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Abstract Urban governance aims to enhance overall social welfare, while residents’ happiness frequently falls by the wayside. Civilization, as a critical factor influencing residents’ happiness, has not yet been fully understood regarding its impact and mechanisms. This paper uses the China Family Panel Studies data, which includes around 50,000 samples ranging from 2010 to 2020, to construct a multi-period difference-in-differences model. It finds that China’s highest honor for urban brands, the civilized city program, leads to an average increase of 2.6% in residents’ happiness as measured by life satisfaction. This happiness effect is robust but temporary, gradually diminishing within five years following the honor. The happiness effect is heterogeneous across different waves and city sizes and is effective only for urban residents. Mechanism analysis indicates the happiness effect of the civilized city program through three channels: government efforts, social trust, and identity recognition. Additionally, our research indicates that the civilized city initiative improves residents’ perception of environmental quality and reduces income inequality. These findings provide insights into understanding how the civilization tournament policy promotes happiness.

Abstract Gender role attitudes have been shown to play a critical role in individuals’ fertility intentions. However, the underlying mechanism is unclear. The present study examined whether parental sacrifice mediates the relationship between gender role attitudes and fertility intentions, and whether subjective well-being plays a moderating role. A sample of 446 Chinese adults aged 18 to 45 (Mage = 32.78, SDage = 5.63, 60.93% female) completed the Gender Role Attitude Scale, Parental Sacrifice Scale, Index of Well-Being, and Fertility Attitude Scale. Multiple regression analyses showed that traditional gender role attitudes positively predicted fertility intentions, while egalitarian gender role attitudes negatively predicted fertility intentions. Moreover, parental sacrifice was found to partially mediate the relationship between gender role attitudes and fertility intentions. Additionally, subjective well-being was identified as a moderator of the mediating effect of parental sacrifice. Specifically, for individuals with low subjective well-being, parental sacrifice played a partially mediating role. However, for individuals with high subjective well-being, the mediating effect of parental sacrifice was not significant, and gender role attitudes directly influenced fertility intentions. This study adds to our understanding of the connection between gender role attitudes and fertility intentions of adults, providing important information for policymakers and professionals aiming to promote fertility intentions.

Abstract Background There are few thorough studies assessing predictors of severe encephalitis, despite the poor prognosis and high mortality associated with severe encephalitis. The study aims to evaluate the clinical predictors of mortality and poor outcomes at hospital discharge in patients with severe infectious encephalitis in intensive care units. Method In two Chinese hospitals, a retrospective cohort study comprising 209 patients in intensive care units suffering from severe infectious encephalitis was carried out. Univariate and multivariate logistic regression analyses were used to identify the factors predicting mortality in all patients and poor outcomes in all survivors with severe infectious encephalitis. Results In our cohort of 209 patients with severe encephalitis, 22 patients died, yielding a mortality rate of 10.5%. Cerebrospinal fluid pressure ≥ 400mmH2O (OR = 7.43), abnormal imaging (OR = 3.51), abnormal electroencephalogram (OR = 7.14), and number of rescues (OR = 1.12) were significantly associated with an increased risk of mortality in severe infectious encephalitis patients. Among the 187 survivors, 122 (65.2%) had favorable outcomes, defined as the modified Rankine Scale (mRS) score (0 ~ 3), and 65(34.8%) had poor outcomes (mRS scores 4 ~ 5). Age (OR = 1.02), number of rescues (OR = 1.43), and tubercular infection (OR = 10.77) were independent factors associated with poor outcomes at discharge in all survivors with severe infectious encephalitis. Conclusions Multiple clinical, radiologic, and electrophysiological variables are independent predictive indicators for mortality and poor outcomes in patients with severe encephalitis in intensive care units. Identifying these outcome predictors early in patients with severe encephalitis may enable the implementation of appropriate medical treatment and help reduce mortality rates.

The discovery of an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein involved in the process of cell injury through ferroptosis, has the potential to ameliorate cell damage. In this study, we aimed to investigate the potential of berberine (BBR) as an inhibitor of ACSL4 in order to suppress endothelial ferroptosis and provide protection against atherosclerosis. An atherosclerosis model was created in ApoE-/- mice by feeding a high fat diet for 16 weeks. Additionally, a mouse model with endothelium-specific overexpression of ACSL4 was established. BBR was administered orally to assess its potential therapeutic effects on atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low density lipoprotein (ox-LDL) to simulate atherosclerotic endothelial damage in vitro. The interaction between ACSL4 and BBR has been confirmed, with BBR playing a role in inhibiting erastin-induced ferroptosis by regulating ACSL4. Additionally, BBR has been found to inhibit lipid deposition, plaque formation, and collagen deposition in the aorta, thereby delaying the progression of atherosclerosis. It also restored the abnormal expression of ferroptosis-related proteins in atherosclerotic vascular endothelial cells both in vivo and in vitro. In conclusion, BBR, acting as an ACSL4 inhibitor, can improve atherosclerosis by inhibiting ferroptosis in endothelial cells. This highlights the potential of targeted inhibition of vascular endothelial ACSL4 as a strategy for treating atherosclerosis, with BBR being a candidate for this purpose.

IntroductionTo explore the impact of donors’ COVID-19 status on allogeneic stem cell transplantation (allo-HSCT), we compared the transplant outcomes of 74 participants.MethodsThis multi-center retrospective study included nine participants receiving grafts from COVID-19 positive donors (CPD), 45 from COVID-19 experienced donors (CED), and 20 from COVID-19 naive donors (CND). We evaluated engraftment, complications, and survival rates among the three groups.ResultsAll apheresis procedures were successful with no significant differences in CD34+ cells or lymphocytes in grafts among the three groups. All patients achieved engraftment by day 30 post-HSCT. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 55.6%, 20%, and 10% in the CPD, CED, and CND groups, respectively (p = 0.024). Multivariate analysis indicated that COVID-19 positivity in donors at the time of apheresis was an independent risk factor for II-IV aGVHD (p = 0.020, OR = 12.159, 95% CI 1.783 -135.760). No differences were observed among the groups in terms of chronic GVHD, viral infection, or sinusoidal obstruction syndrome. The 6-month overall survival and disease-free survival rates were also similar among the three groups.DiscussionOur results suggest that the COVID-19-positive status of donors might not impact graft collection, engraftment, or short-term survival of allo-HSCT recipients but might increase the risk of aGVHD. Further research is needed to explore the influence of donors’ COVID-19 status on long-term complications and survival in allo-HSCT recipients.

