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Abstract Background Obesity is characterized by excessive fat accumulation, which is related with abnormal pluripotency of mesenchymal stem cells (MSCs). Recently, there is growing evidence that the disorder of maternal vitamin D (VD) intake is a well-known risk factor for long-term adverse health outcomes to their offspring. Otherwise, less is known of its repercussion and underlying mechanisms on the different differentiation potential of MSCs. Methods Four-week-old female C57BL/6J mice were fed with different VD reproductive diets throughout the whole pregnancy and lactation. The characteristics of BMSCs from their seven-day male offspring, VDR knockdown establishment of HuMSCs and HuMSCs under the different VD interventions in vitro were confirmed by flow cytometry, RT-PCR, and immunofluorescence. The roles of VD on their mitochondrial dysfunction and differentiation potential were also investigated. Then their remaining weaned male pups were induced by administrating high-fat-diet (HFD) for 16 weeks and normal fat diet was simultaneously as controls. Their lipid accumulation and adipocytes hypertrophy were determined by histological staining and related gene expressions. Results Herein, it was proved that imbalance of early-life VD intake could significantly aggravate the occurrence of obesity by inducing the adipogenesis through affecting the VD metabolism and related metabolites (P

Abstract Exposure to nutritional or environmental factors in early life determines susceptibility to nonalcoholic fatty liver disease (NAFLD). The effect of paternal preconceptional n‐3 polyunsaturated fatty acids (n‐3 PUFAs) on offspring NAFLD development remains unknown. Herein, a mouse model that weaning male mice (F0) received diet supplementation of normal n‐3 PUFA content (n‐6:n‐3 PUFA ratio = 4.3:1) or high n‐3 PUFA content (n‐6:n‐3 ratio = 1.5:1) for 12 weeks, and an n‐3 PUFA‐deficient diet as control, was used for the production of next generation. The F1 and F2 offspring were generated by mating F0 and F1 male mice with virgin female mice, respectively, and after weaning, were fed a high‐fat diet to induce NAFLD. The paternal n‐3 PUFA supplementation improved the scores of steatosis, inflammation and ballooning, and the fibrosis in the liver of two generations, with expressional upregulation of genes associated with fat oxidation (Atgl, Ppara, or Cpt1a), and downregulation of inflammatory genes (Ccl2, Tnf‐α, F4/80, CD206, or CD11c) and fibrosis genes (Tgf‐β, Timp1, or Col1a1). The lessened brown adipose tissue whitening, altered gut bacterial compositions, and altered expression of the imprinted genes (H19, Igf2, and Plagl1) might mediate the impact of paternal n‐3 PUFAs on offspring's NAFLD development, which was dose‐dependent. The data indicate that preconceptional higher paternal intake of n‐3 PUFAs might have intergenerational and transgenerational alleviating impact on obesity‐associated NAFLD development in the offspring through multiple pathways.

AbstractAcute myocardial infarction, characterized by high morbidity and mortality, has now become a serious health hazard for human beings. Conventional surgical interventions to restore blood flow can rapidly relieve acute myocardial ischemia, but the ensuing myocardial ischemia-reperfusion injury (MI/RI) and subsequent heart failure have become medical challenges that researchers have been trying to overcome. The pathogenesis of MI/RI involves several mechanisms, including overproduction of reactive oxygen species, abnormal mitochondrial function, calcium overload, and other factors that induce cell death and inflammatory responses. These mechanisms have led to the exploration of antioxidant and inflammation-modulating therapies, as well as the development of myocardial protective factors and stem cell therapies. However, the short half-life, low bioavailability, and lack of targeting of these drugs that modulate these pathological mechanisms, combined with liver and spleen sequestration and continuous washout of blood flow from myocardial sites, severely compromise the expected efficacy of clinical drugs. To address these issues, employing conventional nanocarriers and integrating them with contemporary biomimetic nanocarriers, which rely on passive targeting and active targeting through precise modifications, can effectively prolong the duration of therapeutic agents within the body, enhance their bioavailability, and augment their retention at the injured myocardium. Consequently, these approaches significantly enhance therapeutic effectiveness while minimizing toxic side effects. This article reviews current drug delivery systems used for MI/RI, aiming to offer a fresh perspective on treating this disease.

Purpose: This study aimed to investigated the key chemical components and the effect of the aqueous extract of Schisandra sphenanthera (SSAE) on alcoholic liver disease (ALD) and the related molecular mechanism. Methods: This study employed UPLC-Q-TOF-MS/MS to identify the chemical compositions in SSAE. ALD rat model was established through oral administration of white spirit. Transcriptome sequencing, weighted gene co-expression network construction analysis (WGCNA), and network pharmacology were used to predict key compositions and pathways targeted by SSAE for the treatment of ALD. Enzyme-linked immunosorbent assay (ELISA), biochemical kits, hematoxylin-eosin (HE) staining, Western blotting (WB) analysis, and immunohistochemical analysis were used to validate the mechanism of action of SSAE in treating ALD. Results: Active ingredients such as schisandrin A, schisandrol A, and schisandrol B were found to regulate the PI3K/AKT/IKK signaling pathway. Compared to the model group, the SSAE group demonstrated significant improvements in cellular solidification and tissue inflammation in the liver tissues of ALD model rats. Additionally, SSAE regulated the levels of a spartate aminotransferase (AST), alanine aminotransferase (ALT), alcohol dehydrogenase (ADH), and aldehyde Dehydrogenase (ALDH) in serum (P

As a response of the coastal oceans to more severe anthropogenic disturbance, increasing coastal primary production has been more frequently observed in recent years. This raises the question of how this progressive change reshapes the long-term carbon sequestration in the coastal oceans. With this question in mind, we investigated the sediment organic matter (OM) preserved on the shelf of the northern South China Sea (NSCS) where high primary production has been observed. Across this sediment core, relatively low total organic carbon content of around 0.60% was observed. Fatty acids with less carbon numbers exhibit exponential decreases downward with degradation rate constants ranging from 0.10 to 0.17 y-1, no matter they were from single sources (14:0 presumably from marine OM and ai-15:0, i-15:0, 15:0 from bacterial OM) or mixed sources (16:0). Meanwhile fatty acids with more carbon numbers, either 18:0 and 24:0 from mixed sources, or 26:0 and 28:0 presumably from terrestrial input, were less varied in concentrations with depth. This demonstrates a preferential decomposition of labile fatty acids during the early diagenesis of coastal sediment organic matter. A decrease of labile fatty acids δ13C values was observed with the decomposition, from which kinetic isotope fractionations were predicted ranging from 0.7 to 1.5‰. This provides an isotopic constraint of the mixing model to quantify labile organic matter from terrestrial input and local phytoplankton production, from which declined contribution of local phytoplankton production to labile fatty acids was identified in more recent sediment. This finding together with the low organic carbon content and rapid removal of fatty acids in the top sediment, demonstrates the poor preservation of labile organic matter on the shelf of NSCS, implying that the increasing primary production has not enhanced the coastal carbon sequestration yet, but rather leads to more intensified respiration with a potential risk to increase the CO2 outgassing from the coastal oceans.

Allergic respiratory diseases can increase serum carcinoembryonic antigen levels. We report three cases experiencing allergic symptoms that proved refractory to inhaled corticosteroids but exhibited a positive response to long-term treatment with oral corticosteroids. This response was characterized by a synchronous alteration in serum eosinophil counts and carcinoembryonic antigen levels. Immunofluorescence assays indicated localized carcinoembryonic antigen production within eosinophils. In addition, we conducted a systematic review of patients exhibiting similar characteristics on PubMed. After comprehensively reviewing this unique pathophysiological condition, we herein introduced a novel term “Allergic hyper-carcinoembryonic antigen syndrome,” defined by the following criteria: (1) recurrent asthmatic attacks; (2) eosinophilia or pulmonary eosinophilic infiltrations accompanied by elevated serum carcinoembryonic antigen levels; (3) pulmonary lesions determined by imaging or biopsy; (4) exclusion of malignancy and infections; and (5) responsive to systemic corticosteroids. Allergic hyper-carcinoembryonic antigen syndrome suggests systemic corticosteroids should be introduced early when managing allergic patients with both eosinophilia and elevated serum carcinoembryonic antigen levels.

