Search

Da-Peng Wang,1 Kai-Yan Jin,1 Peng Zhao,2 Qi Lin,3 Kai Kang,4 Jian Hai1 1Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai, 200065, People’s Republic of China; 2Institute for Translational Medicine, Institute for Biomedical Engineering and Nanoscience, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, People’s Republic of China; 3Department of Pharmacy, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 4Department of Research and Surveillance Evaluation, Shanghai Center for Health Promotion, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Da-Peng Wang; Jian HaiDepartment of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, No. 389, Xincun Road, Putuo District, Shanghai, 200065, People’s Republic of ChinaFax +86-21-66111093Email wdpboj@126.com; haijiandoct@zoho.com.cnIntroduction: Brain ischemia is a common neurological disorder worldwide that activates a cascade of pathophysiological events involving decreases in oxygen and glucose levels. Despite substantial efforts to explore its pathogenesis, the management of ischemic neuronal injury remains an enormous challenge. Accumulating evidence suggests that VEGF modified nanofiber (NF) materials and the fatty-acid amide hydrolase (FAAH) inhibitor URB597 exert an influence on alleviating ischemic brain damage. We aimed to further investigate their effects on primary hippocampal neurons, as well as the underlying mechanisms following oxygen–glucose deprivation (OGD).Methods: Different layers of VEGF-A loaded polycaprolactone (PCL) nanofibrous membranes were first synthesized by using layer-by-layer (LBL) self-assembly of electrospinning methods. The physicochemical and biological properties of VEGF-A NF membranes, and their morphology, hydrophilicity, and controlled-release of VEGF-A were then estimated. Furthermore, the effects of VEGF-A NF and URB597 on OGD-induced mitochondrial oxidative stress, inflammatory responses, neuronal apoptosis, and endocannabinoid signaling components were assessed.Results: The VEGF-A NF membrane and URB597 can not only promote hippocampal neuron adhesion and viability following OGD but also exhibited antioxidant/anti-inflammatory and mitochondrial membrane potential protection. The VEGF-A NF membrane and URB597 also inhibited OGD-induced cellular apoptosis through activating CB1R signaling. These results indicate that VEGF-A could be controlled-released by LBL self-assembled NF membranes.Discussion: The VEGF-A NF membrane and URB597 displayed positive synergistic neuroprotective effects through the inhibition of mitochondrial oxidative stress and activation of CB1R/PI3K/AKT/BDNF signaling, suggesting that a VEGF-A loaded NF membrane and the FAAH inhibitor URB597 could be of therapeutic value in ischemic cerebrovascular diseases.Keywords: brain ischemia, cannabinoid receptor, fatty-acid amide hydrolase, mitochondrial oxidative stress, nanofiber, VEGF-A

Abstract Vertical federated learning (VFL) can learn a common machine learning model over vertically partitioned datasets. However, VFL are faced with these thorny problems: (1) both the training and prediction are very vulnerable to stragglers; (2) most VFL methods can only support a specific machine learning model. Suppose that VFL incorporates the features of centralised learning, then the above issues can be alleviated. With that in mind, this paper proposes a new VFL scheme, called FedBoost, which makes private parties upload the compressed partial order relations to the honest but curious server before training and prediction. The server can build a machine learning model and predict samples on the union of coded data. The theoretical analysis indicates that the absence of any private party will not affect the training and prediction as long as a round of communication is achieved. Our scheme can support canonical tree‐based models such as Tree Boosting methods and Random Forests. The experimental results also demonstrate the availability of our scheme.

Abstract Currently, even the most effective anti-cancer therapies are often limited by the development of drug resistance and tumor relapse, which is a major challenge facing current cancer research. A deep understanding of the molecular and biochemical bases of drug efficacy that can help predict the clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, have facilitated studies identifying and elucidating the underlying mechanisms. In this review, we focus on several important issues on cancer drug resistance and provide a framework for understanding the common ways by which cancers develop resistance to therapeutic agents. With the increasing arsenal of novel anticancer agents and techniques, there are now unprecedented opportunities to understand and overcome drug resistance. The proteolysis targeting chimera (PROTAC) technology, immunotherapy, nanomedicine, and real-time monitoring of drug response all provide effective approaches for combating drug resistance. In addition to the advancement of therapeutic technologies, the revolution of treatment concept is also of great importance. We can take advantage of the interplay between drug sensitive and resistant subclones for combating cancer. However, there remains a long way to go in the protracted war against cancer drug resistance.