Abstract Objectives This study aims to decrease the scan time and enhance image quality in pediatric total-body PET imaging by utilizing multimodal artificial intelligence techniques. Methods A total of 270 pediatric patients who underwent total-body PET/CT scans with a uEXPLORER at the Sun Yat-sen University Cancer Center were retrospectively enrolled. 18F-fluorodeoxyglucose (18F-FDG) was administered at a dose of 3.7 MBq/kg with an acquisition time of 600 s. Short-term scan PET images (acquired within 6, 15, 30, 60 and 150 s) were obtained by truncating the list-mode data. A three-dimensional (3D) neural network was developed with a residual network as the basic structure, fusing low-dose CT images as prior information, which were fed to the network at different scales. The short-term PET images and low-dose CT images were processed by the multimodal 3D network to generate full-length, high-dose PET images. The nonlocal means method and the same 3D network without the fused CT information were used as reference methods. The performance of the network model was evaluated by quantitative and qualitative analyses. Results Multimodal artificial intelligence techniques can significantly improve PET image quality. When fused with prior CT information, the anatomical information of the images was enhanced, and 60 s of scan data produced images of quality comparable to that of the full-time data. Conclusion Multimodal artificial intelligence techniques can effectively improve the quality of pediatric total-body PET/CT images acquired using ultrashort scan times. This has the potential to decrease the use of sedation, enhance guardian confidence, and reduce the probability of motion artifacts.

Purposes To achieve stable and efficient energy storage in the new elastic potential energy storage system, it is first necessary to establish an accurate mathematical model to reveal the operating characteristics of the energy storage box, and complete the calculation and configuration model of its capacity and power; Second, a strong robust control algorithm is needed to achieve the fast torque response while effectively suppressing disturbances. Methods In this paper, an accurate mathematical model of the energy storage system was established. Combined with the backstepping control algorithm, the direct torque adaptive control method of the permanent magnet synchronous motor is designed, and a new robust control strategy for the energy storage process of the elastic potential energy storage system is formed. Conclusions Through experiments, it has been proven that this control strategy has a fast torque response speed and can quickly match the rapidly increasing reverse torque of the energy storage box with minimal pulsation. At the same time, it can effectively restrain the unique moment of inertia parameter disturbance of the energy storage system, and then achieve stable and efficient energy storage.

Binders play a crucial role in enhancing the cycling stability of silicon anodes in next-generation Li-ion batteries. However, traditional linear polymer binders have difficulty withstanding the volume expansion of silicon during cycling. Herein, inspired by the fact that animals’ claws can grasp objects firmly, a claw-like taurine-grafted-poly (acrylic acid) binder (Tau-g-PAA) is designed to improve the electrochemical performance of silicon anodes. The synergistic effects of different polar groups (sulfo and carboxyl) in Tau-g-PAA facilitate the formation of multidimensional interactions with silicon nanoparticles and the diffusion of Li ions, thereby greatly improving the stability and rate performance of silicon anodes, which aligns with results from density functional theory (DFT) simulations. As expected, a Tau-g-PAA/Si electrode exhibits excellent cycling performance with a high specific capacity of 1003 ​mA ​h ​g−1 ​at 1 ​C (1 ​C ​= ​4200 ​mA ​h ​g−1) after 300 cycles, and a high rate performance. The design strategy of using polar small molecule-grafted polymers to create claw-like structures could inspire the development of better binders for silicon-based anodes.

Background: The failure of high-flow nasal cannula (HFNC) oxygen therapy can necessitate endotracheal intubation in patients, making timely prediction of the intubation risk following HFNC therapy crucial for reducing mortality due to delays in intubation. Objectives: To investigate the accuracy of ChatGPT in predicting the endotracheal intubation risk within 48 h following HFNC therapy and compare it with the predictive accuracy of specialist and non-specialist physicians. Methods: We conducted a prospective multicenter cohort study based on the data of 71 adult patients who received HFNC therapy. For each patient, their baseline data and physiological parameters after 6-h HFNC therapy were recorded to create a 6-alternative-forced-choice questionnaire that asked participants to predict the 48-h endotracheal intubation risk using scale options ranging from 1 to 6, with higher scores indicating a greater risk. GPT-3.5, GPT-4.0, respiratory and critical care specialist physicians and non-specialist physicians completed the same questionnaires (N = 71) respectively. We then determined the optimal diagnostic cutoff point, using the Youden index, for each predictor and 6-h ROX index, and compared their predictive performance using receiver operating characteristic (ROC) analysis. Results: The optimal diagnostic cutoff points were determined to be ≥ 4 for both GPT-4.0 and specialist physicians. GPT-4.0 demonstrated a precision of 76.1 %, with a specificity of 78.6 % (95%CI = 52.4–92.4 %) and sensitivity of 75.4 % (95%CI = 62.9–84.8 %). In comparison, the precision of specialist physicians was 80.3 %, with a specificity of 71.4 % (95%CI = 45.4–88.3 %) and sensitivity of 82.5 % (95%CI = 70.6–90.2 %). For GPT-3.5 and non-specialist physicians, the optimal diagnostic cutoff points were ≥5, with precisions of 73.2 % and 64.8 %, respectively. The area under the curve (AUC) in ROC analysis for GPT-4.0 was 0.821 (95%CI = 0.698–0.943), which was the highest among the predictors and significantly higher than that of non-specialist physicians [0.662 (95%CI = 0.518–0.805), P = 0.011]. Conclusion: GPT-4.0 achieves an accuracy level comparable to specialist physicians in predicting the 48-h endotracheal intubation risk following HFNC therapy, based on patient baseline data and physiological parameters after 6-h HFNC therapy.

AbstractContext Derazantinib—an orally bioavailable, ATP competitive, multikinase inhibitor—has strong activity against fibroblast growth factor receptors (FGFR)2, FGFR1, and FGFR3 kinases. It has preliminary antitumor activity in patients with unresectable or metastatic FGFR2 fusion-positive intrahepatic cholangiocarcinoma (iCCA).Objective This experiment validates a novel sensitive and rapid method for the determination of derazantinib concentration in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and applies it to the study of drug-drug interaction between derazantinib and naringin in vivo.Materials and methods A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. The pharmacokinetics of derazantinib (30 mg/kg) was investigated in Sprague-Dawley (SD) rats divided into two groups (with the oral pretreatment of 50 mg/kg naringin or not).Results The newly optimized UPLC-MS/MS method was suitable for the determination of derazantinib in rat plasma. It was also successfully employed to evaluate the effect of naringin on derazantinib metabolism in rats. After pretreatment with naringin, there was no significant difference in the pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, CLz/F, and Cmax) of derazantinib when compared with derazantinib alone.Conclusion Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment.

In practical conditions, near-field acoustic holography (NAH) requires the measurement environment to be a free sound field. If vibrating objects are located above the reflective ground, the sound field becomes non-free in the presence of a reflecting surface, and conventional NAH may not identify the sound source. In this work, two types of half-space NAH techniques based on the Helmholtz equation least-squares (HELS) method are developed to reconstruct the sound field above a reflecting plane. The techniques are devised by introducing the concept of equivalent source in HELS-method-based NAH. Two equivalent sources are tested. In one technique, spherical waves are used as the equivalent source, and the sound reflected from the reflecting surface is regarded as a linear superposition of orthogonal spherical wave functions of different orders located below the reflecting surface. In the other technique, some monopoles are considered equivalent sources, and the reflected sound is considered a series of sounds generated by simple sources distributed under the reflecting surface. The sound field is reconstructed by matching the pressure measured on the holographic surface with the orthogonal spherical wave source in the vibrating object and replacing the reflected sound with an equivalent source. Therefore, neither technique is related to the surface impedance of the reflected plane. Compared with the HELS method, both methods show higher reconstruction accuracy for a half-space sound field and are expected to broaden the application range of HELS-method-based NAH techniques.

