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Abstract The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi proteins as a monomer or dimer, the dynamic regulation within the APJR dimer during activation remains poorly understood. In this study, we present the structures of the APJR dimer and monomer complexed with its endogenous ligand apelin-13. In the dimeric structure, apelin-13 binds exclusively to one protomer that is coupled with Gi proteins, revealing a distinct ligand-binding behavior within APJR homodimers. Furthermore, binding of an antagonistic antibody induces a more compact dimerization by engaging both protomers. Notably, structural analyses of the APJR dimer complexed with an agonistic antibody, with or without Gi proteins, suggest that G protein coupling may promote the dissociation of the APJR dimer during activation. These findings underscore the intricate interplay between ligands, dimerization, and G protein coupling in regulating APJR signaling pathways.

Abstract Mechanical testing with sub-sized specimens plays an important role in the nuclear industry, facilitating tests in confined experimental spaces with lower irradiation levels and accelerating the qualification of new materials. The reduced size of specimens results in different material behavior at the microscale, mesoscale, and macroscale, in comparison to standard-sized specimens, which is referred to as the “specimen size effect.” Although analytical models have been proposed to correlate the properties of sub-sized specimens to standard-sized specimens, these models lack broad applicability across different materials and testing conditions. The objective of this study is to create the first large public dataset of tensile properties for sub-sized specimens used in nuclear structural materials. We performed an extensive literature review of relevant publications and extracted over 1,000 tensile testing records comprising 55 columns including material type and composition, manufacturing information, irradiation conditions, specimen dimensions, and tensile properties. The dataset can serve as a valuable resource to investigate the specimen size effect and develop computational methods to correlate the tensile properties of sub-sized specimens.

The differential settlement of subgrade, which is an important problem in the operation of high-speed railway. In order to study the effects of subgrade differential settlement on the service performance of CRTS II slab track and the stability of train operation, a vehicle–slab track–subgrade system coupling dynamic model was established. The concrete damage of track structure was considered based on damage mechanics theory. Dynamic simulations were carried out using the proposed model. The results show that the subgrade differential settlement will increase the dynamic response of the vehicle system. The dynamic response of the vehicle system is positively correlated with the settlement amplitude. The acceleration of vehicle body and the rate of wheel load reduction are sensitive to the subgrade settlement within the settlement wavelength ranging from 10 m to 20 m. Under the subgrade differential settlement and the dynamic action of the vehicles, concrete damage occurs earlier in the supporting layer and the concrete damage variable of the supporting layer is larger compared to the precast slab.

Abstract Background Diabetes mellitus (DM) can cause severe complications, including diabetic foot ulcers (DFU). There is a significant gap in understanding the single-cell ecological atlas of DM and DFU tissues. Methods Single-cell RNA sequencing data were used to create a detailed single-cell ecological landscape of DM and DFU. Enrichment analysis identified pathways involved in cellular subpopulations, and pseudo-time analysis inferred cell development processes. A gene regulatory network explored the role of transcription factors in DFU progression, and a potential herbal drug-target gene interaction network was constructed. Results In the DFU group, immune cells were activated, with notable changes in several subpopulations. ATP5E was significantly overexpressed in Naive T cells, fibroblasts, endothelial cells, and CD8+ T cells in DM patients. Specific immune cell subsets, such as Naive T_RGCC, CTL_TYROBP_CL4, Mac_SLC40A1, and M1_CCL3L1, likely contribute to DFU formation through overactivation and proliferation, leading to tissue damage and ulcer exacerbation. Key genes TPP1, TLR4, and RIPK2 were identified, and 88 active ingredients in the herbal drug-target network showed strong correlations with these targets. Herbs like Angelica dahurica, Angelica sinensis, Boswellia carterii, liquorice, myrrh, and Semen armeniacae amarae were included. Conclusions This study offers insights into DM and DFU cytology. T cells in DFU are activated, attacking normal tissues and worsening tissue damage. The ATP5E gene may be related to the ecological remodeling of DM, and TPP1, TLR4, and RIPK2 are potential targets for DFU treatment.

Abstract Background Osteosarcoma (OS), the most prevalent primary malignant bone tumor in children and adolescents, arises from bone-forming mesenchymal cells. Despite advancements in surgical resection and neoadjuvant chemotherapy (cisplatin, doxorubicin, and methotrexate), chemotherapy resistance remains a significant challenge, leading to poor survival rates in patients with metastatic or recurrent OS. Methods In this study, we focused on the role of OTULIN, a key linear deubiquitinating enzyme, in OS chemoresistance. In addition, mechanistic investigations were carried out to identify potential downstream targets of OTULIN involved in cisplatin resistance. Results Our results demonstrated that OTULIN expression was significantly upregulated in OS tissues and cell lines following cisplatin treatment but not in response to doxorubicin or methotrexate. High OTULIN expression was associated with reduced survival in sarcoma patients. Furthermore, immunohistochemical analysis of prechemotherapy and postchemotherapy OS tissues revealed increased OTULIN expression in postchemotherapy samples. In vitro results demonstrated that OTULIN plays a critical role in mediating cisplatin resistance in OS. Mechanistically, GPX4 could be a downstream target of OTULIN, conferring cisplatin resistance to OS by blocking the mitochondrial apoptotic pathway but not ferroptosis. Specifically, OTULIN prevents the proteasomal degradation of GPX4 by reducing its ubiquitin level, thereby conferring resistance to cisplatin in OS cells. Conclusion This study highlights the importance of OTULIN in OS chemoresistance and provides a promising approach for targeting the OTULIN-GPX4 axis to improve the prognosis of OS patients. Our findings offer new insights into the molecular mechanisms underlying OS chemoresistance and suggest potential therapeutic targets for future clinical interventions.

Abstract This study focuses on the active earth pressure distribution of finite soil masses in urban proximity engineering, with a specific emphasis on nonlimit conditions. Through laboratory model tests, the relationship between the nonlimit earth pressure and displacement of the finite soil mass is investigated. Furthermore, the distribution law of the nonlimit earth pressure is explored, considering the influence of the existing structure, proximity distance, and soil cover thickness of the existing structure on the nonlimit earth pressure distribution within the finite soil mass. The findings indicate the following: (1) the distribution of the nonlimit active earth pressure along the depth of the retaining walls is nonlinear, exhibiting an initial increase, followed by a decrease near the bottom of the existing structure and then another decrease after an initial increase; (2) the nonlimit active earth pressure and ultimate active earth pressure of semi-infinite soil are greater than those of finite soil; (3) as the proximity distance increases, the nonlimit active earth pressure of finite soil gradually increases, and the rate of decrease in earth pressure at the existing structure floor decreases; (4) with increasing soil cover thickness of the existing structure, the nonlimit active earth pressure and ultimate active earth pressure of finite soil gradually increase, and the position of change along the depth of the retaining walls initially increases, then decreases, and finally continues to increase with increasing depth. The aforementioned research offers a foundation for determining the appropriate finite soil pressure in proximity engineering.