Abstract While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10−7, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10−6 circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

Abstract Background Vascular health has been associated with cognition but related evidence is limited in Chinese. The objective of this study was to examine the association of vascular aging assessed by arterial stiffness and blood pressure with cognitive function in an unselected Chinese population. Methods In the Tianning Cohort (N = 5158), indicators of arterial stiffness and blood pressure including carotid-femoral pulse wave velocity (cfPWV), ankle-brachial index (ABI), pulse pressure (PP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured. Cognitive function was assessed using the Mini Mental State Examination (MMSE) questionnaire. We applied Poisson regression and logistic regression to examine the associations of vascular aging and blood pressure with cognitive function. Results 76 (1.47%) participants had impaired cognitive function diagnosed by a MMSE score of less than 24 points. Participants with a higher level of PP were more likely to have a decreased score of MMSE (β=-0.0121, P

0–3 type ferroelectric–phosphor composite ceramics cannot be prepared by the traditional solid-state sintering (SSS) method due to the strong chemical reaction between ferroelectrics and phosphors during high-temperature sintering. The cold sintering process (CSP) may solve this issue by densifying ceramics at ultralow sintering temperatures. In this work, dense 0–3 type 0.8BaTiO3–0.2CaTiO3:Pr3+ (0.8BT–0.2CT:Pr3+) binary composite ceramics were fabricated at an ultralow temperature of 225 °C via CSP with the Ba(OH)2·8H2O hydrated flux. The effects of the Ba(OH)2·8H2O content, sintering temperature, and sintering time on the microstructure and densification of the ceramics were investigated. The density of the composite ceramics prepared by the optimized sintering parameters reaches 89%. Both energy-dispersive X-ray (EDX) spectroscopy and X-ray diffraction (XRD) confirm the existence of BT and CT:Pr3+ phases in the prepared ceramics. A strong ferroelectric performance is obtained, and the luminescent properties of CT:Pr3+ are preserved for the ceramics. Furthermore, the 0.8BT–0.2CT:Pr3+ composite ceramics prepared by CSP have stronger photoluminescence and photo-stimulated luminescence than their counterparts prepared by cold sintering assistance (CSA) and SSS methods. Therefore, CSP is a promising method for combining luminescent and ferroelectric properties into 0–3 type composite ceramics.

BackgroundThe Magnesium depletion score (MDS) serves as a novel metric for quantifying magnesium deficiency in the human body, comprehensively assessing four indicators: diuretic use, proton pump inhibitor use, estimated glomerular filtration rate, and alcohol abuse. However, there have been no studies examining the potential association between MDS and depression.MethodsThe study population for this cross-sectional study comprised adults from the National Health and Nutrition Examination Survey database from 2009 to 2018. Participants with a score of 10 or above on the Patient Health Questionnaire-9 were defined as having depression. We employed multivariable logistic regression models to investigate the association between MDS and depression. Furthermore, subgroup analyses were conducted to assess potential differences in this association among populations with diverse characteristics.ResultsA total of 13,197 participants were included in this study. After adjusting for all covariates, a significant positive correlation was observed between MDS and depression. Specifically, for every unit increase in MDS, the likelihood of developing depression increased by 13% (OR = 1.13, 95% CI: 1.04–1.22, p = 0.0025). This positive correlation was consistent across MDS groups, with a 19% increase in depression likelihood in the medium group (OR = 1.19, 95% CI: 1.01–1.41, p = 0.0404) and a 58% increase in the high group (OR = 1.58, 95% CI: 1.21–2.07, p = 0.0007), using the low subgroup as a reference. Subgroup analyses revealed significant differences in the relationship between MDS and depression across races, marital statuses, and hypertension status.ConclusionOur study has uncovered a significant positive association between MDS and depression. Reducing MDS in individuals may play a positive role in both the prevention and treatment of depression.

Abstract Lung cancer (LC) is the leading cause of cancer‐related mortality worldwide. Radiotherapy is the main component of LC treatment; however, its efficacy is often limited by radioresistance development, resulting in unsatisfactory clinical outcomes. Here, we found that LC radiosensitivity is up‐regulated by decreased expression of long‐chain acyl‐CoA synthase 6 (ACSL6) after irradiation. Deletion of ACSL6 results in significant elevation of Friend leukemia integration 1 transcription factor (FLI1) and a marked decline of collagens (COLs). Blocking of ACSL6 impairs the tumor growth and upregulates FLI1, which reduces the levels of COLs and compromises irradiation‐induced autophagy, leading to considerable therapeutic benefits during radiotherapy. Moreover, the direct interaction between ACSL6 and FLI1 and engagement between FLI1 and COLs indicates the involvement of the ACSL6‐FLI1‐COL axis. Finally, the potently adjusted autophagy flux reduces its otherwise contributive capability in surviving irradiation stress and leads to satisfactory radiosensitization for LC radiotherapy. These results demonstrate that enhanced ACSL6 expression promotes the aggressive performance of irradiated LC through increased FLI1‐COL‐mediated autophagy flux. Thus, the ACSL6‐FLI1‐Col‐autophagy axis may be targeted to enhance the radiosensitivity of LC and improve the management of LC in radiotherapy.

