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Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Abstract Extreme global warming can produce hydroclimate changes that remain poorly understood for sub-tropical latitudes. Late Palaeocene-early Eocene (LPEE; ~58-52 Ma) proto-Mediterranean zones of the western Tethys offer opportunities to assess hydroclimate responses to massive carbon cycle perturbations. Here, we reconstruct LPEE hydroclimate conditions of these regions and find that carbon cycle perturbations exerted controls on orbitally forced hydroclimate variability. Long-term (~6 Myr) carbon cycle changes induced a gradual precipitation/moisture reduction, which was exacerbated by some short-lived (

Abstract Despite the potential of small molecules and recombinant proteins to enhance the efficiency of homology-directed repair (HDR), single-stranded DNA (ssDNA) donors, as currently designed and chemically modified, remain suboptimal for precise gene editing. Here, we screen the biased ssDNA binding sequences of DNA repair-related proteins and engineer RAD51-preferred sequences into HDR-boosting modules for ssDNA donors. Donors with these modules exhibit an augmented affinity for RAD51, thereby enhancing HDR efficiency across various genomic loci and cell types when cooperated with Cas9, nCas9, and Cas12a. By combining with an inhibitor of non-homologous end joining (NHEJ) or the HDRobust strategy, these modular ssDNA donors achieve up to 90.03% (median 74.81%) HDR efficiency. The HDR-boosting modules targeting an endogenous protein enable a chemical modification-free strategy to improve the efficacy of ssDNA donors for precise gene editing.

Renal cell carcinoma (RCC) is a type of tumor with high morbidity and recurrence rates. The application of circulating tumor cells (CTCs) in RCC remains controversial. Hence, we performed a meta-analysis to elucidate the diagnostic and prognostic value of CTCs in RCC. To obtain a precise conclusion, a systematic search was conducted in Pubmed, Cochrane Database, Embase and Web of Science up to Dec 01, 2022. We also further identified the references in relevant studies. The diagnostic accuracy variables (sensitivity, specificity) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to access precise of CTCs and relationship between CTCs and disease stages, respectively. Heterogeneity test, sensitivity analysis, meta-regression and publishing bias were also applied. A total of 12 studies involving 767 patients were considered to be included in the final meta-analysis. The results revealed that the overall sensitivity, specificity of CTC detection in RCC were 45% (95%CI, 32-60%) and 99% (95%CI, 97-100%), respectively. In subgroup analysis, diagnostic sensitivity of CTCs in clear cell renal cell carcinoma (ccRCC) (69%, 95%CI; 50-88%) was significantly higher than other RCC subtypes (34%, 95%CI; 21-48%) (p

To study the flow and strength characteristics of coal slime based backfill materials, orthogonal tests were used to design one cemented backfill material combining coal slime, high-water-content materials, cement, and fly ash. By using range, analysis of variance, and multi-variate regression analysis, influences of four key factors on the initial setting time, bleeding ratio, diffusivity, compressive strength, and shear strength of the backfill material were studied. These four factors include coal slurry water mass per cent concentration (A), high water material mass / slurry water mass (B), cement mass / slurry water mass (C) and fly ash mass / slurry water mass (D). Results show that initial setting time, diffusivity, compressive strength, and shear strength of the backfill material are 52−67 min, 42.0−76.5 cm, 0.076−0.247 MPa, and 0.033−0.139 MPa, respectively, all distributed in wide ranges. For initial setting time, the four factors are listed in a descending order as B>C>A>D according to their influences; for the compressive strength, the four factors are ranked as D>C>A>B; for the shear strength, the four factors are listed in an order as C>D>A>B. Mathematical equations between A, B, C, D and initial setting time, diffusivity, compressive strength, and shear strength were gotten, initial setting time and A, B presents quadratic function relation, and C, D present exponential relation; diffusivity and A, B, C presents quadratic function relation, and D presents trigonometric relation; compressive strength and A, D presents exponential relation, and B, C presents quadratic function relation; shear strength and A, B presents quadratic function relation, and C, D presents exponential relation.One prediction model for characteristic parameters, namely, fluidity and strength, of the coal slime based backfill material under action of various factors was established and calibrated.

