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Abstract Suppression of Tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor/ Toll-like receptor superfamily, and its specific ligand is Interleukin-33 (IL-33). IL-33/ ST2 signaling has been implicated in numerous inflammatory and allergic diseases, as well as in promoting malignant behavior of tumor cells and angiogenesis. However, the precise role of ST2 in gastric cancer angiogenesis remains incompletely elucidated. We observed a significant correlation between high expression of ST2 in gastric cancer tissues and poor prognosis, along with various clinicopathological features. In vitro experiments demonstrated that the IL-33/ ST2 axis activates the PI3K/AKT/NF-κB signaling pathway through TRAF6, thereby promoting VEGFA-mediated tumor angiogenesis; meanwhile sST2 acts as a decoy receptor to regulate the IL-33/ST2L axis. Consistent findings were also observed in subcutaneous xenograft tumor models in nude mice. Furthermore, we investigated the molecular mechanism by which IL-33 promotes ST2L expression in GC cells via upregulation of transcription factors YY1 and GATA2 through intracellular signaling pathways.

Abstract Ultrahigh-voltage electricity systems are a vital part of energy networks, often across wide regions passing through mountainous terrains. The instability of slopes forming tower foundations along transmission lines poses a large risk to the entire energy network. Moreover, the tower foundations along extra-high-voltage electricity transmission lines are a very special type of element that are also highly vulnerable to landslides. In this study, an integrative risk assessment framework, including a hazard assessment, vulnerability analysis for the specified element at risk, and consequence estimation, is proposed to quantify the direct and indirect risks of landslides to power transmission lines. The Yanzi landslide, where a tower of the major ultrahigh-voltage transmission line from Sichuan (western China) to Shanghai (eastern China) has just been constructed, is taken as a case study. The correlation between landslide displacement and tower structure tilting is studied. In terms of the precipitation return period, factors of safety, failure probability, and deformation are simulated. A physical vulnerability curve is fitted by assuming a Weibull relationship between the horizontal deformation (hazard intensity) of the landslide and the tower inclination ratio. The total risk is calculated as the sum of the direct and indirect losses, among which the potential indirect risk due to tower damage is much greater than the direct risk. This work demonstrates the importance of landslide treatment strategies along electricity transmission lines by considering the potential indirect risks. The risk assessment model of landslides affecting ultrahigh-voltage electricity transmission lines proposed in this study could be useful for other types of indirect landslide risk evaluations.

In order to study the effect of intermittent ozone treatment on the storage quality and preservation of kiwifruit, ‘Hayward’ kiwifruit were fumigated with different concentrations (0, 21.4, 42.8 and 64.2 mg/m3) of ozone once every seven days during storage at (0.0 ± 0.5) ℃. Quality indexes and the antioxidant enzyme activity of superoxide dismutase (SOD) and ascorbate peroxidase (APX) were measured regularly during storage. The results showed that compared with the control group, ozone treatment at all concentrations effectively reduced fruit mass loss rate, soft fruit rate and decay rate, inhibited the increase of total soluble solid (TSS) and malondialdehyde (MDA) contents, delayed the decrease of titratable acid (TA) content and fruit hardness, and maintained higher vitamin C (VC), total phenol and flavonoid contents. The preservative effect of ozone at 42.8 mg/m3 was better than those at 21.4 and 64.2 mg/m3 concentrations. After 140-day storage, the hardness and VC content in the 42.8 mg/m3 treatment group were 76.92% and 43.10% higher than those in the control group, respectively. The peak values of catalase (CAT) and peroxidase (POD) activity were 36.53% and 89.31% higher than those of the control group, respectively. Ozone treatment also effectively controlled the soft fruit rate and decay rate of kiwifruit during the shelf-life period. On the 9th day, the decay rate of the 42.8 mg/m3 treatment group was 16.67%, which was 63.77% lower than that of the control group. It is concluded that intermittent ozone treatment at a concentration of 42.8 mg/m3 can effectively slow down the senescence process and improve the storage quality and nutritional value of kiwifruit.

Abstract Colorectal cancer (CRC) is the third most common malignancy, with increasing prevalence and mortality. How the ethoxy-erianin phosphate (EBTP) mediates CRC development remains unclear. Therefore, the current study evaluated the effects of EBTP on the proliferation, migration, and angiogenesis of CRC cells using CCK-8, Wound-healing, Transwell, and Tube formation assays. RNA sequencing and molecular docking techniques helped predict that EBTP could inhibit angiogenesis by regulating PIK3R2 expression while clarifying the mechanism behind EBTP-mediated CRC angiogenesis. Subsequently, several in vitro experiments indicated that PIK3R2 overexpression significantly improved the proliferation, migration, and angiogenesis of CRC cells while knocking down PIK3R2 expression inhibited their proliferation, migration, and angiogenesis. Simultaneously, PIK3R2 expression in CRC cells gradually decreased with increased EBTP concentration and action duration. Moreover, PIK3R2 overexpression in CRC cells could reverse the inhibitory EBTP effect in angiogenesis. Mouse experiments also depicted that EBTP inhibited CRC angiogenesis by down-regulating PIK3R2 expression. In addition, EBTP could inhibit PI3K/AKT pathway activity and indirectly control PIK3R2 expression through the lncRNA TMPO-AS1/miR-126-3p axis. Our findings highlighted that EBTP could inhibit CRC angiogenesis using the TMPO-AS1/miR-126-3p/PIK3R2/PI3k/AKT axis, providing a novel strategy for anti-angiogenic therapy in CRC.