ObjectiveTo estimate the contribution of direct-drinking water provided in school to dietary intake (DI) and recommended nutrient intake (RNI) of calcium and magnesium, and to explore its influence on the height in school-age children.MethodsTap water and direct-drinking water samples were collected from schools in Taicang City to test the contents of calcium and magnesium, and compared by one-way ANOVA and post-hoc test. Contribution rates of direct-drinking water to DI and RNI were calculated by using the contents of calcium and magnesium and data from the Nutrition and Health Status Survey 2021. A retrospective cohort was conducted among 4,850 first-grade children consuming direct-drinking water in Taicang City from 24 primary schools in 2019. Group 1 (1,070 boys and 946 girls) consumed UF-process water with normal calcium and magnesium contents and Group 2 (1,548 boys and 1,286 girls) consumed NF/RO-process water with very low calcium and magnesium contents. During 2019–2023, the height and height growth were analyzed with the Student’s t-test.ResultsThe highest calcium content was examined in tap water samples, followed by direct-drinking water samples supplied through a UF, NF, and RO system (F = 1,227.725, p 0.05).ConclusionDirect-drinking water processed through a NF or RO system should be cautiously adopted in primary and secondary schools. A UF system is preferred in schools where no health concerns are associated with water quality.

Geometries, stabilities, bonding nature, and vibrational properties of bimetallic KMgn0/– (n = 2–12) clusters have been comprehensively studied by CALYPSO code within DFT calculations. The results reveal the structural transition from 2D to 3D at n = 3. From n ≥ 8, the geometry of KMgn0/– transfers a hollow framework with a six-atom triangular prism unit. By comparing the geometry of neutral and anionic KMgn0/– clusters, most of them are structurally different. In all doped clusters, the K atoms tend to localize on the convex positions of the skeleton and play the role of electron donors. Two highly stable clusters KMg9 and KMg9– have been found, and studies showed that the prominent stability benefits from their compact magnesium structural motifs and quasi-full/full shell electronic configurations. Additionally, bonding nature analysis reflects there is much weak K-Mg interaction than Mg-Mg interaction in the KMg90/– clusters. The spectroscopic properties based on the PES, IR and Raman spectra have also been discussed.

Polygalae radix (PR) is the dried root of Polygala tenuifolia Willd. and Polygala sibirica L. and enjoys the reputation as the “key medicine for nourishing life.” In this study, information about “Polygala tenuifolia Willd.,” “Polygala sibirica L.,” and “Yuanzhi” was retrieved from scientific databases, including Google Scholar, Baidu Scholar, Web of Science, PubMed, CNKI, and Wan Fang Data. Information from Chinese herbal medicine classics, Yaozhi Data, and the Gaide Chemical Network was also collected. Information related to botany, phytochemistry, pharmacology, toxicity, industrial applications, and processing is summarized in this paper to tap its potentialities and promote its further development and clinical application. More than 320 metabolites have been isolated from PR; saponins, xanthones, and oligosaccharide esters are the main functional metabolites. Pharmacological research shows that its pharmacological action mainly focuses on resisting nervous system diseases, and it also has the functions of anti-oxidation, anti-inflammation, anti-tumor, anti-pathogenic microorganisms and others. The gastrointestinal irritation of its saponins impeded its application, but this irritation can be reduced by controlling the dosage, compatibility with other herbs, or processing. The future progress of PR faces opportunities and challenges. More attention should be paid to the traditional application and processing methods of PR recorded in ancient books. The lack of safety and clinical studies has limited its application and transformation of achievements. Moreover, it is one-sided to take the content of only a few metabolites as the index of processing optimization and quality control, which cannot reflect the full pharmacological and toxicological activities of PR.

ObjectiveThis study aims to investigate the inhibitory effect of Polydatin (PD) on endoplasmic reticulum (ER) stress following subarachnoid hemorrhage (SAH) and to elucidate the underlying mechanisms.MethodsA standard intravascular puncture model was established to mimic SAH in mice. Neurological functions were assessed using neurological scoring, Grip test, and Morris water maze. Brain edema and Evans blue extravasation were measured to evaluate blood-brain barrier permeability. Western blot and quantitative real-time polymerase chain reaction (PCR) analyses were performed to examine protein and mRNA expressions related to ER stress. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was used to detect cell apoptosis, and transmission electron microscopy was used to observe the ultrastructure of the endoplasmic reticulum.ResultsThe results indicated that PD significantly reduced brain edema and Evans blue extravasation after SAH, improving neurological function. Compared to the SAH group, the expression levels of ER stress-related proteins including glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were significantly lower in the PD-treated group. Moreover, PD significantly enhances the protein expression of Sirtuin 1 (SIRT1). Validation with sh-SIRT1 confirmed the critical role of SIRT1 in ER stress, with PD’s inhibitory effect on ER stress being dependent on SIRT1 expression. Additionally, PD attenuated ER stress-mediated neuronal apoptosis and SAH-induced ferroptosis through upregulation of SIRT1.ConclusionPD alleviates ER stress following SAH by upregulating SIRT1 expression, thereby mitigating early brain injury. The protective effects of PD are mediated through SIRT1, which inhibits ER stress and reduces neuronal apoptosis and ferroptosis.