This study investigates the crucial role of immune- and epithelial-mesenchymal transition (EMT)-associated genes and non-coding RNAs in glioma development and diagnosis, given the challenging 5-year survival rates associated with this prevalent CNS malignant tumor. Clinical and RNA data from glioma patients were meticulously gathered from CGGA databases, and EMT-related genes were sourced from dbEMT2.0, while immune-related genes were obtained from MSigDB. Employing consensus clustering, novel molecular subgroups were identified. Subsequent analyses, including ESTIMATE, TIMER, and MCP counter, provided insights into the tumor microenvironment (TIME) and immune status. Functional studies, embracing GO, KEGG, GSVA, and GSEA analyses, unraveled the underlying mechanisms governing these molecular subgroups. Utilizing the LASSO algorithm and multivariate Cox regression, a prognostic risk model was crafted. The study unveiled two distinct molecular subgroups with significantly disparate survival outcomes. A more favorable prognosis was linked to low immune scores, high tumor purity, and an abundance of immune infiltrating cells with differential expression of non-coding RNAs, including miRNAs. Functional analyses illuminated enrichment of immune- and EMT-associated pathways in differentially expressed genes and non-coding RNAs between these subgroups. GSVA and GSEA analyses hinted at abnormal EMT status potentially contributing to glioma-associated immune disorders. The risk model, centered on OS-EMT-ICI genes, exhibited promise in accurately predicting survival in glioma. Additionally, a nomogram integrating the risk model with clinical characteristics demonstrated notable accuracy in prognostic predictions for glioma patients. In conclusion, OS-EMT-ICI gene and non-coding RNA expression emerges as a valuable indicator intricately linked to immune microenvironment dysregulation, offering a robust tool for precise prognosis prediction in glioma patients within the OBMRC framework.

The Asteraceae are widely distributed throughout the world, with diverse functions and large genomes. Many of these genes remain undiscovered and unstudied. In this study, we discovered a new gene ClNUM1 in Chrysanthemum lavandulifolium and studied its function. In this study, bioinformatics, RT-qPCR, paraffin sectioning, and tobacco transgenics were utilized to bioinformatically analyze and functionally study the three variable splice variants of the unknown gene ClNUM1 cloned from C. lavandulifolium. The results showed that ClNUM1.1 and ClNUM1.2 had selective 3′ splicing and selective 5′ splicing, and ClNUM1.3 had selective 5′ splicing. When the corresponding transgenic tobacco plants were subjected to abiotic stress treatment, in the tobacco seedlings, the ClNUM1.1 gene and the ClNUM1.2 gene enhanced salt and low-temperature tolerance and the ClNUM1.3 gene enhanced low-temperature tolerance; in mature tobacco plants, the ClNUM1.1 gene was able to enhance salt and low-temperature tolerance, and the ClNUM1.2 and ClNUM1.3 genes were able to enhance low-temperature tolerance. In summary, there are differences in the functions of the different splice variants and the different seedling stages of transgenic tobacco, but all of them enhanced the resistance of tobacco to a certain extent. The analysis and functional characterization of the ClNUM1 gene provided new potential genes and research directions for abiotic resistance breeding in Chrysanthemum.

Abstract The present study combined a supervised machine learning framework with an unsupervised method, finite mixture modeling, to identify prognostically meaningful subgroups of diverse chronic pain patients undergoing interdisciplinary treatment. Questionnaire data collected at pre-treatment and 1-year follow up from 11,995 patients from the Swedish Quality Registry for Pain Rehabilitation were used. Indicators measuring pain characteristics, psychological aspects, and social functioning and general health status were used to form subgroups, and pain interference at follow-up was used for the selection and the performance evaluation of models. A nested cross-validation procedure was used for determining the number of classes (inner cross-validation) and the prediction accuracy of the selected model among unseen cases (outer cross-validation). A four-class solution was identified as the optimal model. Identified subgroups were separable on indicators, predictive of long-term outcomes, and related to background characteristics. Results are discussed in relation to previous clustering attempts of patients with diverse chronic pain conditions. Our analytical approach, as the first to combine mixture modeling with supervised, targeted learning, provides a promising framework that can be further extended and optimized for improving accurate prognosis in pain treatment and identifying clinically meaningful subgroups among chronic pain patients.