Abstract Background Cancer survivors face elevated risks of heart failure (HF) and death, with cardiac dysfunction being a significant concern. Current evaluations often emphasize systolic function while insufficiently addressing diastolic function. This study aims to investigate the prevalence of diastolic dysfunction and assess its prognostic implications in long-term cancer survivors. Methods We analyzed participants from the Atherosclerosis Risk in Communities (ARIC) Study with complete echocardiographic assessments and documented cancer histories. Diastolic function was classified by guideline criteria: normal (≤ 1 abnormal parameter), indeterminate (2 abnormal parameters), and dysfunction (≥ 3 abnormal parameters). The primary outcomes were incident HF and all-cause death. Diastolic dysfunction prevalence was compared between cancer survivors and non-cancer participants after propensity score matching. Cox regression, Kaplan–Meier, and restricted cubic spline (RCS) analyses were used to assess associated risks. Results A total of 5322 participants were included, with 18.4% (N = 979) being cancer survivors. The mean age of cancer survivors at echocardiography was 76.3 (5.10) years, with a median of 12.17 years since diagnosis. There were no significant differences in diastolic dysfunction prevalence (12.26% vs 10.73%, P = 0.29) after matching. Cox regression revealed a graded association between diastolic dysfunction and risks of HF and death. Fully adjusted hazard ratios were 2.59 (95% CI: 1.59–4.20, P

Abstract Background Sorafenib is a standard therapeutic agent for advanced hepatocellular carcinoma (HCC). However, its efficacy is moderate, as the survival of patients is prolonged for only a few months, and the response rate is low. The mechanism of low efficacy remains unclear. In this study, we investigated the effect of Toll-like receptor 3 (TLR3) on the effects of sorafenib on HCC. Methods Polyinosinic-polycytidylic acid [poly(I: C)] was used as a double-stranded RNA analog and TLR3 agonist in subsequent experiments. After orthotopic implantation of HCC tumors in BALBc nu/nu or C57BL/6 mice, survival time, tumor growth, and metastasis in the abdomen and lungs were analyzed. Flow cytometry and cytotoxicity assays were used to analyze NK cells isolated from the spleen or peripheral blood. ELISA was used to detect the expression of plasma interferon (IFN)-γ and monocyte chemoattractant protein (MCP)-1. In addition, the expression of phosphorylated-extracellular regulated kinase 1/2 (pERK1/2), phosphorylated-protein kinase B (pAKT), ERK1/2 and AKT was analyzed by Western blotting. Results Sorafenib reduced the number and activity of NK cells in tumor-bearing mice and simultaneously decreased the levels of MCP-1 and IFN-γ in the plasma. The combination of sorafenib and poly(I: C) synergistically inhibited tumor growth and metastasis in tumor xenograft mice and prolonged survival. Poly(I: C) not only exerts a direct inhibitory effect on tumor growth and metastasis by targeting the TLR3 receptor on tumor cells but also facilitates the proliferation and activation of NK cells, indirectly impeding tumor progression. Mechanistically, poly(I: C) decreased the sorafenib-induced inhibition of ERK phosphorylation and increased the phosphorylation of IκB in NK cells, thereby enhancing NK cell function. Conclusion Activation of TLR3 can enhance the antitumor effect of sorafenib on HCC. The combination of a TLR3 activator and sorafenib may be a new strategy for the treatment of HCC.

Abstract Gas-insulated switchgear (GIS) employs sulfur hexafluoride (SF6) as an insulating medium to shield electrical gadget. However, SF6 can decompose under sure situations, generating dangerous sulfur-based totally compounds which include SO2, SOF2, and SO2F2. These byproducts pose enormous dangers to both protection and environmental integrity. Efficiently adsorbing and disposing of those compounds is critical for ensuring operational reliability and reducing environmental dangers. This study investigates the adsorption and degradation mechanisms of SF₆ decomposition compounds (SO₂, SOF₂, and SO₂F₂) on boron nitride nanocones (BNNCs) using density functional theory (DFT) and ab initio molecular dynamics (AIMD) simulations. Our comprehensive analysis covers five distinct systems, exploring individual and combined adsorption scenarios. The findings reveal that the apex of BNNCs plays a crucial role in the adsorption process, showing high efficiency in adsorbing SO₂ (adsorption energy − 1.22 eV) and facilitating the catalytic breakdown of SOF₂ (adsorption energy − 1.57 eV). The positively charged potential at the nanocone’s apex significantly influences the dissociation and subsequent adsorption of fluorine atoms, with an energy barrier for F dissociation at the apex (1.8 kcal/mol) much lower than at the sidewall (5.3 kcal/mol). In gas mixtures, SO₂ preferentially binds to the apex region of BNNCs, with a bond length of approximately 1.38 Å. BNNCs demonstrate superior adsorption capabilities for SO₂ and SOF₂ compared to other boron nitride nanostructures, with adsorption energies up to 89% higher. The electron transfer analysis reveals that BNNC complexes act as potent electron donors, particularly in the case of BNNC@3SO₂F₂. Additionally, BNNCs show significant potential as sensors for detecting SO₂F₂, with a rapid recovery time of 4.67 ps and a notable decrease in the Fermi level energy to -4.97 eV upon adsorption. The study also provides insights into the angular distribution and charge density difference profiles, offering a detailed understanding of the adsorption mechanisms. These findings have important implications for improving the safety and efficiency of gas-insulated switchgear (GIS) and contribute to the development of more effective environmental protection solutions in electrical power systems.

Turbot (Scophthalmus maximus) is one of the most economically important fish in the northern coastal areas of China. Recently, low salinity stress is an important factor influencing the development of the turbot industry. Lately, the industry has faced challenges posed by low salinity stress, a key factor influencing turbot development. Salinity fluctuations represent a crucial environmental stressor in aquaculture, impacting osmotic pressure and inducing abnormal energy metabolism. Our preliminary research had identified that low salinity stress contributes to lipid metabolism disorders in turbot. This study aims to investigate the impact of varying lipid concentration levels on the lipid metabolism disorders induced by low salinity stress. To achieve this, feeding experiments were conducted with different lipid concentration levels under low salinity stress conditions, determining the optimal lipid requirement for turbot to cope with reduced salinity. Three salinity gradients (10, 20, and 30) were employed, with four lipid concentration gradients (8%, 12%, 16%, and 20%) for each salinity group. The results revealed that at a lipid concentration of 16%, no significant difference in the growth performance of juvenile turbot was observed between the salinities of 20 and 30. However, the growth performance under a salinity of 10 was lower than that under salinities of 20 and 30. Notably, under a salinity of 10, the growth performance of juvenile turbot increased with higher lipid concentrations, reaching its peak at 20%, surpassing values under the salinities of 20 and 30. Regarding the expression of genes related to lipid metabolism, under the salinities of 10 and 20, the expression levels of genes related to lipid synthesis, lxrα, cyp7a1, and srebp-1, showed a trend of first increasing and then decreasing with increasing lipid concentration, particularly under the salinity of 10. The expression level of the 12% lipid group was higher than that of other groups and the expression level of the 20% lipid group was significantly lower than that of other groups (P < 0.05). In addition, under a salinity of 10, the expression levels of acc and fas also showed a similar situation. They were both suppressed in the 20% lipid group, and the expression levels were higher in the 12% lipid group. The expression level of the gene apoa-IV related to lipid absorption in the 20% lipid group under a salinity of 10 was markedly higher than that in other groups under the same salinity conditions (P < 0.05) and it showed a change with salt under the condition of 20% lipid concentration. The increasing and decreasing trends were contrary to the trends in other lipid groups. The aforementioned results show that after low-salt stress affects lipid metabolism, feeds with different lipid concentrations can alleviate the adverse effects of the stress from the perspectives of lipid synthesis and lipid absorption, and this mitigation effect is more reflected at the level of lipid absorption, thereby improving growth performance under low salt stress. The results reveal the adaptability of fish to low salt from the perspective of salinity affecting lipid metabolism, enrich the concentration of fish stress physiology, and provide theoretical and technical support for the breeding of low-salt tolerant turbot varieties.