Abstract Media bias widely exists in the articles published by news media, influencing their readers’ perceptions, and bringing prejudice or injustice to society. However, current analysis methods usually rely on human efforts or only focus on a specific type of bias, which cannot capture the varying magnitudes, connections, and dynamics of multiple biases, thus remaining insufficient to provide a deep insight into media bias. Inspired by the Cognitive Miser and Semantic Differential theories in psychology, and leveraging embedding techniques in the field of natural language processing, this study proposes a general media bias analysis framework that can uncover biased information in the semantic embedding space on a large scale and objectively quantify it on diverse topics. More than 8 million event records and 1.2 million news articles are collected to conduct this study. The findings indicate that media bias is highly regional and sensitive to popular events at the time, such as the Russia-Ukraine conflict. Furthermore, the results reveal some notable phenomena of media bias among multiple U.S. news outlets. While they exhibit diverse biases on different topics, some stereotypes are common, such as gender bias. This framework will be instrumental in helping people have a clearer insight into media bias and then fight against it to create a more fair and objective news environment.

Abstract Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

Media power, the impact that media have on public opinion and perspectives, plays a significant role in maintaining internal stability, exerting external influence, and shaping international dynamics for nations /regions. However, prior research has primarily concentrated on news content and reporting time, resulting in limitations in evaluating media power. To more accurately assess media power, we use news content, news reporting time, and news emotion simultaneously to explore the emotional contagion between media. We use emotional contagion to measure the mutual influence between media and regard the media with greater impact as having stronger media power. We propose a framework called Measuring Media Power via Emotional Contagion (MMPEC) to capture emotional contagion among media, enabling a more accurate assessment of media power at the media and national/regional levels. MMPEC also interprets experimental results through correlation and causality analyses, ensuring explainability. Case analyses confirm the higher accuracy of MMPEC compared to other baseline models, as demonstrated in the context of COVID-19-related news, yielding compelling and interesting insights.

Abstract Solute carrier family 26 member 9 (SLC26A9) is a member of the Slc26a family of multifunctional anion transporters that functions as a Cl- channel in parietal cells during acid secretion. We explored the role of SLC26A9 in colorectal cancer (CRC) and its related mechanisms through clinical samples from CRC patients, CRC cell lines and mouse models. We observed that SLC26A9 was expressed at low levels in the cytoplasm of adjacent tissues, polyps and adenomas but was significantly increased in colorectal adenocarcinoma. Moreover, increased levels of SLC26A9 were associated with a high risk of disease and poor prognosis. In addition, downregulation of SLC26A9 in CRC cells induced cell cycle arrest and apoptosis but inhibited cell proliferation and xenograft tumor growth both in vitro and in vivo. Mechanistic analysis revealed that SLC26A9 was colocalized with β-catenin in the nucleus of CRC cells. The translocation of these two proteins from the cytoplasm to the nucleus reflected the activation of Wnt/β-catenin signaling, and promoted the transcription of downstream target proteins, including CyclinD1, c-Myc and Snail, but inhibited the expression of cytochrome C (Cyt-c), cleaved Caspase9, cleaved Caspase3 and apoptosis-inducing factor (AIF). CRC is accompanied by alteration of epithelial mesenchymal transition (EMT) markers. Meanwhile, further studies showed that in SW48 cells, overexpressing SLC26A9 was cocultured with the β-catenin inhibitor XAV-939, β-catenin was downregulated, and EMT was reversed. Our study demonstrated SLC26A9 may be responsible for alterations in the proliferative ability and aggressive potential of CRC by regulating the Wnt/β-catenin signaling pathway.

ObjectiveThis study aims to analyze the awareness of influenza prevention and control and the behavioral attitudes toward the work among parents and staff in schools in Taicang City and the impact of the vaccination rate among students on influenza outbreaks in schools. The findings can provide references for the development of effective control strategies for the spread of influenza.MethodsAn anonymous questionnaire survey was conducted on 10,962 students from 20 schools in Taicang City, with class as the unit of analysis. The survey investigated their awareness of influenza prevention and control, their attitudes, and the vaccination coverage.ResultsFrom January to June 2023, a total of 388 influenza outbreaks were reported in schools in Taicang City, involving 77 schools. There were 3,475 confirmed cases, with an average infection rate of 18.53%. In schools where influenza outbreaks had occurred, the incidence rate of those who received influenza vaccine was significantly lower than those who did not, and the vaccine protection rate was 28.22%. The knowledge awareness rates of “the main transmission routes of influenza” and “influenza vaccination can prevent influenza” among parents of students were 95.49 and 93.16%, respectively. The differences between schools involved in the epidemic and non-epidemic were statistically significant (p