In machine learning (ML)-based hydrological forecasting, particularly in medium- and long-term prediction, judicious predictor selection is paramount, as it ultimately determines the forecast accuracy. This study pioneered an advanced predictor-screening method that synergizes the mutual information (MI) and random forest (RF) technologies through minimum-redundancy-maximum-relevance-recursive feature elimination-random forest (mRMR-RFE-RF) method, blending both filtering and wrapping techniques. This method was rigorously tested through a detailed case study in the Danjiangkou basin, where a comprehensive analysis of 1560 meteorological factors was conducted. Employing three sophisticated ML algorithms—RF, eXtreme Gradient Boosting (XGB), and Light Gradient Boosting (LGB)—we developed precipitation forecasting models. Furthermore, we performed an in-depth rationality analysis of high-frequency predictors. The findings from our study show that this novel hybrid screening strategy markedly outperformed conventional singular predictor-screening methods in enhancing the accuracy of precipitation forecasting when integrated into these forecasting models. Moreover, it assured the validity of the high-frequency forecast factors employed. Therefore, this innovative method not only elevates the accuracy of medium- and long-term precipitation forecasting but also contributes a novel perspective to the methodology of predictor selection in hydrological forecasting models.

Accurate medium- and long-term hydrological forecasting is crucial for sustainable water management, infrastructure planning, and ecosystem conservation. This study integrates visual geometry group convolution neural network algorithm (VGGNet)-driven precipitation similarity analysis with hydrological modeling to enhance streamflow forecasting accuracy. Traditional process-driven hydrological models, which rely on detailed physical mechanisms, often falter in data-scarce regions, whereas data-driven models, despite their simplicity, lack interpretability. By combining these approaches, we propose a novel methodology that leverages the image recognition capabilities of convolutional neural network, specifically VGGNet, to perform precipitation similarity analysis. This method transforms monthly precipitation data into daily forecasts, addressing the challenge of temporal downscaling. The Danjiangkou Basin in China serves as the study area, with historical precipitation and streamflow data from 1982 to 2015. The VGGNet model identifies historical months with similar precipitation patterns, and the Soil and Water Assessment Tool model is used to predict streamflow. Results demonstrate significant improvements in forecasting accuracy, with Pearson Correlation Coefficient of 0.89 and Nash-Sutcliffe Efficiency of 0.79. This integrated approach shows promise for advancing medium- and long-term hydrological forecasting techniques, providing a robust tool for effective water resource management.

The accurate prediction of climate patterns is crucial for effective environmental management and strategic planning, particularly in the face of increasing climate variability and extreme weather events. This study focuses on enhancing the predictive accuracy of global climate models by integrating a random forest algorithm with seasonal bias correction, which is aimed at forecasting changes in precipitation and temperature across various climate scenarios. Our approach significantly improves the precision of climate forecasts by using a comprehensive dataset that includes historical climate data and future projections under Representative Concentration Pathways. For precipitation, after implementing seasonal bias correction, the Correlation Coefficient improved from 0.826 to 0.860, and the Nash–Sutcliffe Efficiency increased from 0.633 to 0.735. In addition, the Mean Absolute Error and Root Mean Square Error decreased, thereby enhancing the model's reliability in predicting extreme precipitation events. Temperature forecasts also benefited from the Random Forest model, achieving a Correlation Coefficient of up to 0.987, indicating a strong predictive performance. These improvements highlight the potential of machine learning methods in refining climate models, thus providing more accurate tools for policymakers and planners to manage climate risks. Furthermore, the successful application of these advanced statistical techniques underscores the importance of continuous innovation in climate science, ensuring that climate projections remain relevant and reliable in informing global climate resilience and adaptation strategies.

The maintenance of biodiversity and ecological balance heavily relies on the diversity of insects. In order to investigate the impacts of elevation and human disturbance, as well as their interactions on insect diversity, we conducted an intensive survey of insects in the Hengduan Mountain Range, which is situated on the southeastern periphery of the Tibetan Plateau in China. A total of 50 line transects were established in this study to investigate the impact of elevation and human disturbance on insect diversity and distribution patterns. Designed insect surveys were conducted at various elevations and levels of human disturbance, and statistical methods such as generalized linear modeling and redundancy analysis were employed for data analysis. The results of this study indicated a negative correlation between insect diversity and elevation. Additionally, moderate disturbance was found to have a positive impact on insect diversity to some extent. The explanatory power of the model for the distribution of insect diversity could be improved if elevation and human disturbance were included as an interaction effect into the model, and there were differences in the effects of human disturbances on insect diversity at different elevation levels. The highest insect diversity was observed under low disturbance conditions below elevation of ~2200 m, whereas above this threshold, insect diversity was the highest under moderate disturbance compared to low disturbance. The response of different insect taxa to the interactions of elevation and human disturbance varied. The findings imply that when formulating strategies for managing insect diversity, it is crucial to thoroughly consider the interaction of environmental factors and disturbance response of individual insect taxa.

Rosemary (Rosmarinus officinalis L) is a medicinal and edible plant. Rosemary essential oil (REO) is the principal constituent of rosemary and possesses anti-inflammatory and antioxidant properties. In this study, we evaluated the cell viability and anti-inflammatory activity of REO through the MTT assay and LPS-induced NO production in mouse RAW264.7 cells, respectively. The optimal formulation for the preparation of REO- microemulsion (REO-ME) was determined employing reversed-phase emulsification in conjunction with pseudo-triphasic diagrams. Transcriptomics, combined with network pharmacology, was employed to identify key signaling pathways, and molecular docking analysis was performed to investigate the relationship between the active ingredients of REO-ME and the key targets. The results showed that REO-ME is an O/W type ME. In addition, further pharmacodynamic experiments showed that REO-ME inhibits the expression of inflammatory factors such as IL-6, IL-1β, and TNF-α by regulating the key targets in the IL-17 signaling pathway, thereby to alleviating UC.

ObjectiveThe aim of this study was to identify the molecular subtypes of breast cancer based on chromatin regulator-related genes.MethodsThe RNA sequencing data of The Cancer Genome Atlas–Breast Cancer cohort were obtained from the official website, while the single-cell data were downloaded from the Gene Expression Omnibus database (GSE176078). Validation was performed using the Molecular Taxonomy of Breast Cancer International Consortium dataset. Furthermore, the immune characteristics, tumor stemness, heterogeneity, and clinical characteristics of these molecular subtypes were analyzed. The correlation between chromatin regulators and chemotherapy resistance was examined in vitro using the quantitative real-time polymerase chain reaction (qRT-PCR) and Cell Counting Kit-8 (CCK8) assays.ResultsThis study identified three stable molecular subtypes with different prognostic and pathological features. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction analyses revealed that the differentially expressed genes were associated with disease processes, such as mitotic nuclear division, chromosome segregation, condensed chromosome, and specific chromosome region. The T stage and subtypes were correlated with the clinical features. Tumor heterogeneity (mutant-allele tumor heterogeneity, tumor mutational burden, purity, and homologous recombination deficiency) and tumor stemness (RNA expression-based stemness score, epigenetically regulated RNA expression-based stemness score, DNA methylation-based stemness score, and epigenetically regulated DNA methylation-based stemness score) significantly varied between the three subtypes. Furthermore, Western blotting, qRT-PCR, and CCK8 assays demonstrated that the expression of ASCL1 was positively correlated with chemotherapy resistance in breast cancer.ConclusionThis study identified the subtypes of breast cancer based on chromatin regulators and analyzed their clinical features, gene mutation status, immunophenotype, and drug sensitivity. The results of this study provide effective strategies for assessing clinical prognosis and developing personalized treatment strategies.