Objective: To investigate the effects of repeated vaccination with ancestral SARS-CoV-2 (Wuhan-hu-1)-based inactivated, recombinant protein subunit or vector-based vaccines on the neutralizing antibody response to Omicron subvariants. Methods: Individuals who received four-dose vaccinations with the Wuhan-hu-1 strain, individuals who were infected with the BA.5 variant alone without prior vaccination, and individuals who experienced a BA.5 breakthrough infection (BTI) following receiving 2-4 doses of the Wuhan-hu-1 vaccine were enrolled. Neutralizing antibodies against D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 were detected using a pseudovirus-based neutralization assay. Antigenic cartography was used to analyze cross-reactivity patterns among D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 and sera from individuals. Results: The highest neutralizing antibody titers against D614G were observed in individuals who only received four-dose vaccination and those who experienced BA.5 BTI, which was also significantly higher than the antibody titers against XBB.1.5, EG.5.1, and BA.2.86. In contrast, only BA.5 infection elicited comparable neutralizing antibody titers against the tested variants. While neutralizing antibody titers against D614G or BA.5 were similar across the cohorts, the neutralizing capacity of antibodies against XBB.1.5, EG.5.1, and BA.2.86 was significantly reduced. BA.5 BTI following heterologous booster induced significantly higher neutralizing antibody titers against the variants, particularly against XBB.1.5 and EG.5.1, than uninfected vaccinated individuals, only BA.5 infected individuals, or those with BA.5 BTI after primary vaccination. Conclusions: Our findings suggest that repeated vaccination with the Wuhan-hu-1 strain imprinted a neutralizing antibody response toward the Wuhan-hu-1 strain with limited effects on the antibody response to the Omicron subvariants.

Copper-based brazing filler materials are commonly employed in vacuum brazing techniques to achieve joining of plasma-facing components for ITER. In this work, gas-driven permeation (GDP) and thermal desorption spectroscopy (TDS) experiments have been performed to study the hydrogen isotopes permeation and retention behavior in two types of brazing filler materials (CuMnNi and CuGeNi metals). Experimental results show that CuMnNi filler exhibits the similar deuterium (D) permeability with CuMnNi filler but lower diffusion coefficients than CuGeNi filler. Three distinct peaks are observed between 380 K and 980 K for CuMnNi filler. However, no evident desorption peak is observed for CuGeNi filler. CuGeNi filler may be considered as a potential brazing filler material for reducing tritium inventory.

Abstract The sensitivity of tree growth to precipitation regulates their responses to drought, and is a crucial metric for predicting ecosystem dynamics and vulnerability. Sensitivity may be changing with continuing climate change, yet a comprehensive assessment of its change is still lacking. We utilized tree ring measurements from 3,044 sites, climate data and CO2 concentrations obtained from monitoring stations, combined with dynamic global vegetation models to investigate spatiotemporal changes in the sensitivity over the past century. We observed an increasing sensitivity since around 1950. This increased sensitivity was particularly pronounced in arid biomes due to the combined effect of increased precipitation and elevated CO2. While elevated CO2 reduced the sensitivity of the humid regions, the intensified water pressure caused by decreased precipitation still increased the sensitivity. Our findings suggest an escalating vulnerability of tree growth to precipitation change, which may increase the risk of tree mortality under future intensified drought.

