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Abstract Background Mannitol is frequently utilized to achieve intracranial brain relaxation during the retrosigmoid approach for auditory brainstem implantation (ABI). Hypertonic saline (HS) is an alternative for reducing intracranial pressure; however, its application during ABI surgery remains under-investigated. We aimed to compare the efficacy and safety between HS and mannitol for maintaining brain relaxation. Methods This single-center retrospective cohort study included pediatric patients undergoing ABI surgery from September 2020 to January 2022 who received only 4.54% HS or 20% mannitol for brain relaxation. The analysis involved initial doses, subsequent doses, and dosing intervals of the two hyperosmolar solutions, as well as the time elapsed from meningeal opening to the first ABI electrode placement attempt. Additionally, the analysis encompassed electrolyte testing, hemodynamic variables, urine output, blood transfusion, second surgeries, adverse events, intensive care unit length of stay, and 30-day mortality. Results We analyzed 68 consecutive pediatric patients; 26 and 42 in the HS and mannitol groups, respectively. The HS group exhibited a reduced rate of supplementary use (7.7% vs. 31%) and lower total urine volume. Perioperative outcomes, mortality, and length of intensive care unit stay did not exhibit significant between-group differences, despite transient increases in blood sodium and chloride observed within 2 h after HS infusion. Conclusions In pediatric ABI surgery, as an osmotherapy for cerebral relaxation, 4.54% HS demonstrated a lower likelihood of necessitating additional supplementation than 20% mannitol. Furthermore, the diuretic effect of HS was weak and the increase in electrolyte levels during surgery was temporary and slight.

Abstract Myocardial ischemia-reperfusion injury (MIRI) is a significant complication following reperfusion therapy after myocardial infarction. Mitochondrial oxidative stress is a critical factor in MIRI, and Sirtuin 3 (SIRT3), as a major mitochondrial deacetylase, plays a key protective role, with its activity potentially regulated by O-GlcNAcylation. This study used the H9C2 cell line to establish a simulated ischemia/reperfusion (SI/R) model, we utilized co-immunoprecipitated to validate the relationship between O-GlcNAc transferase (OGT) and SIRT3, demonstrated SIRT3 O-GlcNAcylation sites through LC–MS/MS, and performed site mutations using CRISPR/Cas9 technology. The results were validated using immunoblotting. SIRT3 and superoxide dismutase 2 (SOD2) activities were detected using a fluorometric assay, while mitochondrial reactive oxygen species (MROS) levels and cellular apoptosis were assessed using immunofluorescence. We have identified an interaction between SIRT3 and OGT, where SIRT3 undergoes dynamic O-GlcNAcylation at the S190 site, facilitating SIRT3 deacetylase activity. During SI/R, elevated levels of O-GlcNAcylation activate SOD2 by promoting SIRT3 enzyme activity, thereby inhibiting excessive MROS production. This significantly mitigates the occurrence of malignant autophagy in myocardial cells during reperfusion, promoting their survival. Conversely, blocking SIRT3 O-GlcNAcylation at the S190 site exacerbates SI/R injury. We demonstrate that O-GlcNAcylation is a crucial post-translational modification (PTM) of SIRT3 during SI/R, shedding light on a promising mechanism for future therapeutic approaches.

BackgroundSystemic Lupus Erythematosus (SLE) is acknowledged for its significant influence on systemic health. This study sought to explore potential crosstalk genes, pathways, and immune cells in the relationship between SLE and moyamoya disease (MMD).MethodsWe obtained data on SLE and MMD from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify common genes. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these shared genes. Hub genes were further selected through the least absolute shrinkage and selection operator (LASSO) regression, and a receiver operating characteristic (ROC) curve was generated based on the results of this selection. Finally, single-sample Gene Set Enrichment Analysis (ssGSEA) was utilized to assess the infiltration levels of 28 immune cells in the expression profile and their association with the identified hub genes.ResultsBy intersecting the important module genes from WGCNA with the DEGs, the study highlighted CAMP, CFD, MYO1F, CTSS, DEFA3, NLRP12, MAN2B1, NMI, QPCT, KCNJ2, JAML, MPZL3, NDC80, FRAT2, THEMIS2, CCL4, FCER1A, EVI2B, CD74, HLA-DRB5, TOR4A, GAPT, CXCR1, LAG3, CD68, NCKAP1L, TMEM33, and S100P as key crosstalk genes linking SLE and MMD. GO analysis indicated that these shared genes were predominantly enriched in immune system process and immune response. LASSO analysis identified MPZL3 as the optimal shared diagnostic biomarkers for both SLE and MMD. Additionally, the analysis of immune cell infiltration revealed the significant involvement of activation of T and monocytes cells in the pathogenesis of SLE and MMD.ConclusionThis study is pioneering in its use of bioinformatics tools to explore the close genetic relationship between MMD and SLE. The genes CAMP, CFD, MYO1F, CTSS, DEFA3, NLRP12, MAN2B1, NMI, QPCT, KCNJ2, JAML, MPZL3, NDC80, FRAT2, THEMIS2, CCL4, FCER1A, EVI2B, CD74, HLA-DRB5, TOR4A, GAPT, CXCR1, LAG3, CD68, NCKAP1L, TMEM33, and S100P have been identified as key crosstalk genes that connect MMD and SLE. Activation of T and monocytes cells-mediated immune responses are proposed to play a significant role in the association between MMD and SLE.

Abstract Background Post-anesthetic emergence agitation is common after general anesthesia and may cause adverse consequences, such as injury as well as respiratory and circulatory complications. Emergence agitation after general anesthesia occurs more frequently in nasal surgery than in other surgical procedures. This study aimed to assess the occurrence of emergence agitation in patients undergoing nasal surgery who were extubated under deep anesthesia or when fully awake. Methods A total of 202 patients (18–60 years, American Society of Anesthesiologists classification: I–II) undergoing nasal surgery under general anesthesia were randomized 1:1 into two groups: a deep extubation group (group D) and an awake extubation group (group A). The primary outcome was the incidence of emergence agitation. The secondary outcomes included number of emergence agitations, sedation score, vital signs, and incidence of adverse events. Results The incidence of emergence agitation was lower in group D than in group A (34.7% vs. 72.8%; p