Abstract Background Metaplastic breast cancer(MBC) is a specific pathological type of invasive breast cancer. There are few studies related to MBC due to its rarity. This study aimed to analyse the differences in clinicopathological characteristics and prognosis between Metaplastic breast cancer and triple-negative invasive ductal carcinoma (TN-IDC). Methods We retrospectively compared the clinicopathological characteristics of patients diagnosed with MBC and TN-IDC at the Fourth Hospital of Hebei Medical University between 2011 and 2020 in a 1:2 ratio. The log-rank test was used to compare the two groups’ disease-free survival (DFS) and overall survival (OS). For MBCs, we performed univariate and multivariate analyses using the Cox proportional hazards model to determine the characteristics that impacted OS and DFS. Results A total of 81 patients with MBC and 162 patients with TN-IDC were included in this study. At initial diagnosis, MBC patients had larger tumour diameters(P = 0.03) and fewer positive lymph nodes (P = 0.04). Patients with MBC were more likely to have organ metastases after surgery (P = 0.03). Despite receiving the same treatment, MBC patients had worse DFS (HR = 1.66, 95%CI 0.90–3.08, P = 0.11) and OS (HR = 1.98, 95% CI 1.03–3.81, P = 0.04), and OS was statistically significant. Positive lymph nodes at initial diagnosis were associated with worse DFS (HR = 3.98, 95%CI 1.05–15.12, P = 0.04) and OS (HR = 3.70, 95%CI 1.03–13.34, P = 0.04) for patients with MBC. The efficacy of platinum-based agents is insensitive for MBC patients receiving chemotherapy. In addition, patients treated with preoperative chemotherapy had worse DFS compared to patients treated with postoperative chemotherapy (HR = 3.51, 95%CI 1.05–11.75, P = 0.04). Conclusions The clinicopathological characteristics and prognosis of MBC and TN-IDC differ in many ways. Further studies are required to determine suitable treatment guidelines for patients with MBC.

Abstract Background Previous studies have linked gut microbiota with cancer etiology, but the associations for specific gut microbiota are causal or owing to bias remain to be elucidated. Methods We performed a two‐sample Mendelian randomization (MR) analysis to assess the causal effect of gut microbiota on cancer risk. Five common cancers, including breast, endometrial, lung, ovarian, and prostate cancer as well as their subtypes (sample sizes ranging from 27,209 to 228,951) were included as the outcomes. Genetic information for gut microbiota was obtained from a genome‐wide association study (GWAS) comprising 18,340 participants. In univariable MR (UVMR) analysis, the inverse variance weighted (IVW) method was conducted as the primary method, with the robust adjusted profile scores, weighted median, and MR Egger used as supplementary methods for causal inference. Sensitivity analyses including the Cochran Q test, Egger intercept test, and leave‐one‐out analysis were performed to verify the robustness of the MR results. Multivariable MR (MVMR) was performed to evaluate the direct causal effects of gut microbiota on the risk of cancers. Results UVMR detected a higher abundance of genus Sellimonas predicted a higher risk of estrogen receptor‐positive breast cancer (OR = 1.09, 95% CI 1.05–1.14, p = 2.01 × 10−5), and a higher abundance of class Alphaproteobacteria was associated with a lower risk of prostate cancer (OR = 0.84, 95% CI 0.75–0.93, p = 1.11 × 10−3). Sensitivity analysis found little evidence of bias in the current study. MVMR further confirmed that genus Sellimonas exerted a direct effect on breast cancer, while the effect of class Alphaproteobacteria on prostate cancer was driven by the common risk factors of prostate cancer. Conclusion Our study implies the involvement of gut microbiota in cancer development, which provides a novel potential target for cancer screening and prevention, and might have an implication for future functional analysis.

Abstract Background Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. Methods Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. Results A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95–0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97–0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11–0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. Conclusions For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

The interaction between fig wasps and their host fig trees (Ficus spp.) is a striking example of an obligate pollination mutualism. Male and female fig wasps are confined within their natal patch instead of panmictic; under this circumstance, mating only occurs between individuals of the same patch. This is known as a local mate competition (LMC). It pays foundresses to invest mainly in daughters and to only produce enough sons to ensure that all female offspring can be fertilized, but in nature, pollinating fig wasps may face many problems with host quality, such as limitation of oviposition sites and the nutrition deficiency of the host fig. The sex ratio of wasps can determine the stability of fig–fig wasp mutualistic system and, thus, the stability of other species associated with it. In this study, we controlled the quality of host figs in three ways. The results showed that the host fig age can influence the sex ratio of pollinator offspring, while the foundress numbers and the presence of pollen have no significant effect on it. A compelling explanation for this result is that the sex-dependent mortality occurs. This is a novel finding of how host quality influences the interaction of fig and fig wasps, which can also help us understand the evolution and stability mechanism of this symbiotic system.

Pueraria thomsonii Radix. as an important edible and medicinal plant in China, its effects and mechanisms on alcoholic liver disease (ALD) remain unclear. Herein, we investigated the effects and mechanisms of the water extracts of Pueraria thomsonii (WEPT) in the ALD rat model induced by Chinese Baijiu. The results revealed that, a total of 23 compounds were obtained from the WEPT by UPLC-Q-TOF-MS. Compared with the model group, WEPT group showed a significant decrease in liver index and serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST) and Cytochrome P450 2E1 (CYP2E1) levels in the livers, with a significant increase in ethanol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) levels in the livers, significantly reduced the expression of HSP90, p-AKT, p-IKK and NOX4 in the liver tissues. Our study demonstrates that Pueraria thomsonii Radix may be beneficial food for alcoholic liver disease, by inhibited the PI3K/AKT and NOX4/ROS signaling pathways.

BackgroundCurrently, it remains unclear regarding the association between tumor-infiltrating lymphocytes (TILs) and the efficacy of postoperative radiotherapy in primary tumors. Here we attempted to investigate the effect of TILs depending on the presence of postmastectomy radiotherapy (PMRT) on the prognosis in pT1-2N1M0 breast cancer.MethodsThe clinical data of pT1-2N1M0 breast cancer patients undergoing mastectomy and axillary lymph node dissection were retrospectively analyzed. The effect of TILs on the prognosis was assessed based on the infiltration degree (low: TILs ≤10%, high: TILs >10%), and then the prognosis of patients with low and high infiltration of TILs was analyzed based on presence or absence of PMRT.ResultsTotally 213 patients were eligible for the study, including 162 cases of low infiltration and 51 of high infiltration. High-infiltration patients tended to be ER/PR-negative, HER2-positive, and have high histological grade. The infiltration in triple-negative and HER2-positive subtypes was higher compared with Luminal A subtype. Regarding local-regional recurrence-free survival, recurrence-free survival, and overall survival (OS) rates, the differences were all inapparent whether in high- and low-infiltration patients or in high-infiltration patients with/without PMRT. Compared with those without PMRT, low-infiltration patients with PMRT showed a significantly increased OS rate (92.8% vs. 80.0%, p=0.023). Multivariate analysis further confirmed PMRT as an independent predicator of OS in low-infiltration patients (HR: 0.228, 95%CI: 0.081-0.644, p=0.005).ConclusionHigh infiltration of TILs in pT1-2N1M0 breast cancer may be associated with clinicopathological factors. Low-infiltration patients, but not high-infiltration patients, may derive survival benefits from PMRT.