The tumor microenvironment is increasingly acknowledged as a critical contributor to cancer progression, mediating genetic and epigenetic alterations. Beyond diverse cellular interactions from the microenvironment, physicochemical factors such as tumor acidosis also significantly affect cancer dynamics. Recent research has highlighted that tumor acidosis facilitates invasion, immune escape, metastasis, and resistance to therapies. Thus, noninvasive measurement of tumor acidity and the development of targeted interventions represent promising strategies in oncology. Techniques like contrast-enhanced ultrasound (CEUS) can effectively assess blood perfusion, while ultrasound-stimulated microbubble cavitation (USMC) has proven to enhance tumor blood perfusion. We therefore aimed to determine whether CEUS assesses tumor acidity and whether USMC treatment can modulate tumor acidity. Firstly, we tracked CEUS perfusion parameters in MCF7 tumor models and compared them with in vivo tumor pH recorded by pH microsensors. We found that the peak intensity and area under curve of tumor contrast-enhanced ultrasound correlated well with tumor pH. We further conducted USMC treatment on MCF7 tumor-bearing mice, tracked changes of tumor blood perfusion and tumor pH in different perfusion regions before and after the USMC treatment to assess its impact on tumor acidity and optimize therapeutic ultrasound pressure. We discovered that USMC with 1.0 Mpa significantly improved tumor blood perfusion and tumor pH. Furthermore, tumor vascular pathology and PGI2 assays indicated that improved tumor perfusion was mainly due to vasodilation rather than angiogenesis. More importantly, analysis of glycolysis-related metabolites and enzymes demonstrated USMC treatment can reduce tumor acidity by reducing tumor glycolysis. These findings support that CEUS may serve as a potential biomarker to assess tumor acidity and USMC is a promising therapeutic modality for reducing tumor acidosis.

IntroductionHigh-alkalinity water is a serious health hazard for fish and can cause oxidative stress and metabolic dysregulation in fish livers. However, the molecular mechanism of liver damage caused by high alkalinity in fish is unclear. MethodsIn this study, 180 carp were randomly divided into a control (C) group and a high-alkalinity (A25) group and were cultured for 56 days. High-alkalinity-induced liver injury was analysed using histopathological, whole-transcriptome, and metabolomic analyses. ResultsMany autophagic bodies and abundant mitochondrial membrane damage were observed in the A25 group. High alkalinity decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity and the total antioxidant capacity (T-AOC) and increased the malondialdehyde (MDA) content in liver tissues, causing oxidative stress in the liver. Transcriptome analysis revealed 61 differentially expressed microRNAs (miRNAs) and 4008 differentially expressed mRNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that mammalian target of rapamycin (mTOR), forkhead box O (FoxO), mitogen-activated protein kinase (MAPK), and the autophagy signalling pathway were the molecular mechanisms involved. High alkalinity causes oxidative stress and autophagy and results in autophagic damage in the liver. Bioinformatic predictions indicated that Unc-51 Like Kinase 2 (ULK2) was a potential target gene for miR-140-5p, demonstrating that high alkalinity triggered autophagy through the miR-140-5p–ULK2 axis. Metabolomic analysis revealed that the concentrations of cortisol 21-sulfate and beta-aminopropionitrile were significantly increased, while those of creatine and uracil were significantly decreased. DiscussionThe effects of high alkalinity on oxidative stress and autophagy injury in the liver were analysed using whole-transcriptome miRNA-mRNA networks and metabolomics approaches. Our study provides new insights into liver injury caused by highly alkaline water.

Using first-principles calculations, we have systematically studied thermodynamic stability, electronic structure and mechanical properties of Mo-Re binary alloys. The alloying element Re prefers to occupy the substitution position with a formation energy of 0.10 eV in Mo rather than the tetrahedron/octahedron interstitial position. The charge transfers are obviously present between Re and Mo atoms, which can be confirmed by the Bader charge analysis. The density of states (DOS) demonstrates that the d orbitals of Re and Mo atoms are hybridized, revealing that Re and its adjacent Mo atoms can form the directional bond containing covalent components. On the basis of above studies on the most stable occupancy structure, the mechanical quantities (the elastic constants Cij, bulk modulus B, Young’s modulus E, shear modulus G, Poisson’s ratio v, and B/G) have been analyzed for three Mo-Re alloys with the low Re content, which are Mo127Re1, Mo53Re1 and Mo15Re1, respectively. All these mechanical quantities of both Mo127Re1 and Mo53Re1 alloys are nearly the same as that of perfect Mo, while all these mechanical quantities of Mo15Re1 alloy are obviously larger or smaller than that of perfect Mo. This demonstrates that Mo15Re1 alloy has significantly different mechanical characteristics from Mo127Re1 and Mo53Re1 alloys as well as perfect Mo. These results can provide a significant reference for the application of Mo-Re alloys in future fusion fields.

Fuzzing is a technique that was used to detect potential vulnerabilities and errors in software or systems by generating random, abnormal, or invalid test cases.When applying fuzzing to the kernel, more complex and challenging obstacles were encountered compared to user-space applications.The kernel, being a highly intricate software system, consists of numerous interconnected modules, subsystems, and device drivers, which presented challenges such as a massive codebase, complex interfaces, and runtime uncertainty.Traditional fuzzing methods could only generate inputs that simply satisfied interface specifications and explicit call dependencies, making it difficult to thoroughly explore the kernel.In contrast, evolutionary kernel fuzzing employed heuristic evolutionary strategies to dynamically adjust the generation and selection of test cases, guided by feedback mechanisms.This iterative process aimed to generate higher-quality test cases.Existing work on evolutionary kernel fuzzing was examined.The concept of evolutionary kernel fuzzing was explained, and its general framework was summarized.The existing work on evolutionary kernel fuzzing was classified and compared based on the type of feedback mechanism utilized.The principles of how feedback mechanisms guided evolution were analyzed from the perspectives of collecting, analyzing, and utilizing runtime information.Additionally, the development direction of evolutionary kernel fuzzing was discussed.