The historical stockpile of chromium slag in China is large, and the hexavalent chromium in slag leachate is highly toxic and migratory. In order to investigate the migration and transformation pattern of Cr(Ⅵ) in groundwater under the combined effect of pollution source, site hydrogeological condition and hydrogeochemical process, a hexavalent chromium contaminated site was taken as an example in this study, the spatial distribution, hydrogeochemical characteristic, occurrence form and proportion of Cr(Ⅵ) in groundwater, and the main factors affecting migration and transformation of Cr(Ⅵ) are analyzed by sampling and testing groundwater samples, and the combination using of methods such as Kriging interpolation, factor analysis, hydrogeochemical calculation, Piper diagram and ion ratio. The results show that (1) the two aquifers below ground surface 40 m are polluted by Cr(Ⅵ), but the size and degree are different obviously. (2) The main forms of Cr(Ⅵ) in groundwater are \begin{document}${\mathrm{CrO}}_4^{2-} $\end{document} and \begin{document}${\mathrm{HCrO}}_4^- $\end{document}, \begin{document}${\mathrm{Cr}}_2{\mathrm{O}}_7^{2-} $\end{document} content is extremely low, and the anions of samples with high Cr(Ⅵ) concentration are mainly \begin{document}${\mathrm{HCO}}_3^- $\end{document} and \begin{document}${\mathrm{SO}}_4^{2-} $\end{document}, the cations are mainly Na+ and Ca2+. (3) Precipitation leaching and seepage result in the leachate containing large amounts of Na+, \begin{document}${\mathrm{SO}}_4^{2-} $\end{document} and Cr(Ⅵ) entering groundwater. The increasing pH, high concentrations of \begin{document}${\mathrm{HCO}}_3^- $\end{document} and dissolution of iron oxides under low oxidizing environment in groundwater can facilitate the migration of Cr(Ⅵ). Manganese oxides and organic matter are able to change Cr(Ⅵ) content through redox reaction. Evaporation also plays an important role on the enrichment of Cr(Ⅵ) in groundwater. The results of this research can provide strong support for risk management and post remediation of chromium slag contaminated sites.

In 2020, severe diarrhea occurred in four-month-old fattening pigs from nine farms in Shandong Province, China. Fecal samples were collected from diseased pigs and tested by PCR for the presence of mammalian orthoreovirus (MRV), porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV), porcine rotavirus A (PoRVA), transmissible gastroenteritis virus (TGEV), porcine kobuvirus (PKV), and pseudorabies virus (PRV). The viral RNA of MRV and PEDV was detected in the fecal samples. The genome sequences of MRV and PEDV were successfully amplified from the same fecal sample. Genomic and phylogenetic analysis showed that the MRV isolate named MRV2-SD/2020 belongs to serotype 2 MRV (MRV2) and may originate from the reassortment of human and porcine MRVs. Compared with other MRV2 strains, there were four other unique amino acid mutations (L274I, F302L, V347I, and T440M) in the receptor binding region. For the PEDV isolate named PEDV-SD/2020, the nearly complete genome was amplified from the positive fecal samples. Phylogenetic analysis showed that it was classified into the G2a genotype. Compared with CV777 and other PEDV variant strains, its spike (S) protein exhibited two unique mutations (S663T and L966M). This study first reports the co-infection of PEDV and MRV2 in the pigs and provides a new direction for the prevention and control of the diarrhea diseases.

Abstract The progestin regimen is one of the main therapeutic strategies for women with endometrial cancer who undergo conservative management. Although many patients respond well to initial therapy, progestin‐refractory disease inevitably emerges, and the molecular basis underlying progestin resistance has not been comprehensively elucidated. Herein, they demonstrated progestin results in p38‐dependent IDH1 Thr 77 phosphorylation (pT77‐IDH1). pT77‐IDH1 translocates into the nucleus and is recruited to chromatin through its interaction with OCT6. IDH1‐produced α‐ketoglutarate (αKG) then facilitates the activity of OCT6 to promote focal adhesion related target gene transcription to confer progestin resistance. Pharmacological inhibition of p38 or focal adhesion signaling sensitizes endometrial cancer cells to progestin in vivo. The study reveals p38‐dependent pT77‐IDH1 as a key mediator of progestin resistance and a promising target for improving the efficacy of progestin therapy.

Green, low-carbon circular economy and the development model of energy-saving and environmental protection are emerging worldwide, and the world's economies have taken the energy-saving and environmental protection industry as a strategic emerging industry to cultivate and develop. Coordinating finance and technological innovation is crucial to promoting the healthy development of Energy-Saving and Environmental Protection Enterprises (ESEPEs). According to industry classification, this paper divides 121 ESEPEs into 12 categories as research objects. Firstly, the DEA-SBM model is used to calculate financing efficiency (FE) and technological innovation efficiency (TIE). Subsequently, the changes in the two efficiencies are analyzed from the perspectives of time series, industry, and annual mean value, and the changes of the two efficiencies are analyzed from the perspectives of time series, industry, and annual average values. Secondly, through the coupling coordination degree (CCD) model, the development status of the coupling coordination between the two efficiencies is innovated expounded. Finally, the Tobit regression model is used to discuss the factors influencing CCD from the whole and industry perspectives. The results show that: (1) TIE is generally lower than FE, and FE shows a downward trend while TIE shows an upward trend. (2) CCD between the two efficiencies is Near dysfunction, and TIE restricts the development of CCD between the two efficiencies to a certain extent. (3) R&D intensity, enterprise size, and government subsidy intensity have a significant positive impact on CCD between FE and TIE of ESEPEs, while the impact of other factors is not significant.

This study introduces a novel fluxgate current sensor with a compact, ring-shaped configuration that exhibits improved performance through the integration of magnetization residence times and neural networks. The sensor distinguishes itself with a unique magnetization profile, denoted as M waves, which emerge from the interaction between the target signal and ambient magnetic interference, effectively enhancing interference suppression. These M waves highlight the non-linear coupling between the magnetic field and magnetization residence times. Detection of these residence times is accomplished using full-wave rectification circuits and a Schmitt trigger, with a digital output provided by timing sequence detection. A dual-layer feedforward neural network deciphers the target signal, exploiting this non-linear relationship. The sensor achieves a linearity error of 0.054% within a measurement range of 15 A. When juxtaposed with conventional sensors utilizing the residence-time difference strategy, our sensor reduces linearity error by more than 40-fold and extends the effective measurement range by 150%. Furthermore, it demonstrates a significant decrease in ambient magnetic interference.