Ionospheric augmentation is one of the most important dependences of PPP-RTK. Because of the dispersive features of the ionosphere, the ionospheric information is usually coupled with satellite- and receiver-related biases. This will pose a hidden trouble of inconsistent ionospheric corrections if different numbers of reference stations are involved in calculation. In this paper, we aimed at introducing a consistent regional vertical ionospheric model (RVIM) by estimating receiver biases. We first presented the inconsistent ionospheric corrections under sparse networks. Then the RVIM is compared with the International GNSS Service (IGS) final global ionospheric map (GIM) product, and the average of differences between them is 1.13 TECU. Furthermore, the slant ionospheric corrections were employed as a reference to evaluate both RVIM and GIM. The mean RMS values are 1.48 and 2.23 TECU for the RVIM and GIM, respectively. Finally, we applied the RVIM into PPP-RTK. Results indicate that the PPP-RTK with RVIM constraints achieves improvements in horizontal errors, vertical errors, and convergence time by 43.45, 29.3, and 22.6% under the 68% confidence level, compared with the conventional PPP-AR.

Abstract Background The single nucleotide polymorphisms (SNPs) in the fatty acid desaturases and elongases might associate with the endogenous synthesis of polyunsaturated fatty acids (PUFAs). However, the related epidemiological evidence is still conflicting. So we aimed to clearly evaluate the interactions between maternal DHA-rich n-3 PUFAs supplementation and the known 26 SNPs on the profiles of PUFAs in the colostrum using a Chinese birth cohort. Methods Totally, 1050 healthy mother-infant pairs were enrolled in this study at gestational 6–8 weeks when they established their pregnancy files at Fuxing Hospital affiliated to Capital Medical University in Beijing from January to December 2018. Meanwhile, their venous blood samples were obtained for DNA extraction to detect the genotypes of SNPs in the Fads1, Fads2, Fads3, Elovl2 and Elovl5 using the Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry. Then the colostrum samples were collected to determine the profiles of PUFAs by gas chromatography. Results Maternal DHA-rich n-3 PUFAs supplementation from the early and middle pregnancy could reduce the infant BMI at birth, and impact the profiles of PUFAs in the colostrum, as higher n-3 PUFAs (EPA, DHA, DHA/ALA and DHA/EPA), lower n-6 PUFAs (AA and AA/LA) and ∑-6/n-3ΣPUFAs. Moreover, there were significant correlations between multiple SNPs and the profiles of n-6 PUFAs (rs76996928 for LA, rs174550, rs174553 and rs174609 for AA, rs174550 and rs76996928 for AA/LA) and n-3 PUFAs in the colostrum (rs174448, rs174537, rs174550, rs174553, rs174598, rs3168072, rs174455 and rs174464 for ALA, rs174550, rs174553 and rs174598 for EPA, rs174455 and rs174464 for DHA, rs174448 and rs3168072 for DHA/EPA) using the multiple linear regressions by adjusting the maternal age, gestational week, mode of delivery, infant sex and BMI at birth, and all these above significant SNPs had the cumulative effects on the profiles of PUFAs. Furthermore, the pairwise comparisons also showed the meaningful interactions between maternal DHA-rich n-3 PUFAs supplementation and related genotypes of SNPs (rs76996928 for LA, rs174598 for EPA, rs174448 for DHA and DHA/EPA) on the contents of PUFAs in the colostrum. Conclusions Results from this birth cohort study proved that the pregnant women with the following SNPs such as Fads3 rs174455 T, Fads3 rs174464 A and Fads1 rs174448 G alleles should pay more attention on their exogenous DHA supplementation from the early and middle pregnancy for the blocked endogenous synthesis. Trial registration: This study was approved by the Ethics Committee of Beijing Pediatric Research Institution, Beijing Children’s Hospital affiliated to Capital Medical University (2016–08), which was also registered at the website of http://www.chictr.org.cn/showproj.aspx?proj=4673 (No: ChiCTR-OCH-14004900).

Der Einsatz von Learning Analytics etabliert sich zunehmend an Hochschulen. Im Rahmen eines vom BMBWF kofinanzierten Projekts wurde sowohl auf Ebene der Lehrveranstaltung als auch auf Ebene des Studiums angesetzt. Tools und Qualifizierungsmaßnahmen wurden entwickelt, die Studierende und ihre Interessen ins Zentrum stellen. Das Projekt verfolgt somit einen studierendenzentrierten Ansatz, der Autonomie und Freiwilligkeit der Teilnahme in den Vordergrund rückt. An den drei beteiligten Universitäten wurden Dashboards, wie der Learner’s Corner sowie Begleitmaßnahmen (Mentoring, Tutorials, …) entwickelt und empirisch überprüft. Außerdem wurden ethische und datenschutzrechtliche Richtlinien im Rahmen eines interdisziplinär erarbeiteten Kriterienkatalogs entwickelt. Im Beitrag wird der Einsatz von Learning-Analytics-Tools auf unterschiedlichen Ebenen (Moodle-Plug-ins, Anwendung zur Visualisierung des Studienfortschritts) anhand von aus dem Projekt ausgewählten Schwerpunkten exemplarisch veranschaulicht und einzelne empirische Ergebnisse werden vorgestellt. Dieses Projekt wurde am 1. Juni 2023 im Rahmen einer Online-Veranstaltung des BMBWF präsentiert. Die Präsentationsunterlagen finden Sie hier.

Objective: To investigate the dominant metabolic enzymes of six effective components (astragaloside IV, glycyrrhizic acid, calycosin-glucuronide, formononetin, ononin, calycosin-7-O-β-D- glucoside) of Huangqi Liuyi decoction extract (HQD).Methods: Mouse liver microsomes were prepared. The effects of specific inhibitors of CYP450 enzymes on the metabolism of six effective components of HQD were studied using liver microsomal incubation in vitro.Results: The chemical inhibitors of CYP2C37 inhibit the metabolism of glycyrrhizic acid and astragaloside IV. Formononetin and astragaloside IV metabolism is inhibited by the chemical inhibitors of CYP2C11. The chemical inhibitors of CYP2E1 and CYP1A2 inhibit the metabolism of calycosin-glucuronide. Chemical CYP3A11 inhibitors prevent formononetin and glycyrrhizic acid from being metabolized. However, no inhibitor significantly affected the metabolism of ononin and calycosin-7-O-β-D-glucoside.Conclusion: CYP2C37 may be involved in the metabolism of astragaloside IV and glycyrrhizic acid, the metabolism of astragaloside IV and formononetin may be related to CYP2C11, the metabolism of calycosin-glucuronide may be related to CYP1A2 and CYP2E1, and CYP3A11 may be involved in the metabolism of glycyrrhizic acid and formononetin. This research provides an experimental basis for exploring the pharmacokinetic differences caused by metabolic enzymes.

Accurate medium and long-term precipitation forecasting plays a vital role in disaster prevention and mitigation and rational allocation of water resources. In recent years, there are various methods for medium- and long-term precipitation forecasting based on machine learning algorithms. However, machine learning has a high demand for the size of sample data. Therefore, this article proposes a data augmentation algorithm based on the K-means clustering algorithm and synthetic minority oversampling technique (SMOTE), which can effectively enhance sample information. Besides, through constructing random forest (RF), extreme gradient boosting (XGB), recurrent neural network (RNN), and long short-term memory (LSTM) are, respectively, constructed as the models to forecast monthly grid precipitation of the Danjiangkou River Basin. This study aims to improve the accuracy of medium- and long-term precipitation forecasting. The main results are the following two aspects: 1) in most years, the anomaly correlation coefficient and Pg score of SMOTE-km-XGB and SMOTE-km-RF exceed that of XGB and RF; furthermore, compared with the other three methods, SMOTE-km-XGB method is more suitable for precipitation forecasting in the studied basin in this article; and 2) the forecasting results of two deep learning methods (RNN and LSTM) show that the sample data processed by the K-means clustering algorithm and SMOTE data augmentation algorithm have not achieved considerable results in deep learning. This study improves the accuracy of precipitation forecast by expanding and balancing the information of sample data, and provides a new research idea for improving the accuracy of medium- and long-term hydrological forecasting.

