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BackgroundUnexplained recurrent pregnancy loss (URPL) is a clinical dilemma in reproductive fields. Its diagnosis is mainly exclusionary after extensive clinical examination, and some of the patients may still face the risk of miscarriage.MethodsWe analyzed follicular fluid (FF) from in vitro fertilization (IVF) in eight patients with URPL without endocrine abnormalities or verifiable causes of abortion and eight secondary infertility controls with no history of pregnancy loss who had experienced at least one normal pregnancy and delivery by direct data-independent acquisition (dDIA) quantitative proteomics to identify differentially expressed proteins (DEPs). In this study, bioinformatics analysis was performed using online software including g:profiler, String, and ToppGene. Cytoscape was used to construct the protein–protein interaction (PPI) network, and ELISA was used for validation.ResultsGene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEPs are involved in the biological processes (BP) of complement and coagulation cascades. Apolipoproteins (APOs) are key proteins in the PPI network. ELISA confirmed that APOB was low-expressed in both the FF and peripheral blood of URPL patients.ConclusionDysregulation of the immune network intersecting coagulation and inflammatory response is an essential feature of URPL, and this disequilibrium exists as early as the oogenesis stage. Therefore, earlier intervention is necessary to prevent the development of URPL. Moreover, aberrant lipoprotein regulation appears to be a key factor contributing to URPL. The mechanism by which these factors are involved in the complement and coagulation cascade pathways remains to be further investigated, which also provides new candidate targets for URPL treatment.

Idiopathic pulmonary fibrosis (IPF) garners considerable attention due to its high fatality rate and profound impact on quality of life. Our study conducts a comprehensive literature review on IPF using bibliometric analysis to explore existing hot research topics, and identifies novel diagnostic and therapeutic targets for IPF using bioinformatics analysis. Publications related to IPF from 2013 to 2023 were searched on the Web of Science Core Collection (WoSCC) database. Data analysis and visualization were conducted using CiteSpace and VOSviewer software primarily. The gene expression profiles GSE24206 and GSE53845 were employed as the training dataset. The GSE110147 dataset was employed as the validation dataset. We identified differentially expressed genes (DEGs) and differentially expressed genes related to oxidative stress (DEOSGs) between IPF and normal samples. Then, we conducted Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The hub genes were screened by protein–protein interaction (PPI) networks and machine learning algorithms. The CIBERSORT was used to analyze the immune infiltration of 22 kinds of immune cells. Finally, we conducted the expression and validation of hub genes. The diagnostic efficacy of hub genes was evaluated by employing Receiver Operating Characteristic (ROC) curves and the associations between hub genes and immune cells were analyzed. A total of 6,500 articles were identified, and the annual number of articles exhibited an upward trend. The United States emerged as the leading contributor in terms of publication count, institutional affiliations, highly cited articles, and prolific authorship. According to co-occurrence analysis, oxidative stress and inflammation are hot topics in IPF research. A total of 1,140 DEGs were identified, and 72 genes were classified as DEOSGs. By employing PPI network analysis and machine learning algorithms, PON2 and TLR4 were identified as hub genes. A total of 10 immune cells exhibited significant differences between IPF and normal samples. PON2 and TLR4, as oxidative stress-related genes, not only exhibit high diagnostic efficacy but also show close associations with immune cells. In summary, our study highlights oxidative stress and inflammation are hot topics in IPF research. Oxidative stress and immune cells play a vital role in the pathogenesis of IPF. Our findings suggest the potential of PON2 and TLR4 as novel diagnostic and therapeutic targets for IPF.

This study selects Beijing from 1980 to 2020 as the research area, utilizing high temporal resolution land use data to analyze through the habitat quality module of the InVEST model. Unlike previous research, this study employs the Theil-Sen Median method and Mann-Kendall test to analyze the trend changes in habitat quality more accurately. This method has significant advantages in dealing with non-linear and non-normally distributed data over long time series, providing a more accurate and reliable analysis of habitat quality trends. Methodologically, the study first collects and organizes the land use type data of Beijing from 1980 to 2020, then uses the habitat quality module of the InVEST model to process and analyze the data of each year, assessing the impact of different land use types on habitat quality. Subsequently, the Theil-Sen Median method and Mann-Kendall test are used to analyze the time series trend of habitat quality, to identify and quantify the trend and significance of habitat quality changes. The results show that over the past 40 years, the area of construction land in Beijing has significantly expanded, leading to a compression of other types of land. The spatial distribution of habitat quality shows a clear difference between the two sides divided by a line connecting the northeast and southwest, with the west side being the area of good habitat quality and the east side being poorer. In the past 10 years, the overall habitat quality has improved, but most areas still show a decreasing trend, especially in the western and northern mountainous areas where habitat quality has significantly declined. Based on these findings, it is recommended that future urban planning and land management should pay more attention to the protection and improvement of habitat quality, especially the restoration work for areas with poor habitat quality.