Abstract Background CircRNAs participate in the development of hepatocellular carcinoma (HCC). This work aims to explore the key tumor promoting circRNA as a gene therapy target. Methods The differentially expressed gene circRNAs in HCC tumor tissues was identified by mining GSE121714 dataset. EdU staining, wound healing, transwell invasion assay, TUNEL staining and western blotting examined proliferation, migration, invasion, apoptosis and epithelial mesenchymal transition (EMT). Xenograft mouse model and orthotopic transplantation tumor mouse model were constructed to verify the role of hsa_circ_001726 in growth and metastasis of HCC. The relationship among CCT2, E2F6, hsa_circ_001726, miR-671-5p and PRMT9 was identified by RNA-fluorescence in situ hybridization, luciferase reporter assay and RNA Immunoprecipitation. Results Eleven differentially expressed circRNAs were found in HCC tumors. Among them, hsa_circ_001726 was highly expressed in HCC tumors and cells, which was transcribed from CCT2. As a transcription factor of CCT2, E2F6 knockdown inactivated CCT2 promoter and reduced hsa_circ_001726 expression. Moreover, hsa_circ_001726 elevated PRMT9 expression by sponging miR-671-5p, and then activated Notch signaling pathway. Additionally, hsa_circ_001726 deficiency repressed malignant phenotypes of HCC cells, including proliferation, migration, invasion, EMT and apoptosis. In vivo, hsa_circ_001726 deficiency reduced tumor growth and lung metastasis of HCC in xenograft mouse models and orthotopic transplantation tumor mouse models. Conclusion Hsa_circ_001726 functioned as an oncogene in HCC, which was derived from CCT2 and regulated by E2F6. Hsa_circ_001726 elevated PRMT9 expression by sponging miR-671-5p, and then activated Notch signaling pathway, thereby accelerating malignant phenotypes of HCC. Therefore, targeting hsa_circ_001726 may be a new avenue for HCC treatment.

In recent years, software vulnerabilities have been causing a multitude of security incidents, and the early discovery and patching of vulnerabilities can effectively reduce losses.Traditional rule-based vulnerability detection methods, relying upon rules defined by experts, suffer from a high false negative rate.Deep learning-based methods have the capability to automatically learn potential features of vulnerable programs.However, as software complexity increases, the precision of these methods decreases.On one hand, current methods mostly operate at the function level, thus unable to handle inter-procedural vulnerability samples.On the other hand, models such as BGRU and BLSTM exhibit performance degradation when confronted with long input sequences, and are not adept at capturing long-term dependencies in program statements.To address the aforementioned issues, the existing program slicing method has been optimized, enabling a comprehensive contextual analysis of vulnerabilities triggered across functions through the combination of intra-procedural and inter-procedural slicing.This facilitated the capture of the complete causal relationship of vulnerability triggers.Furthermore, a vulnerability detection task was conducted using a Transformer neural network architecture equipped with a multi-head attention mechanism.This architecture collectively focused on information from different representation subspaces, allowing for the extraction of deep features from nodes.Unlike recurrent neural networks, this approach resolved the issue of information decay and effectively learned the syntax and semantic information of the source program.Experimental results demonstrate that this method achieves an F1 score of 73.4% on a real software dataset.Compared to the comparative methods, it shows an improvement of 13.6% to 40.8%.Furthermore, it successfully detects several vulnerabilities in open-source software, confirming its effectiveness and applicability.

Objective Despite the increasing use of AI applications as a clinical decision support tool in healthcare, patients are often unaware of their use in the physician's decision-making process. This study aims to determine whether doctors should disclose the use of AI tools in diagnosis and what kind of information should be provided. Methods A survey experiment with 1000 respondents in South Korea was conducted to estimate the patients’ perceived importance of information regarding the use of an AI tool in diagnosis in deciding whether to receive the treatment. Results The study found that the use of an AI tool increases the perceived importance of information related to its use, compared with when a physician consults with a human radiologist. Information regarding the AI tool when AI is used was perceived by participants either as more important than or similar to the regularly disclosed information regarding short-term effects when AI is not used. Further analysis revealed that gender, age, and income have a statistically significant effect on the perceived importance of every piece of AI information. Conclusions This study supports the disclosure of AI use in diagnosis during the informed consent process. However, the disclosure should be tailored to the individual patient's needs, as patient preferences for information regarding AI use vary across gender, age and income levels. It is recommended that ethical guidelines be developed for informed consent when using AI in diagnoses that go beyond mere legal requirements.