Satellite precipitation products (SPPs) have become a significant data source in hydrometeorology, especially for ungauged or sparsely gauged basins, and satellite estimates can supplement the lack of precipitation information. However, satellite remote sensing precipitation products have various degrees of uncertainty which may be related to studied area, precipitation type, and other factors. In addition, the applicability of the same satellite product may not be consistent in different regions. This study focuses on statistical evaluations of five SPPs (TRMM_3B42v7, TRMM_3B42RT, PERSIANN_CDR, CMORPH_CRT, and IMERG_Final) and further improves their accuracy by using the principal component regression-based merging model over two different topography regions. The utilities of all the precipitation sets were then investigated using the Xinanjiang hydrological model to access the influence of the combined product in hydrological response and relative improvements. Results show that the original TRMM_3B42v7, CMORPH_CRT, and IMERG_Final products exhibit much better performance than other two products for precipitation estimation, while the accuracy of TRMM 3B42RT varies greatly between two regions. The merged IMERG_Final and CMORPH_CRT significantly improved the results in two basins. In summary, the merging method combines satellite- and ground-based precipitation to produce a finer spatial distribution, while attention should be paid to the effect of merging method with respect to different satellite information within different basins. This study provides quantitative precipitation estimation analysis of SPPs in different regions and the applicability of merging methods for different SPPs, and thus, will provide useful guidelines for future utilizations of SPPs and merging schemes in regional hydrological applications

The planet is facing climate and biodiversity loss crises that impact all of humanity and yet globally, women remain underrepresented in leading solutions to these urgent conservation challenges. As one of the world’s largest conservation non-profit organizations, The Nature Conservancy (TNC) provided a large case-study for understanding inequity for women in the conservation sector. In 2018, all 1,789 conservation and science staff at TNC were surveyed to understand how they are able to develop their careers and contribute to conservation research and decision making. Of the 904 responses (490 men and 414 women), results show that men influence conservation and science decisions more than women; women face multiple barriers across their conservation careers due to gender bias; women experience sexual harassment and discrimination, as well as fear retaliation more than men; and men reported the sector as a more equitable and favorable place for women than women themselves experienced. Our data demonstrates that gender equality (equal representation of men and women) does not automatically mean that women no longer face systemic inequity and that intersectional issues such as race, location and caring responsibilities can all make it even more difficult for women to excel. Respondents drew from experiences across their conservation careers, to suggest how the conservation sector could address these issues. Based on our findings, we recommend practical ways the conservation sector can improve gender equity, including via workplace and cultural change measures, as well as changes to recruitment, pay transparency, and career development policies.

Abstract Hepatectomy and transplantation are the main surgical therapies for HCC patients, and radiotherapy or chemotherapy is often used as adjuvant treatment. Researches have evaluated the independent predictors of HCC, but evidence for factors predicting the efficacy of chemotherapy is rare. Patients diagnosed with HCC between 2010 and 2015 from the SEER database were included and randomly divided into non-chemotherapy and chemotherapy groups. The predictors of CSS and OS were analyzed with the Cox proportional-hazards regression model and Fine and Gray’s competing risk model. Although there was no significant difference in survival analysis between the chemotherapy and non-chemotherapy groups, the cumulative cancer-specific mortality of most HCC patients was decreased in the chemotherapy group. AJCC stage, tumor size, grade, surgery and radiotherapy were predictors of OS and CSS in the non-chemotherapy group, while AJCC stage, tumor size, AFP, grade and surgery in the chemotherapy group. Surgery combined with chemotherapy was applicable to all AJCC stage patients. Surgery was the major treatment option for patients in AJCC I and AJCC II stage, and chemotherapy in AJCC III and AJCC IV stage. In conclusion, the study provided population-based estimates of the prognostic factors in HCC patients with or without chemotherapy.

Background: Maternal exogenous docosahexaenoic acid (DHA)-rich n-3 polyunsaturated fatty acids (PUFAs) intake during the pregnancy, especially DHA, has inconsistent effects on reducing the fat storage of the infants in different clinical studies. Objectives: We sought to determine the effects of maternal exogenous DHA-rich n-3 PUFAs capsule intake from the different pregnancy periods on the weight gain of their infants through modifying the DNA methylation status of obesity-associated genes in the umbilical cord blood. Design: A prospective 3-year follow-up study after the pregnancy was enrolled in this cohort from May to October 2016. They were divided into different groups according to the initial time of exogenous DHA capsule intake through the questionnaires (S1 – early trimester, S2 – mid-trimester, S3 – late trimester, and control – without). The concentrations and compositions of DHA were determined by gas chromatography. We applied quantitative DNA methylation states of the obesity-associated genes in the umbilical cord blood. The growth outcomes and relevant Z-scores were recorded at birth and 1 and 2 years. The correlations between DNA methylation status of the obesity-associated genes with the consents of DNA and body mass index (BMI) values were investigated as the measures. Results: In total, 205 pregnant women and their infants were eligible for this follow-up study. The concentrations and compositions of DHA in the colostrum and umbilical cord blood were higher in the S1 and S2 groups than those in the control and S3 groups as well as the decreased weight, BMI, weight for age Z-score (WAZ) and BMI for age Z-score (BMI Z) at birth and 1 and/or 2 years, and higher levels of global DNA methylation and many CpG sites in the obesity-associated genes, such as CpG2, CpG9, CpG11, and CpG16 of PPAR-γ; CpG2,3, CpG4-6, CpG8, CpG9,10, CpG11, CpG15,16, and average of CCAAT/enhancer binding protein α (C/EBP-α); CpG1 and average of adiponectin; CpG1, CpG2, CpG3, CpG5, CpG6, CpG7, and average of insulin-like growth factor 2 (IGF-2); CpG6, CpG7, CpG9, CpG16, CpG23, and CpG24 of leptin, which were more obvious in the S1 group when compared with those in the S2 group. These above hypermethylation levels of CpG sites were negatively correlated with the BMI and positively related with the changes of DHA in the colostrum and umbilical cord blood. Conclusions: Maternal exogenous DHA-rich n-3 PUFAs intake from early- and mid- trimesters of the pregnancy may avoid the development of obesity among Chinese Han infants until 2 years by modulating DNA methylation states of obesity-associated genes, which could provide attractive targets for prenatal prevention of the metabolic disorders.

Abstract The traditional track correlation methods have problems such as limitation of the application scenarios, unstable performances and poor practicalities. To solve those problems, a new adaptive track correlation method for multiple scenarios was proposed in this paper using the theories and methods from machine learning. Through interpreting and translating the track correlation problem in the field of information fusion into the classification recognition problem in the field of machine learning, the new method was derived based on deep convolutional neural networks. The association performance and adaptation capabilities of the proposed method had been validated by simulation experiments. The results show that the proposed method is better than the traditional methods with respect to association performance and adaptation capabilities, and can solve the track association problems for multiple scenarios, for example sensors have systematic errors and targets are dense or in formation. Thus, it can be predicted that the proposed method would have a well‐applied foreground.

The flat peach is a high economic value table fruit possessing excellent quality and a unique aroma. This article investigated the quality characteristics and aroma fingerprinting of flat peaches (Qingpan, QP; Ruipan 2, R2; Ruipan 4, R4; Wanpan, WP) from Xinjiang in terms of taste, antioxidant capacity, and volatile aroma compounds using high-performance liquid chromatography (HPLC) and HS-SPME-GC-MS. The results showed that the flat peaches had a good taste and high antioxidant capacity, mainly due to the high sugar–low acid property and high levels of phenolic compounds. This study found that sucrose (63.86~73.86%) was the main sugar, and malic acid (5.93~14.96%) and quinic acid (5.25~15.01%) were the main organic acids. Furthermore, chlorogenic acid (main phenolic compound), epicatechin, rutin, catechin, proanthocyanidin B1, and neochlorogenic acid were positively related to the antioxidant activity of flat peaches. All flat peaches had similar aroma characteristics and were rich in aromatic content. Aldehydes (especially benzaldehyde and 2-hexenal) and esters were the main volatile compounds. The aroma fingerprinting of flat peaches consisted of hexanal, 2-hexenal, nonanal, decanal, benzaldehyde, 2,4-decadienal, dihydro-β-ionone, 6-pentylpyran-2-one, 2-hexenyl acetate, ethyl caprylate, γ-decalactone, and theaspirane, with a “peach-like”, “fruit”, and “coconut-like” aroma. Among them, 2,4-decadienal, 2-hexenyl acetate, and theaspirane were the characteristic aroma compounds of flat peaches. The results provide a theoretical basis for the industrial application of the special aroma of flat peaches.