Abstract Background Although numerous studies have shown that bariatric surgery results in sustained weight loss and modifications in gut microbiota composition and cognitive function, the exact underlying mechanisms are unclear. This study aimed to investigate the effects of bariatric surgery on cognitive function through the microbiota-gut-brain axis (MGBA). Methods Demographic data, serum samples, fecal samples, cognitive assessment scales, and resting-state functional connectivity magnetic resonance imaging (rs-fMRI) scans were obtained from 39 obese patients before and after (6 months) laparoscopic sleeve gastrectomy (LSG). PCA analysis, OPLS-DA analysis, and permutation tests were used to conduct fecal 16 S microbiota profiling, serum metabolomics, and neuroimaging analyses, and a bariatric surgery-specific rs-fMRI brain functional connectivity network was constructed. Spearman correlation analysis and Co-inertia analysis were employed to correlate significant alterations in cognitive assessment scales and resting-state functional connectivity difference networks with differential serum metabolites and 16 S microbiota data to identify key gut microbiota and serum metabolic factors. Results LSG significantly reduced the weight of obese patients, with reductions of up to 28%. Furthermore, cognitive assessment scale measurements revealed that LSG enhanced cognitive functions, including memory (HVLT, p = 0.000) and executive function (SCWT, p = 0.008). Also, LSG significantly altered gut microbiota composition (p = 0.001), with increased microbial abundance and diversity (p 1). Spearman correlation analysis among cognitive assessment scales, gut microbiota species, and serum metabolites revealed correlations with 68 gut microbiota species and 138 serum metabolites (p

Since the impoundment of Three Gorges Reservoir (TGR) in 2003, numerous slopes have experienced noticeable movement or destabilization owing to reservoir level changes and seasonal rainfall. One case is the Outang landslide, a large-scale and active landslide, on the south bank of the Yangtze River. The latest monitoring data and site investigations available are analyzed to establish spatial and temporal landslide deformation characteristics. Data mining technology, including the two-step clustering and Apriori algorithm, is then used to identify the dominant triggers of landslide movement. In the data mining process, the two-step clustering method clusters the candidate triggers and displacement rate into several groups, and the Apriori algorithm generates correlation criteria for the cause-and-effect. The analysis considers multiple locations of the landslide and incorporates two types of time scales: long-term deformation on a monthly basis and short-term deformation on a daily basis. This analysis shows that the deformations of the Outang landslide are driven by both rainfall and reservoir water while its deformation varies spatiotemporally mainly due to the difference in local responses to hydrological factors. The data mining results reveal different dominant triggering factors depending on the monitoring frequency: the monthly and bi-monthly cumulative rainfall control the monthly deformation, and the 10-d cumulative rainfall and the 5-d cumulative drop of water level in the reservoir dominate the daily deformation of the landslide. It is concluded that the spatiotemporal deformation pattern and data mining rules associated with precipitation and reservoir water level have the potential to be broadly implemented for improving landslide prevention and control in the dam reservoirs and other landslide-prone areas.

Abstract. Background:. Breast cancer is ranked among the most prevalent malignancies in the Chinese female population. However, comprehensive reports detailing the latest epidemiological data and attributable disease burden have not been extensively documented. Methods:. In 2018, high-quality cancer surveillance data were recorded in 700 population-based cancer registries in China. We extracted data on female breast cancers (International Classification of Diseases, Tenth Revision [ICD-10]: C50) and estimated the incidence and mortality in 2022 according to the baseline data and corresponding trends from 2010 to 2018. Pathological types were classified according to the ICD for Oncology, 3rd Edition codes. Disability-adjusted life years (DALYs) were calculated as the sum of the years of life lost (YLLs) and years lived with disability (YLDs). Results:. In 2022, approximately 357,200 new female breast cancer cases and 75,000 deaths occurred in China, accounting for 15.59% and 7.94% of total new cancer cases and deaths, respectively. The age-standardized incidence rate (ASIR) was 33.04 per 100,000. When analyzed by pathological type, the ASIRs for papillary neoplasms, invasive breast carcinoma, rare and salivary gland-type tumors, and other types were 1.13, 29.79, 0.24, and 1.88 per 100,000, respectively. The age-standardized mortality rate (ASMR) was 6.10 per 100,000. A total of 2,628,000 DALYs were found to be attributable to female breast cancer in China, comprising 2,278,300 YLLs and 349,700 YLDs. The ASIR, ASMR, and age-standardized rate (ASR) for DALYs in urban areas were consistently higher than those in rural areas. We observed a four-fold increase in the ASIR and ASR for DALYs and an eight-fold increase in the ASMR among females over 55 years compared with those aged under 55 years. Conclusion:. These data provide invaluable insights into the latest epidemiology of female breast cancer in China and highlight the urgency for disease prevention and control strategy formulation.

Abstract Polymer nanoparticles that can sharply sense and detect biological signals in cells are promising candidates for biomedical and theranostic nanomaterials. However, the response ability of current polymer assemblies poorly matches the requirement of trace concentration level (10−6 ~ 10−9 mol/L) of cellular biosignals due to their linear signal input-to-function output mode, which impedes their practical applications in vivo. Here we report a kind of nanobowl system with pH-tunable invaginated morphology that can nonlinearly amplify the response abilities toward biosignals by modulating the surface concavity. Compared to conventional spherical nanoparticles, nonspherical nanobowls with a specific concave structure reduce the critical response threshold of polymers by up to 5 orders of magnitude, from millimole to nanomole level, covering most of biosignal concentration windows. Moreover, we find that this nonlinear signal gain effect is originated from the collective impact of a single signal on transitioning the polymer chain aggregation state of individual assemblies, rather than just altering a certain unit or chain. This nonlinear signal-to-response mechanism is potential to solve the tricky problems of probing and sensing endogenous signals with trace physiological concentration.