Accurate road networks are of great importance to online food delivery (OFD) services. In recent years, various data sources have been used to extract road information. Remote sensing images and Global Positioning System (GPS) trajectories can provide complementary information about roads, and the fusion of these two data sources allows to enhance the accuracy of automatic road extraction. To make full use of the information available from these two data sources, we developed a decoder fusion model based on the dilated Res-U-Net (DF-DRUNet) which fuses the remote sensing images and GPS trajectories in an efficient way to extract the road network. The DF-DRUNet model is built on two components: First, two independent dilated Res-U-Net models are used, where one model uses remote sensing images as input whilst the other model takes GPS trajectories as input. Second, we fused the decoders from the modalities based on a gated fusion module, which can help to learn the selection from these two input modalities. Based on the road extraction from the DF-DRUNet model, we also developed various refinement strategies, i.e., noise removal, skeleton extraction, topology construction, and vectorization. Numerical experiments were conducted using the DF-DRUNet model and baseline models from the real dataset of remote sensing images and GPS trajectories. The quantitative evaluation shows that the DF-DRUNet model can integrate remote sensing images and GPS trajectories effectively and achieve the highest performance of F1-score (0.857) and IoU (0.746) among all baseline fusion models. Moreover, the proposed DF-DRUNet model needs relatively fewer parameters and takes shorter training time.

Based on the parallel rock samples of tight oil reservoirs, the imbibition comparison experiments respecting to formation water and active water under different experimental conditions have been initiated. With adoption of the experimental measures i.e. Nuclear Magnetic Resonance (NMR), the micro-production mechanism of the enforcement of the imbibition oil recovery effect by the active agent has been analyzed. Surfactant may promote the imbibition effect of samples with different wettability, different water saturation and different sizes. The imbibition recovery ratios of No. 1 hydrophilic core in formation water and active water are respective 15.79% and 17.68%, and the active water imbibition increased by 1.88%, with an enforcement ratio of 11.97%. The imbibition recovery ratios of No. 3 lipophilic core in formation water and active water are respective 10.64% and 13.26%, and the active water imbibition increased by 2.62%, with an enforcement ratio of​ 24.62%. The enforcement effect of surfactant on the lipophilic core is higher than that on the hydrophilic core. The enforcement ratio of No. 1 core in macropores is 8.78%, and that of No. 3 rock is 36.14%, indicating that the surfactant can effectively reduce the seepage resistance of the lipophilic cores and enhance the imbibition recovery ratio of macropores. The increase magnitude and the enforcement ratio of the imbibition recovery of No. 4 low water-contained core are lower than those of No. 6 high water-contained core, indicating that the surfactant has a greater impact on the imbibition of high water-contained cores. The enforcement ratio in active water imbibition in core No. 4 is 28.59% in micropores and 15.46% in macropores; and respective 1460.74% and 9.56% for No. 6 core. The enforcement ratios of micropores in the two cores are both higher than those in macropores. It shows that the surfactant has a great influence on the permeability of micropores in the core. The increment magnitude in active water imbibition of small No. 2 core is 22%, and that of No. 2 large core is 26.93%, indicating that the surfactant has a greater impact on the imbibition of large cores.

Abstract Background Selective fetal growth restriction (sFGR) is an extreme complication that significantly increases the risk of perinatal mortality and long-term adverse neurological outcomes in offspring, affecting approximately 15% of monochorionic diamniotic (MCDA) twin pregnancies. The lack of longitudinal cohort studies hinders the early prediction and intervention of sFGR. Methods We constructed a prospective longitudinal cohort study of sFGR, and quantified 25 key metabolites in 337 samples from maternal plasma in the first, second, and third trimester and from cord plasma. In particular, our study examined fetal growth and brain injury data from ultrasonography and used the Ages and Stages Questionnaire-third edition subscale (ASQ-3) to evaluate the long-term neurocognitive behavioral development of infants aged 2–3 years. Furthermore, we correlated metabolite levels with ultrasound data, including physical development and brain injury indicators, and ASQ-3 data using Spearman’s-based correlation tests. In addition, special combinations of differential metabolites were used to construct predictive models for the occurrence of sFGR and fetal brain injury. Results Our findings revealed various dynamic patterns for these metabolites during pregnancy and a maximum of differential metabolites between sFGR and MCDA in the second trimester (n = 8). The combination of l-phenylalanine, l-leucine, and l-isoleucine in the second trimester, which were closely related to fetal growth indicators, was highly predictive of sFGR occurrence (area under the curve [AUC]: 0.878). The combination of l-serine, l-histidine, and l-arginine in the first trimester and creatinine in the second trimester was correlated with long-term neurocognitive behavioral development and showed the capacity to identify fetal brain injury with high accuracy (AUC: 0.94). Conclusions The performance of maternal plasma metabolites from the first and second trimester is superior to those from the third trimester and cord plasma in discerning sFGR and fetal brain injury. These metabolites may serve as useful biomarkers for early prediction and promising targets for early intervention in clinical settings.