Abstract The health of young people is crucial for the future and development of a nation. It is the collective responsibility and imperative mission of society to ensure the holistic well-being, both physically and mentally, of young individuals. Therefore, it is essential to thoroughly comprehend the factors that influence their health in order to expedite the exploration of effective solutions. The objective of this study is to comprehend the mechanisms that underlie the correlation between physical exercise behavior and psychological resilience among teenagers, while also examining the mediating role played by social sensitivity and need to belong. So put forward the hypothesis: (1) physical exercise behavior can positively predict the psychological resilience. (2) Social sensitivity and need to belong plays a mediating role between physical exercise behavior and psychological resilience. (3) Social sensitivity and need to belong plays a chain mediating role between physical exercise behavior and psychological resilience. Using the cluster sampling method, a total of 1106 students (with an average age of 15.7 and a standard deviation of 0.598) who met the requirements were surveyed from Shandong Province in China. Standard scales were utilized to assess Physical Exercise Behavior, Psychological Resilience, Social Sensitivity, and Need to Belong. For data analysis, Pearson's correlation analysis and bias-corrected percentile Bootstrap method were sequentially conducted. (1) The present study did not find any significant methodological bias, and the observed correlations between physical exercise behavior, psychological resilience, social sensitivity, and need to belong were all statistically significant; (2) Based on the self-determination theory, this study elucidates the relationship between physical exercise behavior and psychological resilience among teenagers. The findings indicate that physical exercise behavior positively predicts the need to belong and psychological resilience, while negatively predicting social sensitivity. Similarly, social sensitivity negatively predicts the need to belong and psychological resilience. Moreover, the need to belong directly and positively predicts psychological resilience. Importantly, all hypotheses proposed in this paper were empirically supported. (3) The indirect effect of the path mediated by social sensitivity is 0.009, while the indirect effect of the path mediated by need to belong is 0.033. Additionally, the combined indirect effect of both social sensitivity and need to belong as mediating variables is 0.014. (4) The cumulative sum of all these indirect effects amounts to 0.056. Based on the self-determination theory, we propose a chain mediation model, specially, physical exercise behavior can significantly positively predict psychological resilience, among which, social sensitivity and need to belong play a significant mediating role between Physical exercise behavior and psychological resilience. In addition, the adoption of good physical exercise behavior can enhance the psychological resilience of adolescents by diminishing social sensitivity and augmenting the need to belong.

The detachment of 9-fluorenylmethyloxycarbonyl (Fmoc) from the amino group is widely performed in chemical synthesis reactions, involving peptides, nucleosides, polymers and some other organic compounds. Reported methods for Fmoc release mainly referred to traditional bases. Limited information about carboxylic acid-participating Fmoc detachment has been documented. This study mainly investigated the role of acetic acid (HAc), 3-methoxypropionic acid (MPA), 2-methoxyacetic acid (MAA) in the process of Fmoc deprotection in gas phase. The home-made nano emitter was used to spray the mixed solution of the three carboxylic acids and different Fmoc protected amino acids, which flew into the inlet of mass spectrometer (MS), to monitor the key adduct ions derived from the reaction of carboxylic acids and protected amino acids, such as Gly, Ala, Val, Leu, Pro, Met and Phe. Furthermore, the effects of substrate structures on the formation of the adduct in MS and its dissociation in MS/MS were discussed. The results showed that the relative abundance of MAA adducts were significantly higher than that of HAc adducts and MPA adducts for the same Fmoc protected amino acid, and only MAA related adducts can dissociate into fragments with 20% collision energy (CE). This is due to the special structure of MAA, which has a methoxy group providing a lone pair of electrons to the acidic hydrogen at the second position of the carboxylic acid. Thus, the methoxy group weakly interacted with the H at the 9th position of Fmoc ring, promoting the formation of the adducts of MAA and Fmoc protected amino acid to decrease the energy barrier of the transition state for the 9th H release process. All the [Xf+MAA-H]- adducts can generate two kinds of successor ions upon 20% CE, one is the Fmoc removal fragment, another is only MAA loss fragment. Interestingly, [Pf+MAA-H]- mainly gave fragments of the Fmoc removal products, whereas the other six compounds with relatively low abundance ratio mostly produced fragments by neutral MAA loss. This difference of the fragmentation pathways may be owing to the structure of Pf, which has no H in nitrogen atom and suppresses the formation of intermolecular hydrogen bonding. Thus, the formation of intermolecular hydrogen bond between the MAA and Pf is preferred, which benefits [Pf+MAA-H]- dissociation into Fmoc removal products. In summary, the structures of both carboxylic acids and amino acids play a vital role in formation of adducts and detachment of Fmoc group, and the research is helpful for the understanding in the mechanism of molecular ion reactions in gas phase.