ObjectivesHelicobacter pylori (H. pylori) is a type of bacteria that infects the stomach lining, and it is a major cause of chronic gastritis (CG). H. pylori infection can influence the composition of the gastric microbiota. Additionally, alterations in the gut microbiome have been associated with various health conditions, including gastrointestinal disorders. The dysbiosis in gut microbiota of human is associated with the decreased secretion of gastric acid. Chronic atrophic gastritis (CAG) and H. pylori infection are also causes of reduced gastric acid secretion. However, the specific details of how H. pylori infection and CG, especially for CAG, influence the gut microbiome can vary and are still an area of ongoing investigation. The incidence of CAG and infection rate of H. pylori has obvious regional characteristics, and Fujian Province in China is a high incidence area of CAG as well as H. pylori infection. We aimed to characterize the microbial changes and find potential diagnostic markers associated with infection of H. pylori as well as CG of subjects in Jinjiang City, Fujian Province, China.ParticipantsEnrollment involved sequencing the 16S rRNA gene in fecal samples from 176 cases, adhering to stringent inclusion and exclusion criteria. For our study, we included healthy volunteers (Normal), individuals with chronic non-atrophic gastritis (CNAG), and those with CAG from Fujian, China. The aim was to assess gut microbiome dysbiosis based on various histopathological features. QIIME and LEfSe analyses were performed. There were 176 cases, comprising 126 individuals who tested negative for H. pylori and 50 who tested positive defined by C14 urea breath tests and histopathological findings in biopsies obtained through endoscopy. CAG was also staged by applying OLGIM system.ResultsWhen merging the outcomes from 16S rRNA gene sequencing results, there were no notable variations in alpha diversity among the following groups: Normal, CNAG, and CAG; OLGIM I and OLGIM II; and H. pylori positive [Hp (+)] and H. pylori negative [Hp (–)] groups. Beta diversity among different groups show significant separation through the NMDS diagrams. LEfSe analyses confirmed 2, 3, and 6 bacterial species were in abundance in the Normal, CNAG, and CAG groups; 26 and 2 species in the OLGIM I and OLGIM II group; 22 significant phylotypes were identified in Hp (+) and Hp (–) group, 21 and 1, respectively; 9 bacterial species exhibited significant differences between individuals with CG who were Hp (+) and those who were Hp (–).ConclusionThe study uncovered notable distinctions in the characteristics of gut microbiota among the following groups: Normal, CNAG, and CAG; OLGIM I and OLGIM II; and Hp (+) and Hp (–) groups. Through the analysis of H. pylori infection in CNAG and CAG groups, we found the gut microbiota characteristics of different group show significant difference because of H. pylori infection. Several bacterial genera could potentially serve as diagnostic markers for H. pylori infection and the progression of CG.

Allergic diseases in children are major public health concerns due to their widespread and rising prevalence. Food-specific immunoglobulin G4(FS-IgG4) has been detected in patients with allergic diseases, but its clinical significance is still debated. In the present study, 407 children with allergic diseases were recruited and categorized into three groups according to the different systems involved: the respiratory system group, the skin system group, and a multiple system group, with the collection of clinical symptoms and serum antibodies, including total immunoglobulin E (IgE), house dust mite (HDM) IgE, food-specific IgE (FS-IgE), and FS-IgG4. Part of these patients were followed up with the intervention of FS-IgG4-guided diet elimination with or without add-on probiotics supplement. The analysis at baseline revealed distinct serum levels of different antibodies. The positive rate of FS-IgG4 in all groups was more than 80%, and the proportion of total IgE and FS-IgG4 both positive in the multi-system group was the highest (p=0.039). Egg and milk were the foods with the highest positive rate of FS-IgG4 in all groups. After diet elimination for more than 3 months, serum FS-IgG4 in children significantly decreased (P

Cytokine release syndrome (CRS) can be induced by immune checkpoint inhibitors (ICIs). Although the incidence of CRS is low, it is often underreported. Here, we report two severe CRS cases and summarize and review 51 patients with ICI-induced CRS to explore the possible contributing factors to the disease prognosis and provide assistance for therapy. Our analysis found that the population with ICI-induced CRS consists mainly of male patients with an average age of 61.74 years. The primary malignant tumor type was lung cancer, and the clinical stage of most patients was stage IV. Notably, patients who experience a longer time to CRS onset, higher IL-6 levels, and lower platelet counts may be more likely to develop severe CRS. Cardiovascular, respiratory, neurological, and coagulation toxicities are more common in higher-grade CRS and may serve as markers for patient experiencing ICU admission, oxygen supplementation, hypotension, high-dose vasopressors usage, and intubation.

Potassium (K) is an essential macronutrient for plant growth and development and influences yield and quality of agricultural crops. Maize (Zea mays) is one of the most widely distributed crops worldwide. In China, although maize consumes a large amount of K fertilizer, the K uptake/utilization efficiency (KUE) of maize cultivars is relatively low. Elucidation of KUE mechanisms and development of maize cultivars with higher KUE are needed. Maize KUE is determined by K+ uptake, transport, and remobilization, which depend on a variety of K+ channels and transporters. We review basic information about K+ channels and transporters in maize, their functions and regulation, and the roles of K+ in nitrogen transport, sugar transport, and salt tolerance. We discuss challenges and prospects for maize KUE improvement.

The low objective response rates and severe side effects largely limit the clinical outcomes of immune checkpoint blockade (ICB) therapy. Here, a tumor “self-killing” therapy based on gene-guided OX40L anchoring to tumor cell membrane was reported to boost ICB therapy. We developed a highly efficient delivery system HA/PEI-KT (HKT) to co-deliver the OX40L plasmids and unmethylated CG-enriched oligodeoxynucleotide (CpG). On the one hand, CpG induced the expression of OX40 on T cells within tumors. On the other hand, OX40L plasmids achieved the OX40L anchoring on the tumor cell membrane to next promote T cells responses via OX40/OX40L axis. Such synergistic tumor “self-killing” strategy finally turned “cold” tumors to “hot”, to sensitize tumors to programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade therapy, and promoted an immune-mediated tumor regression in both B16F10 and 4T1 tumor models, with prevention of tumor recurrence and metastasis. To avoid the side effects, the gene-guided OX40L anchoring and PD-L1 silencing was proposed to replace the existing antibody therapy, which showed negligible toxicity in vivo. Our work provided a new possibility for tumor “self-killing” immunotherapy to treated various solid tumors.