Objective Multitargeted tyrosine kinase inhibitors (TKIs) have been approved as second‐line therapy in refractory sarcoma, prolonging progression‐free survival (PFS) but with short‐lived duration of disease control. Fruquintinib is a TKI that specifically inhibits vascular endothelial growth factor receptor‐1,2,3 with no metabolism by liver enzymes. In this retrospective study, we assessed the efficacy and safety of fruquintinib‐based treatment in patients with refractory sarcoma after developing several lines of TKI resistance. Methods We retrospectively analyzed the clinical data of patients with refractory sarcoma after they had developed several lines of resistance to TKIs and who received fruquintinib‐based treatment from November 2021 to August 2023. The primary endpoint was the progression‐free survival rate at 4 months (4m‐PFSR). Secondary endpoints were the median PFS, overall survival (OS), objective response rate, disease control rate, and adverse effects (AEs). PFS and OS were estimated using the Kaplan–Meier method. A log‐rank test was used to compare survival curves between different clinical and pathological factors. Cox proportional hazards analysis was performed to identify PFS‐related prognostic factors. Results We included 124 patients: 56 (45.2%) with osteosarcoma, 28 (22.6%) with Ewing sarcoma, seven (5.6%) with chondrosarcoma, and 33 (26.6%) with soft tissue sarcomas (STS). Only 18 (14.5%) patients received monotherapy with fruquintinib. With a median follow‐up time of 6.8 (interquartile range [IQR], 4.6–9.4) months, 22 (17.7%) patients had partial response and 78 (62.9%) had stable disease. The 4m‐PFSR was 58.4% (95% confidence interval [CI], 49.6%–67.1%). The median PFS and OS were 4.4 (95% CI, 3.9–5.0) months and 11.4 (95% CI, 10.3–12.5) months. In multivariate analysis, a high hazard ratio for progression was associated with target lesions located outside the lung and bone with 1.79 (95% CI, 1.10–2.93; p = 0.020). Eighty‐eight AEs were recorded in 47 (37.9%) patients; the most common were pneumothorax (18/124, 14.5%), diarrhea (8/124, 6.5%), oral mucositis (7/124, 5.6%), and thrombocytopenia (7/124, 5.6%). Conclusions Fruquintinib may be a potential option for patients with refractory sarcoma after developing several lines of TKI resistance, with a satisfactory efficacy and safety profile in combination therapy. However, the degree of contribution of fruquintinib to results is unclear when combined with other effective substances. Additional prospective trials of fruquintinib should be conducted, especially involving different pathological types and combination regimens.

Abstract Purpose Compared with open surgery, arthroscopic anterior talofibular ligament (ATFL) repair has many advantages and good clinical outcome. Inferior extensor retinaculum (IER) reinforcement is a supplement procedure that increase the strength of the ATFL. There is still no gold standard for arthroscopic ATFL repair. The purposes of this study were to describe a simplified technique for arthroscopic ATFL repair with IER reinforcement and to analyze its preliminary clinical results. Methods Twenty-seven patients with chronic lateral ankle instability (CLAI) who underwent this simplified surgery were analyzed in this retrospective study. The patients’ characteristics and operative times were evaluated. Intraoperative photos, radiographs from the anterior drawer test and talar tilt test and postoperative MR images were recorded. The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and visual analog scale (VAS) score were also recorded. With the assistance of a needle, we performed ATFL repair and IER reinforcement with one Pushlock anchor and nonabsorbable sutures. Results No complications namely skin necrosis, superficial fibular nerve injury or wound infection, were reported. The AOFAS score and VAS score improved from 64.74 ± 9.47 and 6.00 ± 1.56 to 90.74 ± 6.46 and 1.07 ± 1.09, respectively. The talar advancement and talar tilt angle were improved after surgery. One year after the operation, the ATFL appeared to be continuous on MR images. Conclusion In this study, we proposed a simple and effective arthroscopic ATFL repair with IER reinforcement technique. The short-term follow-up examination revealed satisfactory clinical outcomes. Our technique might be a new surgical option for the treatment of CLAI.

Abstract Purpose To investigate the application value of support vector machine (SVM) model based on diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) and amide proton transfer- weighted (APTW) imaging in predicting isocitrate dehydrogenase 1(IDH-1) mutation and Ki-67 expression in glioma. Methods The DWI, DCE and APTW images of 309 patients with glioma confirmed by pathology were retrospectively analyzed and divided into the IDH-1 group (IDH-1(+) group and IDH-1(-) group) and Ki-67 group (low expression group (Ki-67 ≤ 10%) and high expression group (Ki-67 > 10%)). All cases were divided into the training set, and validation set according to the ratio of 7:3. The training set was used to select features and establish machine learning models. The SVM model was established with the data after feature selection. Four single sequence models and one combined model were established in IDH-1 group and Ki-67 group. The receiver operator characteristic (ROC) curve was used to evaluate the diagnostic performance of the model. Validation set data was used for further validation. Results Both in the IDH-1 group and Ki-67 group, the combined model had better predictive efficiency than single sequence model, although the single sequence model had a better predictive efficiency. In the Ki-67 group, the combined model was built from six selected radiomics features, and the AUC were 0.965 and 0.931 in the training and validation sets, respectively. In the IDH-1 group, the combined model was built from four selected radiomics features, and the AUC were 0.997 and 0.967 in the training and validation sets, respectively. Conclusion The radiomics model established by DWI, DCE and APTW images could be used to detect IDH-1 mutation and Ki-67 expression in glioma patients before surgery. The prediction performance of the radiomics model based on the combination sequence was better than that of the single sequence model.