Abstract Background The pathogenesis of moyamoya disease (MMD) is unclear. Inflammation and immune imbalance have been identified as potential factors contributing to the occurrence and progression of MMD. However, the specific proteins and metabolites responsible for triggering this process are yet to be established. The purpose of this study is to identify differentially expressed proteins and metabolites in patients with MMD and perform Kyoto Encyclopedia of Genes and Genomes pathway integration analysis to pinpoint crucial proteins and metabolites involved in the disease. Methods We performed untargeted metabolomic and data‐independent acquisition proteomic analyses on the serum samples of individuals with MMD and healthy controls (HC). Results In patients with MMD versus HC, 24 proteins and 60 metabolites, including 21 anionic metabolites and 39 cationic metabolites, which were significantly different, were identified. In patients with MMD, several proteins involved in inflammation and immune metabolism, such as tubulin beta‐6 and complement C4, were found to have significantly altered levels. Similarly, many metabolites involved in inflammation and immune metabolisms, such as dimethyl 4‐hydroxyisophthalate, beta‐nicotinamide mononucleotide, 2‐(3‐(4‐pyridyl)‐1H‐1,2,4‐triazol‐5‐yl)pyridine, and PC (17:1/18:2), were significantly altered. Intriguingly, these proteins and metabolites are involved in the progression of atherosclerosis through immune and inflammatory pathways, although some have never been reported in MMD. Moreover, integrated proteomics and metabolomics studies were conducted to determine shared pathways involving cholesterol metabolism, vitamin digestion, fat digestion, and absorption pathways of proteins and metabolites, which warrant further investigation. Conclusions Significant increases in pro‐inflammatory and immunosuppressive abilities have been observed in patients with MMD, accompanied by significant reductions in anti‐inflammatory and immune regulation. Various metabolites and proteins implicated in these processes have been identified for the first time. These findings hold immense significance for comprehending the pathogenesis of MMD and for the development of future drug therapies.

Abstract The procollagen C-protease enhancer (PCOLCE) has been identified to influence tumor growth and metastasis in multiple cancers. However, the relationship between PCOLCE activity and the progression of gliomas remains largely unknown. Glioma RNA-seq data were derived from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas databases for analysis. Kaplan–Meier survival curve, clinical characterization correlation, univariate and multivariate Cox, and receiver operating characteristic curve analyses were performed to assess the prognostic role of PCOLCE. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to determine the functions or pathways associated with PCOLCE. The ESTIMATE and CIBERSORT algorithms, Spearman’s rank correlation analysis, and Tumor Immune Estimation Resource (TIMER) databases were used to explore the relationship between PCOLCE and immune infiltration. Correlation analysis between PCOLCE, related genes, and immune cell markers was conducted using the TIMER database. Immunophenoscore assays were performed to determine differential PCOLCE expression levels in glioma. The sensitivity of multi-drugs were determined to explore potential chemotherapeutic agents in between PCOLCE. Compared to normal brain tissue, PCOLCE expression was increased in glioma and correlated with shorter overall survival (OS). Furthermore, significant differences were observed in the immune scores and immune cell infiltration levels. PCOLCE is positively associated with immune checkpoints and many immune markers. Additionally, PCOLCE expression was higher in gliomas with higher IPS Z-scores in CGGA. High expression of PCOLCE increased sensitivity to multiple chemotherapy agents in CGGA (P

Abstract Background To compare the aneuploidy rate in spontaneous abortion chorionic villus (SA-CV) after D5 and D6 thawed-frozen blastocyst transfer(TBT). Methods This retrospective cohort study recruited 522 patients with early spontaneous abortion from March 2012 to January 2020 in the our center. The aneuploidy rate of SA-CV was compared according to the blastocyst development stage: D5 group (n = 398) and D6 group (n = 124). Results Patients’ characteristics, including age, body mass index, follicle-stimulating hormone, fertilization methods, type of infertility, infertility duration, and gestational age when abortion, did not differ between the two groups (all P > 0.05). Although the mean number of embryos was significantly higher in D6 than in the D5 group (P 35 years or ≤ 35 years), the difference between the D5 and D6 groups remained not statistically significant (P = 0.247 and P = 0.690). Multivariate logistic analysis showed that women’s age was independently associated with the aneuploidy rate (OR = 0.891; 95% CI: [0.854–0.930]; P 35 years group than in the age ≤ 35 years group (61.0% vs. 39.4%, P

Abstract Introduction The potential adverse effects of prolonged exposure to anesthetics in pediatric patients with severe‐to‐profound sensorineural hearing loss remain unclear. This study aimed to examine whether early bilateral cochlear implantation involving long‐duration anesthetic exposure caused greater developmental impairment than that with unilateral cochlear implantation. Methods This prospective observational study included normally developing infants with bilateral severe‐to‐profound sensorineural hearing loss aged 6 months to 2 years who were candidates for unilateral/bilateral cochlear implantation surgery. Baseline (T0), 6‐month (T1), and 1‐year (T2) Gesell Scale scores were measured. The outcomes included fine motor, adaptability, gross motor, language, and social skills scale 6 and 12 months postoperatively. Result The 90 enrolled children with bilateral severe‐to‐profound sensorineural hearing loss (unilateral n = 43; bilateral n = 47) had a younger bilateral group (11.00 ± 3.66 vs. 15.63 ± 6.99 months, p

Shale is composed of a rock matrix and bedding planes with a layered structure, resulting in significant anisotropy in its mechanical properties. In order to study the anisotropic mechanical properties of shale, the shale samples were prepared in different orientations with respect to the bedding planes, and the composition and microstructure of shale were first analyzed by X-ray diffractometer (XRD) and scanning electron microscope (SEM), and then the uniaxial and triaxial compression experiment on shale samples with five different bedding angles (the angle between the loading direction and the normal direction of the bedding planes, 0°, 30°, 45°, 60°, and 90°) were conducted under five confining pressures (0, 10, 20, 30, and 40 MPa), respectively; meanwhile, the acoustic emission (AE) test was carried out in the uniaxial test. The results indicate that the mechanical properties and parameters of shale have obvious anisotropy, and the AE characteristics of shale samples with different bedding angles are significantly different during uniaxial loading. Furthermore, the compressive strength and elastic modulus of the shale samples first decrease and then increase with the increase in the bedding angle under different confining pressures. Moreover, according to the anisotropic grade of compressive strength, the shale has moderate anisotropy. In addition, the failure mode of the shale samples is also anisotropic, and varies with the bedding angle and confining pressure.

Abstract Background and aims A novel non–insulin-based metabolic score for insulin resistance (METS‐IR) index has been proposed as a simple and reliable alternative insulin resistance (IR) marker, but its the predictive value in asymptomatic adults with coronary artery calcification (CAC) remains unclear. Methods and results We enrolled 1576 participants without cardiovascular disease (CVD), who underwent multidetector computed tomography. Logistic regression, restricted cubic spline models and receiver operating characteristic (ROC) curves were used to examine the association between METS-IR, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride glucose index (TyG index) and CAC. In multivariate logistic regression analysis, the increase in METS-IR was independently associated with a higher prevalence of CAC (all P

Despite great success in generation of ultralong organic phosphorescence (UOP) by suppressing non-radiative transitions through attractive interactions, consideration of repulsive interactions on UOP remains largely unexplored. Here, the authors introduce carboxyl groups into organic phosphors, enabling formation of the intense repulsive interactions between the isolated molecules and the matrix in rigid environment.