Abstract Background Despite the extensive research on data mining algorithms, there is still a lack of a standard protocol to evaluate the performance of the existing algorithms. Therefore, the study aims to provide a novel procedure that combines data mining algorithms and simplified preprocessing to establish reference intervals (RIs), with the performance of five algorithms assessed objectively as well. Methods Two data sets were derived from the population undergoing a physical examination. Hoffmann, Bhattacharya, Expectation Maximum (EM), kosmic, and refineR algorithms combined with two-step data preprocessing respectively were implemented in the Test data set to establish RIs for thyroid-related hormones. Algorithm-calculated RIs were compared with the standard RIs calculated from the Reference data set in which reference individuals were selected following strict inclusion and exclusion criteria. Objective assessment of the methods is implemented by the bias ratio (BR) matrix. Results RIs of thyroid-related hormones are established. There is a high consistency between TSH RIs established by the EM algorithm and the standard TSH RIs (BR = 0.063), although EM algorithms seems to perform poor on other hormones. RIs calculated by Hoffmann, Bhattacharya, and refineR methods for free and total triiodo-thyronine, free and total thyroxine respectively are close and match the standard RIs. Conclusion An effective approach for objectively evaluating the performance of the algorithm based on the BR matrix is established. EM algorithm combined with simplified preprocessing can handle data with significant skewness, but its performance is limited in other scenarios. The other four algorithms perform well for data with Gaussian or near-Gaussian distribution. Using the appropriate algorithm based on the data distribution characteristics is recommended.

AI is undeniably revolutionizing medical research and patient care across diverse fields. Chronic disease nursing care, a pivotal aspect of clinical management, has significantly reaped the benefits of AI across numerous dimensions. Understanding the operational principles of artificial intelligence before implementation is crucial, avoiding indiscriminate replacement of all tasks with AI. Nurses serve as the primary force in symptom group research, expanding beyond diabetes to encompass various chronic diseases; their primary responsibility involves recording patients’ daily symptoms and vital signs. However, a substantial portion of current AI research excludes nurses from the developmental phase, encompassing them solely in user and feedback populations. The comprehensive design of the symptom analysis and long-term management approach necessitates the guidance and oversight of nurses; however, their current insufficient involvement might stem from nursing staff's comparatively limited comprehension of AI and their ambiguous perception of their role's value in AI. Therefore, an imperative exploration of nurses’ roles in symptom analysis and long-term management, leveraging the latest research in these areas, is vital to pinpoint breakthroughs in nurses’ AI involvement in the future.

RNA modifications are mostly dynamically reversible post-transcriptional modifications, of which m6A is the most prevalent in eukaryotic mRNAs. A growing number of studies indicate that RNA modification can finely tune gene expression and modulate RNA metabolic homeostasis, which in turn affects the self-renewal, proliferation, apoptosis, migration, and invasion of tumor cells. Endometrial carcinoma (EC) is the most common gynecologic tumor in developed countries. Although it can be diagnosed early in the onset and have a preferable prognosis, some cases might develop and become metastatic or recurrent, with a worse prognosis. Fortunately, immunotherapy and targeted therapy are promising methods of treating endometrial cancer patients. Gene modifications may also contribute to these treatments, as is especially the case with recent developments of new targeted therapeutic genes and diagnostic biomarkers for EC, even though current findings on the relationship between RNA modification and EC are still very limited, especially m6A. For example, what is the elaborate mechanism by which RNA modification affects EC progression? Taking m6A modification as an example, what is the conversion mode of methylation and demethylation for RNAs, and how to achieve selective recognition of specific RNA? Understanding how they cope with various stimuli as part of in vivo and in vitro biological development, disease or tumor occurrence and development, and other processes is valuable and RNA modifications provide a distinctive insight into genetic information. The roles of these processes in coping with various stimuli, biological development, disease, or tumor development in vivo and in vitro are self-evident and may become a new direction for cancer in the future. In this review, we summarize the category, characteristics, and therapeutic precis of RNA modification, m6A in particular, with the purpose of seeking the systematic regulation axis related to RNA modification to provide a better solution for the treatment of EC.

ObjectivesCardiovascular magnetic resonance-feature tracking (CMR-FT) enables quantification of myocardial deformation and may be used as an objective measure of myocardial involvement in ST-elevation myocardial infarction (STEMI). We sought to investigate the associations between myocardial dyssynchrony parameters and myocardium damage for STEMI.MethodsWe analyzed 65 patients (45–80 years old) with anterior STEMI after primary percutaneous coronary intervention during 3–7 days [observational (STEMI) group] and 60 healthy volunteers [normal control (NC) group]. Myocardial dyssynchrony parameters were derived, including global and regional strain, radial rebound stretch and displacement, systolic septal time delay, and circumferential stretch.ResultsCMR characteristics, including morphologic parameters such as left ventricular ejection fraction (LVEF) (45.3% ± 8.2%) and myocardium damage in late gadolinium enhancement (LGE) (19.4% ± 4.7% LV), were assessed in the observation group. The global radial strain (GRS) and global longitudinal strain (GLS) substantially decreased in anterior STEMI compared with the NC group (GRS: 19.4% ± 5.1% vs. 24.8% ± 4.0%, P

BackgroundPrevious animal studies have suggested that air pollution (AP) exposure may be a potential risk factor for obesity; however, there is limited epidemiological evidence available to describe the association of obesity with AP exposure.MethodsA retrospective cross-sectional study was conducted on 11,766 participants across mainland China in 2015. Obesity was assessed using body mass index (BMI), waist circumference (WC), and visceral adiposity index (VAI). The space-time extremely randomized tree (STET) model was used to estimate the concentration of air pollutants, including SO2, NO2, O3, PM1, PM2.5, and PM10, matched to participants’ residential addresses. Logistic regression models were employed to estimate the associations of obesity with outdoor AP exposure. Further stratified analysis was conducted to evaluate whether sociodemographics or lifestyles modified the effects.ResultsIncreased AP exposure was statistically associated with increased odds of obesity. The odds ratio (ORs) and 95% confidence interval (CI) of BMI-defined obesity were 1.21 (1.17, 1.26) for SO2, 1.33 (1.26, 1.40) for NO2, 1.15 (1.10, 1.21) for O3, 1.38 (1.29, 1.48) for PM1, 1.19 (1.15, 1.22) for PM2.5, and 1.11 (1.09, 1.13) for PM10 per 10 μg/m3 increase in concentration. Similar results were found for central obesity. Stratified analyses suggested that elderly participants experienced more adverse effects from all 6 air pollutants than middle-aged participants. Furthermore, notable multiplicative interactions were found between O3 exposure and females as well as second-hand smokers in BMI-defined obesity.ConclusionsThis study suggested that outdoor AP exposure had a significant association with the risk of obesity in the middle-aged and elderly Chinese population. Elderly individuals and women may be more vulnerable to AP exposure.

Abstract Aneuploid refers to the gene dosage imbalance due to copy number alterations. Aneuploidy is generally harmful to the growth, development and reproduction of organisms according to the numerous research. However, it has rarely been reported on whether aneuploid have a relevant pattern of genome expression between the parental and its offspring generations. In this study, mRNA sequencing analysis was performed on rice (Oryza sativa L.) primary trisomes 11 and 12, same primary trisomes and normal individuals in their filial generation. We systematically summarized the changes in gene expression patterns that occur on cis genes and on trans genes between parental and filial generations. In T11 and T12, the ratio of cis-gene expression showed intermediate type in parents and dosage compensation in filial generations, which maybe due to more genes being downregulated. The trans genes were also affected by aneuploidy and manifested as cis-related. The strains with normal chromosomes in filial generations, there are still aneuploid-sensitive genes differentially expressed in their genomes, indicating that the effect of aneuploidy is far-reaching and could not be easily eliminated. Meanwhile, among these differentially expressed genes, genes with low-expression level were more likely to be upregulated, while genes with medium- and high-expression level were easy to be downregulated. For the different types of rice aneuploid, upregulated genes were mainly associated with genomic imbalance while downregulated genes were mainly influenced by the specific added chromosome. In conclusion, our results provide new insights into the genetic characterization and evolution of biological aneuploidy genomes.