Saxifraga giraldiana Engler is a common subalpine and alpine plant belonging to Saxifragaceae. However, the genetic diversity of this species has remained to be explored. In this study, we have assembled and characterized the complete chloroplast genome of S. giraldiana, filling this knowledge gap and uncovering its genetic composition. The chloroplast genome is 147,267 bp long and contains 131 genes, including 85 protein-coding genes, 38 tRNA genes, and eight rRNA genes. Furthermore, we have performed a phylogenetic analysis of 19 representative species within Saxifraga. As a result, we have found that S. giraldiana, together with S. implicans and S. stellariifolia, forms a monophyletic group. These findings have implications for the conservation and utilization of S. giraldiana.

Abstract Faults play a crucial role in shaping the formation and damage patterns of landslides in the mountainous region, particularly in Qinling-Daba (Qinba) area in China. On 6 October 2022, following a 4-day rainfall event totaling 221.5 mm, a landslide occurred in Hanwang Town, Shaanxi Province. The left boundary of the landslide coincided with a fault, which influence the formation and movement development of the landslide. To further understand and quantified the formation process and damage mechanism of the landslide, a comprehensive study was conducted, incorporating field investigations, local rainfall data, and various methods including unmanned aerial vehicles (UAVs), numerical simulations, and laboratory test. The results indicate that fault dictate the formation of the Lijiaping landslide by influencing the mechanical strength of the rock mass and the catchment topography in the landslide area. Due to fault, the rock mass in the landslide area is high fragmentation, with a softening coefficient of about 0.52. Weathering resulted in numerous residual and slope sediments in the landslide area, providing ample material for the landslide. Meanwhile, the fault activity led to a wedge-shaped topography in the landslide area, with an average Terrain Wetness Index (TWI) of 3.43, significantly higher than the Hanwang Township average of 1.47. This creates a hydrogeological structure favorable for landslides. Numerical simulations revealed that the maximum velocity of the landslide reached 5.05 m/s and the maximum displacement was 53.18 m, both occurring in the central part of the landslide. These findings offer crucial scientific insights for understanding and preventing similar geological hazards.

Abstract Background Subarachnoid hemorrhage (SAH) is a severe stroke subtype that lacks effective treatment. Exosomes derived from human dental pulp stem cells (DPSCs) are a promising acellular therapeutic strategy for neurological diseases. However, the therapeutic effects of DPSC-derived exosomes (DPSC-Exos) on SAH remain unknown. In this study, we investigated the therapeutic effects and mechanisms of action of DPSC-Exos in SAH. Materials and methods SAH was established using 120 male Sprague-Dawley rats. One hour after SAH induction, DPSC-Exos were administered via tail vein injection. To investigate the effect of DPSC-Exos, SAH grading, short-term and long-term neurobehavioral assessments, brain water content, western blot (WB), immunofluorescence staining, Nissl staining, and HE staining were performed. The role of miR-197-3p/FOXO3 in regulating pyroptosis was demonstrated through miRNA sequencing, bioinformatics analysis, and rescue experiments. The SAH model in vitro was established by stimulating BV2 cells with hemoglobin (Hb) and the underlying mechanism of DPSC-Exos was investigated through WB and Hoechst/PI staining. Results The expressions of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were increased after SAH. DPSC-Exos alleviated brain edema and neuroinflammation by inhibiting the expression of FOXO3 and reducing NLRP3 inflammasome activation, leading to improved neurobehavioral functions at 24 h after SAH. In vitro, the expression of the NLRP3 inflammasome components (NLRP3 and caspase1-p20), GSDMD-N, and IL-18 was inhibited in BV2 cells pretreated with DPSC-Exos. Importantly, DPSC-Exos overexpressing miR-197-3p had a more obvious protective effect than those from NC-transfected DPSCs, while those from DPSCs transfected with the miR-197-3p inhibitor had a weaker protective effect. Functional studies indicated that miR-197-3p bound to the 3ʹ-untranslated region of FOXO3, inhibiting its transcription. Furthermore, the overexpression of FOXO3 reversed the protective effects of miR-197-3p. Conclusions DPSC-Exos inhibited activation of the NLRP3 inflammasome and related cytokine release via the miR-197-3p/FOXO3 pathway, alleviated neuroinflammation, and inhibited microglial pyroptosis. These findings suggest that using DPSC-Exos is a promising therapeutic strategy for SAH. Graphical Abstract

IntroductionAcupoint Catgut Embedding (ACE) is an extended and developed form of traditional acupuncture that serves as a composite stimulation therapy for various diseases. However, its local stimulation effects on acupoints remain unclear. Acupuncture can activate mechanically sensitive calcium ion channels, TRPV2 and TRPV4, located on various cell membranes, promoting Ca2+ influx in acupoint tissues to exert effects. Whether ACE can form mechanical physical stimulation to regulate these channels and the related linkage effect requires validation.MethodsThis study investigates the influence of TRPV2 and TRPV4 ion channels on the local stimulation effects of ACE by embedding PGLA suture at the Zusanli (ST36) acupoint in rats and using TRPV2 and TRPV4 inhibitors. Flow cytometry, immunofluorescence, Western blot, and Real-time quantitative PCR were employed to detect intracellular Ca2+ fluorescence intensity, the expression of macrophage (Mac) CD68 and mast cell (MC) tryptase, as well as the protein and mRNA expression of TRPV2 and TRPV4 in acupoint tissues after PGLA embedding.ResultsThe results indicate that ACE using PGLA suture significantly increases the mRNA and protein expression of TRPV2 and TRPV4, Ca2+ fluorescence intensity, and the expression of Mac CD68 and MC tryptase in acupoint tissues, with these effects diminishing over time. The increasing trends are reduced after using inhibitors, particularly when both inhibitors are used simultaneously. Furthermore, correlation analysis shows that embedding PGLA suture at the ST36 acupoint regulates Mac and MC functions through Ca2+ signaling involving not only TRPV2 and TRPV4 but multiple pathways.DiscussionThese results suggest that embedding PGLA suture at the ST36 acupoint generates mechanical physical stimulation and regulates TRPV2 and TRPV4 ion channels, which couple with Ca2+ signaling to form a linkage effect that gradually weakens over time. This provides new reference data for further studies on the stimulation effects and clinical promotion of ACE.