Abstract Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II–III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open‐label, parallel‐group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6–1.5 h, indicating rapid absorption. Inter‐individual variability was moderate, and individuals carrying non‐functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half‐life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.

In the wake of the COVID-19 pandemic, there has been an increasing focus towards infant immunity. The development and maintenance of the immune system are significantly influenced from birth, and is shaped by early-life infant feeding behavior. Hence, the knowledge, attitude, and practice (KAP) of parents play a crucial role in shaping the immune system of infants. A total of 2369 parents across 19 cities in China were surveyed using a self-designed online questionnaire. The KAP questionnaire assessed three domains: immunity, gut microbiota, and biotics (prebiotics, probiotics, and synbiotics). The questionnaire also included questions on infant health. An overwhelming majority of parents (97.90%) placed high value on their children’s immunity, and 40.40% of them reported an increased level of concern following the COVID-19 pandemic. Diarrhea (78.80%), colds (75.70%), nighttime crying (73.80%), regurgitation (71.70%) and food retention (66.50%) were the major health issues reported. Knowledge scores toward immunity and gut microbiota were positively correlated to attitude and practice scores, respectively. Attitude scores toward immunity, gut microbiota and biotics were positively correlated to their respective practice scores. Parental knowledge score on immunity was negatively correlated with diarrhea, colds, regurgitation and food retention. On the other hand, parental practice scores toward immunity were negatively correlated with food retention. In regards to gut microbiota, parental knowledge score was negatively correlated with diarrhea, regurgitation and food retention; parental attitude score was negatively correlated with nighttime crying whereas practice score was negatively correlated with diarrhea, regurgitation, food retention and nighttime crying. Attitude score toward biotics was negatively correlated with nighttime crying and practice scores toward biotics was negatively correlated with colds, food retention and nighttime crying. This study demonstrated that significant gaps and misunderstandings exist among parents regarding immunity, gut microbiota health, and biotics. Both public education and interventions are crucial to enhance parental knowledge and practices, thereby improving infant immunity.

Among civilization diseases, the number of individuals suffering from type 2 diabetes (T2DM) is expected to increase to more than a billion in less than 20 years, which is associated with, e.g., populational aging, poor diet, sedentary lifestyle, genetic predispositions, and immunological factors. T2DM affects many organs and is characterized by insulin resistance, high glucose levels, and adipocyte dysfunction, which are related to senescence. Although this type of cellular aging has beneficial biological functions, it can also act unfavorable since senescent adipocytes resist apoptosis, enhance cytokine secretion, downregulate cell identity genes, and acquire the senescence-associated secretory phenotype that renders a more oxidative environment. Opposing T2DM is possible via a wide variety of senotherapies, including senolytics and senomorphics; nevertheless, further research is advised to expand therapeutic possibilities and benefits. Consequences that ought to be deeply researched include secretory phenotype, chronic inflammation, increasing insulin resistance, as well as impairment of adipogenesis and functioning of adipocyte cells. Herein, despite reviewing T2DM and fat tissue senescence, we summarized the latest adipocyte-related anti-diabetes solutions and suggested further research directions.

Abstract Background The use of structural and perfusion brain imaging in combination with behavioural information in the prediction of cognitive syndromes using a data-driven approach remains to be explored. Here, we thus examined the contribution of brain structural and perfusion imaging and behavioural features to the existing classification of cognitive syndromes using a data-driven approach. Methods Study participants belonged to the community-based Biomarker and Cognition Cohort Study in Singapore who underwent neuropsychological assessments, structural-functional MRI and blood biomarkers. Participants had a diagnosis of cognitively normal (CN), subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and dementia. Cross-sectional structural and cerebral perfusion imaging, behavioural scale data including mild behaviour impairment checklist, Pittsburgh Sleep Quality Index and Depression, Anxiety and Stress scale data were obtained. Results Three hundred seventy-three participants (mean age 60.7 years; 56% female sex) with complete data were included. Principal component analyses demonstrated that no single modality was informative for the classification of cognitive syndromes. However, multivariate glmnet analyses revealed a specific combination of frontal perfusion and temporo-frontal grey matter volume were key protective factors while the severity of mild behaviour impairment interest sub-domain and poor sleep quality were key at-risk factors contributing to the classification of CN, SCI, MCI and dementia (p < 0.0001). Moreover, the glmnet model showed best classification accuracy in differentiating between CN and MCI cognitive syndromes (AUC = 0.704; sensitivity = 0.698; specificity = 0.637). Conclusions Brain structure, perfusion and behavioural features are important in the classification of cognitive syndromes and should be incorporated by clinicians and researchers. These findings illustrate the value of using multimodal data when examining syndrome severity and provide new insights into how cerebral perfusion and behavioural impairment influence classification of cognitive syndromes.