Objective: Our study aims to summarize and analyze the clinical characteristics of transient infantile hypertriglyceridemia (HTGTI) and variants in the glycerol-3-phosphate dehydrogenase 1 (GPD1) gene and the effect of HTGTI on the protein structure of GPD1.Methods: Retrospective analysis, using the general data, symptoms, signs, and auxiliary examinations, was performed on patients with HTGTI, which were confirmed by genetic testing in our hospital and reported cases online. The clinical data were analyzed using statistical and bioinformatic approaches.Results: A total of 31 genetically confirmed HTGTI patients were collected from our hospital and cases reported in the literature. The clinical manifestations showed the median age of onset was 6.0 (1.9, 12.0) months. All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly. Just a few children were reported with jaundice, cholestasis, and obesity (3.2–6.5%). The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up. In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia. Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis. Statistical differences in triglyceride (TG) level were observed in the ≤6 months group compared with the older groups and in the 13 months to 6 years group with >6 years group (H = 22.02, P < 0.05). The restricted cubic spline model showed that severe HTG decreased in the early stage of infants to the normal level; however, it rebounded again to a mild or moderate level after the following days. The genetic test revealed that the main variant types of the GPD1 gene were missense variants (51.6%), followed by splicing variants (35.5%) and nonsense variants (12.9%). Of patients, 87.1% had homozygous variants, with the most frequent loci being c.361-1G > C and c.895G > A.Conclusion: The common manifestations of HTGTI were HTG, hepatomegaly, elevated liver transaminases, and hepatic steatosis in early infancy. However, the recurrence of aberrant HTG may pose long-term detrimental effects on HTGTI patients.

Valerian volatile oil can be used in the treatment of insomnia; however, the active components and mechanisms of action are currently unclear. Therefore, we used transcriptome sequencing and weight coefficient network pharmacology to predict the effective components and mechanism of action of valerian volatile oil in an insomnia model induced by intraperitoneal injection of para-Chlorophenylalanine (PCPA) in SD rats. Valerian essential oil was given orally for treatment and the contents of 5-hydroxytryptamine receptor 1 A (5-HT1AR), γ-aminobutyric acid (GABA), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA) in the hippocampus of rats in each group were detected by enzyme-linked immunosorbent assay (ELISA), western blot, Polymerase Chain Reaction (PCR), and immunohistochemistry. The results showed that after treatment with valerian essential oil, insomnia rats showed significantly prolonged sleep duration and alleviated insomnia-induced tension and anxiety. Regarding the mechanism of action, we believe that caryophyllene in valerian essential oil upregulates the 5-HT1AR receptor to improve the activity or affinity of the central transmitter 5-HT, increase the release of 5-HT, couple 5-HT with a G protein coupled receptor, convert adenosine triphosphate (ATP) into cAMP (catalyzed by ADCY5), and then directly regulate the downstream pathway. Following pathway activation, we propose that the core gene protein kinase PKA activates the serotonergic synapse signal pathway to increase the expression of 5-HT and GABA, thus improving insomnia symptoms and alleviating anxiety. This study provides a theoretical basis for the application of valerian volatile oil in health food.

Microwave heating acts as an environmental stimulus factor to induce rapid shape changes in 4D-printed stereoscopic models over time. The influence of microwave power and model structure on the shape change behavior was explored, and the applicability of the deformed method to other vegetable-based gels was verified. The results described that the G′, G″, η, and proportion of bound water of yam gels increased with the increase in yam powder content, and the yam gel with 40% content had the best printing effect. The IR thermal maps showed the microwaves first gathered in the designed gully region caused the swelling phenomenon, which induced the printed sample to undergo a bird-inspired “spreading of wings” process within 30 s. Increasing the microwave power and microwave heating time were able to increase the bending angles and dehydration rates of the printed samples, thus improving the deformed degree and deformed speed. Different model base thicknesses (4, 6, 8, and 10 mm) also had significant effects on the shape change of the printed structures. The efficiency of the shape changes of 4D-printed structures under microwave induction can be judged by studying the dielectric properties of the materials. In addition, the deformed behaviors of other vegetable gels (pumpkin and spinach) verified the applicability of the 4D deformed method. This study aimed to create 4D-printed food with personalized and rapid shape change behavior, providing a basis for the application scenarios of 4D-printed food.

Vegetables contain important bioactive substances which have unique tastes and aromas and provide beneficial effects to human health. In this study, multiflavor blended soy sauce was prepared with the juice of eight kinds of vegetables, dried shrimp boiled stock, and six kinds of commercial soy sauce as raw materials, and thermal ultrasound was used as the sterilization method. The effects of adding different formulas of vegetable and seafood stock on the basic physical and chemical parameters, nutrition, antioxidant activity, flavor, and taste of soy sauce were investigated. The results showed that the basic physicochemical indices such as pH, total acid, color, soluble solids, and amino acid nitrogen of the product with a ratio of soy sauce to vegetable-seafood stock of 1:0.5 (v/v) could meet the production standards of soy sauce, and its flavor, taste, and sensory scores were relatively good, with the highest likeability (overall acceptability). The mixed soy sauce with a ratio of 1:2 (v/v) had higher vegetable and seafood flavors, and different vegetable flavors (celery, carrot, and onion) were more obvious, but its nutritional index was relatively low. Multiflavor vegetable-soy sauce can be used for quick cooking by chefs of catering enterprises, and may be used as a seasoning bag for prefabricated dishes and convenient foods, attracting increasing attention from manufacturers and consumers.

Abstract The role of organic anion transporting polypeptide 1B3 (SLCO1B3) in breast cancer is still controversial. The clinical immunohistochemical results showed that a greater proportion of patients with negative lymph nodes, AJCC stage I, and histological grade 1 (P

Brain drug delivery remains a major difficulty for several challenges including the blood–brain barrier, lesion spot targeting, and stability during circulation. Blood cells including erythrocytes, platelets, and various subpopulations of leukocytes have distinct features such as long-circulation, natural targeting, and chemotaxis. The development of biomimetic drug delivery systems based on blood cells for brain drug delivery is growing fast by using living cells, membrane coating nanotechnology, or cell membrane-derived nanovesicles. Blood cell-based vehicles are superior delivery systems for their engineering feasibility and versatile delivery ability of chemicals, proteins, and all kinds of nanoparticles. Here, we focus on advances of blood cell-based biomimetic carriers for from blood to brain drug delivery and discuss their translational challenges in the future.

We previously reported that the structural modifications of pentacyclic triterpenoids including oleanolic acid resulted in enhanced hyaluronidase inhibitory activity but whether this applies to other pentacyclic triterpenoids such as betulinic acid (BA) is unknown. Herein, we synthesized BA derivatives with an α,β-unsaturated ketene moiety and evaluated for their: 1) hyaluronidase inhibitory activity and, 2) anti-inflammatory effects against lipopolysaccharides (LPS) induced inflammation. Compared to BA, the BA derivatives exerted improved anti-hyaluronidase activity (26.3%–72.8% vs. 22.6%) and anti-inflammatory effects by reducing nitrite production in BV2 cells (3.9%–46.8% vs. 3.4%) and RAW264.7 cells (22.7%–49.2% vs. 20.4%). BA derivatives inhibited LPS-induced production of pro-inflammatory cytokines in THP-1 cells (15.2%–22.4%). BA derivatives also exerted promising anti-inflammatory effects against hyaluronic acid fragment induced nitrite production (8.6%–35.6%) in THP-1 cells. BA derivatives showed augmented anti-hyaluronidase and anti-inflammatory effects but further biological evaluations using in vivo models are warranted to confirm their efficacy.