Abstract The low ion transport is a major obstacle for low‐temperature (LT) sodium‐ion batteries (SIBs). Herein, a core‐shell structure of bismuth (Bi) nanospheres coated with carbon (Bi@C) is constructed by utilizing a novel Bi‐based complex (1,4,5,8‐naphthalenetetracarboxylic dianhydride as the ligand) as the precursor, which provides an effective template to fabricate Bi‐based anodes. At −40°C, the Bi@C anode achieves a high capacity, which is equivalent to 96% of that at 25°C, benefitting from the core‐shell nanostructured engineering and Na+‐ether‐solvent cointercalation process. The special Na+‐diglyme cointercalation behavior may effectively reduce the activation energy and accelerate the Na+ diffusion kinetics, enabling the excellent low‐temperature performance of the Bi@C electrode. As expected, the fabricated Na3V2(PO4)3//Bi@C full‐cell delivers impressive rechargeability in the ether‐based electrolyte at −40°C. Density functional theory calculations and electrochemical tests also reveal the fast reaction kinetic mechanism at LT, thanks to a much lower diffusion energy barrier (167 meV) and a lower reaction activation energy (32.2 kJ mol−1) of Bi@C anode in comparison with that of bulk Bi. This work provides a rational design of Bi‐based electrodes for rechargeable SIBs under extreme conditions.

ABSTRACT: Outbreaks of short beak and dwarfism syndrome (SBDS), caused by a novel goose parvovirus (NGPV), have occurred in China since 2015. The NGPV, a single-stranded DNA virus, is thought to be vertically transmitted. However, the mechanism of NGPV immune evasion remains unclear. In this study, we investigated the impact of NGPV infection on the Cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway in duck embryonic fibroblast (DEF) cells. Our findings demonstrate that NGPV infection stimulates the mRNA expression of cGAS but results in weak IFN-β induction. NGPV impedes the expression of IFN-β and downstream interferon-stimulated genes, thereby reducing the secretion of IFN-β induced by interferon-stimulating DNA (ISD) and poly (I: C). RNA-seq results show that NGPV infection downregulates interferon mRNA expression while enhancing the mRNA expression of inflammatory factors. Additionally, the results of viral protein over-expression indicate that VP1 exhibits a remarkable ability to inhibit IFN-β expression compared to other viral proteins. Results indicated that only the intact VP1 protein could inhibit the expression of IFN-β, while the truncated proteins VP1U and VP2 do not possess such characteristics. The immunoprecipitation experiment showed that both VP1 and VP2 could interact with IRF7 protein, while VP1U does not. In summary, our findings indicate that NGPV infection impairs the host's innate immune response by potentially modulating the expression and secretion of interferons and interferon-stimulating factors via IRF7 molecules, which are regulated by the VP1 protein.

Introduction We aim to assess the association between smoking behavior and intracranial aneurysms (IAs) and the effect of smoking cessation medications on IAs at the genetic level. Methods Causal effects of four phenotypes: 1) age at initiation of regular smoking, 2) cigarettes smoked per day, 3) smoking cessation, and 4) smoking initiation on IAs, were analyzed using two-sample inverse-variance weighted Mendelian randomization analyses. The effects of genes interacting with the smoking cessation medications were analyzed using cis-expression quantitative trait loci genetic instruments on IAs using summary statistics-based Mendelian randomization analyses. Colocalization analyses were then used to test whether the genes shared causal variants with IAs. The role of confounding phenotypes as potential causative mechanisms of IAs at these gene loci was tested. Results Cigarettes smoked per day (OR=2.89; 95% CI:1.85–4.51) and smoking initiation on IAs (OR=4.64; 95% CI: 2.64–8.15) were significantly associated with IA risk. However, age at initiation of regular smoking (OR=0.54; 95% CI: 0.10–2.8) and smoking cessation (OR=6.80; 95% CI: 0.01–4812) had no overall effect on IAs. Of 88 genes that interacted with smoking cessation medications, two had a causal effect on IA risk. Genetic variants affecting HYKK levels showed strong evidence of colocalization with IA risk. Higher HYKK levels in the blood were associated with a lower IA risk. Gene target analyses revealed that cigarettes/ day could be a main mediator of HYKK’s effect on IA risk. Conclusions This study provides evidence supporting that smoking initiation on IAs and cigarettes/day may increase IA risk. Increased HYKK gene expression may reduce IA risk. This can be explained by the increased number of cigarettes consumed daily. HYKK could also reduce IA risk due to the positive effect of continuous abstinence and varenicline therapy on smoking cessation.