Abstract The electromagnetic force used in electromagnetic forming is mainly divided into attraction and repulsion. Dual-coil attractive electromagnetic forming can be used in the field of sheet pit repair. However, the magnetic field and eddy current generated by the two coils compete with each other, and the energy utilization rate is low. Therefore, a compensation coil is introduced, and an electromagnetic forming scheme of a three-coil dual-power sheet based on mixed force is proposed and verified by simulation. It is found that the three-coil mixed force can effectively improve the competition between the magnetic field and eddy current. The loading of the mixing force is not a simple superposition of attraction and repulsion, but the mutual promotion of the two. The forming displacement of the three-coil mixed force forming scheme is 582% higher than that of the dual-coil attraction forming scheme, and 89% higher than that of the attract first and then repel forming scheme. The forming effect of the three-coil mixing force is related to the number of turns of the compensation coil. The research results can improve the energy utilization rate of electromagnetic forming and provide a new idea for the loading scheme of electromagnetic forming force field.

Abstract Background Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this question by assessing the influences of PTSD, APOE ε4 genotypes, DNA methylation, and other variables on the age- and dementia-associated biomarkers Aβ40, Aβ42, GFAP, NfL, and pTau-181 measured in plasma. Our primary hypothesis was that PTSD would be associated with elevated levels of these markers. Methods Analyses were based on data from a PTSD-enriched cohort of 849 individuals. We began by performing factor analyses of the biomarkers, the results of which identified a two-factor solution. Drawing from the ATN research framework, we termed the first factor, defined by Aβ40 and Aβ42, “Factor A” and the second factor, defined by GFAP, NfL and pTau-181, “Factor TN.” Next, we performed epigenome-wide association analyses (EWAS) of the two-factor scores. Finally, using structural equation modeling (SEM), we evaluated (a) the influence of PTSD, age, APOE ε4 genotype and other covariates on levels of the ATN factors, and (b) tested the mediating influence of the EWAS-significant DNAm loci on these associations. Results The Factor A EWAS identified one significant locus, cg13053408, in FANCD2OS. The Factor TN analysis identified 3 EWAS-significant associations: cg26033520 near ASCC1, cg23156469 in FAM20B, and cg15356923 in FAM19A4. The SEM showed age to be related to both factors, more so with Factor TN (β = 0.581, p

Abstract Cosmic inflation can enter an ultraslow-roll (USR) stage, if there is a plateau on the inflaton potential. During this stage, the primordial curvature perturbation $${{\mathscr {R}}}_k$$ R k and its power spectrum $${{\mathscr {P}}}_{{\mathscr {R}}}$$ P R can be remarkably enhanced on small scales. In this work, an analytical approximation is provided to systematically study the evolution of $${{\mathscr {R}}}_k$$ R k in the USR inflation. We first discuss the asymptotic solutions of the moduli and arguments of $${{\mathscr {R}}}_k$$ R k and its time derivative $${{\mathscr {R}}}_{k,N}$$ R k , N on the sub- and super-horizon scales separately and find that all these solutions have simple exponential forms. Then, $${{\mathscr {R}}}_k$$ R k on five typical scales are investigated in order. Our analytical approximation predicts that $${{\mathscr {R}}}_k$$ R k first revolves around the origin in the complex plane, but if it crosses the horizon around the start of the USR stage, there appears a subsequent linear evolution towards or away from the origin. This behavior naturally explains the shape of $${{\mathscr {P}}}_{{\mathscr {R}}}$$ P R from the sharp dip to the peak and matches the numerical results perfectly. Moreover, the minimum of $${{\mathscr {P}}}_{{\mathscr {R}}}$$ P R is exactly proved to be nonvanishing. Our analytical approximation will help the model building in primordial black hole and gravitational wave physics.

By considering the joint effects of the Kelvin–Helmholtz (KH) and Rayleigh–Taylor (RT) instabilities, this paper presents an interpretation of the wavy patterns that occur in explosive welding. It is assumed that the elasticity of the material at the interface effectively determines the wavelength, because explosive welding is basically a solid-state welding process. To this end, an analytical model of elastic hydrodynamic instabilities is proposed, and the most unstable mode is selected in the solid phase. Similar approaches have been widely used to study the interfacial behavior of solid metals in high-energy-density physics. By comparing the experimental and theoretical results, it is concluded that thermal softening, which significantly reduces the shear modulus, is necessary and sufficient for successful welding. The thermal softening is verified by theoretical analysis of the increase in temperature due to the impacting and sliding of the flyer and base plates, and some experimental observations are qualitatively validated. In summary, the combined effect of the KH and RT instabilities in solids determines the wavy morphology, and our theoretical results are in good qualitative agreement with experimental and numerical observations.