Streptococcal toxic shock syndrome (STSS) caused by group A streptococcus is a rare condition that rapidly developed to multiple organ failure even death. Therefore, prompt diagnosis, initiate appropriate antibiotics and other supportive treatments are critical. Here we reported a case of STSS caused by group A streptococcus infection. A healthy 39-year-old man presented a sudden pain in the left lower extremity, followed by a high fever (40.0 °C) with dizziness, nausea, and shortness of breath. Twenty-four hours before the visit, the patient showed anuria. The patient was then admitted to the intensive care unit. Blood examination revealed elevated levels of inflammatory markers and creatinine. He suffered from septic shock, dysfunction of coagulation, acute kidney dysfunction, acute respiratory distress syndrome, and acute liver function injury. The diagnosis was obtained through clinical manifestation and metagenomic next-generation sequencing (mNGS) drawn from the pustule and deep soft tissue (lower limb) samples while all bacterial cultures came back negative. The pustule mNGS report detected a total of 132 unique group A streptococcus sequence reads, representing 96.3% of microbial reads while the soft tissue mNGS report identified a total of 142474 unique group A streptococcus sequence reads, representing 100% of microbial reads. The patient was treated with aggressive fluid resuscitation, antibiotics comprising piperacillin/tazobactam and clindamycin, respiratory support, following the delayed surgical debridement. Intravenous immunoglobulin was also used for 5 days. On the 14th day after admission, he was transferred to the general ward for follow-up treatment. Our case highlighted, for the first time, the key role of mNGS in the early diagnosis of culture-negative invasive group A streptococcal infection. The case also suggested that clindamycin combined with beta-lactam antibiotics and adjunction of intravenous immunoglobulin therapy with delayed debridement performed well in the management of unstable STSS patients.

The significance of maternal appropriate calcium intakes for energy metabolism in the offspring has been recognized. Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome. So in this study, we proposed that there were long-term effects of maternal calcium status on the progress of NAFLD by altering the intestinal microbiota and lipid metabolism with attention to potential sex differences among the mouse offspring. Thirty-four-week female C57BL/6 J mice were subjected to obtain low, normal and high calcium reproductive diets throughout the gestation and lactation. After weaning, both the male and female mouse offspring were fed with the high-fat diet for 16 weeks, with the normal diet as control. Biochemical indicators in the plasma and hepatic tissue were measured using ELISA or enzymatic methods. The expression of lipid metabolism, inflammatory and fibrosis related genes was determined by RT-PCR. The intestinal microbiota was analyzed by 16S rRNA high-throughput sequencing. Maternal normal and low calcium intake could, respectively, inhibit the progress of high-fat diet induced NAFLD in the male and female mouse offspring, which was characterized by the least lipid droplets, inflammatory infiltration and fibrosis, the lowest concentrations of free fatty acids and triglyceridethe lowest expression of genes involving in de novo lipogenesis and the highest expression of genes related to lipid oxidation and hydrolysis, inflammatory, and fibrosis. Pyrosequencing of 16S rRNA genes revealed that the male mouse offspring with maternal normal calcium intake and the female mouse offspring with maternal low calcium intake, after the high-fat diet feeding, had distinct intestinal microbiota, which was closer to thosein mice with the normal diet feeding. Analysis of the functional features for the different microbiota was compatible with the expression of genes associated with lipogenesis, lipid oxidation and hydrolysis. Thus, there is a sex-specific manner for maternal calcium requirement to inhibit the progress of offspring NAFLD, that might be less for the female offspring and more for the male offspring.

Browning seriously affects the quality of fresh-cut fruits, and its mechanism was thought to be polyphenol oxidase (PPO) in the past. A way of non-different PPO browning was found in our previous studies. However, the landscape of this browning way is still unclear in “Fuji” apples. Multi-omics (methylomics, transcriptomics, and proteomics) methods were performed to the global profiles of DNA methylation and gene and protein expression. We employed two natural bud mutation varieties of apple as materials and found a positive correlation between browning index (BI) and methylation (5mC%, MdCMT3, and MdCMT3c) and a negative correlation between BI and demethylation (MdROS1 and MdDME). DNA methylation inhibitor 5-azacytidine can delay apple browning. Further analysis showed that methylated-NCA1 and OMT1 increased significantly in apple browning. Methylated-NCA1 might inhibit NCA1 gene expression and resulted in the decline of catalase activity, thereafter significantly increased apple browning. These findings insight into a new pathway and landscape that DNA hypermethylation significantly accelerated the browning in “Fuji” apple.

Background: Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer (NSCLC), is associated with poor prognosis. However, current stage-based clinical methods are insufficient for survival prediction and decision-making. This study aimed to establish a novel model for evaluating the risk of LUAD based on hypoxia, immunity, and epithelial-mesenchymal transition (EMT) gene signatures.Methods: In this study, we used data from TCGA-LUAD for the training cohort and GSE68465 and GSE72094 for the validation cohorts. Immunotherapy datasets GSE135222, GSE126044, and IMvigor210 were obtained from a previous study. Using bioinformatic and machine algorithms, we established a risk model based on hypoxia, immune, and EMT gene signatures, which was then used to divide patients into the high and low risk groups. We analyzed differences in enriched pathways between the two groups, following which we investigated whether the risk score was correlated with stemness scores, genes related to m6A, m5C, m1A and m7G modification, the immune microenvironment, immunotherapy response, and multiple anti-cancer drug sensitivity.Results: Overall survival differed significantly between the high-risk and low-risk groups (HR = 4.26). The AUCs for predicting 1-, 3-, and 5-year survival were 0.763, 0.766, and 0.728, respectively. In the GSE68465 dataset, the HR was 2.03, while the AUCs for predicting 1-, 3-, and 5-year survival were 0.69, 0.651, and 0.618, respectively. The corresponding values in the GSE72094 dataset were an HR of 2.36 and AUCs of 0.653, 0.662, and 0.749, respectively. The risk score model could independently predict OS in patients with LUAD, and highly correlated with stemness scores and numerous m6A, m5C, m1A and m7G modification-related genes. Furthermore, the risk model was significantly correlated with multiple immune microenvironment characteristics. In the GSE135222 dataset, the HR was 4.26 and the AUC was 0.702. Evaluation of the GSE126044 and IMvigor210 cohorts indicated that PD-1/PD-LI inhibitor treatment may be indicated in patients with low risk scores, while anti-cancer therapy with various drugs may be indicated in patients with high risk scores.Conclusion: Our novel risk model developed based on hypoxia, immune, and EMT gene signatures can aid in predicting clinical prognosis and guiding treatment in patients with LUAD.

The push-plate kiln is a kind of kiln equipment widely used in the oxygen-free sintering of high-temperature alloy materials. Its flow field monitoring has an important application value for the manufacturing industry. However, traditional simulation methods cannot meet the requirements of real-time applications due to the high computational cost and being time-consuming. The rapid development of artificial intelligence technology will empower the traditional manufacturing industry. In this paper, we propose a data-driven digital twin framework for real-time flow field prediction by combining the CFD modeling simulation, IoT, and deep learning technologies. The framework integrates geometric, rule, physical, and neural network models to achieve the real-time simulation of physical and twin objects. The proper orthogonal decomposition (POD) and multiscale convolutional neural network (MCNN) are innovatively embedded into the framework. The POD is used to map high-dimensional data to low-dimensional features, and the MCNN is used to construct models predicting low-dimensional features for fast flow field prediction. The effectiveness of the proposed model is verified by the push-plate kiln case. The results show that the digital twin can quickly predict multi-physics fields based on the perceptual data to achieve the real-time evaluation of the operating state of the push-plate kiln.