Background: Thyroid nodules, although mostly benign and symptomless, have a small chance of being cancerous, necessitating accurate diagnosis. This study aims to develop and validate a nomogram for differentiating malignant and non-malignant thyroid nodules in individuals with type 2 diabetes. Methods: The study included 484 patients with both thyroid nodules and type 2 diabetes who underwent thyroid gland lobectomy at Wenzhou Medical University Hospital. Optimal cutoff values for continuous variables were determined using ROC curve analysis. Significant factors identified in univariable analysis were used to construct the nomogram. The monocyte-to-high-density lipoprotein cholesterol ratio (MHR) was visualized through a histogram and scatter diagram. Discriminatory power was assessed using ROC analysis, and calibration curves ensured consistency. Decision curve analysis (DCA) evaluated clinical benefits. Results: The cohort was divided into a training group (70%) and an internal validation group (30%). The scatter diagram revealed a correlation between MHR levels and the proportion of goiter cases, with higher MHR levels associated with increased goiter incidence. The histogram showed higher average MHR levels in goiter patients compared to those with papillary thyroid carcinoma (PTC) in both groups. Multivariate logistic regression identified age, total cholesterol (TC), triglyceride (TG), fasting blood sugar (FSG), fibrinogen, lymphocyte-to-monocyte ratio (LMR), and MHR as independent predictive factors for malignancy in thyroid nodules with type 2 diabetes. The nomogram achieved high discrimination, with C-index values of 0.901 (training data set) and 0.760 (internal validation data set). Calibration curves displayed good agreement, and DCA demonstrated significant net clinical benefits. Conclusions: MHR is associated with sex, serum cholesterol levels, and peripheral blood cell counts, making it a potential novel biomarker for differentiating between PTC and goiter in type 2 diabetes patients.

BackgroundA recent phase III clinical trial (NCT03981796) evaluated the efficacy and safety of dostarlimab combined with carboplatin-paclitaxel (DOS-CP) compared to placebo combined with carboplatin-paclitaxel (PLB-CP) as a first-line treatment for advanced endometrial cancer (EC). The NCT03981796 trial demonstrated that DOS-CP significantly improved progression-free survival and overall survival of patients with advanced EC while maintaining an acceptable safety profile. However, DOS-CP is expensive and its cost-effectiveness has not been evaluated. This study aims to evaluate the cost-effectiveness of DOS-CP compared to PLB-CP as a first-line treatment for advanced EC from the perspective of the Chinese healthcare system.MethodsA Markov model with three health states was developed to evaluate the cost-effectiveness of DOS-CP as a first-line treatment for advanced EC. Clinical efficacy data were derived from the NCT03981796 trial, and drug costs were determined based on national tender prices. Other costs and utility values were obtained from published literature. The outcomes assessed included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of the model was assessed through one-way sensitivity analysis and probabilistic sensitivity analysis.ResultsIn comparison to PLB-CP, the ICER of DOS-CP was $98,276.61/QALY for the overall population, $53,063.61/QALY for the dMMR subgroup, and $124,088.56/QALY for the pMMR subgroup. All of these ICER values were higher than the willingness-to-pay threshold of $38,201 per QALY. The most important variable that affected the results of the model was the discount rate, the cost of dostarlimab, and the utility value for progressive disease.ConclusionFrom the perspective of the Chinese healthcare system, DOS-CP is unlikely to be a cost-effective first-line treatment option for advanced EC.

Background: The EMPOWER-LUNG 3 clinical trial has shown that cemiplimab plus chemotherapy (CCT) significantly extended overall survival (OS) and progression-free survival (PFS) for patients with advanced non-small cell cancer (NSCLC) compared to placebo plus chemotherapy (PCT). However, the cost-effectiveness of this new treatment option remains unknown. Thus, we evaluated the cost-effectiveness of CCT versus (vs.) PCT as the first-line treatment for patients with advanced NSCLC from the perspective of the Chinese healthcare system.Methods: We constructed a Markov model to evaluate the cost-effectiveness of CCT as the first-line treatment for patients with advanced NSCLC. The transition probabilities were extracted from the survival data of the EMPOWER-LUNG 3 trial. The drugs’ costs were referred from national tender prices, while other model input parameters were derived from the EMPOWER-LUNG 3 trial and published literature. The outcome parameters mainly included quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to evaluate the robustness of the model outcomes.Results: Compared to PCT, in the CCT regimen, an additional $79,667 was spent in terms of the total cost and with an additional 0.31 QALYs, resulting in an ICER value of $253,148/QALY. Sensitivity analysis indicated that the hazard ratio (HR) of OS, the cost of cemiplimab (100 mg), and the HR of PFS, all significantly impacted the model’s results. The probability of CCT (vs. PCT) being cost-effective was 0% at a willingness-to-pay threshold of $38,201/QALYs in China. The scenario analysis showed that when the price of cemiplimab was reduced to less than $184.09/100 mg, the CCT regimen could be considered cost-effective as the first-line treatment for patients with advanced NSCLC compared to the PCT.Conclusion: In China, the CCT was not cost-effective as the first-line treatment for patients with advanced NSCLC.

The large-scale integration of renewable energy resources in the power system challenges its economic and secure operation. Particularly, the increasing penetration of renewable energy will result in insufficient system voltage regulation and reactive power support capabilities, and may cause high risks of nodal voltage and branch flow violations. Therefore, to hedge the operational risks under the worst realization of uncertainties of renewable energy sources, a two-stage robust unit commitment (UC) model is developed. Meanwhile, the convexified AC power flow model is incorporated in the robust UC model to more accurately characterize the real-time operating status of power systems. On this basis, an AC power flow-constrained robust unit commitment (ACRUC) model is formulated. A circular linearization method is then adopted to handle the quadratic constraints in the original AC power flow model, transforming them into tractable linear constraints. Furthermore, to reduce the computational complexity caused by the large-scale newly-added constraints after the linearization process, a customized redundant constraint identification (RCI) method is developed, in which two different modes (i.e., cold and warm start modes) are designed considering the difference in base case system operating condition for linearizing branch losses. Then, the redundant network security constraints could be identified by solving a series of relatively simple optimization subproblems. Numerical results on the modified NERL-118 test system indicate that the proposed model could accurately depict actual operation and scheduling conditions, and also verify that the proposed customized RCI method could effectively reduce the problem scale and improve the solution efficiency.