Abstract Reprogrammed cell metabolism is deemed as one of the hallmarks of cancer. Hexosamine biosynthesis pathway (HBP) acts as an “energy sensor” in cells to regulate metabolic fluxes. Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the rate-limiting enzyme of HBP, is broadly found with elevated expression in human cancers though its exact and concrete role in tumorigenesis still remains unknown and needs further investigation. P38 mitogen-activated protein kinase (MAPK) is an important component of stress-signaling pathway and plays a critical role in cell fate decision, whereas the underlying mechanism of its activation under nutrient stress also remains elusive. In this study, we show that glucose deprivation induces the interaction of GFAT1 with transforming growth factor β-activated kinase 1 binding protein 1 (TAB1) in a TAB1 S438 phosphorylation-dependent manner. Subsequently, the binding of GFAT1 to TAB1 facilitates TTLL5–GFAT1–TAB1 complex formation, and the metabolic activity of GFAT1 for glutamate production further contributes to TTLL5-mediated TAB1 glutamylation. In consequence, TAB1 glutamylation promotes the recruitment of p38α MAPK and thus drives p38 MAPK activation. Physiologically, GFAT1-TAB1-p38 signaling promotes autophagy occurrence and thus protects tumor cell survival under glucose deficiency. Clinical analysis indicates that both GFAT1 and TAB1 S438 phosphorylation levels correlate with the poor prognosis of lung adenocarcinoma patients. These findings altogether uncover an unidentified mechanism underlying p38 MAPK signaling regulation by metabolic enzyme upon nutrient stress and provide theoretical rationality of targeting GFAT1 for cancer treatment.

Apoptosis is a physiological process that occurs in all cell types of the human body, and it profoundly changes the fate of hair by affecting hair follicle cells. This review outlines the cellular changes, intrinsic biochemical characteristics, and mechanisms underlying apoptosis and summarizes the hair follicle life cycle, including development, cycle stages, and corresponding cellular changes. Finally, the relationship between apoptosis and the hair cycle is discussed and the significance of apoptosis in hair loss conditions and drug treatments is highlighted. Apoptosis induces cellular changes and exhibits distinctive properties through intricate signaling pathways. Hair follicles undergo cyclic periods of growth, regression, and dormancy. Apoptosis is closely correlated with the regression phase by triggering hair follicle cell death and shedding. Regulation of apoptosis in hair follicles plays an essential role in hair loss due to maladies and drug treatments. Mitigating apoptosis can enhance hair growth and minimize hair loss. A comprehensive understanding of the correlation between apoptosis and the hair cycle can facilitate the development of novel treatments to prevent hair loss and stimulate hair regeneration.

Hair serves important physiological functions, including temperature regulation and scalp protection. However, excessive shedding not only impacts these functions but can also significantly affect mental health and quality of life. Tianma Gouteng decoction (TGD) is a traditional Chinese medicine used for the treatment of various conditions, including hair loss. However, the associated mechanism underlying its anti-alopecia effect remains unknown. Therefore, this study aims to elucidate these mechanisms by employing systematic biology approaches, as well as in vitro and in vivo experimental validation. The chemical constituents of Tianma Gouteng decoction were identified using UHPLC-MS/MS, from which 39 potential bioactive components were screened, while an additional 131 putative Tianma Gouteng decoction beneficial components were extracted from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) database. We then applied a dual-dimensional network pharmacology approach to analyze the data, followed by validation studies combining molecular docking techniques with in vivo and in vitro experiments. From the 39 bioactive components, including quercetin, luteolin, fisetin, wogonin, oroxylin A, boldine, tetrahydroalstonine, and galangin A, 782 corresponding targets were identified. In particular, GSK3β and β-catenin exhibited strong binding activity with the bioactive compounds. Hence, construction of a bioactive component-target network revealed that the mechanism underlying the anti-alopecia mechanism of Tianma Gouteng decoction primarily involved the Wnt/β-catenin signaling pathway. Moreover, C57BL/6J mice exhibited measurable improvements in hair follicle regeneration following treatment with Tianma Gouteng decoction. Additionally, β-catenin and p-GSK3β levels were upregulated, while GSK3β was downregulated in Tianma Gouteng decoction-treated animals and dermal papilla cells compared to control group. These in vivo and in vitro outcomes validated the targets and pathways predicted in the network pharmacology analysis of Tianma Gouteng decoction. This study provides a systematic analysis approach to identify the underlying anti-alopecia mechanisms of Tianma Gouteng decoction, further providing theoretical support for clinical assessment of Tianma Gouteng decoction.

Abstract Background Early identification of the occurrence of arrhythmia in patients with acute myocardial infarction plays an essential role in clinical decision-making. The present study attempted to use machine learning (ML) methods to build predictive models of arrhythmia after acute myocardial infarction (AMI). Methods A total of 2084 patients with acute myocardial infarction were enrolled in this study. (All data is available on Github: https://github.com/wangsuhuai/AMI-database1.git) . The primary outcome is whether tachyarrhythmia occurred during admission containing atrial arrhythmia, ventricular arrhythmia, and supraventricular tachycardia. All data is randomly divided into a training set (80%) and an internal testing set (20%). Apply three machine learning algorithms: decision tree, random forest (RF), and artificial neural network (ANN) to learn the training set to build a model, then use the testing set to evaluate the prediction performance, and compare it with the model built by the Global Registry of Acute Coronary Events (GRACE) risk variable set. Results Three ML models predict the occurrence of tachyarrhythmias after AMI. After variable selection, the artificial neural network (ANN) model has reached the highest accuracy rate, which is better than the model constructed using the Grace variable set. After applying SHapley Additive exPlanations (SHAP) to make the model interpretable, the most important features are abnormal wall motion, lesion location, bundle branch block, age, and heart rate. Among them, RBBB (odds ratio [OR]: 4.21; 95% confidence interval [CI]: 2.42–7.02), ≥ 2 ventricular walls motion abnormal (OR: 3.26; 95% CI: 2.01–4.36) and right coronary artery occlusion (OR: 3.00; 95% CI: 1.98–4.56) are significant factors related to arrhythmia after AMI. Conclusions We used advanced machine learning methods to build prediction models for tachyarrhythmia after AMI for the first time (especially the ANN model that has the best performance). The current study can supplement the current AMI risk score, provide a reliable evaluation method for the clinic, and broaden the new horizons of ML and clinical research. Trial registration Clinical Trial Registry No.: ChiCTR2100041960.