Abstract Background Factor XII (FXII or F12) deficiency is a rare inherited disorder, typically lacking haemorrhagic symptoms. There is limited literature exists on FXII deficiency and mutations within the Chinese population. This study aimed to characterize the spectrum of F12 gene mutations in a Chinese cohort and to investigate the relationship between FXII mutations and clinical phenotypes. Methods Genetic and clinical data from 51 unrelated probands with FXII deficiency, along with their families, were meticulously collected and analysed. Results Genetic analysis revealed that 94.1% of probands carried genetic defects, with 29 mutations pinpointed in the F12 gene. Of these, 18 mutations were previously reported for the first time by our research group, including c.303_304delCA, c.1078G > A, c.1285 C > T, among others. Of the mutations, 17 are missense, constituting 58.6% of the total. Additionally, 11 are deletions or insertions, of which 8 result in frameshifts, while the remaining one is a nonsense mutation. These mutations were predominantly concentrated in two crucial regions: the catalytic domain and the kringle domain. The most frequently observed mutations were c.1681G > A, closely followed by c.1561G > A and c.1078G > A, indicating a dominance among these mutations. Additionally, a prevalent polymorphism at position 46 was observed in the majority of probands, with 47.1% having the 46T/T genotype and 13.7% having the 46 C/T genotype, which may potentially impact FXII activity. The broad spectrum of asymptomatic FXII deficiency observed within the Han population of East China. Conclusions We speculate on the potential impact of recurrent mutations on the efficacy of new drugs being developed to target FXII for thrombosis prevention and treatment. Furthermore, it is important to explore their influence on FXII-related pathways beyond the activation of the contact pathway in the coagulation cascade.

Abstract Background Brain microglia and infiltrating monocyte-derived macrophages are vital in preserving blood vessel integrity after stroke. Understanding mechanisms that induce immune cells to adopt vascular-protective phenotypes may hasten the development of stroke treatments. IL-33 is a potent chemokine released from damaged cells, such as CNS glia after stroke. The activation of IL-33/ST2 signaling has been shown to promote neuronal viability and white matter integrity after ischemic stroke. The impact of IL-33/ST2 on blood-brain barrier (BBB) integrity, however, remains unknown. The current study fills this gap and reveals a critical role of IL-33/ST2 signaling in macrophage-mediated BBB protection after stroke. Methods Transient middle cerebral artery occlusion (tMCAO) was performed to induce ischemic stroke in wildtype (WT) versus ST2 knockout (KO) male mice. IL-33 was applied intranasally to tMCAO mice with or without dietary PLX5622 to deplete microglia/macrophages. ST2 KO versus WT bone marrow or macrophage cell transplantations were used to test the involvement of ST2+ macrophages in BBB integrity. Macrophages were cocultured in transwells with brain endothelial cells (ECs) after oxygen-glucose deprivation (OGD) to test potential direct effects of IL33-treated macrophages on the BBB in vitro. Results The ST2 receptor was expressed in brain ECs, microglia, and infiltrating macrophages. Global KO of ST2 led to more IgG extravasation and loss of ZO-1 in cerebral microvessels 3 days post-tMCAO. Intranasal IL-33 administration reduced BBB leakage and infarct severity in microglia/macrophage competent mice, but not in microglia/macrophage depleted mice. Worse BBB injury was observed after tMCAO in chimeric WT mice reconstituted with ST2 KO bone marrow, and in WT mice whose monocytes were replaced by ST2 KO monocytes. Macrophages treated with IL-33 reduced in vitro barrier leakage and maintained tight junction integrity after OGD. In contrast, IL-33 exerted minimal direct effects on the endothelial barrier in the absence of macrophages. IL-33-treated macrophages demonstrated transcriptional upregulation of an array of protective factors, suggesting a shift towards favorable phenotypes. Conclusion Our results demonstrate that early-stage IL-33/ST2 signaling in infiltrating macrophages reduces the extent of acute BBB disruption after stroke. Intranasal IL-33 administration may represent a new strategy to reduce BBB leakage and infarct severity.

Abstract WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.

Abstract Background Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC. Patients and methods This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 − mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 − subtype. The median treatment was 6 cycles (range, 2 − 8 cycles). In the full cohort, TNBC, and HR + HER2 − subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed. Conclusion ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.

Abstract Background Heart failure is a disease that threatens global public safety. In recent years, the obesity paradox has been studied in cardiovascular disease and other fields. With the progress of aging, metabolic changes and regulation of fat function, it also provides many bridges for the dialogue between disease and molecular metabolism. The purpose of this study is to investigate the effect of obesity on the outcome of adult intensive care patients with heart failure combined with age factors. Method Data were derived from the fourth-generation Medical Information Marketplace for Intensive Care (MIMIC-IV version2.1) using structured query language on the Navicat (12.0.11) platform. People were divided into two groups based on the body mass index (BMI), one group with BMI ≥ 30 kg/m² and another group with BMI

Abstract Not all patients with glioblastoma multiforme (GBM) eligible for systemic chemotherapy after upfront surgery and radiotherapy finally receive it. The information on patients with GBM was retrieved from the surveillance, epidemiology, and end results database. Patients who underwent upfront surgery or biopsy and external beam radiotherapy between 2010 and 2019 were eligible for systemic chemotherapy. The available patient and tumor characteristics were assessed using multivariable logistic regression and chi-squared test. Out of the 16,682 patients eligible, 92.1% underwent systemic chemotherapy. The characteristics linked to the lowest systemic chemotherapy utilization included tumors of the brain stem/cerebellum (P = 0.01), former years of diagnosis (P = 0.001), ≥ 80 years of age (P

Abstract Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash (n = 1), neutropenia (n = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC.

Abstract Background Pig organ xenotransplantation is a potential solution for the severe organ shortage in clinic, while immunogenic genes need to be eliminated to improve the immune compatibility between humans and pigs. Current knockout strategies are mainly aimed at the genes causing hyperacute immune rejection (HAR) that occurs in the first few hours while adaptive immune reactions orchestrated by CD4 T cell thereafter also cause graft failure, in which process the MHC II molecule plays critical roles. Methods Thus, we generate a 4‐gene (GGTA1, CMAH, β4GalNT2, and CIITA) knockout pig by CRISPR/Cas9 and somatic cell nuclear transfer to compromise HAR and CD4 T cell reactions simultaneously. Results We successfully obtained 4KO piglets with deficiency in all alleles of genes, and at cellular and tissue levels. Additionally, the safety of our animals after gene editing was verified by using whole‐genome sequencing and karyotyping. Piglets have survived for more than one year in the barrier, and also survived for more than 3 months in the conventional environment, suggesting that the piglets without MHC II can be raised in the barrier and then gradually mated in the conventional environment. Conclusions 4KO piglets have lower immunogenicity, are safe in genomic level, and are easier to breed than the model with both MHC I and II deletion.