Abstract Background The alveolar epithelial type II cell (AT2) and its senescence play a pivotal role in alveolar damage and pulmonary fibrosis. Cell circadian rhythm is strongly associated with cell senescence. Differentiated embryonic chondrocyte expressed gene 1 (DEC1) is a very important circadian clock gene. However, the role of DEC1 in AT2 senescence and pulmonary fibrosis was still unclear. Results In this study, a circadian disruption model of light intervention was used. It was found that circadian disruption exacerbated pulmonary fibrosis in mice. To understand the underlying mechanism, DEC1 levels were investigated. Results showed that DEC1 levels increased in lung tissues of IPF patients and in bleomycin-induced mouse fibrotic lungs. In vitro study revealed that bleomycin and TGF-β1 increased the expressions of DEC1, collagen-I, and fibronectin in AT2 cells. Inhibition of DEC1 mitigated bleomycin-induced fibrotic changes in vitro and in vivo. After that, cell senescence was observed in bleomycin-treated AT2 cells and mouse models, but these were prevented by DEC1 inhibition. At last, p21 was confirmed having circadian rhythm followed DEC1 in normal conditions. But bleomycin disrupted the circadian rhythm and increased DEC1 which promoted p21 expression, increased p21 mediated AT2 senescence and pulmonary fibrosis. Conclusions Taken together, circadian clock protein DEC1 mediated pulmonary fibrosis via p21 and cell senescence in alveolar epithelial type II cells.

Abstract Heart failure is the prevalent complication of acute myocardial infarction. We aim to identify a biomarker for heart failure post-acute myocardial infarction. This observational study includes 1062 and 1043 patients with acute myocardial infarction in the discovery and validation cohorts, respectively. The outcomes are in-hospital and long-term heart failure events. S100A8/A9 is screened out through proteomic analysis, and elevated circulating S100A8/A9 is independently associated with heart failure in discovery and validation cohorts. Furthermore, the predictive value of S100A8/A9 is superior to the traditional biomarkers, and the addition of S100A8/A9 improves the risk estimation using traditional risk factors. We finally report causal effect of S100A8/A9 on heart failure in three independent cohorts using Mendelian randomization approach. Here, we show that S100A8/A9 is a predictor and potentially causal medicator for heart failure post-acute myocardial infarction.

Objective The relationship between vitiligo and cardiovascular diseases remains controversial. This study aimed to systematically review the evidence comparing cardiovascular disease risk factors between patients with vitiligo and controls and to perform a meta-analysis of the results.Data sources A comprehensive database search was performed for all studies in PubMed, EMBASE, and Cochrane Central Register databases from inception to November, 2023. The main keywords used were vitiligo, hypertension, diabetes, hyperlipidemia, metabolic syndrome, obesity, smoking, alcohol consumption, C-reactive protein, and homocysteine.Study selection Only observational studies and no randomized controlled trials were included. Of the 1269 studies initially selected, the full texts of 108 were assessed for eligibility, and 74 were ultimately included in the analysis.Data extraction and synthesis Three reviewers independently extracted the following data: study design, number and characteristics of participants, inclusion indicators, and disease duration. A meta-analysis of the single-group rates was performed for the diabetes, hypertension, hyperlipidemia, and obesity groups. Random-effects or fixed-effects models were used to calculate the sample-size weighted averages for the indicators included in the studies.Main outcomes and measures The primary outcomes were co-morbidity analysis and co-morbidity rates of vitiligo with metabolic syndrome, obesity, hyperlipidemia, hypertension, and diabetes mellitus. Secondary outcomes were factors associated with vitiligo and cardiovascular disease.Results This meta-analysis concluded that comorbidities in patients with vitiligo included metabolic syndrome, diabetes, obesity, hyperlipidemia, and hypertension, with comorbidity rates of 28.3%, 6.0%, 38.5%, 43.0%, and 15.8%, respectively. Simultaneously, we showed that the vitiligo group differed significantly from the control group in the following aspects: fasting blood glucose, insulin, systolic and diastolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, homocysteine, C-reactive protein, smoking, and alcohol consumption. However, no significant differences were observed between the vitiligo and control groups in terms of waist circumference, body mass index, or phospholipid levels.Limitations The vast majority of the studies were from Eastern countries; therefore, extrapolation of these results to Western populations is questionable. The significant heterogeneity may be due to different protocols, doses, durations, center settings, population registries, etc., which severely compromise the validity of the results.Conclusion This study summarized not only the factors associated with, but also those not associated with, cardiovascular disease in patients with vitiligo. This study provides a foundation for the prevention and treatment of cardiovascular disease in patients with vitiligo.

ABSTRACTBackground Endometrial cancer is a malignant tumour with a high incidence and mortality rate, and obesity is one of the most significant risk factors for the disease. However, it remains unclear whether leptin affects cell activity, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT).Materials and methods Samples of endometrial cancer tissue were obtained from clinical patients and nude mice Enzyme-linked immunosorbent assays (ELISAs) were performed to assess leptin levels. Western blotting, immunohistochemical (IHC) and immunofluorescence (IF) analyses were conducted to detect EMT, JAK2/STAT3 signalling pathway proteins, and cell proliferation biomarkers. Cell Counting Kit-8 (CCK-8) assays, 5-ethynyl-2’-deoxyuridine (EdU) staining, and Transwell assays were used to evaluate cell activity, proliferation, migration, and invasion, respectively.Results ELISA, western blot and immunohistochemistry (IHC) analyses showed that leptin was highly expressed, and the JAK2/STAT3 signalling pathway was activated in endometrial cancer patients. Cell-based experiments showed that adipocytes secreted leptin, which increased the levels of leptin, and also promoted cell migration and invasion, EMT transition, and cell activity and proliferation. Leptin accelerated cell progression and promoted EMT via the JAK2/STAT3 signalling pathway in a dose-dependent manner. The tumour-promoting effect of leptin on endometrial cancer cells was further verified by in vivo experiments, in which leptin promoted tumour growth and activated the JAK2/STAT3 signalling pathway.Conclusion Leptin secreted by adipocytes promotes EMT transition and endometrial cancer progression via the JAK2/STAT3 signalling pathway in a dose-dependent manner.Highlights Endometrial cancer patients have high levels of leptinLeptin promotes EMT transition via the JAK2/STAT3 signalling pathwayLeptin promotes endometrial cancer progression via the JAK2/STAT3 signalling pathwayLeptin promotes endometrial cancer in a dose-dependent manner