Based on the classic IPCC carbon emission calculation theory, this paper calculates the agricultural carbon emissions intensity and efficiency in Zhejiang Province from 2011 to 2020. The LMDI model is further adapted to carry out the influence factors of agricultural carbon emissions. In addition, the grey prediction model GM (1, 1) is used to predict the carbon emissions of Zhejiang Province from 2022 to 2025. The results show that the agricultural carbon emissions and carbon emission intensity in Zhejiang Province have a downward trend. Further, it is concluded that Shaoxing, Hangzhou, Jiaxing, and Huzhou are the cities with low emission and high efficiency, and Wenzhou is the city with high emission and low efficiency. Meanwhile, the improvement of Total Factor Productivity (TFP) results from the joint action of Technical Progress Efficiency (TECH) and Technical Efficiency (EFF). TECH is greater than EFF, and Scale Efficiency (SE) and Pure Technical Efficiency (PTE) contributions change with the years. In general, the contribution of PTE is more significant than that of SE, and its improvement mainly rests on technical progress. Among the factors influencing agricultural carbon emission efficiency, agricultural carbon emission intensity and labor force size have inhibiting effects on agricultural carbon emission efficiency growth. In contrast, agricultural industrial structure, economic development, and urbanization positively affect agricultural carbon emission efficiency. The prediction results show that the overall carbon emissions of Zhejiang Province will get a downward trend. Finally, based on these findings, we offer policy implications.

Background and aimsGrowing studies have focused on the effect of lead exposure on human circulatory system, while the relationship between lead exposure and subclinical myocardial injury (SC-MI) is still poorly known. Therefore, this study was to explore the effect of lead exposure on SC-MI.MethodsThe study included 6,272 individuals aged 40 and older without cardiovascular disease (CVD) from the third National Health and Nutrition Examination Survey. Blood lead was used as an alternative marker of lead exposure. Multivariable logistic regression models, restricted cubic spline and threshold effect analyses were performed to investigate the effect of blood lead on SC-MI.ResultsAfter adjusting for age, sex, race, diabetes, hypertension, systolic blood pressure, body mass index, waist-to-hip ratio, triglycerides, total cholesterol, creatinine, fasting plasma glucose and hemoglobin Alc, higher blood lead level was independently related to higher risk of SC-MI (OR 1.047, 95% CI [1.018, 1.077]; P = 0.003). Restricted cubic spline curve showed that there was a non-linear correlation between blood lead and SC-MI. Threshold effect analysis determined that the inflection point of blood lead was 3.8 ug/dl. When the blood lead level was higher than 3.8 ug/dl, there was an independent positive correlation between blood lead level and the risk of SC-MI (OR 1.031, 95% CI [1.009, 1.053]; P < 0.01). And similar associations were also observed among subgroups of male, ≤60 years, >60 years, never smoker, non-Hispanic White, non-Hispanic Black or without hypertension and diabetes.ConclusionsBlood lead was non-linearly related to SC-MI in population free from CVD.

BackgroundAlthough studies have shown that higher waist-hip ratio (WHR) is closely related to higher risk of metabolism-related diseases, the relationship between WHR and subclinical myocardial injury (SC-MI) is unknown. This study was to evaluate the effect of WHR on SC-MI in the general population free from cardiovascular disease.MethodsThe cross-sectional study included 6253 participants without cardiovascular disease (CVD) from the third National Health and Nutrition Examination Survey (NHANES III) for further analysis. Restricted cubic spline, multivariable logistic regression models and subgroup analyses were performed to assess the association between WHR and SC-MI.ResultsThe multivariate logistic regression showed that after adjusting for potential confounding factors, participants in the higher quartiles had higher risk of developing SC-MI than those in the first quartile of WHR [Q3, OR (95% CI): 1.523 (1.159, 2.000), P = 0.002; Q4, OR (95% CI): 1.719 (1.279, 2.311), P < 0.001], and this relationship was robust among the participants aged ≥ 50 years, with hypertension and without diabetes. Every 0.1 unit increase in WHR, as a continuous variable, increased the risk of SC-MI by more than 20% [OR (95% CI): 1.233 (1.092, 1.392), P = 0.001]. And restricted cubic spline analysis showed that there was a linear positive correlation between WHR and the risk of SC-MI.ConclusionsWHR may be an independent risk factor for SC-MI in the general population free from CVD.

There is a close relationship between environmental resource efficiency and the high-quality development of the river basin economy. Improving urban environmental resource efficiency is of great significance to the high-quality development of the river basin. Based on the environmental panel data of cities in the Yangtze River Basin from 2004 to 2020, this paper applies the DEA-Malmquist index model to explore the static characteristics and dynamic changes in the overall environmental resource efficiency of cities in the Yangtze River Basin. Then, the spatial and temporal aspects of the environment are discussed by combining the kernel density function method. The Tobit regression model is used to analyze the factors affecting the environmental resource efficiency of cities in the Yangtze River Basin and its importance. Finally, the grey prediction model is utilized to predict the undesirable output data of cities in the Yangtze River Basin from 2023 to 2025. The results show that the overall urban environmental resource efficiency level in the Yangtze River Basin is high. However, the number of cities that achieve DEA efficiency is less than that of non-DEA efficient cities. The Total Factor Productivity (TFP) of cities shows a “high-low-high” trend, and the technical efficiency change (Effch) and pure technical efficiency change (Pech) have an improvement trend. Industrial structure, regional factors, and openness are positively correlated with environmental resource efficiency, during the economic scale and environmental governance level negatively moderate environmental resource efficiency. The forecast results show that the undesired output of cities in the Yangtze River Basin has been somewhat controlled.

Mitochondria are essential for cell growth, fission, differentiation, and survival, particularly in undivided cells with high energy requirements, such as cardiomyocytes. The morphology and position of mitochondria change with the activity of mitochondrial fission proteins and mitochondrial fusion proteins. These regulatory mechanisms substantially affect cardiomyocyte energy supply and normal function. In mitochondrial fission, dynamin-related protein 1 (Drp1) is involved in the separation and degradation of damaged mitochondria, and accurately regulates mitochondrial renewal and number. Recent studies have revealed a variety of post-translational modification (PTMs) of Drp1, including phosphorylation, SUMOylation, acetylation, O-GlcNAcylation, and S-sulfhydration. These modifications ensure that Drp1 continues to function normally in various signaling pathways, by modulating its activity, stability, and subcellular localization. This article provides an overview of the relationship between Drp1 PTMs and cardiovascular diseases such as heart failure, myocardial infarction, and myocardial ischemia-reperfusion, and describes how these modifications can be targeted and regulated, to help guide cardiovascular disease treatment.