Abstract The drug development process consumes 9–12 years and approximately one billion US dollars in costs. Due to the high finances and time costs required by the traditional drug discovery paradigm, repurposing old drugs to treat cancer and rare diseases is becoming popular. Computational approaches are mainly data-driven and involve a systematic analysis of different data types leading to the formulation of repurposing hypotheses. This study presents a novel scoring algorithm based on chemical and genomic data to repurpose drugs for 669 diseases from 22 groups, including various cancers, musculoskeletal, infections, cardiovascular, and skin diseases. The data types used to design the scoring algorithm are chemical structures, drug-target interactions (DTI), pathways, and disease-gene associations. The repurposed scoring algorithm is strengthened by integrating the most comprehensive manually curated datasets for each data type. At DrugRepo score ≥ 0.4, we repurposed 516 approved drugs across 545 diseases. Moreover, hundreds of novel predicted compounds can be matched with ongoing studies at clinical trials. Our analysis is supported by a web tool available at: http://drugrepo.org/ .

Abstract Background Currently, the direct method is the main approach for establishment of reference interval (RI). However, only a handful of studies have described the effects of sample size on establishment of RI and estimation of sample size. We describe a novel approach for estimation of the sample size when establishing RIs using the transformed parametric and non-parametric methods. Methods A total of 3,697 healthy participants were enrolled in this study. We adopted a two-layer nested loop sample size estimation method to determine the effects of sample size on RI, using thyroid-related hormone as an example. The sample size was selected as the calculation result when the width of the confidence interval (CI) of the upper and lower limit of the RI were both stably

Understanding the characteristics of the aragonite saturation state (Ωarag) is necessary for assessing impacts of ocean acidification, especially in coastal oceans. Based upon surveys conducted in August and October 2022, the distribution and controlling processes of Ωarag were investigated in the North Yellow Sea near the Yalu River estuary. Surface water Ωarag values exhibited substantial variations of 1.14 to 3.79 for the input of river-diluted water and community production, whereas bottom water Ωarag values ranged from 1.82 to 2.40 in August. In addition, surface water Ωarag was further reduced to 1.07–2.37 in October due to the combined effects of seawater temperature decreasing and the upwelling of bottom water with low Ωarag values, while Ωarag values lowed to 1.04–2.14 in bottom water. Considerably low Ωarag values during summer and autumn in nearshore areas, especially in the Yalu River estuary, were resulted from the input of river-diluted water, while the net community respiration and remineralization induced the low bottom water Ωarag values in offshore areas. We suggest that integrated and multidisciplinary studies are required to quantify the trends and dynamics of acidification and its synergistic effects on the marine ecosystem in estuarine and coastal oceans.

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66 μM in human liver microsomes (HLM), while 0.62 μM in rat liver microsomes (RLM) and 2.90 μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0−t), AUC(0−∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.

In this study, the flax (Linum usitatissimum L.) genes associated with resistance to the disease pasmo (Septoria linicola (Speg.) Garassini) were mapped using genome resequencing and bulked segregant analysis (BSA) of genomic DNA of the pasmo-resistant parent y62–9, pasmo-susceptible parent y64–5, and F2 generation segregants. Pasmo resistance genes were identified using Gene Ontology (GO) functional prediction and gene annotation methods. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the biological information and molecular mechanisms associated with the flax-pathogen interaction. The results of a quantitative real-time PCR analysis revealed that the levels of expression of the three genes Lus10003106, Lus10022077, and Lus10021999 differed between the y62–9 (pasmo-resistant) and y64–5 (pasmo-susceptible) parental flax lines after the inoculation of plants with the pasmo pathogen. Thus, these genes may play key roles in the resistance of flax to pasmo. The results of this study provide a foundation to support future studies of the pathogenesis of flax disease and the discovery and cloning of resistance genes and development of new molecular markers toward the development of pasmo-resistant flax varieties.

Background: This study aimed to investigate the pharmacokinetics, safety, and immunogenicity of recombinant humanized anti-human IL-6R monoclonal antibody injection, LZM008, and evaluate the pharmacokinetic similarity between LZM008 and tocilizumab (ACTEMRA®) in Chinese healthy male subjects.Research design and methods: In this randomized, double-blinded, paralleled, two-center Phase I clinical trial, 96 subjects were randomized with a 1:1 ratio to receive 4 mg/kg intravenous dose of LZM008 or ACTEMRA® and evaluated for 28 days. The pharmacokinetic bioequivalence was assessed by the maximum serum concentration (Cmax), the area under the serum concentration–time curve (AUC) from time 0 to the last detectable drug concentration (AUC0-t), and AUC0-∞. The statistical analysis was conducted using SAS Enterprise Guide statistical software. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Anti-drug antibodies (ADAs) were measured by a bridged electrochemiluminescence immunoassay.Results: LZM008 (N = 49) and ACTEMRA® (N = 47) groups showed similar pharmacokinetic properties. After a single intravenous infusion of 4 mg/kg LZM008, the Cmax and AUC0-∞ values of LZM008 reached 87.99 μg/mL and 11,526.70 h*μg/mL, respectively, with Tmax 1.98 h, and the half-life (t1/2) was 83.45 h. The 90% confidence intervals of ratios for Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00%–125.00%. After infusion, one (2.0%) subject in the LZM008 group and three (6.4%) subjects in the ACTEMRA® group showed positive ADA test results. The incidence of treatment emergent adverse events (TEAEs) was comparable in LZM008 and ACTEMRA® groups (98.0% versus 100%), with the decrease in blood fibrinogen and neutrophil counts being the most common TEAEs.Conclusion: The pharmacokinetic characteristics and immunogenicity exhibited by LZM008 were similar to those of the reference product, ACTEMRA®. The safety profiles of LZM008 were similar in the two groups with mild–moderate adverse effects.Trial Registration: The trial is registered at www.chinadrugtrials.org.cn (CTR20190889).

The Ångström–Prescott formula is commonly used in climatological calculation methods of solar radiation simulation. Aiming at the characteristics of a vast area, few meteorological stations, and uneven distribution in the tropical regions of China, in order to obtain the optimal parameters of the global solar radiation calculation model, this study proposes a suitable monthly global solar radiation model based on the single-station approach and the between-groups linkage of the A–P model, which utilizes monthly measured meteorological data from 80 meteorological stations spanning the period from 1996 to 2016 in the tropical zone of China, considering the similarity in changes of monthly sunshine percentage between stations. The applicability and accuracy of the correction parameters (a and b coefficients) were tested and evaluated, and then the modified parameters were extended to conventional meteorological stations through Thiessen polygons. Finally, the spatial distribution of solar radiation in the tropical region of China was simulated by kriging, IDW, and spline interpolation techniques. The results show the following: (1) The single-station model exhibited the highest accuracy in simulating the average annual global solar radiation, followed by the model based on the between-groups linkage. After optimizing the a and b coefficients, the simulation accuracy of the average annual global solar radiation increased by 5.3%, 8.1%, and 4.4% for the whole year, dry season, and wet season, respectively. (2) Through cross-validation, the most suitable spatial interpolation methods for the whole year, dry season, and wet season in the tropical zone of China were IDW, Kriging, and Spline, respectively. This research has positive implications for improving the accuracy of solar radiation prediction and guiding regional agricultural production.