BackgroundThe relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis.MethodsThe inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN.ResultsThe IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08–1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05–1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC–IgAN and 14 MFI–IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates.ConclusionsGenetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

Cerebral ischemia-reperfusion injury (I/RI) is one of the principal pathogenic factors in the poor prognosis of ischemic stroke, for which current therapeutic options to enhance neurological recovery are notably insufficient. Dental pulp stem cell-derived extracellular vesicles (DPSC-EVs) have promising prospects in stroke treatment and the specific underlying mechanisms have yet to be fully elucidated. The present study observed that DPSC-EVs ameliorated the degree of cerebral edema and infarct volume by reducing the apoptosis of neurons. Furthermore, the miRNA sequencing and functional enrichment analysis identified that miR-877–3p as a key component in DPSC-EVs, contributing to neuroprotection and anti-apoptotic effects. Following target prediction and dual-luciferase assay indicated that miR-877–3p interacted with Bcl-2-associated transcription factor (Bclaf1) to play a function. The miR-877–3p inhibitor or Bclaf1 overexpression reversed the neuroprotective effects of DPSC-EVs. The findings reveal a novel therapeutic pathway where miR-877–3p, transferred via DPSC-EVs, confers neuroprotection against cerebral I/RI, highlighting its potential in promoting neuronal survival and recovery post-ischemia.

Abstract Background Epithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients. Methods We retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People’s Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021. Results A total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated. Conclusions The combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma. Trial registration This study was approved in the Medical Ethics Committee of Peking University People’s Hospital on October 28, 2022 (No.: 2022PHD015-002). The study was registered in Clinicaltrials.gov with identifier no. NCT05656222.

Immune checkpoint blockade (ICB) therapy potently revives T cell's response to cancer. However, patients suffered with tumors that had inadequate infiltrated immune cells only receive limited therapeutic benefits from ICB therapy. Synthetic biology promotes the alternative strategy of harnessing tumor-targeting bacteria to synthesize therapeutics to modulate immunity in situ. Herein, we engineered attenuated Salmonella typhimurium VNP20009 with gene circuits to synthetize granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 7 (IL-7) within tumors, which recruited dendritic cells (DCs) and enhanced T cell priming to elicit anti-tumor response. The bacteria-produced GM-CSF stimulated the maturation of bone marrow-derived dendritic cells (BMDCs), while IL-7 promoted the proliferation of spleen isolated T cells and inhibited cytotoxicity T cell apoptosis in vitro. Virtually, engineered VNP20009 prefer to colonize in tumors, and inhibited tumor growth by enhancing DCs and T cell infiltration. Moreover, the tumor-toxic GZMB+ CD8+ T cell and IFN-γ+ CD8+ T cell populations conspicuously increased with the treatment of engineered bacteria. The combination of GM–CSF–IL-7-VNP20009 with PD-1 antibody synergistically stunted the tumor progress and metastasis.

Abstract Severe trauma could induce sepsis due to the loss of control of the infection, which may eventually lead to death. Accurate and timely diagnosis of sepsis with severe trauma remains challenging both for clinician and laboratory. Combinations of markers, as opposed to single ones, may improve diagnosis. We compared the diagnostic characteristics of routinely used biomarkers of sepsis alone and in combination, trying to define a biomarker panel to predict sepsis in severe patients. This prospective observational study included patients with severe trauma (Injury severity score, ISS = 16 or more) in the emergency intensive care unit (EICU) at a university hospital. Blood samples were collected and plasma levels of procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6) and serum amyloid A (SAA) were measured using commercial enzyme linked immunosorbent assay (ELISA) kits. A total of 100 patients were eligible for analysis. Of these, 52 were diagnosed with sepsis. CRP yielded the highest discriminative value followed by PCT. In multiple logistic regression, SAA, CRP, and PCT were found to be independent predictors of sepsis. Bioscore which was composed of SAA, CRP, and PCT was shown to be far superior to that of each individual biomarker taken individually. Therefore, compared with single markers, the biomarker panel of PCT, CRP, and SAA was more predictive of sepsis in severe polytrauma patients.