Background: Asthma is a complex respiratory disease characterized by airway inflammation and remodeling. MicroRNAs (miRNAs) mediate various cellular processes including macrophage polarization and play an important role in the pathogenesis of asthma. In present study, we aimed to screen miRNA profiling involved in macrophage polarization and investigate its possible functions and mechanisms.Methods: An OVA-sensitized mouse model was established and 2-chloroadenosine (2-CA) was used to interfere with macrophages. The airway inflammation and remodeling were assessed. The identification and function of M2 alveolar macrophages were assessed by flow cytometry, RT-qPCR, arginase activity and co-culture experiment. Microarray screening was used to select miRNAs which were related to macrophage polarization and RNA interference (RNAi) technique was performed to confirm the function of the selected miRNA and its target gene.Results: Alveolar macrophages of asthmatic mice showed significant M2 polarization. 2-CA alleviated airway inflammation and remodeling as well as M2 polarization. In vitro, IL-4-induced M2 macrophages promoted the proliferation of α-SMA-positive cells. And miRNA profiling showed a remarkable increased expression of miR-378a-3p in IL-4 induced M2 macrophages. Dual luciferase reporter assay confirmed growth factor receptor binding protein 2 (GRB2) was a target gene of miR-378a-3p. A miR-378a-3p inhibitor and knockdown of GRB2 repolarized alveolar macrophages from M1 to M2 phenotype.Conclusion: Our findings suggest that miR-378a-3p/GRB2 pathway regulates the polarization of alveolar macrophages which acts as a potential therapeutic target for airway inflammation and remodeling in asthma.

The dysregulation of NLRP3 inflammasome plays a critical role in pathogenesis of various human inflammatory diseases, thus NLRP3 inflammasome activation must be tightly controlled at multiple levels. However, the underlying mechanism regulating NLRP3 inflammasome activation remains unclear. Herein, the effects of Tripartite motif-containing protein 65 (TRIM65) on NLRP3 inflammasome activation and the underlying molecular mechanism were investigated in vitro and in vivo. Inhibition or deletion of Trim65 could significantly strengthen agonist induced NLRP3 inflammasome activation in THP-1 cells and BMDMs, indicated by increased caspase-1 activation and interleukin-1β secretion. However, TRIM65 had no effect on poly (dA: dT)-induced AIM2 inflammasome activation or flagellin-induced IPAF inflammasome activation. Mechanistically, immunoprecipitation assays demonstrated that TRIM65 binds to NACHT domain of NLRP3, promotes lys48- and lys63- linked ubiquitination of NLRP3 and restrains the NEK7-NLRP3 interaction, thereby inhibiting NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β secretion. In vivo, three models of inflammatory diseases were used to confirm the suppression role of TRIM65 in NLRP3 inflammasome activation. TRIM65-deficient mice had a higher production of IL-1β induced by lipopolysaccharide in sera, and more IL-1β secretion and neutrophil migration in the ascites, and more severity of joint swelling and associated IL-1β production induced by monosodium urate, suggesting that TRIM65 deficiency was susceptible to inflammation. Therefore, the data elucidate a TRIM65-dependent negative regulation mechanism of NLRP3 inflammasome activation and provide potential therapeutic strategies for the treatment of NLRP3 inflammasome-related diseases.

Objective Single nucleotide polymorphisms (SNPs) of pentraxin 3 ( PTX3 ) are associated with various outcomes of lung infections. This study aimed to analyze the relationship between PTX3 polymorphisms and the severity of community-acquired pneumonia (CAP). Methods This is a retrospective case-control study comprising 43 patients with severe CAP (SCAP) and 97 patients with non-severe CAP. Three SNPs in the PTX3 gene (rs2305619, rs3816527, and rs1840680) from peripheral blood samples were genotyped by real-time polymerase chain reaction. The association between each SNP and the CAP severity was analyzed by logistic regression analysis. Results We found that the rs1840680 polymorphism was significantly associated with CAP clinical severity. However, no such association was observed for the genotypes and allele frequencies of rs2305619 or rs3816527. The PTX3 rs1840680 AG genotype was an independent factor for a lower risk of SCAP after multivariate logistic regression analysis. Male sex and coronary heart disease were associated with an increased risk of SCAP. Conclusions The PTX3 rs1840680 AG genotype was found to be associated with a lower risk of SCAP, and may serve as a potential protective biomarker to help clinical judgment and management.

Quantitative PCR (qPCR), the most accurate and sensitive technique for quantifying mRNA expression, and choice of appropriate reference genes for internal error controlling in qPCR are essential to understanding the molecular mechanisms that drive the obesity epidemic and its comorbidities. In this study, using the high-fat diet (HFD)-induced obese mouse model, we assessed the expression of 10 commonly used reference genes to validate gene-expression stability in adipose tissue, liver, and muscle across different time points (4, 8, 12, and 16 weeks after HFD feeding) during the process of obesity. The data were analyzed by the GeNorm, NormFinder, BestKeeper, and Delta-Ct method, and the results showed that the most stable reference genes were different for a specific organ or tissue in a specific time point; however, PPIA, RPLP0, and YWHAZ were the top three most stable reference genes in qPCR experiments on adipose, hepatic tissues, and muscles of mice in diet-induced obesity. In addition, the mostly used genes ACTB and GAPDH were more unstable in the fat and liver, the ACTB mRNA levels were increased in four adipose tissues, and the GAPDH mRNA levels were decreased in four adipose tissues and liver after HFD feeding. These results suggest that PPIA, RPLP0, or YWHAZ may be more appropriate to be used as reference gene than ACTB and GAPDH in the adipose tissue and liver of mice during the process of high-fat diet-induced obesity.

To better understand the sources and recycling of labile organic matter in coastal water, we studied the carbon isotope signature of particulate organic carbon (POC) and particulate amino acids, a major group of labile organic compounds, on the shelf of the northern South China Sea. In addition, we were able to compare effects of hypoxia on labile organic matter at one station on the shelf. We found that carbon-weighted average δ13C values of particulate amino acids (wAAδ13C) were generally higher at more productive offshore stations than nearshore stations. This amino acid δ13C distribution suggests that the labile fraction of organic matter in coastal water originated primarily from local primary production. In contrast, bulk POC δ13C (PO13C) values showed little spatial variation on the NSCS shelf. The different patterns of wAAδ13C and PO13C distributions indicate a combined effect of POM lability and physical processes on the isotopic distribution of organic materials on this productive shelf. Moreover, the amino acid δ13C in coastal hypoxic water suggests local primary production as the most likely source of labile organic matter that drives hypoxia on the NSCS shelf. No clear difference was observed in particulate amino acid δ13C distribution between hypoxic and oxic waters.

Tiantian Tangs Beitrag untersucht die multiple Bedeutung des Spurbegriffs zwischen Spurenlesen bzw. Spürsinn und fasst so den medientheoretischen Stand der gegenwärtigen Dinge zusammen. Dabei wird aus bildungswissenschaftlicher Sicht betont, dass Spuren auch angesichts des digitalen Fußabdrucks gerade in einer vernetzten Wissens- und Informationsgesellschaft nicht einfach auf ein ihnen Dahinterliegendes bezogen sind, sondern vielmehr auf weitere Spuren verweisen. Gerade angesichts der Diskussionen zu Poststrukturalismus und Postmoderne kann mithin festgehalten werden, das Spuren sich vielmehr verspuren, als dass sie im polizeilichen Sinne auf Täterinnen und Täter bezogen sind. Dabei wird auch herausgearbeitet, wie angesichts von Informatik und mithin Algorithmik ein zeitgemäßer Spurbegriff modelliert und angewendet werden kann, um (mediale) Bildungsprozesse beschreiben zu können.

The NLRP3 inflammasome is key to the regulation of innate immunity against pathogens or stress, but the underlying signaling regulation is still unclear. Here the authors show that chloride intracellular channels (CLIC) interface between mitochondria stress and inflammasome activation to modulate inflammatory responses.