Patient blood management is an evidence-based concept that seeks to minimize blood loss by maintaining adequate hemoglobin levels and optimizing hemostasis during surgery. Since the coronavirus disease 2019 pandemic, patient blood management has gained significance due to fewer blood donations and reduced amounts of blood stored for transfusion. Recently, the prevalence of postpartum hemorrhage (PPH), as well as the frequency of PPH-associated transfusions, has steadily increased. Therefore, proper blood transfusion is required to minimize PPH-associated complications while saving the patient’s life. Several guidelines have attempted to apply this concept to minimize anemia during pregnancy and bleeding during delivery, prevent bleeding after delivery, and optimize recovery methods from anemia. This study systematically reviewed various guidelines to determine blood loss management in pregnant women.

Abstract Increasing evidence has demonstrated that drug resistance can be acquired in cancer cells by kinase rewiring, which is an obstacle for efficient cancer therapy. However, it is technically challenging to measure the expression of protein kinases on large scale due to their dynamic range in human proteome. We employ a lysine-targeted sulfonyl fluoride probe, named XO44, which binds to 133 endogenous kinases in intact lenvatinib-resistant hepatocellular carcinoma (HCC) cells. This analysis reveals cyclin-dependent kinase 6 (CDK6) upregulation, which is mediated by ERK/YAP1 signaling cascade. Functional analyses show that CDK6 is crucial in regulation of acquired lenvatinib resistance in HCC via augmentation of liver cancer stem cells with clinical significance. We identify a noncanonical pathway of CDK6 in which it binds and regulates the activity of GSK3β, leading to activation of Wnt/β-catenin signaling. Consistently, CDK6 inhibition by palbociclib or degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with lenvatinib in vitro. Interestingly, palbociclib not only exerts maximal growth suppressive effect with lenvatinib in lenvatinib-resistant HCC models but also reshapes the tumor immune microenvironment. Together, we unveil CDK6 as a druggable target in lenvatinib-resistant HCC and highlight the use of a chemical biology approach to understand nongenetic resistance mechanisms in cancer.

【Objective】 Change in groundwater in Qingtongxia Irrigation areas is mainly due to the leaching of drainage ditches and infiltration of field irrigation. The exchange between surface water and groundwater is frequent but complex. This paper analyzes the hydrochemical relationship between water in drainage ditches and their adjacent shallow groundwater. 【Method】 The study was based on hydrochemical data measured from water samples taken from both drainage ditches and shallow groundwater. Their correlations and transformation were analyzed using statistics, Gibbs model, Piper chart, Schoeller chart, cation alternating adsorption chart and other methods. 【Result】 The water in the drainage ditches was more alkaline in the off-irrigation period, and slightly alkaline or alkaline in the irrigation period. In contrast, the shallow groundwater was neutral or weakly alkaline in the off-irrigation period and weakly alkaline or alkaline in the irrigation period. The TDS of the water in the drainage ditches was higher in irrigation period than in off-irrigation period, while the TDS of the shallow groundwater remained approximately same, though it was significantly higher than that of the drainage ditches. The content of cations in the water in both the drainage ditches and shallow groundwater were ranked in the order of Na+>Ca2+>Mg2+>K+, while the anions were in the order of Cl->SO42->HCO3-. The difference in ion concentration in the shallow groundwater near the drainage ditches was greater in the vertical direction than in the horizontal direction. The δ18O and δD in the ditch water and shallow groundwater were approximately the same during both irrigation and off-irrigation periods, and their spatial variation was small. The isotope dilution by shallow groundwater was noticeable at the depth of 30 m. 【Conclusion】 The chemical compositions of ditch water and shallow groundwater are controlled by evaporation or rock weathering, in addition to hydrodynamic mixing. The hydrochemistry in the shallow groundwater in the south of the area depends on rock weathering, while that in the middle and north of the area is largely modulated by evaporation. Depending on the depth of groundwater table, the drainage ditch can ether discharge or drain the groundwater due to the rise of groundwater table following irrigation. The average ratio of irrigation water withdrawal was 81.54%. For regions where groundwater table is deep, the drainage ditch is the main source of groundwater, accounting for 84.62% of water supply to the groundwater.

Abstract Background The hepatitis B virus X (HBx) protein is an established cause of hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). Whether arginine methylation regulates ferroptosis involved in HBx-induced HCC progression has not been reported. This study aimed to explore whether HBx-regulated protein arginine methyltransferase 9 (PRMT9) mediates the involvement of ferroptosis in the development of HCC. Methods and results HBx inhibited ferroptosis through promoting PRMT9 expression in HCC cells. PRMT9 suppressed ferroptosis to accelerate HCC progression in vivo. PRMT9 targeted HSPA8 and enhanced arginine methylation of HSPA8 at R76 and R100 to regulate ferroptosis in HCC. HSPA8 overexpression altered the transcriptome profile of HepG2 cells, in particular, ferroptosis and immune-related pathways were significantly enriched by differentially expressed genes, including CD44. HSPA8 overexpression up-regulated CD44 expression and knockdown of CD44 significantly reversed the inhibition of ferroptosis caused by PRMT9 overexpression. Conclusions In conclusion, HBx/PRMT9/HSPA8/CD44 axis is a vital signal pathway regulating ferroptosis in HCC cells. This study provides new opportunities and targets for the treatment of HBV-induced HCC. Graphical Abstract