Abstract COVID-19 increased global mortality in 2019. Cystitis became a contributing factor in SARS-CoV-2 and COVID-19 complications. The complex molecular links between cystitis and COVID-19 are unclear. This study investigates COVID-19-associated cystitis (CAC) molecular mechanisms and drug candidates using bioinformatics and systems biology. Obtain the gene expression profiles of IC (GSE11783) and COVID-19 (GSE147507) from the Gene Expression Omnibus (GEO) database. Identified the common differentially expressed genes (DEGs) in both IC and COVID-19, and extracted a number of key genes from this group. Subsequently, conduct Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on the DEGs. Additionally, design a protein–protein interaction (PPI) network, a transcription factor gene regulatory network, a TF miRNA regulatory network, and a gene disease association network using the DEGs. Identify and extract hub genes from the PPI network. Then construct Nomogram diagnostic prediction models based on the hub genes. The DSigDB database was used to forecast many potential molecular medicines that are associated with common DEGs. Assess the precision of hub genes and Nomogram models in diagnosing IC and COVID-19 by employing Receiver Operating Characteristic (ROC) curves. The IC dataset (GSE57560) and the COVID-19 dataset (GSE171110) were selected to validate the models' diagnostic accuracy. A grand total of 198 DEGs that overlapped were found and chosen for further research. FCER1G, ITGAM, LCP2, LILRB2, MNDA, SPI1, and TYROBP were screened as the hub genes. The Nomogram model, built using the seven hub genes, demonstrates significant utility as a diagnostic prediction model for both IC and COVID-19. Multiple potential molecular medicines associated with common DEGs have been discovered. These pathways, hub genes, and models may provide new perspectives for future research into mechanisms and guide personalised and effective therapeutics for IC patients infected with COVID-19.

The efficiency of AlGaInP micro light-emitting diodes (micro-LEDs) was far weaker than that of GaN-based micro-LEDs in structure and performance. Consequently, there was an urgent demand to enhance their efficiency. In this study, a citric acid treatment strategy is proposed to improve the efficiency of red micro-LEDs, and the etching uniformity of different concentrations was first confirmed. We optimized the concentration of citric acid to 1:1 and modulated the wet etching time at 0, 30, 60, 90, and 120 s to treat the sidewalls of devices. Under an injection current density of 68 nA/cm2, the forward voltage (Vf) of micro-LEDs after soaking in citric acid ranged from 1.40 to 1.45 V. Compared with the sample operated at the forward voltage without citric acid sidewall treatment, AlGaInP micro-LEDs displayed significantly enhanced forward voltage. This indicates that citric acid effectively removed N-GaAs without damaging the electrical properties of the devices. Among all citric acid-treated micro-LEDs, the sample with a 60 s wet etching process showed the best improvement, with the light output power and external quantum efficiency (EQE) increased by 31.08% and 5.4%, respectively. Our proposed method to treat AlGaInP micro-LEDs presents promising opportunities for the future development of high-performance optoelectronics.

The zirconium alloy cladding of PWR fuel rods which undergo high neutron irradiation during service, will cause significant changes in its microstructure, thereby affecting its macroscopic performance. Therefore, the study of neutron irradiation behavior of zirconium alloy cladding is a focus of nuclear field. However, due to the strong radioactivity of materials after neutron irradiation, relevant experiments must be conducted in a hot cell. Therefore, research on the microstructure of irradiated fuel cladding is a difficult task. In this study, the microstructure of M5TM zirconium alloy cladding material after neutron irradiation was studied by means of transmission electron microscope in the hot cell facility of China Institute of Atomic Energy. The samples were from commercial pressurized water reactor AFA3G type spent fuel rods with burnup of 14 GW·d/tU and 41 GW·d/tU, respectively. A cladding sample with a length of about 10 mm from the fuel rod was cut, and the defueling and chemical cleaning in the hot cell were carried out to obtain a clean cladding sample. Then, mechanical sampling methods was used to prepare a thin slice sample of the cladding with 3 mm diameter. Finally, the electrolytic twin-jet thinning method was used to prepare the cladding transmission electron microscopy observation and analysis sample. In addition, to compare the structural changes of zirconium alloy cladding before and after irradiation, the same method was used to prepare un-irradiated observation and analysis samples of the same material. The observation and analysis results of the un-irradiated and irradiated samples reveal that there are native second phase particles (SPPs) inside the matrix structure of the un-irradiated zirconium alloy cladding, and the overall interior of the matrix is with few nano precipitates and no obvious dislocation structure observed. After irradiation, there is no significant difference in the size and distribution of the native SPPs in the matrix compared to the un-irradiated sample, but significant nano precipitates and high-density dislocation structures appear. As the fuel burnup increases, the size of nano precipitates increases. The similarity of dislocation structures between low and high burnup samples indicates that under the burnup of 14 GW·d/tU, the dislocation structures generated by irradiation in the zirconium alloy cladding basically reach saturation state. The results of selected area electron diffraction (SAED) indicate that although there are some amorphous structures in the native SPPs in the matrix after irradiation, the bcc crystal structure is still the main structure, indicating that the SPPs maintain certain irradiation stability at the burnup of 41 GW·d/tU. In addition, the EDS results of the SPPs indicate that with the increase of fuel burnup, the content of Nb element tends to be depleted. Analysis suggests that after neutron irradiation, the Nb atoms in the SPPs of zirconium alloy expand into the Zr matrix, promoting the precipitation of Nb elements in the form of nano Nb rich phases in the Zr matrix.

AbstractAureoboletus raphanaceus is a member of boletoid mushroom, which is named after its distinctive radish smell. The mitochondrial genome and phylogenetic relationships with other boletes need to be investigated to gain a comprehensive understanding of it. In this study, we sequenced the mitochondrial genome of A. raphanaceus using next-generation sequencing technology and found that its mitochondrial genome is a circular DNA molecule measuring 42,157 bp. It consists of 15 core protein-coding genes, 27 transfer RNA genes, and two ribosomal RNA genes. The mitochondrial genome had a base composition of A (39.89%), C (11.06%), G (11.67%), and T (37.38%), with a GC content of 22.73%. A phylogenetic tree based on 22 mitochondrial genomes was constructed, which provided the first insights into the phylogenetic relationships of this species with related boletes.