Abstract Objective To evaluate the diagnostic values of serum platelet count (PC), mean platelet volume ratio (MPV), platelet count to mean platelet volume ratio (PVR), platelet to lymphocyte ratio (PLR), platelet to neutrophil ratio (PNR), PC/Albumin-globulin ratio (PC/AGR), and PC/C-reactive protein (PC/ CRP) in the diagnosis of periprosthetic joint infection (PJI). Methods The medical records were retrospectively analyzed of the 158 patients who had undergone hip or knee revisions from January 2018 to May 2022. Of them, 79 cases were diagnosed with PJI and 79 with aseptic loosening (AL). PJI was defined using the Musculoskeletal Infection Society criteria. The plasma levels of CRP, the erythrocyte sedimentation rate (ESR), PC, MPV, PVR, PLR, PNR, PC/AGR, and PC/CRP in the 2 groups were recorded and analyzed. In addition, tests were performed according to different joint types. The receiver operating characteristic curve was used to calculate the sensitivity and specificity of each indicator. The diagnostic value for each indicator was calculated according to the area under the curve (AUC). Results The PC, PVR, PLR and PC/AGR levels in the PJI group were significantly higher than those in the AL group, while PC/CRP levels were significantly lower (P

Abstract Tyrosine phosphorylation on Ras by Src kinase is known to uncouple Ras from upstream regulation and downstream communication. However, the mechanisms by which phosphorylation modulates these interactions have not been detailed. Here, the major mono-phosphorylation level on tyrosine64 is quantified by 31P NMR and mutagenesis. Crystal structures of unphosphorylated and tyrosine64-phosphorylated Ras in complex with a BeF3 − ground state analogue reveal “closed” Ras conformations very different from those of the “open” conformations previously observed for non-hydrolysable GTP analogue structures of Ras. They deliver new mechanistic and conformational insights into intrinsic GTP hydrolysis. Phosphorylation of tyrosine64 delivers conformational changes distant from the active site, showing why phosphorylated Ras has reduced affinity to its downstream effector Raf. 19F NMR provides evidence for changes in the intrinsic GTPase and nucleotide exchange rate and identifies the concurrent presence of a major “closed” conformation alongside a minor yet functionally important “open” conformation at the ground state of Ras. This study expands the application of metal fluoride complexes in revealing major and minor conformational changes of dynamic and modified Ras proteins.

ABSTRACTPorous geopolymers have been the promising subject over the last decade owing to the functional domains from high surface area, structural stability upon heat and chemists, as well as eco-friendly and economy. Especially, the nano-sized geopolymers are playing a significant role in extensive applications. Here, we summarize recent progress in the development of nanoporous geopolymers in the applications of adsorption as well as catalyst supporter. Generally, microporous geopolymers were synthesized through gas bubbling or combination of zeolite to form partial porous structure, while mesoporous geopolymers were produced by the using of various structure directing agent. However, it remains a challenge to obtain functional materials with narrow porous distribution. Our recent work show that the uses of well-defined template method give rise to finely designed nanoporous geopolymers, which exhibited extremely excellent adsorptivity, solid acidic capacity as well as effective carbon-replication. We discussed well the relationship between nanoporosity regulation and corresponding performances to conclude that just using the bubbling, the compositing of zeolite, or traditional rough template method is difficult to form homogeneous pore structures. By analyzing the connection between the uniform porous structure and its related properties, the well-defined template-method would be recommended to generate emerging nanoporous structures with superior functions.