Background: Emergence agitation (EA) is very common in paediatric patients during recovery from general anaesthesia, but underlying mechanisms remain unknown. This prospective study was designed to profile preoperative urine metabolites and identify potential biomarkers that can predict the occurrence of EA.Methods: A total of 224 patients were screened for recruitment; of those, preoperative morning urine samples from 33 paediatric patients with EA and 33 non-EA gender- and age-matched patients after being given sevoflurane general anaesthesia were analysed by ultra-high-performance liquid chromatography (UHPLC) coupled with a Q Exactive Plus mass spectrometer. Univariate analysis and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) were used to analyse these metabolites. The least absolute shrinkage and selection operator (LASSO) regression was used to identify predictive variables. The predictive model was evaluated through the receiver operating characteristic (ROC) analysis and then further assessed with 10-fold cross-validation.Results: Seventy-seven patients completed the study, of which 33 (42.9%) patients developed EA. EA and non-EA patients had many differences in preoperative urine metabolic profiling. Sixteen metabolites including nine aromatic amino acid metabolites, acylcarnitines, pyridoxamine, porphobilinogen, 7-methylxanthine, and 5′-methylthioadenosine were found associated with an increased risk of EA, and they all exhibited higher levels in the EA group than in the non-EA group. The main metabolic pathways involved in these metabolic changes included phenylalanine, tyrosine and tryptophan metabolisms. Among these potential biomarkers, L-tyrosine had the best predictive value with an odds ratio (OR) (95% CI) of 5.27 (2.20–12.63) and the AUC value of 0.81 (0.70–0.91) and was robust with internal 10-fold cross-validation.Conclusion: Urinary aromatic amino acid metabolites are closely associated with EA in paediatric patients, and further validation with larger cohorts and mechanistic studies is needed.Clinical Trial Registration:clinicaltrials.gov, identifier NCT04807998

In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase(OGA) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA, we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein–coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a, Gm7788, Gm41780, Trpc7, Gm29036, and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication during ovarian stimulation. Even though the incidence of OHSS was relatively low in clinical practice, the consequence can be potentially devastating and life-threatening. Abnormal lipid metabolism may relate to the pathological development of OHSS, but there is still a research gap in the lipidomic research. So here in our study, an ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS) based lipidomic analysis was performed using follicular fluid samples obtained from 17 patients undergoing OHSS. The lipid profiles of OHSS patients were characterized by increased cholesterol ester (ChE) and decreased lysophosphatidylcholine (LPC), phosphatidylinositol (PI), sphingomyelin (SM), dimethylphosphatidylethanolamine (dMePE) and lysodimethylphosphatidylethanolamine (LdMePE). Totally 10 lipids including LPC(18:0), SM(d18:1/16:0), PC(18:0/18:1), PC(20:2/20:5), PC(16:0/18:1), TG(16:0/18:1/18:1), TG(16:0/18:2/18:2), TG(16:0/16:1/18:1), ChE(20:4) and TG(8:0/8:0/10:0) were selected as differential lipids. In conclusion, this study demonstrated the alteration of various lipids in OHSS patients, which suggested the key role of lipids during the development of OHSS and shed light on the further pathophysiological research of OHSS.

BackgroundGrowing studies have shown that insulin resistance (IR) is associated with cardiovascular disease (CVD), while the association between IR and subclinical myocardial injury (SC-MI) remains unclear. Hence we aimed to assess the association between IR and SC-MI.MethodsIn this cross-sectional study, we enrolled 6043 individuals (age: 58.43 ± 13.08 years; 46.2% men) free from CVD from the third National Health and Nutrition Examination Survey. A novel metabolic score for insulin resistance (METS-IR) was used as alternative markers of IR. Multivariate logistic regression and restricted cubic spline were performed to evaluate the associations between METS-IR and SC-MI.ResultsThe multivariate logistic regression analysis showed that after adjusting for cardiovascular metabolic risk factors, higher METS-IR was independently correlated with higher risk of SC-MI [as a quartile variable, Q4 vs Q1, OR (95% CI): 1.395 (1.147, 1.698), P = 0.001, P for trend < 0.001; as a continuous variable, per 10-unit increment, OR (95% CI): 1.869 (1.524, 2.292), P < 0.001]. Restricted cubic spline indicated that there was a J-curve connection between METS-IR and SC-MI. Threshold effect analysis ascertained an inflection point of 37 of METS-IR. The ORs (95% CIs) of per 10-unit increase of METS-IR for SC-MI were 0.707 (0.538, 0.928) and 1.327 (1.210, 1.456) on the left and right sides of the inflection point (P < 0.05), respectively. Subgroup analysis showed that the association between METS-IR and SC-MI was only statistically significant in participants without diabetes.ConclusionsMETS-IR was nonlinearly related to SC-MI in the general population without CVD.

Stem cell–based therapy plays a pivotal role in the regeneration of damaged endometrium. Previous studies have demonstrated the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) through diverse administration ways. However, the homing, survival, and differentiation potential of these differently administered BMSCs are poorly defined, and the best route of administration is not well-defined. Herein, we aim to compare the engraftment, retaining time, and therapeutic efficiency of differently administered BMSCs. To achieve this, GFP/Luc-labeled BMSCs administered in two modes were assessed in a thin endometrium rat model: either into the damaged horns directly or through the ipsilateral iliac artery. The retaining time and hemi-quantitative distribution were evaluated by in vivo bioluminescence imaging and immunohistological analysis. Locally administered BMSCs were strongly detected in the abdomen at the first 4 days post treatment but underwent a rapid decrease in luminescent signal afterward and were rarely found 28 days after treatment. In contrast, the retaining time of BMSCs injected through the iliac artery was longer, reflected by more GFP-positive cells detected in the uterine section 28 days post treatment. Differentiation toward endometrial stromal cells was observed. Both routes of administration contributed to the restoration of the damaged endometrium, showing a comparable increase in the endometrial thickness and a decrease in fibrosis. However, more importantly, higher expression of LIF and VEGF, better recruitment, and longer retainment were found in the intra-arterial administration, contributing to the establishment of the optimal administration mode in clinical practice.