In order to obtain the resistance performance and economic navigation posture of a new unmanned survey catamaran, a calm water resistance simulation of this catamaran is conducted by model tests, the empirical formula method, and the computational fluid dynamics (CFD) method. Further, the CFD method is used to explore the influence of different longitudinal positions of the center of gravity on the hull and perimeter waveform, and a suitable installation position is selected for the multi-beam acoustic equipment. The results show that the CFD method can accurately predict the navigation posture and resistance at all speeds, while the empirical formula method is mainly suitable when the speed is low (FrΔ

Objective Osteosarcoma is a primary malignancy originating from mesenchymal tissue characterized by rapid growth, early metastasis and poor prognosis. Ginsenoside Rg5 (G‐Rg5) is a minor ginsenoside extracted from Panax ginseng C.A. Meyer which has been discovered to possess anti‐tumor properties. The objective of current study was to explore the mechanism of G‐Rg5 in the treatment of osteosarcoma by network pharmacology and molecular docking technology. Methods Pharmmapper, SwissTargetPrediction and similarity ensemble approach databases were used to obtain the pharmacological targets of G‐Rg5. Related genes of osteosarcoma were searched for in the GeneCards, OMIM and DrugBank databases. The targets of G‐Rg5 and the related genes of osteosarcoma were intersected to obtain the potential target genes of G‐Rg5 in the treatment of osteosarccoma. The STRING database and Cytoscape 3.8.2 software were used to construct the protein–protein interaction (PPI) network, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) platform was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. AutoDock vina software was used to perform molecular docking between G‐Rg5 and hub targets. The hub genes were imported into the Kaplan–Meier Plotter online database for survival analysis. Results A total of 61 overlapping targets were obtained. The related signaling pathways mainly included PI3K‐Akt signaling pathway, Proteoglycans in cancer, Lipid and atherosclerosis and Kaposi sarcoma‐associated herpesvirus infection. Six hub targets including PIK3CA, SRC, TP53, MAPK1, EGFR, and VEGFA were obtained through PPI network and targets‐pathways network analyses. The results of molecular docking showed that the binding energies were all less than –7 kcal/mol. And the results of survival analysis showed TP53 and VEGFA affect the prognosis of sarcoma patients. Conclusion This study explored the possible mechanism of G‐Rg5 in the treatment of osteosarcoma using network pharmacology method, suggesting that G‐Rg5 has the characteristics of multi‐targets and multi‐pathways in the treatment of osteosarcoma, which lays a foundation for the follow‐up experimental and clinical researches on the therapeutic effects of G‐Rg5 on osteosarcoma.

This study assessed the knowledge of 12- to 15-year-old male junior high school students of HPV and HPV vaccines and their willingness to be vaccinated against it. From March to May 2023, students from six junior high schools in Zhejiang Province were randomly selected to complete an online, anonymous, self-administered questionnaire. Of the 1786 students, 618 (34.6%) reported knowledge of HPV vaccine. In general, junior high school boys have low general knowledge about HPV, the consequences of HPV infection, and the effects of HPV vaccination. Multivariate analysis showed that the subgroup scoring 6–7 on the measure of the consequences of HPV infection(7 questions with 1 score for each correct answer) compared to the subgroup scoring 0, the subgroups scoring 2 and 3 on the measure of the preventive effect of HPV vaccine(3 questions with 1 score for each correct answer) compared to the subgroup scoring 0 were were more likely to be willing to be vaccinated against HPV. Hearing that someone close to them had cancer, believing that men also need to be vaccinated against HPV, knowing that someone close to them had been vaccinated against HPV, and being concerned about cervical cancer in their female sexual partners were all more likely to generate positive responses. HPV vaccine education for this group of students should emphasize the possibility and consequences of HPV infection in males, along with the importance and benefits of HPV vaccination; actual cases of vaccination in students around them can be used to achieve this goal.