Previous researches show that the dissolution of carbonate rocks can be characterized by dissolution rate equation, but the form of characterization is quite different, which is mainly reflected in the undersaturated state far from equilibrium. In order to further determine the dissolution characteristics of carbonate rocks in the undersaturated state and the characterization form of dissolution rate, first of all, the fracture dissolution test of carbonate rocks was carried out, and the influence of CO2 partial pressure and initial concentrations of Ca2+ on dissolution was discussed. Based on the test results, the dissolution rate equation in the undersaturated state was constructed. Then, the carbonate rock fracture seepage dissolution coupling model was used, calibrating and verifying the parameters of the quantitative model through numerical simulation. The results indicate that: (1) The participation of CO2 accelerates the dissolution expansion of carbonate rocks, and the higher the initial Ca2+ concentration of the solution, the higher the degree of dissolution inhibition of carbonate rocks. (2) The average dissolution rate of carbonate rock fractures under the action of CO2 increased by 1.82−2.29 times. (3) Under the same interval flow rate conditions for different initial Ca2+ solutions, the difference of Ca2+ concentration in distilled water decreased by 0.0915 mmol/L, and the initial Ca2+ concentration of 0.352, 0.476，0.581 mmol/L decreased by 0.0742, 0.0536，0.0474 mmol/L, respectively. (4) The dissolution kinetics is controlled by the linear rate law under the highly undersaturated state. With the increase of the concentration of Ca2+ in the solution, the dissolution kinetics becomes nonlinear, and the threshold of Ca2+ concentration between the two is 0.4 times the saturated of Ca2+ concentration. The study provides a reference for quantitative evaluation of karst development and evolution.

The grain-drying process plays a critical role in grain storage and quality assurance. In recent years, with the advancement of low-carbon and intelligent technologies, the control technology of grain dryers has significantly improved. This paper systematically reviews the development status of grain dryer control technology from the perspective of low-carbon and intelligentization, analyzing the technological differences in control systems between domestic and international approaches. Current research challenges include the insufficient integration of control technologies with the drying process, limited control variables, the inadequate application of intelligent control strategies, and unstable sensor accuracy. To enhance the performance of grain-drying systems, this paper suggests optimizing control mechanisms, adopting efficient and environmentally friendly energy sources, improving sensor performance, introducing advanced intelligent control algorithms, and strengthening system monitoring capabilities. Looking ahead, with the further integration of AI, IoT, and green energy, grain-drying control systems are expected to evolve towards greater intelligence, remote operation, and low carbonization, providing technical support for enhancing drying efficiency and environmental performance.

Infill drilling is one of the most effective methods of improving the performance of polymer flooding. The difficulties related to infill drilling are determining the optimal numbers and placements of infill wells. In this study, an improved Archimedes optimization algorithm with a Halton sequence (HS-AOA) was proposed to overcome the aforementioned difficulties. First, to optimize infill well placement for polymer flooding, an objective function that considers the economic influence of infill drilling was developed. The novel optimization algorithm (HS-AOA) for infill well placement was subsequently developed by combining the AOA with the Halton sequence. The codes were developed in MATLAB 2023a and connected to a commercial reservoir simulator, Computer Modeling Group (CMG) STARS, Calgary, AB, Canada to carry out infill well placement optimization. Finally, the HS-AOA was compared to the basic AOA to confirm its reliability and then used to optimize the infill well placements for polymer flooding in a typical offshore oil reservoir. The results showed that the introduction of the Halton sequence into the AOA effectively increased the diversity of the initial objects in the AOA and prevented the HS-AOA from becoming trapped in the local optimal solutions. The HS-AOA outperformed the AOA. This approach was effective for optimizing the infill well placement for polymer flooding processes. In addition, infill drilling could effectively and economically improve the polymer flooding performance in offshore oil reservoirs. The net present value (NPV) of the polymer flooding case with infill wells determined by HS-AOA reached USD 3.5 × 108, which was an increase of 7% over that of the polymer flooding case. This study presents an effective method for optimizing infill well placement for polymer flooding processes. It can also serve as a valuable reference for other optimization problems in the petroleum industry, such as joint optimization of well control and placement.

In the original publication [...]

(1) Background: Air rudders are used to control the flight attitude of aircraft, and their surface quality directly affects flight accuracy and safety. (2) Method: Traditional positioning methods can only obtain defect location information at the image level but cannot determine the defect’s physical surface position on the air rudder, which lacks guidance for subsequent defect repair. We propose a defect physical surface positioning method based on a camera mapping model. (3) Results: Repeated positioning experiments were conducted on three typical surface defects of the air rudder, with a maximum absolute error of 0.53 mm and a maximum uncertainty of 0.26 mm. Through hardware systems and software development, the real-time positioning function for surface defects on the air rudder was realized, with the maximum axial positioning error for real-time defect positioning being 0.38 mm. (4) Conclusions: The proposed defect positioning method meets the required accuracy, providing a basis for surface defect repair in the air rudder manufacturing process. It also offers a new approach for surface defect positioning in similar products, with engineering application value.

PurposeBrain metastasis (BM) from non-small cell lung cancer (NSCLC) is a serious complication severely affecting patients’ prognoses. We aimed to compare the clinicopathological features and prognosis of synchronous and metachronous BM from NSCLC.MethodsClinical data of 461 patients with brain metastases from NSCLC who visited the Cancer Hospital of China Medical University from 2005 to 2017 were retrospectively collected. We analyzed the pathophysiological characteristics of synchronous and metachronous BM from NSCLC and survival rates of the patients. Propensity score matching analysis was used to reduce bias between groups. In addition, we used the Kaplan-Meier method for survival analysis, log-rank test to compare survival rates, and Cox proportional hazards regression model for multivariate prognosis analysis.ResultsAmong 461 patients with BM, the number of people who met the inclusion criteria was 400 cases, and after 1:2 propensity score matching,130 had synchronous BM and 260 had metachronous BM. The survival time was longer for metachronous BM in driver mutation-negative patients with squamous cell carcinoma than synchronous BM. Conversely, metachronous and synchronous BM with gene mutations and adenocarcinoma showed no differences in survival time. Multivariate analysis showed that metachronous BM was an independent prognostic factor for overall survival. Furthermore, the pathological type squamous cell carcinoma and Karnofsky Performance Status score

Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model.Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1 g/0.5 g, 1 g/1 g, 2 g/1 g, and 2 g/2 g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline.Results: The PK/PD indexes that best described the bacterial killing from baseline in log10 CFU/mL at 24 h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT > MIC, MIC with FL058 at 4 mg/L) for meropenem and the percent time of free drug above 1 mg/L (%fT > 1 mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT > MIC of meropenem and 40, 48, and 64 for %fT > 1 mg/L of FL058, respectively. The PK/PD index of %fT > 1 mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem.Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection.

Objective To explore the effect and mechanism of TRAF3 on IgG-induced apoptosis and inflammation of human podocyte cell (HPC). Methods HPC cells were cultured in vitro and induced with purified IgG from lupus nephritis (LN) patients to create an inflammatory environment for 24h. The cells were divided into six groups of control, IgG-LN, IgG-LN plus siRNA, IgG-LN plus si-TRAF3, IgG-LN plus STING inhibitor H-151 (1 μmol/L) and IgG-LN plus si-TRAF3 and STING activator ADU-S100 (10 μmol/L). CCK-8 assay was utilized for detecting HPC cell viability; Flow cytometry for examining cell apoptosis; real-time polymerase chain reaction (RT-PCR) for measuring IFN-α mRNA level in HPC cells in each group; enzyme-linked immunosorbent assay (ELISA) for measuring the levels of interferon-alpha (IFN-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α); Western blot for detecting the expressions of TRAF3 and STING protein; co-inmunoprecipitation (Co-IP) for verifying the interaction between TRAF3 and STING. Results TRAF3 silencing inhibited IgG-induced cell apoptosis and secretion of inflammatory factors (P

Abstract Head and neck squamous cell carcinoma (HNSCC) is a heterogeneity pathological malignant cancer with leading causes of morbidity and mortality. EGFR inhibitors, immune checkpoint inhibitors have become novel treatments. However, the mechanism still remained uncertain. Several studies have confirmed that the circadian rhythms induce multiple malignancies developing. We utilized multi-omics analysis to demonstrate the crosstalk between circadian clock genes and tumor microenvironment in HNSCC. Firstly, we performed the LASSO Cox regression analysis based on the 16 important clock genes. A 7-gene risk model was successfully established in TCGA and validated in GEO datasets. Next, CIBERSORT and ESTIMATE methods were performed to display the immune landscape of high risk and low risk groups, and the results showed that high abundance of mast cells activated, dendritic cells activated and neutrophils were positively correlated with poor OS. To further identify hub genes, Kaplan Meier plot was applied in all TCGA and GEO datasets and two hub genes (PER2, and PER3) were identified, especially PER3, which was found strongly associated with immune score, PDCD1, CD4 + and CD8 + T cells in HNSCCC. Moreover, to explore the innate mechanism of circadian-induced pathway, we constructed a circadian-related ceRNA regulatory network containing 34 lncRNAs, 3 miRNAs and 4 core circadian genes. In-vitro experiments also verified that Per2 or Per3 could suppressed the proliferation, migration and invasion of HNSC. This study unraveled the association between PER3 and prognosis in patients with HNSC and the innate mechanism remains to be elucidated.