ObjectiveCompare the prediction effects of the seasonal autoregressive integrated moving average (SARIMA), exponential smoothing (ETS), trigonometric box-cox transform, ARMA residuals, trend, and seasonal components (TBATS), and neural network autoregressive (NNAR) time series models on mumps incidence rate in Jiangxi province, to provide a reference for mumps prevention and control. MethodsMumps case and incidence rate data reported in Jiangxi province from January 1, 2010 to December 31, 2019 were collected from the China Disease Prevention and Control Information System. The reported mumps incidence rates from January 2010 to December 2018 were used as the training set, and SARIMA, ETS, TBATS, and NNAR models were constructed using R 4.1.2 software to predict the mumps incidence rates from January to December 2019. Root mean squared error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) were used to compare the fitting and prediction effects of the four models. ResultsThe reported mumps incidence rates in Jiangxi province in 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, and 2019 were 20.49/100 000, 32.03/100 000, 31.89/100 000, 19.95/100 000, 12.22/100 000, 14.10/100 000, 16.56/100 000, 16.21/100 000, 14.29/100 000, and 21.14/100 000, respectively, with an average annual reported incidence rate of 19.84/100 000 from 2010 to 2019. Mumps incidence in Jiangxi province showed obvious seasonality, with the main peak from April to July and a secondary peak from November to January of the following year. The fitted values of the four models showed consistent trends with the actual values. Except for the high MAPE (32.01%) of the SARIMA model, the MAPEs of the other three models were all < 15%, with the NNAR model having fitted values closer to the actual values and the lowest RMSE, MAE, and MAPE of 0.20, 0.14, and 8.24%, respectively. Except for the SARIMA model, the predicted value trends of the other three models were consistent with the actual values, and their MAPEs were all < 15%, with the TBATS and ETS models having the best prediction effects. ConclusionThe ETS, TBATS, and NNAR models have good fitting and prediction effects on mumps incidence rates in Jiangxi province, and the prediction results can provide theoretical guidance for mumps prevention and control in the region.

River ecosystems are vital for maintaining ecosystem balance but rapid development in China’s Yangtze River Basin has led to severe ecological degradation. Therefore, this study aimed to evaluate the aquatic ecosystem health of the Jialing River Basin, investigate the influencing factors of the aquatic ecology, and predict the succession trend of the phytoplankton community. Phytoplankton was collected in the Jialing River (Nanchong section) and one of its tributaries (Xichong River). Morphological identification methods, random forest, neutral community model, and modified stochasticity ratio were used to analyze phytoplankton composition, environmental drivers, and community assembly mechanisms. The results showed that 1) Bacillariophyta, Cryptophyta, and Chlorophyta were the dominant phyla in the Jialing River, followed by Cyanobacteria. The structure of the phytoplankton community was affected by seasonal changes and differences in the tributary and mainstem. 2) Overall, the autumn phytoplankton community α-diversity index was significantly higher than that of spring (P

Co-exposure to ground-level ozone (O3) and fine particles (PM2.5, ≤ 2.5 µm in diameter) has become a primary scenario for air pollution exposure of urbanites in China. Recent studies have suggested a synergistic effect of PM2.5 and O3 on induction of lung inflammatory injury. However, the underlying mechanisms for respiratory toxicity induced by this co-exposure have not been adequately elucidated. In this study, a realistic exposure was based to set up the co-exposure condition of an animal model. Specifically, eighty male C57BL/6 mice (10 months old) were randomly divided into four groups: control, O3, PM2.5 and co-exposure (O3 + PM2.5). Mice in the co-exposure group breathed O3 and orally inhaled PM2.5 suspension. The scenario for O3 exposure was 0.6 ppm, 4 h/d, for 30 consecutive days while that for PM2.5 exposure was oral inhalation of PM2.5 suspension (5.6 mg/kg bw) once every other day and 4 h prior to O3 exposure. After last exposure, bronchoalveolar lavage fluids (BALF) were collected for inflammatory biomarker measurement, 16S rRNA sequencing and metabolite profiling. Lung tissues were processed for histological examination. The results demonstrated that co-exposure to O3 and PM2.5 exacerbated the pathological changes and inflammatory response induced by O3 or PM2.5. Further studies revealed that co-exposure to O3 and PM2.5 increased the abundance of Prevotella in the airways and caused more severe metabolic disorders compared to O3 or PM2.5 exposure. Spearman correlation analysis demonstrated correlations among airway microbiota dysbiosis, metabolic disorder, inflammation, and pathological alterations induced by co-exposure to O3 and PM2.5. In summary, co-exposure to O3 and PM2.5 worsens airway inflammatory injury, possibly through interrelated airway microbiota dysbiosis and metabolic disorder.

Background: Recent research suggests that the emerging neutrophil-albumin ratio (NAR) has a significant correlation with the survival outcomes across a range of tumors, yet its predictive significance for nasopharyngeal carcinoma (NPC) remains insufficiently investigated. This study aimed to evaluate the relationship between the neutrophil-to-albumin ratio (NAR) and overall survival (OS) in patients with NPC, as well as to develop a corresponding prognostic model. Methods: This retrospective analysis included 861 NPC patients treated with concurrent chemoradiotherapy (CCRT), who were randomly divided into a training group (n = 605) and a validation group (n = 256). To identify factors associated with OS and construct a prognostic nomogram, both univariate and multivariate Cox regression analyses were performed. The nomogram's prognostic accuracy was evaluated and independently validated. Results: The NAR score successfully segregated NPC patients into two categories with significantly different OS (HR = 0.536; 95 % CI: 0.296–0.972, P = 0.040). Through multivariate analysis, factors such as age, T stage, N stage, and NAR score were identified as independent predictors of OS, leading to the creation of a prognostic nomogram. This nomogram demonstrated superior predictive capability for OS [C-index = 0.702 (95 % CI: 0.636–0.768)], surpassing that of the conventional staging system [C-index = 0.651 (95 % CI: 0.549–0.752)]. The findings underwent internal validation within an independent cohort. Conclusions: The NAR, an emergent biomarker combining nutritional and inflammatory status, offers a practical, low-cost, and non-invasive prognostic measure for NPC patients treated with CCRT. Additionally, the prognostic nomogram derived from NAR surpasses traditional staging systems in predictive accuracy.

Due to the codon bias of different species, codon optimization is usually carried out in the process of heterologous protein expression. At present, there are a variety of codon optimization tools. However, the optimized sequences may still have high or low points of local guanine and cytosine (GC) content, which is not conducive to the primer design of gene subcloning, and also makes it difficult to perform the experiment of synthesizing the whole gene with DNA fragments by polymerase chain reaction (PCR) reaction. In this study, we present a stand-alone software written in Python, with which users can manually check and adjust the GC content of sequence-optimized genes. The software takes the codon frequency of Escherichia coli as default and can work with other species as well. It provides a Graphical User Interface (GUI) interface, which allows users to change codons and intuitively see the effect of codon changes on local GC content. Our program brings convenience for the optimization of gene GC content and the subsequent gene cloning experiments.

In this paper, we report a novel method for enhancing the flame retardancy of wood-based paper by utilizing natural biomaterials. The research constructed a bilayered structure coating on paper fiber surfaces, incorporating mixed starch (MS), adenosine triphosphate (ATP), and phytic acid (PA) as natural bio-based flame retardants. The structural configuration of the coating comprises MS/ATP and MS/PA, which were sequentially assembled as bottom and top parts, respectively, through pneumatic spraying. The surface morphological features and elemental distribution analysis of treated paper indicated that bio-materials were successfully assembled, which resulted in a uniform flame retardant coating on the paper fiber surface. Compared to the untreated paper, the limiting oxygen index of 20 bilayers (BL) treated paper increased substantially from 19.07% to 24.00%, and the thermogravimetric analysis showed out the residual char yield enhanced from 23.80% to 38.10% under nitrogen atmosphere. The cone calorimeter test results of 20 BL treated paper have approximately a 50.00% reduction than the untreated paper in both peak and total heat release rates. During thermal exposure, the top and bottom parts of the bilayered structure coating are successively flame retarded prior to paper fiber degrading. The method presented in this paper provides an environmentally sustainable approach for producing flame retardant wood-based paper.

Using CO2-derived dimethyl carbonate (DMC) instead of diphenyl carbonate (DPC) as a carbonyl source for synthesizing bio-based polycarbonates is a green and cost-effective route. However, the synthesis of high-performance polycarbonates via the DMC route remains challenging due to the poor reactivity and selectivity of DMC compared to DPC. Herein, we designed a series of highly active protic ionic liquid (PIL) catalysts for the synthesis of poly(isosorbide carbonate) (PIC) from DMC with ISB. The influences of the structures of anion and cation on the catalytic activity of PILs were systematically studied. Compared with the reported aprotic IL catalysts, the unique reactive hydrogen of the cation in PILs could form a strong hydrogen bond interaction with the carbonyl group of DMC, resulting in higher reactivity of the carbonyl carbon of DMC. Moreover, the nucleophilicity of the anion could be easily tuned by adjusting the pKa value, which effectively realized the balance of the reactivity difference between exo-OH and endo-OH in ISB. Among them, [DBUH][Im] showed the highest catalytic activity, and the weight-average molecular weight (Mw) and glass transition temperature of PIC reached 55,700 g/mol and 160 °C, respectively. Combined with NMR analyses and DFT calculations, the mechanism that exhibited the synergetic catalytic effect of anion-cation for the polymerization of DMC and ISB was presented.

Purpose: The limited understanding of long-term estradiol (E2) suppression poses challenges to the effectiveness of adjuvant therapy with aromatase inhibitors (AI), necessitating comprehensive serum E2 monitoring to address this issue. Therefore, our objective was to investigate serum E2 levels in women undergoing adjuvant AI treatment and evaluate the significance of such monitoring. Patients and methods: In this prospective cohort study, we recruited women who had received adjuvant AI treatment, including those who underwent ovarian function suppression (OFS). Serum E2 levels were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary endpoint was the proportion of women with E2 levels exceeding 2.72 pg/mL, indicating inadequate suppression achieved with AI therapy. Results: A total of 706 patients were enrolled, including 482 women with OFS in combination with AI. Among them, 116 women (16.4 %) exhibited E2 levels exceeding 2.72 pg/mL. The majority of serum E2 elevations (77.6 %) occurred within the first two years of initiating endocrine therapy. Younger age, no prior chemotherapy, shorter duration of the current treatment regimen, and lower follicle stimulating hormone (FSH) levels were associated with inadequate E2 suppression. Serum E2 concentrations demonstrated dynamic variations and occasional rebound following adjuvant AI therapy. Conclusions: Despite receiving adjuvant AI treatment for nearly two years, a certain proportion of patients failed to achieve the adequate threshold of E2 suppression. Our findings emphasize the significance of monitoring serum E2 levels during adjuvant AI therapy, particularly within the first two years. Further research is imperative to facilitate a more comprehensive comprehension of E2 monitoring.

The dynamic performance of three slab ballastless tracks in the China Railway Track System (CRTS), which is supported by a simply supported box girder under various train loads, were comprehensively investigated with refined rigid-flexible coupled models. A refined rigid-flexible coupled model of vehicle-multi layer track-bridge system was developed to investigate the dynamic performance of three various CRTS slab tracks (i.e., CRTS I, II, III) under various conditions of train models, speeds and loads, respectively. The numerical analysis was conducted by using the combination of ANSYS and Universal Mechanism. It shows that the developed refined model has the capability of simulating the vehicle-slab track-bridge interaction with consideration multi-layer track structures, and the model predictions agree reasonably well with the experimentally measured wheel load reduction rate, lateral displacement and lateral acceleration of the bridge under different train speeds. The parameters of derailment system, vertical and lateral acceleration, the wheel-rail contact force, and Sperling index gradually become larger with the increase of the train speed, especially when the speed increases to 350 km/h. In addition, there is a significant increase in vertical wheel-rail contact force while a decrease in Sperling index when the train with full load capacity. Furthermore, the CRTS III slab track has demonstrated a better dynamic performance of track and bridge structures in comparison to CRTS I and CRTS II slab ballastless tracks.

Background Ovarian clear cell carcinoma (OCCC) is a rare and chemo-resistant subtype of ovarian cancer. While immunotherapy has demonstrated effectiveness in some OCCC cases, the mechanisms for heterogeneous immunoreactivity and potential combinatory strategies remain unclear.Methods Tumor samples from 13 patients with OCCC underwent single-cell mRNA-seq and TCR-seq to generate 1 40 683 cells transcriptome, while additionally 31 formalin-fixed paraffin-embedded samples were used for immunohistochemistry. Spatial transcriptomics of two OCCC samples and bulk RNA-seq of 58 patients were incorporated for spatial and interpatient level explorations. Serum tumor markers and radiologic images of three patients with OCCC who received combinatory VEGF and PD-1 inhibition were retrospectively analyzed.Results OCCC exhibited a dynamic immune architecture shaped by genetic and therapeutic pressure. ARID1A mutation linked to baseline immune activation, correlated with an enrichment of neoantigen-reactive CXCL13+ CTLA4+ CD8+ T cells (p

Abstract Background Radioresistance is the leading cause of death in advanced cervical cancer (CC). Dysregulation of RNA modification has recently emerged as a regulatory mechanism in radiation and drug resistance. We aimed to explore the biological function and clinical significance of 5-methylcytosine (m5C) in cervical cancer radiosensitivity. Methods The abundance of RNA modification in radiotherapy-resistant and sensitive CC specimens was quantified by liquid chromatography-tandem mass spectrometry. The essential RNA modification-related genes involved in CC radiosensitivity were screened via RNA sequencing. The effect of NSUN6 on radiosensitivity was verified in CC cell lines, cell-derived xenograft (CDX), and 3D bioprinted patient-derived organoid (PDO). The mechanisms of NSUN6 in regulating CC radiosensitivity were investigated by integrative m5C sequencing, mRNA sequencing, and RNA immunoprecipitation. Results We found a higher abundance of m5C modification in resistant CC samples, and NSUN6 was the essential m5C-regulating gene concerning radiosensitivity. NSUN6 overexpression was clinically correlated with radioresistance and poor prognosis in cervical cancer. Functionally, higher NSUN6 expression was associated with radioresistance in the 3D PDO model of cervical cancer. Moreover, silencing NSUN6 increased CC radiosensitivity in vivo and in vitro. Mechanistically, NDRG1 was one of the downstream target genes of NSUN6 identified by integrated m5C-seq, mRNA-seq, and functional validation. NSUN6 promoted the m5C modification of NDRG1 mRNA, and the m5C reader ALYREF bound explicitly to the m5C-labeled NDRG1 mRNA and enhanced NDRG1 mRNA stability. NDRG1 overexpression promoted homologous recombination-mediated DNA repair, which in turn led to radioresistance in cervical cancer. Conclusions Aberrant m5C hypermethylation and NSUN6 overexpression drive resistance to radiotherapy in cervical cancer. Elevated NSUN6 expression promotes radioresistance in cervical cancer by activating the NSUN6/ALYREF-m5C-NDRG1 pathway. The low expression of NSUN6 in cervical cancer indicates sensitivity to radiotherapy and a better prognosis.

Abstract Background Cardiac arrest after coronary artery bypass grafting (CABG) is a serious complication with low survival rate. The prognosis of patients with cardiac arrest in the general ward is worse than that in the intensive care unit (ICU) because of the delayed and poor rescue conditions. Methods This retrospective study included patients who experienced cardiac arrest after CABG surgery between January 2010 and December 2019 at the Fuwai Hospital. Differences in cardiac arrest between the ICU and the general ward were compared. The patients were divided into shockable and non-shockable rhythm groups, and the differences between the two groups were compared. Finally, we proposed a management protocol for cardiac arrest in the general ward. Results We retrospectively analyzed 41,450 patients who underwent CABG only, of whom 231 (0.56%) experienced cardiac arrest post-surgery in the ICU (185/231) or in the general ward (46/231). The rescue success rate and 30-day survival rate of the patients with cardiac arrest in the general ward were 76.1% (35/46) and 58.7% (27/46), respectively. The incidence of the different arrhythmia types of cardiac arrest in the general ward compared with that in the ICU was different (P = 0.010). The 30-day survival rate of the non-shockable rhythm group was 31.8% (7/22), which was worse than that of the shockable rhythm group (83.3% [20/24]; P = 0.001). Kaplan–Meier survival analysis showed that the prognosis of the non-shockable group was poor (P

Abstract Background Properly understanding the origin and progression of the thoracic aortic aneurysm (TAA) can help prevent its growth and rupture. For a better understanding of this pathogenesis, the aortic blood flow has to be studied and interpreted in great detail. We can obtain detailed aortic blood flow information using magnetic resonance imaging (MRI) based computational fluid dynamics (CFD) with a prescribed motion of the aortic wall. Methods We performed two different types of simulations—static (rigid wall) and dynamic (moving wall) for healthy control and a patient with a TAA. For the latter, we have developed a novel morphing approach based on the radial basis function (RBF) interpolation of the segmented 4D-flow MRI geometries at different time instants. Additionally, we have applied reconstructed 4D-flow MRI velocity profiles at the inlet with an automatic registration protocol. Results The simulated RBF-based movement of the aorta matched well with the original 4D-flow MRI geometries. The wall movement was most dominant in the ascending aorta, accompanied by the highest variation of the blood flow patterns. The resulting data indicated significant differences between the dynamic and static simulations, with a relative difference for the patient of 7.47±14.18% in time-averaged wall shear stress and 15.97±43.32% in the oscillatory shear index (for the whole domain). Conclusions In conclusion, the RBF-based morphing approach proved to be numerically accurate and computationally efficient in capturing complex kinematics of the aorta, as validated by 4D-flow MRI. We recommend this approach for future use in MRI-based CFD simulations in broad population studies. Performing these would bring a better understanding of the onset and growth of TAA.

Abstract Background Asthma’s complexity, marked by airway inflammation and remodeling, is influenced by hypoxic conditions. This study focuses on the role of Hypoxia-Inducible Factor-1 Alpha (HIF-1α) and P53 ubiquitination in asthma exacerbation. Methods High-throughput sequencing and bioinformatics were used to identify genes associated with asthma progression, with an emphasis on GO and KEGG pathway analyses. An asthma mouse model was developed, and airway smooth muscle cells (ASMCs) were isolated to create an in vitro hypoxia model. Cell viability, proliferation, migration, and apoptosis were assessed, along with ELISA and Hematoxylin and Eosin (H&E) staining. Results A notable increase in HIF-1α was observed in both in vivo and in vitro asthma models. HIF-1α upregulation enhanced ASMCs’ viability, proliferation, and migration, while reducing apoptosis, primarily via the promotion of P53 ubiquitination through MDM2. In vivo studies showed increased inflammatory cell infiltration and airway structural changes, which were mitigated by the inhibitor IDF-11,774. Conclusion The study highlights the critical role of the HIF-1α-MDM2-P53 axis in asthma, suggesting its potential as a target for therapeutic interventions. The findings indicate that modulating this pathway could offer new avenues for treating the complex respiratory disorder of asthma.

Images and videos provide a wealth of information for people in production and life. Although most digital information is transmitted via optical fiber, the image acquisition and transmission processes still rely heavily on electronic circuits. The development of all-optical transmission networks and optical computing frameworks has pointed to the direction for the next generation of data transmission and information processing. Here, we propose a high-speed, low-cost, multiplexed parallel and one-piece all-fiber architecture for image acquisition, encoding, and transmission, called the Multicore Fiber Acquisition and Transmission Image System (MFAT). Based on different spatial and modal channels of the multicore fiber, fiber-coupled self-encoding, and digital aperture decoding technology, scenes can be observed directly from up to 1 km away. The expansion of capacity provides the possibility of parallel coded transmission of multimodal high-quality data. MFAT requires no additional signal transmitting and receiving equipment. The all-fiber processing saves the time traditionally spent on signal conversion and image pre-processing (compression, encoding, and modulation). Additionally, it provides an effective solution for 2D information acquisition and transmission tasks in extreme environments such as high temperatures and electromagnetic interference.

Abstract The importance of fuel mixing for the progress of the scramjet engine is indisputable. The present article shows the importance of the non-equal multi-injector system for effective fuel distribution and flame holding inside the combustion segment of a scramjet engine. The supersonic air and fuel jet flow in the non-equal nozzle arrangement is simulated via computational fluid dynamic technique. Two injector types of circular and rectangular nozzle have been analyzed to attain flow characteristics of hydrogen jets at supersonic cross flow. Mach contour is also analyzed for these jet arrangements to show the interface of the jet in the non-equal jet arrangement. Besides, addition of internal air jet is also simulated and evaluated in this research. Our investigation shows that the diffusion height of the fuel jet is higher when a rectangular non-equal nozzle is applied. The circular nozzle is more active in the spreading of the fuel in the combustor and the use of an internal air jet effectively increases fuel in a combustor of the scramjet.

Abstract Background Factor XI (FXI) deficiency is an autosomal hemorrhagic disorder characterized by reduced plasma FXI levels. Multiple ancestral variants in the F11 gene have been identified in Ashkenazi Jews and other selected European populations. However, there are few reports of predominant variants in Chinese and/or East Asian populations. The aim of this study is to characterize the genotypes and phenotypes of FXI deficiency and identify the predominant variants. Results Of the 41 FXI-deficient patients, 39 exhibited severe FXI defects, considerably more than those with partial defects. The APTT levels showed a negative correlation with FXI activity levels (coefficient=-0.584, P

Abstract Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients are at a high risk of developing metastases in the brain. However, research focusing on treatment strategies for hormonal receptor positive (HR+), HER2+ BC patients with brain metastases (BM) remains limited. Thus, a multi-center, prospective trial was conducted in China. Women over the age of 18 who were naive to whole brain radiotherapy and had estrogen receptor (ER)/progesterone-receptor (PgR) positive, HER2+ BM were treated with palbociclib, fulvestrant, trastuzumab and pyrotinib, until disease progression or the development of intolerable side effects. The primary endpoint was objective response rate (ORR) in the central nervous system (CNS). This ongoing study is still recruiting participants and is registered with ClinicalTrials.gov (NCT04334330). This report presents the findings from an interim analysis. From December 4, 2020, to November 2, 2022, 15 patients were enrolled. Among the 14 patients who were evaluable for clinical response, the ORR was 35.7% (95% CI: 12.8–64.9%), with a CNS–ORR of 28.6% (95% CI: 8.4–58.1%). The median follow-up period was 6.3 months (range, 2.1–14.3 months), during which the median progression-free survival (PFS) was 10.6 months (95% CI: 4.3–16.9 months), and the median time to CNS progression was 8.5 months (95% CI: 5.9–11.1 months). The most common adverse event was diarrhea (93%), with 33% having grade 3 and 6.7% having grade 4. The study suggests that the combination of palbociclib, trastuzumab, pyrotinib and fulvestrant offers a promising chemo-free treatment strategy for HR+, HER2+ BC patients with BM.

Abstract GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for therapeutic interventions, including monoclonal antibodies, CAR-T cells, and T-cell engagers. Despite its therapeutic potential, the insufficient understanding regarding of the receptor’s structure and antibody recognition mechanism has impeded the progress of effective therapeutic development. Here, we present the structure of GPRC5D in complex with a preclinical-stage single-chain antibody (scFv). Our structural analysis reveals that the GPRC5D presents a close resemblance to the typical Class C GPCRs in the transmembrane region. We identify a distinct head-to-head homodimer arrangement and interface mainly involving TM4, setting it apart from other Class C homo- or hetero-dimers. Furthermore, we elucidate the binding site engaging a sizable extracellular domain on GPRC5D for scFv recognition. These insights not only unveil the distinctive dimer organization of this unconventional Class C GPCR but also hold the potential to advance drug development targeting GPRC5D for the treatment of multiple myeloma.

Abstract Background Despite evidence supporting the high correlation of the novel platelet-to-albumin ratio (PAR) with survival in diverse malignancies, its prognostic relevance in nasopharyngeal carcinoma (NPC) remains underexplored. This study aimed to examine the link between PAR and overall survival (OS) in NPC and to establish a predictive model based on this biomarker. Methods We retrospectively assembled a cohort consisting of 858 NPC patients who underwent concurrent chemoradiotherapy (CCRT). Utilizing the maximally selected log-rank method, we ascertained the optimal cut-off point for the PAR. Subsequently, univariate and multivariate Cox proportional hazards models were employed to discern factors significantly associated with OS and to construct a predictive nomogram. Further, we subjected the nomogram’s predictive accuracy to rigorous independent validation. Results The discriminative optimal PAR threshold was determined to be 4.47, effectively stratifying NPC patients into two prognostically distinct subgroups (hazard ratio [HR] = 0.53; 95% confidence interval [CI]: 0.28–0.98, P = 0.042). A predictive nomogram was formulated using the results from multivariate analysis, which revealed age greater than 45 years, T stage, N stage, and PAR score as independent predictors of OS. The nomogram demonstrated a commendable predictive capability for OS, with a C-index of 0.69 (95% CI: 0.64–0.75), surpassing the performance of the conventional staging system, which had a C-index of 0.56 (95% CI: 0.65–0.74). Conclusions In the context of NPC patients undergoing CCRT, the novel nutritional-inflammatory biomarker PAR emerges as a promising, cost-efficient, easily accessible, non-invasive, and potentially valuable predictor of prognosis. The predictive efficacy of the nomogram incorporating the PAR score exceeded that of the conventional staging approach, thereby indicating its potential as an enhanced prognostic tool in this clinical setting.

Abstract Effects of short-term exposure to ambient air pollution on systemic immunological and inflammatory biomarkers in rural population have not been adequately characterized. From May to July 2021, 5816 participants in rural villages of northern Henan Province, China, participated in this cross-sectional study. Blood biomarkers of systemic inflammation were determined including peripheral white blood cells (WBC), eosinophils (EOS), basophils (BAS), monocytes (MON), lymphocytes (LYM), neutrophils (NEU), neutrophil-lymphocyte ratio (NLR), and serum high-sensitivity C-reactive protein (hs-CRP). The concentrations of ambient fine particulate matter (PM2.5), PM10, nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) were assessed up to 7 days prior to the blood draw. A generalized linear model was used to analyze the associations between air pollution exposure and the above-mentioned blood biomarkers. Significantly positive associations were revealed between PM2.5, CO and WBC; CO, O3 and LYM; PM2.5, PM10, SO2, CO and NEU; PM2.5, PM10, SO2, CO and NLR; PM2.5, PM10, SO2, NO2, CO, O3 and hs-CRP. Meanwhile, negative associations were found between SO2 and WBC; PM2.5, PM10, NO2, CO, or O3 and EOS; PM2.5, SO2, or CO and BAS; SO2, NO2 or O3 and MON; PM2.5, PM10, SO2, or NO2 and LYM. Moreover, men, individuals with normal body mass index (BMI), current smokers, and those older than 60 years were found vulnerable to air pollution effects. Taken together, short-term exposure to air pollution was associated with systemic inflammatory responses, providing insight into the potential mechanisms for air pollution-induced detrimental systemic effects in rural residents.

ABSTRACT Aim This study aims to investigate the association of glycemia risk index (GRI), a novel composite metric derived from continuous glucose monitoring (CGM), with arterial stiffness in patients with type 2 diabetes. Materials and Methods A total of 342 adults with type 2 diabetes were enrolled between April and June 2023 from 11 communities in Shanghai, China. Medical examinations, including measurements of anthropometric parameters, blood pressure, and venous blood samples were conducted. Brachial‐ankle pulse wave velocity (baPWV) was examined to evaluate arterial stiffness. All the participants underwent a 14 day CGM recording and GRI was calculated from the CGM data. Results The mean age was 70.3 ± 6.8 years, and 162 (47.4%) were male. Participants with a higher baPWV had significantly higher levels of GRI and hyperglycemia component (both P for trend

Abstract The purpose of this study was to explore the diagnostic implications of ubiquitination-related gene signatures in Alzheimer's disease. In this study, we first collected 161 samples from the GEO database (including 87 in the AD group and 74 in the normal group). Subsequently, through differential expression analysis and the iUUCD 2.0 database, we obtained 3450 Differentially Expressed Genes (DEGs) and 806 Ubiquitin-related genes (UbRGs). After taking the intersection, we obtained 128 UbR-DEGs. Secondly, by conducting GO and KEGG enrichment analysis on these 128 UbR-DEGs, we identified the main molecular functions and biological pathways related to AD. Furthermore, through the utilization of GSEA analysis, we have gained insight into the enrichment of functions and pathways within both the AD and normal groups. Further, using lasso regression analysis and cross-validation techniques, we identified 22 characteristic genes associated with AD. Subsequently, we constructed a logistic regression model and optimized it, resulting in the identification of 6 RUbR-DEGs: KLHL21, WDR82, DTX3L, UBTD2, CISH, and ATXN3L. In addition, the ROC result showed that the diagnostic model we built has excellent accuracy and reliability in identifying AD patients. Finally, we constructed a lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) regulatory network for AD based on six RUbR-DEGs, further elucidating the interaction between UbRGs and lncRNA, miRNA. In conclusion, our findings will contribute to further understanding of the molecular pathogenesis of AD and provide a new perspective for AD risk prediction, early diagnosis and targeted therapy in the population.