Resistance to sorafenib, an effective first-line treatment for advanced hepatocellular carcinoma (HCC), greatly compromised the prognosis of patients. The extracellular matrix is one of the most abundant components of the tumor microenvironment. Beyond acting as a physical barrier, it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance. With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation, we discovered that fibronectin extra domain A (FN-EDA) derived from cancer-associated fibroblasts played a critical role in sorafenib resistance. Mechanistically, FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway, thereby countering the oxidative stress induced by sorafenib. Moreover, we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model, which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues, and through the analysis of HCC samples obtained from The Cancer Genome Atlas (TCGA) database. Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.

Abstract Background Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal‐jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats. Methods High‐fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro. Results DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)‐activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system‐related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system‐related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors. Conclusions DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway—and not solely by improving blood glucose—to improve oxidative stress in the heart of diabetic cardiomyopathy rats.

Background: Moyamoya disease (MMD), characterized by chronic cerebrovascular pathology, poses a rare yet significant clinical challenge, associated with elevated rates of mortality and disability. Despite intensive research endeavors, the exact biomarkers driving its pathogenesis remain enigmatic. Methods: The expression patterns of GSE189993 and GSE141022 were retrieved from the Gene Expression Omnibus (GEO) repository to procure differentially expressed genes (DEGs) between samples afflicted with MMD and those under control conditions. The Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine with Recursive Feature Elimination (SVM-RFE), and Random Forest (RF) algorithms were employed for identifying candidate diagnostic genes associated with MMD. Subsequently, these candidate genes underwent validation in an independent cohort (GSE157628). The CMAP database was ultimately employed to forecast drugs pertinent to MMD for clinical translation. Results: A collective of 240 DEGs were discerned. Functional enrichment scrutiny unveiled the enrichment of the cholesterol metabolism pathway, salmonella infection pathway, and allograft rejection pathway within the MMD cohort. EPDR1, DENND3, and NCSTN emerged as discerned diagnostic biomarkers for MMD. The CMAP database was ultimately employed to scrutinize the ten most auspicious pharmaceutical compounds for managing MMD. Finally, after validation through in vitro experiments, EPDR1, DENND3, and NCSTN were identified as the key genes. Conclusion: EPDR1, DENND3, and NCSTN have emerged as potential novel biomarkers for MMD. The involvement of T lymphocytes, neutrophilic granulocytes, dendritic cells, natural killer cells, and plasma cells could be pivotal in the pathogenesis and advancement of MMD.

Abstract We propose a physics‐informed convolutional decoder (PICD) framework for inverse modeling of heterogenous groundwater flow. PICD stands out as a direct inversion method, eliminating the need for repeated forward model simulations. The framework combines data‐driven and physics‐driven approaches by integrating monitoring data and domain knowledge into the inversion process. PICD utilizes a convolutional decoder to effectively approximate the spatial distribution of hydraulic heads, while Karhunen–Loève expansion (KLE) is employed to parameterize hydraulic conductivities. During the training process, the stochastic vector in KLE and the parameters of the convolutional decoder are adjusted simultaneously to minimize the data‐mismatch and the physical violation. The final optimized stochastic vectors correspond to the estimation of hydraulic conductivities, and the trained convolutional decoder can predict the evolution and distribution of hydraulic heads. Various scenarios of groundwater flow are examined and results demonstrate the framework's capability to accurately estimate heterogeneous hydraulic conductivities and to deliver satisfactory predictions of hydraulic heads, even with sparse measurements.

Summary: The ongoing emergence of SARS-CoV-2 variants poses challenges to the immunity induced by infections and vaccination. We conduct a 6-month longitudinal evaluation of antibody binding and neutralization of sera from individuals with six different combinations of vaccination and infection against BA.5, XBB.1.5, EG.5.1, and BA.2.86. We find that most individuals produce spike-binding IgG or neutralizing antibodies against BA.5, XBB.1.5, EG.5.1, and BA.2.86 2 months after infection or vaccination. However, compared to ancestral strain and BA.5 variant, XBB.1.5, EG.5.1, and BA.2.86 exhibit comparable but significant immune evasion. The spike-binding IgG and neutralizing antibody titers decrease in individuals without additional antigen exposure, and

Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant cancer cells; however, potential therapeutic targets remain elusive. This study investigated ferroptosis vulnerability and dihydroorotate dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU.