyde (MDA) and superoxide dismutase (SOD) levels and related NOX/ROS/NF-κB signaling pathway indicators were observed. Results: XTTG improved blood lipid levels and pathological aortic changes of ApoE−/− mice with HFD feeding, inhibited HAVSMCs proliferation and lipid droplet aggregation induced by ox-LDL, reduced MDA content, increased SOD content, inhibited NOX4 and p22phox protein expression, downregulated ROS content, inhibited IKK-α, IKK-β, NF-κB protein and mRNA expression and the phosphorylation of NF-κB. Conclusion: XTTG can inhibit NOX/ROS/NF-κB signaling pathway, reduce damages caused by oxidative stress, and exert anti-AS effects.