Background: Exposure to anesthetics during early life may impair cognitive functions. However, the underlying mechanisms remain largely unknown. We set out to determine effects of sevoflurane anesthesia on folate metabolism and myelination in young non-human primates, mice and children. Methods: Young rhesus macaque and mice received 2.5 to 3% sevoflurane daily for three days. DNA and RNA sequencing and immunohistochemistry among others were used in the studies. We performed unbiased transcriptome profiling in prefrontal cortex of rhesus macaques and mice after the sevoflurane anesthesia. We constructed a brain blood barrier-crossing AAV-PHP.EB vector to harbor ERMN expression in rescue studies. We measured blood folate levels in children after anesthesia and surgery. Findings: We found that thymidylate synthase (TYMS) gene was downregulated after the sevoflurane anesthesia in both rhesus macaque and mice. There was a reduction in blood folate levels in children after the anesthesia and surgery. Combined with transcriptome and genome-wide DNA methylation analysis, we identified that ERMN was the primary target of the disrupted folate metabolism. Myelination was compromised by the anesthesia in the young mice, which was rescued by systematic administration of folic acid or expression of ERMN in the brain through brain-specific delivery of the adeno-associated virus. Moreover, folic acid and expression of ERMN alleviated the cognitive impairment caused by the sevoflurane anesthesia in the mice. Interpretation: General anesthesia leads to disrupted folate metabolism and subsequently defects in myelination in the developmental brain, and ERMN is the important target affected by the anesthesia via epigenetic mechanisms. Keywords: Sevoflurane, Folate, Methylation, ERMN, Myelination, Neurotoxicity

Abstract Background Oxidative stress and neuroinflammation are considered the major central events in the process of Parkinson’s disease (PD). Nrf2 is a key regulator of endogenous defense systems. New finds have contacted activation of Nrf2 signaling with anti-inflammatory activities. Therefore, the outstanding inhibition of neuroinflammation or potent Nrf2 signaling activation holds a promising strategy for PD treatment. Icariin (ICA), a natural compound derived from Herba Epimedii, presents a number of pharmacological properties, including anti-oxidation, anti-aging and anti-inflammatory actions. Recent studies have confirmed ICA exerted neuroprotection against neurodegenerative disorders. However, the underlying mechanisms were not fully elucidated. Methods In the present study, mouse nigral stereotaxic injection of 6-hydroxydopamine (6-OHDA)-induced PD model was performed to investigate ICA-conferred dopamine (DA) neuroprotection. In addition, adult Nrf2 knockout mice and primary rat midbrain neuron-glia co-culture was applied to elucidate whether ICA-exerted neuroprotection was through an Nrf2-dependent mechanism. Results Results indicated that ICA attenuated 6-OHDA-induced DA neurotoxicity and glial cells-mediated neuroinflammatory response. Furtherly, activation of Nrf2 signaling pathway in glial cells participated in ICA-produced neuroprotection, as revealed by the following observations. First, ICA enhanced Nrf2 signaling activation in 6-OHDA-induced mouse PD model. Second, ICA failed to generate DA neuroprotection and suppress glial cells-mediated pro-inflammatory factors production in Nrf2 knockout mice. Third, ICA exhibited neuroprotection in primary neuron-glia co-cultures but not in neuron-enriched cultures (without glial cells presence). Either, ICA-mediated neuroprotection was not discerned after Nrf2 siRNA treatment in neuron-glia co-cultures. Conclusions Our findings identify that ICA attenuated glial cells-mediated neuroinflammation and evoked DA neuroprotection via an Nrf2-dependent manner.

BackgroundTumor mutation burden has been proven to be a good predictor for the efficacy of immunotherapy, especially in patients with hypermutation. However, most research focused on the analysis of hypermutation in individual tumors, and there is a lack of integrated research on the hypermutation across different cancers. This study aimed to characterize hypermutated patients to distinguish between these patients and non-hypermutated patients.MethodsA total of 5,980 tumor samples involving 23 types of solid tumors from the in-house database were included in the study. Based on the cutoff value of tumor mutation burden (TMB), all samples were divided into hypermutated or non-hypermutated groups. Microsatellite instability status, PD-L1 expression and other mutation-related indicators were analyzed.ResultsAmong the 5,980 tumor samples, 1,164 were selected as samples with hypermutation. Compared with the non-hypermutated group, a significant increase in the mutation rates of DNA mismatch repair genes and polymerase genes was detected in the hypermutated group, and there was an overlap between high TMB and high microsatellite instability or high PD-L1. In addition, we found that EGFR, KRAS and PIK3CA had a high frequency of both single nucleotide variation and copy number variation mutations. These identified mutant genes were enriched in the oncogenic signaling pathway and the DNA damage repair pathway. At the same time, the somatic cell characteristics and distribution of the two groups were significantly different.ConclusionsThis study identified genetic and phenotypic characteristics of hypermutated tumors and demonstrated that DNA damage repair is critically involved in hypermutation.

The single-phase polycrystalline copper oxide (Cu2O) films were prepared on sapphire substrates by radio frequency (RF) magnetron sputtering technology which was characterized by low cost and high efficiency. The influences of oxygen flow rate on physical characteristics of the prepared films were investigated. The XRD results showed that the single-phase Cu2O film exhibited a (110) preferred orientation through the analysis of texture coefficient. The AFM images exhibited that the prepared Cu2O film had the highest surface roughness with a distinctive quadrangular surface morphology. The optical transmittance of the single-phase Cu2O film was under 35% and the band gap energy was calculated to be 2.30 eV, the absorption spectra included the peak wavelength of solar radiation and the high absorptivity made it to be a suitable absorbing material. The Hall measurement indicated that all the samples exhibited p-type conductivity. The resistivity, mobility and carrier concentration of the single-phase Cu2O film was 4625 Ω·cm, 1.87 cm2/v·s and 7.227×1014 cm−3, respectively.

BackgroundChildren who are exposed to anesthesia multiple times may undergo cognitive impairment during development. The underlying mechanism has been revealed as anesthesia-induced cognitive deficiency in young rodents and monkeys. However, the molecular mechanism of sevoflurane-induced neural development toxicity is unclear.MethodsBy combining RNA sequencing analysis of macaques’ prefrontal cortex and human neural differentiation, this study investigates the mechanism of sevoflurane-induced neurotoxicity in primates.ResultsThe level of dual specificity protein phosphatase 4 (Dusp4) was significantly downregulated in non-human primates after sevoflurane treatment. We further uncovered the dynamical expression of Dusp4 during the human neural differentiation of human embryonic stem cells and found that knockdown of Dusp4 could significantly inhibit human neural differentiation.ConclusionThis study indicated that Dusp4 is critically involved in the sevoflurane-induced inhibition of neural differentiation in non-human primate and the regulation of human neural differentiation. It also suggested that Dusp4 is a potential therapeutic target for preventing the sevoflurane-induced neurotoxicity in primates.

Abstract Background Single nucleotide polymorphisms (SNPs) in 3′-untranslated region (UTR) of genes related with cell-matrix adhesions and migration might affect miRNA binding and potentially affect the risk of cancer. The present study aimed to screen SNPs in 3′ UTR of cancer-related genes and investigate their contribution to the susceptibility of lung cancer. Methods Seven SNPs were selected and genotyped in a case-control study (322 lung cancer patients and 384 controls) among Chinese Han population. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by logistic regression adjusted for age and gender in multiple genetic models. Results In stratified analyses by gender, three (rs1064607, rs3796283 and rs2378456) of LPP gene were associated with a significantly increased susceptibility for lung cancer among male population. Besides, LPP rs2378456 weakened lung cancer risk in female. LPP rs1064607 polymorphism was significantly correlated with increased risk of lung adenocarcinoma. Furthermore, AA genotype of TNS3 rs9876 polymorphism was associated with lymphatic metastasis. Conclusion Our results provides evidence for the impact of LPP polymorphisms on the susceptibility to lung cancer in Chinese population.