The NAC gene family has transcription factors specific to plants, which are involved in development and stress response and adaptation. In this study, ZmNAC89, an NAC gene in maize that plays a role in saline–alkaline tolerance, was isolated and characterized. ZmNAC89 was localized in the nucleus and had transcriptional activation activity during in vitro experiments. The expression of ZmNAC89 was strongly upregulated under saline–alkaline, drought and ABA treatments. Overexpression of the ZmNAC89 gene in transgenic Arabidopsis and maize enhanced salt tolerance at the seedling stage. Differentially expressed genes (DEGs) were then confirmed via RNA-sequencing analysis with the transgenic maize line. GO analyses showed that oxidation–reduction process-regulated genes were involved in ZmNAC89-mediated salt–alkaline stress. ZmNAC89 may regulate maize saline–alkali tolerance through the REDOX pathway and ABA signal transduction pathway. From 140 inbred maize lines, 20 haplotypes and 16 SNPs were found in the coding region of the ZmNAC89 gene, including the excellent haplotype HAP20. These results contribute to a better understanding of the response mechanism of maize to salt–alkali stress and marker-assisted selection during maize breeding.

Introduction: Hypoxic-ischemic encephalopathy (HIE) is a crucial cause of neonatal death and neurological sequelae, but currently there is no effective therapy drug for HIE. Both oxidative stress and apoptosis play critical roles in the pathological development of HIE. Myricetin, a naturally extracted flavonol compound, exerts remarkable effects against oxidative stress, apoptosis, and inflammation. However, the role and underlying molecular mechanism of myricetin on HIE remain unclear.Methods: In this study, we established the neonatal rats hypoxic-ischemic (HI) brain damage model in vivo and CoCl2 induced PC12 cell model in vitro to explore the neuroprotective effects of myricetin on HI injury, and illuminate the potential mechanism.Results: Our results showed that myricetin intervention could significantly reduce brain infarction volume, glia activation, apoptosis, and oxidative stress marker levels through activating NRF2 (Nuclear factor-E2-related factor 2) and increase the expressions of NRF2 downstream proteins NQO-1 and HO-1. In addition, the NRF2 inhibitor ML385 could significantly reverse the effects of myricetin.Conclusion: This study found that myricetin might alleviate oxidative stress and apoptosis through NRF2 signaling pathway to exert the protective role for HI injury, which suggested that myricetin might be a promising therapeutic agent for HIE.

BackgroundThe relationship between thyroid function parameters and metabolic dysfunction-associated fatty liver disease (MAFLD) remains controversial. Additionally, little is known about the relationship between thyroid function parameters and MAFLD in the Chinese population.MethodsWe conducted a retrospective cross-sectional study involving 177,540 individuals with thyroid function tests and MAFLD diagnosis from 2010-2018. The association between thyroid function parameters and MAFLD was evaluated on a continuous scale with restricted cubic spline (RCS) models and by the prior-defined centile categories with multivariable-adjusted logistic regression models. Thyroid function parameters included free triiodothyronine (FT3), free tetra-iodothyronine (FT4), and thyroid stimulating hormone (TSH). Additionally, fully adjusted RCS models stratified by sex, age, and location were studied.ResultsIn the RCS models, the risk of MAFLD increased with higher levels of FT3 when FT3

Tumor nanovaccines have potential applications in the prevention and treatment of malignant tumors. However, it remains a longstanding challenge in exploiting efficient nanocarriers for inducing potent specifically cellular immune responses. Toward this objective, we herein explore an intensive tumor immunotherapeutic strategy by combining mannosylated nanovaccines and gene regulated PD-L1 blockade for immune stimulation and killing activity. Here, we fabricate a mannose modified PLL-RT (Man-PLL-RT) mediated nanovaccines with dendritic cells (DCs) targeting capacity. Man-PLL-RT is capable of co-encapsulating with antigen (ovalbumin, OVA) and adjuvant (unmethylated cytosine-phosphate-guanine, CpG) by electrostatic interaction. This positively charged Man-PLL-RT/OVA/CpG nanovaccines can facilitate the endocytosis, maturation and cross presentation in DCs. However, the nanovaccines arouse limited inhibition of tumor growth, which is mainly due to the immunosuppressed microenvironment of tumors. Combining tumor nanovaccines with gene regulated PD-L1 blockade leads to an obvious tumor remission in B16F10 melanoma bearing mice. The collaborative strategy provides essential insights to boost the benefits of tumor vaccines by regulating the checkpoint blockade with gene therapy.

The growth simulation of urban underground space (UUS) under the consideration of ecological constraints can effectively reveal the characteristics and trends of UUS changes, and provide a basis for planning the construction of sustainable and livable ecological cities. Therefore, this study considers urban ecological space as a constraint mechanism for UUS development and conducts a simulation study of the dynamic and complex UUS growth process, with a view toward guiding UUS planning under a long-term overall vision. In this study, a patch-based cellular automaton (CA) model is constructed to simulate the dynamic and complex growth process of UUS, subject to the ecological constraints generated by the agent-based land allocation optimization model. The spatial drivers of UUS growth simulation are determined based on the Random Forest (RF) algorithm. The results of the research case in Tianfu New District, Chengdu City, demonstrate that UUS expansion with ecological constraints exhibits sustainable characteristics. However, the growth rate of the UUS development scale is significantly lower when ecological constraints are present compared to when they are not. This study’s results contribute to urban management by finding a balance between UUS development and ecological space conservation, and providing theoretical support for rational UUS planning and decision making in the construction of low-carbon cities.

Lung adenocarcinoma (LUAD) is a prevalent type of thoracic cancer with a poor prognosis and high mortality rate. However, the exact pathogenesis of this cancer is still not fully understood. One potential factor that can contribute to the development of lung adenocarcinoma is DNA methylation, which can cause changes in chromosome structure and potentially lead to the formation of tumors. The baculoviral IAP repeat containing the 5 (BIRC5) gene encodes the Survivin protein, which is a multifunctional gene involved in cell proliferation, migration, and invasion of tumor cells. This gene is elevated in various solid tumors, but its specific role and mechanism in lung adenocarcinoma are not well-known. To identify the potential biomarkers associated with lung adenocarcinoma, we screened the methylation-regulated differentially expressed genes (MeDEGs) of LUAD via bioinformatics analysis. Gene ontology (GO) process and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to investigate the biological function and pathway of MeDEGs. A protein–protein interaction (PPI) network was employed to explore the key module and screen hub genes. We screened out eight hub genes whose products are aberrantly expressed, and whose DNA methylation modification level is significantly changed in lung adenocarcinoma. BIRC5 is a bona fide marker which was remarkably up-regulated in tumor tissues. Flow cytometry analysis, lactate dehydrogenase release (LDH) assay and Micro-PET imaging were performed in A549 cells and a mouse xenograft tumor to explore the function of BIRC5 in cell death of lung adenocarcinoma. We found that BIRC5 was up-regulated and related to a high mortality rate in lung adenocarcinoma patients. Mechanically, the knockdown of BIRC5 inhibited the proliferation of A549 cells and induced pyroptosis via caspase3/GSDME signaling. Our findings have unraveled that BIRC5 holds promise as a novel biomarker and therapeutic target for lung adenocarcinoma. Additionally, we have discovered a novel pathway in which BIRC5 inhibition can induce pyroptosis through the caspase3-GSDME pathway in lung adenocarcinoma cells.

Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and synthesized a novel compound called aloe-emodin derivative (AED), which belongs to the aloe-emodin (AE) family of compounds. AED was formed by covalent binding of monomethyl succinate to the anthraquinone mother nucleus of AE using chemical synthesis techniques. The purpose of this study was to investigate the effects and mechanisms of AED in treating DCM. We induced type 2 diabetes in Sprague–Dawley (SD) rats by administering a high-fat diet and streptozotocin (STZ) injections. The rats were randomly divided into six groups: control, DCM, AED low concentration (50 mg/kg/day), AED high concentration (100 mg/kg/day), AE (100 mg/kg/day), and positive control (glyburide, 2 mg/kg/day) groups. There were eight rats in each group. The rats that attained fasting blood glucose of ˃16.7 mmol/L were considered successful models. We observed significant improvements in cardiac function in the DCM rats with both AED and AE following four weeks of intragastric treatment. However, AED had a more pronounced therapeutic effect on DCM compared to AE. AED exhibited an inhibitory effect on the inflammatory response in the hearts of DCM rats and high-glucose-treated H9C2 cells by suppressing the pyroptosis pathway mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain 3 (NLRP3) inflammasome. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes showed a significant enrichment in the NOD-like receptor signaling pathway compared to the high-glucose group. Furthermore, overexpression of NLRP3 effectively reversed the anti-pyroptosis effects of AED in high-glucose-treated H9C2 cells. This study is the first to demonstrate that AED possesses the ability to inhibit myocardial pyroptosis in DCM. Targeting the pyroptosis pathway mediated by the NLRP3 inflammasome could provide a promising therapeutic strategy to enhance our understanding and treatment of DCM.

This study aimed to explore the pharmacokinetics (PK) and safety of oral (PO) and intravenous (IV) lefamulin in healthy Chinese subjects and to evaluate the efficacy of the intravenous administration regimen using pharmacokinetic/pharmacodynamic (PK/PD) analysis. This study was a randomized, open-label, single- and multiple-dose, intravenous and oral administration study. PK parameters were calculated, and the probability of target attainment (PTA) and the cumulative fraction of response (CFR) after IV administration of lefamulin 150 mg 1 h q12 h were analyzed with Monte Carlo simulations. Lefamulin exhibited extensive distribution. The mean steady-state AUC0–24 h of 150 mg lefamulin IV and 600 mg lefamulin PO were 10.03 and 13.96 μg·h/mL, respectively. For Streptococcus pneumoniae and Staphylococcus aureus, based on the free-drug AUC over MIC ratio (fAUC/MIC) target of 1-log10 cfu reduction, the PK/PD breakpoints were 0.25 and 0.125 mg/L, respectively. The CFR was over 90% for both types of strains with 95% protein binding rate, suggesting that the regimen was microbiologically effective. Lefamulin was safe and well-tolerated. The PK of lefamulin in healthy Chinese subjects were consistent with that in foreign countries. Lefamulin demonstrated the microbiological effectiveness against Streptococcus pneumoniae and Staphylococcus aureus.

Abstract Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Abstract Spontaneous bacterial peritonitis (SBP) is a life-threatening complication in patients with cirrhosis. We aimed to develop an explainable machine learning model to achieve the early prediction and outcome interpretation of SBP. We used CatBoost algorithm to construct MODEL-1 with 46 variables. After dimensionality reduction, we constructed MODEL-2. We calculated and compared the sensitivity and negative predictive value (NPV) of MODEL-1 and MODEL-2. Finally, we used the SHAP (SHapley Additive exPlanations) method to provide insights into the model’s outcome or prediction. MODEL-2 (AUROC: 0.822; 95% confidence interval [CI] 0.783–0.856), liked MODEL-1 (AUROC: 0.822; 95% CI 0.784–0.856), could well predict the risk of SBP in cirrhotic ascites patients. The 6 most influential predictive variables were total protein, C-reactive protein, prothrombin activity, cholinesterase, lymphocyte ratio and apolipoprotein A1. For binary classifier, the sensitivity and NPV of MODEL-1 were 0.894 and 0.885, respectively, while for MODEL-2 they were 0.927 and 0.904, respectively. We applied CatBoost algorithm to establish a practical and explainable prediction model for risk of SBP in cirrhotic patients with ascites. We also identified 6 important variables closely related to the occurrence of SBP.

While immunotherapy is a promising cancer treatment option, durable benefits are often rare due to immune escape. Here, the authors combine epigenetic regulation with gene therapy-mediated immune checkpoint blockade and show efficient anti-tumour effects and immune response in vivo.

With the fierce labor market competition, the family population’s size continues to expand, and the conflict between work and family requirements for individual roles becomes increasingly intense. Most studies focus on work–family conflict as an antecedent variable, and few studies use work–family conflict as an outcome variable. This study aimed to explore the underlying mechanism of the relationship between gender role attitudes and work–family conflict. Two models were tested using conditional process analysis for testing direct and indirect effects on a sample of 324 employees: A serial multiple mediation model, and the multiple mediation model including the moderating role of education level and subjective socioeconomic status. The results suggested that (1) gender role attitudes significantly and positively predicted work–family conflict. (2) Parental sacrifice and subjective well-being played multiple mediating roles between gender role attitudes and work–family conflict. (3) Education level moderated the relationship between gender role attitudes and parental sacrifice, as evidenced by the fact that low education level amplified the positive predictive effect of gender role attitudes on parental sacrifice. (4) Subjective socioeconomic status moderated the relationship between gender role attitudes and subjective well-being, suggesting that high subjective socioeconomic status amplified the negative predictive effect of gender role attitudes on subjective well-being. This work contributes to the understanding of the process underlying the relationship between gender role attitudes and work–family conflict, and to the literature reporting the possible moderated role of education level and subjective socioeconomic status on the influence outcomes of gender role attitudes. Theoretical and practical implications are also discussed.

BackgroundRheumatic heart disease (RHD) remains the leading cause of preventable death and disability in children and young adults, killing an estimated 320,000 individuals worldwide yearly.Materials and methodsWe utilized the Bayesian age-period cohort (BAPC) model to project the change in disease burden from 2020 to 2030 using the data from the Global Burden of Disease (GBD) Study 2019. Then we described the projected epidemiological characteristics of RHD by region, sex, and age.ResultsThe global age-standardized prevalence rate (ASPR) and age-standardized incidence rate (ASIR) of RHD increased from 1990 to 2019, and ASPR will increase to 559.88 per 100,000 population by 2030. The global age-standardized mortality rate (ASMR) of RHD will continue declining, while the projected death cases will increase. Furthermore, ASPR and cases of RHD-associated HF will continue rising, and there will be 2,922,840 heart failure (HF) cases in 2030 globally. Female subjects will still be the dominant population compared to male subjects, and the ASPR of RHD and the ASPR of RHD-associated HF in female subjects will continue to increase from 2020 to 2030. Young people will have the highest ASPR of RHD among all age groups globally, while the elderly will bear a greater death and HF burden.ConclusionIn the following decade, the RHD burden will remain severe. There are large variations in the trend of RHD burden by region, sex, and age. Targeted and effective strategies are needed for the management of RHD, particularly in female subjects and young people in developing regions.

Abstract The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.