Abstract Background Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. Methods This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. Results Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). Conclusions Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

Abstract Background It was reported the paraspinal muscle played an important role in spinal stability. The preoperative paraspinal muscle was related to S1 screw loosening. But the relationship between preoperative and postoperative change of psoas major muscle (PS) and S1 pedicle screw loosening in degenerative lumbar spinal stenosis (DLSS) patients has not been reported. This study investigated the effects of preoperative and follow-up variations in the psoas major muscle (PS) on the first sacral vertebra (S1) screw loosening in patients with DLSS. Methods 212 patients with DLSS who underwent lumbar surgery were included. The patients were divided into the S1 screw loosening group and the S1 screw non-loosening group. Muscle parameters were measured preoperatively and at last follow-up magnetic resonance imaging. A logistic regression analysis was performed to investigate the risk factors for S1 screw loosening. Results The S1 screw loosening rate was 36.32% (77/212). The relative total cross-sectional areas and relative functional cross-sectional areas (rfCSAs) of the PS at L2–S1 were significantly higher after surgery. The increased rfCSA values of the PS at L3–S1 in the S1 screw non-loosening group were significantly higher than those in the S1 screw loosening group. The regression analysis showed male, lower CT value of L1 and longer segment fusion were independent risk factors for S1 screw loosening, and postoperative hypertrophy of the PS was a protective factor for S1 screw loosening. Conclusions Compared to the preoperative muscle, the PS size increased and fatty infiltration decreased after surgery from L2–3 to L5–S1 in patients with DLSS after short-segment lumbar fusion surgery. Postoperative hypertrophy of the PS might be considered as a protective factor for S1 screw loosening. MRI morphometric parameters and postoperative selected exercise of PS for DLSS patients after posterior lumbar fusion surgery might contribute to improvement of surgical outcome.

The Lower Silurian Longmaxi Formation on the southwestern margin of the Sichuan Basin holds significant shale gas reserves. The characteristics and formation stages of fractures play a crucial role in shale gas accumulation and productivity. Focusing on the Longmaxi Formation in the Tiangongtang area, this study employed core analysis, FMI (Formation Micro-Imager) logging, rock acoustic emission experiments, carbon-oxygen isotope analysis of fracture fillings, fluid inclusion homogenization temperature testing, and burial-thermal evolution history analysis to investigate the development characteristics and formation periods of natural fractures in the shale. The results indicate that the natural fractures in the Longmaxi Formation in the study area are characterized by the coexistence of tectonic vertical and low-angle fractures. The core fractures exhibit high development density, short extension, and high filling degree. Comparison of imaging log fracture dip angles, core fracture cross-cutting relationships, fracture filling fluid inclusion tests, and rock acoustic emission experiments suggested that the fractures in the Longmaxi Formation in the Tiangongtang area were associated with three tectonic events. Combined with burial-thermal evolution history analysis, the formation periods were confirmed as follows: the first stage involved NW-oriented and NNE-oriented planar shear fractures, and NEE-oriented cross-sectional shear fractures formed during the mid-late Yanshanian period (130-62 Ma) with tectonic stress orientation near SN (345°±5°) and inclusion homogenization temperatures of 185-206 ℃; the second stage involved NE-oriented and NW-oriented planar shear fractures, and NNW-trending cross-sectional shear fractures formed during the late Yanshanian to mid-Himalayan period (62-34 Ma) with tectonic stress orientation near EW (80°±5°) and inclusion homogenization temperatures of 165-184 ℃; the third stage involved near SN-oriented and NEE-oriented planar shear fractures, and NE-oriented cross-sectional shear fractures formed from the mid-Himalayan period to present (34 Ma to present) with tectonic stress orientation near NW (315°±5°) and inclusion homogenization temperatures of 125-162 ℃. Based on the geomechanical background, a three-stage tectonic fracture evolution model for the Longmaxi Formation in the Tiangongtang area was established.

Background: Spinal cord injury (SCI) is a devastating neurological disease in which astrocytes play a central role. Understanding the relationship between different subtypes of astrocytes and neuron subtypes during the progression of SCI is critical to understanding the disease. Methods and results: In this study, single-cell RNA sequencing (scRNA-seq) was used to analyze the transcriptome data of acute, subacute and intermediate stages of SCI in mice as well as normal tissues. Different subtypes of astrocytes and neuronal cells were identified and their dynamic changes and functionalities during the development of SCI. An intriguing discovery was the identification of a specific subtype of astrocytes characterized by unique expression of Gap43, Vim, Aldoc, and Mt1. This subtype of cells shows similarities in gene expression with neurons and potentially transitioned into neurons during the course of SCI. Furthermore, we have uncovered the important role of the glycolytic pathway in this cellular transformation process. Furthermore, through cellular interaction analysis, we validated pathways (mdk-ptprz1,ptn-ptprz1,ptn-sdc3) associated with the potential conversion of these specific cell subsets into neurons. Finally, these cells were observed by fluorescence microscopy and critical gene expressions were validated by Western blot. Conclusions: The results of this study not only deepen our understanding of the mechanisms underlying SCI, but also provide new insights and opportunities for the development of novel therapeutic strategies and interventions.

The poultry red mite (PRM), Dermanyssus gallinae, a significant ectoparasite causing diseases in poultry, is globally prevalent and necessitates effective control strategies. There are restrictions on the use of acaricides in poultry across several nations due to worries about medication residues. Consequently, finding safe and efficient treatments for PRM is imperative. Fluralaner solution has emerged as a potential therapeutic agent, distinguished by its rapid onset, enduring efficacy, and lack of a withdrawal period for egg production. To ascertain the optimal dosage and therapeutic efficacy of fluralaner solution in PRM treatment, this study evaluated blood biochemical parameters and mite populations across various treatment groups. A cohort of 500 laying hens was randomly assigned to one of five treatment groups, each comprising 100 individuals:high-dose group (0.1 ml/kg-bw, group 4 ×, coop 1), medium-dose group (0.05 ml/kg-bw, group 2 ×, coop 5), low-dose group (0.025 ml/kg-bw, group 1 ×, coop 2), drug-control group (Intervet Productions, 0.05 ml/kg-bw recommended dose, coop 3) and blank control group (coop 4). Hens received their respective dosages of the fluralaner solution via oral administration on Days 0 (D0) and 7 (D7) of the experimental period. Over the study's ninety days, blood biochemical markers and mite counts in each coop were measured to evaluate the drug's safety, effectiveness, and ideal dosage. Data analysis was performed utilizing SPSS software. The study findings indicated that, for effective PRM infestation treatment, a dosage of 0.5 mg fluralaner per kilogram of body weight (equivalent to 0.05 ml) administered daily, followed by a subsequent dose post a 7-day interval, is recommended. Additionally, clinical observations coupled with blood biochemical assessments confirmed the safety of fluralaner across the three tested dosage levels in hens.

When readers encounter information conflicting with the predictive inferences made earlier, they may update the outdated ones with new ones, a process known as predictive inference revision. The current study examined the revision of disconfirmed predictive inferences by the primarily weakly activated, thus low-competitive inference alternatives during Chinese narrative text reading among Chinese native speakers. We conducted an event-related brain potential (ERP) experiment to study the predictive inference revision with increasingly supportive information for the low-competitive predictive inference alternatives. It serves as the very first attempts to study the predictive inference revision mechanisms by combining a larger range of ERP components, including frontal-Post-N400-Positivity (f-PNP) as an index of revision to examine the influences of the alternative inferences at later stages of reading comprehension. Our results showed that readers could detect inconsistent information (P300), disconfirm the incorrect predictive inferences before successfully integrating the low-competitive alternative predictive inferences with their current situation model (N400), engaging themselves in a second-pass reanalysis process incurring processing costs (P600), and revising the disconfirmed predictive inferences (f-PNP) at a later stage of reading comprehension. Results of this study are supportive of relevant theories in assuming that predictive inference revision does not happen immediately upon encountering conflicting information but happens slowly and incrementally. Our results also unfold the post-revision mechanisms by suggesting the remaining activation and lingering influences of the disconfirmed inferences in the forthcoming reading process.