In this work, we reported the effects of sputtering power on the structure, optical and electrical properties of InN nanodots prepared on Al2O3 substrate by magnetron sputtering.The results showed that the as-grown InN films exhibited uniform nanodot morphology and the size of the InN nano grains increased with the sputtering power was increased. The InN nanodot exhibited highly c-axis prefered orientation with mainly InN (002) diffraction. The optical band gap of InN samples showed an decreasing trend with the increase in sputteirng power. Moreover, the electrical properties of the InN samples were discussed in detail by hall effect and the carrier concentration and mobility could be adjusted from 3.233×1019 to 1.655×1020 cm-3 and 1.151 to 10.101 cm2/v•s, respectively. These results will lay a good fundation for the applicaion of InN material in the field of gas sensers and light emitting diodes.

Abstract Background Chromatin modification at mitosis is closely related to transcriptional reactivation in the subsequent cell cycle. We reasoned this process is deregulated by oncogenic signals, which would contribute to mitotic stress resistance in pancreatic cancer. Here, we show DMAP1/Bub3 complex mediates mitotic stress-induced cellular apoptosis, while this effect is counteracted by c-Src in pancreatic cancer cells. Our study aims to uncover an unidentified mechanism underlying the distinct response to mitotic stress between normal cells and pancreatic cancer cells. Methods The interaction between Bub3 and DMAP1 upon mitotic stress signaling was determined through molecular and cell biological methods. The inhibitory effect of c-Src on DMAP1/Bub3-mediated DNA methylation and gene transcription profile was investigated. The association between c-Src-mediated DMAP1 phosphorylation and paclitaxel activity in vivo and clinicopathologic characteristics were analyzed. Results Mitotic arrest induced p38-dependent phosphorylation of Bub3 at Ser211, which promotes DMAP1/Bub3 interaction. DMAP1/Bub3 complex is recruited by TAp73 to the promoter of anti-apoptotic gene BCL2L1, thus mediates the DNA methylation and represses gene transcription linked to cell apoptosis. Meanwhile, DMAP1 was highly phosphorylated at Tyr 246 by c-Src in pancreatic cancer cells, which impedes DMAP1/Bub3 interaction and the relevant cellular activites. Blocking DMAP1 pTyr-246 potentiates paclitaxel-inhibited tumor growth. Clinically, DMAP1 Tyr 246 phosphorylation correlates with c-Src activity in human pancreatic cancer specimens and poor prognosis in pancreatic cancer patients. Conclusions Our findings reveal a regulatory role of Bub3 in DMAP1-mediated DNA methylation upon mitotic stress and provide the relevance of DMAP1 pTyr-246 to mitotic stress resistance during pancreatic cancer treatment.

Improved therapeutics are needed for treating breast cancer. Here they show the druggability of myoferlin with a small molecule inhibitor in breast cancer and demonstrate its anti-breast cancer effects in vitro and in vivo.

Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer. Keywords: HDACs, EphA2, WW437, Breast cancer, Growth, Metastasis

Abstract Background The sensitivity and specificity of non-invasive diagnostic methods for endometriosis, especially at early stages, are not optimal. The clinical diagnostic indicator cancer antigen 125 (CA125) performs poorly in the diagnosis of minimal endometriosis, with a sensitivity of 24%. Therefore, it is urgent to explore novel diagnostic biomarkers. We evaluated the metabolomic profile variation of the eutopic endometrium between minimal-mild endometriosis patients and healthy women by ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS). Methods Our study comprised 29 patients with laparoscopically confirmed endometriosis at stages I-II and 37 infertile women who underwent diagnostic laparoscopy combined with hysteroscopy from January 2014 to January 2015. Eutopic endometrium samples were collected by pipelle endometrial biopsy. The metabolites were quantified by UHPLC-ESI-HRMS. The best combination of biomarkers was then selected by performing step-wise logistic regression analysis with backward elimination. Results Twelve metabolites were identified as endometriosis-associated biomarkers. The eutopic endometrium metabolomic profile of the endometriosis patients was characterized by a significant increase in the concentration of hypoxanthine, L-arginine, L-tyrosine, leucine, lysine, inosine, omega-3 arachidonic acid, guanosine, xanthosine, lysophosphatidylethanolamine and asparagine. In contrast, the concentration of uric acid was decreased. Metabolites were filtered by step-wise logistic regression with backward elimination, and a model containing uric acid, hypoxanthine, and lysophosphatidylethanolamine was constructed. Receiver-operating characteristic (ROC) analysis confirmed the prognostic value of these parameters for the diagnosis of minimal/mild endometriosis with a sensitivity of 66.7% and a specificity of 90.0%. Conclusions Metabolomics analysis of the eutopic endometrium in endometriosis was effectively characterized by UHPLC-ESI-HRMS-based metabolomics. Our study supports the importance of purine and amino acid metabolites in the pathophysiology of endometriosis and provides potential biomarkers for semi-invasive diagnosis of early-stage endometriosis.

Following publication of the work [1], authors reported the “flow cytometery plots” panel in Fig. 4e contained an inter-duplication in error.

In colorectal cancer, EGFR signalling is implicated in metastasis. Here, the authors unravel a mechanism through which EGF stimulation induces MIIP phosphorylation, leading to MIIP interacting with RelA—this prevents RelA deactylation and enhances transcriptional activity, facilitating metastasis.

Abstract Background Laryngeal squamous cell carcinoma (LSCC) is one of the most prevalent malignant neoplasms of the upper respiratory tract. Studies have confirmed that an unstable chromosome constitution promotes the progress of laryngeal tumorigenesis, and ACYP2 has been confirmed as a telomere length‐related gene. However, to date, the association between ACYP2 polymorphisms and LSCC susceptibility has not been investigated. Methods We performed this study to explore the effect of 11 single‐nucleotide polymorphisms (SNPs) in ACYP2 on LSCC susceptibility in Chinese Han males. Unconditional logistic regression analysis adjusted for age was used to calculate the odds ratios and 95% confidence intervals. Results Based on allele and genotype models, our results showed that rs1682111 variant was significantly associated with a decreased LSCC susceptibility (p

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41419-021-03529-7

The authors regret that the incorrect identification of “omega-3 arachidonic acid” published in the original manuscript [1].

Emerging Microbes & Infections (2017) 6, e54; doi:10.1038/emi.2017.39; published online 21 June 2017